Secondary Cell Group (SCG) Security Key Update for Selective SCG Activation in Wireless Systems

Description

MAPT MODULATING COMPOSITIONS AND METHODS OF USING THEM CROSS-REFERENCE TO RELATED ORDERS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 460,874, filed April 20, 2023; U.S. Provisional Application No. 63 / 520,070, filed August 16, 2023; and U.S. Provisional Application No. 63 / 619,022, filed January 9, 2024. The invention in each of the preceding applications is considered part of, and is incorporated by reference in its entirety into, the invention in this application. REFERENCE FOR AN ELECTRONIC LISTING OF SEQUENCES

[0002] The contents of the electronic sequence listing (A127870019WO00-SEQ-JIB.xml; Size: 210,445 bytes; and Creation date: April 18, 2024) are incorporated herein by reference in their entirety. SUMMARY

[0003] The present invention relates to compounds, compositions and methods for modulating the expression or activity of microtubule-associated tau protein (MAPT). In certain embodiments, the compounds, compositions and methods can be used to reduce MAPT mRNA expression in a cell or animal. In certain embodiments, the compounds, compositions and methods can be used to reduce the amount of MAPT protein in a cell or animal.

[0004] In certain modalities, the animal has a disease, disorder, or condition related to the CNS. In certain modalities, the disease, disorder, or condition is a neurodegenerative disease, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, supranuclear palsy. Petition 870250116482, dated 12 / 17 / 2025, p. 484 / 975 2 / 459 progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, or Dravet syndrome. Certain compounds, compositions, and methods provided herein are directed to reduce a disease, disorder, or condition related to the CNS or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment in an animal.In certain embodiments, the compounds and compositions provided herein are potent and tolerable and inhibit MAPT expression, which may be used to treat, prevent, improve or delay the progression of a disease, disorder or condition related to the CNS or a symptom thereof or a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment.

[0005] In certain embodiments, the compounds and compositions comprise one or more features that are effective in increasing potency. In certain embodiments, the compounds and compositions comprise one or more features that are effective in increasing tolerability. In certain embodiments, compounds and compositions comprise one or more features that are effective in targeting the compound or composition to a cell or tissue. In certain embodiments, the compounds and compositions are more potent, have a longer duration of action, or have greater therapeutic value than publicly disclosed compounds. Petition 870250116482, dated 12 / 17 / 2025, pp. 485 / 975 3 / 459 BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 shows exemplary compounds of the present invention comprising one or more ligands.

[0007] Figure 2 shows exemplary compounds of the present invention comprising one or more ligands of tropomyosin receptor kinase B (TrkB).

[0008] Figure 3 shows exemplary compounds of the present invention comprising one or more ligands of the cannabinoid receptor type 1 (CBi).

[0009] Figure 4 shows exemplary compounds of the present invention comprising one or more α4β1 / 7 integrin ligands. DETAILED DESCRIPTION

[0010] It should be understood that both the preceding summary and the detailed description below are merely illustrative and explanatory and are not restrictive of the modalities, as claimed. The section titles used herein are for organizational purposes only and should not be interpreted as limiting the subject matter described.

[0011] All documents, or parts of documents, cited in this application, including but not limited to patents, patent applications, articles, books, treatises, and GenBank, NCBI and other sequence reference records are hereby expressly incorporated by reference for the parts of the document discussed herein, as well as in their entirety as of the filing date of this application.

[0012] It is understood that the sequence established in each SEQ ID The NO contained herein is independent of any modification to a sugar chemical moiety, an internucleosidic bond, or a nucleobase, even if shown in context with a modified compound. As such, compounds defined by a SEQ ID NO may independently comprise one or more modifications to a sugar chemical moiety, an internucleosidic bond, or a nucleobase. Petition 870250116482, dated 12 / 17 / 2025, p. 486 / 975 4 / 459 a nucleobase. Oligomeric compounds referenced by Compound Number or Ref ID NO indicate a combination of nucleobase sequence, chemical modification, and motif.

[0013] Here, the use of the singular includes the plural unless specifically indicated otherwise. For example, the articles “a” and “an” are used here to refer to one or more of one (i.e., at least one) grammatical object of the article. As an example, “an element” means one element or more than one element, for example, a plurality of elements. As used here, the use of or means and / or unless otherwise indicated. Furthermore, the use of the term “including,” as well as other forms such as “includes” and “included,” is not limiting and is used interchangeably with the phrase “including but not limited to.” Definitions

[0014] Unless otherwise indicated, the following terms have the following meanings: “Microtubule-Associated Tau Protein,” used interchangeably with the term “MAPT,” refers to any nucleic acid or protein of MAPT. Exemplary sequences of MAPT nucleotides and amino acids can be found, for example, in GenBank accession number NM_001377265.1 (incorporated herein as SEQ ID NO: 1) and in nucleotides 2624000 to 2761000 of NT_010783.14 (incorporated herein as SEQ ID NO: 2). Additional examples of MAPT sequences are readily available in public databases, for example, GenBank, UniProt, and OMIM. More information about MAPT can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=MAPT. MAPT, as used herein, also refers to variations of the MAPT gene, including variants provided in the SNP database. Numerous sequence variations within the MAPT gene have been identified and can be found by Petition 870250116482, dated 12 / 17 / 2025, pp. 487 / 975 5 / 459 example, in NCBI dbSNP and UniProt (see, for example, www.ncbi.nlm.nih.gov / snp / ?term=MAPT). “MAPT mRNA” means an mRNA that encodes a MAPT protein. MAPT can be mentioned in uppercase or lowercase letters.

[0015] “Specific MAPT inhibitor” refers to any agent capable of specifically inhibiting the expression or activity of MAPT RNA and / or MAPT protein at the molecular level. For example, specific MAPT inhibitors include nucleic acids (including oligonucleotide compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of MAPT RNA and / or MAPT protein.

[0016] “2'-O-methoxyethyl” or “2'-MOE” means a 2'O(CH2)2-OCH3 modification. A 2'-O-methoxyethyl modified sugar is a sugar modified with 2'-O(CH2)2-OCH3 in place of the 2'-OH group of a ribosyl ring.

[0017] “5' start site” means the nucleotide of the target nucleic acid or region that is aligned to the nucleoside plus 3' of an antisense oligonucleotide.

[0018] “3' stop site” means the nucleotide of the target nucleic acid or region that is aligned to the 5' plus nucleoside of an antisense oligonucleotide.

[0019] About means within ±10% of a value. For example, if it is stated “a compound achieved approximately 70% MAPT inhibition”, it is implied that MAPT levels are inhibited within a range of 60% to 80%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range.

[0020] “Administering” or “administering” refers to the routes of introducing a compound or composition given herein to a Petition 870250116482, dated 12 / 17 / 2025, p. 488 / 975 6 / 459 individual to perform its intended function. For example, routes of administration that may be used include, but are not limited to, intrathecal (IT) administration, intracerebroventricular (ICV) administration, parenteral administration such as subcutaneous administration, intravenous administration, intramuscular administration, intra-arterial administration, intraperitoneal administration or intracranial administration, for example, intrathecal or intracerebroventricular administration.

[0021] “Improvement” refers to an improvement or decrease in at least one indicator, sign, or symptom of an associated disease, disorder, or condition. In certain modalities, improvement includes a delay or slowdown in the progression or severity of one or more indicators of a condition or disease. The progression or severity of the indicators may be determined by subjective or objective measures, which are known to individuals skilled in the technique.

[0022] Animal refers to a human or non-human animal, including but not limited to mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including but not limited to monkeys and chimpanzees.

[0023] “Antisense oligonucleotide” or “antisense strand” means an oligonucleotide that includes a region that is complementary to a target nucleic acid, for example, a MAPT RNA or a region thereof.

[0024] “Complementarity” in reference to an oligonucleotide means the nucleobase sequence of that oligonucleotide or one or more regions thereof that is complementary to the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposite directions. Complementary nucleobases, as described herein, are limited to the following pairs: adenine (A) Petition 870250116482, dated 12 / 17 / 2025, pp. 489 / 975 7 / 459 and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G), unless otherwise specified. Complementary oligonucleotides and / or nucleic acids need not have nucleobase complementarity in each nucleoside and may include one or more nucleobase mismatches. Conversely, “fully complementary” or “100% complementary” in reference to oligonucleotides means that such oligonucleotides have nucleobase matches in each nucleoside without any nucleobase mismatches.

[0025] “Composition” or “pharmaceutical composition” means a mixture of substances suitable for administration to an individual. For example, a composition may comprise one or more compounds or salts thereof and a sterile aqueous solution.

[0026] “Co-administration” means the administration of two or more compounds in any manner in which the pharmacological effects of both are manifested in the patient. Co-administration does not require that both compounds be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of both compounds need not manifest at the same time. The effects only need to overlap for a period of time and do not need to be coextensive. Co-administration includes the parallel or sequential administration of one or more compounds.

[0027] “Conjugated group” means a group of atoms that is attached to an oligonucleotide. A conjugated group is optionally attached to an oligonucleotide via a conjugated ligand. A conjugated group can, for example, alter the distribution, targeting, or half-life of a compound into which it is incorporated. Conjugated groups include lipids (or lipophilic chemical moieties), ligands, and other targeting chemical moieties. Petition 870250116482, dated 12 / 17 / 2025, pp. 490 / 975 8 / 459

[0028] “Conjugated ligand” means a group of atoms comprising at least one bond connecting a chemical moiety linked to an oligonucleotide.

[0029] “Identity” in reference to an oligonucleotide means the nucleobase sequence of that oligonucleotide or one or more regions thereof that corresponds to the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof. The identity of an oligonucleotide with another oligonucleotide or nucleic acid need not require that every nucleobase be compatible and may include one or more different nucleobases. In contrast, “completely identical” or “100% identity” in reference to oligonucleotides means that such oligonucleotides have the same nucleobase at every relative position along their length as the other oligonucleotide or nucleic acid.

[0030] “Individual” means a human or non-human animal selected for treatment or therapy.

[0031] “Inhibiting expression or activity” with reference to a target nucleic acid or protein means reducing or blocking the expression or activity of such target relative to the expression or activity in an untreated or control sample, which does not necessarily indicate a complete elimination of expression or activity.

[0032] As used herein, the term “internucleoside bond” is the covalent bond between adjacent nucleosides in an oligonucleotide. As used herein, “modified internucleoside bond” means any internucleoside bond other than a phosphodiester internucleoside bond. “Phosphorothioate internucleoside bond” is a modified internucleoside bond in which one of the non-bridge oxygen atoms of a phosphodiester internucleoside bond is replaced by a sulfur atom. Petition 870250116482, dated 12 / 17 / 2025, pp. 491 / 975 9 / 459

[0033] Representative internucleoside linkages with a chiral center include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center may be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in specific stereochemical configurations, as described in more detail below. Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides described herein may be stereorandom or be in a specific stereochemical configuration.

[0034] The compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as, for example, tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

[0035] The term “isotopic variant” refers to a therapeutic agent (e.g., a modified compound and / or oligonucleotide disclosed herein) that contains an unnatural proportion of an isotope in one or more atoms that constitute such therapeutic agent. In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), Petition 870250116482, dated 12 / 17 / 2025, pp. 492 / 975 10 / 459 phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I) and iodine-131 (131I).In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (H), deuterium (2H), tritium (3H), carbon-11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), chlorine-37 (37Cl), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I).

[0036] It is understood that, in a therapeutic agent (for example, a modified compound and / or oligonucleotide disclosed herein), any hydrogen may be 2H, for example, or any carbon may be 13C, for example, or any nitrogen may be 15N, for example, or any oxygen may be 18O, for example, when feasible according to the judgment of an expert. In certain embodiments, an “isotopic variant” of a therapeutic agent contains unnatural proportions of deuterium (D).

[0037] “Lipid” or “lipophilic chemical portion” refers to an aliphatic, cyclic (such as alicyclic) or polycyclic (such as polyalicyclic) compound, such as a steroid (e.g., sterol) or a linear or branched aliphatic hydrocarbon. The term lipid includes cholesterol, retinoic acid, cholic acid, adamanthanate acetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bisO(hexadecyl)glycerol, geranyloxyhexianol, hexadecylglycerol, borneol, Petition 870250116482, dated 12 / 17 / 2025, pp. 493 / 975 11 / 459 menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl or phenoxazine. The term lipid includes a saturated or unsaturated C4-C30 hydrocarbon chain (e.g., C4-C30 alkyl or alkenyl). In certain embodiments, the lipophilic chemical portion contains a saturated or unsaturated C5-C20 hydrocarbon chain (e.g., a linear C5C20 alkyl or alkenyl). In certain embodiments, the lipophilic chemical portion contains a saturated or unsaturated C14-C20 hydrocarbon chain (e.g., a linear C14-C20 alkyl or alkenyl). In certain embodiments, the lipophilic chemical portion contains a saturated or unsaturated C6-C18 hydrocarbon chain (e.g., a linear C6-C18 alkyl or alkenyl).In certain embodiments, the lipophilic chemical portion contains a saturated or unsaturated C16 hydrocarbon chain (e.g., a linear C16 alkyl or alkenyl). In certain embodiments, the lipophilic chemical portion contains a saturated or unsaturated C17 hydrocarbon chain (e.g., a linear C17 alkyl or alkenyl). In certain embodiments, the lipophilic chemical portion contains a saturated or unsaturated C18 hydrocarbon chain (e.g., a linear C18 alkyl or alkenyl). In certain embodiments, the lipophilic chemical portion contains a saturated or unsaturated C22 hydrocarbon chain (e.g., a linear C22 alkyl or alkenyl).

[0038] “Incompatibility” or “non-complementary” means a nucleobase of a first oligonucleotide or nucleic acid that is not complementary to the corresponding nucleobase of a second oligonucleotide or nucleic acid when the first oligonucleotide / nucleic acid and the second oligonucleotide / nucleic acid are aligned in an antiparallel orientation. For example, Petition 870250116482, dated 12 / 17 / 2025, pp. 494 / 975 12 / 459 nucleobases, including but not limited to a universal nucleobase, inosine and hypoxanthine, are capable of hybridizing with at least one nucleobase, but are still incompatible or non-complementary with respect to the nucleobase to which they are hybridized. As another example, a nucleobase of a first oligonucleotide / nucleic acid that is not capable of hybridizing with the corresponding nucleobase of a second oligonucleotide / nucleic acid when the first and second oligonucleotides are aligned in an antiparallel orientation is an incompatible or non-complementary nucleobase.

[0039] “Modified oligonucleotide” means an oligonucleotide in which at least one sugar, nucleobase or internucleoside linkage is modified.

[0040] “Modular” refers to the alteration or adjustment of a characteristic in a cell, tissue, organ, or organism. For example, modulating MAPT RNA can mean increasing or decreasing the level of MAPT RNA and / or MAPT protein in a cell, tissue, organ, or organism. A “modulator” effects the change in the cell, tissue, organ, or organism. For example, a MAPT compound can be a modulator that decreases the amount of MAPT RNA and / or MAPT protein in a cell, tissue, organ, or organism.

[0041] “Motif” means the pattern of unmodified and modified sugar fractions, nucleobases and / or internucleoside linkages in an oligonucleotide.

[0042] Nucleic acid refers to molecules composed of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0043] Nucleobase means a heterocyclic chemical moiety capable of pairing with a base of another nucleic acid. According Petition 870250116482, dated 12 / 17 / 2025, pp. 495 / 975 13 / 459 used here, a “naturally occurring nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). A “modified nucleobase” is a naturally occurring nucleobase that is chemically modified. A “universal base” or “universal nucleobase” is a nucleobase that is different from both a naturally occurring and a modified nucleobase and is capable of pairing with any nucleobase.

[0044] “Nucleobase sequence” means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independently of any sugar or internucleoside bond.

[0045] “Nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and the sugar moiety are each independently modified or unmodified. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase.

[0046] “Oligomeric compound” means a compound comprising one or more oligonucleotides and, optionally, one or more additional features, such as a conjugated group or a terminal group. Examples of oligomeric compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, RNA interference compounds (RNAi compounds), microRNA-targeted oligonucleotides, occupation-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds). RNAi compounds include double-stranded compounds (e.g., short interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics) that Petition 870250116482, dated 12 / 17 / 2025, pp. 496 / 975 14 / 459 operate at least in part via the RNA-induced silencing complex (RISC) pathway, resulting in specific sequence degradation and / or sequestration of a target nucleic acid through a process known as RNA interference (RNAi). The term “RNAi compound” is intended to be equivalent to other terms used to describe nucleic acid compounds that are capable of mediating sequence-specific RNA interference, for example, RNA interfering agent (iRNA), iRNA agent, RNAi agent, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, and others. Furthermore, the term “RNAi” is intended to be equivalent to other terms used to describe sequence-specific RNA interference.

[0047] “Oligomeric duplex” means a duplex formed by two oligomeric compounds with complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound”. The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary protruding nucleosides. In some embodiments, the terms “duplexed oligomeric compound” and “modified oligonucleotide” are used interchangeably. In other embodiments, the terms “oligomeric duplex” and “compound” are used interchangeably.

[0048] Oligonucleotide means a polymer of linked nucleosides, each of which may be modified or unmodified, independent of each other.

[0049] Parenteral administration means administration by injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intra-arterial administration, intraperitoneal administration, or Petition 870250116482, dated 12 / 17 / 2025, pp. 497 / 975 15 / 459 intracranial administration, for example, intrathecal or intracerebroventricular administration.

[0050] “Pharmaceutically acceptable vehicle or diluent” means any substance suitable for use in administration to an individual. In certain embodiments, a pharmaceutically acceptable vehicle or diluent assists in the administration of a compound for absorption by an individual and may be included in the compositions of the present invention without causing a significant adverse toxicological effect in the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions and the like. For example, a pharmaceutically acceptable vehicle may be a sterile aqueous solution, such as PBS or water for injection. One skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0051] “Pharmaceutically acceptable salt” means or refers to physiologically and pharmaceutically acceptable salts of compounds, such as oligomeric compounds or oligonucleotides, i.e., salts that retain the desired biological activity of the original compound and do not impart undesirable toxicological effects to it.

[0052] “Tropomyosin Receptor Kinase B” or “TrkB”, as it may be used interchangeably herein, means the receptor for the brain-derived neurotrophic factor (BDNF) protein encoded by the NTRK2 gene. TrkB is also known as tyrosine kinase receptor B, BDNF / NT-3 growth factor receptor, and neurotrophic tyrosine kinase receptor type 2.

[0053] As used herein, a pharmaceutically acceptable salt is any salt of a compound provided herein that retains its biological properties and is not toxic or undesirable for pharmaceutical use. Pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts that are prepared with Petition 870250116482, dated 12 / 17 / 2025, pp. 498 / 975 16 / 459 relatively non-toxic acids or bases, depending on the specific substituents found in the modified compounds or oligonucleotides described herein.

[0054] When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient quantity of the desired base, pure or in a suitable inert solvent.

[0055] When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient quantity of the desired acid, pure or in a suitable inert solvent.

[0056] Thus, the compounds of the present invention can exist as salts, as with pharmaceutically acceptable acids. These salts can be derived from a variety of organic and inorganic counterions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, laurylsulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic. Petition 870250116482, dated 12 / 17 / 2025, pp. 499 / 975 17 / 459 cyclohexylsulfamic, quinic, muconic and similar acids; or (2) salts formed when an acidic proton present in the original compound is either (a) replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion, or alkali or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc and barium hydroxide, ammonia, or (b) coordinates with an organic base, such as aliphatic, alicyclic or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 119).

[0057] Pharmaceutically acceptable salts also include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, for example, hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate,. Petition 870250116482, dated 12 / 17 / 2025, pages 500 / 975 18 / 459 Lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate and the like. In some embodiments, the pharmaceutically acceptable salt of the modified compounds and oligonucleotides disclosed herein is a sodium or potassium salt. In some embodiments, the pharmaceutically acceptable salt of the modified compounds and oligonucleotides disclosed herein is a sodium salt.

[0058] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In some embodiments, the compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into basic or acidic addition salts. The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present invention.

[0059] “Pharmaceutical agent” means a compound that provides a therapeutic benefit when administered to an individual.

[0060] “Phosphorothioate linkage” means a modified phosphate linkage in which one of the non-bridge oxygen atoms is replaced by a sulfur atom.

[0061] “Portion” means a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. In certain Petition 870250116482, dated 12 / 17 / 2025, pp. 501 / 975 In 19 / 459 embodiments, a moiety is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a moiety is a defined number of contiguous nucleobases of an oligonucleotide.

[0062] “Prevent” refers to delaying or stopping the onset, development or progression of a disease, disorder or condition for a period of time.

[0063] “RNA interference compound” or “RNAi compound” means a compound that acts, at least in part, via an RNA-induced silencing complex (RISC) or Ago2 pathway, but not via RNase H, to modulate a target nucleic acid and / or a protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNA, including microRNA mimics.

[0064] “Sense oligonucleotide” or “sense strand” means the strand of a double-stranded compound that includes a region that is substantially complementary to a region of the compound’s antisense strand.

[0065] “Specifically inhibit” with reference to a target nucleic acid or protein means to reduce or block the expression or activity of the target nucleic acid or protein, minimizing or eliminating effects on non-target nucleic acids or proteins.

[0066] “Subunit” with reference to an oligonucleotide means a nucleotide, nucleoside, nucleobase or sugar or a modified nucleotide, nucleoside, nucleobase or sugar as provided herein.

[0067] “Target nucleic acid”, “target RNA” and “target nucleic acid” all mean a nucleic acid capable of being targeted by the compounds described herein.

[0068] “Target region” means a portion of a target nucleic acid to which one or more compounds are directed. Petition 870250116482, dated 12 / 17 / 2025, pp. 502 / 975 20 / 459

[0069] “Targeting chemical moiety” means a conjugated group that provides increased affinity for a selected target, for example, molecule, cell or cell type, compartment, for example, a cellular or organ compartment, tissue, organ or body region, as, for example, compared to a compound lacking such a chemical moiety.

[0070] “Terminal group” means a chemical group or group of atoms that is covalently attached to a terminal of an oligonucleotide.

[0071] “Therapeutically effective amount” or “effective amount” means an amount of a compound, pharmaceutical agent, or composition that provides a therapeutic benefit to an individual. A “therapeutically effective amount” or “effective amount” is an amount sufficient for a compound to achieve a stated purpose in relation to its absence (e.g., to achieve the effect for which it is administered, to treat, prevent, or improve a disease, or to reduce one or more symptoms of a disease or condition). An example of a “therapeutically effective amount” or “effective amount” is an amount sufficient to contribute to the treatment, prevention, improvement, or reduction of a symptom or symptoms of a disease. A reduction of a symptom or symptoms (and grammatical equivalents of that term) means the decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s).A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to an individual, will have the intended prophylactic effect, for example, preventing or delaying the onset (or recurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology or condition, or its symptoms. The term “therapeutically effective amount,” as used herein, refers to the quantity. Petition 870250116482, dated 12 / 17 / 2025, p. 503 / 975 21 / 459 of the therapeutic agent sufficient to provide a therapeutic benefit to an individual, such as treating, preventing, or improving the disease or disorder or symptom thereof, as described above. For example, for a given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy may also be expressed as times increase or decrease. For example, a therapeutically effective amount may have at least a 1.2-time, 1.5-time, 2-time, 5-time, or greater effect over a control.

[0072] The term treat or treatment refers to any indication of successful therapy or improvement of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as reduction, remission, or decrease in symptoms, or making the injury, pathology, or condition more tolerable for the patient; slowing the rate of degeneration or decline; making the endpoint of degeneration less debilitating; improving the patient's physical or mental well-being. Treatment or symptom improvement may be based on objective or subjective parameters, including the results of a physical examination. The term "treat" and its conjugations may include the prevention of an injury, pathology, condition, or disease. In modalities, treat is prevent. In modalities, treat does not include prevention.

[0073] “Treat” or “treatment” as used herein (and also well understood in the art) also broadly includes any approach to obtain beneficial or desired results in an individual’s condition, including clinical results. Beneficial or desired clinical results may include, but are not limited to, relief or improvement of one or more symptoms or conditions, reduction in the extent of a disease, stabilization (i.e., no worsening) of the condition. Petition 870250116482, dated 12 / 17 / 2025, pp. 504 / 975 22 / 459 of the disease, prevention of the transmission or spread of a disease, delay or slowing of the progression of the disease, improvement or palliation of the disease state, reduction of disease recurrence, partial or total remission, detectable or undetectable. In other words, “treatment,” as used herein, includes any cure, improvement, or prevention of a disease. Treatment may prevent the occurrence of the disease; inhibit the spread of the disease; alleviate the symptoms of the disease; remove all or part of the underlying cause of the disease; shorten the duration of the disease; or do a combination of these things.

[0074] “Treat” and “treatment” as used herein include prophylactic treatment. Treatment methods include administering to an individual a therapeutically effective amount of a compound described herein. The administration step may consist of a single administration or may include a series of administrations. The duration of the treatment period depends on a variety of factors, such as the severity of the condition, the patient’s age, the concentration of the compound, the activity of the compositions used in treatment, or a combination thereof. It will also be noted that the effective dosage of an agent used for treatment or prophylaxis may increase or decrease over the course of a specific treatment or prophylaxis regimen. In some cases, chronic administration may be necessary. For example, the compositions are administered to the individual in an amount and for a duration sufficient to treat the patient."Treat" refers to the administration of a pharmaceutical compound or composition to an animal to effect a change or improvement in a disease, disorder, or condition in the animal.

[0075] Certain compounds of the present invention have asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that can be defined, in Petition 870250116482, dated 12 / 17 / 2025, pages 505 / 975 23 / 459 Absolute stereochemical terms, such as (R) or (S) or (D) or (L) for amino acids, and individual isomers are covered by the scope of the present invention. The compounds of the present invention do not include those known in the art to be too unstable to synthesize and / or isolate. The present invention is intended to include compounds in racemic and optically pure forms. Optically active (R) and (S) or (D) and (L) isomers can be prepared using chiral synthons or chiral reagents or solved using conventional techniques. When the compounds described herein contain olefinic linkages or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0076] As used herein, the term isomers refers to compounds having the same number and type of atoms, and therefore the same molecular weight, but differing in the arrangement or structural configuration of the atoms.

[0077] The term tautomer, as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0078] It will be evident to an individual skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

[0079] Unless otherwise indicated, the structures described herein shall also include all stereochemical forms of the structure (i.e., the R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds present are within the scope of the invention.

[0080] As used here, “chirally enriched population” Petition 870250116482, dated 12 / 17 / 2025, pp. 506 / 975 24 / 459 means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules that would be expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules with multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.

[0081] Unless otherwise indicated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopic enrichment atoms. For example, compounds that have the structures presented, except for the substitution of a hydrogen by a deuterium or tritium, or the substitution of a carbon by a carbon enriched with 13C or a carbon enriched with 14C, are within the scope of this invention.

[0082] As used herein, “stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center with a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be, but is not necessarily, the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that Petition 870250116482, dated 12 / 17 / 2025, pp. 507 / 975 25 / 459 was not designed to control stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside bond. Certain Modalities

[0083] In certain aspects, the invention relates to methods, compounds and compositions for inhibiting MAPT. In certain embodiments, MAPT is specifically inhibited. In certain embodiments, MAPT is specifically degraded. In certain embodiments, MAPT expression is inhibited. In certain embodiments, MAPT translation is inhibited. In certain embodiments, MAPT activity is inhibited. In certain embodiments, MAPT expression, translation or activity is reduced by at least 10% relative to the expression, translation or activity in an untreated or control sample. For example, in certain modalities, the expression, translation, or activity of MAPT is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% compared to the expression, translation, or activity in an untreated or control sample.In certain embodiments, the expression, translation, or activity of MAPT is reduced as measured by any suitable assay, including but not limited to an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq).

[0084] In certain aspects, the invention relates to compounds targeting a MAPT nucleic acid. In certain embodiments, the MAPT nucleic acid has the sequence established in GenBank accession number NM_001377265.1 (incorporated herein as SEQ ID NO: 1), and nucleotides 2624000 to 2761000 of NT_010783.14 (incorporated herein as SEQ ID NO: 2). Petition 870250116482, dated 12 / 17 / 2025, pp. 508 / 975 26 / 459

[0085] In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded.

[0086] Certain embodiments provide a compound comprising a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of the SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.

[0087] Certain embodiments provide a compound comprising a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.

[0088] Certain embodiments provide a compound comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.

[0089] In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO: 1 or 2. In certain embodiments, the modified oligonucleotide comprises at least one selected modification of a modified internucleosidic bond, a modified sugar, and a modified nucleobase. In certain embodiments, the compound is double-stranded.

[0090] Certain modalities provide a compound that Petition 870250116482, dated 12 / 17 / 2025, pp. 509 / 975 27 / 459 comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.

[0091] In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences provided in Tables 2 and 3, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a complementarity region with respect to the first modified oligonucleotide.

[0092] Certain embodiments provide a compound comprising a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second Petition 870250116482, dated 12 / 17 / 2025, pp. 510 / 975 28 / 459 modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.

[0093] Certain embodiments provide a compound comprising a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide with 19 to 23 nucleosides linked in length having a complementarity region with respect to the first modified oligonucleotide.

[0094] Certain embodiments provide a compound comprising a first modified oligonucleotide comprising a 5'-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a SEQ ID NO: 1 or 2 region, and a second modified oligonucleotide comprising one or more ligands described herein (for example, one or more tropomyosin B receptor (TrkB) ligands, one or more cannabinoid receptor type 1 (CB1) ligands, or one or more α4β1 / 7 integrin ligands). In certain embodiments, the first modified oligonucleotide comprises a 5'-terminal nucleoside comprising the 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification.

[0095] In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, by Petition 870250116482, dated 12 / 17 / 2025, page 511 / 975 29 / 459 minus 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., from 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any nucleobase sequence of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.

[0096] In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide of any preceding compound has at least 80%, at least 85%, Petition 870250116482, dated 12 / 17 / 2025, page 512 / 975 30 / 459 less than 90% or at least 95% complementarity or identity with SEQ ID NO: 1 or 2 in length. In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide has at least 1, at least 2, or at least 3 mismatches with a region of SEQ ID NO: 1 or 2. In certain embodiments, the complementarity region between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 14 to 30 nucleoside links in length. In certain embodiments, the complementarity region between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 14 to 23 nucleoside links in length. In certain embodiments, the complementarity region between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 19 to 23 nucleoside links in length.In certain embodiments, the region of complementarity between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 21 to 23 nucleoside links in length. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

[0097] In certain embodiments, the modified oligonucleotide or first modified oligonucleotide of any preceding compound comprises at least one modification selected from a modified internucleosidic bond, a modified sugar, and a modified nucleobase. In certain embodiments, the second modified oligonucleotide of any preceding compound comprises at least one modification selected from the group consisting of a modified internucleosidic bond, a modified sugar, and a modified nucleobase. In Petition 870250116482, dated 12 / 17 / 2025, page 513 / 975 31 / 459 In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage. In certain embodiments, the phosphorothioate internucleoside linkage or methylphosphonate internucleoside linkage is at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide. In certain embodiments, the modified sugar comprises a selected group modification consisting of a halogen, an alkoxy group, and a bicyclic sugar. In certain embodiments, the modified sugar comprises a 2'-F modification. In certain embodiments, the modified sugar comprises a 2'-OMe modification. In certain embodiments, each nucleoside of the first modified oligonucleotide comprises a modified sugar. In certain embodiments, each nucleoside of the second modified oligonucleotide comprises a modified sugar.In certain embodiments, the modified sugar comprises a selected modification of the group consisting of a halogen, an alkoxy group, and a bicyclic sugar, or a combination thereof. In certain embodiments, the modified sugar comprises a selected modification of the group consisting of 2'-MOE, 2'-F, and 2'-OMe, or a combination thereof. In certain embodiments, the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

[0098] In certain embodiments, the compound of any previous embodiment comprises a conjugated group. In certain embodiments, the conjugated group is attached to the 5' end of the modified oligonucleotide. In certain embodiments, the conjugated group is a targeting chemical moiety. In Petition 870250116482, dated 12 / 17 / 2025, page 514 / 97532 / 459 In certain embodiments, the targeting chemical portion comprises one or more ligands. In certain embodiments, the targeting chemical portion comprises one or more ligands selected from one or more tropomyosin B receptor (TrkB) ligands, one or more cannabinoid receptor type 1 (CBi) ligands, and one or more α4β1 / 7 integrin ligands. In certain embodiments, the targeting chemical portion comprises one or more TrkB ligands. In certain embodiments, the targeting chemical portion comprises one or more CB1 ligands. In certain embodiments, the targeting chemical portion comprises one or more α4β1 / 7 integrin ligands. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide. In certain embodiments, one or more TrkB linkers are attached to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide.In certain embodiments, one or more CB1 linkers are attached to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide. In certain embodiments, one or more α4β1 / 7 integrin linkers are attached to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide.

[0099] In certain embodiments, the TrkB linker of a modified oligonucleotide is of Formula (I) or a salt, solvate or hydrate thereof: Formula (I), where: Petition 870250116482, dated 12 / 17 / 2025, pp. 515 / 975 33 / 459 R1 is the modified oligonucleotide; L1, L2, L3 and L4 are as described here; R2 is hydrogen, -OR7, -SR8 or -NR9R10; R3 is hydrogen, -OR11, -SR12 or -NR13R14; R4 is hydrogen, -OR15, -SR16 or -NR17R18; R5 is hydrogen, -OR19, -SR20 or -NR21R22; R6 is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted OAc, -NH2, optionally substituted -NHAc, -SH or =O; R7R8R9R10R11R12R13R14R15R16R17R18R19R20 R21 and R22 are, each independently, hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; Y is CH2, NH, S, or O; and Z is optionally substituted aryl or optionally substituted heteroaryl.

[0100] In certain modalities, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 and R22 are each independently optionally substituted unsaturated or partially unsaturated alkyl. In certain embodiments, R7, R8, R9 and R10 are each independently alkenyl. In certain embodiments, R7, R8, R9 and R10 are each independently alkynyl.

[0101] In certain embodiments, R2 is OR7. In certain embodiments, R3 is OR11. In certain embodiments, R7 and R11 are each independently hydrogen, optionally substituted alkyl, or optionally substituted alkenyl. In certain embodiments, one or both R7 and R11 are each independently Petition 870250116482, dated 12 / 17 / 2025, page 516 / 975 34 / 459 hydrogen. In certain embodiments, one or both R7 and R11 are each independently optionally substituted alkyl. In certain embodiments, one or both R7 and R11 are each independently unsaturated or partially unsaturated optionally substituted alkyl. In certain embodiments, one or both R7 and R11 are each independently alkenyl. In certain embodiments, R7 is optionally substituted alkyl and R11 is hydrogen. In certain embodiments, R7 is hydrogen and R11 is optionally substituted alkyl. In certain embodiments, R7 is alkenyl and R11 is hydrogen. In certain embodiments, R7 is hydrogen and R11 is optionally substituted alkenyl.

[0102] In certain embodiments, the TrkB linker of a modified oligonucleotide is selected from the following formulas or a salt, solvate or hydrate thereof: Formula (II-B), Formula (II-C), where: R1 is the modified oligonucleotide; L1, L2, L3, L4 and R1 are as described here.

[0103] In certain embodiments, the TrkB ligand of a Petition 870250116482, dated 12 / 17 / 2025, p. 517 / 975 35 / 459 modified oligonucleotide is of formula (XXXXXVII) or a salt, solvate or hydrate thereof: Formula (XXXXXVII), where: L1, L2, L3, L4 and R1 are as described here; R11 and R13 are, each independently, hydrogen or optionally substituted alkyl absent; R12, R14 and R15 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R16 is hydrogen, halogen, -CN, -N3, -SOn16R1A, -SOv16 NR16BR16C, -NHNR16BR16C, -ONR16BR16C, -NHC(O)NHNR16BR16C, -NHC(O)NR16BR16C, -N(O)m16, -NR16BR16C, -C(O)R16D, -C(O)OR16D, C(O)NR16BR16C, -OR16A, -NR16BSO2R16A, -NR16BC(O)R16D, -NR16BC(O)OR16D, -NR16BOR16D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and are, each independently, either a single bond or a double bond, wherein if — is a single bond, then it is a double bond and R13 is absent; and also wherein if it is a single bond, then =^= is a double bond and R11 is absent; Petition 870250116482, dated 12 / 17 / 2025, page 518 / 975 36 / 459 R16A, R16B, R16C and R16D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or the substituents R16B and R16C attached to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; z3 is 0, 1, 2, 3, 4, or 5; n16 is 0, 1, 2, 3, or 4; and v16 and m16 are each independently 1 or 2.

[0104] In certain embodiments, the TrkB linker of a modified oligonucleotide is of the formula (XXXXXIX) or a salt, solvate or hydrate thereof: R17\ w HO (R19)z5 Formula (XXXXXIX), where: L1, L2, L3, L4 and R1 are as described here; R17, R18 and R19 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; z4 is 0, 1, or 2; and z5 is 0, 1, 2, or 3. Petition 870250116482, dated 12 / 17 / 2025, p. 519 / 975 37 / 459

[0105] In certain embodiments, the TrkB linker of a modified oligonucleotide is of the formula (XXXXXX) or a salt, solvate or hydrate thereof: (R21)z7 (r20)z6)z8 C -------l1-l2-l3-l4-r1 XR23^R24 Formula (XXXXXX), where: L1, L2, L3, L4 and R1 are as described here; R20 is hydrogen, halogen, -CN, -N3, -SOn20R1A, SOv2oNR20BR20C, -NHNR20BR20C, -ONR20BR20C, -NHC(O)NHNR20BR20C, -NHC(O)NR20BR20C, -N(O)m20, -NR20BR20C, -C(O)R20D, -C(O)OR20D, C(O)NR20BR20C, -OR20A, -NR20BSO2R20A, -NR20BC(O)R20d;-NR20BC(O) OR20D, -NR20BOR20D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R21 is hydrogen, halogen, -CN, -N3, -SOn21R1A, SOv2iNR21BR21C, -NHNR21BR21C, -ONR21BR21C, -NHC(O)NHNR21BR21C, -NHC(O)NR21BR21C, -N(O)m21, -NR21BR21C, -C(O)R21d, -C(O)OR21d, C(O)NR21BR21C, -OR21A, -NR21BSO2R21A, -NR21BC(O)R21d;-NR21BC(O) OR21D, -NR21BOR21D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R22 and R23 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or Petition 870250116482, dated 12 / 17 / 2025, pp. 520 / 975 38 / 459 optionally substituted heteroaryl; R24 is hydrogen, halogen, -CN, -N3, -SOn24R24A, SOv24NR24BR24C, -NHNR24BR24C, -ONR24BR24C, -NHC(O)NHNR24BR24C, -NHC(O)NR24BR24C, -N(O)m24, -NR24BR24C, -C(O)R24D, -C(O)OR24D, C(O)NR24BR24C, -OR24A, -NR24BSO2R24A, -NR24BC(O)R24D;-NR24BC(O) OR24D, -NR24BOR24D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R20A r20B R20C r20D r21A r21B r21C r21D r24A r24B r24C and R24D are, each independently, hydrogen, halogen, -CF3, CCl3, -CBr3, -CI3-COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; The substituents R20B, R20C, R21B, R21C, R24B, R24C, R24B and R24C attached to the same nitrogen atom can optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n21, n22, n24, z6 and z8 are each independently 0, 1, 2, 3 or 4; v20, v21, v24, m20, m21, and m24 are each independently 1 or 2; and z7 is 0, 1, or 2.

[0106] In certain embodiments, the CB1 linker of a modified oligonucleotide is of the formula (XXXXXXI) or a salt, solvate or hydrate thereof: Petition 870250116482, dated 12 / 17 / 2025, p. 521 / 975 39 / 459 Formula (XXXXXXI) where: L1, L2, L3, L4 and R1 are as described here; X1 is NR10 or CR11R12; R10, R11 and R12 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R19 is hydrogen, -SOn19R19A, -SOv19NR19BR19C, -NHNR19BR19C, -ONR19BR19C, -NHC(O)NHNR19BR19C, -NHC(O)NR19BR19C, NR19BR19C, -C(O)R19D, -C(O)OR19D, -C(O)NR19BR19C, -OR19A, -NR19BSO2R19A, -NR19BC(O)R19D, -NR19BC(O)OR19D, -NR19BOR19D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R19A, R19B, R19C, R19D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein the substituents R19B and R19C attached to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Petition 870250116482, dated 12 / 17 / 2025, p. 522 / 975 40 / 459 replaced; n19 is 0, 1, 2, 3, or 4; and v19 is 1 or 2.

[0107] In certain embodiments, the α4β1 / 7 integrin linker of a modified oligonucleotide is of the formula (XXXXXXII) or a salt, solvate or hydrate thereof: Formula (XXXXXXII) where L1, L2, L3, L4 and R1 are as described here; R2 is H, polyethylene glycol (PEG), optionally substituted heteroalkyl or optionally substituted heteroaryl; and R3 and R4 are, each independently, H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl.

[0108] In certain embodiments, the α4β1 / 7 integrin linker of a modified oligonucleotide is of the formula (XXXXXXIII) or a salt, solvate or hydrate thereof: Formula (XXXXXXIII) where L1, L2, L3, L4 and R1 are as described here; R2, R3, R4 and R5 are each independently H, halogen, optionally substituted alkyl, optionally -O-alkyl Petition 870250116482, dated 12 / 17 / 2025, p. 523 / 975 41 / 459 substituted, cycloalkyl or absent; R8 is optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)-cycloalkyl or optionally substituted (C1-C4) alkylene-(C1-C4)-alkoxy; and R6 and R7 are each independently H, halogen, alkyl or optionally substituted alkyl, optionally substituted heteroalkyl, f or

[0109] In certain embodiments, the α4β1 / 7 integrin linker of a modified oligonucleotide is of the formula (XXXXXXIV) or a salt, solvate or hydrate thereof: Formula (XXXXXXIV) where L1, L2, L3, L4 and R1 are as described herein; R2 is H, -CONHR4, -CH2OR4, -(CH2)2OR4, -CH2NHCOR4 or OR4; R3 is H, optionally substituted alkyl or optionally substituted cycloalkyl; R4e H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heteroaryl; Petition 870250116482, dated 12 / 17 / 2025, page 524 / 975 42 / 459 Rké -OH or absent; and X is H, optionally substituted CH2, optionally substituted NH, or cycloalkyl.

[0110] In certain embodiments, the α4β1 / 7 integrin linker of a modified oligonucleotide is of the formula (XXXXXXXXIII) or a salt, solvate, or hydrate thereof: in what L1, L2, L3, L4 and R1 are as described herein; R2 is H, -CONHR3, -CH2OR3, -(CH2)2OR3, -CH2NHCOR3or OR3; each instance of R3 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heteroaryl; and X is H or halogen.

[0111] In certain embodiments, L1, L2, L3 and L4 are each independently absent a linkage, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker or an optionally substituted heteroaryl linker.

[0112] In certain embodiments, L1 is an optionally substituted heteroaryl ligand.

[0113] In certain embodiments, L1 is an optionally substituted unsaturated heteroaryl, an optionally substituted heteroaryl Petition 870250116482, dated 12 / 17 / 2025, pp. 525 / 975 43 / 459 substituted or an optionally substituted saturated or partially unsaturated heterocycloalkyl ligand.

[0114] In certain modalities, L1 comprises the structure: N-\ .

[0115] In certain embodiments, L1 is an optionally substituted heteroalkyl ligand. In certain embodiments, the optionally substituted heteroalkyl ligand is an optionally substituted heteroalkyl or optionally substituted C1-C10 alkyl chain in which one or more carbon atoms are substituted by O, N, or S.

[0116] In certain modalities, L1 comprises the structure: hn^ ^n^· Y^o ouo.

[0117] In certain modalities, L1 comprises the structure: V or -N(CH3)-.

[0118] In certain embodiments, L2 is an optionally substituted PEG binder.

[0119] In certain embodiments, the PEG ligand has five PEG units in length. In certain embodiments, the PEG ligand has four PEG units in length. In certain embodiments, the PEG ligand has three PEG units in length.

[0120] In certain embodiments, L2 is an optionally substituted alkyl ligand. In certain embodiments, L2 is an optionally substituted C1-20 alkyl ligand. In certain embodiments, L2 is an optionally substituted C8 alkyl ligand. In certain embodiments, L3 is an optionally substituted heteroaryl ligand. Petition 870250116482, dated 12 / 17 / 2025, page 526 / 975 44 / 459 replaced.

[0121] In certain embodiments, L3 is an optionally substituted unsaturated heteroaryl ligand, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl ligand.

[0122] In certain modalities, L3 comprises the structure:

[0123] In certain embodiments, L4 is an optionally substituted heteroalkyl ligand. In certain embodiments, the heteroalkyl ligand is substituted by one or more =O substituents.

[0124] In certain embodiments, the heteroalkyl linker comprises two substituents joined to form an optionally substituted carbocyclyl ring.

[0125] In certain modalities, L4 comprises the structure: I've got a salt from the same, in which X is O or S.

[0126] In certain modalities, L4 comprises the structure: OH ,0-P-0 II or a salt thereof, where X is O or S.

[0127] In certain modalities, L1-L2-L3-L4 comprises the structure: Petition 870250116482, dated 12 / 17 / 2025, p. 527 / 975 45 / 459 Petition 870250116482, dated 12 / 17 / 2025, p. 528 / 975 46 / 459 Petition 870250116482, dated 12 / 17 / 2025, p. 529 / 975 47 / 459 Petition 870250116482, dated 12 / 17 / 2025, pp. 530 / 975 48 / 459 or a salt of it, where X is O or S.

[0128] In certain embodiments, the TrkB linker of a modified oligonucleotide is selected from the following formulas or a salt, solvate or hydrate thereof: i ΠΡ:: Ba.tiB Formula (III), Λϊ-IM ·Ν W'X. fÍJV V:T TXJ U^.-M Ul« CÁ Formula (IV), .-L _ ->l GH \ ιΓ 51 L-j1 “YVjr^ oOo □ ·Η_. ΐ μ IIA'1111 Formula (V), % H OR s ΪX = 0 or S Petition 870250116482, dated 12 / 17 / 2025, p. 531 / 975 49 / 459 Formula (VI), Formula (VII), X = O or s H=Έ-O-π Petition 870250116482, dated 12 / 17 / 2025, p. 532 / 975 50 / 459 Formula (XI), Formula (XII), Formula (XIII), Petition 870250116482, dated 12 / 17 / 2025, p. 533 / 975 51 / 459 Petition 870250116482, dated 12 / 17 / 2025, p. 534 / 975 52 / 459 Formula (XIX), Formula (XX), Petition 870250116482, dated 12 / 17 / 2025, pp. 535 / 975 53 / 459 Formula (XXIII), BA-173 BA-201 Petition 870250116482, dated 12 / 17 / 2025, p. 536 / 975 54 / 459 BA-196 Formula (XXIX) BA-197 Formula (XXX) Formula (XXXIV) Petition 870250116482, dated 12 / 17 / 2025, p. 537 / 975 55 / 459 ,N. O^ZN 'N Formula (XXXXXXV) .Ν_ Ο^Ζ^Ν 'Ν Formula (XXXXXXVI) O^ / ^N 'N OH Formula (XXXXXXVII) o Formula (XXXXXXIX) Formula (XXXXXXX) Petition 870250116482, dated 12 / 17 / 2025, p. 538 / 975 56 / 459 O^Z^N 'N Formula (XXXXXXXI) the Formula (XXXXXXXII) Formula (XXXXXXXIII), where: R is the modified oligonucleotide; and X is either S or O.

[0129] In certain embodiments, the CBi linker of a modified oligonucleotide is selected from the following formulas or a salt, solvate or hydrate thereof: Formula (XXXXXXXIV) Petition 870250116482, dated 12 / 17 / 2025, p. 539 / 975 57 / 459 V N. R Ó OP-OH X R ó OP-OH II X R O OP-OH X / N HN Formula (XXXXXXXV) N H οΓΛΛ o Formula (XXXXXXXVI) Formula (XXXXXXXVII) Formula (XXXXXXXVIII) where: R is the modified oligonucleotide; and X is either S or O.

[0130] In certain embodiments, the α4β1 / 7 integrin linker of a modified oligonucleotide is selected from the following formulas or a salt, solvate, or hydrate thereof: Petition 870250116482, dated 12 / 17 / 2025, pp. 540 / 975 58 / 459 Formula (XXXXXXXIX) Formula (XXXXXXX) OH ROP=X Formula (XXXXXXXI) Formula (XXXXXXXXII) Petition 870250116482, dated 12 / 17 / 2025, page 541 / 975 59 / 459 Formula (XXXXXXXXIV) where: R is the modified oligonucleotide; and X is either S or O.

[0131] In certain embodiments, the compound of any previous embodiment comprises a lipid. In certain embodiments, the lipid is linked to an internucleosidic bond of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more lipids. In certain embodiments, one or more lipids are linked to one or more internucleosidic bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide.

[0132] In certain embodiments, the compound of any previous embodiment comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to an internucleosidic bond of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises Petition 870250116482, dated 12 / 17 / 2025, page 542 / 975 60 / 459 one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to one or more internucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide.

[0133] In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C4-C30 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C5C20 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C14-C20 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated and unsaturated C16 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated and unsaturated C17 hydrocarbon chain.In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated and unsaturated C18 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated and unsaturated C22 hydrocarbon chain.

[0134] In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to an internucleosidic bond of a modified oligonucleotide (e.g., a second modified oligonucleotide or sense oligonucleotide). In certain embodiments, the internucleosidic bond occurs between Petition 870250116482, dated 12 / 17 / 2025, p. 543 / 975 61 / 459 nucleosides that are within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of a terminal end (e.g., the 5' and / or 3' end) of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage occurs between nucleosides that are within 5 positions of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage occurs between nucleosides that are within 5 positions of the 3' end of the modified oligonucleotide.

[0135] In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 2 and 3 of the 5' end of the modified oligonucleotide.In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 3' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the 3' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 2 and 3. Petition 870250116482, dated 12 / 17 / 2025, pp. 544 / 975 62 / 459 of the 3' end of the modified oligonucleotide.

[0136] In certain embodiments, the internucleosidic linkage of the modified oligonucleotide is selected from any of Formulas XXXXXIII-XXXXXVI. In certain embodiments, the modified oligonucleotide comprises any of Formulas XXXV-XXXXXVI.

[0137] In certain embodiments, the modified oligonucleotide comprises Formula (XXXV) or a salt, solvate or hydrate thereof: Q3Q4^q' r3 Formula (XXXV), where: Y is -C(=O)N(RC)- or -N(RC)C(=O)-; Q1 and Q3 are, each independently -H, -OR4, a ligand, a ligand or a lipid; Q2 and Q4 are, each independently, a linkage, the ® iH x , a ligand, a ligand or a lipid; RCé independently -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; each R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Petition 870250116482, dated 12 / 17 / 2025, pp. 545 / 975 63 / 459 substituted or unsubstituted alkynyl, -OR6, -N(R6) or -SR6; each R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7) or -SR7; R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; each R6 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R8 is independently a substituted or unsubstituted heteroaryl; each R9 is independently a substituted or unsubstituted heteroaryl; Each instance of Z1 or Z2 is independently a C1-C6 alkylene or C2-C6 alkenylene bond; and each X is independently O or S; or a salt of it.

[0138] In certain embodiments, the modified oligonucleotide comprises Formula (XXXVI) or a salt, solvate or hydrate thereof: Formula (XXXVI), where: Petition 870250116482, dated 12 / 17 / 2025, p. 546 / 975 64 / 459 RCé -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6) or -SR6; each R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7) or -SR7; R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; each R6 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R8 is independently a substituted or non-substituted heteroaryl ring; each R9 is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

[0139] In certain embodiments, the modified oligonucleotide comprises Formula (XXXVII) or a salt, solvate or hydrate thereof: Petition 870250116482, dated 12 / 17 / 2025, p. 547 / 975 65 / 459 Formula (XXXVII), where: each R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6) or -SR6; each R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7) or -SR7; R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; each R6 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R8 is independently a substituted or non-substituted heteroaryl ring; each R9 is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

[0140] In certain embodiments, the modified oligonucleotide comprises Formula (XXXVIII) or a salt, solvate or hydrate thereof: Petition 870250116482, dated 12 / 17 / 2025, p. 548 / 975 66 / 459 Formula (XXXVIII), where: each R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6) or -SR6; each R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7) or -SR7; R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; each R6 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R8 is independently a substituted or non-substituted heteroaryl ring; each R9 is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

[0141] In certain embodiments, the modified oligonucleotide comprises Formula (XXXIX) or a salt, solvate or Petition 870250116482, dated 12 / 17 / 2025, p. 549 / 975 67 / 459 hydrate of the same: Formula (XXXIX), where: each R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6) or -SR6; each R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7) or -SR7; R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; each R6 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R8 is independently a substituted or non-substituted heteroaryl ring; each R9 is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

[0142] In certain embodiments, the modified oligonucleotide comprises the formula (XXXX) or a salt, solvate or hydrate Petition 870250116482, dated 12 / 17 / 2025, pp. 550 / 975 68 / 459 of the same: Formula (XXXX), where: each R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR6, -N(R6) or -SR6; each R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR7, -N(R7) or -SR7; R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; each R6 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R8 is independently a substituted or unsubstituted heteroaryl ring; each R9 is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

[0143] In certain embodiments, the oligonucleotide Petition 870250116482, dated 12 / 17 / 2025, p. 551 / 975 69 / 459 modified comprises Formula (XXXXI) or a salt, solvate or hydrate thereof: muemU Formula (XXXXI) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0144] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXII) or a salt, solvate or hydrate thereof: © (DMe *p<° OR5mAemA Formula (XXXXII) Petition 870250116482, dated 12 / 17 / 2025, pp. 552 / 975 70 / 459 where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0145] In certain embodiments, the modified oligonucleotide comprises the formula (XXXXIII) or a salt, solvate or hydrate thereof: mAemU Formula (XXXXIII) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0146] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXIV) or a salt, solvate or hydrate thereof: Petition 870250116482, dated 12 / 17 / 2025, pp. 553 / 975 71 / 459 mAemG Formula (XXXXIV) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0147] In certain embodiments, the modified oligonucleotide comprises the formula (XXXXV) or a salt, solvate or hydrate thereof: mAemC Formula (XXXXV) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S. Petition 870250116482, dated 12 / 17 / 2025, pp. 554 / 975 72 / 459

[0148] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXVI) or a salt, solvate or hydrate thereof: mUemA Formula (XXXXVI) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0149] In certain embodiments, the modified oligonucleotide comprises Formula (XXXXVII) or a salt, solvate or hydrate thereof: mUemG Formula (XXXXVII) Petition 870250116482, dated 12 / 17 / 2025, pages 555 / 975 73 / 459 where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0150] In certain embodiments, the modified oligonucleotide comprises the formula (XXXXVIII) or a salt, solvate or hydrate thereof: mUefC Formula (XXXXVIII) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0151] In certain embodiments, the modified oligonucleotide comprises the formula (XXXXIX) or a salt, solvate or hydrate thereof: Petition 870250116482, dated 12 / 17 / 2025, pp. 556 / 975 74 / 459 o NH NH R4O^O II X NH2 © ÕMeΛOR5fGemU Formula (XXXXIX) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0152] In certain embodiments, the modified oligonucleotide comprises the formula (XXXXX) or a salt, solvate or hydrate thereof: o NH NH2r4ck?o II X NH NH2 .. / o' 'FXOR5mGefG Formula (XXXXX) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and Petition 870250116482, dated 12 / 17 / 2025, pp. 557 / 975 75 / 459 each X is independently O or S.

[0153] In certain embodiments, the modified oligonucleotide comprises the formula (XXXXXI) or a salt, solvate or hydrate thereof: mGemC Formula (XXXXXI) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0154] In certain embodiments, the modified oligonucleotide comprises the formula (XXXXXII) or a salt, solvate or hydrate thereof: Petition 870250116482, dated 12 / 17 / 2025, pp. 558 / 975 76 / 459 mCemA Formula (XXXXXII) where: R4 and R5 are independently an oligonucleotide, or R4 and R5 are joined to form a single oligonucleotide; and each X is independently O or S.

[0155] In certain embodiments, the modified oligonucleotide comprises an internucleosidic linkage of one of the following formulas: HN \ ^17^35XS / VWV'7VWV5' Formula (XXXXXIII),5' Formula (XXXXXIV), f Formula (XXXXXV),5' Formula (XXXXXVI).

[0156] In certain embodiments, the compound of any of the foregoing embodiments comprises a 5'-phosphonate modification. For example, in certain embodiments, a modified oligonucleotide comprises one or more sugars with a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide comprises a 5'-phosphonate modification. In certain embodiments, the modified oligonucleotide comprises a 5'-terminal nucleoside (e.g., 5'-terminal) comprising the 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification Petition 870250116482, dated 12 / 17 / 2025, pp. 559 / 975 77 / 459 is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-ethylenephosphonate modification. In certain embodiments, the modified oligonucleotide is either the first modified oligonucleotide or an antisense oligonucleotide.

[0157] Certain embodiments provide a compound comprising: a first modified oligonucleotide comprising a 5'-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1 or 2; and a second modified oligonucleotide comprising one or more ligands.

[0158] In some embodiments, the first modified oligonucleotide comprises a 5'-terminal nucleoside comprising the 5'-phosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-ethylenephosphonate modification.

[0159] In some embodiments, the second modified oligonucleotide comprises one or more ligands selected from one or more TrkB ligands, one or more CB1 ligands, and one or more α4β1 / 7 integrin ligands. In some embodiments, one or more TrkB ligands, one or more CBi ligands, or one or more α4β1 / 7 integrin ligands are attached to the 5' end of the second modified oligonucleotide. In some embodiments, one or more TrkB ligands, one or more CBi ligands, or one or more α4β1 / 7 integrin ligands are attached to the 3' end of the second modified oligonucleotide. In some Petition 870250116482, dated 12 / 17 / 2025, pp. 560 / 975 In 78 / 459 embodiments, one or more TrkB linkers, one or more CBi linkers, or one or more α4β1 / 7 integrin linkers are attached to the 5' and 3' ends of the second modified oligonucleotide. In some embodiments, one or more TrkB linkers are selected from any of Formulas I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, and XXXXXXIX-XXXXXXXIII; one or more CBi linkers are selected from any of Formulas XXXXXXI and XXXXXXXIV-XXXXXXXVIII; and one or more α4β1 / 7 integrin linkers are selected from any of Formulas XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXXIV.

[0160] In some embodiments, the second modified oligonucleotide comprises one or more TrkB ligands. In some embodiments, the one or more TrkB ligands are selected from any of Formulas I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXVXXXXXXVII and XXXXXXIX-XXXXXXXIII. In some embodiments, the one or more TrkB ligands are selected from any of Formulas XXIX-XXXI and XXXXXXV. In some embodiments, the second modified oligonucleotide comprises one TrkB ligand. In some embodiments, the second modified oligonucleotide comprises two TrkB ligands. In some embodiments, the second modified oligonucleotide comprises at least two TrkB ligands. In some embodiments, the at least two TrkB ligands are the same. In some embodiments, the at least two TrkB ligands are different.

[0161] In some embodiments, the second modified oligonucleotide comprises one or more CB1 ligands.In some embodiments, one or more CB1 ligands are selected from either Formulas XXXXXXI and XXXXXXXIV-XXXXXXXVIII. In some embodiments, one or more CB1 ligands are selected from either Formulas XXXXXXXIV-XXXXXXXVI. In some embodiments, the second modified oligonucleotide comprises one. Petition 870250116482, dated 12 / 17 / 2025, pp. 561 / 975 79 / 459 CBi ligand. In some embodiments, the second modified oligonucleotide comprises two CBi ligands. In some embodiments, the second modified oligonucleotide comprises at least two CBi ligands. In some embodiments, the at least two CBi ligands are the same. In some embodiments, the at least two CBi ligands are different.

[0162] In some embodiments, the second modified oligonucleotide comprises one or more α4β1 / 7 integrin linkers. In some embodiments, the one or more α4β1 / 7 integrin linkers are selected from any of Formulas XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXXXIV. In some embodiments, the one or more α4β1 / 7 integrin linkers are selected from any of Formulas XXXXXXXXI, XXXXXXXXII and XXXXXXXXIV. In some embodiments, the second modified oligonucleotide comprises one α4β1 / 7 integrin linker. In some embodiments, the second modified oligonucleotide comprises two α4β1 / 7 integrin linkers. In some embodiments, the second modified oligonucleotide comprises at least two α4β1 / 7 integrin linkers. In some embodiments, at least two α4β1 / 7 integrin ligands are the same. In some embodiments, at least two α4β1 / 7 integrin ligands are different.

[0163] In some embodiments, the second modified oligonucleotide comprises one or more lipids. In some embodiments, the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In some embodiments, the substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C4-C30 hydrocarbon chain. In some embodiments, the substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C5-C20 hydrocarbon chain. In some Petition 870250116482, dated 12 / 17 / 2025, p. 562 / 975 In some embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C14-C20 hydrocarbon chain. In some embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C16 hydrocarbon chain, a saturated or unsaturated C17 hydrocarbon chain, a saturated or unsaturated C18 hydrocarbon chain, or a saturated or unsaturated C22 hydrocarbon chain.

[0164] In some embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are attached to an internucleosidic linkage of the second modified oligonucleotide. In certain embodiments, the internucleosidic linkage occurs between nucleosides that are within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of a terminal end (e.g., the 5' and / or 3' end) of the second modified oligonucleotide. In certain embodiments, the internucleosidic linkage occurs between nucleosides that are within 5 positions of the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleosidic linkage occurs between nucleosides that are within 5 positions of the 3' end of the second modified oligonucleotide.

[0165] In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the end Petition 870250116482, dated 12 / 17 / 2025, pp. 563 / 975 81 / 459 5' of the second modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 2 and 3 of the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 3' end of the second modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the 3' end of the second modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 2 and 3 of the 3' end of the second modified oligonucleotide.

[0166] In some embodiments, the internucleosidic linkage of the second modified oligonucleotide is selected from any of the XXXXXIII-XXXXXVI Formulas. In some embodiments, the second modified oligonucleotide comprises any of the XXXV-XXXXXVI Formulas.

[0167] In some embodiments, the first modified oligonucleotide has 14 to 30 linked nucleosides in length. In some embodiments, the second modified oligonucleotide has 14 to 30 linked nucleosides in length having a complementarity region with respect to the first modified oligonucleotide. In some embodiments, the first modified oligonucleotide has a nucleobase sequence comprising at least 14 contiguous nucleobases from any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In some embodiments, the second modified oligonucleotide has a nucleobase sequence comprising at least 14 nucleobases. Petition 870250116482, dated 12 / 17 / 2025, pp. 564 / 975 82 / 459 contiguous from any of the SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In some embodiments, the first modified oligonucleotide is selected from any of the IA reference IDs in Table 3. In some embodiments, the second modified oligonucleotide is selected from any of the IS reference IDs in Table 3.

[0168] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any of the reference IDs listed in Table 3 and a second modified oligonucleotide with 14 to 21 nucleosides linked in length that are fully complementary to the first modified oligonucleotide.

[0169] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any of the IA reference IDs listed in Table 3 and a second modified oligonucleotide selected from the group consisting of any of the IS reference IDs listed in Table 3. In certain embodiments, the second modified oligonucleotide comprises any one or more TrkB ligands provided herein. In certain embodiments, the TrkB ligand is selected from Formulas I-XXXIV, XXXXXVII, XXXXXIXXXXXXX, XXXXXXV-XXXXXXVII and XXXXXXIX-XXXXXXXIII, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the TrkB ligand is selected from Formulas XXIX-XXXI and XXXXXXV, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the TrkB ligand via a phosphodiester group.In certain embodiments, the modified oligonucleotide is attached to the TrkB linker via a phosphorothioate group. In certain embodiments, one is provided here. Petition 870250116482, dated 12 / 17 / 2025, pp. 565 / 975 83 / 459 compound selected from the group consisting of any of the compounds listed in Table 3.

[0170] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any of the reference ID NOs IA listed in Table 3 and a second modified oligonucleotide selected from the group consisting of any of the reference ID NOs IS listed in Table 3. In certain embodiments, the second modified oligonucleotide comprises any one or more CB1 ligands provided herein. In certain embodiments, the CBi ligand is selected from Formulas XXXXXXI and XXXXXXXIVXXXXXXXVIII, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the CB1 ligand is selected from Formulas XXXXXXXIV-XXXXXXXVI, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the CB1 ligand via a phosphodiester group.In certain embodiments, the modified oligonucleotide is attached to the CB1 linker via a phosphorothioate group. In certain embodiments, a compound selected from the group consisting of any of the compounds listed in Table 3 is provided here.

[0171] Certain embodiments provide a compound comprising a first modified oligonucleotide selected from the group consisting of any of the reference ID NOs IA listed in Table 3 and a second modified oligonucleotide selected from the group consisting of any of the reference ID NOs IS listed in Table 3. In certain embodiments, the second modified oligonucleotide comprises any one or more α4β1 / 7 integrin linkers provided herein. In certain embodiments, the α4β1 / 7 integrin linker is selected from Formulas Petition 870250116482, dated 12 / 17 / 2025, pp. 566 / 975 84 / 459 XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the α4β1 / 7 integrin linker is selected from Formulas XXXXXXXXI, XXXXXXXXII, and XXXXXXXXIV, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the α4β1 / 7 integrin linker via a phosphodiester group. In certain embodiments, the modified oligonucleotide is attached to the α4β1 / 7 integrin linker via a phosphorothioate group. In certain embodiments, a compound selected from the group consisting of any of the compounds listed in Table 3 is provided herein.

[0172] In certain embodiments, the pharmaceutically acceptable salt of the modified oligonucleotides provided herein is a sodium salt or a potassium salt. In certain embodiments, the pharmaceutically acceptable salt of the compounds provided herein is a sodium salt or a potassium salt.

[0173] In certain embodiments, a population of modified oligonucleotides is provided herein, in which all phosphorothioate internucleosidic bonds of the modified oligonucleotide are stereorandom. In certain embodiments, a population of compounds is provided herein, in which all phosphorothioate internucleosidic bonds of the modified oligonucleotide are stereorandom.

[0174] In certain embodiments, the compound of any previous embodiment is in a pharmaceutically acceptable salt form. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt.

[0175] Certain modalities provide a composition Petition 870250116482, dated 12 / 17 / 2025, pp. 567 / 975 85 / 459 comprising the compound of any of the preceding embodiments and a pharmaceutically acceptable vehicle.

[0176] Certain modalities provide a composition comprising a compound of any previous modality, for use in therapy.

[0177] Certain modalities provide a method of treating, preventing, or improving a disease, disorder, or condition associated with MAPT in an individual, comprising administering to the individual a compound targeted at MAPT, treating, preventing, or improving the disease.

[0178] In certain embodiments, the compound or composition of any prior embodiment is administered to an individual. In certain embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment.

[0179] In certain modalities, administration of the compound inhibits or reduces or improves a disease, disorder or condition related to the CNS or a symptom thereof or a neurodegenerative disease or a symptom thereof, including tachypathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment.

[0180] In certain embodiments, a compound or composition comprising a compound of any embodiment Petition 870250116482, dated 12 / 17 / 2025, pp. 568 / 975 86 / 459 prior is administered to an individual in a therapeutically effective amount. In certain embodiments, a compound or composition comprising a compound from any prior embodiment is administered to an individual in a dosage sufficient to provide about 1 to 100 mg / kg of the individual's body weight. In certain embodiments, a compound or composition comprising a compound from any prior embodiment is administered to an individual at a fixed dose of about 25 mg to about 1000 mg. In certain embodiments, the compound or composition is administered to the individual one or more times daily up to the dosage level or fixed dose.

[0181] In certain embodiments, a compound or composition comprising a compound of any of the foregoing embodiments is administered to an individual daily, weekly, monthly, quarterly, or annually. In certain embodiments, a compound or composition comprising a compound of any of the foregoing embodiments is administered to an individual approximately once per quarter (i.e., once every three months) to approximately once per year. In certain embodiments, a compound or composition comprising a compound of any of the foregoing embodiments is administered to an individual approximately once per quarter, approximately once every six months, or approximately once per year.

[0182] Certain modalities provide a method of inhibiting MAPT expression in a cell, comprising contacting the cell with a MAPT-targeted compound, thereby inhibiting MAPT expression in the cell. In certain modalities, the cell is in the liver of an individual. In certain modalities, the individual has or is at risk of having a disease, disorder, or condition related to the CNS or a symptom thereof or a disease. Petition 870250116482, dated 12 / 17 / 2025, pp. 569 / 975 87 / 459 neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment.

[0183] Certain modalities provide a method for reducing or inhibiting a disease, disorder or condition related to the CNS or a symptom thereof or a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment in an individual, comprising administering a MAPT-targeted compound to the individual, thereby reducing or inhibiting a disease, disorder or condition related to the CNS or a symptom thereof or a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment in the individual.In certain modalities, the individual has or is at risk of having a disease, disorder, or condition related to the CNS or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including tachypathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment. In certain modalities, the compound is a MAPT-targeted compound. In certain modalities, the compound is any of the above compounds. In certain modalities... Petition 870250116482, dated 12 / 17 / 2025, pp. 570 / 975 88 / 459 The compound or composition is administered parenterally. In certain embodiments, the compound or composition is administered intrathecally (IT).

[0184] Certain modalities provide for the use of a MAPT-targeted compound to treat, prevent, or improve a disease, disorder, or condition associated with MAPT. In certain modalities, the disease, disorder, or condition is a CNS-related disease, disorder, or condition or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment. In certain modalities, the compound is a MAPT-targeted compound. In certain modalities, the compound is any of the foregoing compounds.

[0185] Certain embodiments provide for the use of a MAPT-targeted compound in the manufacture of a medicament to treat, prevent, or improve a disease, disorder, or condition associated with MAPT. In certain embodiments, the disease, disorder, or condition is a CNS-related disease, disorder, or condition or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment. In certain embodiments, the compound is a MAPT-targeted compound. In certain embodiments, the compound is any of the foregoing compounds.

[0186] In certain embodiments, any of the compounds Petition 870250116482, dated 12 / 17 / 2025, p. 571 / 975 89 / 459 shown in Figures 1-4, Table A, Table 2 and Table 3 can be used in any aspect of the invention. In some embodiments of a compound, composition, method or use of the invention, the compound is any of the compounds shown in Figures 1-4, Table A, Table 2 and Table 3.

[0187] In certain embodiments, any of the compounds shown in Figures 1-4 may be used in any aspect of the invention. In some embodiments of a compound, composition, method or use of the invention, the compound is any of the compounds shown in Figures 1-4.

[0188] In certain embodiments, any of the compounds in Table 2 may be used in any aspect of the invention. In some embodiments of a compound, composition, method or use of the invention, the compound is any of the compounds in Table 2.

[0189] In certain embodiments, any of the compounds in Table 3 may be used in any aspect of the invention. In some embodiments of a compound, composition, method or use of the invention, the compound is any of the compounds in Table 3.

[0190] In certain embodiments, any of the compounds in Table A may be used in any aspect of the invention. In some embodiments of a compound, composition, method, or use of the invention, the compound is any of the compounds in Table A. In some embodiments of any aspect of the invention, the compound is selected from any of compounds 1-285 in Table A. Table A, shown below, provides the following for each of compounds 1-285: antisense (“A”) and sense (“S”) strand nucleobase sequences (SEQ ID NO) shown with strand modifications (as defined in Table 1) and, where a sense strand comprises a ligand, the type of ligand (e.g., a TrkB ligand, a CB1 ligand, or an α4β1 / 7 integrin ligand as described herein) at the end. Petition 870250116482, dated 12 / 17 / 2025, p. 572 / 975 90 / 459 5' (“5'-Binder”) and / or at the 3' end (“3'-Binder”) of the sense tape. In some embodiments, the 5' binder and / or the 3' binder are attached to the sense tape by means of a binder. In some embodiments, the binder comprises polyethylene glycol (PEG). In some embodiments, the binder comprises a PEG chain of one, two, three, four, five, six, seven, or eight PEG units in length. In certain embodiments, the binder comprises a PEG chain of one PEG unit in length. In certain embodiments, the binder comprises a PEG chain of two PEG units in length. In certain embodiments, the binder comprises a PEG chain of three PEG units in length. In certain embodiments, the binder comprises a PEG chain of four PEG units in length. In certain embodiments, the binder comprises a PEG chain of five PEG units in length. In certain embodiments, the binder comprises a PEG chain of six PEG units in length.In certain embodiments, the linker comprises a PEG chain of seven PEG units in length. In certain embodiments, the linker comprises a PEG chain of eight PEG units in length. In some embodiments, the linker comprises an optionally substituted heteroaryl group or an optionally substituted heterocyclyl group. In certain embodiments, the linker comprises PEG and an optionally substituted heteroaryl group or an optionally substituted heterocyclyl group. Petition 870250116482, dated 12 / 17 / 2025, pp. 573 / 975 Table A. Exemplary Compounds Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 1 A vU*fU*mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG.fA.mG.fC.mU*mU*mU 11 S TrkB mA*mG.mC.mU.mC.mG.fC.mA.fU.fG.fG.fU.mC.mA.mG.mU.mA.mA.mA.mA*mA*dQ 81 2 A vU*fU*mU.fA.mC.fA.mA.fA.mG.fA.mG.fA.mA.fU.mU.fG.mG.fU.mU.fA.mG*mC*mC 12 S TrkB mC*mU.mA.mA.mC.mC.fA.mA.fU.fU.fC.fU.mC.mU.mU.mU.mG.mU.mA.mA*mA*dQ 82 3 A vU*fC*mU.fU.mA.fC.mA.fA.mA.fG.mA.fG.mA.fA.mC.fU.mG.fG.mU.fU.mA*mG*mC 13 S TrkB mU*mA.mA.mC.mC.mA.fG.mU.fU.fC.fU.fC.mU.mU.mU.mG.mU.mA.mA.mG*mA*dQ 83 4 A vA*fG*mU.fC.mC.fU.mU.fA.mC.fA.mA.fA.mG.fA.mG.fA.mA.fC.mU.fG.mG*mU*mU 14 S TrkB mC*mC.mA.mG.mU.mU.fC.mU.fC.fU.fU.fU.mG.mU.mA.mA.mG.mG.mA.mC*mU*dQ 84 5 A vU*fG*mA.fU.mG.fA.mG.fG.mG.fG.mU.fA.mU.fA.mG.fG.mC.fA.mG.fU.mG*mA*mU 15 S TrkB mC*mA.mC.mU.mG.mC.fC.mU.fA.fU.fA.fC.mC.mC.mC.mU.mC.mA.mU.mC*mA*dQ 85 6 A vA*fA*mC.fA.mU.fC.mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG*mC*mU 16 S TrkB mC*mU.mG.mA.mA.mC.fA.mU.fA.fU.fA.fC.mA.mU.mA.mG.mA.mU.mG.mU*mU*dQ 86 7 A vU*fC*mU.fA.mA.fA.mC.fC.mA.fU.mG.fA.mU.fU.mU.fU.mA.fG.mG.fC.mU*mG*mG 17 S TrkB mA*mG.mC.mC.mU.mA.fA.mA.fA.fU.fC.fA.mU.mG.mG.mU.mU.mU.mA.mG*mA*dQ 87 8 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 18 S TrkB mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU*mA*dQ 88 9 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19 S TrkB mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ 89 10 A vA*fU*mA.fG.mC.fA.mA.fA.mC.fA.mG.fG.mA.fU.mA.fC.mA.fG.mU.fC.mU*mC*mA 20. 91 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 574 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mA*mG.mA.mC.mU.mG.fU.mA.fU.fC.fC.fU.mG.mU.mU.mU.mG.mC.mU.mA*mU*dQ 90 11 A vA*fC*mC.fG.mA.fA.mG.fA.mA.fA.mU.fC.mA.fU.mG.fG.mG.fA.mC.fU.mU*mG*mC 21 S TrkB mA*mA.mG.mU.mC.mC.fC.mA.fU.fG.fA.fU.mU.mU.mC.mU.mU.mC.mG.mG*mU*dQ 91 12 A vA*fC*mU.fA.mU.fA.mU.fA.mG.fA.mC.fA.mU.fU.mC.fA.mC.fA.mG.fA.mC*mA*mG 22 S TrkB mG*mU.mC.mU.mG.mU.fG.mA.fA.fU.fG.fU.mC.mU.mA.mU.mA.mU.mA.mG*mU*dQ 92 13 A vU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA.mG*mC*mU 23 S TrkB mC*mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC*mA*dQ 93 14 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 15 A vU*fG*mG.fC.mU.fU.mU.fU.mU.fU.mG.fU.mC.fA.mU.fC.mG.fC.mU.fU.mC*mC*mA 25 S TrkB mG*mA.mA.mG.mC.mG.fA.mU.fG.fA.fC.fA.mA.mA.mA.mA.mA.mG.mC.mC*mA*dQ 95 16 A vU*fU*mG.fG.mC.fU.mU.fU.mU.fU.mU.fG.mU.fU.mA.fU.mC.fG.mC.fU.mU*mC*mC 26 S TrkB mA*mA.mG.mC.mG.mA.fU.mA.fA.fC.fA.fA.mA.mA.mA.mA.mG.mC.mC.mA*mA*dQ 96 17 A vU*fU*mU.fG.mG.fC.mU.fU.mU.fU.mU.fU.mG.fU.mC.fA.mU.fC.mG.fC.mU*mU*mC 27 S TrkB mA*mG.mC.mG.mA.mU.fG.mA.fC.fA.fA.fA.mA.mA.mA.mG.mC.mC.mA.mA*mA*dQ 97 18 A vU*fU*mC.fA.mA.fC.mU.fG.mG.fU.mU.fU.mG.fU.mA.fG.mA.fC.mU.fA.mU*mU*mU 28 S TrkB mA*mU.mA.mG.mU.mC.fU.mA.fC.fA.fA.fA.mC.mC.mA.mG.mU.mU.mG.mA*mA*dQ 98 19 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC 29 S TrkB mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG*mA*dQ 99 20 A vA*fU*mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG.mC.fU.mG*mC*mU 30. 92 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 575 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mC*mA.mG.mC.mU.mG.fA.mA.fC.fA.fU.fA.mU.mA.mC.mA.mU.mA.mG.mA*mU*dQ 100 21 A vA*fC*mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG.mC*mU*mG 31 S TrkB mG*mC.mU.mG.mA.mA.fC.mA.fU.fA.fU.fA.mC.mA.mU.mA.mG.mA.mU.mG*mU*dQ 101 22 A vU*fA*mA.fG.mC.fA.mU.fA.mA.fA.mC.fA.mG.fA.mC.fA.mA.fA.mU.fC.mC*mA*mA 32 S TrkB mG*mG.mA.mU.mU.mU.fG.mU.fC.fU.fG.fU.mU.mU.mA.mU.mG.mC.mU.mU*mA*dQ 102 23 A vU*fA*mC.fA.mC.fU.mA.fU.mA.fU.mA.fG.mA.fU.mA.fU.mU.fC.mA.fC.mA*mG*mA 33 S TrkB mU*mG.mU.mG.mA.mA.fU.mA.fU.fC.fU.fA.mU.mA.mU.mA.mG.mU.mG.mU*mA*dQ 103 24 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 34 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 104 25 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 37 S TrkB mU*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 107 26 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 38 S TrkB mC*mU.mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA* dQ 108 27 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mG*mA 39 S TrkB mU*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 109 28 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mG 40 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 110 29 A vU*fG*mA.fU.mG.fA.mG.fG.mG.fG.mU.fA.mU.fA.mG.fG.mC.fA.mG.fU.mG*mA*mU 41 S TrkB mU*mC.mA.mC.mU.mG.mC.fC.mU.fA.fU.fA.fC.mC.mC.mC.mU.mC.mA.mU.mC*mA*dQ 111. 93 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 576 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 30 A vU*fG*mA.fU.mG.fA.mG.fG.mG.fG.mU.fA.mU.fA.mG.fG.mC.fA.mG.fU*mG*mA 42 S TrkB mU*mC.mA.mC.mU.mG.mC.fC.mU.fA.fU.fA.fC.mC.mC.mC.mU.mC.mA.mU.mC*mA*dQ 112 31 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 43 S TrkB mG*mC.mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU*mA*dQ 113 32 A vA*fC*mC.fG.mA.fA.mG.fA.mA.fA.mU.fC.mA.fU.mG.fG.mG.fA.mC.fU.mU*mG*mC 44 S TrkB mC*mA.mA.mG.mU.mC.mC.fC.mA.fU.fG.fA.fU.mU.mU.mC.mU.mU.mC.mG.mG*mU*dQ 114 33 A vA*fC*mC.fG.mA.fA.mG.fA.mA.fA.mU.fC.mA.fU.mG.fG.mG.fA.mC.fU*mU*mG 45 S TrkB mC*mA.mA.mG.mU.mC.mC.fC.mA.fU.fG.fA.fU.mU.mU.mC.mU.mU.mC.mG.mG*mU*dQ 115 34 A vU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA.mG*mC*mU 46 S TrkB mG*mC.mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC*mA*dQ 116 35 A vU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA*mG*mC 47 S TrkB mG*mC.mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC*mA*dQ 117 36 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU*fG*mC 48 S TrkB mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG*mA*dQ 118 37 A vU*fC*mU.fU.mU.fU.mA.fC.mU.fG.mA.fC.mC.fA.mU.fG.mC.fG.mA.fG.mC*mU*mU 49 S TrkB mG*mC.mU.mC.mG.mC.fA.mU.fG.fG.fU.fC.mA.mG.mU.mA.mA.mA.mA.mG*mA*dQ 119 38 A vA*fA*mC.fU.mG.fG.mU.fU.mU.fG.mU.fA.mG.fA.mC.fU.mA.fU.mU.fU.mG*mC*mA 50 S TrkB mG*mC.mA.mA.mA.mU.mA.fG.mU.fC.fU.fA.fC.mA.mA.mA.mC.mC.mA.mG.mU*mU*dQ 120 39 A vU*fC*mA.fA.mC.fU.mG.fG.mU.fU.mU.fG.mU.fA.mG.fA.mC.fU.mA.fU.mU*mU*mG 51 S TrkB mA*mA.mA.mU.mA.mG.mU.fC.mU.fA.fC.fA.fA.mA.mC.mC.mA.mG.mU.mU.mG*mA*dQ 121. 94 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 577 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 40 A vU*fC*mU.fU.mA.fC.mA.fA.mA.fG.mA.fG.mA.fA.mC.fU.mG.fG.mU.fU.mA*mG*mC 52 S TrkB mC*mU.mA.mA.mC.mC.mA.fG.mU.fU.fC.fU.fC.mU.mU.mU.mG.mU.mA.mA.mG*mA*dQ 122 41 A vU*fA*mA.fC.mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA*mG*mC 53 S TrkB mC*mU.mG.mA.mA.mC.mA.fU.mA.fU.fA.fC.fA.mU.mA.mG.mA.mU.mG.mU.mU*mA*dQ 123 42 A vA*fA*mC.fA.mG.fA.mC.fA.mA.fA.mU.fC.mC.fA.mA.fC.mU.fA.mC.fA.mA*mC*mU 54 S TrkB mG*mU.mU.mG.mU.mA.mG.fU.mU.fG.fG.fA.fU.mU.mU.mG.mU.mC.mU.mG.mU*mU*dQ 124 43 A vU*fA*mU.fA.mA.fA.mC.fA.mG.fA.mC.fA.mA.fA.mU.fC.mC.fA.mA.fC.mU*mA*mC 55 S TrkB mU*mA.mG.mU.mU.mG.mG.fA.mU.fU.fU.fG.fU.mC.mU.mG.mU.mU.mU.mA.mU*mA*dQ 125 44 A vU*fC*mA.fU.mA.fA.mA.fC.mA.fG.mA.fC.mA.fA.mA.fU.mC.fC.mA.fA.mC*mU*mA 56 S TrkB mA*mG.mU.mU.mG.mG.mA.fU.mU.fU.fG.fU.fC.mU.mG.mU.mU.mU.mA.mU.mG*mA*dQ 126 45 A vA*fA*mG.fC.mA.fU.mA.fA.mA.fC.mA.fG.mA.fU.mA.fA.mA.fU.mC.fC.mA*mA*mC 57 S TrkB mU*mU.mG.mG.mA.mU.mU.fU.mA.fU.fC.fU.fG.mU.mU.mU.mA.mU.mG.mC.mU*mU*dQ 127 46 A vA*fC*mC.fU.mC.fU.mU.fU.mA.fC.mA.fA.mG.fU.mA.fU.mU.fU.mC.fA.mA*mG*mA 58 S TrkB mC*mU.mU.mG.mA.mA.mA.fU.mA.fC.fU.fU.fG.mU.mA.mA.mA.mG.mA.mG.mG*mU*dQ 128 47 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mC*mU*mC 59 S TrkB mA*mG.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA*mA*dQ 129 48 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60 S TrkB mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ 130 49 A vA*fU*mU.fC.mA.fU.mC.fC.mC.fA.mA.fU.mC.fU.mC.fU.mG.fC.mU.fG.mU*mG*mG 61 S TrkB mC*mA.mC.mA.mG.mC.mA.fG.mA.fG.fA.fU.fU.mG.mG.mG.mA.mU.mG.mA.mA*mU*dQ 131. 95 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 578 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 50 A vA*fU*mG.fG.mA.fG.mU.fU.mU.fG.mU.fG.mC.fA.mA.fG.mG.fU.mC.fA.mG*mC*mG 62 S TrkB mC*mU*mG.mA.mC.mC.fU.mU.fG.fC.fA.fC.mA.mA.mA.mC.mU.mC.mC.mA*mU*dQ 132 51 A vU*fA*mU.fG.mG.fA.mG.fU.mU.fU.mG.fU.mG.fU.mA.fA.mG.fG.mU.fC.mA*mG*mC 63 S TrkB mC*mU.mG.mA.mC.mC.mU.fU.mA.fC.fA.fC.fA.mA.mA.mC.mU.mC.mC.mA.mU*mA*dQ 133 52 A vA*fA*mA.fG.mC.fU.mC.fU.mA.fG.mC.fU.mG.fU.mA.fC.mA.fC.mG.fA.mA*mG*mC 64 S TrkB mC*mU.mU.mC.mG.mU.mG.fU.mA.fC.fA.fG.fC.mU.mA.mG.mA.mG.mC.mU.mU*mU*dQ 134 53 A vU*fC*mA.fU.mA.fC.mA.fG.mU.fA.mU.fA.mU.fU.mC.fU.mA.fU.mC.fU.mA*mG*mC 65 S TrkB mC*mU.mA.mG.mA.mU.mA.fG.mA.fA.fU.fA.fU.mA.mC.mU.mG.mU.mA.mU.mG*mA*dQ 135 54 A vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66 S TrkB mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ 136 55 A vU*fU*mU.fU.mU.fG.mC.fU.mG.fG.mA.fA.mU.fU.mC.fU.mG.fG.mU.fG.mG*mC*mG 67 S TrkB mG*mC.mC.mA.mC.mC.mA.fG.mA.fA.fU.fU.fC.mC.mA.mG.mC.mA.mA.mA.mA*mA*dQ 137 56 A vU*fG*mA.fU.mC.fC.mC.fC.mU.fG.mA.fU.mU.fU.mU.fG.mG.fA.mG.fG.mU*mU*mC 68 S TrkB mA*mA.mC.mC.mU.mC.mC.fA.mA.fA.fA.fU.fC.mA.mG.mG.mG.mG.mA.mU.mC*mA*dQ 138 57 A vA*fU*mA.fA.mA.fC.mA.fG.mA.fC.mA.fA.mA.fU.mC.fC.mA.fA.mC.fU.mA*mC*mA 69 S TrkB mG*mU.mA.mG.mU.mU.mG.fG.mA.fU.fU.fU.fG.mU.mC.mU.mG.mU.mU.mU.mA*mU*dQ 139 58 A vU*fC*mU.fU.mC.fA.mG.fU.mC.fC.mU.fA.mA.fU.mC.fC.mU.fG.mU.fG.mC*mU*mU 70 S TrkB mA*mG.mC.mA.mC.mA.mG.fG.mA.fU.fU.fA.fG.mG.mA.mC.mU.mG.mA.mA.mG*mA*dQ 140 59 A vU*fU*mU.fG.mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*mG*mC 71 S TrkB mC*mU.mU.mA.mC.mA.mA.fC.mU.fC.fC.fU.fG.mC.mA.mU.mC.mA.mC.mA.mA*mA*dQ 141. 96 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 579 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 60 A vU*fU*mU.fA.mU.fC.mU.fG.mC.fC.mA.fG.mC.fA.mC.fU.mG.fA.mU.fC.mA*mC*mC 72 S TrkB mG*mU.mG.mA.mU.mC.mA.fG.mU.fG.fC.fU.fG.mG.mC.mA.mG.mA.mU.mA.mA*mA*dQ 142 61 A vU*fG*mG.fC.mA.fU.mA.fC.mA.fG.mU.fA.mU.fA.mU.fC.mC.fU.mA.fU.mC*mU*mA 73 S TrkB mA*mG.mA.mU.mA.mG.mG.fA.mU.fA.fU.fA.fC.mU.mG.mU.mA.mU.mG.mC.mC*mA*dQ 143 62 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19 S TrkB mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ 89 63 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 64 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19 S TrkB mA*mG.mA.mUêmA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ 89 65 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 66 A 9U*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19 S TrkB mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ 89 67 A 9U*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19 S TrkB mA*mG.mA.mUêmA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC*mA*dQ 89 68 A 9U*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 69 A 9U*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94. 97 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 580 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 70 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mAêmU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 71 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mUêfC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 72 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 73 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 74 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 75 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 76 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 77 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 78 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 79 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94. 98 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 581 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 80 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 81 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 82 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 83 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 84 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 85 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 86 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG[ê1]mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 87 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG[ê2]mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 88 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 89 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149. 99 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 582 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 90 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 91 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ 130 92 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ 130 93 A eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66 S TrkB mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ 136 94 A eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66 S TrkB mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ 136 95 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ 130 96 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG*mC*mC 144 S TrkB mG*mG.mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ 150 97 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ 130 98 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60 S TrkB mG*mG.mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA*dQ 150 99 A eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66 S TrkB mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ 136. 100 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 583 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 100 A eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG*mA*mG 146 S TrkB mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ 136 101 A eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC*fG*mA 147 S TrkB mU*mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ 151 102 A eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66 S TrkB mU*mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA*dQ 151 103 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mUêmG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 104 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mUêmG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 105 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60 S TrkB mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC*mA TrkB 152 106 A eU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66 S TrkB mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA*mA TrkB 153 107 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 108 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 109 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94. 101 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 584 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 110 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 111 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mAêmU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 112 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mUêmG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 113 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mGêfG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 114 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mUêfC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 115 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mAêmA.mA.mA.mG.mC.mA.mA*mA*dQ 94 116 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mAêmA.mA.mG.mC.mA.mA*mA*dQ 94 117 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mAêmA.mG.mC.mA.mA*mA*dQ 94 118 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mAêmG.mC.mA.mA*mA*dQ 94 119 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mGêmC.mA.mA*mA*dQ 94. 102 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 585 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 120 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mCêmA.mA*mA*dQ 94 121 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA*mA*dQ 94 122 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 123 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 124 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA TrkB 149 125 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 126 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mAêmA.mA.mA.mG.mC.mA.mA*mA*dQ 94 127 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mAêmA.mA.mA.mG.mC.mA.mA*mA*dQ 94 128 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mAêmA.mA.mA.mG.mC.mA.mA*mA*dQ 94 129 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mAêmA.mAêmA.mG.mC.mA.mA*mA*dQ 94. 103 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 586 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 130 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mAêmA.mA.mG.mC.mA.mA*mA*dQ 94 131 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mAêmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.m C 152 132 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.m C 152 133 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mUêmA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 152 134 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mAêmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 152 135 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 152 136 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 152 137 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.m C TrkB 152 138 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24. 104 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 587 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S c6*mC*mG.mC.mAêmU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 139 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mUêfC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 140 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 141 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 142 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG[ê1]mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*d Q 94 143 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG[ê2]mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*d Q 94 144 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mUêmG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 145 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mAêmU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 146 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mGêfG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 147 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24. 105 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 588 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S c6*mC*mG.mC.mA.mU.mG.fG.mUêfC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 148 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mAêmA.mA.mA.mG.mC.mA.mA*mA*dQ 94 149 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mAêmA.mA.mG.mC.mA.mA*mA*dQ 94 150 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mAêmA.mG.mC.mA.mA*mA*dQ 94 151 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mAêmG.mC.mA.mA*mA*dQ 94 152 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mGêmC.mA.mA*mA*dQ 94 153 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mCêmA.mA*mA*dQ 94 154 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA*mA*dQ 94 155 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mAêmA.mAêmA.mG.mC.mA.mA*mA*dQ 94 156 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mAêmA.mA.mG.mC.mA.mA*mA*dQ 94 157 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24. 106 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 589 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mAêmA.mA.mA.mG.mC.mA.mA*mA*dQ 94 158 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S c6*mG*mC.mU.mUêmA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t 6.mC 152 159 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S c6*mG*mC.mU.mU.mAêmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t 6.mC 152 160 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.m C 152 161 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.m C 152 162 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB t6.mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6. mC TrkB 152 163 A eU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mC*mU*mC 59 S c6*mA*mG.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*d Q*c6 129 164 A eU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC*mC 177. 107 / 459 Petição 870250116482, de 17 / 12 / 2025, pág. 590 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TrkB 154 165 A eU*fU*mU.fG.mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*mG*mC 71 S TrkB mC*mU.mU.mA.mC.mA.mA.fC.mU.fC.fC.fU.fG.mC.mA.mU.mC.mA.mC.mA.mA.mA*dQ TrkB 141 166 A eU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA.mG*mC*mU 23 S TrkB mC*mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC.mA*dQ TrkB 93 167 A eU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG*fA*mG 178 S TrkB mC*mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC.mA*dQ TrkB 93 168 A eU*fG*mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fU.mA.fU.mG.fC.mG.fA*mG*mC 47 S TrkB mG*mC*mU.mC.mG.mC.mA.fU.mA.fG.fU.fC.fA.mG.mU.mA.mA.mA.mA.mG.mC.mA*dQ TrkB 116 169 A eU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19 S TrkB mU*mA.mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ TrkB 155 170 A eU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC*mU*mA 179 S TrkB mU*mA.mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ TrkB 155 171 A eU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU*fC*mU 180 S TrkB mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ TrkB 89 172 A eA*fC*mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG.mC*mU*mG 31 S TrkB mA*mG.mC.mU.mG.mA.mA.fC.mA.fU.fA.fU.fA.mC.mA.mU.mA.mG.mA.mU.mG.mU*dQ TrkB 157 173 A eA*fC*mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA.fG*mC*mU 181 S TrkB mA*mG.mC.mU.mG.mA.mA.fC.mA.fU.fA.fU.fA.mC.mA.mU.mA.mG.mA.mU.mG.mU*dQ TrkB 157 174 A eA*fC*mA.fU.mC.fU.mA.fU.mG.fU.mA.fU.mA.fU.mG.fU.mU.fC.mA*fG*mC. 108 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 591 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mG*mC.mU.mG.mA.mA.fC.mA.fU.fA.fU.fA.mC.mA.mU.mA.mG.mA.mU.mG.mU*dQ TrkB 101 175 A eU*fA*mA.fC.mU.fG.mG.fU.mU.fU.mG.fU.mA.fG.mA.fC.mU.fA.mU.fU.mU*mG*mC 183 S TrkB mC*mA.mA.mA.mU.mA.mG.fU.mC.fU.fA.fC.fA.mA.mA.mC.mC.mA.mG.mU.mU.mA*dQ TrkB 159 176 A eU*fC*mU.fA.mA.fA.mG.fU.mC.fC.mC.fA.mG.fG.mU.fC.mU.fG.mC.fA.mA*mA*mG 184 S TrkB mU*mU.mU.mG.mC.mA.mG.fA.mC.fC.fU.fG.fG.mG.mA.mC.mU.mU.mU.mA.mG.mA*dQ TrkB 160 177 A eU*fU*mA.fU.mG.fC.mA.fU.mG.fU.mG.fG.mA.fG.mC.fU.mG.fA.mG.fC.mA*mG*mC 185 S TrkB mC*mU.mG.mC.mU.mC.mA.fG.mC.fU.fC.fC.fA.mC.mA.mU.mG.mC.mA.mU.mA.mA*dQ TrkB 161 178 A eU*fA*mA.fC.mA.fG.mA.fC.mA.fG.mC.fA.mU.fG.mG.fC.mU.fU.mC.fC.mA*mG*mC 186 S TrkB mC*mU.mG.mG.mA.mA.mG.fC.mC.fA.fU.fG.fC.mU.mG.mU.mC.mU.mG.mU.mU.mA*dQ TrkB 162 179 A eA*fG*mC.fA.mG.fA.mA.fC.mA.fG.mA.fC.mA.fG.mC.fA.mU.fG.mG.fC.mU*mU*mC 187 S TrkB mA*mA.mG.mC.mC.mA.mU.fG.mC.fU.fG.fU.fC.mU.mG.mU.mU.mC.mU.mG.mC.mU*dQ TrkB 163 180 A eU*fC*mU.fU.mC.fA.mG.fU.mC.fC.mU.fA.mA.fU.mC.fC.mU.fG.mU.fG.mC*mU*mU 70 S TrkB mA*mG.mC.mA.mC.mA.mG.fG.mA.fU.fU.fA.fG.mG.mA.mC.mU.mG.mA.mA.mG.mA*dQ TrkB 140 181 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.m C 152 182 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mCêmA*mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ.t6.m C 149 183 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24. 109 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 592 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mC*mG.mCêmA*mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ TrkB 149 184 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 152 185 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 152 186 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 94 187 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêMA*mA*dQ 94 188 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mAêmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 152 189 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*C16 152 190 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S C18*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 130 191 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAêmC*mA*dQ*t6.m C 152 192 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145. 110 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 593 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAêmC*mA*dQ*t6.m C TrkB 152 193 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAêmC.mA*dQ TrkB 130 194 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAêmC.mA*dQ TrkB 130 195 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 149 196 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mCêmU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 130 197 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mAêmC.mA*dQ TrkB 130 198 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188 S TrkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 164 199 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188 S TrkB mC*mU.mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA* dQ TrkB 165 200 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mG*mG 190 S TrkB mC*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêMA.mA*dQ TrkB 166 201 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mA*mA*mG 191. 111 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 594 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mU*mU.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 167 202 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU*mG*mA 192 S TrkB mC*mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 168 203 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU*mG*mA 192 S TrkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêMA.mA*dQ TrkB 164 204 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mG*mG 194 S TrkB mC*mC.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 166 205 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC*mC*mA 195 S TrkB mU*mG.mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 171 206 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG*fC*mC 196 S TrkB mG*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 172 207 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mG*mG 197 S TrkB mC*mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 168 208 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mG*mG 197 S TrkB mC*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 174 209 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU*mG*mG 199 S TrkB mC*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêMA.mA*dQ TrkB 174 210 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fG.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 200 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fC.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 176 211 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145. 112 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 595 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6.m C 152 212 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*C22 152 213 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 214 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mCêmA*mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ.t6.m C 149 215 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188 S TrkB mC*mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 168 216 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188 S TrkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêMA.mA*dQ TrkB 164 217 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mG*mG 190 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 94 218 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêMA*mA*dQ 94 219 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mC*mU*mC 59 S TrkB mA*mG.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TrkB 129 220 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fU.mC*mU*mC 209. 113 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 596 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mA*mG.mA.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TrkB 201 221 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG.fC.mU*mU*mC 210 S TrkB mA*mA.mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TrkB 202 222 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG*fU*mC 211 S TrkB mG*mA.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TrkB 203 223 A vU*fU*mG.fA.mU.fG.mC.fA.mG.fG.mA.fG.mU.fU.mG.fU.mA.fA.mG*fC*mU 212 S TrkB mA*mG.mC.mU.mU.mA.fC.mA.fA.fC.fU.fC.mC.mU.mG.mC.mA.mU.mC.mA.mA*dQ TrkB 204 224 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC*mC 177 S TrkB mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TrkB 154 225 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mU*mC 213 S TrkB mA*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TrkB 205 226 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC 214 S TrkB mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TrkB 154 227 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA*mG*mU 215 S TrkB mA*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TrkB 205 228 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA*fA*mG 216 S TrkB mC*mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TrkB 206 229 A vU*fU*mG.fU.mG.fA.mU.fG.mC.fA.mG.fG.mA.fU.mU.fU.mG.fU.mA.fA.mG*mC*mU 217 S TrkB mG*mC.mU.mU.mA.mC.mA.fA.mA.fU.fC.fC.fU.mG.mC.mA.mU.mC.mA.mC.mA.mA*dQ TrkB 154 230 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188. 114 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 597 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mAêmA.mA*dQ TrkB 164 231 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fU.mG*mA*mG 188 S TrkB mU*mC.mA.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TrkB 164 232 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG*fC*mC 196 S TrkB mG*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TrkB 172 233 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TrkB 94 234 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mGêmC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TrkB 94 235 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 236 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mAêmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 130 237 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*c 6 130 238 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ TrkB 130 239 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ TrkB 94. 115 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 598 / 975 Name Ribbon 5'-Binder Modified Ribbons (5'-3') 3'-Binder SEQ ID NO: 240 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.4*SU.fU.mG.mG* c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 241 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S Integrin α4βΐ / 7 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 242 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S CB1 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 243 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S CB1 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.m C CB1 149 244 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S Integrin α4βΐ / 7 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.m C Integrin α4βΐ / 7 149 245 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 246 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S CB1 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 247 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.m C TrkB 149. 116 / 459 Petition 870250116482, de 17 / 12 / 2025, pág. 599 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 248 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.m C Integrina α4βΐ / 7 149 249 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 250 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S c6*mC*mG.mC.mA.mU.mG.fGêmU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*t6.m C TrkB 149 251 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 252 A eU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S Integrina α4βΐ / 7 c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA*mA*dQ 94 253 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6 .mC 152 254 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S CB1 c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6 .mC 152 255 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145. 117 / 459 Petition 870250116482, of 12 / 17 / 2025, p. 600 / 975 Name Ribbon 5'-Binder Modified Ribbons (5'-3') 3'-Ligand SEQ ID NO: S Integrin α4βΐ / 7 c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.m6.mA.UC.m*mA .mC 152 256 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S Integrin α4βΐ / 7 16.mG*mC*mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6. mC Integrin □4β1 / 7 152 257 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S CB1 c6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*t6 .mC 152 258 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c 6 TrkB 94 259 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c 6 TrkB 94 260 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c 6 TrkB 94 261 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c 6 TrkB 94. 118 / 459 Petition 870250116482, of 12 / 17 / 2025, p. 601 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: 262 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c 6 TrkB 94 263 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c 6 TrkB 94 264 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c 6 TrkB 94 265 A vU*fU*mU.fG.mC.fU.mU.fU.mU.fA.mC.fU.mG.fA.mC.fC.mA.fU.mG.fC.mG*mA*mG 24 S TrkB c6*mC*mG.mC.mA.mU.mG.fG.mU.fC.fA.fG.fU.mA.mA.mA.mA.mG.mC.mA.mA.mA*dQ*c 6 TrkB 94 266 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 18 S TrkB c6*mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU.mA*dQ*c6 TrkB 88 267 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 18 S Integrina α4βΐ / 7 c6*mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU.mA*dQ*c6 Integrina □4β1 / 7 88 268 A vU*fA*mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fU.mU.fA.mU.fC.mU.fA.mG*mC*mC 18 S CB1 c6*mC*mU.mA.mG.mA.mU.fA.mA.fG.fA.fU.fA.mU.mA.mC.mU.mG.mU.mA.mU.mA*dQ*c6 CB1 88 269 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19. 119 / 459 Petição 870250116482, de 17 / 12 / 2025, pág. 602 / 975 Nome Fita 5'-Ligante Fitas modificadas (5'-3') 3'-Ligante SEQ ID NO: S TrkB c6*mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ*c 6 TrkB 89 270 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19 S Integrina α4βΐ / 7 c6*mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ*c 6 Integrina □4β1 / 7 89 271 A vU*fG*mC.fA.mU.fA.mC.fA.mG.fU.mA.fU.mA.fU.mC.fC.mU.fA.mU.fC.mU*mA*mG 19 S CB1 c6*mA*mG.mA.mU.mA.mG.fG.mA.fU.fA.fU.fA.mC.mU.mG.mU.mA.mU.mG.mC.mA*dQ*c 6 CB1 89 272 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC 29 S TrkB c6*mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG.mA*dQ*c6 TrkB 99 273 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC 29 S Integrina α4β1 / 7 c6*mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG.mA*dQ*c6 Integrina □4β1 / 7 99 274 A vU*fC*mU.fA.mU.fG.mU.fA.mU.fA.mU.fG.mU.fU.mC.fA.mG.fC.mU.fG.mC*mU*mC 29 S CB1 c6*mG*mC.mA.mG.mC.mU.fG.mA.fA.fC.fA.fU.mA.mU.mA.mC.mA.mU.mA.mG.mA*dQ*c6 CB1 99 275 A vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.rkTmCA.6mG* c6*mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA.mA*d Q*c6 TrkB 136 276 A vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC 66. 120 / 459 Petition 870250116482, of 12 / 17 / 2025, p. 603 / 975 Ribbon Name 5'-Binder Modified Ribbons (5'-3') 3'-Binder SEQ ID NO: S Integrin α4βΐ / 7 c6*mC*mU.mC.mG.mC.mA.mU.fG.mA.mA.mA.mA.mA Q*c6 Integrin α4βΐ / 7 136 277 A vU*fU*mG.fC.mU.fU.mU.fU.mA.fC.mU.fG.mA.fU.mC.fA.mU.fG.mC.fG.mA*mG*mC.66 S c6*mC*mU.mC.mG.mC.mA.mU.fG.mA.fU.fC.fA.fG.mU.mA.mA.mA.mA.mG.mC.mA.mA*d Q*c6 CB1 136 278 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB AC6*mG*mC.mU.mU.mAêmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*A C6 130 279 A fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB AC6*mG*mC.mU.mU.mAêmC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*A C6 TrkB 130 280 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB AC6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ* AC6 TrkB 130 281 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB AC6*mG*mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ* AC6 TrkB 130 282 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA*fG*mC 145 S TrkB AC6*mG*mCêmU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*A C6 TrkB 130. 121 / 459 Petition 870250116482, of 12 / 17 / 2025, p. 604 / 975 Ribbon Name 5'-Binder Modified Ribbons (5'-3') 3'-Binder SEQ ID NO: 283 A eU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mU.fA AC6*mG*mCêmU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA*dQ*A C6 TrkB 130 284 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60 S TrkB AC6*mG*mG.mC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA *dQ*AC6 TrkB 150 285 A vU*fG*mU.fG.mA.fU.mG.fC.mA.fG.mG.fA.mG.fU.mU.fG.mU.fA.mA.fG.mC*mC*mU 60 S TrkB AC6*mG*mGêmC.mU.mU.mA.mC.fA.mA.fC.fU.fC.fC.mU.mG.mC.mA.mU.mC.mA.mC.mA *dQ*AC6 TrkB 150 122 / 459 Petition 870250116482, of 12 / 17 / 2025, p. 605 / 975 123 / 459 Determined Indications

[0191] In certain aspects, the invention relates to methods of inhibiting MAPT expression, which may be useful for treating, preventing, or improving a MAPT-associated disease in an individual by administering a compound that targets MAPT. In certain embodiments, the compound may be a specific MAPT inhibitor. In certain embodiments, the compound may be an antisense oligonucleotide, an oligomeric compound, or an oligonucleotide targeting MAPT (for example, a compound of any of the compounds shown in Figures 1-4, Table A, Table 2, and Table 3).

[0192] In certain aspects, the invention relates to the treatment, prevention or improvement of a disease, disorder or condition associated with MAPT. In certain embodiments, diseases, disorders or conditions associated with MAPT that are treatable, preventable and / or improveable with the methods provided herein include a disease, disorder or condition related to the CNS or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment.Certain compounds provided herein are targeted to compounds and compositions that reduce a disease, disorder, or condition related to the CNS or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment in an animal. Petition 870250116482, dated 12 / 17 / 2025, pp. 606 / 975 124 / 459

[0193] In certain embodiments, a method for treating, preventing, or improving a MAPT-associated disease in an individual comprises administering to the individual a compound comprising a specific MAPT inhibitor, treating, preventing, or improving the disease. In certain embodiments, the individual is identified as having or being at risk of having a MAPT-associated disease. In certain embodiments, the disease is a CNS-related disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23, linked nucleosides) of length having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of the SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) and having a nucleobase sequence comprising the nucleobase sequence of any of the following SEQ IDs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a sequence of... Petition 870250116482, dated 12 / 17 / 2025, pp. 607 / 975 125 / 459 nucleobases comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., from 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any nucleobase sequence of the SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.In any of the above embodiments, the compound may be single-stranded or double-stranded. In certain embodiments, a single-stranded compound may have to... Petition 870250116482, dated 12 / 17 / 2025, pp. 608 / 975 126 / 459 to 30, 14 to 23, 14 to 20, 16 to 20, or 14 to 16 nucleosides linked lengthwise. In certain embodiments, a single-stranded compound may have 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides linked lengthwise. In certain embodiments, a double-stranded compound may comprise two oligonucleotides of equal or different lengths, as described elsewhere herein. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity in relation to. Petition 870250116482, dated 12 / 17 / 2025, pp. 609 / 975 127 / 459 first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide 19 to 23 nucleosides linked in length having a complementarity region with respect to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain modalities, the compound is administered to the individual via intrathecal (IT) administration.In certain modalities, administration of the compound improves, preserves, or prevents a disease, disorder, or condition related to the CNS or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment in an animal.

[0194] In certain embodiments, a method for treating, preventing or improving a disease, disorder or condition related to the CNS or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment in an animal comprises administering to the individual a compound comprising a specific MAPT inhibitor, treating, preventing or improving a disease, disorder or condition related to the CNS or a symptom thereof or a Petition 870250116482, dated 12 / 17 / 2025, pp. 610 / 975 128 / 459 neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any nucleobase sequence of the SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) and having a nucleobase sequence comprising the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23, nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least. Petition 870250116482, dated 12 / 17 / 2025, page 611 / 975 129 / 459 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked lengthwise) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the sequences of Nucleobases of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In either of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the preceding embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, a compound comprises a first. Petition 870250116482, dated 12 / 17 / 2025, p. 612 / 975 130 / 459 modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any nucleobase sequence of SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide with 19 to 23 nucleosides linked in length having a region of complementarity with respect to the first modified oligonucleotide. In certain embodiments, the administration of... Petition 870250116482, dated 12 / 17 / 2025, page 613 / 975 131 / 459 compound improves, preserves, or prevents a disease, disorder, or condition related to the CNS, or a symptom thereof, or a neurodegenerative disease, or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment in an animal. In certain modalities, the individual is identified as having or being at risk of having a disease associated with MAPT.

[0195] In certain embodiments, a method for inhibiting MAPT expression in an individual with, or at risk of having, a MAPT-associated disease comprises administering to the individual a compound comprising a specific MAPT inhibitor, thereby inhibiting MAPT expression in the individual. In certain embodiments, administration of the compound inhibits MAPT expression in the liver. In certain embodiments, the disease is a CNS-related disease. In certain embodiments, the individual has, or is at risk of having, a CNS-related disease, disorder or condition or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment.In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a sequence of... Petition 870250116482, dated 12 / 17 / 2025, pp. 614 / 975 132 / 459 nucleobases comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any nucleobase sequence of SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) and having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of the SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. Petition 870250116482, dated 12 / 17 / 2025, pp. 615 / 975 In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.In any of the above embodiments, the compound can be single-stranded or double-stranded. In any of the above embodiments, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first oligonucleotide. Petition 870250116482, dated 12 / 17 / 2025, pp. 616 / 975 134 / 459 modified. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide 19 to 23 nucleosides linked in length having a complementarity region with respect to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual intrathecally (IT).In certain modalities, administration of the compound improves, preserves, or prevents a disease, disorder, or condition related to the CNS or a symptom thereof, a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment.

[0196] In certain modalities, a method of inhibiting Petition 870250116482, dated 12 / 17 / 2025, page 617 / 975 135 / 459 MAPT expression in a cell involves placing the cell in contact with a compound comprising a specific MAPT inhibitor, thereby inhibiting MAPT expression in the cell. In certain embodiments, the cell is a hepatocyte. In certain embodiments, the cell is in the liver. In certain embodiments, the cell is in the liver of an individual who has, or is at risk of having, a CNS-related disease, disorder or condition or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any nucleobase sequence of the SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) and having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group that... Petition 870250116482, dated 12 / 17 / 2025, p. 618 / 975 136 / 459 consists of the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and a second modified oligonucleotide having a... Petition 870250116482, dated 12 / 17 / 2025, page 619 / 975 137 / 459 nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In any of the above embodiments, the compound may be single-stranded or double-stranded. In any of the above embodiments, the compound may be an antisense oligonucleotide or oligomeric compound.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or sequence of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or sequence of the SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide. In certain embodiments, a compound comprises a first oligonucleotide. Petition 870250116482, dated 12 / 17 / 2025, pp. 620 / 975 138 / 459 modified having a nucleobase sequence selected from the group consisting of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and sequence of the SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide 19 to 23 nucleosides linked in length having a complementarity region with respect to the first modified oligonucleotide.

[0197] In certain embodiments, a method for reducing or inhibiting a disease, disorder or condition related to the CNS or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment in an individual who has, or is at risk of having, a MAPT-associated disease comprises administering to the individual a compound comprising a specific MAPT inhibitor, thereby reducing or inhibiting a disease, disorder or condition related to the CNS or a symptom thereof or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE),Corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment in the individual. In certain modalities, the individual has, or is at risk of having, a disease, disorder, or condition related to the CNS or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, syndrome, Petition 870250116482, dated 12 / 17 / 2025, pp. 621 / 975 139 / 459 Dravet or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) and having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a... Petition 870250116482, dated 12 / 17 / 2025, page 622 / 975 140 / 459 modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of the SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In either of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the previous modalities, the compound can be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least. Petition 870250116482, dated 12 / 17 / 2025, pp. 623 / 975 141 / 459 20, at least 21, at least 22, at least 23 contiguous nucleobases from any nucleobase sequence of SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a complementarity region with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide 19 to 23 nucleosides linked in length having a complementarity region with respect to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual intrathecally (IT). In certain modalities, the individual is identified as having, or being at risk of having, a disease associated with MAPT. Petition 870250116482, dated 12 / 17 / 2025, pp. 624 / 975 142 / 459

[0198] Certain embodiments are designed for a compound comprising a specific MAPT inhibitor for use in the treatment of a disease, disorder, or condition associated with MAPT. In certain embodiments, the disease, disorder, or condition is a CNS-related disease, disorder, or condition or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked lengthwise) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) and having a nucleobase sequence comprising the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. Petition 870250116482, dated 12 / 17 / 2025, pages 625 / 975 143 / 459 In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157. Petition 870250116482, dated 12 / 17 / 2025, pp. 626 / 975 144 / 459 159-168, 171-172, 174, 176 and 201-206. In any of the above embodiments, the compound may be single-stranded or double-stranded. In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and... Petition 870250116482, dated 12 / 17 / 2025, pp. 627 / 975 145 / 459 209-217 and SEQ ID Nos: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide with 19 to 23 nucleosides linked in length having a complementarity region with respect to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual by intrathecal (IT) administration.

[0199] Certain embodiments are designed for a compound comprising a specific MAPT inhibitor for use in reducing or inhibiting a disease, disorder or condition related to the CNS or a symptom thereof or a neurodegenerative disease or a symptom thereof, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment.In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) and having a nucleobase sequence comprising. Petition 870250116482, dated 12 / 17 / 2025, pp. 628 / 975 146 / 459 the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a sequence of... Petition 870250116482, dated 12 / 17 / 2025, pp. 629 / 975 147 / 459 nucleobase selected from the group consisting of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide 19 to 23 nucleosides linked in length having a complementarity region with respect to the first modified oligonucleotide.

[0200] Certain embodiments are directed to the use of a compound comprising a specific MAPT inhibitor for the manufacture or preparation of a medicament to treat a disease associated with MAPT. Certain embodiments are directed to the use of a compound comprising a specific MAPT inhibitor for the preparation of a medicament to treat a disease, disorder, or condition associated with MAPT. In certain embodiments, the disease, disorder, or condition is a CNS-related disease, disorder, or condition or a symptom thereof. In certain embodiments, the disease, disorder, or condition is a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment.In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least. Petition 870250116482, dated 12 / 17 / 2025, pp. 630 / 975 148 / 459 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of the SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) and having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any nucleobase sequence of the SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of... Petition 870250116482, dated 12 / 17 / 2025, pp. 631 / 975 149 / 459 nucleobase sequence of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In either of the foregoing embodiments, the compound may be single-stranded or double-stranded.In any of the previous modalities, the compound can be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., from 14 to 30, by. Petition 870250116482, dated 12 / 17 / 2025, pp. 632 / 975 150 / 459 example, 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a complementarity region with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide 19 to 23 nucleosides linked in length having a complementarity region with respect to the first modified oligonucleotide.

[0201] Certain embodiments are developed using a compound comprising a specific MAPT inhibitor for the manufacture or preparation of a medicament to reduce or inhibit a CNS-related disease, disorder, or condition or a symptom thereof in an individual who has, or is at risk of having, a CNS-related disease, disorder, or condition or a symptom thereof associated with MAPT. In certain embodiments, the CNS-related disease, disorder, or condition is a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome, or cognitive impairment. Certain embodiments are Petition 870250116482, dated 12 / 17 / 2025, pp. 633 / 975 151 / 459 developed for the use of a compound comprising a specific MAPT inhibitor for the preparation of a medicament to treat a disease, disorder or condition associated with MAPT. In certain embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, Dravet syndrome or cognitive impairment. In certain embodiments, the compound comprises an antisense oligonucleotide targeting MAPT. In certain embodiments, the compound comprises an oligonucleotide targeting MAPT.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked lengthwise) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) and having a nucleobase sequence comprising the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. Petition 870250116482, dated 12 / 17 / 2025, pp. 634 / 975 152 / 459 In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.In certain embodiments, a compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any nucleobase sequence of the SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, a compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and a second modified oligonucleotide having a nucleobase sequence selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 81-143, 149-155, 157. Petition 870250116482, dated 12 / 17 / 2025, pp. 635 / 975 153 / 459 159-168, 171-172, 174, 176 and 201-206. In any of the above embodiments, the compound may be single-stranded or double-stranded. In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases of any nucleobase sequence of SEQ ID NOs: 1173, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide.In certain embodiments, a compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 nucleosides linked in length) having a region of complementarity with respect to the first modified oligonucleotide. In certain embodiments, a compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and... Petition 870250116482, dated 12 / 17 / 2025, pp. 636 / 975 154 / 459 209-217 and SEQ ID Nos: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide with 19 to 23 nucleosides linked in length having a region of complementarity with respect to the first modified oligonucleotide.

[0202] In any of the foregoing methods or uses, the compound may be an oligomeric compound. In any of the foregoing methods or uses, the compound may be single-stranded or double-stranded. In any of the foregoing methods or uses, the compound may be targeted to MAPT. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. In certain embodiments, the compound comprises one or more modified oligonucleotides. In certain embodiments, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, a modified oligonucleotide has 8 to 80 linked nucleosides in length, 10 to 30 linked nucleosides in length, 14 to 30 linked nucleosides in length, 14 to 23 linked nucleosides in length, or 19 to 23 linked nucleosides in length.In certain embodiments, a modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to any of the nucleobase sequences recited in SEQ IDs 1 and 3 along its length. In certain embodiments, a modified oligonucleotide comprises at least one modified internucleoside bond, at least one modified sugar, and / or at least one modified nucleobase. In certain embodiments, the modified internucleoside bond is a phosphorothioate internucleoside bond. In certain embodiments, the modified sugar is a bicyclic sugar, 2'-MOE, 2'-F, or 2'-OMe. In certain embodiments... Petition 870250116482, dated 12 / 17 / 2025, pp. 637 / 975 In 155 / 459 embodiments, the modified nucleobase is 5-methylcytosine. In any of the preceding embodiments, each modified oligonucleotide independently has 12 to 30, 14 to 30, 14 to 25, 14 to 24, 14 to 23, 16 to 23, 17 to 23, 18 to 23, 19 to 23, 19 to 22, or 19 to 20 nucleosides linked in length. In certain embodiments, a modified oligonucleotide has at least 1, at least 2, or at least 3 mismatches with a SEQ ID NO: 1 and 2 region.

[0203] In any of the foregoing methods or uses, the compound comprises a first and a second modified oligonucleotide, wherein there is a region of complementarity between a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the region of complementarity between the first oligonucleotide and the second oligonucleotide is 14 to 23, 19 to 23, or 21 to 23 nucleosides linked in length. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide comprises at least one selected modification of a modified internucleosidic bond, a modified sugar, and a modified nucleobase.In certain embodiments, the second modified oligonucleotide comprises at least one selected group modification consisting of a modified internucleosidic linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the modified internucleosidic linkage is a phosphorothioate internucleosidic linkage or a methylphosphonate internucleosidic linkage. In certain embodiments, the modified internucleosidic linkage is at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first or second modified oligonucleotide. In certain embodiments, the first or second oligonucleotide... Petition 870250116482, dated 12 / 17 / 2025, pp. 638 / 975 The modified 156 / 459 comprises one or more modified sugars. In certain embodiments, each nucleoside of the first or second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a selected modification of the group consisting of a halogen, an alkoxy group, and a bicyclic sugar. In certain embodiments, the modified sugar comprises a selected modification of the group consisting of 2'-MOE, 2'-F, and 2'-OMe or a combination thereof. In certain embodiments, the first or second modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the first or second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

[0204] In any of the foregoing methods or uses, in certain embodiments, a compound comprises a conjugated group. In certain embodiments, the conjugated group is attached to the 5' end of a modified oligonucleotide. In certain embodiments, the conjugated group is attached to the 3' end of a modified oligonucleotide. In certain embodiments, a conjugated group is attached to the 5' end of a modified oligonucleotide, and a conjugated group is attached to the 3' end of the modified oligonucleotide. In certain embodiments, the conjugated group is a targeting chemical moiety. In certain embodiments, the targeting chemical moiety comprises one or more ligands. In certain embodiments, the targeting chemical moiety comprises one or more TrkB ligands. In certain embodiments, the one or more TrkB ligands are attached to the 5' or 3' end of the oligonucleotide or to both the 5' and 3' ends of the oligonucleotide.In certain embodiments, the TrkB binder is selected from the Formulas. Petition 870250116482, dated 12 / 17 / 2025, p. 639 / 975 157 / 459 I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII and XXXXXXIX-XXXXXXXIII, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the TrkB linker via a phosphodiester group. In certain embodiments, the modified oligonucleotide is attached to the TrkB linker via a phosphorothioate group. In certain embodiments, the conjugated group comprises one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In certain embodiments, the modified oligonucleotide comprises one or more linkers and one or more lipids. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, one or more lipids are attached to an internucleosidic linkage of the modified oligonucleotide.In certain embodiments, the internucleosidic linkage of the modified oligonucleotide is selected from any of the Formulas XXXXXIIIXXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises any of the Formulas XXXV-XXXXXVI. In certain embodiments, the modified oligonucleotide comprises one or more TrkB linkers and one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, one or more TrkB linkers are attached to the 5' end of the modified oligonucleotide. In certain embodiments, one or more TrkB linkers are attached to the 3' end of the modified oligonucleotide.In certain embodiments, one or more TrkB ligands are attached to the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, one or more lipids (by Petition 870250116482, dated 12 / 17 / 2025, pp. 640 / 975 158 / 459 For example, one or more substituted or unsubstituted alkyl or alkenyl groups are attached to an internucleosidic linkage of the modified oligonucleotide. In certain embodiments, one or more TrkB linkers are selected from any of Formulas IXXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII and XXXXXXIX-XXXXXXXIII, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide, and the internucleosidic linkage of the modified oligonucleotide is selected from any of Formulas XXXXXIII-XXXXXVI, or a salt, solvate or hydrate thereof.In certain embodiments, one or more TrkB ligands are selected from any of Formulas I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII, and XXXXXXIXXXXXXXXIII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide, and the modified oligonucleotide also comprises any of Formulas XXXV-XXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide.

[0205] In any of the foregoing methods or uses, in certain embodiments, a compound comprises a conjugated group. In certain embodiments, the conjugated group is attached to the 5' end of a modified oligonucleotide. In certain embodiments, the conjugated group is attached to the 3' end of a modified oligonucleotide. In certain embodiments, a conjugated group is attached to the 5' end of a modified oligonucleotide, and a conjugated group is attached to the 3' end of the modified oligonucleotide.In certain embodiments, the conjugated group is a targeting chemical moiety. In certain embodiments, the targeting chemical moiety comprises one or more ligands. In certain embodiments, the targeting chemical moiety comprises one or more CB1 ligands. In certain embodiments, one or more CB1 ligands are attached to... Petition 870250116482, dated 12 / 17 / 2025, pp. 641 / 975 159 / 459 5' end or 3' end of the oligonucleotide or both 5' and 3' ends of the oligonucleotide. In certain embodiments, the CBi linker is selected from Formulas XXXXXXI and XXXXXXXIV-XXXXXXXVIII, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the CB1 linker via a phosphodiester group. In certain embodiments, the modified oligonucleotide is attached to the CB1 linker via a phosphorothioate group. In certain embodiments, the conjugated group comprises one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In certain embodiments, the modified oligonucleotide comprises one or more linkers and one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide.In certain embodiments, one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups) are attached to an internucleosidic linkage of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage of the modified oligonucleotide is selected from any of Formulas XXXXXIIIXXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises any of Formulas XXXV-XXXXXVI. In certain embodiments, the modified oligonucleotide comprises one or more CB1 linkers and one or more lipids. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, one or more CBi linkers are attached to the 5' end of the modified oligonucleotide. In certain embodiments, one or more CB1 linkers. Petition 870250116482, dated 12 / 17 / 2025, pp. 642 / 975160 / 459 are attached to the 3' end of the modified oligonucleotide. In certain embodiments, one or more CBi linkers are attached to the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, one or more lipids are attached to an internucleosidic linkage of the modified oligonucleotide. In certain embodiments, one or more CB1 linkers are selected from any of Formulas XXXXXXI and XXXXXXXIVXXXXXXXVIII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide, and the internucleosidic linkage of the modified oligonucleotide is selected from any of Formulas XXXXXIII-XXXXXVI, or a salt, solvate, or hydrate thereof.In certain embodiments, one or more CB1 ligands are selected from any of Formulas XXXXXXI and XXXXXXXIVXXXXXXXVIII, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide, and the modified oligonucleotide also comprises any of Formulas XXXV-XXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide.

[0206] In any of the foregoing methods or uses, in certain embodiments, a compound comprises a conjugated group. In certain embodiments, the conjugated group is attached to the 5' end of a modified oligonucleotide. In certain embodiments, the conjugated group is attached to the 3' end of a modified oligonucleotide. In certain embodiments, a conjugated group is attached to the 5' end of a modified oligonucleotide, and a conjugated group is attached to the 3' end of the modified oligonucleotide.In certain embodiments, the conjugated group is a targeting chemical moiety. In certain embodiments, the targeting chemical moiety comprises one or more ligands. In certain embodiments, the targeting chemical moiety comprises one or more α4β1 / 7 integrin ligands. In certain embodiments... Petition 870250116482, dated 12 / 17 / 2025, pp. 643 / 975 In certain embodiments, one or more α4β1 / 7 integrin linkers are attached to the 5' or 3' end of the oligonucleotide or to both the 5' and 3' ends of the oligonucleotide. In certain embodiments, the α4β1 / 7 integrin linker is selected from Formulas XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXXXIV, or a salt, solvate, or hydrate thereof, where R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is attached to the α4β1 / 7 integrin linker via a phosphodiester group. In certain embodiments, the modified oligonucleotide is attached to the α4β1 / 7 integrin linker via a phosphorothioate group. In certain embodiments, the conjugated group comprises one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups). In certain embodiments, the modified oligonucleotide comprises one or more linkers and one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups).In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, one or more lipids (e.g., one or more substituted or unsubstituted alkyl or alkenyl groups) are attached to an internucleosidic linkage of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage of the modified oligonucleotide is selected from any of Formulas XXXXXIIIXXXXXVI, or a salt, solvate, or hydrate thereof, wherein R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises any of Formulas XXXV-XXXXXVI. In certain embodiments, the modified oligonucleotide comprises one or more α4β1 / 7 integrin linkers and one or more lipids. In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide. In certain embodiments, one or more α4β1 / 7 integrin linkers are attached to... Petition 870250116482, dated 12 / 17 / 2025, p. 644 / 975 162 / 459 5' end of the modified oligonucleotide. In certain embodiments, one or more α4β1 / 7 integrin linkers are attached to the 3' end of the modified oligonucleotide. In certain embodiments, one or more α4β1 / 7 integrin linkers are attached to both the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, one or more lipids are attached to an internucleosidic linkage of the modified oligonucleotide. In certain embodiments, one or more α4β1 / 7 integrin linkers are selected from any of Formulas XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide, and the internucleosidic linkage of the modified oligonucleotide is selected from any of Formulas XXXXXIII-XXXXXVI, or a salt, solvate or hydrate thereof.In certain embodiments, one or more α4β1 / 7 integrin linkers are selected from any of Formulas XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide, and the modified oligonucleotide also comprises any of Formulas XXXVXXXXXVI, or a salt, solvate or hydrate thereof, wherein R is the modified oligonucleotide.

[0207] In any of the foregoing methods or uses, in certain embodiments, a compound comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is attached to an internucleoside bond of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are attached to one or more internucleoside bonds of the modified oligonucleotide. In Petition 870250116482, dated 12 / 17 / 2025, pp. 645 / 975 163 / 459 In certain embodiments, the modified oligonucleotide is the second modified oligonucleotide or sense oligonucleotide. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C4-C30 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C5-C20 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C14-C20 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated and unsaturated C16 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated and unsaturated C17 hydrocarbon chain.In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated and unsaturated C18 hydrocarbon chain. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated and unsaturated C22 hydrocarbon chain.

[0208] In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to an internucleosidic bond of a modified oligonucleotide (for example, a second modified oligonucleotide or sense oligonucleotide). In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to an internucleosidic bond of a modified oligonucleotide (for example, a second modified oligonucleotide or sense oligonucleotide). In certain embodiments, the internucleosidic bond occurs between Petition 870250116482, dated 12 / 17 / 2025, p. 646 / 975 164 / 459 nucleosides that are within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of a terminal end (e.g., the 5' and / or 3' end) of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage occurs between nucleosides that are within 5 positions of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage occurs between nucleosides that are within 5 positions of the 3' end of the modified oligonucleotide.

[0209] In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 2 and 3 of the 5' end of the modified oligonucleotide.In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 3' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the 3' end of the modified oligonucleotide. In certain embodiments, the internucleosidic linkage is between positions 2 and 3. Petition 870250116482, dated 12 / 17 / 2025, pp. 647 / 975 165 / 459 of the 3' end of the modified oligonucleotide.

[0210] In certain embodiments, the internucleosidic linkage of the modified oligonucleotide is selected from any of Formulas XXXXXIII-XXXXXVI. In certain embodiments, the modified oligonucleotide comprises any of Formulas XXXV-XXXXXVI.

[0211] In any of the foregoing methods or uses, in certain embodiments, a compound comprises a 5'-phosphonate modification. For example, in certain embodiments, a modified oligonucleotide comprises one or more sugars with a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide comprises a 5'-phosphonate modification. In certain embodiments, the modified oligonucleotide comprises a 5'-terminal nucleoside (e.g., 5'-terminal) comprising the 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-ethylenephosphonate modification.In certain embodiments, the modified oligonucleotide is either the first modified oligonucleotide or the antisense oligonucleotide.

[0212] In any of the foregoing methods or uses, the compound comprises a first modified oligonucleotide selected from the group consisting of any of the reference ID NOs IA in Table 3 and a second modified oligonucleotide with 14 to 23 nucleosides linked in length fully complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first oligonucleotide Petition 870250116482, dated 12 / 17 / 2025, pp. 648 / 975 A modified 166 / 459 selected from any of the reference ID NOs IA in Table 3 and a second modified oligonucleotide selected from any of the reference ID NOs IS in Table 3. In certain embodiments, the compound is in a pharmaceutically acceptable salt form. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt. In certain embodiments, a composition comprises the compound from any of the preceding embodiments and a pharmaceutically acceptable carrier.

[0213] In any of the foregoing methods or uses, a compound or composition comprising a compound of any of the foregoing embodiments is administered to an individual in a therapeutically effective amount. In certain embodiments, a compound or composition comprising a compound of any of the foregoing embodiments is administered to an individual in a dosage sufficient to provide about 1 to 100 mg / kg of the individual’s body weight. In certain embodiments, a compound or composition comprising a compound of any of the foregoing embodiments is administered to an individual in a fixed dose of about 25 mg to about 1000 mg. In certain embodiments, the composition is administered to the individual one or more times daily up to the dosage level or fixed dose.

[0214] In any of the foregoing methods or uses, a compound or composition comprising a compound of any of the foregoing embodiments is administered to an individual daily, weekly, monthly, quarterly, or annually. In certain embodiments, a compound or composition comprising a compound of any of the foregoing embodiments is administered to an individual approximately once per quarter (i.e., once per quarter). Petition 870250116482, dated 12 / 17 / 2025, p. 649 / 975 167 / 459 once every three months) to about once a year. In certain embodiments, a compound or composition comprising a compound of any of the foregoing embodiments is administered to an individual about once a quarter, about once every six months, or about once a year. Certain Compounds

[0215] In certain aspects, the invention relates to a compound comprising or consisting of an oligomeric compound. In certain embodiments, the oligomeric compound comprises a nucleobase sequence complementary to that of a target nucleic acid.

[0216] In certain aspects, the invention relates to a compound comprising or consisting of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid.

[0217] In certain aspects, the invention relates to a compound comprising or consisting of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide has a nucleobase sequence complementary to that of a target nucleic acid.

[0218] In certain aspects, the invention relates to a compound that is a single-stranded compound. In certain embodiments, the single-stranded compound comprises or consists of an oligomeric compound. In certain embodiments, such an oligomeric compound comprises or consists of an oligonucleotide and, optionally, a conjugated group. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. In certain embodiments, the oligonucleotide or oligonucleotide Petition 870250116482, dated 12 / 17 / 2025, pp. 650 / 975 The modified 168 / 459 single-stranded compound comprises a self-complementary nucleobase sequence.

[0219] In certain aspects, the invention relates to a compound that is a double-stranded compound. In certain embodiments, the double-stranded compound comprises or consists of an oligomeric compound. In certain embodiments, the double-stranded compound comprises a first oligonucleotide and a second oligonucleotide. In certain embodiments, the first oligonucleotide has a region complementarity with a target nucleic acid and the second oligonucleotide has a region complementarity with the modified first oligonucleotide. In certain embodiments, the double-stranded compound comprises a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a region of complementarity with a target nucleic acid. In certain embodiments, the double-stranded compound comprises a modified first oligonucleotide and a modified second oligonucleotide.In certain embodiments, the first modified oligonucleotide has a region complementary to a target nucleic acid, and the second modified oligonucleotide has a region complementary to the first modified oligonucleotide. In certain embodiments, an oligonucleotide or modified oligonucleotide of a double-stranded compound is an RNA oligonucleotide. In such embodiments, the thymine nucleobase in the modified oligonucleotide is replaced by a uracil nucleobase.

[0220] In certain embodiments, a compound described herein comprises a conjugated group. In certain embodiments, the first oligonucleotide or first modified oligonucleotide of a double-stranded compound comprises a conjugated group. In certain embodiments, the second oligonucleotide or second Petition 870250116482, dated 12 / 17 / 2025, pp. 651 / 975 169 / 459 A modified oligonucleotide of a double-stranded compound comprises a conjugated group. In certain embodiments, a first oligonucleotide or first modified oligonucleotide and a second oligonucleotide or second modified oligonucleotide of a double-stranded compound each comprise a conjugated group.

[0221] In certain embodiments, a compound has 14 to 30 linked nucleosides in length. In certain embodiments, the first oligonucleotide or first modified oligonucleotide of a double-stranded compound has 14 to 30 linked nucleosides in length. In certain embodiments, the second oligonucleotide or second modified oligonucleotide has 14 to 30 linked nucleosides in length. In certain embodiments, the oligonucleotides or modified oligonucleotides of a double-stranded compound are blunt-terminated at one or both ends of the compound. In certain embodiments, the oligonucleotides or modified oligonucleotides of a double-stranded compound include non-complementary pendant nucleosides at one or both ends of the compound.

[0222] In certain embodiments, a compound has a nucleobase sequence comprising at least 14 contiguous nucleobases of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217. In certain embodiments, one of the oligonucleotides or modified oligonucleotides of a double-stranded compound has a nucleobase sequence comprising at least 14 contiguous nucleobases of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200, and 209-217.

[0223] Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, microRNA targeting oligonucleotides, Petition 870250116482, dated 12 / 17 / 2025, pp. 652 / 975 170 / 459 occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and single-stranded RNAi compounds (e.g., small hairpin RNAs (shRNAs), single-stranded siRNAs (ssRNAs), and microRNA mimics).

[0224] In certain embodiments, a compound described herein has a sequence of nucleobases which, when written in the 5' to 3' direction, comprises the reverse complement of the target region of a target nucleic acid to which it is directed.

[0225] In certain embodiments, a compound described herein comprises an oligonucleotide with 12 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 12 to 23 linked subunits in length. In certain embodiments, the compound described herein comprises an oligonucleotide with 14 to 30 linked subunits in length. In certain embodiments, the compound described herein comprises an oligonucleotide with 14 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 15 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 15 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 16 to 30 linked subunits in length.In certain embodiments, a compound described herein comprises an oligonucleotide of 16 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide of 17 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide of 17 to 23 linked subunits in length. In certain embodiments, a compound described... Petition 870250116482, dated 12 / 17 / 2025, pp. 653 / 975 171 / 459 herein comprises an oligonucleotide of 18 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide of 18 to 23 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide of 19 to 30 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide of 19 to 23 linked subunits in length. In other words, such oligonucleotides have 12 to 30 linked subunits, 12 to 23 linked subunits, 14 to 30 linked subunits, 14 to 23 linked subunits, 15 to 30 linked subunits, 15 to 23 linked subunits, 16 to 30 linked subunits, 16 to 23 linked subunits, 17 to 30 linked subunits, 17 to 23 linked subunits, 18 to 30 linked subunits, 18 to 23 linked subunits, 19 to 30 linked subunits, or 19 to 23 linked subunits, respectively.In certain embodiments, a compound described herein comprises an oligonucleotide with 14 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 16 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 17 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 18 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 19 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 20 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 21 linked subunits in length. In certain embodiments, a compound described... Petition 870250116482, dated 12 / 17 / 2025, pp. 654 / 975 172 / 459 herein comprises an oligonucleotide with 22 linked subunits in length. In certain embodiments, a compound described herein comprises an oligonucleotide with 23 linked subunits in length. In other embodiments, a compound described herein comprises an oligonucleotide with 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 23, 18 to 24, 18 to 25, 18 to 50, 19 to 23, 19 to 30, 19 to 50, 20 to 23 or 20 to 30 linked subunits. In certain embodiments, the compound described herein comprises an oligonucleotide with 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 linked subunits of length, or a range defined by any two of the above values.

[0226] In certain embodiments, the compound may further comprise an additional chemical moiety, such as a conjugated group or delivery moiety. In certain embodiments, such compounds are oligomeric compounds, and the additional chemical moiety is attached to an oligonucleotide. In certain embodiments, a conjugated group is attached to a nucleoside of an oligonucleotide.

[0227] In certain embodiments, compounds can be shortened or truncated. For example, one or more subunits can be deleted from the 5' end (5' truncation) or, alternatively, from the 3' end (3' truncation) of an oligonucleotide.

[0228] In certain embodiments, the compounds may be elongated. For example, one or more subunits may be attached to the 3' or 5' end of an oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, Petition 870250116482, dated 12 / 17 / 2025, pages 655 / 975 173 / 459 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) are attached to the 5' end of an oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 3' end of an oligonucleotide. In certain embodiments, at least one or more subunits may be attached to the 3' or 5' end of an oligonucleotide in a double-stranded compound, creating a 3' and / or 5' end overhang. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 5' end of both oligonucleotides of a double-stranded compound.In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 3' end of both oligonucleotides of a double-stranded compound. In certain embodiments, the subunits are attached to both oligonucleotides of a double-stranded compound at the same end (for example, the subunits are attached to the 3' end of one oligonucleotide and the subunits are attached to the 5' end of the other oligonucleotide). In certain embodiments, when subunits are attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide may be the same or may be different.In certain embodiments, when subunits are attached to both oligonucleotides of a compound. Petition 870250116482, dated 12 / 17 / 2025, pages 656 / 975 In a 174 / 459 double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is the same. In certain embodiments, when subunits are attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is different. This scenario, where subunits are attached to both oligonucleotides of a double-stranded compound at the same end, can occur at one or both ends of a double-stranded compound. In certain embodiments, the subunits attached to the 3' and / or 5' end are modified.

[0229] In certain embodiments, the compounds described herein are oligonucleotides. In certain embodiments, the compounds described herein are modified oligonucleotides. In certain embodiments, the compounds described herein are antisense oligonucleotides. In certain embodiments, the compounds described herein are oligomeric compounds. In certain embodiments, the compounds described herein are RNAi compounds. In certain embodiments, the compounds described herein are siRNA compounds.

[0230] In certain embodiments, a compound described herein may comprise any of the MAPT-targeted oligonucleotide sequences described herein. In certain embodiments, the compound may be double-stranded.

[0231] In certain embodiments, the compound comprises an oligonucleotide comprising at least one moiety of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobases of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, the compound comprises an oligonucleotide comprising at least one moiety of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobases of any of the following SEQ ID NOs: Petition 870250116482, dated 12 / 17 / 2025, pp. 657 / 975 175 / 459 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217. In certain embodiments, the compound comprises a second oligonucleotide. In certain embodiments, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 contiguous nucleobase moieties of any of the SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.

[0232] In certain embodiments, the compound comprises ribonucleotides in which the oligonucleotide has uracil (U) in place of thymine (T) for any of the sequences provided herein. In certain embodiments, the compound comprises deoxyribonucleotides in which the oligonucleotide has thymine (T) in place of uracil (U) for any of the sequences provided herein. Certain Mechanisms

[0233] In certain embodiments, the compounds described herein comprise or consist of modified oligonucleotides. In certain embodiments, the compounds described herein comprise or consist of antisense oligonucleotides. In certain embodiments, the compounds comprise or consist of oligomeric compounds. In certain embodiments, the compounds described herein are capable of hybridizing with a target nucleic acid. In certain embodiments, the compounds described herein selectively affect one or more target nucleic acids. Such compounds comprise a nucleobase sequence that hybridizes with one or more target nucleic acids, resulting in one or more desired activities, and does not hybridize with one or more non-target nucleic acids, or does not hybridize with one or more non-target nucleic acids in such a way as to result in significant undesired activity.

[0234] In certain embodiments, hybridization of a compound described herein with a target nucleic acid results in Petition 870250116482, dated 12 / 17 / 2025, pp. 658 / 975 176 / 459 recruitment of one or more proteins that cause cleavage of the target nucleic acid. For example, certain compounds described herein, or a portion of a compound, are loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain compounds described herein result in cleavage of the target nucleic acid by Argonaute. The compounds loaded into the RISC are RNAi compounds. RNAi compounds can be double-stranded (siRNA) or single-stranded (ssRNA).

[0235] In certain embodiments, hybridization of compounds described herein with a target nucleic acid does not result in the recruitment of a protein that cleaves that target nucleic acid. In certain such embodiments, hybridization of the compound with the target nucleic acid results in altered splicing of the target nucleic acid. In certain embodiments, hybridization of the compound with a target nucleic acid results in the inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain such embodiments, hybridization of the compound with the target nucleic acid results in altered RNA processing. In certain such embodiments, hybridization of the compound with a target nucleic acid results in altered translation of the target nucleic acid.

[0236] The activities resulting from the hybridization of a compound with a target nucleic acid can be observed directly or indirectly. In certain embodiments, the observation or detection of an activity involves the observation or detection of a change in the quantity of a target nucleic acid or protein encoded by such target nucleic acid, a change in the proportion of splicing variants of a nucleic acid or protein, and / or a phenotypic change in a cell or animal. Certain Modifications Petition 870250116482, dated 12 / 17 / 2025, p. 659 / 975 177 / 459

[0237] In certain aspects, the invention relates to compounds comprising or consisting of oligonucleotides. Oligonucleotides consist of linked nucleosides. In certain embodiments, oligonucleotides may be unmodified RNA or DNA or may be modified. In certain embodiments, oligonucleotides are modified oligonucleotides. In certain embodiments, modified oligonucleotides comprise at least one modified sugar, modified nucleobase, or modified internucleosidic linkage relative to an unmodified RNA or DNA. In certain embodiments, an oligonucleotide has a modified nucleoside. A modified nucleoside may comprise a modified sugar, a modified nucleobase, or a modified sugar and a modified nucleobase. Modified oligonucleotides may also include end modifications, for example, 5' end modifications and 3' end modifications. Sugar Modifications and Reasons

[0238] In certain embodiments, a modified sugar is a substituted furanosyl sugar or a non-bicyclic modified sugar. In certain embodiments, a modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, a modified sugar is a sugar substitute. A sugar substitute may comprise one or more of the substitutions described herein.

[0239] In certain embodiments, a modified sugar is a substituted furanosyl or non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar comprises one or more substituent groups, including, but not limited to, substituent groups in the 2', 3', 4' and 5' positions.

[0240] In certain modalities, the substitutes in position Petition 870250116482, dated 12 / 17 / 2025, pp. 660 / 975 178 / 459 2' substituents include, but are not limited to, F and OCH3 (“OMe”, “O-methyl” or “methoxy”). In certain embodiments, suitable substituent groups at the 2' position for non-bicyclic modified sugars include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, F, Cl, Br, SCH3, SOCH3, SO2CH3, ONO2, NO2, N3 and NH2. In certain embodiments, substituent groups at the 2' position include, but are not limited to, O-(C1-C10) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, alkynyl, wherein alkyl, alkenyl and alkynyl may be substituted or unsubstituted C1 to C10 alkyl or alkenyl and C2 to C10 alkynyl.In certain embodiments, these 2' substituent groups may be further substituted by one or more substituent groups independently selected from among hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl. In certain embodiments, the substituent groups at the 2' position include, but are not limited to, O[(CH2)nO]mCH3, O(CH2)nOCH3, O(CH2)nCH3, O(CH2)nONH2, O(CH2)nNH2, O(CH2)nSCH3, and O(CH2)nON[(CH2)nCH3)]2, where neither are independently from 1 to about 10. In certain embodiments, the substituent groups at the 2' position include, but are not limited to, OCH2CH2OCH3 (“MOE”), O(CH2)2ON(CH3)2 (“DMAOE”), O(CH2)2O(CH2)2N(CH3)2 (“DMAEOE”), and OCH2C(=O)-N(H)CH3 (“NMA”).

[0241] In certain embodiments, suitable substituent groups at the 4' position for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, substituent groups at the 5' position Petition 870250116482, dated 12 / 17 / 2025, pp. 661 / 975 179 / 459 suitable for non-bicyclic modified sugars include, but are not limited to, methyl (“Me” or “CH3”) (R or S), vinyl and methoxy. In certain embodiments, the 5' modification is a 5'-monophosphate ((HO)2(O)PO-5'); 5'-diphosphate ((HO)2(O)POP(HO)(O)-O-5'); 5'-triphosphate ((HO)2(O)PO-(HO)(O)POP(HO)(O)-O-5'); cap 5'-guanosine (7-methylated or unmethylated) (7m-GO-5'-(HO)(O)PO-(HO)(O)P-OP(HO)(O)-O-5'); Adenosine 5'-cap (Appp) and any modified or unmodified nucleotide cap structure (NO-5'(HO)(O)PO(HO)(O)POP(HO)(O)-O-5'); 5'-monothiophosphate (phosphorothioate; (HO)2(S)PO-5'); 5'-monodithiophosphate (phosphorodithioate; (HO)(HS)(S)P-O5'), 5'phosphorothiolate ((HO)2(O)PS-5'); any additional combination of oxygen / sulfur substituted monophosphate, diphosphate and triphosphates (e.g., 5'-alpha-thiotriphosphate, 5'-gamma-thiotriphosphate, etc.), 5'phosphoramidates ((HO)2(O)P-NH-5', (HO)(NH2)(O)PO-5'), 5'-alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., for example, RP(OH)(O)-O-5'-, 5'-alkenylphosphonates (for example, vinyl, substituted vinyl), (OH)2(O)P-5'-CH2-), 5'-alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCH2-), ethoxymethyl, etc., for example, RP(OH)(O)-O-5'-). In certain embodiments, one or more sugars comprise a 5-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. In certain embodiments, one or more sugars comprise a 5-vinylphosphonate modification. In certain embodiments, one or more sugars comprise a 5-ethylenephosphonate modification. In certain embodiments, the 5' modification is at the end of an oligonucleotide. In certain embodiments, the 5' modification is at the end of an antisense oligonucleotide.In certain embodiments, the substituents described here for positions 2', 4' and 5' may be added to others. Petition 870250116482, dated 12 / 17 / 2025, pp. 662 / 975 180 / 459 specific positions on the sugar. In certain embodiments, such substituents may be added to the 3' position of the sugar at the 3'-terminal nucleoside or to the 5' position of the 5'-terminal nucleoside. In certain embodiments, a non-bicyclic modified sugar may comprise more than one non-bridge sugar substituent. In some of these embodiments, non-bicyclic modified sugar substituents include, but are not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including the R and S isomers). In certain embodiments, modified sugar substituents include those described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US2013 / 0203836.

[0242] In certain embodiments, a modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed by a bridge connecting two atoms in the first ring, thus forming a bicyclic structure. In certain embodiments, a bicyclic sugar comprises a bridging substituent linking two atoms of the furanosyl ring to form a second ring. In certain embodiments, a bicyclic sugar does not comprise a chemical moiety of yl.furanosyl. A “bicyclic nucleoside” (“BNA”) is a nucleoside possessing a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a bridge between the 4' and 2' atoms of the furanose ring. In certain embodiments, the bicyclic sugar comprises a bridge between the 5' and 3' atoms of the furanose ring. In certain such embodiments, the furanose ring is a ribose ring.In certain embodiments, the 4' to 2' linkage substituents include, but are not limited to, 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2' (“LNA”), 4'-CH2-S-2', 4'-(CH2)2-O-2' (“ENA”), 4'-CH(CH3)-O2' (“restricted ethyl” or “cEt” when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CH2OCH3)-O-2' (“restricted MOE” or “cMOE”) and analogs thereof (e.g., U.S. Patent No. 7,399,845), Petition 870250116482, of 17 / 12 / 2025, page 663 / 975. 181 / 459 C(CH3)(CH3)-O-2' and its analogues (e.g., US Patent No. 8,278,283), 4'-CH2-N(OCH3)-2' and its analogues (e.g., US Patent No. 8,278,425), 4'-CH2-ON(CH3)-2' (e.g., US Patent Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2', where R is H, C1-C12 alkyl or a protecting group (e.g., US Patent No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134) and 4'-CH2-C(=CH2)-2' and its analogues (e.g., U.S. Patent No. 8,278,426). The entire content of each of the above items is incorporated herein by reference. Additional representative U.S. patents and U.S. patent publications teaching the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: U.S. Patents Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; and US 2009 / 0012281, US 2013 / 0190383; and WO 2013 / 036868, the full contents of which are incorporated herein by reference. Any of the foregoing bicyclic nucleosides may be prepared having one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, for example, WO 99 / 14226). The bicyclic nucleosides specified herein are in the βD configuration unless otherwise specified.

[0243] In certain embodiments, a modified sugar is a sugar substitute. In certain embodiments, a sugar substitute has the oxygen atom replaced, for example, by a sulfur, carbon, or nitrogen atom. In certain of these embodiments, the sugar substitute may also comprise linking and / or non-linking substituents, as described herein. In certain embodiments, the sugar substitutes comprise rings having more than 5 atoms. In some of these embodiments, the sugar substitute Petition 870250116482, dated 12 / 17 / 2025, pp. 664 / 975 182 / 459 comprises a cyclobutyl chemical moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute comprises a six-membered ring in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute comprises a tetrahydropyran (“THP”) in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute comprises a morpholino in place of the pentofuranosyl sugar. Representative U.S. patents teaching the preparation of such modified sugar structures include, but are not limited to, U.S. Patents Nos. 4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677, 8,088,904; 8,440,803; and 9,005,906, the entire content of each of the foregoing is incorporated herein by reference.

[0244] In some embodiments, the sugar substitutes comprise acyclic chemical moieties. In certain embodiments, the sugar substitute is an unblocked nucleic acid (“UNA”). A UNA is an unblocked acyclic nucleic acid in which any of the sugar bonds have been removed, forming an unblocked sugar residue. In one example, UNA also encompasses a monomer where the C1'-C4' bonds have been removed (i.e., the carbon-oxygen-carbon covalent bond between carbons C1' and C4'). In another example, the C2'-C3' bond (i.e., the carbon-carbon covalent bond between carbons C2' and C3') of the sugar has been removed. Representative US publications teaching the preparation of UNA include, but are not limited to, US Patent No. 8,314,227; and US Patent Publications No. 2013 / 0096289; 2013 / 0011922; and 2011 / 0313020, the complete content of each of which is incorporated herein by reference. In certain modalities, Petition 870250116482, dated 12 / 17 / 2025, pages 665 / 975 183 / 459 Sugar substitutes comprise peptide nucleic acid (“PNA”), acyclic butylic nucleic acid (see, for example, Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865) and nucleosides and oligonucleotides described in Manoharan et al., US2013 / 130378, the full content of which is incorporated herein by reference. Many other sugar ring systems and bicyclic and tricyclic sugar substitutes are known in the art and can be used in modified nucleosides.

[0245] In certain aspects, the invention relates to compounds comprising at least one oligonucleotide wherein the nucleosides of that oligonucleotide comprise one or more types of modified sugars and / or unmodified sugars arranged along the oligonucleotide or region thereof in a defined pattern or “sugar motif”. In certain cases, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

[0246] In certain embodiments, an oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region with two outer “wing” regions and a central or inner “gap” region. The gap and wing regions form a contiguous sequence of nucleosides, wherein the majority of nucleoside sugars of each of the wings differ from the majority of nucleoside sugars of the gap. In certain embodiments, the wing regions comprise a majority of modified sugars and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleosides of the gap are deoxynucleosides. Compounds with a gapmer sugar motif are described, for example, in U.S. Patent 8,790,919, the full contents of which are incorporated herein by reference.

[0247] In certain modalities, one or both of the Petition 870250116482, dated 12 / 17 / 2025, pp. 666 / 975 184 / 459 oligonucleotides of a double-stranded compound comprise a triplet sugar motif. An oligonucleotide with a triplet sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is at or near the cleavage site of the oligonucleotide. In certain embodiments, an oligonucleotide of a double-stranded compound may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. Compounds with a triplet sugar motif are disclosed, for example, in U.S. Patent 10,668,170, the full contents of which are incorporated herein by reference.

[0248] In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise a quadruple sugar motif.An oligonucleotide with a quadruple sugar motif comprises four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruple is at or near the cleavage site. In certain embodiments, an oligonucleotide of a double-stranded compound may contain more than one quadruple sugar motif. In certain embodiments, the identical sugar modification of the quadruple sugar motif is a 2'-F modification. For a double-stranded compound with a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically around positions 10, 11, and 12 from the 5' end.In certain embodiments, the quadruple sugar motif is located at positions 8, 9, 10, 11; at positions 9, 10, 11, 12; at positions 10, 11, 12, 13; at positions 11, 12, 13, 14; or at positions 12, 13, 14, 15 of the sense oligonucleotide, counting from the first nucleoside at the 5' end of the sense oligonucleotide, or counting from the first paired nucleotide within the duplex region from the 5' end. Petition 870250116482, dated 12 / 17 / 2025, pp. 667 / 975 185 / 459 of the sense oligonucleotide. In certain embodiments, the quadruple sugar motif is located at positions 8, 9, 10, 11; at positions 9, 10, 11, 12; at positions 10, 11, 12, 13; at positions 11, 12, 13, 14; or at positions 12, 13, 14, 15 of the antisense oligonucleotide, counting from the first nucleoside at the 5' end of the antisense oligonucleotide, i.e., counting from the first paired nucleotide within the duplex region at the 5' end of the antisense oligonucleotide. The cleavage site may change according to the length of the duplex region of the double-stranded compound and may change the position of the quadruple accordingly.

[0249] In certain embodiments, an oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both oligonucleotides of a double-stranded compound comprise an alternating sugar motif. An oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternate with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, if A, B, and C each represent a type of modification in the nucleoside, the alternating motif may be “ABABABABABAB...,” “AABBAABBAABB...,” “AABAABAABAAB...,” “AAABAAABAAAB...,” “AAABBBAAABBB...,” or “ABCABCABCABC...” etc.In certain embodiments, the alternating sugar motif is repeated by at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleobases along an oligonucleotide. In certain embodiments, the alternating sugar motif is composed of two different sugar modifications. In certain embodiments, the sugar motif... Petition 870250116482, dated 12 / 17 / 2025, pages 668 / 975 186 / 459 alternating comprises 2'-OMe and 2'-F sugar modifications.

[0250] In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications provided herein. In certain embodiments, each oligonucleotide of a double-stranded compound independently possesses one or more sugar motifs provided herein. In certain embodiments, an oligonucleotide containing a sugar motif is fully modified such that each nucleoside, except the nucleosides that make up the sugar motif, comprises a sugar modification. Nucleobase modifications and motifs

[0251] In certain embodiments, the compounds described herein comprise modified oligonucleotides. In certain embodiments, the modified oligonucleotides comprise one or more nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not comprise a nucleobase, referred to as basic nucleosides.

[0252] In certain embodiments, modified nucleobases are selected from among: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines and N-2, N-6 and O-6 substituted purines. In certain embodiments, the modified nucleobases are selected from among: 2-aminopropyladenine, 5-hydroxymethylcytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C^CCH3) uracil, 5-propynylcytosine, 6-azouracyl, 6-azocytesine, 6-azotimine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil and 5-Petição 870250116482, dated 12 / 17 / 2025, page 669 / 975 187 / 459 halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-desazaguanine, 7-desaza-adenine, 3-desazaguanine, 3-desaza-adenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, expanded-size bases and fluorinated bases. Other modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)1,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced by other heterocycles, for example, 7-desazaadenine, 7-desaguanosine, 2-aminopyridine, and 2-pyridone.

[0253] Other nucleobases include those disclosed in Patent US 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, Ρ. ed. Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859; Kroschwitz, J.L., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, international edition, 1991, 30, 613; Sanghvi, YS, chapter 15, dsRNA Research and Applications, pages 289-302; Antisense Research and Applications, Crooke, ST and Lebleu, Β., Eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke ST, Ed., CRC Press, 2008, pp. 163-166 and 442-443 (Chapters 6 and 15), each of which is incorporated herein by reference.

[0254] Publications teaching the preparation of certain modified nucleobases mentioned above, as well as other modified nucleobases, include, without limitation, U.S. Patent Publications Nos. 2003 / 0158403 and 2003 / 0175906; U.S. Patents Nos. 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,985; Petition 870250116482, dated 12 / 17 / 2025, pages 670 / 975 188 / 459 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588; 5,830,653; 5,808,027; 6,005,096; 6,015,886; 6,147,200; 6,166,197; 6,166,199; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the full content of which is incorporated herein by reference.

[0255] In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, the oligonucleotides comprise modified and / or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methylcytosines.

[0256] In certain embodiments, the modified oligonucleotides comprise a block of modified nucleobases. In some of these embodiments, the block is at the 3' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 3' end of the oligonucleotide. In certain embodiments, the block is at the 5' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5' end of the oligonucleotide. Modifications and motifs of internucleoside bonding

[0257] A 3' to 5' phosphodiester bond is the bond Petition 870250116482, dated 12 / 17 / 2025, pp. 671 / 975 189 / 459 natural internucleoside bonds of RNA and DNA. In certain embodiments, the compounds described herein have one or more modified, i.e., non-natural, internucleoside bonds. Certain non-natural internucleoside bonds may confer desirable properties, such as increased cellular uptake, greater affinity for target nucleic acids, and greater stability in the presence of nucleases. Representative modified internucleoside bonds containing phosphorus include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates and phosphorothioates (“P=S”), and phosphorodithioates (“HS-P=S”). Representative non-phosphorus internucleoside linking groups include, but are not limited to, methylenemethylimino (-CH2-N(CH3)-O-CH2), thiodiester, thionocarbamate (-OC(=O)(NH)-S-); siloxane (-O-SiH2-O-); and N,N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-).Methods for preparing phosphorus-containing and phosphorus-free internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, among others, phosphotriesters, methylphosphonates, MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl and thioformacetal (3'-S-CH2-O-5'). Other neutral internucleosidic linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester, and amides (see, for example: Carbohydrate Modifications in Antisense Research; YS Sanghvi and PD Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Other neutral internucleosidic linkages include nonionic linkages comprising mixed components of N, O, S, and CH2.

[0258] In certain embodiments, the compounds provided herein comprise at least one modified internucleosidic bond. A modified internucleosidic bond may be Petition 870250116482, dated 12 / 17 / 2025, pp. 672 / 975 190 / 459 placed at any position of an oligonucleotide. For double-stranded compounds, a modified internucleosidic bond can be placed within the sense oligonucleotide, antisense oligonucleotide, or both oligonucleotides of the double-stranded compound.

[0259] In certain embodiments, the internucleosidic linkage modification can occur in each nucleoside of an oligonucleotide. In certain embodiments, the internucleosidic linkage modifications can occur in an alternating pattern along an oligonucleotide. In certain embodiments, essentially each internucleosidic linkage group is a phosphate internucleosidic linkage (P=O). In certain embodiments, each internucleosidic linkage group of a modified oligonucleotide is a phosphorothioate (P=S). In certain embodiments, each internucleosidic linkage group of a modified oligonucleotide is independently selected from a phosphorothioate and phosphate internucleosidic linkage. In certain embodiments, the pattern of internucleosidic linkage modification in each oligonucleotide of a double-stranded compound is the same.In certain embodiments, the pattern of internucleosidic bond modification in each oligonucleotide of a double-stranded compound is different. In certain embodiments, a double-stranded compound comprises 68 modified internucleosidic bonds. In certain embodiments, the modified internucleosidic bonds 6-8 are phosphorothioate internucleosidic bonds or alkylphosphonate internucleosidic bonds. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleosidic bonds at the 5' end and the 3' end or both. In certain embodiments, the modified internucleosidic bonds are phosphorothioate internucleosidic bonds or alkylphosphonate internucleosidic bonds. In certain embodiments, the... Petition 870250116482, dated 12 / 17 / 2025, pp. 673 / 975 191 / 459 antisense oligonucleotide comprises at least two modified internucleosidic bonds at the 5' and 3' ends. In certain embodiments, the modified internucleosidic bonds are phosphorothioate internucleosidic bonds or alkylphosphonate internucleosidic bonds.

[0260] In certain embodiments, a double-stranded compound comprises a protruding region. In certain embodiments, a double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage modification in the protruding region. In certain embodiments, a double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage that links the protruding nucleotide to a paired nucleotide that is adjacent to the protruding nucleotide. For example, there may be at least two phosphorothioate internucleoside linkages between the three terminal nucleosides, wherein two of the three nucleosides are protruding nucleosides, and the third is a paired nucleoside adjacent to the protruding nucleoside. These three terminal nucleosides can be located at the 3' end of the antisense oligonucleotide, at the 3' end of the sense oligonucleotide, at the 5' end of the antisense oligonucleotide, or at the 5' end of the antisense oligonucleotide.

[0261] In certain embodiments, modified oligonucleotides comprise one or more internucleosidic linkages with chiral centers. Representative chiral internucleosidic linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleosidic linkages with chiral centers can be prepared as populations of modified oligonucleotides comprising stereorandom internucleosidic linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In Petition 870250116482, dated 12 / 17 / 2025, pp. 674 / 975 192 / 459 In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside links wherein all phosphorothioate internucleoside links are stereorandom. These modified oligonucleotides can be generated using synthetic methods that result in the random selection of the stereochemical configuration of each phosphorothioate linkage. As is well understood by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more specific phosphorothioate internucleoside links in a specific, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population.In certain embodiments, the particular configuration of the particular phosphorothioate bond is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate bond is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate bond is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate bond is present in at least 99% of the molecules in the population. These enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, for example, methods described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014) and WO 2017 / 015555. In certain embodiments, a population of modified oligonucleotides is... Petition 870250116482, dated 12 / 17 / 2025, pages 675 / 975 193 / 459 enriched for modified oligonucleotides having at least one phosphorothioate group indicated in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched by modified oligonucleotides having at least one phosphorothioate group in the (Rp) configuration. Groups of conjugates

[0262] In certain embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and, optionally, one or more conjugated groups. Conjugated groups may be attached to one or both ends of an oligonucleotide and / or at any internal position. In certain embodiments, a conjugated group is attached to the 3' end of an oligonucleotide. In certain embodiments, a conjugated group is attached to the 5' end of an oligonucleotide. In certain embodiments, the oligonucleotides are covalently linked to one or more conjugated groups.

[0263] In certain embodiments, conjugated groups are terminal groups attached to one or both ends of an oligonucleotide. In certain such embodiments, terminal groups are attached to the 3' end of an oligonucleotide. In certain such embodiments, terminal groups are attached to the 5' end of an oligonucleotide. In certain embodiments, terminal groups include, but are not limited to, capping groups, phosphate groups, protecting groups, modified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified, such as an overhang.

[0264] In certain embodiments, the conjugated groups modify one or more properties of the attached oligonucleotide, including, but not limited to, pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, distribution in Petition 870250116482, dated 12 / 17 / 2025, pp. 676 / 975 194 / 459 tissues, cellular distribution, cellular uptake, loading and clearance. In certain embodiments, conjugated groups increase the affinity of a compound for a selected target, for example, molecule, cell or cell type, compartment, for example, a cellular or organ compartment, tissue, organ or body region, as well as, for example, in comparison to a compound without such a conjugated group. In certain embodiments, conjugated groups confer a new property to the attached oligonucleotide, for example, fluorophores or reporter groups that allow the detection of the oligonucleotide.

[0265] In certain embodiments, the conjugated groups include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin chemical moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid chemical moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores and dyes.

[0266] In certain embodiments, the conjugated groups include an active substance of the drug, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansilsarcosine, 2,3,5-tri-iodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indomethycine, a barbiturate, a cephalosporin, a sulfa, an antidiabetic, an antibacterial or an antibiotic.

[0267] In certain embodiments, conjugated groups are targeting chemical moieties. In certain embodiments, a targeting chemical moiety includes, but is not limited to, a lectin, glycoprotein, lipid, protein, peptide, peptide mimetic, receptor ligand, antibody, thyrotropin, melanotropin, surfactant protein A, carbohydrate, carbohydrate derivative, carbohydrate Petition 870250116482, dated 12 / 17 / 2025, pages 677 / 975 195 / 459 modified, carbohydrate cluster, polysaccharide, modified polysaccharide or polysaccharide derivative, mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetylgalactosamine (GalNAc), multivalent N-acetylglucosamine mannose, multivalent fucose, glycosylated polyamino acids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, vitamin A, biotin or an RGD peptide or RGD peptide mimetic.

[0268] In certain embodiments, the conjugated groups may include, but are not limited to, the conjugated groups described in the following references, such as cholesterol (e.g., Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (e.g., Manoharan et al., Biorg. Med. Chem. Let., 1994, 4:1053-1060), thioether, e.g., hexyl-S-tritylthiol (e.g., Manoharan et al., Ann. NY. Acad. Sci., 1992, 660: 306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3: 2765-2770), thiocholesterol (e.g., Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), aliphatic chains, e.g. do-decan-diol or undecyl residues (e.g., SaisonBehmoaras et al., ΕΜΒΟ J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259: 327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54), phospholipids, e.g., triethyl-ammonium dihexadecyl-rac-glycerol or 1,2-di-Ohexadecyl-rac-glycero-3-H-phosphonate (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36: 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18: 3777-3783), polyamines or polyethy...

Claims

1. Compound characterized in that it comprises a modified oligonucleotide of 14 to 30 linked nucleosides in length having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.

2. Compound characterized in that it comprises a modified oligonucleotide of 14 to 23 nucleosides linked in length having a nucleobase sequence comprising the nucleobase sequence of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.

3. Compound characterized in that it comprises an oligonucleotide modified with a nucleobase sequence selected from the group consisting of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.

4. Compound, according to any one of claims 1 to 3, characterized in that the modified oligonucleotide is at least 80%, at least 85%, at least 90% or at least 95% complementary to SEQ ID NO: 1 or 2.

5. A compound according to any one of claims 1 to 4, characterized in that the modified oligonucleotide comprises at least one selected modification of a modified internucleosidic bond, a modified sugar, and a modified nucleobase.

6. Compound according to any one of claims 1 to 5, characterized in that the compound is double-stranded.

7. Compound characterized by the fact that it comprises a Petition 870250116482, dated 12 / 17 / 2025, page. 943 / 975 2 / 26 first modified oligonucleotide with 14 to 23 linked nucleosides in length having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 contiguous nucleobases from any of the nucleobase sequences of SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide with 14 to 23 nucleosides linked in length having a region of complementarity to the first modified oligonucleotide.

8. A compound characterized in that it comprises a first modified oligonucleotide of 14 to 23 nucleoside-linked length having a nucleobase sequence comprising the nucleobase sequence of any of the SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 or SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206, and a second modified oligonucleotide of 14 to 23 nucleoside-linked length having a region of complementarity to the first modified oligonucleotide.

9. A compound characterized in that it comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217 and SEQ ID NOs: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206 and a second modified oligonucleotide with 19 to 23 nucleosides linked in length having a region of complementarity to the first modified oligonucleotide.

10. Compound, according to any one of claims 7 to 9, characterized in that the first modified oligonucleotide has at least 80%, at least 85%, at least 90% or at least 95% complementarity or identity with SEQ ID NO: 1 or 2 in its length.

11. A compound, according to any one of claims 7 to 10, characterized in that the first modified oligonucleotide has at least 1, at least 2, or at least 3 mismatches with a region of SEQ ID NO: 1 or 2 that has the same length as the first modified oligonucleotide.

12. A compound according to any one of claims 7 to 11, characterized in that the complementarity region between the first modified oligonucleotide and the second modified oligonucleotide has 14 to 23 nucleosides linked in length.

13. A compound according to any one of claims 7 to 11, characterized in that the complementarity region between the first modified oligonucleotide and the second modified oligonucleotide has 19 to 23 nucleosides linked in length.

14. A compound according to any one of claims 7 to 11, characterized in that the complementarity region between the first modified oligonucleotide and the second modified oligonucleotide has 21 to 23 nucleosides linked in length.

15. A compound according to any one of claims 7 to 11, characterized in that the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

16. Compound, according to any one of claims 7 to 15, characterized in that the first modified oligonucleotide comprises at least one modification selected from a modified internucleosidic bond, a modified sugar and a modified nucleobase.

17. A compound according to any one of claims 7 to 16, characterized in that the second modified oligonucleotide comprises at least one selected modification of the group consisting of a modified internucleosidic bond, a modified sugar, and a modified nucleobase.

18. Compound according to any one of claims 5, 16 and 17, characterized in that the modified internucleoside bond is a phosphorothioate internucleoside bond or a methylphosphonate internucleoside bond.

19. Compound according to claim 18, characterized in that the phosphorothioate internucleoside linkage or methylphosphonate internucleoside linkage is at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide.

20. Compound, according to any one of claims 5, 16 and 17, characterized in that the modified sugar comprises a selected modification of the group consisting of a halogen, an alkoxy group and a bicyclic sugar.

21. Compound according to claim 20, characterized in that the modified sugar comprises a 2'-F modification.

22. Compound according to claim 20, characterized in that the modified sugar comprises a 2'-OMe modification.

23. Compound, according to any one of claims 7 to 15, characterized in that each nucleoside of the first modified oligonucleotide comprises a modified sugar. Petition 870250116482, dated 12 / 17 / 2025, pp. 946 / 975 5 / 26 24. A compound, according to any one of claims 7 to 15, characterized in that each nucleoside of the second modified oligonucleotide comprises a modified sugar.

25. Compound according to claim 23 or 24, characterized in that the modified sugar comprises a selected modification of the group consisting of a halogen, an alkoxy group and a bicyclic sugar or a combination thereof.

26. Compound according to claim 25, characterized in that the modified sugar comprises a selected modification of the group consisting of LNA, cEt, 2'-MOE, 2'-F, 2'-OMe and 2'-deoxy or a combination thereof.

27. Compound according to claim 26, characterized in that the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications.

28. Compound according to claim 27, characterized in that the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

29. A compound, according to any of the preceding claims, characterized in that it comprises a conjugated group.

30. Compound according to claim 29, characterized in that the conjugated group is attached to the 5' end of the modified oligonucleotide.

31. Compound according to claim 29 or 30, characterized in that the conjugate group comprises a directing fraction.

32. Compound according to claim 31, characterized in that the targeting fraction comprises one or more ligands selected from one or more ligands of the tropomyosin B (TrkB) receptor, one or more ligands of the cannabinoid receptor type 1 (CBi), and one or more ligands of the α4β1 / 7 integrin.

33. Compound according to claim 32, characterized in that the modified oligonucleotide is the second modified oligonucleotide.

34. Compound according to claim 33, characterized in that one or more TrkB ligands, one or more CBi ligands, or one or more α4β1 / 7 integrin ligands are attached to the 5' end of the modified oligonucleotide.

35. Compound according to claim 33, characterized in that one or more TrkB ligands, one or more CBi ligands, or one or more α4β1 / 7 integrin ligands are attached to the 3' end of the modified oligonucleotide.

36. Compound according to claim 33, characterized in that one or more TrkB ligands, one or more CBi ligands, or one or more α4β1 / 7 integrin ligands are attached to the 5' and 3' ends of the modified oligonucleotide.

37. Compound according to claim 33, characterized in that: one or more TrkB ligands are selected from any of Formulas I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXVXXXXXXVII and XXXXXXIX-XXXXXXXIII; one or more CBi ligands are selected from any of Formulas XXXXXXI and XXXXXXXIV-XXXXXXXVIII; and one or more α4β1 / 7 integrin ligands are selected from any of Formulas XXXXXXII-XXXXXXIV and XXXXXXXIXXXXXXXXXIV.

38. Compound, according to any one of claims 29 to 37, characterized in that the conjugated group comprises one or more lipids. Petition 870250116482, dated 12 / 17 / 2025, pp. 948 / 975 7 / 26 39. Compound according to claim 38, characterized in that the modified oligonucleotide is the second modified oligonucleotide.

40. Compound, according to claim 38 or 39, characterized in that one or more lipids are linked by an internucleosidic bond of the modified oligonucleotide.

41. Compound according to claim 40, characterized in that the internucleosidic linkage of the modified oligonucleotide is selected from any of Formulas XXXXXIII-XXXXXVI.

42. Compound, according to any one of claims 38 to 40, characterized in that the modified oligonucleotide comprises any one of Formulas XXXV-XXXXXVI.

43. Compound, according to any one of claims 32 to 42, characterized in that the modified oligonucleotide comprises one or more TrkB ligands, one or more CBi ligands or one or more α4β1 / 7 integrin ligands.

44. Compound according to claim 43, characterized in that the modified oligonucleotide comprises one or more TrkB ligands.

45. Compound according to claim 44, characterized in that one or more TrkB ligands are selected from any of Formulas I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII and XXXXXXIX-XXXXXXXIII.

46. ​​Compound according to claim 45, characterized in that one or more TrkB ligands are selected from any of Formulas XXIX-XXXI and XXXXXXV.

47. Compound, according to any one of claims 44 to 46, characterized in that Petition 870250116482, dated 12 / 17 / 2025, p. 949 / 975 8 / 26 modified oligonucleotide comprises one or two TrkB linkers.

48. Compound, according to any one of claims 44 to 46, characterized in that the modified oligonucleotide comprises at least two TrkB linkers.

49. Compound according to claim 48, characterized in that at least two TrkB ligands are the same.

50. Compound according to claim 48, characterized in that at least two TrkB ligands are different.

51. Compound according to claim 43, characterized in that the modified oligonucleotide comprises one or more CB1 ligands.

52. Compound according to claim 51, characterized in that one or more CB1 ligands are selected from either of Formulas XXXXXXI and XXXXXXXIVXXXXXXXVIII.

53. Compound according to claim 52, characterized in that one or more CB1 ligands are selected from any of the Formulas XXXXXXXIVXXXXXXXVI.

54. Compound, according to any one of claims 51 to 53, characterized in that the modified oligonucleotide comprises one or two CB1 linkers.

55. Compound, according to any one of claims 51 to 53, characterized in that the modified oligonucleotide comprises at least two CBi linkers.

56. Compound, according to claim 55, characterized in that at least two CB1 binders are the same. Petition 870250116482, dated 12 / 17 / 2025, pp. 950 / 975 9 / 26 57. Compound according to claim 55, characterized in that at least two CBi ligands are different.

58. Compound according to claim 43, characterized in that the modified oligonucleotide comprises one or more α4β1 / 7 integrin linkers.

59. Compound according to claim 58, characterized in that one or more α4β1 / 7 integrin ligands are selected from either of Formulas XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV.

60. Compound according to claim 59, characterized in that one or more α4β1 / 7 integrin ligands are selected from any of Formulas XXXXXXXXI, XXXXXXXXII and XXXXXXXXIV.

61. Compound, according to any one of claims 58 to 60, characterized in that the modified oligonucleotide comprises one or two α4β1 / 7 integrin linkers.

62. Compound, according to any one of claims 58 to 60, characterized in that the modified oligonucleotide comprises at least two α4β1 / 7 integrin linkers.

63. Compound according to claim 62, characterized in that at least two ligands of the α4β1 / 7 integrin are the same.

64. Compound according to claim 62, characterized in that at least two ligands of the α4β1 / 7 integrin are different.

65. Compound, according to any of the claims 44 to 64, characterized in that the modified oligonucleotide comprises one or more lipids.

66. Compound according to claim 65, characterized in that the modified oligonucleotide is the second modified oligonucleotide.

67. Compound, according to any one of claims 44 to 66, characterized in that the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups.

68. Compound according to claim 67, characterized in that one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C4-C30 hydrocarbon chain.

69. Compound according to claim 68, characterized in that one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C5-C20 hydrocarbon chain, optionally in that one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C14-C20 hydrocarbon chain.

70. Compound according to claim 69, characterized in that one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C16 hydrocarbon chain, a saturated or unsaturated C17 hydrocarbon chain, a saturated or unsaturated C18 hydrocarbon chain, or a saturated or unsaturated C22 hydrocarbon chain.

71. Compound, according to any one of claims 67 to 70, characterized in that one or more substituted or unsubstituted alkyl or alkenyl groups are linked to an internucleosidic bond of the modified oligonucleotide.

72. Compound according to claim 71, characterized in that the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 5' end of the modified oligonucleotide.

73. Compound according to claim 72, characterized in that the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the 5' end of the modified oligonucleotide.

74. Compound according to claim 71, characterized in that the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 3' end of the modified oligonucleotide.

75. Compound according to claim 74, characterized in that the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the 3' end of the modified oligonucleotide.

76. Compound, according to any one of claims 71 to 75, characterized in that the internucleosidic linkage of the modified oligonucleotide is selected from any one of Formulas XXXXXIII-XXXXXVI.

77. Compound, according to any one of claims 65 to 76, characterized in that the modified oligonucleotide comprises any one of the Formulas Petition 870250116482, dated 12 / 17 / 2025, page 953 / 975 12 / 26 XXXV-XXXXXVI.

78. Compound, according to any one of claims 1 to 6, characterized in that the modified oligonucleotide comprises a 5'-phosphonate modification.

79. A compound according to any one of claims 7 to 77, characterized in that the first modified oligonucleotide comprises a 5'phosphonate modification.

80. Compound according to claim 78 or 79, characterized in that the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification.

81. A compound characterized in that it comprises: a first modified oligonucleotide comprising a 5'-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1 or 2; and a second modified oligonucleotide comprising one or more ligands.

82. Compound according to claim 81, characterized in that the first modified oligonucleotide comprises a 5'-terminal nucleoside comprising the 5'-phosphonate modification.

83. Compound according to claim 81 or 82, characterized in that the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification.

84. Compound according to any one of claims 81 to 83, characterized in that the 5'-phosphonate modification is a 5'-vinylphosphonate modification.

85. Compound, according to any of the claims 81 to 83, characterized in that the 5'phosphonate modification is a 5'-ethylenephosphonate modification.

86. A compound according to any one of claims 81 to 85, characterized in that the second modified oligonucleotide comprises one or more ligands selected from one or more tropomyosin B (TrkB) receptor ligands, one or more cannabinoid receptor type 1 (CB1) ligands, and one or more α4β1 / 7 integrin ligands.

87. Compound according to claim 86, characterized in that one or more TrkB ligands, one or more CBi ligands, or one or more α4β1 / 7 integrin ligands are attached to the 5' end of the second modified oligonucleotide.

88. Compound according to claim 86, characterized in that one or more TrkB ligands, one or more CBi ligands, or one or more α4β1 / 7 integrin ligands are attached to the 3' end of the second modified oligonucleotide.

89. Compound according to claim 86, characterized in that one or more TrkB ligands, one or more CBi ligands, or one or more α4β1 / 7 integrin ligands are attached to the 5' and 3' ends of the second modified oligonucleotide.

90. Compound according to claim 86, characterized in that: one or more TrkB ligands are selected from any of Formulas I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXVXXXXXXVII and XXXXXXIX-XXXXXXXIII; one or more CB1 ligands are selected from any of Formulas XXXXXXI and XXXXXXXIV-XXXXXXXVIII; and one or more α4β1 / 7 integrin ligands are selected from any of Formulas XXXXXXII-XXXXXXIV and XXXXXXXIX. Petition 870250116482, dated 12 / 17 / 2025, page 955 / 975 14 / 26 XXXXXXXXIV.

91. Compound, according to any one of claims 81 to 90, characterized in that the second modified oligonucleotide comprises one or more TrkB ligands.

92. Compound according to claim 91, characterized in that one or more TrkB ligands are selected from any of Formulas I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXV-XXXXXXVII and XXXXXXIX-XXXXXXXIII.

93. Compound according to claim 92, characterized in that one or more TrkB ligands are selected from any of Formulas XXIX-XXXI and XXXXXXV.

94. Compound, according to any one of claims 91 to 93, characterized in that the second modified oligonucleotide comprises one or two TrkB linkers.

95. Compound, according to any one of claims 91 to 93, characterized in that the second modified oligonucleotide comprises at least two TrkB linkers.

96. Compound according to claim 95, characterized in that at least two TrkB ligands are the same.

97. Compound according to claim 95, characterized in that at least two TrkB ligands are different.

98. Compound, according to any one of claims 81 to 90, characterized in that the second modified oligonucleotide comprises one or more CB1 ligands.

99. Compound according to claim 98, characterized in that one or more CB1 binders are selected from any of Formulas XXXXXXI and XXXXXXXIV - Petition 870250116482, dated 12 / 17 / 2025, pp. 956 / 975 15 / 26 XXXXXXXVIII.

100. Compound according to claim 99, characterized in that one or more CBi ligands are selected from any of the Formulas XXXXXXXIVXXXXXXXVI.

101. Compound, according to any one of claims 98 to 100, characterized in that the second modified oligonucleotide comprises one or two CB1 linkers.

102. Compound, according to any one of claims 98 to 100, characterized in that the second modified oligonucleotide comprises at least two CB1 linkers.

103. Compound according to claim 102, characterized in that at least two CB1 linkers are the same.

104. Compound according to claim 102, characterized in that at least two CB1 linkers are different.

105. Compound, according to any one of claims 81 to 90, characterized in that the second modified oligonucleotide comprises one or more α4β1 / 7 integrin linkers.

106. Compound according to claim 105, characterized in that one or more ligands of the α4β1 / 7 integrin are selected from either of Formulas XXXXXXII-XXXXXXIV and XXXXXXXIX-XXXXXXXXIV.

107. Compound according to claim 106, characterized in that one or more ligands of the α4β1 / 7 integrin are selected from any of Formulas XXXXXXXXI, XXXXXXXXII and XXXXXXXXIV.

108. Compound, according to any of the claims 105 to 107 of Petition 870250116482, dated 12 / 17 / 2025, pp. 957 / 975 16 / 26, characterized in that the second modified oligonucleotide comprises one or two α4β1 / 7 integrin linkers.

109. Compound, according to any one of claims 105 to 107, characterized in that the second modified oligonucleotide comprises at least two α4β1 / 7 integrin ligands.

110. Compound according to claim 109, characterized in that at least two ligands of the α4β1 / 7 integrin are the same.

111. Compound according to claim 109, characterized in that at least two ligands of the α4β1 / 7 integrin are different.

112. Compound, according to any one of claims 81 to 111, characterized in that the second modified oligonucleotide comprises one or more lipids.

113. Compound, according to any one of claims 81 to 111, characterized in that the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups.

114. Compound according to claim 113, characterized in that one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C4-C30 hydrocarbon chain.

115. Compound according to claim 114, characterized in that one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C5-C20 hydrocarbon chain, optionally wherein one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C14-C20 hydrocarbon chain.

116. Compound according to claim 115, characterized in that one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C16 hydrocarbon chain, a saturated or unsaturated C17 hydrocarbon chain, a saturated or unsaturated C18 hydrocarbon chain, or a saturated or unsaturated C22 hydrocarbon chain.

117. Compound, according to any one of claims 113 to 116, characterized in that one or more substituted or unsubstituted alkyl or alkenyl groups are linked to an internucleoside bond of the second modified oligonucleotide.

118. Compound according to claim 117, characterized in that the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 5' end of the modified oligonucleotide.

119. Compound according to claim 118, characterized in that the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the 5' end of the second modified oligonucleotide.

120. Compound according to claim 117, characterized in that the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, positions 7 and 8, positions 8 and 9, positions 9 and 10, positions 10 and 11, positions 11 and 12, positions 12 and 13, or positions 13 and 14 of the 3' end of the modified oligonucleotide.

121. Compound according to claim 120, Petition 870250116482, dated 12 / 17 / 2025, pp. 959 / 975 18 / 26, characterized in that the internucleosidic linkage is between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 4 and 5, positions 5 and 6, positions 6 and 7, or positions 7 and 8 of the 3' end of the modified oligonucleotide.

122. Compound, according to any one of claims 117 to 121, characterized in that the internucleosidic linkage of the second modified oligonucleotide is selected from any one of Formulas XXXXXIII-XXXXXVI.

123. Compound, according to any one of claims 112 to 122, characterized in that the second modified oligonucleotide comprises any one of Formulas XXXV-XXXXXVI.

124. Compound, according to any one of claims 81 to 123, characterized in that the first modified oligonucleotide has from 14 to 30 nucleosides linked in length.

125. A compound according to any one of claims 81 to 124, characterized in that the second modified oligonucleotide has 14 to 30 nucleosides linked in length, having a region of complementarity to the first modified oligonucleotide.

126. A compound according to any one of claims 81 to 125, characterized in that the first modified oligonucleotide has a nucleobase sequence comprising at least 14 contiguous nucleobases of any one of the following SEQ ID NOs: 11-73, 144-147, 177-188, 190-192, 194-197, 199-200 and 209-217.

127. Compound, according to any one of claims 81 to 126, characterized in that the second modified oligonucleotide has a sequence of nucleobases comprising at least 14 contiguous nucleobases of any one of the SEQ ID Nos: 81-143, 149-155, 157, 159-168, 171-172, 174, 176 and 201-206.

128. Compound, according to any one of claims 81 to 127, characterized in that the first modified oligonucleotide is selected from any one of the reference ID numbers IA in Table 3.

129. Compound according to any one of claims 81 to 128, characterized in that the second modified oligonucleotide is selected from any one of the IS reference ID numbers in Table 3.

130. Compound characterized in that it comprises a first modified oligonucleotide selected from the group consisting of any of the reference ID numbers IA in Table 3, and a second modified oligonucleotide with 14 to 21 nucleosides linked in length that are fully complementary to the first modified oligonucleotide.

131. Compound characterized in that it comprises a first modified oligonucleotide selected from the group consisting of any of the IA reference ID numbers in Table 3, and a second modified oligonucleotide selected from the group consisting of any of the IS reference ID numbers in Table 3.

132. Compound characterized in that it comprises a first modified oligonucleotide selected from the group consisting of any of the IA reference ID numbers in Table 3 and / or a second modified oligonucleotide selected from the group consisting of any of the IS reference ID numbers in Table 3.

133. Compound, according to claim 130, 131 or Petition 870250116482, of 12 / 17 / 2025, pp. 961 / 975 20 / 26 132, characterized in that it comprises a conjugated group.

134. Compound according to claim 133, characterized in that the conjugated group is attached to the 5' end of the first or second modified oligonucleotide.

135. Compound according to claim 133 or 134, characterized in that the conjugate group comprises a directing fraction.

136. Compound according to claim 135, characterized in that the targeting fraction comprises one or more ligands selected from one or more tropomyosin B receptor (TrkB) ligands, one or more cannabinoid receptor type 1 (CBi) ligands, and one or more α4β1 / 7 integrin ligands.

137. Compound according to claim 136, characterized in that the modified oligonucleotide is the second modified oligonucleotide.

138. Compound according to claim 137, characterized in that one or more TrkB ligands, one or more CBi ligands, or one or more α4β1 / 7 integrin ligands are attached to the 5' end of the modified oligonucleotide.

139. Compound according to claim 137, characterized in that one or more TrkB ligands, one or more CB1 ligands, or one or more α4β1 / 7 integrin ligands are attached to the 3' end of the modified oligonucleotide.

140. Compound according to claim 137, characterized in that one or more TrkB ligands, one or more CB1 ligands, or one or more α4β1 / 7 integrin ligands are attached to the 5' and 3' ends of the modified oligonucleotide.

141. Compound according to claim 137, characterized in that: one or more TrkB ligands are selected from any one of Formulas I-XXXIV, XXXXXVII, XXXXXIX-XXXXXX, XXXXXXVXXXXXXVII and XXXXXXIX-XXXXXXXIII; one or more CBi ligands are selected from any of Formulas XXXXXXI and XXXXXXXIV-XXXXXXXVIII; and one or more α4β1 / 7 integrin ligands are selected from any of Formulas XXXXXXII-XXXXXXIV and XXXXXXXIXXXXXXXXXIV.

142. Compound, according to any of the preceding claims, characterized by being in a pharmaceutically acceptable salt form.

143. Compound according to claim 142, characterized in that the pharmaceutically acceptable salt is a sodium salt.

144. Compound according to claim 142, characterized in that the pharmaceutically acceptable salt is a potassium salt.

145. Composition characterized in that it comprises a modified compound or oligonucleotide, as defined and any of the preceding claims, and a pharmaceutically acceptable carrier.

146. Composition characterized in that it comprises a modified compound or oligonucleotide, as defined in any of the preceding claims, for use in therapy.

147. A method for treating, preventing, or improving a disease, disorder, or condition associated with MAPT in an individual, characterized by the fact that it comprises administering to the individual a compound targeted at MAPT, treating, preventing, or improving the disease, disorder, or condition.

148. Method characterized by the fact that it is intended to administer the modified compound or oligonucleotide, as defined in any of claims 1 to 144, or composition, as defined in claim 146, to an individual.

149. A method according to claim 147 or 148, characterized in that the disease, disorder or condition is a neurodegenerative disease, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy or Dravet syndrome.

150. A method, according to any one of claims 147 to 149, characterized in that administration of the compound inhibits, reduces, or improves a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, or Dravet syndrome.

151. A method for inhibiting MAPT expression in a cell, characterized in that it comprises contacting the cell with a compound targeting MAPT, thereby inhibiting MAPT expression in the cell.

152. Method according to claim 151, characterized in that the cell is located in the brain of an individual.

153. Method, according to claim 152, characterized in that the individual has, or is at risk of having, a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, or Dravet syndrome.

154. A method for reducing or inhibiting a neurodegenerative disease, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, or Dravet syndrome in an individual, characterized in that it comprises administering a compound targeting MAPT to the individual, thereby reducing or inhibiting a neurodegenerative disease, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, or Dravet syndrome in the individual.

155. A method according to claim 154, characterized in that the individual has, or is at risk of having, a neurodegenerative disease, including tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, or Dravet syndrome.

156. Method, according to any one of claims 147 to 155, characterized in that the compound is a MAPT-targeted compound.

157. Method according to any one of claims 147 to 156, characterized in that the modified compound or oligonucleotide is the modified compound or oligonucleotide as defined in any one of claims 1 to 144, or composition as defined in claim 146.

158. Method according to claim 157, Petition 870250116482, dated 12 / 17 / 2025, pp. 965 / 975 24 / 26, characterized in that the compound or composition is administered parenterally.

159. Method according to claim 157, characterized in that the compound or composition is administered by intrathecal administration.

160. Use of a compound targeting MAPT characterized by the fact that it is intended to treat, prevent or improve a disease, disorder or condition associated with MAPT.

161. Use, according to claim 160, characterized in that the disease, disorder or condition is a neurodegenerative disease, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy or Dravet syndrome.

162. Use, according to claim 160 or 161, characterized in that the compound is a compound targeted to MAPT.

163. Use, according to any one of claims 160 to 162, characterized in that the modified compound or oligonucleotide is the modified compound or oligonucleotide, as defined in any one of claims 1 to 144, or composition, as defined in claim 146.

164. Use of a compound targeting MAPT characterized by the fact that it is intended for the manufacture of a medicament to treat, prevent or improve a disease, disorder or condition associated with MAPT.

165. Use, according to claim 164, characterized in that the disease is a neurodegenerative disease, including a tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), Petition 870250116482, dated 12 / 17 / 2025, pp. 966 / 975 25 / 26 FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglion degeneration (CBD), epilepsy, or Dravet syndrome.

166. Use according to claim 164 or 165, characterized in that the compound is a compound targeted to MAPT.

167. Use, according to any one of claims 164 to 166, characterized in that the modified compound or oligonucleotide is the modified compound or oligonucleotide, as defined in any one of claims 1 to 144, or composition, as defined in claim 146.

168. Method or use, according to any of the preceding claims, characterized in that the compound or composition is administered to an individual approximately once every three months to approximately once a year.

169. Method or use, according to any of the preceding claims, characterized in that the composition or compound is administered to an individual approximately once every three months to approximately once a year.

170. Method for administering a therapeutic oligonucleotide to the brain of an individual, characterized in that it comprises administering a compound, or a stereoisomer, tautomer, prodrug or salt thereof, as defined in any one of claims 1 to 144, or composition, as defined in claim 146, to the individual.

171. Method according to claim 170, characterized in that the therapeutic oligonucleotide is administered to one or more selected brain regions from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal cortex, and spinal cord. Petition 870250116482, dated 12 / 17 / 2025, pp. 967 / 975 26 / 26 172. A method for treating or improving a disease, disorder or symptom thereof in an individual, characterized in that it comprises administering a compound, or a stereoisomer, tautomer, prodrug or salt thereof, as defined in any one of claims 1 to 144, or a composition, as defined in claim 146, to the individual.

173. Method according to claim 172, characterized in that the disease, disorder or symptom thereof is a disease, disorder or symptom of the central nervous system (CNS).

174. Method according to claim 172 or 173, characterized in that the disease, disorder or symptom thereof is Alzheimer's disease or a symptom thereof.

175. Method, according to any one of claims 170 to 174, characterized in that the administration is intrathecal or intracerebroventricular (ICV).

176. A method for administering one or more carrier molecules to a cell or tissue of an individual in vivo, characterized in that it comprises administering to the individual a compound, as defined in any one of claims 1 to 144, or a composition, as defined in claim 146.

177. Method according to claim 176, characterized in that the cell or tissue is a cell or tissue of the CNS.

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