TERAPIA GÊNICA COM PPT1

Abstract

The present invention features PPT1 polypeptides and encoding nucleic acid constructs. Uses of the polypeptides and encoding nucleic acid constructs include producing PPT1 polypeptides, increasing PPT1 activity in a subject; and treating a PPT1 related disorder, such as CLN1 disease in a subject.

Description

[001] This application claims priority over U.S. Provisional Application 63 / 491,205, filed March 20, 2023, U.S. Provisional Application 63 / 584,000, filed September 20, 2023, and U.S. Provisional Application 63 / 600,153, filed November 17, 2023, each of which is incorporated herein by reference in its entirety. REFERENCE TO THE LIST OF SEQUENCES SUBMITTED ELECTRONICALLY

[002] The content of the electronic sequence listing (065830.23WO1.xml; Size: 315,901 bytes; and Creation Date: March 8, 2024) is incorporated into this document by reference in its entirety. FUNDAMENTALS OF THE INVENTION

[003] Palmitoyl Protein Thioesterase 1 (PPT1) is a glycoprotein involved in the removal of fatty acyl groups attached to thioesters, such as palmitate protein. Full-length PPT1 contains 306 amino acids and includes a 27-amino acid signal sequence. Removal of the signal sequence produces mature PPT1. (Bellizzi et al., (2000) PNAS 97:9 4573-4578.)

[004] PPT1 is found in lysosomes, where it assists in the catabolism of lipid-modified proteins. PPT1 is also Petition 870250104513, dated 11 / 14 / 2025, page 9 / 242 2 / 212 found in other locations, such as synaptosomes, synaptic vesicles, blood, and cerebrospinal fluid (CSF). PPT1 is encoded by the CLN1 gene.

[005] Neuronal Ceroid Lipofuscinosis 1 (NCL1) is a progressive neurodegenerative disease resulting from reduced PPT1 activity. NCL1 can be caused by mutations that lead to suppression or reduction of PPT1 activity or expression, resulting in a deficiency in PPT1 lysosomal activity. As the disease progresses, symptoms may include epilepsy, seizures, motor and cognitive deterioration, visual impairment, behavioral disorders, sleep disturbances, and death. NCL1 is also known as CLN1, Batten disease, or Infantile Neuronal Ceroid Lipofuscinosis (INCL), and symptoms begin at around 12 to 18 months. In some cases, mutations in PPT1 may lead to a late onset of symptoms, such as late infantile (around 2 to 4 years), juvenile, or adult onset. NCL1 pathology can occur in different locations, including the brain and spinal cord. (Gorenberg et al.), (2022) PLos Biol. 20(3): e3001590; Simonati and Williams (2022) Front. Neurol. Mar 11;13:811686; Shyng et al., (2017) PNAS 114 (29) E5920E5929; and Bellizzi et al., (2000) PNAS 97(9):4573-4578). Petition 870250104513, dated 11 / 14 / 2025, p. 10 / 242 3 / 212

[006] References that mention potential enzyme replacement and gene therapy treatments for NCL1 include Nelvagal et al., (2022) J. Clin. Invest. 132(20);e163107; Griffey et al., (2004) Neurobiology of Disease 16: 360-369; Griffey et al., (2006) Molecular Therapy 13(3):538-547; Shyng et al., (2017) PNAS 114 (29) E5920-E5929; International Patent Publication WO2017 / 219450; and International Patent Publication WO2020 / 223322. BRIEF SUMMARY OF THE INVENTION

[007] The present invention discloses PPT1 polypeptides and encoding nucleic acid constructs. The PPT1 polypeptides described herein include polypeptides comprising an amino acid sequence of PPT1 and, in different embodiments, additionally comprising a signal sequence, wherein the mature PPT1 or the signal sequence is modified relative to those present in full-length natural human PPT1. PPT1-encoding constructs include nucleic acid sequences encoding PPT1 polypeptides with one or more differences relative to the mature or full-length sequence of naturally occurring human PPT1 and / or comprising a reduced CpG sequence. Uses of the polypeptides and encoding nucleic acid constructs include the production of PPT1 polypeptides; increasing PPT1 activity in an individual; and treating a disorder. Petition 870250104513, dated 11 / 14 / 2025, page 11 / 242 4 / 212 related to PPT1, such as CLN1 disease in an individual.

[008] Reference to a PPT1 polypeptide indicates the presence of a sequence related to the mature sequence and includes one or both full-length sequences comprising a signal sequence or a mature sequence that does not contain a signal sequence. The mature sequence may vary in size depending on the signal sequence and may be subject to further processing. The PPT1 polypeptide sequence may be naturally occurring or a modification of the naturally occurring sequence. Reference to full-length natural human PPT1 indicates SEQ ID NO: 29. The mature natural human PPT1 sequence is provided by SEQ ID NO: 1.

[009] Thus, a first aspect of the present invention describes a polynucleotide comprising a nucleic acid sequence encoding a palmitoylprotein thioesterase-1 (PPT1) polypeptide, wherein the PPT1 polypeptide comprises a PPT1 amino acid sequence with at least 95% identity to the SEQ ID NO: 1 sequence, wherein: (a) the PPT1 polypeptide additionally comprises a signal sequence of any of the SEQ IDs 16-27 or a variant thereof with an amino acid substitution, deletion or insertion; and / or (b) the amino acid sequence of PPT1 comprises a Petition 870250104513, dated 11 / 14 / 2025, p. 12 / 242 5 / 212 substitution of glycine (G), valine (V) or leucine (L) by aspartic acid (D) at its amino terminus; and / or (c) the PPT1 sequence comprises the amino acid sequence leucine-glutamine-histidine-leucine at its N terminus; and / or (d) the nucleic acid sequence comprises a sequence that encodes PPT1 with at least 85% identity to any of the SEQ ID NOs: 61-94.

[0010] The signal sequence of SEQ ID NOs: 16-27 provides signal sequences not present in the human PPT1 of full length of natural occurrence.

[0011] The reference to a substitution of glycine (G), valine (V) or leucine (L) by aspartic acid (D) at its amino terminus indicates that glycine (G), valine (V) or leucine (L) is present at the site corresponding to aspartic acid (D) in the mature native PPT1 sequence (SEQ ID NO: 1). [00 12] Another aspect of the present invention describes a PPT1 polypeptide comprising a PPT1 amino acid sequence with at least 95% identity to the SEQ ID NO: 1 sequence, wherein: (a) the PPT1 polypeptide additionally comprises a signal sequence of any of the SEQ IDs 16-27 or a variant thereof with an amino acid substitution, deletion or insertion; and / or Petition 870250104513, dated 11 / 14 / 2025, p. 13 / 242 6 / 212 (b) the amino acid sequence of PPT1 comprises a substitution of glycine (G), valine (V) or leucine (L) for aspartic acid (D) at its amino terminus; and / or (c) the PPT1 sequence comprises the amino acid sequence leucine-glutamine-histidine-leucine at its N terminus.

[0013] Another aspect of the present invention is directed to an expression cassette comprising a nucleic acid sequence encoding a PPT1 polypeptide and one or more expression control elements operationally coupled to the nucleic acid coding sequence.

[0014] The reference to one or more operationally linked or operationally coupled expression control elements to the nucleic acid encoding a PPT1 polypeptide indicates that the expression control element(s) impact(s) the expression of the PPT1 polypeptide. The expression of the PPT1 polypeptide can be impacted in different ways, such as increased production of PPT1 polypeptide mRNA transcripts, increased nuclear transport and stability of mRNA transcripts, and increased mRNA translation.

[0015] Another aspect of the present invention is directed to a recombinant viral vector nucleic acid comprising (a) an expression cassette comprising a sequence of Petition 870250104513, dated 11 / 14 / 2025, page 14 / 242 7 / 212 nucleic acid encoding a PPT1 polypeptide and one or more expression control elements operationally linked to the coding nucleic acid sequence and (b) 5' and / or 3' viral elements that provide viral packaging and / or replication.

[0016] Another aspect of the present invention is directed to a delivery vehicle comprising a viral or nonviral vector and (a) a PPT1 polypeptide or (b) a recombinant viral vector polynucleotide, expression cassette or nucleic acid comprising a sequence encoding a PPT1 polypeptide.

[0017] Another aspect of the present invention is directed to a pharmaceutical composition comprising (a) a PPT1 polypeptide; (b) a recombinant viral vector polynucleotide, expression cassette or nucleic acid comprising a sequence encoding a PPT1 polypeptide; or (c) an administration vehicle comprising (a) or (b); and a pharmaceutically acceptable carrier.

[0018] Another aspect of the present invention is directed to a method for increasing PPT1 activity, treating a PPT1 disease or disorder, or treating CLN1, in an individual, comprising administering: (a) a PPT1 polypeptide; (b) a recombinant viral vector polynucleotide, expression cassette or nucleic acid comprising a sequence encoding a PPT1 polypeptide; (c) a vehicle Petition 870250104513, dated 11 / 14 / 2025, page 15 / 242 8 / 212 of administration comprising (a) or (b); or (d) a pharmaceutical composition comprising (a), (b) or (c) and a pharmaceutically acceptable carrier.

[0019] Additional aspects of the present invention include: (a) a PPT1 polypeptide; (b) a recombinant viral vector polynucleotide, expression cassette or nucleic acid comprising a sequence encoding a PPT1 polypeptide; (c) an administration vehicle comprising (a) or (b); or (d) a pharmaceutical composition comprising (a), (b) or (c) and a pharmaceutically acceptable carrier; (a), (b), (c) or (d) for use in medicine, enhancing PPT1 activity, treating a PPT1 disease or disorder or treating CLN1 in an individual; and use of (a), (b), (c) or (d) in the preparation of a medicament (e.g., for use in medicine, enhancing PPT1 activity, treating a PPT1-related disorder or treating CLN1 in an individual).

[0020] Additional aspects of the present invention include vector genome plasmids comprising recombinant viral vector nucleic acid encoding a PPT1 polypeptide, methods for producing recombinant viral vector nucleic acid encoding a PPT1 polypeptide, and methods for obtaining a PPT1 polypeptide.

[0021] Other features and advantages of the present invention are evident from further descriptions. Petition 870250104513, dated 11 / 14 / 2025, page 16 / 242 9 / 212 provided in this document, including various examples. The examples provided illustrate different components and methodologies useful in the practice of the present invention. Such examples do not limit the claimed invention. Based on the present description, those skilled in the art may identify and employ other components and methodologies useful for the practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is a schematic of a rAAV PPT1 expression construct (or cassette), comprising different nucleic acid regions; 5' inverted terminal repeat (ITR), elongation factor-1 alpha (EF-1a) promoter, Kozak sequence, signal sequence (SS also referred to as signal peptide), mature PPT1 sequence (human PPT1), bovine growth hormone polyadenylation sequence (bGH-pA), filler sequence, synthetic polyadenylation sequence (synthetic pA) and 3'-ITR.

[0023] Figures 2A and 2B are bar graphs illustrating the levels of PPT1 enzyme activity in HeLa cells with inactivated PPT1 and transfected with rAAV plasmids containing different engineered human PPT1 constructs. PPT1 activity is expressed as a percentage of PPT1 activity from PPT1 with its Petition 870250104513, dated 11 / 14 / 2025, page 17 / 242 10 / 212 native signal peptide in total cell lysates (Figure 2A) and in cell culture supernatants (secreted PPT1) (Figure 2B). The reference to Dead indicates a mutated PPT1 with no enzymatic activity.

[0024] Figures 3A-3C illustrate a PPT1 / tdTomato nucleic acid reporter plasmid from rAAV and the results obtained using the plasmid to evaluate PPT1 secretion from transfected cells. Figure 3A shows different nucleic acid regions of rAAV and tdTomato regions. Figure 3B provides a bar graph showing the ratio between the number of cells with PPT1 and the number of cells transfected with the PPT1 / tdTomato reporter plasmid. Figure 3C provides a bar graph showing the results of Figure 3B, normalized to the native construct. For both Figures 3B and 3C, each point (light circle; average of 30 fields) is an independent transfection (2 to 3 experiments), and the values ​​are mean + SD. P-values ​​by one-way ANOVA, ****p < 0.0001, ***p < 0.001, **p < 0.01.

[0025] Figure 4 illustrates the dose- and time-dependent increase in PPT1 activity detected in the middle of primary cortical neurons of rats transduced with rAAV comprising Sp7-F.PPT1. Cultured neurons were transduced with three multiplicities of infection (MOI) (low, 1E+5; medium, 5E+5 and high, 1E+6) and the activity of Petition 870250104513, dated 11 / 14 / 2025, page 18 / 242 11 / 212 PPT1 in culture medium was analyzed 3, 4, or 6 days after transduction. Dead PPT1 refers to catalytically inactive PPT1. Untreated or diluent-treated cells served as negative controls. Purified recombinant PPT1 was used as a positive control for the assay. Each circle represents the values ​​of independently transduced cells in a single well. Data are mean ± SD.

[0026] Figures 5A, 5B, and 5C illustrate the serum expression and activity of PPT1 at different time points in mice dosed with rAAV comprising Sp7-F viral vector nucleic acid. Figure 5A illustrates the production of PPT1 glycosylated activity in the serum of mice dosed intravenously (IV). Figure 5B shows the serum activity of PPT1 from mice dosed intravenously. Figure 5C shows the serum activity from mice dosed intraparenchymally (IPa) (administered intraparenchymally in the hippocampus by stereotaxic injection). ND, not detected. Data are mean ±SD. P-values ​​by ANOVA *p < 0.05, ***p < 0.001, ****p < 0.0001.

[0027] Figure 6 illustrates the hepatic PPT1 activity of mice intravenously dosed with rAAV containing Sp7-F.PPT1 viral vector nucleic acid. Mice injected with diluent acted as negative controls.

[0028] Figure 7 illustrates an immunohistochemical analysis showing increased PPT1 staining. Petition 870250104513, dated 11 / 14 / 2025, page 19 / 242 12 / 212 (indicated by a black asterisk) in the hippocampus of a mouse after hippocampal administration of rAAV containing nucleic acid from the Sp7-F.PPT1 viral vector.

[0029] Figure 8 provides an automated capillary immunoassay (JESS, ProteinSimple) analysis demonstrating the glycosylation of overexpressed PPT1 in the brain of mice. Recombinant AAV containing nucleic acid from the Sp7-F.PPT1 viral vector or diluent was administered to the hippocampus (four mice per group).

[0030] Figure 9 provides an automated capillary immunoassay (JESS, ProteinSimple) analysis of hippocampal protein extract, untreated (-) or treated (+) with deglycosylase, from two different mice, after administration of rAAV containing Sp7-F.PPT1 viral vector to the hippocampus. The reduction in molecular weight after deglycosylase treatment (bands marked with +) suggested that PPT1 was glycosylated.

[0031] Figure 10 illustrates the PPT1 activity assay in mouse hippocampal lysate, showing PPT1 expression in the mouse brain. A recombinant AAV containing nucleic acid from the Sp7-F.PPT1 viral vector was administered to the hippocampus.

[0032] Figure 11 presents bar charts illustrating the vector genome copy number (VGCN) as an indicator of Petition 870250104513, dated 11 / 14 / 2025, page 20 / 242 13 / 212 viral transduction in different brain regions. Total DNA from frozen tissue was isolated and VGCN was quantified by quantitative PCR (qPCR) using a standard curve. Each circle represents data from one mouse. The height of each bar shows the average. Hpc, hippocampus; Br. Stem, brainstem; crblm, cerebellum; Cerv, cervical spinal cord; Thor, thoracic spinal cord; lumb, lumbar spinal cord. Mice dosed with diluent served as a negative control.

[0033] Figure 12 presents bar graphs showing the fold change (FC) in PPT1 activity in different brain and spinal cord regions of animals injected with rAAV compared to mice injected with diluent. PPT1 activity in tissue lysate was quantified using 4-methylumbelliferyl-6-thiopalmitoyl-ε-glucopyranoside (MUTG) as substrate. A standard curve (prepared using known concentrations of 4 MU) was used to determine PPT1 activity. FC activity was calculated relative to the mean activity of animals injected with diluent. Each circle is the result for one mouse. Data are Mean ± SD. One-way ANOVA, Tukey test, *p < 0.05, ***p < 0.001, ****p < 0.0001.

[0034] Figure 13 presents bar diagrams illustrating the FC in PPT1 activity in the liquid. Petition 870250104513, dated 11 / 14 / 2025, page 21 / 242 14 / 212 cerebrospinal fluid (CSF) of mice injected with rAAV compared to those injected with the diluent. FC is relative to the mean activity level of the diluent group. Each data point in the graph represents data from a single mouse. Data are expressed as Mean ± SD. Statistical analysis involved a one-way ANOVA followed by Tukey's test. *p < 0.05.

[0035] Figure 14 is a scatter plot illustrating the correlation between VGCN and PPT1 enzyme activity in the brain. Spearman's correlation coefficient was r = 0.066, p < 0.0001. Each circle represents data from a brain region of mice dosed with rAAV.

[0036] Figure 15 shows the detection of glycosylated and deglycosylated PPT1 protein in brain lysate analyzed by JESS. Protein extract from brain lysate of the cortex of two independent mice (mouse 1: lanes 1 and 3; mouse 2: lanes 2 and 4) to which rAAV comprising Sp7-F was administered. PPT1 was treated with deglycosylase and analyzed by the JESS assay. The doublet observed in lanes 1-2 indicates two glycosylated forms of PPT1. The reduced molecular weight after treatment with deglycosylase (lanes 3-4) suggests that PPT1 was glycosylated.

[0037] Figures 16A-16H are bar diagrams representing the vector genome copy number (VGCN) as a measure of viral transduction, in various regions: areas Petition 870250104513, dated 11 / 14 / 2025, page 22 / 242 15 / 212 cortical areas (FIG. 16A); thalamus (FIG. 16B); cerebellar cortex (FIG. 16C); hippocampus (FIG. 16D); corpus callosum (FIG. 16E); additional indicated brain areas (FIG. 16F); spinal cord (FIG. 16G); and liver (FIG. 16H). Quantitative PCR (qPCR) using a standard curve was employed to quantify VGCN from frozen tissue DNA. Each data point represents a single sheep. Vertical arrows indicate the sample from the contralateral brain region (compared to the injection side). Open circles correspond to sheep dosed with rAAV comprising Sp7-F.PPT1, while filled circles represent results from sheep dosed with a vector expressing GFP.Data are provided for the following regions: Frontal Cortex (FC), Motor Cortex (MC), Somatosensory Cortex (SSC), Piriform Cortex (PC), Suprasylvian Gyrus (SSG), Ectolateral Gyrus (EcG), Entolateral Gyrus (EnG), Caudate (Cau), Choroid Plexus (Ch Ple), Optic Chiasm (Opt chi), Fornix (For), Periaquaductal Gray Matter (Periaq G), Olfactory Bulb (Ol), Optic Nerve (Op nerve), Hippocampus (HPC), Thalamus (Tha), Corpus Callosum (Cca), Cerebellar Cortex (Cer ctx), Cervical Spinal Cord (SC_Cer), Thoracic Spinal Cord (SC_Tho), and Lumbar Spinal Cord (SC_Lum).

[0038] Figures 17A-17D are bar diagrams showing the expression and functional secretion of PPT1 in the brain and CSF of sheep injected with rAAV comprising the Petition 870250104513, dated 11 / 14 / 2025, page 23 / 242 16 / 212 Sp7-F transgenes.PPT1 (n = 4 sheep) or GFP (n = 2 sheep). Figure 17A is a bar chart illustrating PPT1 activity in the cortex. Figure 17B is a bar chart illustrating PPT1 activity in the thalamus. Figure 17C is a bar chart illustrating PPT1 activity in the cerebellar cortex. Figure 17D is a bar chart illustrating PPT1 activity in the caudate nucleus. PPT1 activity in tissue lysate was quantified using 4-methylumbelliferyl-6-thiopalmitoyl-ε-glucopyranoside (MUTG) as a substrate. Each circle is the result of a tissue puncture of the brain region. N denotes the number of regions from 2 animals dosed with GFP and 4 from animals dosed with PPT1. Data are Mean ± SEM. Statistical analysis using the Mann-Whitney U test, *p < 0.05, ***p < 0.001.

[0039] Figure 18 provides 95% confidence intervals showing the mean PPT1 activity by overall treatment group. After obtaining the logarithm-transformed activity results of all data in Figures 17A-17D and considering the number of perforations and differences in brain regions at the mean value, a hypothesis test for the mean difference of Treatment Type was conducted at the alpha level of 0.05. The estimated mean change in PPT1 relative to GFP was 3.9, with medians of 73 nmols / mg / h for PPT1 vs. 19 nmols / mg / h for GFP. ****p < 0.0001, 2-way weighted ANOVA. Petition 870250104513, dated 11 / 14 / 2025, p. 24 / 242 17 / 212

[0040] Figure 19 is a bar chart showing the percentage change in PPT1 activity in the cerebrospinal fluid (CSF) of sheep dosed with rAAV containing Sp7-F.PPT1 (n = 4 sheep) or GFP (n = 2 sheep). The percentage change is relative to the mean activity of the control (GFP animals). Each circle represents an animal. N denotes the number of animals. Data are Mean ± SEM.

[0041] Figure 20 shows the result of a JESS assay that detects recombinant PPT1 expression in spinal cord tissue lysate from sheep injected with an rAAV vector containing PPT1 (sheep 1-4) or GFP (sheep 1-2). The first band shows the position of the molecular weight pattern (dp). Although protein bands likely representing sheep PPT1 were observed in all individuals, bands for human PPT1 were identifiable only in animals treated with a vector encoding human PPT1. The abbreviations C, T, and L indicate the cervical, thoracic, and lumbar segments of the spinal cord, respectively. kDa, kilodalton.

[0042] Figure 21 illustrates results showing a high level of mean PPT1 activity in the thoracic and lumbar spinal cord segments of sheep dosed with the PPT1-carrying vector. Each circle represents the result for the spinal cord segment of an animal. Data are Mean ± SEM. Petition 870250104513, dated 11 / 14 / 2025, p. 25 / 242 18 / 212

[0043] Figure 22 is a bar chart illustrating a rotarod assessment of knockout (KO) mice for PPT1 dosed with rAAVV (1E+11 vg / animal) comprising Sp7-F.PPT1 (1) or SPARC.PPT1 (2). KO mice were dosed with rAAV via bilateral ICV injection on postnatal day 1 and assessed at 7 months of age. Untreated (Un) or vehicle-treated (Veh) KO mice acted as negative controls. Native refers to the rAAV vector encoding native human PPT1. Each circle represents a mouse. Bars are mean + SEM. One-way ANOVA, Tukey post hoc test, *p < 0.05, ***p < 0.001, ****p < 0.0001.

[0044] Figure 23 illustrates the ability of rAAV-Sp7F.PPT1 and rAAV-SPARC.PPT1 to improve motor coordination and balance, as assessed by the latency to fall from an acceleration rod in Ppt1- / - (KO) mice. Values ​​are mean + SEM. One-way ANOVA, Tukey's post-hoc test. ####p < 0.0001, WT, 7 months vs KO, Un, 7 months; KO, Veh, 7 months. ****p < 0.0001, KO, Veh, 7 months vs all dosed groups except rAAV-Sp7-F.PPT1, high at 9 months. **p < 0.005, KO, Veh, 7 months vs rAAV-Sp7-F.PPT1, high at 9 months. AAV (adeno-associated virus) = adeno-associated virus; ANOVA (analysis of variance) = analysis of variance; CNS - central nervous system; lo (low dose) = low dose (1 x 1011vg / animal); hi (high dose) = high dose (3.82 x 1011vg / animal); KO = Petition 870250104513, dated 11 / 14 / 2025, p. 26 / 242 19 / 212 Ppt1- / -; mo (from the English months) = months; PND (from the English post natal day) = postnatal day; seg = seconds; SEM (from the English Standard error of mean) = standard error of the mean; Un (from the English untreated) = untreated; Veh (from the English vehicle) = vehicle; WT (from the English wild type) = wild type.

[0045] Figure 24 illustrates the effect of rAAV-Sp7-F.PPT1 and rAAV-SPARC.PPT1 on grip strength in Ppt1 / - (KO) mice. Values ​​are mean + SEM. One-way ANOVA, Tukey post-hoc test. #####p < 0.0001, WT, 7 months vs KO, Un, 7 months; KO, Veh, 7 months. ****p < 0.0001, KO, Veh, 7 months vs all treated groups. AAV = adeno-associated virus; ANOVA = analysis of variance; CNS = central nervous system; lo = low dose (Ix1011vg / animal); hi = high dose (3.82x1011 vg / animal); KO = Ppt1- / -; mo = months; PND = postnatal day; seg = seconds; SEM = standard error of the mean; Un = untreated; Veh = vehicle; WT = wild type.

[0046] Figures 25A and 25B illustrate serum PPT1 activity in mice administered rAAV-Sp7-F.PPT1 or rAAV-SPARC.PPT1. Figure 25A illustrates activity at different time points. Figure 25B illustrates activity at 8 months. In each group, the number of mice ranged from 11 to 18. The gender distribution was approximately balanced in each group. Each circle represents a result from a mouse. Each point in Figure 25A and each bar in Figure 25B shows mean + SEM. One-way ANOVA, Petition 870250104513, dated 11 / 14 / 2025, page 27 / 242 20 / 212 Tukey post hoc test performed on Log10 transformed value. ####p < 0.0001, WT vs KO, Un; WT vs KO Veh; **p < 0.01, KO, Veh vs Nativo, lo; ***p < 0.001, KO, Veh vs rAAV-SPARC.PPT1, lo; ***p < 0.0001, KO, Veh vs rAAV- Sp7-F.PPT1, lo; Native, hi; rAAV- Sp7-F.PPT1, hi; rAAV-SPARC.PPT1, hi. AAV = adeno-associated virus; ANOVA = analysis of variance; lo = low dose (IxIO11vg / animal); hi = high dose (3.82x1011 vg / animal); KO = Ppt1- / -; mo = months; LLOQ (from the English "lower limit of quantification") = lower limit of quantification; PND = postnatal day; sec = seconds; DP = standard deviation; Un = untreated; Veh = vehicle; WT = wild type.

[0047] Figures 26A-C provide bar charts showing PPT1 activity in the cortex (Figure 26A), brainstem (Figure 26B), and cerebellum (Figure 26C) of Ppt1- / - mice injected with rAAV-Sp7-F.PPT1 or rAAVSPARC.PPT1. Mice were dosed via bilateral intracerebroventricular injections into PND 1. Native refers to AAV vectors containing the unmodified human PPT1 gene. Bars are mean ± SEM. Each circle represents a mouse.

[0048] Figure 27 is a diagram showing the design of a nucleic acid from rAAV, present in a plasmid. The expression of the human PPT1 sequence is driven by a longer version of the EF1a promoter (SEQ ID NO: 173). SS = Signal sequence. Petition 870250104513, dated 11 / 14 / 2025, p. 28 / 242 21 / 212

[0049] Figures 28A and 28B are bar graphs representing PPT1 expressed in HeLa knockout cells for PPT1 transfected with different AAV plasmids carrying codon-optimized PPT1 sequences. Different codon-optimized PPT1 cDNA constructs (excluding the signal sequence), labeled CO followed by the number on the x-axis, were paired with signal sequences. Figure 28A represents Sp7F or SP7F (codon-optimized). Figure 28B represents SpSPARC or SpSPARC (codon-optimized).

[0050] Figure 29 presents survival curves that illustrate the ability of gene therapy with CNS-targeted AAV, which releases functional human PPT1 in Pptl- / - mice, to prolong survival.

[0051] Figure 30 is a bar chart illustrating the effect of rAAV, comprising nucleic acid encoding Sp7F.PPT1 or SPARC.PPT1, on brain weight in Ppt1- / - mice. Mean ± SD. ***p < 0.0001, one-way ANOVA, Tukey post-hoc test. AAV = adeno-associated virus; CNS = central nervous system; lo = low dose (1x1011 vg / animal); hi = high dose (3.82x1011 vg / animal); KO = Ppt1- / -; PND = postnatal day; Un = untreated; Veh = vehicle; WT = wild type. DETAILED DESCRIPTION OF THE INVENTION

[0052] The present invention discloses PPT1 polypeptides and nucleic acid constructs encoding PPT1 polypeptides. The polypeptides and nucleic acid constructs Petition 870250104513, dated 11 / 14 / 2025, p. 29 / 242 The 22 / 212 encoding molecules can be used, for example, to produce PPT1 polypeptides, increase PPT1 activity in an individual, and / or treat a PPT1-related disease or disorder, such as CLN1.

[0053] Polynucleotides encoding a PPT1 polypeptide can be administered to an individual via viral or nonviral administration. Viral vectors that can be used include retroviral vectors, adenovirus vectors, AAV vectors, and herpes simplex viral vectors. Nonviral administration includes pure DNA and the use of nanoparticles.

[0054] The reference to individual indicates a mammal, such as a human being; a non-human primate, such as a monkey, gibbon, gorilla, chimpanzee, orangutan, and ape; a domestic animal, such as a dog and cat; farm animals, such as birds, ducks, horses, cows, goats, sheep, and pigs; and experimental animals, such as mice, rats, rabbits, sheep, and guinea pigs. A preferred individual is a human being.

[0055] In certain embodiments, PPT1 polypeptides or nucleic acid constructs encoding the PPT1 polypeptide are evaluated for PPT1 expression and efficacy using an ovine model. (See, for example, Nelvagal et al., (2022) J. Clin. Invest. 132(20);e163107, incorporated herein by full reference; and the Examples section provided below.) Petition 870250104513, dated 11 / 14 / 2025, page 30 / 242 23 / 212

[0056] Reference to a percent identity indicated with one or more reference sequences, and similar language throughout the descriptive report that provides a percent identity indicated with one or more reference sequences, provides the indicated percent identity or percent identity range independently of each of the referenced sequences. When determining the percent identity of a polynucleotide, the corresponding RNA and DNA are considered the same unless the context employed indicates otherwise, for example, when providing reference to the polynucleotide as RNA or DNA. Corresponding RNA and DNA include uracil substitution for thymine and ribose structure for deoxyribose structure.

[0057] The reference to a percentage of identical, identity, and similar terminology refers to two sequences with maximum alignment in a specific area. The area provided refers to the indicated reference sequence. For example, the identical or identity sequence to a PPT1 polypeptide of SEQ ID NO: 1 can be calculated by determining the number of identical amino acids in aligned sequences, dividing by the total number of amino acids in SEQ ID NO: 1 (279 amino acids), and multiplying by 100. The percentage of identical or identity for nucleic acid sequences can be Petition 870250104513, dated 11 / 14 / 2025, p. 31 / 242 24 / 212 is determined in an analogous manner, where the nucleotides in the reference sequence are aligned to achieve maximum alignment, taking into account the differences and gaps in nucleotides, dividing by the total number of nucleotides in the reference sequence and multiplying by 100.

[0058] The identity percentage or identity for a PPT1 encoding sequence indicated as comprising two or more exons is determined independently of any intron. For calculation purposes, the intron(s) is / are removed prior to alignment.

[0059] When determining sequence identity with a reference sequence with one or more indicated variations, the specific variation chosen to determine sequence identity is the one that provides the highest sequence identity. For example, SEQ ID NO: 2 provides that X is G, V, or L; and for the purposes of determining sequence identity with SEQ ID NO: 2, the X selected to determine sequence identity is the one that provides the highest sequence identity.

[0060] The terms “nucleic acid” and “polynucleotide” are used interchangeably in this document to refer to all forms of nucleic acid, oligonucleotides, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). When discussing nucleic acids, a Petition 870250104513, dated 11 / 14 / 2025, p. 32 / 242 25 / 212 The sequence or structure of a specific polynucleotide can be described in this document according to the convention that provides the sequence in the 5' to 3' direction.

[0061] In certain embodiments, nucleic acids include genomic DNA, cDNA, antisense DNA / RNA, plasmid DNA, linear DNA (poly- and oligonucleotide), chromosomal DNA, mRNA with or without splicing, rRNA, tRNA, inhibitory DNA or RNA (RNAi, for example, small or short hairpin RNA (sh), microRNA (miRNA), small or short interfering RNA (si), transsplicing RNA or antisense RNA), locked nucleic acid analog (LNA), single- and double-stranded oligonucleotide DNA (ODN), immunostimulatory sequence (ISS), riboswitches and ribozymes.

[0062] In certain embodiments, nucleic acids include naturally occurring, synthetic, and intentionally modified or altered polynucleotides. Nucleic acids can be single, double, or triplex, linear or circular, and can have different lengths.

[0063] According to certain embodiments, the polynucleotide is a single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA) molecule. According to certain embodiments, the dsDNA molecule is a minicircle, a nanoplasmid, an open linear duplex DNA, or a closed-end linear duplex DNA (CELiD / ceDNA / DNA doggybone). According to certain embodiments, the ssDNA molecule is a circular DNA. Petition 870250104513, dated 11 / 14 / 2025, p. 33 / 242 26 / 212 closed or linear open.

[0064] A transgene refers to a nucleic acid that is intended or has been introduced into a cell and operationally linked to a promoter. Transgenes include a heterologous polynucleotide sequence, such as a nucleic acid encoding a PPT1 polypeptide, and a heterologous promoter.

[0065] Certain embodiments are targeted at reduced CpG or depleted CpG. Reduced CpG or depleted CpG refers to (i) a nucleotide sequence in which one or more CpG dinucleotides (or motifs) are removed from a reference nucleic acid sequence; and / or (ii) the percentage of CpGs in a reference polynucleotide is from 0% to 15%. In different embodiments, the percentage of CpGs is 0%, about 0.5%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14% or about 15% of CpGs; and / or up to about 0.5%, up to about 1.0%, up to about 2.0%, up to about 3.0%, up to about 4.0%, up to about 5.0%, up to about 6%, up to about 7%, up to about 8%, up to about 9%, up to about 10%, up to about 11%, up to about 12%, up to about 13%, up to about 14% or up to about 15% of CpGs.

[0066] CpG reasons can be adequately reduced Petition 870250104513, dated 11 / 14 / 2025, p. 34 / 242 27 / 212 or deleted in a nucleotide sequence encoding a PPT1 protein and in other sequences that may be present in specific constructs (e.g., expression cassettes and viral vectors). Other sequences that may be present include non-coding sequences such as 5' and 3' untranslated regions (UTRs), filler sequences, promoters, enhancers; polyadenylation signal, ITRs, and introns.

[0067] The singular forms um, uma, oea include reference to the plural, unless the context clearly indicates otherwise.

[0068] The conjunctive term and / or between multiple cited elements includes individual and combined options. For example, when two elements are joined by and / or, a first option refers to the applicability of the first option without the second, a second option refers to the applicability of the second option without the first, and a third option refers to the applicability of the first and second options together. It is understood that any of the options falls within the meaning and therefore satisfies the requirement of the term and / or. The simultaneous applicability of more than one of the options also falls within the meaning of the term and / or.

[0069] Unless clearly indicated otherwise by the context used, the terms or and have the same meaning as and / or. Petition 870250104513, dated 11 / 14 / 2025, p. 35 / 242 28 / 212

[0070] References to terms such as including, “for example”, as an example, such as, followed by different members or examples, are open descriptions, in which the listed members or examples are illustrative and other members or examples may be provided or used.

[0071] The terms polypeptide, protein, and peptide can be used interchangeably to refer to a sequence of amino acids, regardless of function. Polypeptides and peptides contain at least two amino acids, while proteins contain at least about 10 amino acids. Amino acids include naturally occurring amino acids and amino acids provided by cellular modification.

[0072] The reference to comprehend and variations such as comprehends and comprehending, used in relation to an element or group of elements, is open-ended and does not exclude additional elements or steps of the method not mentioned. Terms such as including, containing, and distinguished by are synonymous with comprehending. In the different aspects and modalities described in this document, the reference to an open-ended term, such as comprehending, may be replaced by consisting of or essentially consisting of.

[0073] The reference to "consisting of" excludes any element, step or ingredient not specified in the listed elements of the claim, where such element, Petition 870250104513, dated 11 / 14 / 2025, page 36 / 242 29 / 212 step or ingredient is related to the claimed invention.

[0074] The reference to “consisting essentially of” limits the scope of a claim to the materials or steps specified and to those that do not materially affect the basic and novel feature(s) of the claimed invention.

[0075] The term “about” refers to a value within 10% of the underlying parameter (i.e., plus or minus 10%). For example, “about 1:10” includes 1.1:10.1 or 0.9:9.9, and “about 5 hours” includes 4.5 hours or 5.5 hours. The term “about” at the beginning of a sequence of values ​​modifies each of the values ​​by 10%.

[0076] All numerical values ​​or numerical ranges include whole numbers within those ranges and fractions of the values ​​or whole numbers within the ranges, unless the context clearly indicates otherwise. Thus, to illustrate, reference to a reduction of 95% or more includes 95%, 96%, 97%, 98%, 99%, 100%, as well as 95.1%, 95.2%, 95.3%, 95.4%, 95.5%, etc., 96.1%, 96.2%, 96.3%, 96.4%, 96.5% and so forth, and reference to a numerical range, such as “1-4”, includes 1, 2, 3, 4, as well as 1.1, 1.2, 1.3, 1.4 and so forth. As a further illustration, “1 to 4 weeks” includes 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28. Petition 870250104513, dated 11 / 14 / 2025, p. 37 / 242 30 / 212 days.

[0077] Additionally, reference to a numerical range, such as “0.01 to 10”, includes 0.011, 0.012, 0.013 etc., as well as 9.5, 9.6, 9.7, 9.8, 9.9 and so forth. For example, a dosage of approximately “0.01 mg / kg to approximately 10 mg / kg” of an individual’s body weight includes 0.011 mg / kg, 0.012 mg / kg, 0.013 mg / kg, 0.014 mg / kg, 0.015 mg / kg etc., as well as 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg and so forth.

[0078] A reference to an integer with more (greater) or less that includes numbers greater or less than the reference number, respectively. Thus, for example, a reference to more than 2 includes 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more; and the administration “two or more” times includes 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more times.

[0079] Various references, including articles and patent publications, are cited or described in the context and throughout the descriptive report. Each of these references is incorporated herein by reference in its entirety. None of the references is admitted as prior art in relation to any inventions described or claimed. In some cases, specific references are indicated as incorporated by reference in this document to emphasize the incorporation. Petition 870250104513, dated 11 / 14 / 2025, page 38 / 242 31 / 212

[0080] The definitions provided in this document, including those in this section and other sections of the application, apply to the entire application.

[0081] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning commonly understood by those skilled in the art to whom this invention belongs.

[0082] The description has been separated into several sections and paragraphs and provides examples of various embodiments. These separations should not be considered as a disconnection of the substance of one paragraph, section, or embodiment from the substance of another paragraph, section, or embodiment. The descriptions provided have broad application and include all combinations of the various sections, paragraphs, and sentences that may be contemplated. The discussion of any embodiment is intended only to exemplify and not to suggest the scope of the description, including the claims (unless otherwise stated in the claims), and is limited to these examples.

[0083] The present invention is described in this document in a general way, using affirmative language to describe the numerous embodiments of the present invention. The present invention also specifically includes embodiments in which a particular subject matter is excluded, in whole or in part, such as substances or materials, steps and conditions of the method, Petition 870250104513, dated 11 / 14 / 2025, p. 39 / 242 32 / 212 protocols or procedures. For example, in certain embodiments of the present invention, materials and / or method steps are excluded. Thus, although the present invention is not generally expressed in this document in terms of what the present invention does not include, embodiments that are not expressly excluded in the present invention are nevertheless described in this document. I. Polypeptide PPT1

[0084] PPT1 polypeptides comprise an amino acid sequence of PPT1 with at least 95% identity to the sequence of SEQ ID NO: 1. In certain embodiments, the polypeptide comprises an amino acid sequence of PPT1 with at least 95% identity to the sequence of SEQ ID NO: 1, wherein: (a) the PPT1 polypeptide additionally comprises a signal sequence of any of the SEQ ID NOs: 16-27 or a variant thereof with an amino acid substitution, deletion or insertion; and / or (b) the PPT1 amino acid sequence comprises a substitution of G, V or L for D at its amino terminus; and / or (c) the PPT1 sequence comprises the leucine-glutamine-histidine-leucine amino acid sequence at its N-terminus. SEQ ID NO: 38 is an example of a full-length polypeptide where the region corresponding to the mature human sequence has a leucine-glutamine-histidine-leucine appended to the N-terminus of the naturally occurring sequence. Petition 870250104513, dated 11 / 14 / 2025, page 40 / 242 33 / 212

[0085] In certain embodiments, a mature sequence contains a deletion at its N-terminus. SEQ ID NO: 37 is an example of a full-length sequence where the mature sequence exhibits an aspartic acid-proline-prolinealanine deletion at the N-terminus of the naturally occurring sequence.

[0086] In certain embodiments, the PPT1 polypeptide comprises an amino acid sequence of PPT1 with at least 96%, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 1.In further embodiments, the polypeptide PPT1 comprises an amino acid sequence of PPT1 with at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 2, and X is glycine; the polypeptide PPT1 comprises an amino acid sequence of PPT1 with at least 96%, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 2, and X is valine; the polypeptide PPT1 comprises an amino acid sequence of PPT1 with at least 96%, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 2, and X is leucine; The PPT1 polypeptide comprises an amino acid sequence of PPT1 with at least 96% identity. Petition 870250104513, dated 11 / 14 / 2025, page 41 / 242 34 / 212 less than 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 3; or the polypeptide PPT1 comprises an amino acid PPT1 comprising the amino acid sequence leucine-glutamine-histidine-leucine in its N-terminal sequence and with at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 4.

[0087] PPT1 is a well-distinguished enzyme, where different amino acids responsible for activity and different mutations resulting in decreased activity are well known. (See, for example, Kumar et al., Advances in Protein Chemistry and Structural Biology (2022) 132:89-109; Bellizzi et al., PNAS (2000) 97(9):4573-4578, and hyperlink: / / www.uniprot.org / uniprotkb / P50897 / entry (December 3, 2022), each of which is incorporated herein by reference in full).

[0088] A signal sequence provides the amino acid sequence of a signal peptide, where signal peptides are short sequences of N-terminated amino acids that provide protein secretion. The terms signal sequence and signal peptide are used interchangeably in this document. Signal sequences direct proteins to or through the secretory pathway of the endoplasmic reticulum and are Petition 870250104513, dated 11 / 14 / 2025, page 42 / 242 35 / 212 are generally cleaved within the endoplasmic reticulum before secretion. Thus, a signal peptide increases the secretion of a polypeptide by the cell compared to the secretion level of the corresponding polypeptide without a signal peptide.

[0089] The presence of a signal sequence in a PPT1 polypeptide facilitates the extracellular secretion of the mature PPT1 polypeptide. The secreted polypeptide can be absorbed by another cell, providing cross-matching.

[0090] In certain embodiments, the signal peptide comprises the amino acid sequence of any of the SEQ ID NOs: 16-27, or comprises an amino acid sequence that differs in any of the SEQ ID NOs: 16-27 by one amino acid. In further embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16; comprises the amino acid sequence of SEQ ID NO: 19; or comprises the amino acid sequence of SEQ ID NO: 23.

[0091] In certain embodiments, the PPT1 polypeptide comprises a signal sequence and a PPT1 sequence in which: (a) the signal sequence comprises the amino acid sequence of any of the SEQ ID NOs: 16-21 and 24-27, or differs from any of the SEQ ID NOs: 16-21 and 24-27 by an amino acid addition, deletion, or substitution; and the PPT1 polypeptide sequence comprises a sequence with at least 95% sequence identity, at least Petition 870250104513, dated 11 / 14 / 2025, p. 43 / 242 36 / 212 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 1; b) the signal sequence comprises the amino acid sequence of any of the SEQ ID NOs: 16-21 and 24-27, the PPT1 polypeptide sequence comprises a sequence with sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 2 and X is G, V or L; (c) the signal sequence comprises the amino acid sequence of SEQ ID NO: 16 or that differs from SEQ ID NO: 16 by an amino acid addition, deletion, or substitution; and the polypeptide sequence PPT1 comprises a sequence with sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 1; (d) the signal sequence comprises the amino acid sequence with SEQ ID NO: 16 and the polypeptide sequence PPT1 comprises a sequence with sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 2 and X is G, V, or L; and (e) The signal sequence comprises the amino acid sequence with SEQ ID NO: 16, and the polypeptide sequence PPT1 comprises the sequence with SEQ ID NO: 2, where X is G. f) the sign sequence comprises the sequence of Petition 870250104513, dated 11 / 14 / 2025, p. 44 / 242 37 / 212 amino acids of SEQ ID NO: 19 or that differs from SEQ ID NO: 19 by an amino acid addition, deletion, or substitution; and the PPT1 polypeptide sequence comprises a sequence with sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 1; h) the signal sequence comprises the amino acid sequence of SEQ ID NO: 19 and the polypeptide sequence PPT1 comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 2 and X is G, V or L; and i) the signal sequence comprises the amino acid sequence with SEQ ID NO: 19 and the polypeptide sequence PPT1 comprises the sequence with SEQ ID NO: 2, where X is G.

[0092] In certain embodiments, the PPT1 polypeptide comprises a signal sequence and a PPT1 sequence, wherein the signal sequence comprises the amino acid sequence of SEQ ID NO: 23 or differs from SEQ ID NO: 23 by an amino acid addition, deletion or substitution; and the PPT1 polypeptide sequence comprises the leucine-glutamine histidine-leucine amino acid sequence at its N-terminus and has a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 4. Petition 870250104513, dated 11 / 14 / 2025, p. 45 / 242 38 / 212

[0093] In certain embodiments, with respect to a PPT1 polypeptide comprising a signal sequence and a PPT1 sequence, the polypeptide comprises an amino acid sequence having a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with any of SEQ ID NOs: 31-42, or differs from any of SEQ ID NOs: 31-42 by 1-10 amino acid differences, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid differences. Reference to amino acid differences indicates any combination of addition, substitution and / or deletion.

[0094] In further embodiments, the polypeptide comprises an amino acid sequence with at least 99% or 100% sequence identity with SEQ ID NO: 31 or differs from SEQ ID NO: 31 by 1-5 amino acids; the polypeptide comprises the amino acid of SEQ ID NO: 31, where X is D or G; the polypeptide comprises an amino acid sequence with at least 99% or 100% sequence identity with SEQ ID NO: 34 or differs from SEQ ID NO: 34 by 1-5 amino acids; the polypeptide comprises the amino acid of SEQ ID NO: 34 where X is D or G; the polypeptide comprises the leucine-glutamine histidine-leucine amino acid sequence at its N-terminus and exhibits at least 99% or 100% sequence identity with SEQ ID NO: 38, or differs from SEQ ID NO: 38 by 1-5 amino acids; or the polypeptide comprises SEQ ID Petition 870250104513, dated 11 / 14 / 2025, page 46 / 242 39 / 212 NO: 30. II. Polynucleotide Comprising a Sequence Encoding PPT1

[0095] A polynucleotide comprising a nucleic acid sequence encoding a PPT1 polypeptide can be used to facilitate the intracellular production and release of a PPT1 polypeptide. In certain embodiments, the polynucleotide comprises a nucleic acid sequence encoding a PPT1 polypeptide, wherein the PPT1 polypeptide comprises a PPT1 amino acid sequence with at least 95% identity to the sequence with SEQ ID NO: 1, wherein: (a) the polypeptide PPT1 additionally comprises a signal sequence of any of the SEQ ID NOs: 16-27 or a variant thereof with an amino acid substitution, deletion or insertion; and / or (b) the amino acid sequence of PPT1 comprises a substitution of glycine (G), valine (V) or leucine (L) for aspartic acid (D) at its amino terminus; and / or (c) the sequence of PPT1 comprises the amino acid sequence leucine-glutamine-histidine-leucine at its N terminus; and / or (d) the nucleic acid sequence comprises a sequence encoding PPT1 with at least 85% identity to any of the SEQ ID NOs: 61-94. Petition 870250104513, dated 11 / 14 / 2025, p. 47 / 242 40 / 212

[0096] In certain embodiments, (a) the polynucleotide encodes a PPT1 polypeptide comprising an amino acid sequence of PPT1 with at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 1; (b) the encoded PPT1 polypeptide comprises an amino acid sequence of PPT1 with at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 2 and X is glycine; (c) the encoded PPT1 polypeptide comprises an amino acid sequence of PPT1 with at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 2, and X is valine;or (d) the encoded PPT1 polypeptide comprises an amino acid sequence of PPT1 with at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 2, and X is leucine. In further embodiments, the nucleic acid sequence encoding any of (a), (b), (c), or (d) comprises a nucleic acid sequence with a sequence identity of at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100% with any of SEQ ID Nos: 61 Petition 870250104513, dated 11 / 14 / 2025, p. 48 / 242; 41 / 212 or a variant thereof, where the first three nucleotides code for G, D, V, or L, or code for G. Nucleotides coding for G, V, D, or L are given in Table 1. Table 1 Glycine Valine Leucine Aspartic acid GGT GTT TTA TTG Codons GGC GTC CTT GAT GGA GGG GTA GTG CTC CTA CTG GAC

[0097] In certain embodiments, the nucleic acid encoding a mature PPT1 amino acid comprises the leucine-glutamine-histidine-leucine amino acid sequence in its N-terminal sequence and exhibits at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity with the sequence of SEQ ID NO: 4.

[0098] In certain embodiments, the nucleic acid encoding a mature PPT1 polypeptide additionally comprises a signal sequence comprising the amino acid sequence of any of the SEQ ID NOs: 16-27, or comprises an amino acid sequence that differs in any of the SEQ ID NOs: 16-27 by one amino acid. In further embodiments, the signal-coding sequence is the sequence of any of the SEQ ID NOs: 43-58. The reference to “signal-coding sequence” indicates a Petition 870250104513, dated 11 / 14 / 2025, p. 49 / 242 42 / 212 nucleotide sequence that codes for the signal sequence or signal peptide.

[0099] In certain embodiments, the polynucleotide comprises the signal coding sequence of any of the SEQ ID NOs: 16-21 and 24-27; SEQ ID NO: 16 or SEQ ID NO: 19.

[00100] In certain embodiments, the signal coding sequence comprises a sequence with a sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, or 100% with any of SEQ ID NOs: 43-47, and the signal sequence comprises the sequence of SEQ ID NO: 16, or differs from SEQ ID NO: 16 by one amino acid. In further embodiments, the nucleic acid sequence comprises the signal coding sequence of any of the SEQ ID NOs: 43, 44, 45, 46, or 47.

[00101] In certain embodiments, the signal coding sequence comprises a sequence with a sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, or 100% with SEQ ID NO: 43 and the signal sequence comprises the sequence of SEQ ID NO: 16, or differs from SEQ ID NO: 16 by one amino acid. In a further embodiment, the signal coding sequence comprises the sequence of SEQ ID NO: 43.

[00102] In certain modes, the signal encoding sequence comprises a sequence with a Petition 870250104513, dated 11 / 14 / 2025, p. 50 / 242 43 / 212 sequence identity of at least 80%, at least 85%, at least 90%, at least 95% or 100% with SEQ ID NO: 50, and the signal coding sequence comprises the sequence of SEQ ID NO: 19, or differs from SEQ ID NO: 19 by one amino acid. In different embodiments, the nucleic acid sequence comprises the sequence of SEQ ID NO: 50.

[00103] In certain embodiments, the signal coding sequence comprises a sequence with a sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, or 100% with SEQ ID NO: 54 and the signal coding sequence comprises the sequence of SEQ ID NO: 23, or differs from SEQ ID NO: 23 by one amino acid. In different embodiments, the nucleic acid sequence comprises the sequence of SEQ ID NO: 54.

[00104] In certain embodiments, the polynucleotide encodes a PPT1 polypeptide comprising a signal sequence and a PPT1 sequence in which: a) the signal sequence comprises SEQ ID NO: 16, the signal encoding sequence comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 43 and the PPT1 sequence comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 1 or SEQ ID NO: 2; Petition 870250104513, dated 11 / 14 / 2025, page 51 / 242 44 / 212 b) the signal encoding sequence comprises the sequence with SEQ ID NO: 43 and the PPT1 sequence comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NOs: 1 or 2; c) the signal encoding sequence comprises the sequence with SEQ ID NO: 43 and the PPT1 sequence comprises a sequence with a sequence identity of at least 97% with SEQ ID NO: 1; d) the signal encoding sequence comprises the sequence with SEQ ID NO: 43 and the PPT1 sequence comprises a sequence with a sequence identity of at least 97% with SEQ ID NO: 2 and X is G, V or L; (e) The signal encoding sequence comprises the sequence with SEQ ID NO: 43, and the PPT1 sequence comprises a sequence with a sequence identity of at least 99% with SEQ ID NO: 2 and X is G; f) the signal encoding sequence comprises the sequence with SEQ ID NO: 43; and the PPT1 sequence comprises the sequence with SEQ ID NO: 1; g) the signal encoding sequence comprises the sequence with SEQ ID NO: 43; and the PPT1 sequence comprises the sequence with SEQ ID NO: 2, where X is G; and h) in different embodiments, the sequence that encodes the polypeptide sequence for any of (a) to (g) Petition 870250104513, dated 11 / 14 / 2025, p. 52 / 242 45 / 212 comprises a sequence with a sequence identity of at least 85%, at least 90%, at least 95%, or 100% with any of the SEQ ID NOs: 61-79 and 80-94, or for any of the SEQ ID NOs: 61-79 and 80-94, where the first three nucleotides are a codon in Table 1.In further embodiments, the sequence encoding the polypeptide sequence for any of (a) to (g) comprises a sequence with a sequence identity of at least 85%, at least 90%, at least 95%, or 100% with any of SEQ ID NOs: 62-64, 71, 74, 78, 79, and 83, wherein the first three nucleotides are a codon from Table 1; the sequence encoding the polypeptide sequence for any of (a) to (g) comprises a sequence with a sequence identity of at least 85%, at least 90%, at least 95%, or 100% with any of SEQ ID NOs: 64, wherein the first three nucleotides are a codon from Table 1; or the sequence that encodes the polypeptide sequence for any of (a) to (g) comprises a sequence with a sequence identity of at least 85%, at least 90%, at least 95% or 100% with SEQ ID NO: 79, where the first three nucleotides are a codon from Table 1.

[00105] In certain embodiments, the polynucleotide encodes a PPT1 polypeptide comprising a signal sequence and a PPT1 sequence in which: a) the signal sequence comprises SEQ ID NO: 19 and a Petition 870250104513, dated 11 / 14 / 2025, page 53 / 242 The 46 / 212 signal encoding sequence comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 50; and the PPT1 sequence comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 1 or SEQ ID NO: 2; b) the signal encoding sequence comprises the sequence with SEQ ID NO: 50 and the PPT1 sequence comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NOs: 1 or 2; c) the signal encoding sequence comprises the sequence with SEQ ID NO: 50 and the PPT1 sequence comprises a sequence with a sequence identity of at least 97% with SEQ ID NO: 1; d) the signal encoding sequence comprises the sequence with SEQ ID NO: 50 and the PPT1 sequence comprises a sequence with a sequence identity of at least 97% with SEQ ID NO: 2 and X is G, V, or L; (e) The signal encoding sequence comprises the sequence with SEQ ID NO: 50, and the PPT1 sequence comprises a sequence with a sequence identity of at least 99% with SEQ ID NO: 2 and X is G; f) the signal encoding sequence comprises Petition 870250104513, dated 11 / 14 / 2025, page 54 / 242 47 / 212 sequence with SEQ ID NO: 50 and the PPT1 sequence comprises the sequence with SEQ ID NO: 1; g) the signal encoding sequence comprises the sequence with SEQ ID NO: 50 and the PPT1 sequence comprises the sequence with SEQ ID NO: 2, where X is G; and h) In different embodiments, the nucleic acid encoding the polypeptide sequence for any of (a) to (g) comprises a sequence with a sequence identity of at least 85%, at least 90%, at least 95%, or 100% with any of the SEQ ID NOs: 61-79 and 80-94, or for any of the SEQ ID NOs: 61-79 and 80-94, wherein the first three nucleotides are a codon from Table 1.

[00106] In certain embodiments, the polynucleotide encodes a PPT1 polypeptide comprising a signal sequence and a PPT1 sequence in which: a) the signal sequence comprises SEQ ID NO: 23, the signal encoding sequence comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 54, and the PPT1 sequence comprises a leucine-glutamine-histidine-leucine at its N-terminus and a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 4; b) the signal encoding sequence comprises Petition 870250104513, dated 11 / 14 / 2025, page 55 / 242 48 / 212 sequence of SEQ ID NO: 54 and the PPT1 sequence comprises a leucine-glutamine histidine-leucine at its N-terminus and a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 4; (c) the signal encoding sequence comprises the sequence with SEQ ID NO: 54 and the PPT1 sequence comprises a leucine-glutamine histidine-leucine at its N-terminus and a sequence identity of at least 97% with SEQ ID NO: 1; (d) the signal encoding sequence comprises the sequence with SEQ ID NO: 54 and the PPT1 sequence comprises a leucine-glutamine-histidine-leucine at its N-terminus and a sequence identity of at least 98% with SEQ ID NO: 4; (e) the signal encoding sequence comprises the sequence with SEQ ID NO: 54 and the PPT1 sequence comprises a leucine-glutamine-histidine-leucine at its N-terminus and a sequence identity of at least 99% with SEQ ID NO: 4; and f) The signal encoding sequence comprises the sequence with SEQ ID NO: 54, and the PPT1 sequence comprises SEQ ID NO: 4.

[00107] In certain embodiments, the nucleic acid (a) encodes a PPT1 polypeptide comprising a sequence Petition 870250104513, dated 11 / 14 / 2025, p. 56 / 242 49 / 212 with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with any of SEQ ID NOs: 29-42, or differs from any of SEQ ID NOs: 29-42 by 1-10 amino acids, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids; (b) encodes a PPT1 polypeptide comprising an amino acid sequence with a sequence identity of at least 99% or 100% with SEQ ID NO: 31 or differs from SEQ ID NO: 31 by 1-5 amino acids; (c) encodes a PPT1 polypeptide comprising the amino acid of SEQ ID NO: 31, where X is D or G; (d) encodes a PPT1 polypeptide comprising an amino acid sequence with at least 99% or 100% sequence identity with SEQ ID NO: 34 or differs from SEQ ID NO: 34 by 1-5 amino acids; (e) encodes a PPT1 polypeptide comprising the amino acid of SEQ ID NO: 34 where X is D or G; (f) encodes a PPT1 polypeptide comprising the amino acid sequence of SEQ ID NO: 38;(g) encodes (b), wherein the nucleic acid comprises a sequence with sequence identity of at least 80%, at least 85%, at least 90%, at least 95% or 100% with SEQ ID NO: 43; (h) encodes (b), wherein the nucleic acid comprises a sequence with sequence identity of at least 85%, at least 90%, at least 95% or 100% with any of SEQ ID NOs: 107-125 and 168; (i) encodes (c), wherein the nucleic acid comprises a sequence with sequence identity of at least 80%, at least 85%,; Petition 870250104513, dated 11 / 14 / 2025, p. 57 / 242 50 / 212 at least 90%, at least 95% or 100% with SEQ ID NO: 99; (h) encodes (c), wherein the nucleic acid comprises a sequence having a sequence identity of at least 85%, at least 90%, at least 95%, or 100% with any of SEQ ID NOs: 126-140 and 161-167; or (i) encodes (f), wherein the nucleic acid comprises a sequence having a sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, or 100% with SEQ ID NO: 103.

[00108] In certain embodiments, the polynucleotide comprises a nucleic acid sequence that encodes a PPT1 polypeptide described in Section I above.

[00109] In certain embodiments, the polynucleotide sequence encoding the PPT1 polypeptide comprises two or more exons encoding the PPT1 polypeptide and one or more introns.

[00110] In certain embodiments, the polynucleotide comprises a sequence encoding PPT1 with a sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, or 100% with the sequence of any of the SEQ IDs NOS: 95-106.

[00111] The reference to a sequence provided in this application, such as in Table 2 below, which includes a stop codon, includes embodiments in which the stop codon is not present, multiple stop codons are present, and different stop codons are present. Petition 870250104513, dated 11 / 14 / 2025, p. 58 / 242 51 / 212

[00112] The reference to a sequence provided in this application, such as in Table 2 below, which encodes a protein that provides a stop codon, includes embodiments in which the stop codon is not present immediately after the provided sequence, one stop codon is present, multiple stop codons are present, and different stop codons are present.

[00113] In certain embodiments, the nucleotide sequences encoding PPT1 contain 0-5, 0-10, or 0-15 CpGs; 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 CpGs; 0%, about 0.5%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, or about 5.0% of CpGs; and / or up to about 0.5%, up to about 1.0%, up to about 2.0%, up to about 3.0%, up to about 4.0%, or up to about 5.0% of CpGs. III. Expression Cassettes

[00114] Polynucleotide expression cassettes contain a nucleic acid encoding a PPT1 polypeptide operationally linked to one or more expression control elements. Expression control can be affected, for example, at the level of transcription, translation, splicing, and message stability. Expression control elements are typically located 5' (“upstream”) or 3' (“downstream”) of a transcribed nucleic acid. Expression control elements may also be Petition 870250104513, dated 11 / 14 / 2025, page 59 / 242 52 / 212 located in the transcript (e.g., in an intron), adjacent to or distant from the transcribed sequence. One or more expression control elements of the same type or of different types may be present. Examples of expression control elements include a promoter, an enhancer, an intron, a polyadenylation signal, a Kozak sequence, posttranscriptional regulatory elements, and a termination sequence.

[00115] A promoter is a region of DNA where transcription is initiated. Generally, the transcribed nucleic acid is located 3' from a promoter sequence. In certain embodiments, a promoter sequence is coupled to an enhancer. Enhancers are regions of DNA that increase transcription from the promoter. Enhancers may be adjacent to or on a promoter, or they may be distal. Typically, enhancers are located upstream of a promoter, but they may be located downstream of or on a promoter sequence.

[00116] Expression control elements, such as a promoter and an enhancer, can be chosen to preferentially drive expression in a specific cell or tissue type. Expression control elements are typically active in specific cells, tissues, or organs because they are recognized by transcriptional activator proteins, or other transcriptional regulators, that Petition 870250104513, dated 11 / 14 / 2025, page 60 / 242 53 / 212 are unique to a specific type of cell, tissue, or organ. (See, for example, Green, M. and Sambrook, J. (2012) Molecular Cloning: A Laboratory Manual. 4th Edition, Vol. II, Cold Spring Harbor Laboratory Press, New York; and Ausubel et al., (2010) Current protocols in molecular biology, John Wiley & Sons, New York).

[00117] The incorporation of tissue-specific regulatory elements into expression constructs provides at least partial tissue tropism for PPT1 protein expression. Reference to a specific promoter or enhancer for a particular cell or tissue type indicates that the promoter or enhancer provides higher levels of expression and / or secretion in the indicated cell or tissue type. Examples of liver-specific promoters are the transthyretin (TTR) gene promoter; the human alpha 1-antitrypsin (hAAT) promoter; the apolipoprotein AI promoter; albumin, Miyatake et al., J. Virol., 71:5124-32 (1997); the hepatitis B virus core promoter, Sandig et al., Gene Ther. 3:1002-9 (1996); alpha-fetoprotein (AFP), Arbuthnot et al., Hum. Gene. Ther., 7:1503-14 (1996); human factor IX promoter; thyroxine-binding globulin (TBG) promoter; minimal TTR enhancer / promoter; alpha-antitrypsin promoter; LSP (845 nt) (requires scAAV without intron); and LSP1 promoter. An example of an active enhancer no. Petition 870250104513, dated 11 / 14 / 2025, page 61 / 242 54 / 212 liver is apolipoprotein E (apoE) HCR-1 and HCR-2 (Allan et al., J. Biol. Chem., 272:29113-19 (1997)).

[00118] Expression control elements also include ubiquitous or promiscuous promoters and promoters / enhancers capable of driving polynucleotide expression in many different cell types. Such elements include the EF1-alpha promoter, the early immediate cytomegalovirus (CMV) promoter / enhancer sequences, the Rous sarcoma virus (RSV) promoter / enhancer sequences, the phosphoglycerate kinase (PKG) promoter, the CAG (composed of the CMV enhancer, the chicken beta-actin (CBA) promoter, and the rabbit beta-globin intron) (see, for example, Boshart et al., (1985) Cell, 41:521-530), the SV40 promoter, the dihydrofolate reductase promoter, and the cytoplasmic bactin promoter.

[00119] Examples of CNS-specific promoters include: neuron-specific promoters such as NSE (neuron-specific enolase), synapsin or NeuN, platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), methyl-CpG-binding protein 2 (MeCP2), Ca2 / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light (NFL) or heavy (NFH), β-globin np2 minigene, promoters of Petition 870250104513, dated 11 / 14 / 2025, page 62 / 242 55 / 212 preproenkephalin (PPE), enkephalin (Enk), and excitatory amino acid carrier 2 (EAAT2); astrocyte-specific promoters, such as glial fibrillary acidic protein (GFAP) and EAAT2 promoters; oligodendrocyte-specific promoters, such as myelin basic protein (MBP) / myelin-associated glycoprotein and oligodendrocyte transcription factor 2 promoter; neuron / hypothalamus-specific promoters, such as proopiomelanocortin (POMC) promoter; and neuron / spinal cord-specific promoter, such as superoxide dismutase 1 (SOD1). (See, for example, U.S. Patent Publication 2021 / 214749 and Adeno-Associated Virus Vectors (2019), Ed. Castle, 1st Edition, Springer New York, New York, NY; both of which are incorporated herein by reference in their entirety.)

[00120] Additional promoters include the SV40 early promoter, the mouse breast tumor virus LTR promoter, the adenovirus late major promoter (Ad MLP), the herpes simplex virus (HSV) promoter, the SFFV promoter, the mouse insulin promoter, the TBG promoter, the desmin promoter and similar muscle-specific promoters, synthetic promoters, hybrid promoters and promoters with multi-tissue specificity.

[00121] Expression control elements can also impact expression in a way that is adjustable. Petition 870250104513, dated 11 / 14 / 2025, page 63 / 242 56 / 212 by a signal or stimulus that increases or decreases expression. A regulatable element that increases the expression of the transcribed nucleic acid in response to a signal or stimulus is also called an “inducible element” (i.e., it is induced by a signal). Typically, the amount of increase or decrease conferred by such elements is proportional to the amount of signal or stimulus present. Particular examples include the zinc-inducible ovine metallothionein (MT) promoter; the steroid hormone-inducible mouse mammary tumor virus (MMTV) promoter; the tetracycline-repressible system (Gossen et al., Proc. Natl. Acad. Sci. USA, 89:5547-5551 (1992)); the tetracycline-inducible system (Gossen et al., Science 268: 1766-1769 (1995); see also Harvey et al., Curr. Opin. Chem. Biol. 2:512-518 (1998)); the RU486-inducible system (Wang et al., Nat. Biotech. 15:239-243 (1997) and Wang et al., Gene Ther.4:432-441 (1997); and the rapamycin-inducible system (Magari et al., J. Clin. Invest. 100:2865-2872 (1997); and Rivera et al., Nat. Medicine. 2:1028-1032 (1996)). Other examples of regulable control elements include those regulated by a specific physiological state, such as temperature, acute phase, or development.

[00122] In certain embodiments, the expression cassette further comprises one or more nucleic acid-independent introns encoding PPT1. A variety of introns Petition 870250104513, dated 11 / 14 / 2025, p. 64 / 242 57 / 212 different introns can be used to increase gene expression. Examples of introns that can be used include rabbit β-globin intron with splicing donor / splicing acceptor, SV40 intron with splice donor / splice acceptor, human β-globin introns, human beta hemoglobin gene intron 2, hFIX int1 (human coagulation factor IX gene intron 1), CBA-rHHB (synthetic intron derived from the fusion of chicken beta-actin gene intron 1 and rabbit beta hemoglobin intron 2), CBA (chicken beta-actin gene intron 1), hGH (human growth hormone gene intron 1), hFIX synth (synthetic intron derived from different portions of the human coagulation factor IX gene and present in the pLIVE vector, Mirus Bio, Madison, WI); Synthetic intron of the beta subunit of human hemoglobin (HBB2) and optimized HBB2;and chimeric introns, such as introns composed of the 5' splice donor of the first human β-globin intron and the 3' branch and acceptor site of the intron that lies between the leader and body of the variable region of the immunoglobulin gene heavy chain. (Buck et al., Int. J. Mol. Sci. (2020), 21, 4197; Ronzitti et al., Mol. Ther. Methods Clin Dev. (2016) July 20;3:16049; and the HBB-IGG intron provided by the pCMVNT™ vector.);

[00123] In certain modalities, the expression cassette comprises a post-transcriptional regulatory element. Post-translational regulatory elements, such as the element Petition 870250104513, dated 11 / 14 / 2025, p. 65 / 242 Woodchuck post-transcriptional regulatory element (WPRE) and hepatitis B regulatory element can increase gene expression. (Buck et al., Int. J. Mol. Sci. (2020), 21, 4197.)

[00124] Polyadenylation signal sequences provide the formation of a polyA tail, which facilitates nuclear export, translation, and / or mRNA stability, and may also be involved in transcription termination. Examples of polyadenylation signal sequences include the SV40 late polyadenylation signal, the bovine growth hormone (bGHpA) polyA signal sequence, synthetic polyA, mouse β-globin pA, rabbit β-globin pA, and H4-based pA. (Buck et al., Int. J. Mol. Sci. (2020), 21, 4197.)

[00125] In certain modalities, the expression cassette comprises a Kozak consensus sequence or a variation thereof. Kozak consensus sequences play a role in initiating translation. The Kozak consensus sequence and its variations are provided, for example, in McClements et al., (2021) Molecular vision, 27, 233-242, incorporated herein by reference.

[00126] In certain embodiments, the expression cassette comprises 5' to 3' operationally coupled to the PPT1 encoding sequence: a promoter or promoter / enhancer, an intron, a Kozak sequence, Petition 870250104513, dated 11 / 14 / 2025, p. 66 / 242 59 / 212 is the coding sequence for PPT1 and a polyadenylation signal. In certain embodiments, the intron comprises the amino acid sequence of SEQ ID NO: 11.

[00127] In certain embodiments, expression cassettes also comprise miRNA target sequences, which in other embodiments are incorporated into the 3' UTR of the expression cassette. A miRNA target sequence is recognized by miRNA present in specific cells or tissues, leading to the degradation of mRNA transcripts. Based on the presence of a given miRNA in specific cells, the incorporation of one or more miRNA target sequences can be used to reduce expression in certain cell or tissue types. Multiple tandem repeats of miRNA target sequences can be used to increase degradation. (Geisle et al., (2016) World Journal of Experimental Medicine 6(2): 37-54).

[00128] In certain embodiments, the expression cassette encodes a PPT1 polypeptide, as provided in Section I above, comprises a nucleic acid sequence encoding a PPT1 polynucleotide, as provided in Section II above; and / or comprises a nucleic acid sequence with a sequence identity of at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% with any of the SEQ ID NOs: 141-143, 169 and 170.

[00129] In certain embodiments, the nucleotide sequence of the expression cassette contains any of Petition 870250104513, dated 11 / 14 / 2025, page 67 / 242 60 / 212 0-5, 0-10, 0-15, 0-50 or 0-100 CpGs; 0, 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 or 30 CpGs; 0%, about 0.5%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14% or about 15% of CpGs; and / or up to about 0.5%, up to about 1.0%, up to about 2.0%, up to about 3.0%, up to about 4.0%, up to about 5.0%, up to about 6%, up to about 7%, up to about 8%, up to about 9%, up to about 10%, up to about 11%, up to about 12%, up to about 13%, up to about 14% or up to about 15% of CpGs. IV. Recombinant Viral Vector Nucleic Acid

[00130] The nucleic acid of the recombinant polynucleotide viral vector contains 5' and / or 3' viral elements that provide viral packaging and may provide additional activities such as self-priming, DNA replication, promoter activity, genomic integration, or episomal concatermerization. The 5' and 3' elements are generally located at or near the 5' and 3' end of the recombinant viral vector nucleic acid and may be natural or modified versions of natural sequences. Examples of 5' and 3' elements include adenovirus ITRs, adeno-associated virus ITRs, and packaging sequences; and long terminal repeats (LTRs, of the Petition 870250104513, dated 11 / 14 / 2025, page 68 / 242 61 / 212 English .Long terminal repeats) of retroviruses 5' and 3' and packaging sequences. (Naso et al., (2017) BioDrugs, 31(4), 317-334; Bulcha et al., (2021) Sig. Transduct. Target Ther. 6:53 (2021); and Liu and Seol (2020) BMB Reports; 53(11) :565-575. )

[00131] The term recombinant, as in a nucleic acid modifier or vector, indicates a combination of elements that does not occur in nature. For example, a recombinant viral vector nucleic acid provides 5' and / or 3' viral elements along with an expression cassette containing one or more elements not naturally associated with the 5' and / or 3' elements. Similarly, a viral vector, such as an rAAV vector, may contain a natural or modified capsid encapsulating the recombinant viral vector nucleic acid.

[00132] In certain embodiments, the viral vector nucleic acid sequence comprises a 5' UTR and a 3' UTR, or a 5' ITR and a 3' ITR and (1) comprises a sequence encoding the polypeptide of Section I above; (2) comprises a nucleic acid sequence encoding a PPT1 polynucleotide, as provided in Section II above; and / or (3) comprises an expression cassette encoding a PPT1 polynucleotide, as provided in Section III above.

[00133] In certain embodiments, the viral vector comprises a polyA signal operationally linked to ITR 3', where the polyA signal antagonizes the transcription potential. Petition 870250104513, dated 11 / 14 / 2025, p. 69 / 242 62 / 212 initiated from ITR 3'. The operationally connected pulley A signal is upstream of ITR 3'.

[00134] In certain embodiments, the viral vector nucleic acid contains any one of 0-5, 0-10, 0-15, 0-50, 0-100 or 0 to 150 CpGs; 0, 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, 44, 46, 47, 48, 49 or 50 CpGs; 0%, about 0.5%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14% or about 15% of CpGs; and / or up to about 0.5%, up to about 1.0%, up to about 2.0%, up to about 3.0%, up to about 4.0%, up to about 5.0%, up to about 6%, up to about 7%, up to about 8%, up to about 9%, up to about 10%, up to about 11%, up to about 12%, up to about 13%, up to about 14% or up to about 15% of CpGs.

[00135] In certain embodiments, the nucleic acid of the recombinant viral vector comprises a sequence with at least 95% identity, at least 97% identity, at least 99% identity, or 100% identity with the sequence of any of the SEQ ID Nos: 144-154, 171, and 172. V. Viral vectors

[00136] In certain embodiments, the gene delivery vehicle is a viral vector comprising a protein capsid. Petition 870250104513, dated 11 / 14 / 2025, page 70 / 242 63 / 212 which encapsulates the nucleic acid of the recombinant viral vector. The viral vector can release the viral vector's nucleic acid to cells or tissues. Depending on the specific vector, the viral vector may additionally comprise a viral envelope. Examples of viral vectors that can be used for gene delivery include adenovirus vectors, rAAV vectors, retrovirus vectors, and herpes simplex vectors.

[00137] Different serotypes exist in different types of viruses. Different serotypes can provide different activities, such as cellular or tissue tropism and the likelihood of generating a host immune response. The term serotype refers broadly to both serologically distinct viruses and non-serologically distinct viruses that may be in a subgroup or variant of a given serotype. Serological distinction can be determined based on the absence of cross-reactivity between antibodies to one capsid compared to another capsid. Such differences in cross-reactivity are usually due to differences in the protein sequences / antigenic determinants of the capsid (e.g., due to differences in the VP1, VP2, and / or VP3 sequences of AAV serotypes).

[00138] As more naturally occurring viral isolates are discovered or capsid mutants are generated, there may or may not be serological differences with Petition 870250104513, dated 11 / 14 / 2025, p. 71 / 242 64 / 212 any of the currently existing serotypes. Thus, in cases where the new virus does not present serological differences, this new virus would be a subgroup or variant of the corresponding serotype. VA Adenovirus Vectors

[00139] Adenoviruses are non-enveloped double-stranded DNA viruses. Recombinant adenovirus vectors comprise recombinant adenovirus nucleic acid lacking one or more proteins involved in viral replication and additionally comprise an adenoviral capsid. Recombinant adenovirus vectors can be produced containing different amounts of adenoviral DNA. The adenovirus (Ad) genome is flanked by hairpin-shaped inverted terminal repeats (ITRs), ranging in length from 30 to 371 bp at their terminals. ITRs serve as self-initiating structures that promote primase-independent DNA replication. A packaging signal located on the left arm of the genome is required for viral genome packaging. (Liu and Seol (2020) BMB Reports; 53(11):565-575; and Bulcha et al., (2021) Sig. Transduct. Target Ther. 6:53).

[00140] In certain embodiments, the recombinant adenovirus vector is a third-generation vector, also called gut-free or helper-dependent. Gut-free vectors can be produced from acid Petition 870250104513, dated 11 / 14 / 2025, page 72 / 242 65 / 212 recombinant adenovirus nucleic acid, where all, or substantially all, viral sequences, except ITRs and packaging signal, are not present. Gutless adenovirus vectors are high-capacity vectors, capable of accommodating up to approximately 36 kb of DNA insertion. The preferred recombinant adenovirus nucleic acid shows approximately 27 kb to approximately 37 kb. Filler sequences can be added to the recombinant adenovirus nucleic acid to increase the nucleic acid size and incorporation into the capsid. Preferred filler sequences avoid coding sequences, repetitive sequences, recombination sequences, and immunogenic sequences. (Liu and Seol (2020) BMB Reports, 53(11):565-575; Bulcha et al., (2021) Sig. Transduct. Target Ther. 6:53; and Sandig et al., PNAS (2000) 97(3):1002-1007, each of which is incorporated herein by full reference).

[00141] In certain embodiments, recombinant adenovirus vectors can be produced based on rare human serotypes or chimpanzee serotypes. The use of rare chimpanzee and human serotypes may be useful in reducing the host immune response against recombinant adenovirus vectors due to pre-existing immunity. (Guo et al., (2018) Human vaccines & immunotherapeutics, 14(7):1679-1685 and Bulcha et al., (2021) Sig. Transduct. Target Ther. 6:53). Petition 870250104513, dated 11 / 14 / 2025, page 73 / 242 66 / 212

[00142] Adenovirus vectors can be produced by supplying viral proteins necessary for vector production in trans using, for example, helper viruses or plasmids and appropriate cell lines. (Liu and Seol (2020) BMB Reports; 53(11):565-575, and Bulcha et al., (2021) Sig. Transduct. Target Ther. 6:53). VB Vectors AAV Recombinants

[00143] Recombinant adeno-associated viral vectors (also referred to in this document as rAAVs) are based on adeno-associated viruses. Adeno-associated viruses are single-stranded DNA viruses containing a 4.7 kb genome flanked by 145 nt ITRs at both ends of the genome. ITR activity is important for self-initiation and packaging, and can also provide additional activity, such as promoter activity. The 5' and 3' ITRs of AAVs can vary in size, and the 5' and 3' inverted repeats do not need to be exact inverted repeats.

[00144] An rAAV vector contains recombinant AAV nucleic acid and a viral capsid. The recombinant rAAV nucleic acid lacks one or more AAV proteins involved in viral replication. In certain embodiments, the rAAV vector contains a 5' and / or 3' AAV ITR along with a DNA insert. In certain embodiments, the rAAV nucleic acid comprises a 5' and / or a 3' ITR independently selected from the 5' and 3' ITRs provided in the ITRs. Petition 870250104513, dated 11 / 14 / 2025, page 74 / 242 67 / 212 AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.10, AAVrh.74, and AAV3B. In other forms, the 5' and 3' ITRs are present, and both ITRs are from the same serotype genome.

[00145] In certain embodiments, ITR 5' comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 8; and ITR 3' independently comprises (a) a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 9; (b) a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 158; (c) a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 159; or (d) a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 160.

[00146] In certain embodiments, ITR 3' comprises a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% with SEQ ID NO: 9; and ITR 5' independently comprises (a) a sequence with a sequence identity Petition 870250104513, dated 11 / 14 / 2025, page 75 / 242 68 / 212 of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 10; (b) a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 156; or (c) a sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with SEQ ID NO: 157.

[00147] Recombinant adeno-associated viral vectors typically accept DNA inserts with a size range generally from about 4 kb to about 5.2 kb. If necessary, a filler sequence can be used to increase the nucleic acid size of the rAAV and packaging efficiency. In different embodiments, the rAAV nucleic acid including the filler shows 4-5.2 kb, 3.0-5.5 kb, 4.0-5.0 kb, 4.3-4.8 kb, about 4.2 kb, about 4.3 kb, about 4.4 kb, about 4.5 kb, about 4.6 kb, or about 4.7 kb. Preferred filler sequences avoid coding sequences, repetitive sequences, recombination sequences, and immunogenic sequences.

[00148] In certain embodiments, rAAV is a self-complementary adeno-associated virus vector (scAAV) or a shorthairpin adeno-associated virus vector (shAAV). The scAAV and the shAAV Petition 870250104513, dated 11 / 14 / 2025, p. 76 / 242 69 / 212 provide a double-stranded nucleic acid from rAAV that can be incorporated into an AAV caspid. scAAV and shAAV comprise inverted dimeric repeats that provide intramolecular double-stranded DNA. scAAV can be produced by mutating an ITR terminal resolution site, so that the rep cannot cut the terminal resolution site. shAAV can use a short hairpin to produce double-stranded AAV nucleic acid. Being double-stranded DNA, scAAV and shAAV provide an advantage in bypassing the DNA synthesis step required for single-stranded rAAV nucleic acid upon entry into a cell. A potential disadvantage of scAAV and shAAV is that the size of the DNA inserts that can be incorporated is reduced by about half compared to single-stranded rAAV nucleic acid. (US Patent 10,457,940; Xie et al., Mol Ther. (2017) 25(6):1363-1374; and McCarty Mol. Ther.(2008) 16(10):1648-1656; each of which is incorporated herein by reference in its entirety).

[00149] Naturally occurring AAV capsids contain the viral proteins VP1, VP2, and VP3 in a ratio of approximately 1:1:10. AAV vectors can be produced where all three viral proteins are based on a specific serotype or where one, two, or all three viral proteins are based on different serotypes.

[00150] The capsid and nucleic acid of AAV Petition 870250104513, dated 11 / 14 / 2025, page 77 / 242 70 / 212 recombinants may be based on the same serotype (or subgroup or variant) or may be different from each other. In certain embodiments, an rAAV nucleic acid has the same serotype genome (e.g., ITRs) as the encapsulating capsid protein.

[00151] In different embodiments, the rAAV capsid comprises a protein with a sequence identity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.9% or 100% identical to a VP1, VP2 or VP3 of any of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.74, AAV3B, AAV-2i8, AAVrh.10, AAVrh.8, AAVHSC, AAV-B1, AAV-AS or AAV1 / rh.10; or VP1 of SEQ ID NO: 12 or SEQ ID NO: 15.

[00152] Recombinant AAV capsids comprising VP1 of SEQ ID NO: 12 are described, for example, in US Patent 9840719; and rAAV capsids comprising VP1 of SEQ ID NO: 15 are described, for example, in US Patent 9,169,299; both patents are incorporated herein by reference.

[00153] In certain embodiments, the AAV capsids Petition 870250104513, dated 11 / 14 / 2025, page 78 / 242 71 / 212 comprise VP1, VP2 and VP3, each independently having a sequence identity of at least 80%, at least 90%, at least 95% or 100% with a VP1, VP2 or VP3 of any of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.74, AAV3B, AAV-2i8, AAVrh.10, AAVrh.8, AAVHSC, AAV-B1, AAV-AS, AAV1 / rh.10, SEQ ID NO: 12 or SEQ ID NO: 15; as well as variants (e.g., capsid variants, such as amino acid insertions, additions, substitutions and deletions) thereof. (See, for example, U.S. Patents 9,909,142 and 9,840,719, which describe RHM4-1, RHM15-1, RHM15-2, RHM15-3 / RHM15-5, RHM15-4, and RHM15-6; U.S. Patent Publication 2013 / 0059732 and U.S. Patent 9,169,299, describing LK01, LK02, and LK03; and U.S. Patent 11,110,153;

[00154] In certain embodiments, the capsid comprises VP1 with the sequence SEQ ID NO: 12; VP2 with the sequence SEQ ID NO: 13; and VP3 having the sequence SEQ ID NO: 14.

[00155] In certain embodiments, the AAV capsid can cross the blood-brain barrier and provide expression in the CNS. Examples of such AAV capsids and the design of AAV capsids capable of providing expression in the CNS are provided in Chen et al., (2021) J. Control. Release 333, 129-138 (e.g., AAV9, AAV-PHP-B, AAV-PHP.eB, AAVrh.10, AAVrh.8, AAVHSC, AAV-B1, AAV-AS, and AAV1 / rh.10), US Patent Petition 870250104513, dated 11 / 14 / 2025, p. 79 / 242 72 / 212 9,585,971, and Goertsen et al., (2022) Nat. Neurosci. 25, 106115 (2022), each of which is incorporated herein by reference in full.

[00156] The AAV genome contains two main genes: rep and cap. Transcription of the rep gene is initiated from two different promoters, resulting in the production of non-structural proteins designated Rep78, Rep68, Rep52, and Rep40. The rep proteins act in genome replication and / or encapsulation. The cap gene encodes structural proteins that make up the capsid (VP1, VP2, and Vp3); a non-structural assembly activator protein (APP), which performs functions related to capsid assembly; and the membrane-associated accessory protein, which may be associated with the production phases of the replication cycle. (Maurer and Weitzman (2020) Hum. Gene Ther. 31(9-10):499-511, incorporated herein by reference in its entirety.)

[00157] AAV requires helper virus functions to complete its replication cycle. Helper virus functions can be provided by different viruses in permissive cell lines. Permissive cell lines are cell lines capable of supporting viral replication. Examples of helper viruses for AAV include adenovirus, HSV-1, HPV-16, and HBoV1, which can be used in conjunction with, for example, permissive primate cells; and baculovirus, which can be used in conjunction Petition 870250104513, dated 11 / 14 / 2025, page 80 / 242 73 / 212 with, for example, permissive insect cells, such as sf9. (Maurer and Weitzman (2020) Hum. Gene Ther. (2020) 31(910):499-511 and Meier et al., (2020) Viruses 19;12(6):662, both incorporated herein by reference in full.)

[00158] Recombinant AAV can be produced by supplying viral proteins necessary for vector production in trans using, for example, helper viruses or plasmids and appropriate cell lines. In certain embodiments, rAAV is produced using a plasmid of the rAAV vector genome. The plasmid comprises the nucleic acid portion of the rAAV finally packaged or encapsulated to form a viral vector (e.g., rAAV). The “plasmid structure” contains elements important for the propagation and production of recombinant viruses. Except for possible cloning remnants of ITR 3' and / or ITR 5', the plasmid structure is not packaged or encapsulated into viral particles.

[00159] The vector genome plasmid may contain regions such as an origin of replication and a selectable marker. Additional sites that may be present include cloning sites.

[00160] Recombinant AAV can be produced from different types of cell lines, including HeLa, A549, BHK, Vero, and HEK293, or derivatives thereof. In certain Petition 870250104513, dated 11 / 14 / 2025, page 81 / 242 74 / 212 modalities, HEK293 cells are used (American Type Culture Collection Accession Number ATCC CRL1573). Other host cell lines suitable for the production of rAAV vectors are described, for example, in Robert et al., (2017) Biotechnol. J. (2017) 12(3), 1600193; and in International Application PCT / US2017 / 024951; the descriptions of which are incorporated herein in full.

[00161] Recombinant AAV can be grown under a variety of different conditions, suitable for providing cell growth and gene expression. References describing the manufacture of rAAV include Clément and Grieger (2016) Mol. Clin. Dev. Methods 16; 3:16002; Robert et al., (2017) Biotechnol. J. 12(3), 1600193; and Adeno-Associated Virus Vectors (2019), Ed. Castle., 1st Edition, Springer New York, New York, NY.; each of which is incorporated herein by reference in its entirety.)

[00162] In certain embodiments, AAV helper functions are introduced into the host cell by transfecting the host cell with an AAV helper construct, before or simultaneously with transfection of an AAV expression vector. A host cell with AAV helper functions may be termed a helper cell or packaging helper cell. AAV helper constructs are therefore sometimes used to provide at least transient expression of the rep and / or cap genes of Petition 870250104513, dated 11 / 14 / 2025, page 82 / 242 75 / 212 AAVs are used to complement the missing functions of AAVs, necessary for productive AAV transduction. AAV helper constructs often lack AAV ITRs and are unable to replicate or package. These constructs may be, for example, in the form of a plasmid, phage, transposon, cosmid, virus, or virion. Several AAV helper constructs have been described, such as the commonly used plasmids pAAV / Ad and pIM29+45, which encode rep and cap expression products. Several other vectors encoding rep and / or cap expression products are known. Recombinant AAV can be produced, for example, in the manner described in US Patent 9,408,904; and in International Applications PCT / US2017 / 025396 and PCT / US2016 / 064414, the descriptions of which are incorporated herein in their entirety.

[00163] In certain embodiments, an rAAV vector is produced by an rAAV-producing cell that comprises the activity of the rAAV helper virus. The genome of the rAAV-producing cell comprises the rAAV nucleic acid, the rep gene, and the cap gene.

[00164] In certain embodiments, an rAAV vector is produced by culturing an rAAV-permissive cell comprising an AAV genome plasmid, wherein the rAAV-permissive cell further comprises the rep and cap genes provided as part of the cell genome and / or by one or more separate plasmids; and helper virus activity, whether Petition 870250104513, dated 11 / 14 / 2025, page 83 / 242 76 / 212 as part of the cellular genome and / or provided by one or more separate plasmids. In other embodiments, (a) the permissive rAAV cell line is a packaging cell, wherein the packaging cell genome comprises the cap gene and the rep gene; (b) the rep gene, the cap gene, and the helper activity are provided by the same plasmid; or (c) the rep gene and the cap gene are provided by a rep / cap plasmid and the helper activity is provided by a helper plasmid.

[00165] In certain modalities involving the use of HSV auxiliary functions, the auxiliary functions are provided by genes encoding at least UL5, UL8, UL52, and ICP8.

[00166] In certain embodiments involving the use of adenovirus helper functions, the helper functions are provided by genes encoding at least EIA, E1B19K, E1B55K, E2A, E4orf6, and RNA VA. In certain embodiments, the RNA El, E2A, and VR functions are provided by a helper plasmid, while additional helper functions are provided by a host strain.

[00167] In certain embodiments, the rAAV vector is obtained by producing rAAV using the methods described in this document and by purifying the rAAV. Purification of rAAV can be performed using techniques such as gradient-based purification, column-based purification, and combined methods. (See, for example, Ayuso et al., (2010), Curr Gene Ther. (2010) 10(6):423-36, incorporated herein by reference in Petition 870250104513, dated 11 / 14 / 2025, page 84 / 242 77 / 212 in its entirety.) VC Retrovirus Vectors

[00168] Retroviruses are enveloped single-stranded RNA viruses comprising 5' and 3' LTRs and a signal packaging sequence located outside the LTR. Different types of retrovirus vectors may contain different amounts of viral genome. In certain embodiments, the retroviral vector is an HIV-based lentiviral vector, retaining all the cis-action sequences necessary for viral RNA packaging, reverse transcription, and proviral DNA integration, while removing all HIV protein-coding genes. Lentiviral vectors have a packaging capacity of up to about 9 kb. If necessary, the filler sequence can be used to increase the nucleic acid size of the rAAV and packaging efficiency. Lentiviral vectors can be produced by supplying the viral proteins necessary for vector production in trans using appropriate plasmids and cell lines. (Bulcha et al., (2021) Sig. Transduct. Target Ther. 6:53.) VI. Non-Viral Vectors

[00169] In certain embodiments, the gene delivery vehicle is a nonviral vector. Nonviral vectors include nanoparticles and naked nucleic acid. Preferred nonviral vectors are nanoparticles. A variety of Petition 870250104513, dated 11 / 14 / 2025, page 85 / 242 78 / 212 different nanoparticles can be employed, including lipid nanoparticles (LNPs), polymeric nanoparticles, lipid polymer nanoparticles (LPNPs), protein- and peptide-based nanoparticles, DNA dendrimers and DNA-based nanocarriers, carbon nanotubes, microparticles, microcapsules, inorganic nanoparticles, peptide cage nanoparticles, and exosomes. (See, for example, Riley and Vermerris Nanomaterials (2017) 201, 7, 94; Thomas et al., Molecules (2019), 24, 3744; Bochicchio et al., (2021), 13, 198; Munagala et al., Cancer Letters (2021), 505, 58; Fu et al., (2020) NanoImpact 20, 100261; Neshat et al., (2020) Current Opin. Biotechnol. 66:1-10; Ouranidis et al., (2022) Biomedicines, 10, 50; and Qin et al., Signal Transduct Target Ther. (2022) May 21; 7(1):166, each of which is incorporated herein by reference in its entirety.

[00170] If desired, a nanoparticle can target a cell type using, for example, bleaching ligands that recognize a receptor on the target cell. Examples of bleaching ligands include carbohydrates (e.g., galactose, mannose, glucose, and galactomannan), endogenous ligands (e.g., folic acid and transferrin), antibodies, and proteins / peptides (e.g., RGD, epidermal growth factor, and Petition 870250104513, dated 11 / 14 / 2025, page 86 / 242 79 / 212 low-density lipoprotein) and peptides. (For example, Teo et al., Advanced Drug Delivery Reviews (2016), 98, 41).

[00171] Nanoparticles can be used to deliver polynucleotide constructs encoding PPT1 to a cell. In different embodiments, nanoparticles can deliver additional therapeutic compounds; and one or more additional compounds are provided on different nanoparticles. The reference to the compound includes small molecules and large molecules (e.g., therapeutic proteins and antibodies).

[00172] The production of different nanoparticles and the incorporation of nucleic acid and other compounds are well known in the art. Examples of publications illustrating the incorporation of nucleic acid into a specific nanoparticle, such as an LPNP and an LNP, include Teo et al., Advanced Drug Delivery Reviews (2016) 98, 41; Bochicchio et al., Pharmaceutics (2021) 13, 198; Mahzabin and Das, IJPSR (2021) 12(1), 65; and Teixeira et al., (2017) Prog. Lipid Res. Oct; 68:1-11 (each of which is incorporated herein by reference in full). Factors that may impact the incorporation of small molecules into a nanoparticle include hydrophobicity and the presence of an ionizable fraction. (See, for example, Nii and Ishii, Int. J. Pharm. (2005) 298:198-205; and Chen et al., J. Control. Release (2018) 286:46-54). Petition 870250104513, dated 11 / 14 / 2025, page 87 / 242 80 / 212 VI.A. Lipid-Based Delivery System

[00173] Lipid-based delivery systems involve the use of a lipid as a component. Examples of lipid-based delivery systems include liposomes, LNPs, micelles, and extracellular vesicles.

[00174] A “lipid nanoparticle” or “LNP” refers to a lipid-based vesicle useful for delivering nucleic acid molecules and with nanoscale dimensions. In different embodiments, the nanoparticle ranges in size from about 10 nm to about 1000 nm, from about 50 nm to about 500 nm, or from about 50 nm to about 200 nm.

[00175] DNA is negatively charged. Thus, it may be beneficial for LNP to understand a cationic lipid such as, for example, an aminolipid. Exemplary aminolipids are described in U.S. Patents 9,352,042, 9,220,683, 9,186,325, 9,139,554, 9,126,966, 9,018,187, 8,999,351, 8,722,082, 8,642,076, 8,569,256, 8,466,122 and 7,745,651 and in U.S. Patent Publications 2016 / 0213785, 2016 / 0199485, 2015 / 0265708, 2014 / 0288146, 2013 / 0123338, 2013 / 0116307, 2013 / 0064894, 2012 / 0172411 and 2010 / 0117125, all of which are incorporated herein in their entirety. In certain embodiments, LNP comprises aminolipids described in U.S. Patent 9,512,073, which is incorporated herein in its entirety. Petition 870250104513, dated 11 / 14 / 2025, page 88 / 242 81 / 212

[00176] The terms “cationic lipid” and “aminolipid” are used interchangeably in this document to include lipids and their salts that have one, two, three, or more fatty acid or fatty alkyl chains and a pH-titratable amino group (e.g., an alkylamino or dialkylamino group). The cationic lipid is typically protonated (i.e., positively charged) at a pH below the pKa of the cationic lipid and is substantially neutral at a pH above the pKa. Cationic lipids may also be titratable lipids. In certain embodiments, cationic lipids comprise a protonable (e.g., pH-titratable) tertiary amine group; C18 alkyl chains, wherein each alkyl chain may independently have one or more double bonds, one or more triple bonds; and ether, ester, or ketal linkages between the main group and the alkyl chains.

[00177] Cationic lipids include 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-di-ylinolenyloxy-N,N-dimethylaminopropane (γ-DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA, also known as DLin-C2K-DMA, XTC2 and C2K), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-KDMA), dilinoleylmethyl-3-dimethylaminopropionate (DLin-M-C2DMA, also known as MC2), (6Z,9Z,28Z,31Z) Petition 870250104513, dated 11 / 14 / 2025, page 89 / 242 82 / 212 heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (DLin-M-C3-DMA, also known as MC3), salts thereof and mixtures thereof. Other cationic lipids also include 1,2-diestearyloxy-N,N-dimethyl-3-aminopropane (DSDMA), 1,2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), 2,2-dilinoleyl-4-(3-dimethylaminopropyl)-[1,3]-dioxolane (DLin-K-C3-DMA), 2,2-dilinoleyl-4-(3-dimethylaminobutyl)-[1,3]-dioxolane (DLin-KC4-DMA), DLen-C2K-DMA, γ-DLen-C2K-DMA and (DLin-MP-DMA) (also known as 1-B11).

[00178] Other cationic lipids include 2,2-dilinoleyl-5-dimethylaminomethyl-[1,3]-dioxane (DLin-K6-DMA), 2,2-dilinoleyl-4-N-methylpepiazino-[1,3]-dioxolane (DLin-KMPZ), 1,2-dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-dilinoleyloxy-3(dimethylamino)acetoxypropane (DLin-DAC), 1,2-dilinoleyloxy3-morpholinopropane (DLin-MA), 1,2-dilinoleoyl-3dimethylaminopropane (DLinDAP), 1,2-dilinoleylthio-3dimethylaminopropane (DLin-S-DMA), 1-linoleyl-2-linoleyloxy3-dimethylaminopropane (DLin-2-DMAP), chloride salt of 1,2-dilinoleyloxy-3-trimethylaminopropane (DLin-TMA.Cl), 1,2-dilinoleoyl-3-trimethylaminopropane chloride salt (DLinTAP.Cl), 1,2-dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), 3-(N,N-dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-dioleylamino)-1,2-propanediol (DOAP), 1,2Petition 870250104513, of 14 / 11 / 2025, pág. 90 / 242 83 / 212 dilinoleiloxi-3-(2-N,N-dimetilamino)etoxipropane (DLin-EGDMA), chloroethiolate de N,N-dioleil-N,N-dimetilamônio (DODAC), chloroethiolate de N-(1-(2,3-dioleiloxi)propil)-N,N,Ntrimetilamônio (DOTMA), bromethiolate de N,N-diestearyl-N,Ndimetilamônio (DDAB), chloroethiolate de N-(1-(2,3dioleoiloxy)propil)-N,N,N-trimetilamônio (DOTAP), 3-(N(N' ,N'-dimetilaminoethane)-carbamoil)colesterol (DC-Chol), bromethiolate de N-(1,2-dimyristiloxiprop-3-yl)-N,N-dimethyl-Nhidroxietil amônio (DMRIE), 2,3-dioleiloxi-N-[2(esperminacarboxamido)ethyl]-N,N-dimethyl-1-propanamínio trifluoroacetate (DOSPA), dioctadecylidoglycyl espermine (DOGS), 3-dimethylamino-2-(cholest-5-en-3-beta-oxybutan-4oxi)-1-(cis,cis-9,12-octadecadienoxy)propane (CLinDMA), 2[5'-(cholest-5-en-3-beta-oxi)-3'-oxapentoxi)-3-dimethyl-1(cis,cis-9',1-2'-octadecadienoxy)propane (CpLinDMA), N,Ndimethyl-3,4-dioleyloxybenzylamine (DMOBA), 1,2-N,N'dioleylcarbamyl-3-dimethylaminopropane (DOcarbDAP), 1,2N,N'-dilinoleylcarbamyl-3-dimethylaminopropane (DLincarbDAP),dexamethasone-sperimine (DS) and disubstituted spermine (D2S) or mixtures thereof.

[00179] Several commercial preparations of cationic lipids can be used, such as LIPOFECTIN® (including DOTMA and DOPE, available from GIBCO / BRL) and LIPOFECTAMINE® (comprising DOSPA and DOPE, available from GIBCO / BRL).

[00180] Additional ionizable lipids that may be Petition 870250104513, dated 11 / 14 / 2025, p. 91 / 242 84 / 212 used include C12-200, 306O110, MC3, cKK-E12, bCKK-E12, Lipid 5, Lipid 9, ATX-002, ATX-003, and Merck-32. US Patent Application Publication 2017 / 0367988 describes Merck-32.

[00181] In additional embodiments, the cationic lipid may be present in an amount of about 10% molar ratio of LNP to about 85% molar ratio of LNP, or from about 50% molar ratio of LNP to about 75% molar ratio of LNP.

[00182] LNP may comprise a neutral lipid. Neutral lipids may comprise a lipid species existing in a neutral or uncharged zwitterionic form at physiological pH. Such lipids include diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramide, sphingomyelin, dihydrosphingomyelin, cephalin, and cerebrosides. The selection of neutral lipids is generally guided by considerations that include particle size and stability. In certain embodiments, the neutral lipid component may be a lipid with two acyl groups (e.g., diacylphosphatidylcholine and diacylphosphatidylethanolamine).

[00183] Lipids with a variety of acyl chain groups of varying chain length and degree of saturation are available or can be isolated or synthesized. In certain embodiments, lipids containing Petition 870250104513, dated 11 / 14 / 2025, page 92 / 242 85 / 212 saturated fatty acids with carbon chain lengths in the range of C14 to C22. In certain embodiments, lipids with mono- or di-unsaturated fatty acids with carbon chain lengths in the range of C14 to C22 are used. Additionally, lipids with mixtures of saturated and unsaturated fatty acid chains may be used. Exemplary neutral lipids include 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), or phosphatidylcholine. Neutral lipids may also be composed of sphingomyelin, dihydrosphingomyelin, or phospholipids with other major groups such as serine and inositol.

[00184] In additional embodiments, which provide neutral lipids, the neutral lipid may be present in an amount of about 0.1% by weight of LNP to about 99% by weight of LNP, or from about 5% by weight of LNP to about 15% by weight of LNP, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, approximately 90%, approximately 95%, or approximately 99%.

[00185] LNP may contain additional components, Petition 870250104513, dated 11 / 14 / 2025, page 93 / 242 86 / 212 such as sterols and polyethylene glycol. Sterols can impart fluidity to LNPs. As used in this document, sterol refers to a natural sterol of plant (phytosterols) or animal (zoosterols) origin, as well as to non-natural synthetic sterols, all distinguished by the presence of a hydroxyl group at position 3 of ring A of the steroid. Suitable sterols include those conventionally used in the area of ​​liposome, lipid vesicle, or lipid particle preparation, most commonly cholesterol. Phytosterols include campesterol, sitosterol, and stigmasterol. Sterols also include sterol-modified lipids, such as those described in US Patent Application Publication 2011 / 0177156. In different modalities that provide a sterol, the sterol is present in an amount of about 1% by weight of LNP to about 80% by weight of LNP or from about 10% by weight of LNP to about 25% by weight of LNP.

[00186] Polyethylene glycol (PEG) is a water-soluble polymer of repeating ethylene PEG units with terminal hydroxyl groups. PEGs are classified by their molecular weights, for example, PEG 2000 has an average molecular weight of about 2,000 daltons, and PEG 5000 has an average molecular weight of about 5,000 daltons. Commercially available PEGs from Sigma Chemical Co. and other companies include monomethoxypolyethylene glycol. Petition 870250104513, dated 11 / 14 / 2025, page 94 / 242 87 / 212 (MePEG-OH), monomethoxypolyethylene glycol succinate (MePEGS), succinimidyl monomethoxypolyethylene glycol succinate (MePEG-S-NHS), monomethoxypolyethylene glycol amine (MePEGNH2), monomethoxypolyethylene glycol tresylate (MePEG-TRES) and monomethoxypolyethylene glycol imidazolyl carbonyl (MePEGIM).

[00187] In certain embodiments relating to PEG, PEG has an average molecular weight of about 550 to about 10,000 daltons and is optionally substituted with alkyl, alkoxy, acyl, or aryl. In other embodiments, PEG is substituted with methyl at the terminal hydroxyl position. In other embodiments, PEG has an average molecular weight of about 750 to about 5,000 daltons, or about 1,000 to about 5,000 daltons, or about 1,500 to about 3,000 daltons, or about 2,000 daltons, or about 750 daltons.

[00188] PEG-modified lipids include PEG-dialkyloxypropyl (PEG-DAA) conjugates described in U.S. Patents 8,936,942 and 7,803,397. PEG-modified lipids (or lipid-polyoxyethylene conjugates) may feature a variety of lipid anchoring moieties to attach the PEG moiety to the surface of the lipid vesicle. Examples of suitable PEG-modified lipids include PEG-modified phosphatidylethanolamine and phosphatidic acid, PEG-ceramide conjugates (e.g., PEG-CerC14 or Petition 870250104513, dated 11 / 14 / 2025, page 95 / 242 88 / 212 PEG-CerC20), described in US Patent 5,820,873, PEG-modified dialkylamines and PEG-modified 1,2-diacyloxypropan-3-amines. In certain embodiments, the PEG-modified lipid may be PEG-modified diacylglycerols and dialkylglycerols. In certain embodiments, the PEG may be present in an amount of about 0.1% by weight of the LNP to about 50% by weight of the LNP, or from about 5% by weight of the LNP to about 15% by weight of the LNP.

[00189] In additional embodiments relating to LNP size, prior to nucleic acid encapsulation, LNPs have a size range of about 10 nm to 500 nm, or about 50 nm to about 200 nm, or 75 nm to about 125 nm.

[00190] In certain embodiments relating to LNP, LNP is described by Billingsley et al., Nano Lett. 2020, 20, 1578 or Billingsley et al., International Patent Publication WO 2021 / 077066 (both incorporated herein by full reference). Billingsley et al. and WO 2021 / 077066 describe LNPs containing PEG anchored to lipids, cholesterol, phospholipids, and ionizable lipids. In certain embodiments, the LNP contains a C14-4 polyamine core and / or has a particle size of approximately 70 nm. C14-4 exhibits the following structure. Petition 870250104513, dated 11 / 14 / 2025, p. 96 / 242 89 / 212

[00191] In certain embodiments, the LNP consists of a cationic lipid or lipopeptide described by U.S. Patent 10,493,031, U.S. Patent 10,682,374, or International Patent Publication WO2021 / 077066 (each of which is incorporated herein by full reference). In certain embodiments, the LNP contains a cationic lipid, a cholesterol-based lipid, and / or one or more PEG-modified lipids. In certain embodiments, the LNP contains CKK-E12 (Dong et al., PNAS (2014) 111(11), 3955):

[00192] In certain embodiments, LNP comprises a modified form of CKK-E12 referred to in this document as bCKK-E12, with the following structure: Petition 870250104513, dated 11 / 14 / 2025, page 97 / 242 90 / 212

[00193] In certain modalities, LNP comprises Lipid 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 as described by Sabnis et al., Molecular Therapy 2018, 26:6, 1509-1519 (incorporated herein by reference in full). In certain modalities, LNP comprises Lipid 5, 8, 9, 10, or 11 as described in Sabnis et al.

[00194] Lipid 5 from Sabnis et al. has the following structure:

[00195] Lipid 9 from Sabnis et al. has the following structure:

[00196] Additional lipids that can be used Petition 870250104513, dated 11 / 14 / 2025, page 98 / 242 91 / 212 include those described by Roces et al. , Pharmaceuticals, 2020, 12, 1095; Jayaraman et al. , Angew. Chem. Int. Ed., 2012, 51, 8529-8533; Maier et al., www.moleculartherapy.org, 2013, Vol.21, No. 8, 1570-1578; Liu et al., Adv. Mater. 2019, 31, 1902575, for example, BAMEA-O16B; Cheng et al., Adv. Mater., 2018, 30, 1805308, e.g., 5A2-SC8; Hajj et al., Small, 2019 15, 1805097, e.g. 306Oi10; Du et al., publication of US Patent Application 20160376224; and Tanaka et al., Adv. Funct. Mater., 2020, 30, 1910575; each of which is incorporated herein by reference in its entirety.

[00197] In further embodiments, the nanoparticle is an LNP. In further embodiments, the LNP in mol% comprises, consists essentially of, or consists of the following components: (1) one or more cationic lipids from about 20% to 65%, one or more phospholipids from about 1% to about 50%, one or more PEG-conjugated lipids from about 0.1% to 10%, and cholesterol from about 0% to about 70%; or (2) one or more cationic lipids from about 20% to 50%, one or more phospholipids from about 5% to about 20%, one or more PEG-conjugated lipids from about 0.1% to 5%, and cholesterol from about 20% to about 60%. In additional embodiments, phospholipid is a neutral lipid; and phospholipid is DOPE or DSPC.

[00198] In certain modalities, LNP, in % by mole, Petition 870250104513, dated 11 / 14 / 2025, page 99 / 242 92 / 212 comprises, consists essentially of, or consists of the following components: (1) cKK-E12 approximately 35%; C14-PEG2000 approximately 2.5%; cholesterol approximately 46.5%; and DOPE approximately 16%; (2) bCKK-E12 approximately 35%; C14-PEG2000 approximately 2.5%; cholesterol approximately 46.5%; and DOPE approximately 16%; (3) Lipid 9 approximately 50%; C14-PEG2000 approximately 1.5%; cholesterol approximately 38.5%; and DSPC approximately 10%; (4) Lipid 5 approximately 50%; C14-PEG2000 approximately 1.5%; cholesterol approximately 38.5%; and DSPC approximately 10%; (5) ionizable lipid, about 50%; DSPC, about 10%; cholesterol, about 37.5%; and stabilizer (PEG-Lipid), about 2.5%; or (6) is LNP GenVoy-ILMTM (Precision NanoSystems). VI.B. Polymer-based nanoparticles

[00199] Polymer-based delivery systems can be made from a variety of different natural and synthetic materials. DNA and other compounds can be trapped within the polymeric matrix of polymeric nanoparticles or can be adsorbed or conjugated onto the surface of the nanoparticles. Examples of polymers commonly used for nucleic acid delivery include poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), poly(ethyleneimine) (PEI) and PEI derivatives, chitosan, dendrimers, polyanhydride, polycaprolactone, polymethacrylates, poly-L-lysine, pullulan, dextran and hyaluronic acid, poly-ε-aminoesters. (Thomas et al., (2019) Petition 870250104513, dated 11 / 14 / 2025, pp. 100 / 242 93 / 212 Molecules 24, 3744).

[00200] Polymer-based nanoparticles can exhibit different sizes, ranging from about 1 nm to about 1000 nm, from about 10 nm to about 500 nm, from about 50 nm to about 200 nm, from about 100 nm to about 150 nm, and from about 150 nm or less. VI.C. Lipid Polymer Nanoparticles

[00201] Lipid polymer nanoparticles are hybrid nanoparticles that provide both a lipid component and a polymeric component and, as such, can be considered an LNP or LPNP. The LPNP configuration can provide an outer polymer and an inner lipid, or an outer lipid and an inner polymer. The presence of two different types of material facilitates the design of nanoparticles to provide delayed release of a component. Different lipid and polymeric components can be selected taking into account the material to be released. (For example, see Teo et al., Advanced Drug Delivery Reviews (2016) 98, 41; Bochicchio et al., Pharmaceutics (2021) 13, 198; Mahzabin and Das, IJPSR (2021) 12(1), 65; and Teixeira et al., (2017) Prog. Lipid Res. Out; 68:1-11). IV.D. Protein and Peptide-Based Nanoparticles

[00202] Protein- and peptide-based systems can employ a variety of different proteins and peptides. Petition 870250104513, dated 11 / 14 / 2025, pp. 101 / 242 94 / 212 Examples of proteins that can be used include gelatin and elastin. Peptide-based systems can employ, for example, cell-penetrating peptides (CPPs).

[00203] CPPs are short peptides (6 to 30 amino acid residues) potentially capable of intracellular penetration to deliver therapeutic molecules. Most CPPs consist primarily of arginine and lysine residues, making them cationic and hydrophilic, but they can also be amphiphilic, anionic, or hydrophobic. CPPs can be derived from natural biomolecules (e.g., HIV-1 Tat protein) or obtained by synthetic methods (e.g., poly-L-lysine, polyarginine) (Singh et al., Drug Deliv. 2018; 25(1):1996-2006).Examples of CPPs include cationic CPPs (highly positively charged), such as the Tat peptide, penetratin, protamine, poly-L-lysine, and polyarginine; amphipathic CPPs (chimeric or fused peptides, constructed from different sources, containing both positively and negatively charged amino acid sequences), such as transportan, VT5, bactericenin-7 (Bac7), proline-rich peptide (PPR), SAP (VRLPPP)3, TP10, pep-1, and MPG; membranotropic CPPs (exhibiting both hydrophobic and amphipathic nature and comprising large and small aromatic residues), such as H625, SPIONs-PEG-CPP, and NPs; and hydrophobic CPPs (containing only... Petition 870250104513, dated 11 / 14 / 2025, page 102 / 242 95 / 212 reasons or supporting residues), such as SG3, PFVYLI, pep-7 and fibroblast growth factors.

[00204] Protein and peptide nanoparticles can be supplied in different sizes, for example, ranging from about 1 nm to about 1000 nm, from about 10 nm to about 500 nm, from about 50 nm to about 200 nm, from about 100 nm to about 150 nm, or from about 150 nm or less. VI. E. Peptide Cage Nanoparticle

[00205] Peptide cage-based delivery systems can be produced from protein material capable of assembling into a cage-like structure, forming a restricted internal environment. Peptide cages may comprise a protein shell that self-assembles to form a protein cage (e.g., a structure with an internal cavity that is naturally accessible to the solvent or can be obtained by altering solvent concentration, pH, or equilibrium ratios). Protein cage monomers may be naturally occurring or variant forms, including amino acid substitutions, insertions, and deletions (e.g., fragments).

[00206] Different types of protein shells can be assembled and loaded with different types of materials. Protein cages can be produced using viral coat protein(s) (e.g., from the protein coat Petition 870250104513, dated 11 / 14 / 2025, page 103 / 242 96 / 212 of the Goat Bean Chlorotic Spot Virus), as well as non-viral proteins (e.g., U.S. Patents 6,180,389 and 6,984,386, U.S. Patent Publication 20040028694 and U.S. Patent Publication 20090035389, each of which is incorporated herein by full reference).

[00207] Examples of protein cages derived from non-viral proteins include: ferritins and apoferritins derived from eukaryotes or prokaryotes, such as 12- and 24-subunit ferritins; and heat shock proteins (HSPs), such as the class of 24-subunit heat shock proteins that form an internal core space, the small HSP from Methanococcus jannaschii, the dodecameric Dsp HSP from E. coli, and the MrgA protein.

[00208] Protein cages can exhibit different core sizes, ranging from about 1 nm to about 1000 nm, from about 10 nm to about 500 nm, from about 50 nm to about 200 nm, from about 100 nm to about 150 nm, or from about 150 nm or less. VI.F. Exosomes

[00209] Exosomes are small biological membrane vesicles and have been used to transport various cargoes, including small molecules, peptides, proteins, and nucleic acids. Exosomes generally vary Petition 870250104513, dated 11 / 14 / 2025, p. 104 / 242 97 / 212 are approximately 30 nm to 100 nm in size and can be absorbed by a cell and transport its cargo. The cargo may be associated with the exosome's surface structure or may be encapsulated within the exosome bilayer.

[00210] Several modifications can be made to exosomes, facilitating cargo release and cell targeting. Modifications to facilitate cargo release include structures for cargo association, such as protein scaffolds and polymers. Modifications for cell targeting include ligand targeting and surface cargo modification. Publications describing the production, modification, and use of exosomes for the release of different cargoes include Munagala et al., Cancer Letters (2021), 505, 58; Fu et al., (2020) NanoImpact 20, 100261; and Dooley et al., (2021) Molecular Therapy 29(5), 1729 (each of which is incorporated herein by reference). VII. Pharmaceutical Compositions

[00211] The pharmaceutical compositions comprise a pharmaceutically acceptable carrier that facilitates the administration and / or storage of PPT1 polypeptides, which encode polynucleotides, viral vectors or non-viral vectors. The reference to “pharmaceutically acceptable” indicates that the components do not cause substantial undesirable biological effects in the quantity used. Carriers Petition 870250104513, dated 11 / 14 / 2025, page 105 / 242 Pharmaceutically acceptable excipients may contain different components, such as one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include salt, sugar, buffer, solvent, preservative, protein, and surfactant. A specific excipient may have more than one function. Examples of pharmaceutically acceptable excipients and carriers that can be used with viral vectors are provided, for example, in International Patent Publication WO2021 / 071835.

[00212] Pharmaceutical compositions can be formulated to be compatible with a specific route of administration or release. Compositions suitable for parenteral administration include aqueous and non-aqueous solutions, suspensions, or emulsions, which are typically sterile preparations and may be isotonic with the blood of the intended recipient. Illustrative examples include water, buffered saline solution, Hanks' solution, Ringer's solution, dextrose, fructose, ethanol, vegetable oils of animal and synthetic origin. Aqueous suspensions for injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.

[00213] In one embodiment, the pharmaceutical composition contains a formulation capable of being injected into an individual. Examples of injectable formulation components include Petition 870250104513, dated 11 / 14 / 2025, page 106 / 242 99 / 212 isotonic and sterile saline solutions, salts (e.g., monosodium or disodium phosphate, sodium chloride, potassium, calcium or magnesium and mixtures of these salts), buffered saline solution, sugars (e.g., dextrose) and water for injection. Pharmaceutical compositions include dry compositions, for example, lyophilized, which, after the addition of sterile water or physiological saline, allow the formation of solutions suitable for administration.

[00214] Additionally, the suspensions can be prepared as oily suspensions suitable for injection. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, facilitating the preparation of concentrated solutions.

[00215] An “effective amount” or “sufficient amount” refers to an amount that provides an indicated or desired effect. The effective amount may be administered, in single or multiple doses, alone or in combination with one or more other compositions (e.g., additional therapeutic agents or immunosuppressants), treatments, protocols, or therapeutic regimens; and provide a long-term or short-term response. Petition 870250104513, dated 11 / 14 / 2025, page 107 / 242 100 / 212

[00216] Pharmaceutical compositions comprising transgenes encoding PPT1 polypeptides may be administered to an individual in order to enable the production of the encoded protein. Administration may be in vivo or ex vivo. In certain embodiments, the pharmaceutical compositions comprise sufficient genetic material to enable a recipient to produce a therapeutically effective amount of a protein in the individual.

[00217] A “therapeutically effective amount” refers to the quantity of an ingredient or active component that elicits the desired or indicated biological or medicinal response in an individual. A therapeutically effective amount can be determined based on observed symptoms and / or through the use of biomarkers associated with a specific disease or disorder. The selection of a specific effective dose can be optimized by considering different factors, including the disease or disorder to be treated or prevented, the symptoms involved, safety and efficacy in animal models, the patient's body mass, and the patient's immune status. The ideal dose to be used in the formulation will also depend on the route of administration and the severity of the disease or disorder, and can be evaluated depending on the patient's circumstances. Effective doses can be extrapolated from dose-response curves derived from in vitro or in vitro testing systems. Petition 870250104513, dated 11 / 14 / 2025, page 108 / 242 101 / 212 animal models.

[00218] In certain embodiments, a pharmaceutical composition comprising an rAAV vector comprises empty AAV capsids. In certain embodiments, in a pharmaceutical composition comprising rAAV vectors and empty AAV capsids, the ratio of empty AAV capsids to the rAAV vector is in or between about 100:1-50:1, about 50:1-25:1, about 25:1-10:1, about 10:11:1, about 1:1-1:10, about 1:10-1:25, about 1:25-1:50 or about 1:50-1:100. In certain embodiments, the ratio of empty AAV capsids to the rAAV vector is approximately 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1.

[00219] Further guidance and examples of pharmaceutical compositions and delivery systems are provided, for example, in Remington: The Science and Practice of Pharmacy (2020) 23rd ed., University of the Sciences in Philadelphia, published by Elsevier; The Merck Index (2013) 15th ed., Whitehouse, NJ; Pharmaceutical Principles of Solid Dosage Forms (1993), Technomic Publishing Co., Inc., Lancaster, PA; and Ansel and Stoklosa, Pharmaceutical Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, MD. VIII. Administration and Treatment

[00220] PPT1 polypeptides and constructs Petition 870250104513, dated 11 / 14 / 2025, p. 109 / 242 102 / 212 coding polynucleotides, viral vectors, and nonviral vectors can be administered to an individual, preferably a human individual, to provide prophylactic treatment, reducing the likelihood or severity of a disease or disorder and / or treating a diagnosed disease or disorder. In certain embodiments, the specific therapeutic agent, route of administration, and / or pharmaceutical composition are selected taking into account the specific disease or disorder to be treated.

[00221] Individuals with a specific disease or disorder, or at increased risk of a specific disease or disorder, can be identified, for example, based on symptoms, PPT1 activity, biomarkers, and genetic markers. Treatment can be carried out, for example, in individuals at increased risk of developing NCL1 symptoms and individuals diagnosed with NCL1.

[00222] NCL1 is a progressive autosomal recessive neurodegenerative disease, whose symptoms vary depending on the onset. The main symptoms include: onset at birth (congenital), microcephaly, dysmorphic features, seizures, and hyperkinetic activity; onset between 6 and 18 months (infantile), decreased head growth, neurodevelopmental regression, and seizures; onset between 2 and 4 years (variant), seizures, neurodevelopmental regression, and behavioral disorders; and onset Petition 870250104513, dated 11 / 14 / 2025, page 110 / 242 103 / 212 between 5 and 7 years (juvenile), visual loss and cognitive decline. (Simonati and Williams (2022) Front. Neurol. 11;13:811686.)

[00223] Different mutations are associated with NCL1. References that provide examples of mutations associated with NCL1 include Sheth et al., (2018) BMC Neurol. 12;18(1):203; Kumar et al., Advances in Protein Chemistry and Structural Biology (2022) 132:89-109; Kousi et al., (2012) Hum. Mutat. 33(1):42-63; and hyperlink: / / www.uniprot.org / uniprotkb / P50897 / entry#disease_variants (January 17, 2023); each of which is incorporated herein by reference in its entirety.

[00224] Due to the progressive nature of NCL1, early treatment is very important. In certain modalities, treatment is initiated before the identification of the main symptoms. Such patients can be identified, for example, based on the level of PPT1 enzyme activity and / or the presence of PPT1 mutations.

[00225] In certain modalities, treatment is performed on a patient diagnosed with NCL1. Diagnosis may be based on symptoms, genetic testing, and / or measurement of enzyme activity.

[00226] Potential routes of administration include subcutaneous, epidermal, intradermal, intrathecal, intraorbital, intramucosal, intranasal, intraperitoneal, Petition 870250104513, dated 11 / 14 / 2025, page 111 / 242 104 / 212 intravenous, intrapleural, intra-arterial, intracavitary, oral, intrahepatic, portal vein, intramuscular, intraparenchymal, intracisternal, intracranial, intracystinal magna, intracerebroventricular or intraventricular. In certain modalities, viral or nonviral vectors are administered to a patient via infusion in a pharmaceutical vehicle.

[00227] Appropriate routes of administration should provide therapeutic delivery to the CNS. CNS administration can be performed via different initial routes of administration, including outside the CNS, for example, intravenous administration outside the brain and spinal cord and into the eye (e.g., intravitreal and subretinal); and direct administration to the brain (e.g., intraparenchymal, intracerebroventricular, and intracisternal) and / or spinal column (e.g., intrathecal). (Zhu et al., (2021) Trends Mol. Med. 27(6):524-537, incorporated herein by full reference.)

[00228] When the initial site of administration is outside the brain, administration to the brain can be facilitated using techniques that provide transport across the blood-brain barrier. Examples of such techniques include disruption of the blood-brain barrier and the use of blood-brain barrier carriers (Chen et al., (2021) J. Control. Petition 870250104513, dated 11 / 14 / 2025, p. 112 / 242 105 / 212 Release 333: 129-138; Bellettato and Scrapa, Italian Journal of Pediatrics (2018) 44(Suppl 2):131; Haumann et al., (2020) SNC Drugs 34, 1121-1131; and Cammalleri et al., (2020) J. Clin. Neurophysiol. 37(2):104-117; each of which is incorporated herein by reference in full). Techniques that facilitate crossing the blood-brain barrier may be used in the delivery vehicle and / or in the PPT1 protein.

[00229] In certain modalities, treatment is performed using expression systems that provide polypeptide expression outside the CNS (e.g., high hepatic expression) in combination with techniques that facilitate PPT1 transport across the blood-brain barrier.

[00230] In certain modalities, treatment is performed using techniques that facilitate the crossing of the blood-brain barrier by the delivery vehicle. In another modality, crossing the blood-brain barrier is facilitated using focused ultrasound in combination with microbubbles (see, for example, Cammalleri et al., (2020) J Clin Neurophysiol. 37(2):104-117, incorporated herein by reference in its entirety).

[00231] In certain embodiments, an AAV capsid is used that provides crossing of the blood-brain barrier or the CNS. Examples of such capsids are provided in Chen et al., (2021) J. Control. Version 333:129-138 (e.g., AAV9, AAV-PHP-B, AAV-PHP.eB, AAVrh.10, AAVrh.8, AAVHSC, AAV-B1, Petition 870250104513, dated 11 / 14 / 2025, p. 113 / 242 106 / 212 AAV-AS and AAV1 / rh.10), US Patent 9,585,971 and US Patent Publication US202 / 1214749, each of which is incorporated herein by reference in its entirety.

[00232] Administration to the CNS can also be performed, for example, by direct administration into the brain using needles or catheters. (For example, International Publication WO 2021 / 108809; Cohen-Pferrer et al., Pediatric Neurology 67 (2017) 23-35; and US Patent 10,369,329; each of which is incorporated herein by full reference.)

[00233] Another example of a technique for administration in the CNS is enhanced convection delivery. Enhanced convection delivery comprises surgical exposure of the brain followed by placement of a catheter directly into the target area, followed by infusion of a therapeutic agent (e.g., US Patent Publication 2022 / 010001; and Debinski et al., (2009) Expert Rev Neurother. 9(10):1519-27; both of which are incorporated herein by reference in full).

[00234] CNS release devices, systems and techniques also include those described, for example, in US Patent 8128600, US Patent Publication 2020 / 0324089, US Patent 11129643, US Patent 11154377, US Patent Publication 2021 / 0343397, Publication of Petition 870250104513, dated 11 / 14 / 2025, page 114 / 242 107 / 212 US Patent 2021 / 0282866, US Patent 9572928, US Patent 8337458, US Patent 10722265 and US Patent Publication 2021 / 214749, each of which is incorporated by reference herein in its entirety.

[00235] The release of the PPT1 polypeptide and the encoding nucleic acid may also provide a benefit in the treatment of PPT1 deficiency or defective lysosomal storage outside the CNS. In certain modalities, administration provides systemic release. In other modalities, treatment involves the use of an expression cassette or viral vectors comprising a ubiquitous or promiscuous promoter. In other modalities, entry into the CNS is facilitated using techniques and / or vectors that facilitate transport across the blood-brain barrier.

[00236] In certain embodiments, the expression cassette comprises a PGK promoter, a CBh promoter or an E1F alpha promoter.

[00237] Ideal doses may vary depending on different factors, such as a specific therapeutic goal, the desired outcome, and the route of administration. The amount, number, frequency, or duration of the dose may be increased or decreased proportionally, taking into account adverse side effects, complications, or other risk factors of the treatment or therapy and the individual's condition. Petition 870250104513, dated 11 / 14 / 2025, page 115 / 242 108 / 212

[00238] A “unit dosage form” refers to a physically discrete unit containing a predetermined effective amount of active ingredient in combination with a pharmaceutically acceptable carrier. Unit dosage forms may be provided, for example, in ampoules and vials, which may include a pharmaceutically acceptable carrier, or as a freeze-dried or lyophilized composition. In the case of a freeze-dried or lyophilized state, a sterile liquid carrier may be added prior to administration. Individual unit dosage forms may be included in multidose kits or containers.

[00239] An “effective amount” achieves the desired or indicated effect. For example, an effective amount for treatment decreases one or more adverse symptoms, reduces the likelihood of one or more symptoms associated with a disease or disorder, or reduces the progression of the disease or disorder. Preferred effective amounts for treatment are effective in decreasing multiple or all adverse symptoms.

[00240] In certain embodiments, a pharmaceutical composition is administered to an individual at a dose adequate to increase PPT1 activity. In certain embodiments, the dose is sufficient to increase PPT1 activity by at least 5%, at least 10%, by Petition 870250104513, dated 11 / 14 / 2025, pp. 116 / 242 109 / 212 minus 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of normal activity; approximately 10% to 200% of average activity, 20% to 150% of average activity, 30% to 100% of average activity; or approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 100%, approximately 110%, approximately 120%, approximately 130%, approximately 140%, or approximately 150% of average activity. In certain modalities, PPT1 activity increases the average activity by 10X, 100X, or 1000X. Average activity refers to the average activity occurring in the general population.

[00241] In different modalities, an appropriate dosage is approximately 0.01 mg / kg to approximately 10 mg / kg of vector per kg of body weight of an individual, approximately 0.01 mg / kg to approximately 0.1 mg / kg of vector per kg of body weight of an individual, approximately 0.1 mg / kg to approximately 1.0 mg / kg of vector per kg of body weight of an individual, or approximately 1.0 mg / kg to approximately 10 mg / kg of vector per kg of body weight of an individual.

[00242] In general, rAAV doses range from at least 1x10⁸ vector genome per kilogram (vg / kg) of the individual's weight, or more, for example, 1x10⁹, 1x10¹⁰, 1x10¹¹, 1x10¹², 1x10¹³ or 1x10¹⁴, or more, vector genome per kilogram (vg / kg) of the individual's weight, to achieve a Petition 870250104513, dated 11 / 14 / 2025, page 117 / 242 110 / 212 therapeutic effect. In different modalities, the dose of rAAV is approximately 5X10¹¹rAAV vg / kg or greater than approximately 5X10¹¹rAAV vg / kg; approximately 1x10¹²rAAV vg / kg or greater than approximately 1x10¹²rAAV vg / kg; approximately 2x10¹²rAAV vg / kg or greater than approximately 2x10¹²rAAV vg / kg; approximately 3x10¹²rAAV vg / kg or greater than approximately 3x10¹²rAAV vg / kg; approximately 4x10¹²rAAV vg / kg or greater than approximately 4x10¹²rAAV vg / kg; approximately 5x10¹²rAAV vg / kg or greater than approximately 5x10¹²rAAV vg / kg; approximately 1x1013rAAV vg / kg or greater than approximately 1x1013rAAV vg / kg; approximately 2x1013rAAV vg / kg or greater than approximately 2x1013rAAV vg / kg; approximately 3x1013rAAV vg / kg or greater than approximately 3x1013rAAV vg / kg; approximately 4x1013rAAV vg / kg or greater than approximately 4x1013rAAV vg / kg; approximately 5x1013rAAV vg / kg or greater than approximately 5x1013rAAV vg / kg; approximately 6x1013rAAV vg / kg or greater than approximately 6x1013rAAV vg / kg.

[00243] Examples of rAAV vg / kg dose ranges include a dose range of approximately 5x1011 to approximately 6x1013 rAAV vg / kg; a dose range of approximately 5x1011 to approximately 5.5x1011 rAAV vg / kg; a dose range of approximately 5.5x1011 to approximately 6x1011 rAAV vg / kg; a dose range of approximately 6x1011 to approximately 6.5x1011 rAAV vg / kg; a dose range of approximately 6.5x1011 to approximately 7x1011 rAAV vg / kg; a dose range of approximately 7x1011 to approximately 7.5x1011 rAAV vg / kg; a dose range of approximately 7.5 x 10¹¹ to approximately 8 x 10¹¹ rAAV vg / kg; a dose range of approximately 8 x 10¹¹ to approximately 8.5 x 10¹¹ Petition 870250104513, dated 11 / 14 / 2025, pp. 118 / 242 111 / 212 rAAV vg / kg; a dose range of approximately 8.5x1011 to approximately 9x1011 rAAV vg / kg; a dose range of approximately 9x1011 to approximately 9.5x1011 rAAV vg / kg; a dose range of approximately 9.5x1011 to approximately 1x1012 rAAV vg / kg; a dose range of approximately 1x1012 to approximately 1.5x1012 rAAV vg / kg; a dose range of approximately 1.5x1012 to approximately 2x1012 rAAV vg / kg; a dose range of approximately 2x1012 to approximately 2.5x1012 rAAV vg / kg; a dose range of approximately 2.5x10¹² to approximately 3x10¹² rAAV vg / kg; a dose range of approximately 3x10¹² to approximately 3.5x10¹² rAAV vg / kg; a dose range of approximately 3.5x10¹² to approximately 4x10¹² rAAV vg / kg; a dose range of approximately 4x10¹² to approximately 4.5x10¹² rAAV vg / kg; a dose range of approximately 4.5x10¹² to approximately 5x10¹² rAAV vg / kg; a dose range of approximately 5x10¹² to approximately 5.5x10¹² rAAV vg / kg; a dose range of approximately 5.5x10¹² to approximately 6x10¹² rAAV vg / kg; a dose range of approximately 6x1012 to approximately 6.5x1012rAAV vg / kg;a dose range of approximately 6.5 x 10¹² to approximately 7 x 10¹² rAAV vg / kg; a dose range of approximately 7 x 10¹² to approximately 7.5 x 10¹² rAAV vg / kg; a dose range of approximately 7.5 x 10¹² to approximately 8 x 10¹² rAAV vg / kg; a dose range of approximately 8 x 10¹² to approximately 8.5 x 10¹² rAAV vg / kg; a dose range of approximately 8.5 x 10¹² to approximately 9 x 10¹² rAAV vg / kg; a dose range of approximately 9 x 10¹² to approximately 9.5 x 10¹² rAAV vg / kg; a dose range of approximately 9.5 x 10¹² to approximately 1 x 10¹³ rAAV vg / kg; a dose range of; Petition 870250104513, dated 11 / 14 / 2025, pp. 119 / 242 112 / 212 approximately 1x1013 to approximately 1.5x1013rAAV vg / kg; a dose range of approximately 1.5x1013 to approximately 2x1013rAAV vg / kg; a dose range of approximately 2x1013 to approximately 2.5x1013rAAV vg / kg; a dose range of approximately 2.5x1013 to approximately 3x1013rAAV vg / kg; a dose range of approximately 3x1013 to approximately 3.5x1013rAAV vg / kg; a dose range of approximately 3.5x1013 to approximately 4x1013rAAV vg / kg; a dose range of approximately 4x1013 to approximately 4.5x1013rAAV vg / kg; a dose range of approximately 4.5x10¹³ to approximately 5x10¹³ rAAV vg / kg; a dose range of approximately 5x10¹³ to approximately 5.5x10¹³ rAAV vg / kg; a dose range of approximately 5.5x10¹³ to approximately 6x10¹³ rAAV vg / kg; a dose range of approximately 6x10¹³ to approximately 1x10¹⁴ rAAV vg / kg.

[00244] In certain modalities, rAAV vg / kg are administered at a dose of approximately 5x10¹¹ vg / kg, approximately 6x10¹¹ vg / kg, approximately 7x10¹¹ vg / kg, approximately 8x10¹¹ vg / kg, approximately 9x10¹¹ vg / kg, approximately 1x10¹² vg / kg, approximately 2x10¹² vg / kg, approximately 3x10¹² vg / kg, approximately 4x10¹² vg / kg, approximately 5x10¹² vg / kg, approximately 6x10¹² vg / kg, approximately 7x10¹² vg / kg, approximately 8x10¹² vg / kg, approximately 9x10¹² vg / kg, approximately 1x10¹³ vg / kg, approximately 2x1013vg / kg, about 3x1013vg / kg, about 4x1013vg / kg, about 5x1013vg / kg, or about 6x1013vg / kg.

[00245] In certain modalities, doses and dose ranges for other viral vectors are as provided in this document with respect to rAAV. For example, in certain Petition 870250104513, dated 11 / 14 / 2025, pp. 120 / 242 113 / 212 modalities, the dose and dose range for recombinant adenoviral vectors, recombinant retrovirus vectors (e.g., lentivirus), and recombinant herpes simplex virus vectors is the same as illustrated previously with respect to rAAV.

[00246] In different modalities, an appropriate dosage for PPT1 administration is approximately 0.01 mg / kg to approximately 25 mg / kg of protein per kg of an individual's body weight, or approximately 0.1 mg / kg to approximately 1.0 mg / kg of protein per kg of an individual's body weight.

[00247] In certain embodiments, the polypeptide constructs, polynucleotide constructs, viral vectors, and nonviral vectors described in this document are administered in combination with additional compounds or treatments for a specific disease or disorder; and / or in combination with a compound that reduces an immune response generated against the polypeptide, polynucleotide, and / or delivery vehicle provided or produced. Additional compounds or treatments may be provided in different embodiments, such as administered separately; and administered or performed before, substantially simultaneously with, or after the administration of the polypeptide constructs, encoding polynucleotide constructs, viral vectors, and nonviral vectors described in this document. Petition 870250104513, dated 11 / 14 / 2025, pp. 121 / 242 114 / 212

[00248] In certain embodiments, the administration of polypeptide constructs, coding polynucleotide constructs, viral vectors, and nonviral vectors described in this document is done in combination with an immunosuppressive agent or regimen. Such agents and regimens may be used, as needed, to achieve immunological tolerance or mitigate the immune response to the produced PPT1 protein, the provided polynucleotides, or the provided delivery vehicles. Examples of immunosuppressive agents and regimens include methotrexate, rituximab, intravenous immunoglobulin (IVIG), omalizumab, ImmTOR® (synthetic vaccine particle (SVP)-rapamycin (rapamycin encapsulated in a biodegradable nanoparticle)), ImmTORIL™ (ImmTOR with a Treg-selective IL-2 agonist), B-cell depletion, immunoadsorption, and plasmapheresis.

[00249] In certain embodiments, the viral or non-viral vector is administered in conjunction with one or more immunosuppressive agents, where one or more immunosuppressive agents are administered before, substantially at the same time as, or after the administration of the vector or non-viral vector. In certain embodiments, the immunosuppressive agent(s) is / are administered concomitantly with the vector or non-viral vector. In certain embodiments, the immunosuppressive agent(s) is / are administered 1-12, 12-24, or 24-48 hours; or 2-4, 4-6, 6-8, 8-10, 10-14, 14-20, 20-25, Petition 870250104513, dated 11 / 14 / 2025, pages 122 / 242 115 / 212 25-30, 30-50 days, or more than 50 days before administration of the viral or non-viral vector. In certain embodiments, the immunosuppressive agent(s) is / are administered 1-12, 12-24, or 24-48 hours; or 2-4, 4-6, 6-8, 8-10, 10-14, 14-20, 20-25, 25-30, 30-50 days, or more than 50 days, after administration of the viral or non-viral vector. The administration of immunosuppressive agents after a period of time following the administration of the vector or non-viral vector may be carried out, for example, if there is a decrease in the encoded protein after the initial expression levels for a period of time, for example, 20-25, 25-30, 30-50, 50-75, 75-100, 100-150, 150-200 or more than 200 days after the administration of the vector or non-viral vector.

[00250] In certain embodiments, the immunosuppressive agent is an anti-inflammatory agent. In certain embodiments, the immunosuppressive agent is a steroid, for example, a corticosteroid. In certain embodiments, the immunosuppressive agent is prednisone, prednisolone, calcineurin inhibitor (e.g., cyclosporine, tacrolimus), MMF (mycophenolic acid, e.g., CellCept®, Myfortic®), CD52 inhibitor (e.g., alemtuzumab), CTLA4-Ig (e.g., abatacept, belatacept), anti-CD3 mAb, anti-LFA-1 mAb (e.g., efalizumab), anti-CD40 mAb (e.g., ASKP1240), anti-CD22 mAb (e.g., epratuzumab), anti-CD20 mAb (e.g., rituximab, orelizumab, Petition 870250104513, dated 11 / 14 / 2025, pp. 123 / 242 116 / 212 ofatumumab, veltuzumab), proteasome inhibitor (e.g., bortezomib), TACI-Ig (e.g., atacicept), anti-C5 mAb (e.g., eculizumab), mycophenolate, azathioprine, sirolimus-everolimus, TNFR-Ig, anti-TNF mAb, tofacitinib, anti-IL-2R (e.g., basiliximab), anti-IL-17 mAb (e.g., secukinumab), anti-IL-6 mAb (e.g., anti-IL-6 antibody sirukumab), anti-IL-6 receptor antibody tocilizumab (Actemra®), IL-10 inhibitor, TGF-beta inhibitor, a B-cell directed antibody (e.g., rituximab), a mammalian target of rapamycin (mTOR) inhibitor (e.g., rapamycin), synthetic vaccine particle (SVPTM)-rapamycin (rapamycin encapsulated in a biodegradable nanoparticle), intravenous gamma globulin (IVIG), omalizumab, methotrexate, a tyrosine kinase inhibitor (e.g., ibrutinib), cyclophosphamide, fingolimod, a B-cell activating factor (BAFF) inhibitor (e.g., anti-BAFF mAb, e.g., belimumab),an inhibitor of a proliferation-inducing ligand (APRIL), an anti-IL-1b mAb (e.g., canakinumab (Haris®)), a C3a inhibitor, a Tregitope (see, for example, US Patent 10,213,496) or a combination and / or derivative thereof.

[00251] Immunosuppression protocols, including the use of rapamycin, alone or in combination with IL-10, may be used to decrease, reduce, inhibit, prevent or Petition 870250104513, dated 11 / 14 / 2025, pp. 124 / 242 117 / 212 block humoral and cellular immune responses to the PPT1 protein. Liver gene transfer with viral vector (e.g., rAAV) and non-viral vector can be used to induce immunological tolerance to the PPT1 protein through the induction of regulatory T cells (Tregs).

[00252] Strategies to reduce (overcome) or avoid humoral immunity to viral vectors, such as rAAV, in systemic gene transfer include: administration of high doses of vectors; use of empty AAV capsids as decoys to adsorb anti-AAV antibodies; administration of immunosuppressive drugs to decrease, reduce, inhibit, prevent, or eradicate the humoral immune response to rAAV; alteration of the rAAV capsid serotype or engineering of the rAAV capsid to make it less susceptible to neutralizing antibodies; use of plasma exchange cycles to adsorb anti-AAV immunoglobulins, thus reducing the anti-AAV antibody titer; and use of administration techniques such as balloon catheters followed by saline flushing. Such strategies are described in Mingozzi et al., (2013) Blood, 122:23-36.Additional strategies include the use of AAV-specific plasmapheresis columns to selectively deplete anti-AAV antibodies without depleting the total plasma immunoglobulin pool, as described in Bertin et al., 2020, Sci. Rep. 10:864. Similar techniques and strategies. Petition 870250104513, dated 11 / 14 / 2025, pages 125 / 242 118 / 212 can be used for other types of viral vectors.

[00253] Empty capsids used as decoy probes can be provided in different ratios to viral vectors. The amounts of empty capsids administered can be calibrated based on the amount (titration) of antibodies produced in a specific individual. In certain embodiments, the ratio between empty AAV capsids and rAAV vector is in or between approximately 100:150:1, approximately 50:1 to 25:1, approximately 25:1 to 10:1, approximately 10:1 to 1:1, approximately 1:1 to 1:10, approximately 1:10 to 1:25, approximately 1:25 to 1:50, or approximately 1:50 to 1:100. In specific aspects, the ratio between the administered empty AAV capsids and the rAAV vector is approximately 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. Preferably, the serotype of the empty capsids is the same as the serotype of the rAAV.

[00254] Strategies to reduce humoral immunity to rAAV (which can be applied to other viral vectors) include methods to remove, deplete, capture, and / or inactivate antibodies against AAV, commonly called apheresis and, more particularly, plasmapheresis when dealing with blood products. Apheresis, or plasmapheresis, is a process in which the plasma of a human individual is circulated ex vivo (extracorporeal) through a device that modifies the plasma by adding, removing, and / or Petition 870250104513, dated 11 / 14 / 2025, pp. 126 / 242 119 / 212 Replacement of components before their return to the patient. Plasmapheresis can be used to remove human immunoglobulins (e.g., IgG, IgE, IgA, IgD) from a blood product (e.g., plasma). This procedure can be employed to deplete, capture, inactivate, reduce, or remove immunoglobulins (antibodies) that bind to AAV, thus reducing the antibody titer against AAV in the treated individual, which may contribute to the neutralization of rAAV. An example is the use of a device composed of an affinity matrix column for the AAV capsid and the passage of a blood product (e.g., plasma) through an affinity matrix for the AAV capsid, resulting in the binding of antibodies to AAV of different isotypes. (See, for example, Bertin et al., (2020) Sci. Rep. 10, 864, incorporated herein by reference in full.)

[00255] In certain embodiments, polypeptide constructs encoding polynucleotide constructs, viral vectors, and nonviral vectors may be used in combination with an agent that blocks, inhibits, or reduces the interaction of IgG with the neonatal Fc receptor (FcRn), such as an anti-FcRn antibody, to reduce IgG recycling and increase IgG clearance in vivo; and / or an agent that decreases circulating antibodies that bind to a PPT1 polypeptide encoding nucleic acid or delivery vehicle. In certain embodiments, antibody binding Petition 870250104513, dated 11 / 14 / 2025, pp. 127 / 242 120 / 212 is reduced or inhibited by an agent that reduces the interaction of IgG with FcRn, a protease, or a glycosidase.

[00256] In certain embodiments, the polypeptide constructs, polynucleotide constructs, viral vectors, and nonviral vectors described in this document are used in combination with an endopeptidase (e.g., IdeS from Streptococcus pyogenes) or a modified variant thereof, or an endoglycosidase (e.g., EndoS from S. pyogenes) or a modified variant thereof. Such treatment may, for example, be performed to reduce or eliminate neutralizing antibodies and allow treatment of patients previously considered ineligible for treatment. Such strategies are described, for example, in Leborgne et al., (2020) Nat. Med., 26:1096-1101.

[00257] In certain modalities, the treatment method in an individual is performed in combination with a compound that reduces the native expression of mutant PPT1, resulting in a mutant PPT1 with reduced activity. The expression of mutant PPT1 can be inhibited, for example, using inhibitory nucleic acid that selectively targets mutant PPT1 coding sequences. The reference to “selective targeting” of mutant PPT1 activity indicates that the expression of the polynucleotide encoding the PPT1 protein, providing increased activity, is not significantly affected. The inhibitory nucleic acid can Petition 870250104513, dated 11 / 14 / 2025, pp. 128 / 242 121 / 212 can be provided in the same polynucleotide and / or vector that encodes the PPT1 protein or using a separate viral or nonviral vector. Examples of inhibitory nucleic acids include a short hairpin RNA (shRNA), a small interfering RNA (siRNA), a microRNA (miRNA), a ribozyme, and an antisense RNA. IX. Kits

[00258] The present invention includes kits with packaging material and one or more components contained therein. A kit typically includes a label or leaflet, including a description of the components or instructions for in vitro, in vivo, or ex vivo use of the components contained therein. A kit may contain a set of such components, for example, PPT1 polypeptide, a viral or non-viral vector, and optionally, a second active ingredient, such as another compound, agent, drug, or composition.

[00259] A kit refers to a physical structure that houses one or more components. The packaging material may keep the components sterile and may consist of materials commonly used for such purposes, such as paper, corrugated fiber, glass, plastic, metal foil, ampoules, vials, and tubes.

[00260] Labels or package inserts may include identifying information for one or more components, dosages, clinical pharmacology of the active ingredient(s), Petition 870250104513, dated 11 / 14 / 2025, pp. 129 / 242 122 / 212 including mechanism of action, pharmacokinetics, and pharmacodynamics. Labels or package inserts may include manufacturer identification information, batch numbers, place and date of manufacture, and expiration dates. Labels or package inserts may include information about a disease for which a component of the kit may be used. Labels or package inserts may include instructions for the clinician or individual on the use of one or more components of the kit in a method, use, treatment protocol, or therapeutic regimen. Instructions may include dosage amounts, frequency or duration, and instructions for the practice of any of the methods, uses, treatment protocols, or prophylactic or therapeutic regimens described in this document.

[00261] Labels or package inserts may include information about one or more benefits that a component may provide, such as a prophylactic or therapeutic benefit. Labels or package inserts may include information about potential adverse side effects, complications, or reactions, such as warnings to the clinician or individual about situations in which it would not be appropriate to use a specific composition. Adverse side effects or complications may also occur when the individual is taking, is taking, or has taken one or more medications that may be incompatible with the composition, or if the individual has taken, is taking, or has taken another treatment protocol or regimen. Petition 870250104513, dated 11 / 14 / 2025, pages 130 / 242 123 / 212 therapeutic which would be incompatible with the composition and therefore the instructions may include information about such incompatibilities.

[00262] Labels or inserts include “printed material”, for example, paper or cardboard, either separate from or affixed to a component, kit or packaging material (for example, a box), or attached to an ampoule, tube or vial containing a component of the kit. Labels or inserts may additionally include computer-readable media, such as a printed barcode label, a disc, an optical disc such as a CD-ROM or DVD-ROM / RAM, DVD, MP3, magnetic tape, or an electrical storage medium such as RAM and ROM, or hybrids thereof, such as magnetic / optical storage media, FLASH media or memory cards. X. mRNA Therapy

[00263] In certain embodiments, the RNA versions of the nucleic acid encoding the PPT1 polypeptides described in this document are provided as an mRNA construct capable of expressing the encoded polypeptide within a cell. The mRNA construct comprises a 5' cap, a 5' UTR, the coding RNA, the 3' UTR, and a poly(A) tail. The UTRs and the poly(A) tail may perform different functions, such as participating in the subcellular localization of the mRNA, regulating translation efficiency, and mRNA stability. The design and Petition 870250104513, dated 11 / 14 / 2025, pp. 131 / 242 124 / 212 The production of mRNA constructs, including different modifications, is illustrated in different publications, such as Ouranidis et al., (2022) Biomedicines, 10, 50; Qin et al., Signal Transduct Target Ther. (2022) 21;7(1):166, and US Patent Publication 2013 / 0259924, each of which is incorporated herein by reference in its entirety.

[00264] In certain embodiments, the mRNA construct is delivered to a cell or individual using nanoparticles. Examples of nanoparticles include those provided in Sections VI (including VI.A. to VI.E. above), Ouranidis et al., (2022) Biomedicines, 10, 50, and US Patent Publication 2013 / 0259924. XI. Additional Aspects and Modalities

[00265] Additional aspects, modalities and examples of combinations thereof include the following: 1) A polynucleotide comprising a nucleic acid sequence encoding a palmitoylprotein thioesterase-1 (PPT1) polypeptide, wherein said PPT1 polypeptide comprises an amino acid sequence of PPT1 with at least 95% identity, at least 97% identity, or at least 99% identity to the sequence with SEQ ID NO: 1, wherein: (a) said polypeptide PPT1 further comprises a signal sequence of any of the SEQ ID NOS: 16-27 or Petition 870250104513, dated 11 / 14 / 2025, pp. 132 / 242 125 / 212 a variant thereof with an amino acid substitution, deletion or insertion; and / or (b) said PPT1 amino acid sequence comprises a substitution of glycine (G), valine (V) or leucine (L) for aspartic acid (D) at its amino terminus; and / or (c) said PPT1 sequence comprises the leucine-glutamine histidine-leucine amino acid sequence at its N terminus; and / or (d) said nucleic acid sequence comprises a sequence encoding PPT1 with at least 85% identity, at least 90% identity, at least 95% identity, at least 99% identity, or 100% identity with any of the SEQ ID Nos: 61-94.

[00266] 2) The polynucleotide of 1, wherein said polypeptide PPT1 additionally comprises said signal sequence comprising the sequence of any of the SEQ ID NOs: 16-27.

[00267] 3) The 2-nucleotide polynucleotide, wherein said nucleic acid comprises a signal coding sequence of any of the SEQ ID Nos: 43-58.

[00268] 4) The polynucleotide of 2, wherein said polypeptide comprises said signal sequence of any of the SEQ ID NOS: 16-21 and 24-27.

[00269] 5) The 4-strand polynucleotide, wherein the said signal sequence comprises the sequence of SEQ ID NOs: 16 or Petition 870250104513, dated 11 / 14 / 2025, pp. 133 / 242 126 / 212 19.

[00270] 6) The 5-nucleotide polynucleotide, wherein said signal sequence comprises the sequence with SEQ ID NO: 16 and said nucleic acid sequence comprises the signal coding sequence with SEQ ID NO: 43 or said signal peptide comprises the sequence with SEQ ID NO: 19 and said nucleic acid sequence comprises the signal coding sequence with SEQ ID NO: 50.

[00271] 7) The polynucleotide of 2, in which said polypeptide comprises the signal coding sequence of SEQ ID NO: 23.

[00272] 8) The polynucleotide of 7, wherein the so-called nucleic acid sequence comprises the signal coding sequence of SEQ ID NO: 54.

[00273] 9) Any polynucleotide from 1 to 6, wherein said amino acid sequence of PPT1 comprises a substitution of G, V, or L for aspartic acid D at its amino terminus and said amino acid sequence of PPT1 has at least 95% identity, at least 97% identity, or at least 99% identity with SEQ ID NO: 1; or comprises SEQ ID NO: 1.

[00274] 10) The 9-nucleotide polynucleotide, wherein the so-called PPT1 amino acid sequence comprises the sequence SEQ ID NO: 2, wherein X is G, X is V, or X is L.

[00275] 11) The polynucleotide of any of 1 to Petition 870250104513, dated 11 / 14 / 2025, pp. 134 / 242 127 / 212 3, 7 or 8, wherein said PPT1 sequence comprises the leucine-glutamine-histidine leucine amino acid sequence at its N-terminus and said PPT1 amino acid sequence exhibits at least 95% identity, at least 97% identity, or at least 99% identity with the sequence of SEQ ID NO: 1.

[00276] 12) The polynucleotide of 11, where the so-called PPT1 sequence comprises SEQ ID NO: 4.

[00277] 13) The polynucleotide of any one from 1 to 12, wherein said nucleic acid comprising a sequence encoding PPT1 comprises a sequence with at least 85% identity, at least 90% identity, at least 95% identity, at least 99% identity with any of the SEQ ID NOs: 61-94, or comprising any of the SEQ ID NOs: 61-94; In additional embodiments, the sequence encoding PPT1 comprises a sequence with at least 85% identity, at least 90% identity, at least 95% identity, or at least 99% identity to any of the SEQ ID Nos: 62-64, 71, 74, 78, 79, or 83;In additional embodiments, the sequence encoding PPT1 comprises a sequence with at least 85% identity, at least 90% identity, at least 95% identity, at least 99% identity with, or includes, the sequence of any of the following SEQ ID Nos: 62-64, 71, 74; Petition 870250104513, dated 11 / 14 / 2025, pages 135 / 242 128 / 212 78, 79, or 83; in a further embodiment, the sequence encoding PPT1 comprises a sequence with at least 85% identity, at least 90% identity, at least 95% identity, at least 99% identity with, or comprises the sequence with SEQ ID NO: 64; in a further embodiment, the sequence encoding PPT1 comprises a sequence with at least 85% identity, at least 90% identity, at least 95% identity, at least 99% identity with, or comprises the sequence with SEQ ID NO: 79.

[00278] 14) The polynucleotide of 1, wherein said polypeptide PPT1 comprises a sequence with at least 99% identity to any of the SEQ ID NOs: 31-42 or comprises any of the SEQ ID NOs: 31-42.

[00279] 15) The 14-nucleotide polynucleotide, in which said PPT1 polypeptide comprises the sequence SEQ ID NO: 31 or SEQ ID NO: 34.

[00280] 16) The polynucleotide of 15, wherein said polypeptide PPT1 comprises the sequence with SEQ ID NO: 31 and said nucleic acid comprises a sequence with a sequence identity of at least 85% identity, at least 90% identity, at least 95% identity, at least 99% identity with any of the SEQ ID NOs: 107-125, and 168; or said polypeptide PPT1 comprises the sequence with SEQ ID NO: 31 where X is G and said nucleic acid comprises a sequence with an identity of Petition 870250104513, dated 11 / 14 / 2025, pp. 136 / 242 129 / 212 sequence of at least 85% identity, at least 90% identity, at least 95%, at least 99% identity with any of the SEQ ID NOs: 107-125 or comprises any of the SEQ NOs: 107-125 and 168. In a further embodiment, said polypeptide PPT1 comprises the sequence of SEQ ID NO: 31 wherein X is G and said nucleic acid comprises a sequence with a sequence identity of at least 85% identity, at least 90% identity, at least 95%, at least 99% identity with SEQ ID NO: 64 or comprises the sequence of SEQ ID NO: 64; In a further embodiment, said polypeptide PPT1 comprises the sequence SEQ ID NO: 31 wherein X is G and said nucleic acid comprises a sequence with a sequence identity of at least 85% identity, at least 90% identity, at least 95%, at least 99% identity with SEQ ID NO: 79 or comprises the sequence SEQ ID NO: 79.

[00281] 17) The polynucleotide of 15, wherein said polypeptide PPT1 comprises the sequence with SEQ ID NO: 34 and said nucleic acid comprises a sequence with a sequence identity of at least 85%, at least 90%, at least 95%, at least 99% identity with any of the SEQ ID NOs: 126-140, and 161-167; or said polypeptide PPT1 comprises the sequence with SEQ ID NO: 34 where X is G and said nucleic acid comprises a sequence with a sequence identity of at least 85% Petition 870250104513, dated 11 / 14 / 2025, pp. 137 / 242 130 / 212 identity, at least 90% identity, at least 95% identity, at least 99% identity with any of the SEQ ID Nos: 126-140, and 161-167 or comprises any of the SEQ Nos: 126-140, and 161-167.

[00282] 18) The polynucleotide of 1, in which said polypeptide PPT1 comprises the sequence SEQ ID NO: 38.

[00283] 19) A palmitoyl-protein thioesterase-1 (PPT1) polypeptide comprising an amino acid sequence of PPT1 with at least 95% identity, at least 97% identity, at least 99% identity with the sequence of SEQ ID NO: 1, where: (a) said polypeptide PPT1 further comprises a signal sequence of any of the SEQ ID NOs: 16-27 or a variant thereof with an amino acid substitution, deletion or insertion; and / or (b) said amino acid sequence of PPT1 comprises a substitution of glycine (G), valine (V) or leucine (L) for aspartic acid (D) at its amino terminus; and / or (c) said PPT1 sequence comprises the amino acid sequence leucine-glutamine-histidine-leucine at its N terminus.

[00284] 20) Polypeptide 19, wherein said polypeptide PPT1 additionally comprises a signal sequence comprising the sequence of any of the SEQ ID NOS: 16-27. Petition 870250104513, dated 11 / 14 / 2025, pp. 138 / 242 131 / 212

[00285] 21) Polypeptide 20, wherein said polypeptide comprises a signal sequence of any of the SEQ ID NOS: 16-21 and 24-27.

[00286] 22) The polypeptide of 21, wherein the so-called signal sequence comprises the sequence of either of the SEQ ID NOs: 16 or 19.

[00287] 23) The polypeptide of 20, in which said polypeptide comprises a signal sequence of SEQ ID NO: 23.

[00288] 24) The polypeptide of any one of 19 to 23, wherein said amino acid sequence of PPT1 comprises a substitution of G, V, or L for aspartic acid D at its amino terminus and said amino acid sequence of PPT1 has at least 97% identity, or at least 99% identity with the sequence of SEQ ID NO: 1.

[00289] 25) The 24-aminopeptide, in which the so-called PPT1 amino acid sequence comprises the sequence SEQ ID NO: 2, where X is G.

[00290] 26) The polypeptide of 19, wherein said PPT1 sequence comprises the amino acid sequence leucine-glutamine histidine-leucine at its N-terminus and said PPT1 amino acid sequence has at least 97% or at least 99% identity with the sequence of SEQ ID NO: 1.

[00291] 27) The polypeptide of 26, in which the said Petition 870250104513, dated 11 / 14 / 2025, pages 139 / 242 Sequence 132 / 212 of PPT1 comprises SEQ ID NO: 4.

[00292] 28) Polypeptide 19, wherein said polypeptide PPT1 comprises a sequence with at least 99% identity or 100% identity with any of the SEQ ID NOS: 31-42.

[00293] 29) Polypeptide 28, wherein said polypeptide PPT1 comprises the sequence SEQ ID NO: 31 wherein X is G, SEQ ID NO: 34 wherein X is G, or SEQ ID NO: 38.

[00294] 30) A polynucleotide comprising a nucleic acid sequence encoding polypeptide PPT1, wherein said PPT1-coding nucleic acid sequence encodes polypeptide PPT1 from any one of 19 to 29.

[00295] 31) A polynucleotide comprising two or more exons that together encode the PPT1 polypeptide of any one of 19 to 29, and one or more introns.

[00296] 32) The polynucleotide of any one of 1 to 18, 30 or 31, wherein said polynucleotide is an expression cassette comprising one or more expression control elements operationally linked to said nucleic acid encoding said polypeptide PPT1.

[00297] 33) The 32-nucleotide, wherein said nucleic acid encoding said polypeptide PPT1 is operationally linked to an upstream promoter and a downstream polyadenylation signal. Petition 870250104513, dated 11 / 14 / 2025, pp. 140 / 242 133 / 212

[00298] 34) The 32-nucleotide, wherein said expression cassette comprises 5' to 3', operationally linked to said nucleic acid encoding said polypeptide PPT1, a promoter, a kozak sequence, said nucleic acid sequence encoding polypeptide PPT1, and a polyadenylation signal.

[00299] 35) The 33 or 34 polynucleotide, wherein said promoter comprises a sequence with at least 95% identity, at least 97% identity, or at least 99% identity with the sequence of SEQ ID NO: 5 or comprises SEQ ID NO: 5 or said promoter comprises a sequence with at least 95% identity, at least 97% identity, or at least 99% identity with the sequence of SEQ ID NO: 173 or comprises SEQ ID NO: 173.

[00300] 36) The polynucleotide of any one of 33 to 35, wherein said polyadenylation signal operationally linked to the nucleotide sequence encoding PPT1 comprises a sequence with at least 95% identity, at least 97% identity, or at least 99% identity with the sequence of SEQ ID NO: 6, or comprises SEQ ID NO: 6.

[00301] 37) The polynucleotide of any one of 32 to 36, wherein said expression cassette comprises a nucleotide sequence with at least 95% identity, at least 97% identity with the sequence of any of the SEQ ID Nos: 141-143, or comprises any of the SEQ Petition 870250104513, dated 11 / 14 / 2025, pp. 141 / 242 134 / 212 ID Nos: 141-143; or said expression cassette comprises a nucleotide sequence with at least 95% identity, at least 97% identity with SEQ ID No: 169 or comprises SEQ ID No: 169; or said expression cassette comprises a nucleotide sequence with at least 95% identity, at least 97% identity with SEQ ID No: 170 or comprises SEQ ID No: 170.

[00302] 38) The polynucleotide of any one of 1 to 18, and 30-37, wherein said polynucleotide is DNA.

[00303] 39) A recombinant viral vector nucleic acid comprising any polynucleotide from 1 to 18 and 30 to 38, and 5' and / or 3' viral elements providing viral packaging and replication.

[00304] 40) The recombinant viral vector nucleic acid of 39, wherein said recombinant viral vector nucleic acid is DNA and comprises an adeno-associated virus (AAV) repeat unit (ITR) flanking the 5' terminus of said polynucleotide and an AAV ITR flanking the 3' terminus of said polynucleotide.

[00305] 41) The recombinant viral vector nucleic acid of 40, wherein said recombinant viral vector nucleic acid comprises a 5' ITR and a 3' ITR of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.10, AAVrh.74 or AAV3B.

[00306] 42) Viral vector nucleic acid Petition 870250104513, dated 11 / 14 / 2025, pages 142 / 242 135 / 212 recombinant of 40, wherein said ITR 5' comprises a sequence with at least 95% identity, at least 97% identity, at least 99% identity with the sequence of SEQ ID NO: 8 or comprises SEQ ID NO: 8; and said ITR 3' comprises a sequence with at least 95% identity, at least 97% identity, at least 99% identity with the sequence of SEQ ID NO: 9 or comprises SEQ ID NO: 9.

[00307] 43) The recombinant viral vector nucleic acid of any of 39 to 42, further comprising a polyadenylation sequence operationally linked to said ITR 3'.

[00308] 44) The recombinant viral vector nucleic acid of any one of 39 to 43, additionally comprising one or more filler sequences.

[00309] 45) The recombinant viral vector nucleic acid of any one of 39 to 44, wherein said recombinant viral vector nucleic acid comprises a sequence with at least 95% identity, at least 97% identity, at least 99% identity, or 100% identity to the sequence of any of the SEQ ID Nos: 144-154; or said recombinant viral vector nucleic acid comprises a sequence with at least 95% identity, at least 97% identity, at least 99% identity, or 100% identity to the sequence SEQ ID No: 171; or said recombinant viral vector nucleic acid comprises Petition 870250104513, dated 11 / 14 / 2025, pp. 143 / 242 136 / 212 a sequence with at least 95% identity, at least 97% identity, at least 99% identity, or 100% identity with the sequence SEQ ID NO: 172.

[00310] 46) A gene delivery vehicle comprising a viral or non-viral vector and the polynucleotide of any one from 1 to 18, 30 to 38, or the nucleic acid of recombinant viral vector of any one from 39 to 45.

[00311] 47) The gene delivery vehicle of 46, wherein said gene delivery vehicle is a viral vector.

[00312] 48) The gene delivery vehicle of 47, wherein said viral vector is a recombinant AAV vector, a recombinant lentiviral vector, or a recombinant adenoviral vector.

[00313] 49) The gene delivery vehicle of 48, wherein said viral vector is a recombinant AAV vector, and said recombinant AAV vector comprises a capsid comprising a VP1, VP2 or VP3 with at least 90% identity, at least 95% identity, or 100% identity with a VP1, VP2 or VP3 sequence of any of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.74, AAV3B, AAV-2i8, AAVrh.10, AAVrh.8, AAVHSC, AAV-B1, AAV-AS, AAV1 / rh.10, SEQ ID NO: 12 or SEQ ID NO: 15.

[00314] 50) The gene delivery vehicle of 49, wherein said capsid is an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.74, AAV3B, AAV Petition 870250104513, dated 11 / 14 / 2025, pp. 144 / 242 137 / 212 2i8, AAVrh.10, AAVrh.8, AAVHSC, AAV-B1, AAV-AS, or AAV1 / rh.10 capsid; or said capsid comprises VP1 of SEQ ID NO: 12 or SEQ ID NO: 15; in a further embodiment the capsid comprises VP1 comprising a sequence of SEQ ID NO: 12, VP2 comprising a sequence of SEQ ID NO: 13, and VP3 comprising a sequence of SEQ ID NO: 14.

[00315] 51) The gene delivery vehicle of 46, wherein said gene delivery vehicle is the non-viral vector.

[00316] 52) The gene delivery vehicle of 51, wherein said nonviral vector is a nanoparticle selected from the group consisting of a lipid nanoparticle (LNP), a polymeric nanoparticle, a lipid polymer nanoparticle (LPNP), a protein or peptide-based nanoparticle, a DNA dendrimer or DNA-based nanocarrier, a carbon nanotube, a microparticle, a microcapsule, an inorganic nanoparticle, a peptide cage nanoparticle, and an exosome.

[00317] 53) Gene release from vehicle 52, wherein the said nonviral vector is an LNP or LPNP.

[00318] 54) A pharmaceutical composition comprising the polynucleotide of any one from 1 to 18 or 30 to 38, the polypeptide of any one from 19 to 29, the recombinant viral vector nucleic acid of any one from 39 to 45, or the gene delivery vehicle of any one from 46 to 53, and a Petition 870250104513, dated 11 / 14 / 2025, pages 145 / 242 138 / 212 pharmaceutically acceptable carrier.

[00319] 55) A method for increasing PPT1 in an individual comprising administering to the individual the polynucleotide of any one from 1 to 18 or 30 to 38, the polypeptide of any one from 19 to 29, the recombinant viral vector nucleic acid of any one from 39 to 45, or the gene delivery vehicle of any one from 46 to 53, or the pharmaceutical composition of 54.

[00320] 56) A method for treating neuronal ceroid lipofuscinosis 1 in an individual, comprising administering to the individual the polynucleotide of any one from 1 to 18 or 30 to 38, the polypeptide of any one from 19 to 29, the recombinant viral vector nucleic acid of any one from 39 to 45, or the gene delivery vehicle of any one from 46 to 53, or the pharmaceutical composition of 54.

[00321] 57) The method of 55 or 56, wherein said administration comprises intraparenchymal, intracystinal or intraventricular administration. In additional embodiments, administration is intraventricular; and administration is intraventricular and results in significant release of rAAV at least in the frontal cortex, parietal cortex, temporal cortex, occipital cortex, thalamus, cerebellar cortex, hippocampus, corpus callosum, spinal cord, caudate nucleus, choroid plexus, optic chiasm, fornix, periaquaductal gray matter, olfactory bulb, and optic nerve. Petition 870250104513, dated 11 / 14 / 2025, pages 146 / 242 139 / 212

[00322] 58) The method of 55 or 56, in which said administration comprises initial administration outside the central nervous system (CNS).

[00323] 59) The method of anyone from 55 to 58, in which said administration is systemic.

[00324] 60) The method of anyone aged 55 to 59, wherein the said individual is a human.

[00325] 61) An AAV vector genome plasmid comprising recombinant viral vector nucleic acid of any 39 to 45.

[00326] 62) The AAV genome plasmid of 61, in which said plasmid does not possess the rep and cap genes.

[00327] 63) A method for producing an rAAV vector comprising the step of cultivating an rAAV-producing cell line comprising rAAV helper virus activity, wherein the genome of said producing cell comprises recombinant viral vector nucleic acid of any one of 39 to 45, a rep gene and a cap gene, wherein said rAAV vector is produced.

[00328] 64) A method for producing an rAAV vector comprising the step of culturing an rAAV-permissive cell comprising the AAV genome plasmid of 61 or 62, wherein said rAAV-permissive cell further comprises (a) rep and cap genes provided either as part of the cell genome or by one or more plasmids Petition 870250104513, dated 11 / 14 / 2025, pp. 147 / 242 140 / 212 separate, and (b) helper virus activity provided by the cell genome and / or provided by one or more separate plasmids.

[00329] 65) The method of 64, wherein said rAAV-permissive cell is a packaging cell, wherein the genome of said packaging comprises a cap gene and a rep gene.

[00330] 66) The method of 64, wherein (a) said rep gene, said cap gene and said auxiliary activity are provided in a single plasmid or (b) said rep gene and said cap gene are provided by a rep / cap plasmid and said auxiliary activity is provided by an auxiliary plasmid.

[00331] 67) A method for obtaining an rAAV vector comprising the steps of (a) producing the rAAV using the method of any of the methods in 63 to 67 and (b) purifying the rAAV. XII. Sequences

[00332] Table 2 provides different nucleic acid and amino acid sequences. In some cases, variable sequences are observed in the description. The underlying notes indicate the signal sequence when present in a complete PPT1 sequence. Some nucleic acid sequences indicated in bold provide a codon. The reference to derived in relation to a signal amino acid sequence indicates that a modification has been made to the native sequence. Petition 870250104513, dated 11 / 14 / 2025, pages 148 / 242 141 / 212

[00333] In different embodiments, a polynucleotide comprises a nucleic acid sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% for any of the nucleic acid sequences provided in Table 2; a polynucleotide comprises a nucleic acid sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% for any of the nucleic acid sequences provided in Table 2, wherein the stop codon shown in bold is not present and / or is replaced by a different stop codon; or a polypeptide comprises an amino acid sequence with a sequence identity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% for any of the amino acid sequences provided in Table 2. Table 2 SEQ ID NO PPT1 madura 1 Native Madura DPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMEDVENSFFLNVNSQVTTVCQ ALAKDPKLQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGQHQGVFSHICLPRCPGERKTL NAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKNLMALKKFVMVKFLNDSIVD PVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDHLQLSEEWFYAHIIPFLG 2 Na Madurai XPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMEDVENSFFLNVNSQVTTVCQ ALAKDPLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGLPRCPGESSHICDFIRKTL NAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNLMALKKFVMVKFLNDSIVD PVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDHLQLSEEWFYAHIIPFLG Onde, Não G3 Madura, or Vão G3 LPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGTLMEDVENSFFLNVNSQVTTVCQALAKD PKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGLPRCPGESSHICDFIRKTLNAGAY SKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKNLMALKKFVMVKFLNDSIVDPVDSE Petition 870250104513, of 14 / 11 / 2025, p. 149 / 242 142 / 212 WFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDHLQLSEEWFYAHIIPFLG 4 Não Nativa Madura LQHLDPPAPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMEDVENSFFLNVNSQVT TVCQALAKDPKLQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGLPRCPGESSHICDFI RKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNLMALKKFVMVKFLND SIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDHLQLSEEWFYAHIIP FLG Components 5 Promoter EF1A GGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCAGTCCCCGAGAAGTTGGGGGGGGGGGGGGG GCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCG CCTTTTTCCCGAGGGTGGGGGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAAC GGGTTTGCCGCCAGAACACAG 6 BGHpCA CTACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCTTGCCTTCCTTGACCCTGGAAGG TGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCACATTGTCTGAGTAGGTGTCATTCT ATTCTGGGGGGTGGGGTGGGCAGGACAAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGG ATGCAGTGGGCTCTATGG 7 pA synthetic CACACAAAAAACCAACACACAGATGTAATGAAAATAAAGATCCTTTATT 8 variant ITR v11CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTT TGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCC T 9 ITR 3’ AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACC AAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAG G 10 5’ITR CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCG CAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCT 11 Íntron GTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTA CTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAG GCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGC GTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTT GATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGG TATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGG GGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTG GCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGG GCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGG AGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTGGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGG GGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCAC TTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAG TGGTTCAAAGTTTTTTTCTTCCATTTCAG Proteína de Capsídeo 12 VP1 MAADGYLPDWLEDNLSEGIREWWDLKPGAPKPKANQQKQDNGRGLVLPGYKYLGPFNGLDKGEPVNAADA AALEHDKAYDQQLQAGDNPYLRYNHADAEFQERLQEDTSFGGNLGRAVFQAKKRVLEPLGLVESPVKTAP GKKRPVEPSPQRSPDSSTGIGKKGQQPAKKRLNFGQTGDSESVPDPQPIGEPPAAPSGVGPNTMAAGGGA PMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGSTNDNTYFGYST PWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFTDSE YQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFEFSYNFED VPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNNMSAQAKNWLPGPCYRQQR VSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSSGVLMFGKQGAGKDNVDYSSVMLTSEEEIKTTNPVATEQYGVVADNLQQQNAAPIVGAVNSQGALPGMVWQNRDVYLQGPIWAKIPHTDGN FHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQAKLASFITQYSTGQVSVEIEWELQKENSKRWNPE Petition 870250104513, dated 11 / 14 / 2025, pages 150 / 242 143 / 212 IQYTSNYYKSTNVDFAVNTEGTYSEPRPIGTRYLTRNL 13 VP2 MAPGKKRPVEPSPQRSPDSSTGIGKKGQQPAKKRLNFGQTGDSESVPDPQPIGEPPAAPSGVGPNTMAAG GGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGSTNDNTYFG YSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQVFT DSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFEFSYN FEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNNMSAQAKNWLPGPCYR QQRVSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSSGVLMFGKQGAGKDNVDY SSVMLTSEEEIKTTNPVATEQYGVVADNLQQQNAAPIVGAVNSQGALPGMVWQNRDVYLQGPIWAKIPHT DGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQAKLASFITQYSTGQVSVEIEWELQKENSKRW NPEIQYTSNYYKSTNVDFAVNTEGTYSEPRPIGTRYLTRNL 14 VP3 MAAGGGAPMADNNEGADGVGSSSGNWHCDSTWLGDRVITTSTRTWALPTYNNHLYKQISNGTSGGSTNDN TYFGYSTPWGYFDFNRFHCHFSPRDWQRLINNNWGFRPKRLNFKLFNIQVKEVTQNEGTKTIANNLTSTI QVFTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFE FSYNFEDVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNNMSAQAKNWLPGPCYRQQRVSTTLSQNNNSNFAWTGATKYHLNGRDSLVNPGVAMATHKDDEERFFPSSGVLMFGKQGAGKD NVDYSSVMLTSEEEIKTTNPVATEQYGVVADNLQQQNAAPIVGAVNSQGALPGMVWQNRDVYLQGPIWAK IPHTDGNFHPSPLMGGFGLKHPPPQILIKNTPVPADPPTTFNQAKLASFITQYSTGQVSVEIEWELQKEN SKRWNPEIQYTSNYYKSTNVDFAVNTEGTYSEPRPIGTRYLTRNL 15 VP1 MAADGYLPDWLEDNLSEGIREWWALQPGAPKPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADA AALEHDKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAP GKKRPVDQSPQEPDSSSGVGKSGKQPARKRLNFGQTGDSESVPDPQPLGEPPAAPTSLGSNTMASGGGAP MADNNEGADGVGNSSGNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISSQSGASNDNHYFGYSTPWG YFDFNRFHCHFSPRDWQRLINNNWGFRPKKLSFKLFNIQVKEVTQNDGTTTIANNLTSTVQVFTDSEYQL PYVLGSAHQGCLPPFPADVFMVPQYGYLTLNNGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYTFEDVPF HSSYAHSQSLDRLMNPLIDQYLYYLNRTQGTTSGTTNQSRLLFSQAGPQSMSLQARNWLPGPCYRQQRLS KTANDNNNSNFPWTAASKYHLNGRDSLVNPGPAMASHKDDEEKFFPMHGNLIFGKEGTTASNAELDNVMI TDEEEIRTTNPVATEQYGTVANNLQSSNTAPTTRTVNDQGALPGMVWQDRDVYLQGPIWAKIPHTDGHFH PSPLMGGFGLKHPPPQIMIKNTPVPANPPTTFSPAKFASFITQYSTGQVSVEIEWELQKENSKRWNPEIQSignal Peptides 16 Sp7 (human chymotrypsinogen B2 signal peptide) 17 NGF (nerve growth factor signal peptide) 18 Insulin signal peptide 19 SPARC (secreted acidic protein-cysteine ​​rich signal peptide) 20 CD33 signal peptide 21 IL34 (interleukin 34 signal peptide) 22 OSM (oncostatin M signal peptide) 23 tPA (tissue plasminogen activator-derived signal peptide) MDAMKRGLCCVLLLCGAVFVSPSARA 24 IL2 (Interleukin-2 derived signal peptide) MYRMQLLSCIALSLALVLLSARA 25 Trypsin-derived signal peptide MNLLLILTFVAAAVVIRA 26 BDNF-1 (Brain-derived neurotrophic factor signal peptide) MTILFLTMVISYFGCARA 27 BDNF-2 (Brain-derived neurotrophic factor signal peptide) MTILFLTMVISYFGCAKA 28 Native PPT1 signal peptide Petition 870250104513, dated 11 / 14 / 2025, pp. 151 / 242 144 / 212 MASPGCLWLLAVALLPWTCASRALQHL Full-length PPT1 (signal sequence is underlined) 29 Native full-length PPT1 protein MASPGCLWLLAVALLPWTCASRALQHLDPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSL EIGKTLMEDVENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVG GQHQGVFGLPRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERG INESYKKNLMALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQL VFLATEGDHLQLSEEWFYAHIIPFLG 30 MASPPGCLWLLAVALLPWTCASRALQHLXPPAPPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSL EIGKTLMEDVENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVG where X is G,V ou L 31 MAFLWLLSCWALLGTTFGXPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMED VENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGL PRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNL MALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDH LQLSEEWFYAHIIPFLG em que X é D, G, V ou L 32 MSMLFYTLITAFLIGIQAXPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMED VENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGL PRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNL MALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDH LQLSEEWFYAHIIPFLG em que X é D, G, V ou L 33 MALWMRLLPLLALLALWGPDPAAAXPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIG KTLMEDVENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQH QGVFGLPRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINE SYKKNLMALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFL ATEGDHLQLSEEWFYAHIIPFLG em que X é D, G,V ou L 34 MRAWIFFLLCLAGRALAXPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMEDV ENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGLP RCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNLM ALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDHL QLSEEWFYAHIIPFLG em que X é D, G, V ou L 35 MPLLLLLPLLWAGARAXPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMEDVE NSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGLPR CPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNLMA LKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDHLQ LSEEWFYAHIIPFLG onde X é D, G, V ou L 36 MPRGFTWLRYLLLGIFLGVARGXPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKT LMEDVENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQG VFGLPRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESY KKNLMALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLAT EGDHLQLSEEWFYAHIIPFLG onde X é D, G, V ou L, Petition 870250104513, dated 11 / 14 / 2025, pp. 152 / 242 145 / 212 37 MGVLLTQRTLLSLVLALLFPDARALPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLME DVENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFG LPRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKN LMALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGD HLQLSEEWFYAHIIPFLG 38 MDAMKRGLCCVLLLCGAVFVSPSARALQHLDPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYV LSLEIGKTLMEDVENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLI SVGGQHQGVFGLPRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQ ERGINESYKKNLMALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNA GQLVFLATEGDHLQLSEEWFYAHIIPFLG 39 MYRMQLLSCIALSLALVLLSARAXPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGK TLMEDVENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQ GVFGLPRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINES YKKNLMALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLA TEGDHLQLSEEWFYAHIIPFLG onde X é D, G,V ou L 40 MNLLLILTFVAAAVVIRAVXLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMEDVEN SFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGLPRC PGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNLMAL KKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDHLQL SEEWFYAHIIPFLG onde X é D, G, V ou L 41 MTILFLTMVISYFGCARAXPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMED VENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGL PRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNL MALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDH LQLSEEWFYAHIIPFLG onde X é D, G, V ou L 42 MTILFLTMVISYFGCAKAXPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEKKIPGIYVLSLEIGKTLMED VENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQFLRAVAQRCPSPPMINLISVGGQHQGVFGL PRCPGESSHICDFIRKTLNAGAYSKVVQERLVQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNL MALKKFVMVKFLNDSIVDPVDSEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDH LQLSEEWFYAHIIPFLG onde X é D, G,V ou L Ácido nucleico que codifica sequência sinal 43 Sp7-F ATGGCCTTTCTGTGGCTGCTGTCCTGCTGGGCCCTGCTGGGGACCACCTTTGGC 44 Sp7-P ATGGCCTTCCTGTGGCTGCTGTCCTGCTGGGCACTGCTGGGCACCACATTTGGC 45 Sp7-3 ATGGCCTTCCTGTGGCTGCTGAGCTGCTGGGCCCTGCTGGGGACCACCTTTGGG 46 Sp7-4 ATGGCCTTCCTGTGGCTCCTGAGCTGCTGGGCCCTCCTGGGGACCACCTTTGGG 47 Sp7-5 ATGGCCTTCCTGTGGCTGCTGAGCTGCTGGGCCCTGCTGGGGACCACATTTGGC 48 NGF-1 ATGTCCATGTTGTTCTACACTCTGATCACAGCTTTTCTGATCGGCATACAGGCG 49 Insulina-1 ATGGCCCTGTGGATGCGCCTCCTGCCCCTGCTGGCGCTGCTGGCCCTCTGGGGACCTGACCCAGCCGCAG CC 50 SPARC-1 ATGAGGGCCTGGATCTTCTTTCTCCTTTGCCTGGCCGGGAGGGCCTTGGCA 51 CD33-1 ATGCCGCTGCTGCTACTGCTGCCCCTGCTGTGGGCAGGGGCCAGGGCT, Petição 870250104513, de 14 / 11 / 2025, pág. 153 / 242 146 / 212 52 IL-34-1 ATGCCCCGGGGCTTCACCTGGCTGCGCTATCTTCTGCTGGGGATCTTCCTTGGCGTGGCCAGGGGG 53 OSM-1 ATGGGGGTACTGCTCACACAGAGGACGCTGCTCAGTCTGGTCCTTGCACTCCTGTTTCCAGACGCTAGAG CC 54 tPA-1 ATGGATGCAATGAAGAGAGGGCTCTGCTGTGTGCTGCTGCTGTGTGGAGCAGTCTTCGTTTCGCCCAGCG CCAGAGCC 55 IL2-1 ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCCTGCTGTCTGCCAGGGCC 56 Tripsina-1 ATGAATCTACTTCTGATCCTTACCTTTGTTGCAGCTGCTGTTGTGATTAGGGCA 57 BDNF-1 ATGACAATCCTCTTCCTGACCATGGTGATTAGCTACTTTGGCTGCGCTAGGGCC 58 BDNF-2 ATGACAATCCTCTTCCTGACCATGGTGATTAGCTACTTTGGCTGCGCTAAGGCC 59 PPT1 nativa ATGGCGTCGCCCGGCTGCCTGTGGCTCTTGGCTGTGGCTCTCCTGCCATGGACCTGCGCTTCTCGGGCGC TGCAGCATCTG Sequências que codificam PPT1 madura 60 PPT1 madura nativa GACCCGCCGGCGCCGCTGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCA TGGGTGCTATTAAAAAAATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAA GACCCTGATGGAGGACGTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAG GCACTTGCTAAGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCAGAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCA AGGTGTTTTTGGACTCCCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTG AATGCTGGGGGCGTACTCCAAAGTTGAGATCGACCTAGGACCTAGGACCATGACCATCA AGGAGGATGTGTATCGCAACCACAGCATCTTCTTGGCAGATAATAAATCAGGAGCGGGGTATCAATGAGTC CTACAAGAAAAACCTGATGGCCCTGAAGAAGTTTGATGGTGAAATTCCTCAATGATTCCATTTGTGGAC CCTGTAGATTCGGAGTGGTTTGGATTCAGACCAGCAGACCAGGATCGATCGATCGATC CCTCCCTGTACACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGC TACAGAAGGGGACCATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATCCTTGGATAA Em variants do mesmo, nucleotides 1 a 3, or L D, codificam D, V1 7-PPT1co1 GGCCCCCCAGCACCTCTTCCCCTGGTGATCTGGCATGGCATGGGGGATAGCTGCTGCAATCCTCTCTCAA TGGGAGCCATTAAAGATGGTGGAGAAGAAATCCAGGGATATATGTTCTGTCCTTGGAGATTGGAAA AACCTTGATGGAAGATGTGGAAAATAGCTTTTTCCTTAATGTGAACTCTCAAGTCACCACAGTGTGCCAG GCCCTGGCCAAGGACCCCAAGCTGCAGCAAGGCTACAATGGGGCTTCTCCCAAGGAGGTCAATTCC TGAGGGCTGTTGCACAGAGGTCCCAGTCCCCGATCGATCGCCGCCGAGCCAGGCCAGAGGTGTCTTTGGGCTCCCCAGGTGTCCAGGGGAGAGCAGCCACATCTGTGACTTCATTAGAAAGACACTA AATGCAGGAGCCTACAGCAAGGTGGTGCAGGAGAGGCTTGTTCAGGCTGAGTACTGGCATGACCCCATTA AGGAAGATGTCTATAGAAACCACAGCATCTCCATGAGACCATGAAGCAGAGAGATTAGA TTACAAGAAGAATCTTATGGCCCTCAAGAAGTTTGATGGTGAAGTTCCTGAATGACTCCATTGTTGAC CCTGTGGACTCTGAATGGTTTGGTTTCTACAGATCAGGACAAGCCAAGGAAACAATCCCCCTGCAAGAGA CCTCCCTGTACACCCAGGACAGGCTGGGCCTGAAAGAAATGGATAATGCTGGCCAACTGGTCTTCCTGGC AACTGAAGGGGACCACCTGCAACTCTCTGAGGAATGGTTCTATGCTCACATCATCCCATTTGGGCTG Em variants of the same, nucleotides codified 1 or 3, or D6 L PPT1co2 GGCCCACCTGCACCACTTCCCTTGGTCATCTGGCATGGCATGGGTGACTCTTGCTGCAATCCCTTATCCA TGGGGGCTATTAAAGATGGTGGAAAGAAGATTCCTGGAATTTATGCTGAGTCTGGAAATTGGAAA GACCCTCATGGAAGATGTTGAAAACAGCTTCTTCTTTGAATGTCAATTCCCAGGTCACCACAGGTGTGTCAG GCTCTGGCAAAGGACCCCAAGCTCCAGCAAGGATATAATGCCATGGGATTTTCCCAAGGTGGCCAGTTCC TGAGGGCAGTGGCTCAGAGATGCCTTCACCCCTTGATTGTCGATTGTCGTC GGGTGTCTTTGGGCTCCCAAGATGCCCAGGAGAAAGCTCTCACATCTGTGACTTTTAGAAAGACCCTGAATGCTGGGGCTTACAGCAAGGTTGTCCAGGAGAGGCTGGTGCAGGCTGAATACTGGCATGACCCCATTA Petition 870250104513, dated 11 / 14 / 2025, pages 154 / 242 147 / 212 AGGAAGATGTGTACAGAAACCACAGTATCTTCTTGGCTGATATCAACCAAGAAAGAGGCATCAATGAGAG CTACAAGAAGAATCTCATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATAGCATTGTGGAC CCTGTAGACTCAGAGTGGTTTGGATTCTACAGGTCTGGCCAGGCTAAGGAGACCATCCCACTGCAAGAGA CAAGCCTTTACACACAGGACAGGCTTGGTCTGAAAGAGATGGATAATGCTGGACAGCTGGTGTTTCTGGC CACTGAAGGGGACCACCTGCAGCTGAGTGAAGAATGGTTCTATGCCCACATCATCCCCTTCTTAGGCTG Em variantes do mesmo, nucleotideos 1 a 3 codificam G, D,V ou L 63 PPT1co3 GGGCCCCCAGCACCCCTGCCTCTGGTCATTTGGCATGGCATGGGGGACTCCTGCTGCAATCCCTTATCCA TGGGGGCCATCAAGAAGATGGTGGAGAAGAAGATCCCTGGAATTTATGTTCTGTCTTAGAAAATAGGAAA AACACTGATGGAAGATGTGGAAAATTCCTCTCTTCCTCAATGTCAACTCCCAGGTAACAACAGTGTGTCAG GCCCTGGCCAAAGACCCCAAATTACAGCAGGGCTACAATGGGGATTCACAGGGAGGCCAATTTTC TCAGAGCTGTTGCTCAGAGATGCCCTTCACCCCATTCGATTGATTGAGTTCA AGGAGTTTTTGGATTACCAAGGTGCCCTGGGGAGAGCTCTCACATTTGTGATTTTTAAAAAAACCTTG AATGCTGGGGCCTACTCAAAGGTGGTCCAGGAGGTTAGTGCAGGCTGAGTATTGGCATGACCCCATTA AGGAAGATGTGTACAGAAACCACTCCATTTGACCATTAGCTGATCGATCGATTGACCATTA CTACAAGAAGAACCTGATGGCCCTCAAGAAGTTTGATGGTGAAATTCCTCAATGACTCCATTGTGGAT CCAGTGGATTCAGAGTGGTTTGGATTCTACAGAAGTGGCCAAGCCAAGGAAACAATACCATTCAGAGA CCAGCCTGTACACCCAGGACAGACTGGCCCTAAGAGAGAGTTGTTGGTTGTT CACTGAGGGGGACCACCTTCAACTCTCTGAAGAATGGTTTTATGCCCACATCATACCCTTTCTGGGGTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 64 PPT1co4 GGCCCTCCAGCACCTCTTCCTTTAGTGATCTGGCATGGCATGGGTGACAGCTGCTGCAACCCACTGTCCA TGGGAGCCATCAAGAAAATGGTGGAGAAAAATTCCAGGAATCTATGTCCTATCCCTGGAGATTGGGAA GACTCTGATGGAAGATGTGGAGAACTCCTTCTTCCTGAATGTCAATTCCCAAGTCACCACAGTCTGCCAG GCCCTGGCCAAAGACCCCAAGCTGCAGCAAGGGTACAATGGGCTTCTCCCAAGGGGGGCAGTTCT AGGAGTCTTTGGGTTGCCCAGATGTCCAGGAGAGAGCAGTCACATCTGTGACTTCATCAGGAAAACACTG AATGCTGGGGCATAGCAAGGTGGTGCAGGAAAGGCTTGCAGGCAGAGTACTGGCATGACCCCATTA AAGAGGATGTGTACAGAAACCACAGCAGTCATTCATTCATCAGTCGATTGAGGAG CTACAAGAAGAATCTGATGGCCCTAAAGAAATTTGTGGGTAAAATTCCTCAATGACTCCATAGTGGAC CCAGTTGACTCTGAGTGGTTTGGATTTTCAGAAGTGGCCAAGCAAAGACCATTCCCCTTCAAGAGA CATCCCTGTACACCCAAGTAGCTGCTGAGAGAGGGATTGGATTGGTT In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 65 7-PPT1co5 GGCCCCCCTGCCCCACTTCCCTTGGTGATATGGCATGGCATGGGAGATTCTTGTTGTAACCCACTGTCAA TGGGGGCCATTAAGAAGATGGTGGAAAAGAAGATCCCTGGAATCTATGTCCTCTCCCTGGAAATTGGGAA GACCCTCATGGAGGATGTGGAAAACTCATCTCTTCCTCAATGTGAACAGCCAGGTCACCACTGTTTGTCAG GCATTAGCAAAGGACCCCAAGCTTCAGCAGGGATACAATGGGGCTTTAGCCAAGGTGGGCAATTCT TGAGAGCAGTGGCACAGAGATGCCCCTCACCCCATCCATCCATGTCCAATGGCCAGTCCA GGGGGTTTTTGGGCTCCCCAGATGCCCTGGTGAATCATCTCACATCTGTGACTTCATCAGAAAAACCTTG AATGCTGGAGCCTACAGTAAGTAGTGCAAAGAGGCTGGTGCAAGCAGAATACTGGCATGATCCCATCA CTACAAGAAAAACCTGATGGCACTGAAGAAGTTTGATGGTCAAAATTCCTCAATGACTCCATTGTGGAC CCTGTGGATTCTGAATGGTTTGGATTTACAGGTCTGGCCAAGCAAAGGAAACCATCCCTCTTCAGGAAA CCAGCCTGTACACACAAGACAGGCTGGGCCTAAAGGAAATGGACAATGCTGGACAATTGGTGTTTTTGGC TACTGAGGGTGACCACCTCCAGCTCTCAGAAGAATGGTTTTATGCTCACATCATCCCCTTCCTGGGTTG Em variants of the same, nucleotides codified 1, 3, D ificam GGCV ou L 66 7-PPT1co6 GGCCCACCTGCTCCATTGCCCCTAGTCATTTGGCATGGGATGGGGGACAGCTGCTGCAATCCTTTATCTA TGGGAGCCATTAAGAAGATGGTGGAGAAAAGATCCCTGGCATATATGTTAAGCCCTGGAGATTGGAAA GACCCTCATGGAAGATGTTGAGAATCTCTTTCTTCCTGAATGTAAACAGCCAAAGTCACCACAGTGCCAA GCTCTGGCCAAGGACCCCAAGCTCCAGCAGGGTTATAATGGGATTCTTCAGGGTGGGCAGTTCC TGAGGGCTGTGGCACAGAGATGCCAACCACCAGATCCAGTCGATTCAGGCC GGGAGTGTTTGGCCTGCCCAGATGTCCAGGTGAGTCCTCTCATATCTGTGACTTTATCAGGAAAACCTTA, Petition 870250104513, of 14 / 11 / 2025, p. 155 / 242 148 / 212 AATGCAGGGGCCTATTCCAAGGTGGTGCAGGAGAGACTTGTCCAGGCTGAGTATTGGCATGATCCCATTA AAGAAGATGTCTATAGAAACCATTCCATCTTCCTGGATATCAACCAGGAAAGAGGGATCAATGAGAG CTACAAGAAGAATCTAATGGCACTGAAGAAGTTTGATGGTGAAATTCCTCAATGATAGTATTGTGGAT CCTGTAGACAGTGAGTGGTTTGGCTTCTACAGAAGTGGACAAGCCAAGAGACCATTCCCTTACAAGAGA CCTCACTCTACACACAGGACAGACTGGCACTGAGAGAGAGTTGGTTGGTT AACAGAGGGGGATCACCTGCAGCTGTCAGAGGAATGGTTTTATGCCCACATCATCCCTTTCCTTGGTTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 67 7-PPT1co7 GGTCCCCCTGCTCCATTGCCTCTGGTCATCTGGCATGGCATGGGTGACTCCTGTTGCAACCCCTTAAGCA TGGGGGCCATCAAGAAGATGGTGGAGAAGAAGATTCCTGGAATCTATGTCTTGTCTTTAGAGATTGGTAA AACCCTCATGGAAGATGTGGAGAATTCCTTCTTCTTTGAATGTGAACTCACAAAGTCACAACAGTCTGCCAG GCCCTGGCAAAGGACCCCAAGCTCCAGCAGGGCTACAATGGGCTTCCCAGGGTGGGCAATTTC TGAGGGCTGTGGCCCAGAGATGTCCCTCACCACCCATTCCATTGCCATGGCCGATTGGCCGAGATT GGGAGTATTTGGGCTTCCCAGGTGCCCAGGAGAATCCAGCCATATCTGTGATTTCATTAGAAAGACCCTC AATGCTGGGGCTTACTCCAAGGTGGTGCAGGAGGTTAGTGCAAGCTGAATACTGGCATGATCCCATAA AGGAGGATGTTTATAGGAACCACAGCATCCATCAGATCTAGAGATCAGATCAGATCATCA CTACAAGAAAAACCTCATGGCCCTGAAGAAGTTTGTTATGGTCAAGTTTCTCAATGACTCCATTTGTGGAT CCTGTAGACTCTGAATGGTTTGGCTTTACAGGAGTGGCCAAGCAAAGAAACCATCCCTCTGCAGGAAA CAAGTCTGTACACTCAGGACAGACTGGCCCTGAGAGAGAGAGGCTGGCTGGCTGAGGCTGACT CACTGAGGGGGACCACCTGCAACTCAGTGAGGAATGGTTCTATGCTCACATAATTCCCTTCCTTGGTTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 68 7-PPT1co8 GGACCTCCTGCTCCTCTGCCCCTGGTCATCTGGCATGGAATGGGAGACAGCTGTTGTAACCCACTCAGTA TGGGAGCCATAAAGAAGATGGTTGAGAAGAAGATTCCTGGCATATATGTACTCAGCTTGGAGATTGGGAA GACCTTGATGGAAGATGTGGAGAACTCATTCTTCTTTGAATGTCAACAGCCAGGTCACCACTGTTTGCCAG GCCCTTGCTAAGGACCCCAACTGCAACAGGGCTACAATGCCATGGGGTTCTCTCAGGGAGGACAGTTCC TCAGAGCAGTGGCACAGAGGTGCCCCAGCCCACCCATGATTAATCTGATCAGTGTTGGAGGGCAGCACCA AGGGGTCTTTGGACTTCCAAGGTGCCCTGGGGAATCCAGCCATATTT AAGAAGATGTATACAGAAACCACAGCATTTTCCTGGCAGATATAAACCAAGAAAGGCATTAATGAGTC CTACAAGAAGAACCTCATGGCCCTGAAGAAATTTGATGGTGAAATTTTTGAATCTATAGTGGAC CCTGTGGATAGTGAGTGGTTTGGTTTCTACAGGAGGAGGAGGAGGGACCGGACC CCTCCCTGTACACACAGGACAGACTGGGCCTAAAGGAAATGGACAATGCAGGCCAGCTAGTGTTCCTGGC CACTGAGGGGACCACCTCCAGCTCTCTGAAGAATGGTTTTATGCCCATATTATCCCTTTTCCTGGGCTG Em variants do mesmo, nucleotides 1 a 3 codified G, D, DV ou L 69 7-PPT1co9 GGCCCTCCAGCTCCCTTGCCTTTAGTCATTTGGCATGGAATGGGAGACTCCTGCTGCAATCCTCTCTCTA TGGGAGCCATAAAAGATGGTAGAGAAAAATTCCTGGAATATATGTCCTAAGCCTGGAAATTGGGAA GACACTCATGGAAGATGTGGAGAACTCCTTCTTCCTCAATGTGAACAGCCAGGTGACCACAGCTGCCAG GCCTTGGCCAAAGACCCTAAGCTTCAGCAAGGCTACAATGGGCTTCAGCCAGGGTGGTCAATTCTC AGGTGTGTTTGGTCTCCCTAGGTGCCCAGGAGAGAGTAGCCATTTGTGACTTCATCAGGAAAACATTG AATGCTGGAGCCTACTCAAAAGTTGTACAAAAGGCTAGTGCAGGCTGAGTACTGGCATGATCCCATCA AGGAAGATGTTCAGGAAACCACAGCATCCATCTGGGAGGATCGATCGATCGATCGATC CTACAAGAAGAACCTGATGGCCCTCAAGAAGTTTGTCATGGTGAAATTCCTCAATGACAGCATTGTTGAT CCTGTTGATTCTGAATGGTTTGGATTCTACAGGTCTGGACAGGCCAAAGAGACCATCCCTCTTCAGGAAA CCTCCCTTTTCACACAGGACAGACTGGGGCTCAAGGAGATGGACAATGCTGGTCAGCTGGTTTTTCTGGC TACAGAGGGAGACCACCTACAGTTGAGTGAAGAGTGGTTCTATGCCCACATCATCCCTTTCCTGGGTTG Em variants of the same, 1m nucleotides encode 3, D, DV ou L 70 7-PPT1co10 GGCCCACCAGCTCCCCTCCCCCTGGTCATTTGGCATGGTATGGGAGACTCCTGTTGTAATCCTCTCTCCA TGGGAGCCATTAAATGGTGGAGAAGAAAATTCCTGGGATCTATGTGCTCTCTCTAGAGATTGGGAA GACCCTGATGGAAGATGTGGAGAACAGCTTTTTTCCTTAATGTGAACAGCCAGGTGACAACTGTCTGTCAA GCATTGGCCAAGGACCCCAAGCTGCAGCAAGGCTACAATGCTATGGGATTCTCTCAGGGGGGCCAGTTCC TGAGGGCTGTGGCCCAGAGATGCCCATCCCCTCCCATGATCAATCTGATATCTGTTGGGGGCCAGCACCA, Petition 870250104513, of 14 / 11 / 2025, p. 156 / 242 149 / 212 GGGAGTTTTTGGGCTGCCCAGATGCCCTGGGGAGAGCTCTCACATCTGTGATTTCATCAGGAAAACTCTC AATGCTGGAGCATATAGCAAGGTGGTGCAGGAGAGGTTGGTGCAGGCAGAGTACTGGCATGACCCCATCA AGGAGGATGTGTACAGAAACCACTCAATTTTCCTGGCAGATATCAACCAAGAGGGGCATCAATGAGTC CTACAAGAAAAACCTGATGGCCCTGAAGAAGTTTGATGGTGAAGTTTCTGAATGATTCTATTGTGGAC CCTGTGGATAGTGAGTGAGTGGTTTGGTTCAGACCAGCAGACCAACCAACCAACCAACCAACCAACCTA CTTCCCTGTACACCCAGGACAGGTTGGGACTCAAAGAGATGGACAATGCTGGACAGCTGGTGTTCCTGGC CACAGAAGGGGACCACCTGCAGCTGAGTGAAGAGTGGTTCTATGCTCATATCATCCCCTTCCTTGGATG Em variants do mesmo, nucleotides 1 a 3, codified G, D, DV ou L 71 PPTlcoll GGCCCCCCTGCCCCTCTTCCCCTGGTCATTTGGCATGGGATGGGTGACTCCTGCTGCAACCCCCTAAGCA TGGGGGCCATCAAGAAGATGGTGGAGAAGAAGATTCCTGGAATTTATGTCCTTAGCCTGGAAATTGGGAA GACCTTAATGGAAGATGTGGAAAACAGCTTTTTCTTAAATGTCAATTCTCAGGTAACAACAGTGCCAA GCCCTGGCCAAGGACCCTAACTGCAGCAGGGCTACAATGGGGCTTCAGCCAGGGTGGACAGTTTC GGGTGTTTTTGGCCTGCCCAGGTGTCCTGGAGAGTCCTCACATATCTGTGACTTCATCAGGAAGACACTG AATGCAGGGGCCTATAGCAAGGTGGTGCAAGAGAGACTGGTTCAGGCTGAATACTGGCATGACCCCATCA AGGAAGATGTTACAGGAACCATAGCATCCTTGCCTTGAGAGGAGGAGGAG CTACAAGAAGAATTTAATGGCTCTAAAGAAATTTGTCATGGTGAAGTTCCTGAATGACTCCATTGTGGAT CCTGTGGACTCTGAGTGGTTTGGGTTCTACAGAAGTGGCCAGGCCAAGGAGACCATCCCCCTGCAGGAGA CAAGCCTGTACACACAGGACAGGCTGGGACTGAAGGAGATGGACAATGCAGGACAGCTGGTGTTCCTGGC TACAGAGGGAGACCACCTGCAGCTCTCAGAGGAATGGTTCTATGCACACATCATTCCCTTTTAGGGTG Em variants do mesmo, nucleotides 1 a 3 codified G, D, DV ou L 72 7PPT1co12 GGACCTCCTGCCCCTCTTCCTTTGGTTATCTGGCATGGGATGGGTGACTCCTGCTGCAATCCTTTAAGCA TGGGGGCTATTAAAGATGGTGGAGAAAAAATTCCTGGAATCTATGTGCTTAGCTTAGAAATAGGGAA GACATTAATGGAAGATGTGGAAAACAGCTTTTTCTTTGAATGTCAACTCAGGTGACTACTGTCTGTCAG GCCCTGGCCAAGGACCCCAAGCTGCAGCAAGGTTACAATGGGGATTCAGCCAGGGTGGTCAGTTTC AGGTGTTTTTGGTCTGCCCAGGTGTCCTGGAGAGTCCTCACATATCTGTGACTTCATCAGGAAGACTCTG AATGCTGGGGCCTATAGCAAAGTAGTCCAGGAGTTGGTGCAGGCTGAATACTGGCATGACCCCATTA AAGAAGATGTCTATAGGAACCATAGCATATTCCATCCTTAGGAGATCGAGGAGGGATC CTACAAGAAAAACTTGATGGCTCTCAAGAAGTTTGATGGTAAAGTTCTTAAATGACTCCATTGTGGAT CCTGTAGACTCAGAGTGGTTTGGGTTCTACAGGTCTGGCCAAGCCAAGAGACCATTCCTCTGCAGGAGA CCAGCCTGTACACACAGGACAGACTGGGACTGAAGGAGATGGACAATGCTGGCCAGCTGGTGTTCCTGGC TACAGAGGGAGACCACCTGCAGCTCTCAGAAGAATGGTTCTATGCTCACATCATTCCCTTTTAGGGTG Em variants do mesmo, nucleotides 1 a 3 codified G, D, DV ou L 73 7-co13 GGTCCCCCTGCTCCTCTGCCTTTGGTGATTTGGCATGGCATGGGTGACTCCTGCTGCAACCCTCTGTCTA TGGGTGCCATTAAAAATGGTGGAAAGAAGATCCCTGGAATTTATGTCCTGTCTTTGGAGATAGGCAA GACTTTGATGGAAGATGTTGAGAATTCCTTTTTCTTAAATGTAAATAGCCAGGTAACCACAGTTTGTCAG GCACTTGCCAAGGACCCCAAGCTGCAGCAAGGCTACAATGCCATGGGCTTCTCCCAGGGAGGGCAGTTTC TGAGAGCAGTGGCTCAGAGGTGCCCCAGCCCTCCAATGATCAATTTGATCTCAGTGGGGGGCCAGCATCA GGGGGTCTTTGGCCTACCTAGGTGCCCTGGAGAGAGCTCTCATATCTGTGACTTCATTAGGAAGACATTA AATGCTGGGGGCATAGTAAGGTGGTGAGGAGGAGGAGGAGCCATGAGTC AGGAAGATGTCTACAGGAACCACAGCATTTTCCTGGCAGACATTAACCAAGAGAGGGGGATCATGAGAG CTACAAGAAAAACCTGATGGCCCTCAAGAAGTTTGATGGTGAAGTTTCTCAATGACAGCATTGTGGAT CCAGTGGATTCTGAGTGGTTTGGGTTCCAGAGAGAGGAGACCAACCAACCAACCATTA CCAGTTTGTACACTCAGGACAGGTTGGGCCTGAAGGAGATGGACAATGCTGGCCAACTGGTGTTCTTGGC CACTGAGGGGGACCACCTACAGCTGAGTGAGGAATGGTTCTATGCCCACATCATCCCTTCTGGGCTG Em variants of the same, nucleotides code 1, D 3, GV ou L 74 PPT1co14 GGACCCCCAGCTCCACTCCCCCTGGTGATCTGGCATGGCATGGGAGATAGCTGTTGCAACCCATTATCCA TGGGGGCCATTAAAGATGGTGGAGAAGAAAATCCCTGGCATTTATGTCCTTAGCCTGGAAATTGGAAA GACCTTAATGGAGGATGTGGAAAACTCCTTCTTCCTCAATGTCAACTCCCAAGTCACCACAGTGTGTCAA GCCCTTGCCAAGGACCCCAAGTTGCAACAGGGCTATAATGCTATGGCTTCTCAGGGAGGCCAGTTTC, Petition 870250104513, of 14 / 11 / 2025, p. 157 / 242 150 / 212 TGAGGGCTGTGGCCCAGAGGTGCCCCTCCCCACCTATGATCAATCTTATCTCTGTGGGTGGACAACACCA AGGTGTCTTTGGGCTGCCCAGGTGCCCTGGGGAGTCCAGCCACATTTGTGACTTCATCAGGAAGACACTA AATGCTGGTGCCTACTCCAAAGTTGTCCAGGAGAGACTGGTGCAAGCAGAATACTGGCATGACCCTATTA AAGAGGATGTCTACAGGAACCACAGCATCTTTCTGGCAGACATCAACCAGGAGAGAGGGATCAATGAATC CTACAAGAAGAACCTCATGGCCCTGAAGAAATTTGTGATGGTTAAGTTTCTCAATGACTCCATTGTGGAC CCTGTGGATTCTGAATGGTTTGGATTTTACAGAAGTGGCCAGGCCAAGGAAACCATCCCTCTGCAGGAGA CATCCCTGTACACACAGGACAGACTGGGCCTGAAGGAGATGGACAATGCTGGGCAGCTAGTGTTCCTGGC TACTGAGGGGGATCATCTTCAGTTGTCTGAAGAATGGTTCTATGCCCACATCATTCCCTTCCTGGGCTG Em variantes do mesmo, nucleotideos 1 a 3 codificam G, D,V ou L 75 7-PPT1co15 GGGCCCCCAGCTCCCTCTTCCCCTGGTGATCTGGCATGGCATGGGAGACTCCTGTTGCAACCCATTAAGCA TGGGGGCTATTAAAAATGGTGGAGAAGAAAATCCCTGGAATTTATGTCCTCTCTCTGGAGATAGGCAA AACCTTAATGGAAGATGTGGAGAACTCCTTCTTCCTCAATGTCAACTCCCAAGTCACCACTGTATGTCAA GCTCTGGCAAAGGACCCCAAATGCAACAGGGATATAATGCCATGGGATTCTCCCAGGGTGGCCAGTTCC TGAGGGCTGTGGCACAGAGATGCCCCCCCATCCTTGATTCAGCCATGTCCA AGGTGTTTTTGGGCTGCCCAGATGCCCTGGGGAGTCCTCTCACATTTGTGACTTCATCAGGAAGACCCTC AATGCTGGAGCCTACTCTAAAGTTGTTCAGGAAAGGCTGGTCCAAGCAGAATACTGGCATGACCCTATAA AAGAGGATGTTTACAGGAACCACAGTATCCATCCATCCATTCGAGGAGGAGGAGCAGCC CTACAAGAAAAACCTCATGGCACTCAAGAAATTTGTGATGGTCAAATTCCTGAATGACTCCATTGTGGAC CCTGTGGATTCTGAGTGGTTTGGATTCTACAGAAGTGGCCAGGCAAAGGAAACCATCCCTCTGCAGGAGA CAAGTCTGTACACCCAGGATAGGTTGGGTCTGAAGGAAATGGATAATGCTGGGCAGCTAGTCTTCCTGGC CACAGAAGGGGACCACCTGCAGCTTTCTGAAGAGTGGTTCTATGCTCACATCATTCCCTTTCTGGGCTG Em variants of the same, nucleotides 1 m encode a G, D, DV ou L 76 7-PPT1co16 GGCCCCCCTGCTCCTCTGCCCCTGGTCATCTGGCATGGGATGGGAGACAGCTGCTGTAACCCTTTATCAA TGGGAGCCATCAAGAAAATGGTGGAGAAGAAGATCCCTGGGATATATGTTCTTAGCTTGGAAATTGGCAA GACTCTCATGGAAGATGTTGAAAACAGCTTCTCCTGAATGTCAATAGCCAAGTGACCACAGGTGTGCCAG GCATTGGCTAAAGACCCCAAGTTGCAGCAAGGCTACAATGGGCTTTTCCCAGGGTGGTCAGTTCC AGGAGTATTTGGACTACCCAGGTGCCCTGGGGAGTCCTCCCATTTGTGACTTTATCAGGAAGACACTG AATGCAGGAGCCTACAGGTGGTTCAGGAGAGACTTGTGCAGGCAGAGTACTGGCATGATCCCATTA AGGAAGATGTGTACAGAAACCATAGTTTTTTCCTGCCATCAGGAGGAGGAGGAGGAG CTACAAGAAAAATCTGATGGCCCTAAAGAAGTTTGTCATGGTCAAGTTCCTGAATGATTCTATAGTGGAC CCTGTGGATTCAGAGTGGTTTGGTTTTTACAGATCAGGGCAAGCCAAGGAAACCATCCCACTGCAGGAAA CAAGCCCTGTACACTCAAGCAAGGAGTTAGGCCTAAAAGCAAGGTTGTTGTTGTTGTT AACAGAGGGGGATCATTTACAGTTATCTGAGGAATGGTTCTATGCCCACATCATCCCCTTCCTTGGTTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 77 7-PPT1co17 GGGCCCCCTGCCCCTCTCCCTTTGGTTATTTGGCATGGCATGGGGGACTCATGCTGTAACCCTTTGAGCA TGGGGGCCATTAAATGGTGGAGAAAGATCCCAGGTTTATGTCTTGTCTCTTAGAAATAGGGAA GACTCTGATGGAAGATGTGGAGAATAGCTTCTTCTTAAATGTGAATTCACAGGTTACCACTGTGTGCCAG GCCCTGGCCAAAGACCCCAAGTTACAGCAGGGATACAATGGGGATTTTTCAGGGTGGTCAGTTCC TGAGGGCAGTGGCCCAGAGATGCCCAAGCCCAATTGATTGTCGATTGGTCGATTGTCAG AGGGGTATTTGGCCTGCCCAGGTGCCCTGGAGAGTCCTCTCATATCTGTGACTTTATCAGGAAGACTTTA AATGCTGGGGCCTACAGCAAGGTGGTCCAGGAGGCTGGTGCAAGCAGAGTATTGGCATGATCCCATAA AGGAGGATGTGTATAGGAACCACTCCATCTTCCTGGCAGACATCAACCAGGAGGGGGATCAATGAGTC TTACAAGAAAAATTTAATGGCCCTGAAGAAGTTTGATGGTGAAGTTCCTCAATGATTCTATTGTGGAC CCTGTGGATTCTGAGTGGTTTGGCTTTACAGGAGTGGCCAGGCCAAGGAAACCATCCCTCTGCAGGAAA CTTCTCTATACACACAGGATAGCTGGGCCTGAAAGAGATGGACAATGCAGGGCAGCTGGTGTTTCTTGC CACTGAGGGTGACCACCTTCAGCTATCTGAGGATTGCCTTGTTGTCTTGTCGTTGTC In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 78 PPT1co18 GGTCCACCAGCTCCTCTGCCCTTGGTCATCTGGCATGGGATGGGGGACTCTTGTTGTAACCCTCTTAGCA TGGGAGCCATTAAGAAGATGGTGGAGAAGAAAATACCTGGCATATATGTCCTGAGCCTGGAGATTGGCAA GACCCTGATGGAGGATGTGGAGAACAGCTCTCTTCCTGAATGTCAATTCCCAGGTGACCACAGGTGTGTCAG, Petition 870250104513, of 14 / 11 / 2025, p. 158 / 242 151 / 212 GCCCTGGCCAAGGACCCCAAGTTGCAGCAAGGCTACAATGCTATGGGCTTTTCAAGGTGGGGCAGTTCC TGAGAGCAGTGGCACAGAGATGTCCTTCACCTCCAATGATCAACCTTATCTCAGTGGGAGGCCAACACCA GGGTGTTTTTGGGTTGCCCAGGTGTCCTGGACCATCAGGACTGACTGACTGACTGACTGGTCGA AATGCAGGGGCCTACAGCAAGGTTGTTCAAGAGAGGCTGGTGCAGGCTGAGTATTGGCATGATCCCATTA AGGAGGATGTGTATAGGAACCACTCCATTTTTGGCAGACATCAATCAGGAGAGGGGCATCAATGAGTC CTACAAGAAGAACCTGATGGCCCTCAAGAAGTTTGTGATGGTCAAGTTTCTGAATGATTCTATTGTGGAT CCAGTGGACTCTGAATGGTTTGGGTTCTACAGATCTGGCCAGGCCAAGGAGACCATCCCACTTCAAGAGA CCAGCCTGTATACCCAAGGACAGATTAGGCTGAGGAGAGAGCCATGCTGCTGCTGCTGCTGATTGGTTTGGGTTCTACAGATCTGGCCAGGCCAAGGAGACCATCCCACTTCAAGAGA CCAGCCTGTACCAGGACA TACAGAGGGGGACCACCTCCAGCTGAGTGAAGAGTGGTTTTATGCCCACATCATACCCTTCCTGGGTTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 79 PPT1co19 GGCCCCCCAGCCCCTCTGCCCCTGGTCATCTGGCATGGCATGGGAGACAGCTGCTGCAACCCTCTCTCCA TGGGAGCCATCAAGAAGATGGTGGAGAAGAAGATCCCTGGAATCTATGTCCTCAGCCTGGAGATTGGGAA GACCCTGATGGAGGATGTGGAGAACTCCTTCTTCCTGAATGTGAACAGCCAGGTGACCACAGGTGCCAG GCCCTGGCCAAGGACCCCAAGCTGCAGCAGGCTACAATGCCATGGCTTCTCCCAGGGAGGCCAGTTCC TGAGGGCTGTGGCCCAGAGATGCCCCTCACCTCCCATGATCAACCTCATCTCTGTGGGAGGCCAGCACCA AGGGGTCTTTGGCCTGCCCAGGTGTCCTGGGGAGAGCAGCCACATCTGTGACTTCATCAGGAAGACCCTG AATGCTGGTGCCTACAGCAAGGTGGTGCAGGAGAGGCTGGTGCAGGCTGAATACTGGCATGACCCCATCA AGGAGGATGTGTACAGGAACCACAGCATCTTCCTGGCAGACATCAACCAGGAGAGAGGCATCAATGAGAG CTACAAGAAGAACCTGATGGCCCTGAGAGAGTTGAGTTGAGTTGAGTTGACTGAGCCATGGCCATGGGAGAGGCATCAATGAGAG CCTGTGGACTCTGAGTGGTTTGGCTTCTACAGGAGTGGCCAGGCCAAGGAGACCATCCCCCTGCAGGAGA CCAGCCTGTACACAGGACAGACTGGGACTGAAGGAGATGGACAATGCTGGGCAGCTGGTGTTCCTGGC CACAGAGGGAGACCACCTGCAGCTCTCAGGAGGCCTTGCCTTGCCTTGCCTTGCCGCTGCTGCCAGCT In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 80 C-PPT1co1 GGACCTCCTGCCCCCTTGCCTCTGGTGATCTGGCATGGCATGGGAGACAGCTGTTGCAACCCCCTCAGCA TGGGTGCCATTAAGAAGATGGTAGAGAAGAAGATACCTGGTATCTATGTGCTCCCTAGATTGGGAA AACTTTGATGGAGGATGTGGAAAATCCTTCTTCCTGAATGTCAATTCCCAGGTCACCACAGGTGCCAG GCTCTGGCAAAGGACCCAAAGCTACAGCAGGGCTATAATGCCATGGGCTTCAGCCAGGGTGGCCAATTCT TGAGGGCAGTGGCTCAGAGGTGTCCATCACCCCATGATTAATCTAATCTGTGGGTGGCCAACACCA AGGTGTCTTTGGTCTCCCCAGGTGTCCTGGGGAGTCCTCACACATATGTGACTTCATCAGGAAGACTCTA AATGCAGGGGGCTTATAGCAAGGTGGTTCAGGAGCTGAGCTGACCATGCCATGGCT AGGAAGATGTGTACAGAAACCACTCAATTTTCCTGGCTGACATCAACCAGGAGGGGTATCAATGAGAG TTACAAGAAACCTCATGGCACTGAAGAAATTTGTGATGGTGAAATTCCTTAATGACTCCATTGTGGAT CCTGTGGACTCAGAATGGTTTGGTTCCAGGAGGACCAGGACCAGGGACCGACC CTAGCCTGTACACCCAGGACAGGCTTGGTCTGAAGGAAATGGACAATGCTGGGCAGCTGGTCTTTCTGGC CACAGAAGGGGACCACCTTCAATTATCAGAGGAGTGGTTCTATGCCCACATCATACCTTTCCTGGGCTG Em variants of the same, nucleotides 1 to 3 encode G, D, DV ou L 81 C-PPT1co2 GGGCCCCCTGCCCCTCTTCCCTTGGTCATATGGCATGGGATGGGAGATTCCTGCTGCAACCCTCTGTCCA TGGGAGCCATTAAGAAGATGGTGGAAAGAAGATCCCTGGAATTTATGTCCTAAGCCTGGAAATTGGGAA AACACTCATGGAAGATGTTGAAAATTCCTCTCTTCCTCAATGTCAATAGTCAGGTAACTACAGTTTGTCAG GCTCTGGCAAAGGACCCCAAGCTGCAGCAGGGCTACAATGGGCTTCTCAGGGAGGACAATTCT TAAGGGCAGTAGCTCAGAGATCCATCCATTCCCATTCCATTGCCATGCCATGTCCAGTCAG AGGGGTTTTTGGCCTCCCCAGATGTCCTGGAGAGAGCAGCCATCTGTGACTTCATCAGGAAGACTCTA AATGCTGGAGCCTACAGTAAGGTTGTACAGGAGGCTTGTTCAGGCTGAGTACTGGCATGACCCCATTA AGGAGGATGTGTATAGGAATCATAGTACTTAGACCTAGAGGAGAGAGAGACCATTAGGAGACCATTA CTACAAGAAGAACCTCATGGCCCTAAAGAAGTTTGTGATGGTGAAGTTTCTCAATGACTCCATTGTTGAC CCTGTGGACTCTGAATGGTTTGGCTTCTACAGGTCTGGCCAAGCCAAGGAGACAATTCCTCTCCAGGAGA CTTCTCTGTACACACAAGTAGCTGCTGGACTAAGAGAGGAGTTGTTGGTTGGTTGGGGACTGGAGGAG CACAGAGGGGGACCACCTGCAGCTTTCTGAGGAGTGGTTCTATGCCCATATTATACCCTTCTTTGGTTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 82 C-PPT1co3 GGTCCCCCAGCTCCTCCCTCTTGTCATCTGGCATGGAATGGGTGACAGCTGCTGCAATCCATTATCCA TGGGAGCCATTAAAGATGGTGGAGAAGAAGATCCCAGGCATCTATGTCTTTGGAAATTGGGAA, Petition 870250104513, of 14 / 11 / 2025, p. 159 / 242 152 / 212 GACACTGATGGAGGATGTGGAGAACTCCTTCTTCTTAAATGTCAACTCACAGGTTACCACAGGTGCCAA GCCCTGGCCAAGGACCCCAAGCTGCAACAGGGTTACAATGCTATGGGTTCTCTCAAGGTGGCCAGTTCC TCAGGGCTGTGGCACAGAGGTGTCCCTCACCACCTATGATTAATCTCATCAGTGTTGGAGGACAGCATCA AGGTGTCTTTGGCCTCCCAAGATGTCCAGGGGAAAGTTCACATCTGTGATTTCATAAGGAAGACCCTC AATGCTGGAGCTTACAGTAAAGTGGTCCAGGAGGAGGAGGCTGACCATCAGCCATCAGTGATTTCATAAGGAAGACCCTC AGGAGGATGTTTATAGAAATCATTCCATCTTCCTGGCAGACATCAACAGGAGAGGGGCATCAATGAGAG CTACAAGAAAAATCTCATGGCCCTGAAGAAGTTTGATGGTGAAATTTCTAAATGATAGTATTGTGGAC CCTGTAGACTCTGAGTGGTTTGGCTTACGAGAGGAGGACCAACCAACCAACCAATC CTAGCCTTTACACACAGGACAGGTTGGGCTTGAAGGAAATGGATAATGCTGGGCAGCTTTGCTCTCTTGC CACAGAGGGGACCACTTGCAGCTCAGTGAGGAGTGGTTTTATGCCCACATCATCCCCTTCCTTGGCTG Em variants do mesmo, nucleotides 1 a codified, D, DV ou L 83 PPT1co20 GGGCCCCCAGCACCCCTGCCTCTGGTCATCTGGCATGGGATGGGAGATTCCTGCTGCAACCCTCTCAGCA TGGGGGCCATTAAAAATGGTGGAGAAGAAGATCCCTGGCATTTATGTCTTGTCCTTGGAGATAGGCAA AACACTAATGGAAGATGTGGAGAACAGCTTCTTCTTAAATGTGAACAGCCAGGTCACCACAGTAGTCAG GCCTTGGCCAAGGACCCCAAGCTCCAGCAGGGCTACAATGGGTTTTTCTCAGGGAGGTCAGTTCC TCAGGGCTGTGGCTCAGAGATGCCCCTCACCACCTATGATCAATCTGATCTCTGTGGGAGGGGCAGCATCA AGGTGTCTTTGGTCTTCCTAGGTGCCCTGGGGAGTCATCCCACATCTGTGACTTCATCAGGAAAACTTTA AATGCTGGAGCCTACAGCAAGGTTCCAGGAAAACTTTA AAGAGGATGTTTACAGAAACCACAGCATCTTCCTGGCAGACATCAATCAAGAGAGGGGCATTAATGAGTC CTACAAGAAAAACCTCATGGCCCTAAAGAAATTTGATGGTGAAATTCTTGAATGACTCCATTGTTGAC CCTGTAGACTCTGAGTGGTTTGGTTCTATAGACCAGCCAACCAACCAATCGACCTTGAAT CCTCCCTGTACACACAAGATAGGCTGGGGTTGAAAGAGATGGATAATGCTGGGCAACTGGTGTTCTTGGC CACTGAGGGTGACCATTTACAGCTTTCAGAGGAATGGTTCTATGCCCACATGV ou L 84 C-PPT1co5 GGGCCTCCAGCCCCCTTACCTTTGGTCATATGGCATGGAATGGGAGACAGTTGTTGCAACCCCCTCTCTA TGGGTGCTATTAAAAATGGTGGAGAAGAAGATACCTGGCATTTATGTCCTCTCCCTGGAAATAGGCAA AACACTGATGGAAGATGTAGAAAACAGCTTTTTCCTCAATGTCAATTCCCAGGTAACAACTGTGTGCCAG GCCCTGGCCAAGGATCCCAAATTCAGCAAGGTTATAATGGGGATTCTCCCAAGGAGGCCAATTTTC TGAGGGCTGTGGCCCAGGGTCCATCCCCCCAATCGAGTCGAGGCCAGGCCAG AGGAGTTTTTGGACTTCCAAGGTGCCCTGGGGAATCCAGCCACATTTGTGACTTCATTAGAAAGACACTC AATGCTGGTGCTTATTCCAAAGTTGTTCAGGAGAGGCTTGCAGGCTGAGTATTGGCATGACCCCATCA AGGAGGATGTTCAGGAATCATTCAATCCATCCTTGAGGATCGATCGATCGATC CTACAAGAAAAACCTCATGGCCTTAAGAAGTTTGTGATGGTGAAGTTCCTAAATGATAGCATAGTTGAC CCAGTGGATTCTGAGTGGTTTGGTTTCTATAGGAGTGGCCAAGCCAAGGAGACCATTCCCCTGCAGGAGA CCTCCCTGTACCCAGGAGGAGGCTTGGTCTCAAGGAGGAGGATTGTCGATTGTTGTT CACTGAGGGGGATCACCTCCAACTCAGTGAAGAATGGTTCTATGCACACATCATCCCCTTCTTGGGCTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 85 C-PPT1co6 GGGCCCCCAGCACCCCTTCCTTTGGTGATATGGCATGGCATGGGTGATAGCTGTTGCAACCCCCTGAGCA TGGGGGCCATCAAGAAAATGGTGGAGAAAAAGATTCCAGGCATATATGCTCTCCCTGGAGATTGGAAA AACCCTCATGGAAGATGTGGAGAACCTTCTTCTTAAATGTGAATAGTCAAGTTACCACAGTGTGCCAG GCACTGGCCAAGGACCCCAAGCTCCAAGGGGTACAATGGGCTTCTCAGGGAGGGCAGTTTC TCAGAGCAGTGGCCCAGATGCCCTTCACCCCATTCCATTGCCATGCCATGCCATTCCAGGGAGGGCAGTTTC GGGGGTATTTGGTCTACCCAGGTGCCCAGGTGAATCCAGCCACATCTGTGACTTCATCAGGAAGACACTG AATGCAGGAGCCTACAGCAAAGTGGTGCAAGAGAGGCTGGTGCAGGCAGAGTACTGGCATGACCCCATCA CTACAAGAAGAACTTGATGGCCCTCAAGAAGTTTGATGGTGAAATTCCTGAATGATTCCATTGTTGAC CCTGTGGATTCTGAGTGGTTTGGATTTTCAGAAAGTGCCAGGCCAAGGAAACAATTCCACTACAAGAGA CCTCCCTCTACACCCAGGACAGGCTGGGCCTCAAAGAAATGGACAATGCTGGCCAGCTGGTGTTTCTGGC TACAGAGGGAGACCATCTGCAGCTGTCAGAGGAGTGGTTCTATGCTCACATCATACCTTTCTTAGGATG Em variants of the same, nucleotides 1 to 3, codified G, DV ou L 86 C-PPT1co7 GGCCCTCCTGCTCCCCTGCCTTTGGTTATCTGGCATGGAATGGGTGACAGCTGTTGCAACCCCTTAAGCA, Petition 870250104513, of 14 / 11 / 2025, p. 160 / 242 153 / 212 TGGGAGCTATTAAGAAAATGGTTGAGAAGAAGATCCCTGGGATCTATGTCCTGAGCTTGGAAATTGGGAA GACACTCATGGAAGATGTGGAGAACTCCTTCTTCCTGAATGTGAATAGCCAAGTGACTACAGTGTGTCAA GCCTTGGCCAAGGACCCCAAGCTGCAGCAGGCTACAATGCCATGGGCTTCTCCCAGGGAGGACAGTTTC TGAGAGCAGTAGCTCAGGTGCCCTTCACCTCCCATGATCAACCTCATCAGTGGGGGGCCAGCACCA GGGAGTGTTTGGGCTGCCCAGGTGCCCTGGGGAGTCATCTCACATCTGTGACTTCATCAAGGAAAACCCTC AATGCTGGGGCCTACAGCAAGGTGGTCCAGGAGACTGGTGCAGGCAGAGTATTGGCATGACCCCATCA AGGAGGATGTCTATAGGAACCACAGCCATTTGACCAGTTCAGCCATCAGATCCATCATTCATGGAACCA CTACAAGAAGAACCTGATGGCCCTGAAGAAGTTTGTGATGGTGAAGTTCCTCAATGATTCTATTGTGGAT CCTGTGGACTCAGAGTGGTTTGGCTTTTACAGATCTGGGCAAGCAAAGGAGACCATTCCCCTGCAGGAAA CATCCCTGTACACCCAGGTAGGCTGGGTCTGAGAGGAGTTGTTGTTGTTGGCTGGCTGGCTGAGGAGGATTGTCGTT TACAGAAGGGGACCATTTACAGCTATCTGAAGAATGGTTTTATGCTCACATTATCCCTTTCCTTGGATG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 87 C-PPT1co8 GGGCCCCCTGCACCTCTGCCCCTGGTCATTTGGCATGGCATGGGTGACTCCTGTTGCAATCCCCTGAGCA TGGGGGCCATCAAGAAGATGGTGGAGAAGAAGATCCCAGGAATCTATGTTCTGTCCTTAGAAATTGGGAA GACTCTGATGGAAGATGTGGAAAACAGCTTCTTCCTGAATGTGAATTCCCAGGTGACCACAGTCTGCCAG GCTCTGGCTAAGGACCCCAAACTCCAGCAGGGCTACAATGCTATGGGATTCTCCCAGGGTGGGCAGTTCC TCAGAGCAGTGGCTCAGAGATGCCCATCACCCCCAATGATCAACCTCATCTCTGTTGGTGGTCAGCATCA AGGTGTCTTTGGACTCCCCAGGTGCCCTGGGGAGTCCTCTCACATCTGTGACTTTATCAGAAAAACCTTA AATGCTGGGGCCTACAGCAAGGTGGTCCAGGAAAGGCTGGTCCAGGCTGAGTACTGGCATGATCCCATCA AGGAAGATGTGTACAGGAACCACTCCATTTTTCTGGCTGACATAAACCAAGAGAGGGGCATCAATGAGTC ATATAAGAAAAACCTGATGGCTCTGAAAAAGTTTGTCATGGTTAAATTCCTCAATGACTCTATTGTGGAC CCTGTTGACTCTGAGTGGTTTGGCTTCTACAGGTCAGGCCAAGCTAAAGAGACCATCCCCCTGCAGGAGA CATCCCTGTACACACAGGACAGGTTAGGACTGAAGGAGATGGACAATGCTGGACAGCTGGTGTTCCTGGC CACAGAGGGTGACCACCTACAGTTGTCAGAAGAATGGTTCTATGCTCACATCATACCCTTCCTTGGTTG Em variantes do mesmo, nucleotídeos 1 a 3 codificam G, D,V ou L 88 C-PPT1co9 GGCCCACCTGCTCCCCTCCCCTTGGTGATATGGCATGGCATGGGAGATAGCTGTTGTAATCCCCTCTCCA TGGGTGCCATTAAGAAGATGGTGGAAAGAAGATTCCTGGAATCTATGCTGTCCCTGGAGATAGGGAA GACTCTGATGGAAGATGTGGAAAATTCCTTCTTCTTTGAATGTCAACTCCCAGGTGACAACTGTATGCCAG GCCTTGGCAAAGGACCCCAAGCTGCAGCAGGATACAATGCCATGGGATTCAGCCAAGGTGGACAGTTTC TGAGAGCAGTAGCCAGAGATGCCAA GGGAGTGTTTGGCCTGCCCAGATGTCCAGGGGAGAGCAGCCACATTTGTGACTTCATCAGGAAAACACTG AATGCTGGGGCCTACAGCAAGGTGGTGCAGGAGAGGCTAGTGCAGGCAGAGTACTGGCATGACCCAATCA AAGAGGATGTTATAGGAACCACAGTATCTTTTTGGACCAGCAGCAGACCATCAGTCGATT CTACAAGAAGAACCTAATGGCCTTGAAGAAATTTGTCATGGTGAAGTTCCTCAATGATTCCATTTGTGGAT CCTGTTGACTCAGAATGGTTTGGATTTTATAGATCAGGCCAGGCCAAAGAAACCATACCACTGCAGGAAA CATCCCTCTACACTCAAGATAGCTGGGGCTGAAGGAGATGGTCGCTGCTGCTGCT TACTGAAGGGGATCACCTCCAGCTAAGTGAGGAGTGGTTCTATGCTCACATCATCCCATTCTTGGCTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 89 C-PPT1co10 GGACCCCCTGCCCCTTTGCCCCTGGTCATTTGGCATGGGATGGGTGACAGCTGCTGCAATCCCCTAAGCA TGGGAGCCATCAAGAAGATGGTGGAAAGAAGATTCCTGGCATTTATGTCCTCTCCCTGGAGATTGGGAA GACCCTGATGGAGGATGTGGAGAACAGCTCTCTTCCTGAATGTGAACTCCCAGGTTACAACAGTTTGCCAG GCCTTAGCCAAGGACCCTAAACTCCAGCAAGGCTACAATGGGCTTCTCTCAGGGTGGGCAGTTTC TGAGGGCTGTGGCACAGAGGTGCCCCAGTCCTCCCATGATCAACCTCATCTCAGTGGGAGGCCAGCACCA GGGTGTTTTTGGGTTGCCAAGATGTCCTGGAGAGAGCTCTCATATCTGTGACTTCATCAGGAAGACACTG AATGCTGGGGCTTATAGCAAGGTGGTACAGGAGGCTGGTGCAGGCTGAGTACTGGCATGACCCCATCA AGGAAGATGTGTACAGGAACCATTCAATCTTCTTGGCAGATATTAACCAGGAGAGGGCATCAATGAAAG CTACAAGAAGAACCTGATGGCCTTGAAGAAATTTGTCATGGTAAAGTTTCTGAATGACTCCATTTGTGGAT CCTGTAGACTCTGAGTGGTTTGGCTTTACAGAAAGTGGCCAAGCCAAGGAAACCATCCCCCTGCAGGAGA CATCTCTGTACACTCAGGACAGGTTGGGACTGAGGAGGAGGAGGCTGGCTGCTGGTT In variants of the same, nucleotides 1 to 3 encode G, D, V or L, Petition 870250104513, of 14 / 11 / 2025, p. 161 / 242 154 / 212 90 C-PPT1co11 GGACCCCCTGCACCTCTGCCCCTTGTTATATGGCATGGGATGGGAGACAGCTGCTGCAATCCCCTCAGCA TGGGTGCCATCAAGAAGATGGTGGAGAAAAAATTCCTGGAATTTATGTCCTCAGCTGGAGATAGGGAA GACACTTATGGAAGATGTGGAAAACAGTTCTTCCTGAATGTGAACTCCCAGGTGACCACTGTGTGCCAG GCACTGGCCAAAGACCCTAAGCTGCAGCAAGGCTACAATGGGCTTCAGCCAGGGGGGTCAGTTTC AGGGGTTTTTGGGCTACCAAGGTGTCCTGGAGAGTCTTCACATATCTGTGACTTCATCAGAAAGACCTTA AATGCAGGGGCCTATAGCAAAGTGGTTCAGGAGAGGCTTGTTCAGGCTGAATACTGGCATGACCCCATCA AAGAGGATGTTCAGGAACCATTCAATCCTTAGGACTGAGTCCAGATCGAGGAGGAG CTACAAGAAAAATCTCATGGCCCTGAAGAAGTTTGTCATGGTGAAGTTTCTCAATGATTCCATTTGTGGAT CCAGTGGATTCAGAGTGGTTTGGCTTTACAGTCAGGCCAAGCTAAGACCATCCCCCTCCAGGAGA CCTCCCTCTACACACAGGACAGACTGGGATTGAGAGAGGAGTTGTTGTTGGTT CACAGAGGGAGACCACCTGCAGCTCAGTGAGGAATGGTTTTATGCTCACATCATTCCCTTCCTTGGTTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 91 C-PPT1co12 GGGCCACCTGCTCCCCTGCCCCTTGTCATCTGGCATGGGATGGGAGACAGCTGCTGCAACCCCCTGTCCA TGGGGGCCATCAAGAAGATGGTGGAGAAGAAAATACCTGGAATATATGTCCTCTCTCTGGAGATTGGCAA GACACTGATGGAAGATGTGGAGAATTCATTTTTTCCTGAATGTCAACTCCCAAGTGACCACAGGTGCCAG GCCTTAGCCAAGGACCCCAAGCTTCAGCAGGGCTACAATGGGGATTCAGCCAGGGAGGGCAATTTC TGAGAGCAGTTGCTCAGAGATGCCCATCCATTCATTCATGTCGATTGTCCAATGTCCAAGTCAG AGGTGTGTTTGGGCTACCCAGATGCCCTGGGGAGTCTAGCCACATCTGTGACTTCATCAGGAAGACTCTG AATGCTGGAGCCTACTCAAAGGTGGTGCAGGAGAGGCTGGTGCAAGCTGAGTACTGGCATGATCCCATAA AGGAGGATGTGTACAGGAACCAGCATCTTCTTAGCAGACATCAACCAAGAGAGGCATCAATGAGTC CTACAAGAAGAACCTCATGGCTCTGAAGAAGTTTGATGGTCAAGTTCCTAAATGATTCTATTGTGGAT CCTGTGGACTCTGAATGGTTTGGATTTCAGACCAGCCAGCCAGCCGACCGACCGAGTC CCTCTCTGTACACACAAGACAGGCTGGGACTCAAGGAGATGGACAATGCTGGACAGCTTGTCTTTCTGGC CACAGAAGGGGACCACCTGCAGCTGTCAGAAGAATGGTTCTATGCTCACATCATACCATCCTTGGTTG Variants of the same, in which nucleotides 1-3 encode G, D,V ou L 92 C-PPT1co13 GGGCCCCCTGCACCTCTCCCCTTGTCATCTGGCATGGGATGGGAGACTCCTGCTGTAACCCTTTATCAA TGGGGGCCATCAAGAAGATGGTAGAGAAAAAATCCAGGAATTTATGTCCTCAGCTGGAAATAGGCAA GACTCTCATGGAAGATGTGGAAAACAGCTCTCTTCCTGAATGTGAATAGCCAGGTCACAACAGGTGCCAG GCCTTAGCTAAAGATCCCAAATTGCAGCAGGGCTACAATGGGGATTTTCCCAGGGAGGGCAATTCC TCAGGGCAGTGGCACAGAGATGCCCTAGCCCAACCATCCATGGCCATGGCC AGGGGTTTTTGGCTTGCCCAGGTGCCCTGGGGAATCTAGCCACATCTGTGACTTTTAAGGAAAAACCCTG AATGCAGGAGCCTACTCAAAAGTGGTCCAGGAGGCTGGTGCAAGCTGAATATTGGCATGATCCCATCA AAGAGGATGTGTATAGGAACCACAGCATCCATCCATCAGACCATCAGAGCAGGAGCA CTACAAGAAAAATTTAATGGCTCTGAAGAAGTTTGTCATGGTAAAGTTTCTCAATGACTCCATTGTGGAC CCTGTGGATTCTGAGTGGTTTGGATTCTATAGAAGTGGACAAGCCAAGAAACCATCCCACTGCAGGAGA CCAGCCTCTACACACAAGACAGATTGGGACTCAAGCAGCAGCCATGTTGGTT TACAGAGGGTGACCATCTGCAGCTGAGTGAAGAATGGTTTTATGCTCACATCATACCATTCCTGGGGTG In variants of the same, nucleotides 1 to 3 encode G, D,V ou L 93 C-PPT1co14 GGGCCACCTGCCCCTCTGCCATTGGTGATTTGGCATGGCATGGGAGATAGCTGCTGCAATCCTCTCTCCA TGGGGGCCATTAAATGGTGGAAAAAAAGATTCCAGGGATTTATGTTGTCTTTAGATTGGGAA GACTCTCATGGAAGATGTGGAGAACAGCTCTCTTCCTGAATGTCAACTCACAGGTCACTACTGTCTGTCAG GCTTTAGCTAAGGACCCCAAACTCCAGCAGGGATACAATGGGCTTCTCAGGGAGGGCAATTTC AGGTGTTTTTGGCTTGCCCAGGTGTCCTGGGGAGAGCTCTCACATCTGTGATTTCATCAAGGAAGACACTC AATGCAGGAGCTTACTCCAAAGTGGTCCAAGAGGCTGGTCCAAGCAGAATACTGGCATGATCCAATTA AAGAAGATGTTTATAGGAACCACAGCATCCAGTCCAATTA CTACAAGAAAAACTTAATGGCCCTGAAGAAGTTTGTGATGGTCAAATTCCTTAATGACTCCATTTGTGGAC CCTGTAGATTCAGAGTGGTTTGGTTTTTATAGAAGTGGCCAGGCTAAAGAGACAATTCCCCTGCAAGAGA CCAGCCTCTACACCCAAGACAGGCTAGGCTGAGAGAGAGTTGATTGCTGACTGCTGACTGCT CACTGAAGGTGACCATCTACAGCTGTCAGAAGAATGGTTCTATGCTCACATCATCCCCTTCCTGGGGTG, Petition 870250104513, of 14 / 11 / 2025, p. 162 / 242 155 / 212 In variants of the same, nucleotides 1 to 3 encode G, D, V or L 94 C-PPT1co16 GGCCCTCCAGCCCCTCTGCCCCTGGTCATCTGGCATGGCATGGGAGACAGCTGCTGTAACCCTCTGTCCA TGGGAGCCATTAAGAAGATGGTGGAGAAGAAGATCCCTGGAATCTATGTCCTGTCCCTGGAGATTGGGAA GACACTGATGGAGGATGTGGAGAATTCCTTCTTCTTAAATGTGAACAGCCAGGTCACCACAGTTGCCAG GCATTGGCCAAGGACCCCAAGCTGCAGCAGGCTACAATGCCATGGGCTTCTCCCAGGGAGGCCAGTTCC TGAGGGCTGTGGCCCAGAGGTGCCCCTCACCTCCCATGATCAACCTGATCTCTGTGGGAGGCCAGCCATCCA AGGTGTGTTTGGCCTGCCCAGGTGCCCTGGGGAGTCCAGCCACATCTGTGACTTCATCAGGAAGACTTTA AATGCTGGAGCCTACAGCAAGGTGGTCCAGGAGGCTGGTGCAGGCAGAATACTGGCATGATCCCATCA CTACAAGAAGAACCTGATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGACTCCATTTGTGGAC CCTGTGGATTCTGAGTGGTTTGGCTTTACAGGTCTGGCCAGGCCAAGGAGACCATCCCTCTGCAGGAGA CCAGCCTGTACACAGGACAGACTGGGACTGAGGAGGAGGGCTGGCTGGCT In variants of the same, nucleotides 1 to 3 encode G, D, V or LSequência que codificam PPT1 de comprimento total 95 Sp7-F signal_PPT1 ATGGCCTTTCTGTGGCTGCTGTCCTGCTGGGCCCTGCTGGGGACCACCTTTGGCGGGCCGCCGGCGCCGC TGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAA AATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTGATGGAGGAC GTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATC CTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCA GAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTC CCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGTACT CCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCG CAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTG ATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGT GGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACA GGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCAT CTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAA Em variantes do mesmo,nucleotídeos GGG mostrados em negrito codificam G, D, V ou L 96 Sp7-P signal_PPT1 ATGGCCTTCCTGTGGCTGCTGTCCTGCTGGGCACTGCTGGGCACCACATTTGGCGGGCCGCCGGCGCCGC TGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAA AATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTGATGGAGGAC GTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATC CTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCA GAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTC CCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGTACT CCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCG CAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTG ATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGT GGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACA GGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCAT CTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAA Emvariants of the same, GGG nucleotides shown in bold encode G, D, V or L 97 NGF-1-derived PPT1 signal ATGTCCATGTTGTTCTACACTCTGATCACAGCTTTCTGTCGGCATACAGGCGGGCCGCGCGCGCCGCGC TGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAA AATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGATTGGGAAGACCCTGATGGAGGAC GTGGAGAACAGCTTCTTCTTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATC CTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTGAGGGCAGTGGCTCA GAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTC CCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGCTGGGGGCGTACT Petition 870250104513, of 14 / 11 / 2025, p. 163 / 242 156 / 212 CCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCG CAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTG ATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGT GGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACA GGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCAT CTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAA Em variantes do mesmo, nucleotídeos GGG mostrados em negrito codificam G, D,V or L 98 PPT1 signal of Insulin-1 ATGGCCCTGTGGATGCGCCTCCTGCCCCTGCTGGCGCTGCTGGCCCTCTGGGGACCTGACCCAGCCAG CCGTGCCGCCGGCGCCGCTGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCAT CATGGGTGCTATTAAAAATGGTGGAGAAAAATACCTGGAATTTACGTCTTATCTTTAGATTGGG AAGACCCTGATGGAGGACGTGGAGAACAGCTTCTTCTTTGAATGTCAATTCCCAAGTAACAACAGTGTC AGGCACTTGCTAAGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCAGGGGAGGCCAATT TCTGAGGGCAGTGGCTCAGAGATGCCCTTCACCTCCCATGATCAATCTGATCCGGTTGGGGGACAACAT TGAATGCTGGGGCGTACTCCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCAT AAAGGAGGATGTGTATCGCAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATGAG ACCCTGTAGATTCGGAGTGGTTTGGATTTTCAGAAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGA GACCTCCCTGTACACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTG GCTACAGAAGGGGACCATTCAGTTGTCTGATTGATTGATTGATTGATCCTTGTTCC AA In variants of the same,GTG nucleotides shown in bold encode G, D,V ou L 99 signal_PPT1 SPARC-1 ATGAGGGCCTGGATCTTCTTTCTCCTTTGCCTGGCCGGGAGGGCCTTGGCAGGGCCGCCGGCGCCGCTGC CGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAAAAT GGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTGATGGAGGACGTG GAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATCCTA AATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCAGAG ATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTCCCT CGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGTACTCCA AAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCGCAA CCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTGATG GCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGTGGT TTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACAGGA CCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCATCTT CAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAA Em variantes do mesmo,GGG nucleotides shown in bold encode G, D, V or L 100 PPT1 signal CD33-1 derivatives ATGCCGCTGCTGCTACTGCTGCCCCTGCTGTGGGCAGGGCCAGGGCTGGCCGCGCGCGCCGCTGCCGT TGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAATGGT GGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGATTGGGAAGACCCTGATGGAGGACGTGGAG AACAGCTTCTTCCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATCCTAAAT TGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCAGAGATG CCCTTCACCTCCCATGATCAATCTGATCGGTCCAGCCGATTGGTTGATTGATTGATTGATTGGTCGATT TGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGTACTCCAAAG TTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAAGGAGGATGTGTATCGCAACCA CAGCATCTTCTTGGCAGATATAAATCAGGAGCGAGGACCATCAGACCATCAGAGACCATGAGGACCAACTGAGGAGGAGGACTGCAAGCAACCA CTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGTGGTTTG GATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACAGGACCG CCTGGGGGCTAAAGGAAATGGACAATGAGGAGAATTCCTCAATGATTGCCTAGCCTAGCCTAGCCTAGGGACA TTGTCTGAAGAATGGTTTTATGCCCACATCATACCATCCTTGGATAA, Petition 870250104513, dated 11 / 14 / 2025, pp. 164 / 242 157 / 212 In variants thereof, GGG nucleotides shown in bold encode G, D, V or L 101 IL34-1-derived PPT1 signal ATGCCCCGGGGCTTCACCTGGCTGCGCTATCTTCTGCTGGGGGATCTTCCTTGGCGTGGCCAGGGGGGGGGC CGCCGGCGCCGCTGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGG TGCTATTAAAAATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACC CTGATGGAGGACGTGGAGAACAGCTTCTTCTTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCAC TTGCTAAGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAG GGCAGTGGCTCAGAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGT GTTTTTGGACTCCCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATG CTGGGGCGTACTCCAAAGTTGTTCAGGAAGCCAGCCCACCGATCGAGGACCATCAAGTTGGACTCCAGTCGAAAACACTGAATG GGATGTGTTATCCGCAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTAC AAGAAAAACCTGATGCCCTGAAGAAGTTTGATGGTGAAATTCCTCAATGATTCCATTTGTGGACCCTG TAGATTCGGAGTGGTTTGGATTCAGATTGGACCAGCACCGACCATTCGATCGATCGATT CCTGTACACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAA Em variantes do mesmo, nucleotídeos GGG mostrados em negrito codificam G, D, V ou L 102 OSM-1 signal_PPT1 ATGGGGGTACTGCTCACACAGAGGACGCTGCTCAGTCTGGTCCTTGCACTCCTGTTTCCAGACGCTAGAG CCCTGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAA AAAAATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTGATGGAG GACGTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGG ATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGC TCAGAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGA CTCCCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGT ACTCCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTA TCGCAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAAAAC CTGATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGG AGTGGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGAC CATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATCCTTGGATAA In variants of the same, the CTG nucleotides shown in bold are coded in bold, V13, or PPT signal derivative of tPA-1 ATGGATGCAATGAAGAGAGGGCTCTGCTGTGTGCTGCTGCTGTGGAGCAGTCTTCGTTTCGCCCAGCG CCAGAGCCCTGCAGCACCTGGACCCGCCGGCGCCGCTGCCGTTGGTGATCTGGCATGGGGATGGGAGACAG CTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAAAATGGTGGAGAAGAAAATACCTGGAATTTACGTC TTATCTTTAGATTGGGAAGACCCTGATGGAGGACGTGGAGAACAGCTTCTTCCTTGAATGTCAATTCCC AAGTAACACGTGTGTTCAGGCCATTAGCCTAGCATTGATTGATTGCCATGCCATGGGAGA CTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCAGAGATGCCCTTCACCTCCCATCAATCAATCTGATC TCGGTTGGGGACAACATCAAGGTGTTTTTGGACTCCCTCGATGCCCAGGAGAGAGCTCTCACATCTGTG ACTTCATCCGAAAAACACTGAATGCTGGAGGGCCGACCTAGCCGACTGAGTCGATCGATC ATACTGGCATGACCCCATAAAGGAGGATGTGTATCGCAACCACAGCATCTTCTTGGCAGATATAAATCAG GAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTGGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGTGGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGA AACCATTTCCCTTACAGGAGACCTCCCTGTACACACAGGACCCTGGGGCTAAAGGAAATGGACAATGCA GGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCACA TCATACCATCCTTGGATAA In variants of the same, CTG nucleotides shown in bold encode G, D, V or L 104 IL-2-1 (derived) PPT ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTCCTGCTGTCTGCCAGGGCCG GGCCGCCGGCGCCGCTGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCAT GGGTGCTATTAAAAATGGTGGAGAAAAATACCTGGAATTTACGTCTTATCTTTAGATTGGGAAG ACCCTGATGGAGGACGTGGAGAACCTTCTTCTTTGAATGTCAATTCCCAGTAACAACAGTGTGTCAGG Petition 870250104513, of 14 / 11 / 2025, p. 165 / 242 158 / 212 CACTTGCTAAGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCAGGGGAGGCCAATTTCT GAGGGCAGTGGCTCAGAGATGCCCTTCACCTCCCATCAATCTGATCGGTTGGGGACAACATCAA GGTGTTTTTGGACTCCCTCGATGCAGGACCATCCATCACTGACTGACTGACTGACTGACTGATTCGACTGGACCAGGACCATCAATCAATTCGACTGACTGATTCGTTGGGGGACAACATCAA ATGCTGGGGCGTACTCCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAA GGAGGATGTGTATCGCAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCC TACAAGAAAAACCTGATGGCCCTGAAGAAGTTTGAGTTGATTGATTGATTGATTGACCATCC CTGTAGATTCGGAGTGGTTTGGATTTTCAGAAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGAC CTCCCTGTACACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCT ACAGAAGGGGACCATCTTCAGTTGTCTGATTGATTGATTGATTGCCATCCATCCATTCATTCAGTTGTTTGGATTGATTGATTGCCATCCATGCATGCAGGACAGCTAGTGTTTCTGGCT In variants of the same, GGG nucleotides shown in bold encode G, D,V ou L 105 Trypsin-1_PPT1 ATGAATCTACTTCTGATCCTTACCTTTGTTGCAGCTGCTGTTGTGATTAGGGCAGTGGACCTGCCGTTGG TGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAAAATGGTGAATGGGA GAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTGATGGAGGACGTGGAGAAC AGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATCCTAAATTGC AGCAAGGCTACAATGCTATGGGATTCTCCGAGGATTGGCCGATTGGCCGGCC TTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTCCCTCGATGC CCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGTACTCCAAAGTTG TTCAGGAACGAACGCCTCGTGCAAGCCGATACTGACCATAGGACCATGAGGAGGAGGATCGAATGC CATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAACCTGATGGCCCTG AAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTTGGACCCTGTAGATTCGGAGTGGTTTGGAT TTTACAGAAGTGGCCAAGCCAGGAACGACCATTCGACCCCTTGACCTTGACCTTGGATTGGACCAGGACCATTCGACCTTGACCTTGGATTGGATTGAATTCCTGAT GGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCATCTTCAGTTG TCTGAAGAATGGTTTTATGCCCACATCATACCATCCTTGGATAA In variants of the same, GTG nucleotides shown in bold encode G,D, V ou L 106 BDNF-1-1 / 2_PPT1 ATGACAATCCTCTTCCTGACCATGGTGATTAGCTACTTTGGCTGCGCTAXGGCCGGGCCGCCGGCGCCGC TGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAA AATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTGATGGAGGAC GTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATC CTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCA GAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTC CCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGTACT CCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCG CAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTG ATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGT GGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACA GGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCAT CTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAA Em que X é A ou G; Em variantes do mesmo,GGG nucleotides shown in bold encode G, D, V or L 107 sp7_7-PPT1co1 ATGGCCTTCCTCTGGCTGCTCAGCTGTTGGGCCTTGCTGGGACCACCTTTGGAGGCCCCCCAGCACCTCTC TTCCCCTGGTGATCTGGCATGGCATGGGGGATAGCTGCTGCAATCCTCTCTCAATGGGAGCCATTAAGAA GATGGTGGAGAAAAATCCCAGGGATATATGTTCTGTCCTTGGAGATTGGAAAAACCTTGATGGAAGAT GTGGAAAATAGCTTTTTCCTTAATGTGAACTCTCAAGTCACCACAGTGTGCCAGGCCCTGGCCAAGGACC CCAAGCTGCAGCAAGGCTACAATGCAATGGGCTTCTCCCAAGGAGGTCAATTCCTGAGGGCTGTTGCACA GAGGTGTCCCA CCCAGGTGTCCAGGGGAGAGCAGCCACATCTGTGACTTCATTAGAAAGACACTAAATGCAGGAGCCTACA GCAAGGTGGTGCAGGAGAGGCTTGTTCAGGCTGAGTACTGGCATGACCCCATTAAGGAAGATGTCTATAG AAACCACAGCATCTTCCTGGCAGATATAACCAAGAAGGAGAGAGAGAGAGATCATTCATTTACA ATGGCCCTCAAGAAGTTTGTGATGGTGAAGTTCCTGAATGACTCCATTGTTGACCCTGTGGACTCTGAAT GGTTTGGTTTCTACAGATCAGGACAAGCCAACAATCCCCCTGCAAGAGACCTCCCTGTACACCCA GGACAGGCTGGGCCTGAAAGAAATGGATAATGCTGGCCAACTGGTCTTCCTGGCAACTGAAGGGGACCAC, Petition 870250104513, of 14 / 11 / 2025, p. 166 / 242 159 / 212 CTGCAACTCTCTGAGGAATGGTTCTATGCTCACATCATCCCATTTTTGGGCTGA 108 sp7_PPT1co2 ATGGCCTTTCTCTGGTTGCTCTCTTGTTGGGCCCTGCTGGGCACAACTTTTGGGGGCCCACCTGCACCAC TTCCCTTGGTCATCTGGCATGGCATGGGTGACTCTTGCTGCAATCCCTTATCCATGGGGGCTATTAAGAA GATGGTGGAAAAGAAGATTCCTGGAATTTATGTGCTGAGTCTGGAAATTGGAAAGACCCTCATGGAAGAT GTTGAAAACAGCTTCTTCTTGAATGTCAATTCCCAGGTCACCACAGTGTGTCAGGCTCTGGCAAAGGACC CCAAGCTCCAGCAAGGATATAATGCCATGGGATTTTCCCAAGGTGGCCAGTTCCTGAGGGCAGTGGCTCA GAGATGCCCTTCACCCCCTATGATCAACCTCATCTCTGTGGGTGGGCAGCATCAGGGTGTCTTTGGGCTC CCAAGATGCCCAGGAGAAAGCTCTCACATCTGTGACTTTATTAGAAAGACCCTGAATGCTGGGGCTTACA GCAAGGTTGTCCAGGAGAGGCTGGTGCAGGCTGAATACTGGCATGACCCCATTAAGGAAGATGTGTACAG AAACCACAGTATCTTCTTGGCTGATATCAACCAAGAAAGAGGCATCAATGAGAGCTACAAGAAGAATCTC ATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATAGCATTGTGGACCCTGTAGACTCAGAGT GGTTTGGATTCTACAGGTCTGGCCAGGCTAAGGAGACCATCCCACTGCAAGAGACAAGCCTTTACACACA GGACAGGCTTGGTCTGAAAGAGATGGATAATGCTGGACAGCTGGTGTTTCTGGCCACTGAAGGGGACCAC CTGCAGCTGAGTGAAGAATGGTTCTATGCCCACATCATCCCCTTCTTAGGCTGA 109 sp7_PPT1co3ATGGCCTTTCTGTGGCTCCTCAGCTGCTGGGCCCTGCTGGGCACCACTTTTGGAGGGCCCCCAGCACCCC TGCCTCTGGTCATTTGGCATGGCATGGGGGACTCCTGCTGCAATCCCTTATCCATGGGGGCCATCAAGAA GATGGTGGAGAAGAAGATCCCTGGAATTTATGTTCTGTCTTTAGAAATAGGAAAAACACTGATGGAAGAT GTGGAAAATTCCTTCTTCCTCAATGTCAACTCCCAGGTAACAACAGTGTGTCAGGCCCTGGCCAAAGACC CCAAATTACAGCAGGGCTACAATGCTATGGGATTCTCACAGGGAGGCCAATTTCTCAGAGCTGTTGCTCA GAGATGCCCTTCACCCCCCATGATCAACCTGATTTCAGTGGGTGGACAACATCAAGGAGTTTTTGGATTA CCAAGGTGCCCTGGGGAGAGCTCTCACATTTGTGATTTTATAAGAAAAACCTTGAATGCTGGGGCCTACT CAAAGGTGGTCCAGGAGAGGTTAGTGCAGGCTGAGTATTGGCATGACCCCATTAAGGAAGATGTGTACAG AAACCACTCCATTTTTTTGGCTGACATCAACCAGGAGAGAGGAATTAATGAATCCTACAAGAAGAACCTG ATGGCCCTCAAGAAGTTTGTGATGGTGAAATTCCTCAATGACTCCATTGTGGATCCAGTGGATTCAGAGT GGTTTGGATTCTACAGAAGTGGCCAAGCCAAGGAAACAATACCACTTCAAGAGACCAGCCTGTACACCCA GGACAGACTGGGCCTAAAGGAAATGGACAATGCAGGTCAGCTTGTTTTCTTGGCCACTGAGGGGGACCAC CTTCAACTCTCTGAAGAATGGTTTTATGCCCACATCATACCCTTTCTGGGGTGA 110 sp7_PPT1co4 ATGGCCTTTTTATGGCTGCTGAGCTGCTGGGCTTTGCTGGGCACCACATTTGGGGGCCCTCCAGCACCTCTTCCTTTAGTGATCTGGCATGGCATGGGTGACAGCTGCTGCAACCCACTGTCCATGGGAGCCATCAAGAA AATGGTGGAGAAGAAAATTCCAGGAATCTATGTCCTATCCCTGGAGATTGGGAAGACTCTGATGGAAGAT GTGGAGAACTCCTTCTTCCTGAATGTCAATTCCCAAGTCACCACAGTCTGCCAGGCCCTGGCCAAAGACC CCAAGCTGCAGCAAGGGTACAATGCTATGGGCTTCTCCCAAGGGGGGCAGTTCTTGAGAGCAGTTGCCCA GAGATGCCCCAGCCCTCCAATGATTAATCTGATCTCTGTGGGAGGTCAGCATCAAGGAGTCTTTGGGTTG CCCAGATGTCCAGGAGAGAGCAGTCACATCTGTGACTTCATCAGGAAAACACTGAATGCTGGGGCATACA GCAAGGTGGTGCAGGAAAGGCTTGTGCAGGCAGAGTACTGGCATGACCCCATTAAAGAGGATGTGTACAG AAACCACAGCATCTTTCTTGCAGACATAAATCAGGAGAGAGGTATCAATGAGTCCTACAAGAAGAATCTG ATGGCCCTAAAGAAATTTGTGATGGTAAAATTCCTCAATGACTCCATAGTGGACCCAGTTGACTCTGAGT GGTTTGGATTTTACAGAAGTGGCCAAGCAAAAGAGACCATTCCCCTTCAAGAGACATCCCTGTACACCCA AGATAGGCTGGGCCTGAAAGAGATGGATAATGCAGGGCAATTGGTGTTCCTTGCTACAGAAGGAGACCAC CTCCAGCTATCTGAAGAGTGGTTCTATGCCCACATCATCCCTTTTCTAGGGTGA 111 sp7_7-PPT1co5 ATGGCCTTTCTGTGGCTGCTGAGCTGCTGGGCCCTGCTGGGGACAACATTTGGAGGCCCCCCTGCCCCAC TTCCCTTGGTGATATGGCATGGCATGGGAGATTCTTGTTGTAACCCACTGTCAATGGGGGCCATTAAGAAGATGGTGGAAAAGAAGATCCCTGGAATCTATGTCCTCTCCCTGGAAATTGGGAAGACCCTCATGGAGGAT GTGGAAAACTCATTCTTCCTCAATGTGAACAGCCAGGTCACCACTGTTTGTCAGGCATTAGCAAAGGACC CCAAGCTTCAGCAGGGATACAATGCTATGGGCTTTAGCCAAGGTGGGCAATTCTTGAGAGCAGTGGCACA GAGATGCCCCTCACCTCCCATGATCAACCTCATCAGTGTAGGAGGCCAGCACCAGGGGGTTTTTGGGCTC CCCAGATGCCCTGGTGAATCATCTCACATCTGTGACTTCATCAGAAAAACCTTGAATGCTGGAGCCTACA GTAAAGTAGTGCAAGAGAGGCTGGTGCAAGCAGAATACTGGCATGATCCCATCAAGGAAGATGTCTACAG GAACCATAGCATCTTCCTGGCTGACATCAACCAGGAGAGGGGAATCAATGAGTCCTACAAGAAAAACCTG ATGGCACTGAAGAAGTTTGTGATGGTCAAATTCCTCAATGACTCCATTGTGGACCCTGTGGATTCTGAAT GGTTTGGATTTTACAGGTCTGGCCAAGCAAAGGAAACCATCCCTCTTCAGGAAACCAGCCTGTACACACA AGACAGGCTGGGCCTAAAGGAAATGGACAATGCTGGACAATTGGTGTTTTTGGCTACTGAGGGTGACCAC CTCCAGCTCTCAGAAGAATGGTTTTATGCTCACATCATCCCCTTCCTGGGTTGA 112 sp7 7-PPT1co6 ATGGCCTTCCTTTGGCTACTGAGCTGCTGGGCCCTTCTGGGCACCACTTTTGGTGGCCCACCTGCTCCAT Petição 870250104513, de 14 / 11 / 2025, pág. 167 / 242 160 / 212 TGCCCCTAGTCATTTGGCATGGGATGGGGGACAGCTGCTGCAATCCTTTATCTATGGGAGCCATTAAGAA GATGGTGGAGAAAAAGATCCCTGGCATATATGTGTTAAGCCTGGAGATTGGAAAGACCCTCATGGAAGAT GTTGAGAATTCTTTCTTCCTGAATGTAAACAGCCAAGTCACCACAGTGTGCCAAGCTCTGGCCAAGGACC CCAAGCTCCAGCAGGGTTATAATGCTATGGGATTCTCTCAGGGTGGGCAGTTCCTGAGGGCTGTGGCACA GAGATGCCCAAGCCCACCAATGATCAACCTCATCAGTGTTGGTGGACAGCATCAGGGAGTGTTTGGCCTG CCCAGATGTCCAGGTGAGTCCTCTCATATCTGTGACTTTATCAGGAAAACCTTAAATGCAGGGGCCTATT CCAAGGTGGTGCAGGAGAGACTTGTCCAGGCTGAGTATTGGCATGATCCCATTAAAGAAGATGTCTATAG AAACCATTCCATCTTCCTGGCTGATATCAACCAGGAAAGAGGGATCAATGAGAGCTACAAGAAGAATCTA ATGGCACTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATAGTATTGTGGATCCTGTAGACAGTGAGT GGTTTGGCTTCTACAGAAGTGGACAAGCCAAAGAGACCATTCCCTTACAAGAGACCTCACTCTACACACA GGACAGACTGGGCCTGAAGGAAATGGACAATGCAGGTCAGCTGGTGTTCCTTGCAACAGAGGGGGATCAC CTGCAGCTGTCAGAGGAATGGTTTTATGCCCACATCATCCCTTTCCTTGGTTGA 113 sp7_7-PPT1co7 ATGGCTTTCCTCTGGCTCTTGAGTTGCTGGGCACTGCTGGGCACCACCTTTGGAGGTCCCCCTGCTCCAT TGCCTCTGGTCATCTGGCATGGCATGGGTGACTCCTGTTGCAACCCCTTAAGCATGGGGGCCATCAAGAAGATGGTGGAGAAGAAGATTCCTGGAATCTATGTCTTGTCTTTAGAGATTGGTAAAACCCTCATGGAAGAT GTGGAGAATTCCTTCTTCTTGAATGTGAACTCACAAGTCACAACAGTCTGCCAGGCCCTGGCAAAGGACC CCAAGCTCCAGCAGGGCTACAATGCCATGGGCTTCTCCCAGGGTGGGCAATTTCTGAGGGCTGTGGCCCA GAGATGTCCCTCACCCCCCATGATCAACTTGATATCAGTTGGAGGCCAGCACCAGGGAGTATTTGGGCTT CCCAGGTGCCCAGGAGAATCCAGCCATATCTGTGATTTCATTAGAAAGACCCTCAATGCTGGGGCTTACT CCAAGGTGGTGCAGGAGAGGTTAGTGCAAGCTGAATACTGGCATGATCCCATAAAGGAGGATGTTTATAG GAACCACAGCATCTTCCTAGCAGATATTAATCAAGAAAGAGGTATCAATGAGTCCTACAAGAAAAACCTC ATGGCCCTGAAGAAGTTTGTTATGGTCAAGTTTCTCAATGACTCCATTGTGGATCCTGTAGACTCTGAAT GGTTTGGCTTTTACAGGAGTGGCCAAGCAAAAGAAACCATTCCTCTGCAGGAAACAAGTCTGTACACTCA GGACAGACTGGGCCTGAAAGAAATGGATAATGCTGGCCAGTTAGTGTTCCTGGCCACTGAGGGGGACCAC CTGCAACTCAGTGAGGAATGGTTCTATGCTCACATAATTCCCTTCCTTGGTTGA 114 sp7_7-PPT1co8 ATGGCTTTCCTCTGGCTGCTCTCCTGTTGGGCTCTTCTTGGGACCACATTTGGGGGACCTCCTGCTCCTC TGCCCCTGGTCATCTGGCATGGAATGGGAGACAGCTGTTGTAACCCACTCAGTATGGGAGCCATAAAGAA GATGGTTGAGAAGAAGATTCCTGGCATATATGTACTCAGCTTGGAGATTGGGAAGACCTTGATGGAAGATGTGGAGAACTCATTCTTCTTGAATGTCAACAGCCAGGTCACCACTGTTTGCCAGGCCCTTGCTAAGGACC CCAAACTGCAACAGGGCTACAATGCCATGGGGTTCTCTCAGGGAGGACAGTTCCTCAGAGCAGTGGCACA GAGGTGCCCCAGCCCACCCATGATTAATCTGATCAGTGTTGGAGGGCAGCACCAAGGGGTCTTTGGACTT CCAAGGTGCCCTGGGGAATCCAGCCATATTTGTGATTTCATCAGAAAGACTCTGAATGCAGGGGCCTATA GTAAAGTTGTTCAAGAAAGGCTGGTGCAGGCAGAATACTGGCATGATCCCATCAAAGAAGATGTATACAG AAACCACAGCATTTTCCTGGCAGATATAAACCAAGAAAGAGGCATTAATGAGTCCTACAAGAAGAACCTC ATGGCCCTGAAGAAATTTGTGATGGTGAAATTTTTGAATGATTCTATAGTGGACCCTGTGGATAGTGAGT GGTTTGGTTTCTACAGGAGTGGGCAGGCCAAGGAGACCATTCCCTTGCAGGAGACCTCCCTGTACACACA GGACAGACTGGGCCTAAAGGAAATGGACAATGCAGGCCAGCTAGTGTTCCTGGCCACTGAGGGGGACCAC CTCCAGCTCTCTGAAGAATGGTTTTATGCCCATATTATCCCTTTCCTGGGCTGA 115 sp7_7-PPT1co9 ATGGCCTTCCTCTGGCTGCTGAGCTGTTGGGCACTGCTGGGCACCACCTTTGGGGGCCCTCCAGCTCCCT TGCCTTTAGTCATTTGGCATGGAATGGGAGACTCCTGCTGCAATCCTCTCTCTATGGGAGCCATAAAGAA GATGGTAGAGAAAAAAATTCCTGGAATATATGTCCTAAGCCTGGAAATTGGGAAGACACTCATGGAAGAT GTGGAGAACTCCTTCTTCCTCAATGTGAACAGCCAGGTGACCACAGTCTGCCAGGCCTTGGCCAAAGACCCTAAGCTTCAGCAAGGCTACAATGCCATGGGCTTCAGCCAGGGTGGTCAATTCCTGAGAGCAGTGGCCCA GAGATGCCCCTCACCACCTATGATTAACCTCATCTCTGTGGGTGGTCAGCACCAAGGTGTGTTTGGTCTC CCTAGGTGCCCAGGAGAGAGTAGCCATATTTGTGACTTCATCAGGAAAACATTGAATGCTGGAGCCTACT CAAAAGTTGTACAAGAAAGGCTAGTGCAGGCTGAGTACTGGCATGATCCCATCAAGGAAGATGTGTACAG AAACCACAGCATCTTTCTGGCTGATATCAATCAGGAGAGGGGGATCAATGAAAGCTACAAGAAGAACCTG ATGGCCCTCAAGAAGTTTGTCATGGTGAAATTCCTCAATGACAGCATTGTTGATCCTGTTGATTCTGAAT GGTTTGGATTCTACAGGTCTGGACAGGCCAAAGAGACCATCCCTCTTCAGGAAACCTCCCTTTACACACA GGACAGACTGGGGCTCAAGGAGATGGACAATGCTGGTCAGCTGGTTTTTCTGGCTACAGAGGGAGACCAC CTACAGTTGAGTGAAGAGTGGTTCTATGCCCACATCATCCCTTTCCTGGGTTGA 116 sp7_7-PPT1co10 ATGGCATTCCTCTGGCTACTCTCTTGCTGGGCTCTGCTGGGCACAACTTTTGGGGGCCCACCAGCTCCCC TCCCCCTGGTCATTTGGCATGGTATGGGAGACTCCTGTTGTAATCCTCTCTCCATGGGAGCCATTAAGAA AATGGTGGAGAAGAAAATTCCTGGGATCTATGTGCTCTCTCTAGAGATTGGGAAGACCCTGATGGAAGAT GTGGAGAACAGCTTTTTCCTTAATGTGAACAGCCAGGTGACAACTGTCTGTCAAGCATTGGCCAAGGACC Petição 870250104513, de 14 / 11 / 2025, pág. 168 / 242 161 / 212 CCAAGCTGCAGCAAGGCTACAATGCTATGGGATTCTCTCAGGGGGGCCAGTTCCTGAGGGCTGTGGCCCA GAGATGCCCATCCCCTCCCATGATCAATCTGATATCTGTTGGGGGCCAGCACCAGGGAGTTTTTGGGCTG CCCAGATGCCCTGGGGAGAGCTCTCACATCTGTGATTTCATCAGGAAAACTCTCAATGCTGGAGCATATA GCAAGGTGGTGCAGGAGAGGTTGGTGCAGGCAGAGTACTGGCATGACCCCATCAAGGAGGATGTGTACAG AAACCACTCAATTTTCCTGGCAGATATCAACCAAGAGAGGGGCATCAATGAGTCCTACAAGAAAAACCTG ATGGCCCTGAAGAAGTTTGTGATGGTGAAGTTTCTGAATGATTCTATTGTGGACCCTGTGGATAGTGAGT GGTTTGGCTTTTACAGAAGTGGCCAAGCTAAGGAAACCATTCCCCTACAAGAAACTTCCCTGTACACCCA GGACAGGTTGGGACTCAAAGAGATGGACAATGCTGGACAGCTGGTGTTCCTGGCCACAGAAGGGGACCAC CTGCAGCTGAGTGAAGAGTGGTTCTATGCTCATATCATCCCCTTCCTTGGATGA 117 sp7_PPT1co11 ATGGCCTTCCTCTGGCTCCTGTCCTGTTGGGCTCTCCTAGGCACCACTTTTGGGGGCCCCCCTGCCCCTC TTCCCCTGGTCATTTGGCATGGGATGGGTGACTCCTGCTGCAACCCCCTAAGCATGGGGGCCATCAAGAA GATGGTGGAGAAGAAGATTCCTGGAATTTATGTCCTTAGCCTGGAAATTGGGAAGACCTTAATGGAAGAT GTGGAAAACAGCTTTTTCTTAAATGTCAATTCTCAGGTAACAACAGTGTGCCAAGCCCTGGCCAAGGACC CTAAACTGCAGCAGGGCTACAATGCTATGGGCTTCAGCCAGGGTGGACAGTTTCTGAGGGCAGTGGCTCAGAGGTGCCCCAGTCCTCCCATGATCAATCTCATCTCTGTGGGAGGCCAGCACCAGGGTGTTTTTGGCCTG CCCAGGTGTCCTGGAGAGTCCTCACATATCTGTGACTTCATCAGGAAGACACTGAATGCAGGGGCCTATA GCAAGGTGGTGCAAGAGAGACTGGTTCAGGCTGAATACTGGCATGACCCCATCAAGGAAGATGTTTACAG GAACCATAGCATCTTCCTTGCTGATATTAATCAAGAGAGGGGCATAAATGAGAGCTACAAGAAGAATTTA ATGGCTCTAAAGAAATTTGTCATGGTGAAGTTCCTGAATGACTCCATTGTGGATCCTGTGGACTCTGAGT GGTTTGGGTTCTACAGAAGTGGCCAGGCCAAGGAGACCATCCCCCTGCAGGAGACAAGCCTGTACACACA GGACAGGCTGGGACTGAAGGAGATGGACAATGCAGGACAGCTGGTGTTCCTGGCTACAGAGGGAGACCAC CTGCAGCTCTCAGAGGAATGGTTCTATGCACACATCATTCCCTTTTTAGGGTGA 118 sp7_7-PPT1co12 ATGGCCTTCCTGTGGCTCTTGTCCTGTTGGGCATTGCTAGGCACCACTTTTGGGGGACCTCCTGCCCCTC TTCCTTTGGTTATCTGGCATGGGATGGGTGACTCCTGCTGCAATCCTTTAAGCATGGGGGCTATTAAGAA GATGGTGGAGAAAAAAATTCCTGGAATCTATGTGCTTAGCTTAGAAATAGGGAAGACATTAATGGAAGAT GTGGAAAACAGCTTTTTCTTGAATGTCAACTCACAGGTGACTACTGTCTGTCAGGCCCTGGCCAAGGACC CCAAGCTGCAGCAAGGTTACAATGCTATGGGATTCAGCCAGGGTGGTCAGTTTCTGAGGGCTGTGGCACA GAGATGCCCCTCACCTCCCATGATCAACCTCATCAGTGTGGGAGGACAGCACCAAGGTGTTTTTGGTCTGCCCAGGTGTCCTGGAGAGTCCTCACATATCTGTGACTTCATCAGGAAGACTCTGAATGCTGGGGCCTATA GCAAAGTAGTCCAGGAGAGGTTGGTGCAGGCTGAATACTGGCATGACCCCATTAAAGAAGATGTCTATAG GAACCATAGCATATTCCTTGCAGATATCAACCAGGAGAGGGGGATCAATGAGAGCTACAAGAAAAACTTG ATGGCTCTCAAGAAGTTTGTGATGGTAAAGTTCTTAAATGACTCCATTGTGGATCCTGTAGACTCAGAGT GGTTTGGGTTCTACAGGTCTGGCCAAGCCAAAGAGACCATTCCTCTGCAGGAGACCAGCCTGTACACACA GGACAGACTGGGACTGAAGGAGATGGACAATGCTGGCCAGCTGGTGTTCCTGGCTACAGAGGGAGACCAC CTGCAGCTCTCAGAAGAATGGTTCTATGCTCACATCATTCCCTTTTTAGGGTGA 119 sp7_7-PPT1co13 ATGGCTTTCCTGTGGTTACTGAGCTGCTGGGCACTGCTGGGCACCACTTTTGGAGGTCCCCCTGCTCCTC TGCCTTTGGTGATTTGGCATGGCATGGGTGACTCCTGCTGCAACCCTCTGTCTATGGGTGCCATTAAGAA AATGGTGGAAAAGAAGATCCCTGGAATTTATGTCCTGTCTTTGGAGATAGGCAAGACTTTGATGGAAGAT GTTGAGAATTCCTTTTTCTTAAATGTAAATAGCCAGGTAACCACAGTTTGTCAGGCACTTGCCAAGGACC CCAAGCTGCAGCAAGGCTACAATGCCATGGGCTTCTCCCAGGGAGGGCAGTTTCTGAGAGCAGTGGCTCA GAGGTGCCCCAGCCCTCCAATGATCAATTTGATCTCAGTGGGGGGCCAGCATCAGGGGGTCTTTGGCCTA CCTAGGTGCCCTGGAGAGAGCTCTCATATCTGTGACTTCATTAGGAAGACATTAAATGCTGGGGCATACAGTAAGGTGGTGCAGGAGAGATTAGTGCAGGCTGAATACTGGCATGATCCCATCAAGGAAGATGTCTACAG GAACCACAGCATTTTCCTGGCAGACATTAACCAAGAGAGGGGGATCAATGAGAGCTACAAGAAAAACCTG ATGGCCCTCAAGAAGTTTGTGATGGTGAAGTTTCTCAATGACAGCATTGTGGATCCAGTGGATTCTGAGT GGTTTGGGTTCTACAGAAGTGGCCAGGCCAAAGAAACCATCCCATTGCAGGAAACCAGTTTGTACACTCA GGACAGGTTGGGCCTGAAGGAGATGGACAATGCTGGCCAACTGGTGTTCTTGGCCACTGAGGGGGACCAC CTACAGCTGAGTGAGGAATGGTTCTATGCCCACATCATCCCTTTTCTGGGCTGA 120 PPT1co14 ATGGCCTTCTTGTGGTTGCTCTCCTGCTGGGCCCTCTTGGGCACAACCTTTGGGGGACCCCCAGCTCCAC TCCCCCTGGTGATCTGGCATGGCATGGGAGATAGCTGTTGCAACCCATTATCCATGGGGGCCATTAAGAA GATGGTGGAGAAGAAAATCCCTGGCATTTATGTCCTTAGCCTGGAAATTGGAAAGACCTTAATGGAGGAT GTGGAAAACTCCTTCTTCCTCAATGTCAACTCCCAAGTCACCACAGTGTGTCAAGCCCTTGCCAAGGACC CCAAGTTGCAACAGGGCTATAATGCTATGGGCTTCTCTCAGGGAGGCCAGTTTCTGAGGGCTGTGGCCCA GAGGTGCCCCTCCCCACCTATGATCAATCTTATCTCTGTGGGTGGACAACACCAAGGTGTCTTTGGGCTG CCCAGGTGCCCTGGGGAGTCCAGCCACATTTGTGACTTCATCAGGAAGACACTAAATGCTGGTGCCTACT Petição 870250104513, de 14 / 11 / 2025, pág. 169 / 242 162 / 212 CCAAAGTTGTCCAGGAGAGACTGGTGCAAGCAGAATACTGGCATGACCCTATTAAAGAGGATGTCTACAG GAACCACAGCATCTTTCTGGCAGACATCAACCAGGAGAGAGGGATCAATGAATCCTACAAGAAGAACCTC ATGGCCCTGAAGAAATTTGTGATGGTTAAGTTTCTCAATGACTCCATTGTGGACCCTGTGGATTCTGAAT GGTTTGGATTTTACAGAAGTGGCCAGGCCAAGGAAACCATCCCTCTGCAGGAGACATCCCTGTACACACA GGACAGACTGGGCCTGAAGGAGATGGACAATGCTGGGCAGCTAGTGTTCCTGGCTACTGAGGGGGATCAT CTTCAGTTGTCTGAAGAATGGTTCTATGCCCACATCATTCCCTTCCTGGGCTGA 121 sp7_7-PPT1co15 ATGGCCTTTCTCTGGTTGCTTTCCTGTTGGGCCCTCTTGGGGACAACCTTTGGGGGGCCCCCAGCTCCTC TTCCCCTGGTGATCTGGCATGGCATGGGAGACTCCTGTTGCAACCCATTAAGCATGGGGGCTATTAAGAA AATGGTGGAGAAGAAAATCCCTGGAATTTATGTCCTCTCTCTGGAGATAGGCAAAACCTTAATGGAAGAT GTGGAGAACTCCTTCTTCCTCAATGTCAACTCCCAAGTCACCACTGTATGTCAAGCTCTGGCAAAGGACC CCAAATTGCAACAGGGATATAATGCCATGGGATTCTCCCAGGGTGGCCAGTTCCTGAGGGCTGTGGCACA GAGATGCCCCTCCCCACCTATGATCAATCTCATCTCTGTGGGTGGACAACATCAAGGTGTTTTTGGGCTG CCCAGATGCCCTGGGGAGTCCTCTCACATTTGTGACTTCATCAGGAAGACCCTCAATGCTGGAGCCTACT CTAAAGTTGTTCAGGAAAGGCTGGTCCAAGCAGAATACTGGCATGACCCTATAAAAGAGGATGTTTACAGGAACCACAGTATCTTCTTGGCAGACATCAACCAGGAGAGGGGCATCAATGAGTCCTACAAGAAAAACCTC ATGGCACTCAAGAAATTTGTGATGGTCAAATTCCTGAATGACTCCATTGTGGACCCTGTGGATTCTGAGT GGTTTGGATTCTACAGAAGTGGCCAGGCAAAGGAAACCATCCCTCTGCAGGAGACAAGTCTGTACACCCA GGATAGGTTGGGTCTGAAGGAAATGGATAATGCTGGGCAGCTAGTCTTCCTGGCCACAGAAGGGGACCAC CTGCAGCTTTCTGAAGAGTGGTTCTATGCTCACATCATTCCCTTTCTGGGCTGA 122 sp7 7-PPT1co16 ATGGCCTTTCTCTGGCTCTTGTCTTGCTGGGCTCTGCTGGGCACCACCTTTGGTGGCCCCCCTGCTCCTC TGCCCCTGGTCATCTGGCATGGGATGGGAGACAGCTGCTGTAACCCTTTATCAATGGGAGCCATCAAGAA AATGGTGGAGAAGAAGATCCCTGGGATATATGTTCTTAGCTTGGAAATTGGCAAGACTCTCATGGAAGAT GTTGAAAACAGCTTCTTCCTGAATGTCAATAGCCAAGTGACCACAGTGTGCCAGGCATTGGCTAAAGACC CCAAGTTGCAGCAAGGCTACAATGCCATGGGCTTTTCCCAGGGTGGTCAGTTCCTGAGGGCAGTGGCTCA GAGGTGCCCTTCACCACCTATGATAAACCTCATCTCTGTGGGAGGGCAACACCAAGGAGTATTTGGACTA CCCAGGTGCCCTGGGGAGTCCTCCCATATTTGTGACTTTATCAGGAAGACACTGAATGCAGGAGCCTACA GCAAGGTGGTTCAGGAGAGACTTGTGCAGGCAGAGTACTGGCATGATCCCATTAAGGAAGATGTGTACAG AAACCATAGTATTTTCCTGGCAGACATCAATCAGGAGAGGGGCATCAATGAGAGCTACAAGAAAAATCTGATGGCCCTAAAGAAGTTTGTCATGGTCAAGTTCCTGAATGATTCTATAGTGGACCCTGTGGATTCAGAGT GGTTTGGTTTTTACAGATCAGGGCAAGCCAAGGAAACCATCCCACTGCAGGAAACAAGCCTGTACACTCA AGACAGGTTAGGCCTAAAAGAGATGGACAATGCTGGCCAGCTTGTGTTCTTGGCAACAGAGGGGGATCAT TTACAGTTATCTGAGGAATGGTTCTATGCCCACATCATCCCCTTCCTTGGTTGA 123 sp7_7-PPT1co17 ATGGCATTTCTGTGGTTGCTCAGCTGTTGGGCCCTCCTTGGAACCACCTTTGGAGGGCCCCCTGCCCCTC TCCCTTTGGTTATTTGGCATGGCATGGGGGACTCATGCTGTAACCCTTTGAGCATGGGGGCCATTAAGAA AATGGTGGAGAAGAAGATCCCAGGTATTTATGTCTTGTCTCTAGAAATAGGGAAGACTCTGATGGAAGAT GTGGAGAATAGCTTCTTCTTAAATGTGAATTCACAGGTTACCACTGTGTGCCAGGCCCTGGCCAAAGACC CCAAGTTACAGCAGGGATACAATGCTATGGGATTTTCTCAGGGTGGTCAGTTCCTGAGGGCAGTGGCCCA GAGATGCCCAAGCCCTCCAATGATTAACCTCATTAGTGTGGGAGGGCAGCATCAAGGGGTATTTGGCCTG CCCAGGTGCCCTGGAGAGTCCTCTCATATCTGTGACTTTATCAGGAAGACTTTAAATGCTGGGGCCTACA GCAAGGTGGTCCAGGAGAGGCTGGTGCAAGCAGAGTATTGGCATGATCCCATAAAGGAGGATGTGTATAG GAACCACTCCATCTTCCTGGCAGACATCAACCAGGAGAGGGGGATCAATGAGTCTTACAAGAAAAATTTA ATGGCCCTGAAGAAGTTTGTGATGGTGAAGTTCCTCAATGATTCTATTGTGGACCCTGTGGATTCTGAGTGGTTTGGCTTTTACAGGAGTGGCCAGGCCAAGGAAACCATCCCTCTGCAGGAAACTTCTCTATACACACA GGATAGGCTGGGCCTGAAAGAGATGGACAATGCAGGGCAGCTGGTGTTTCTTGCCACTGAGGGTGACCAC CTTCAGCTATCTGAGGAATGGTTTTATGCTCACATCATCCCCTTCCTGGGGTGA 124 sp7_PPT1co18 ATGGCTTTCCTGTGGCTGCTTAGCTGCTGGGCCCTTCTTGGGACCACCTTTGGGGGTCCACCAGCTCCTC TGCCCTTGGTCATCTGGCATGGGATGGGGGACTCTTGTTGTAACCCTCTTAGCATGGGAGCCATTAAGAA GATGGTGGAGAAGAAAATACCTGGCATATATGTCCTGAGCCTGGAGATTGGCAAGACCCTGATGGAGGAT GTGGAGAACAGCTTCTTCCTGAATGTCAATTCCCAGGTGACCACAGTGTGTCAGGCCCTGGCCAAGGACC CCAAGTTGCAGCAAGGCTACAATGCTATGGGCTTTTCACAAGGTGGGCAGTTCCTGAGAGCAGTGGCACA GAGATGTCCTTCACCTCCAATGATCAACCTTATCTCAGTGGGAGGCCAACACCAGGGTGTTTTTGGGTTG CCCAGGTGTCCTGGTGAGAGCAGCCATATCTGTGACTTTATCAGGAAGACACTGAATGCAGGGGCCTACA GCAAGGTTGTTCAAGAGAGGCTGGTGCAGGCTGAGTATTGGCATGATCCCATTAAGGAGGATGTGTATAG GAACCACTCCATCTTTTTGGCAGACATCAATCAGGAGAGGGGCATCAATGAGTCCTACAAGAAGAACCTG ATGGCCCTCAAGAAGTTTGTGATGGTCAAGTTTCTGAATGATTCTATTGTGGATCCAGTGGACTCTGAAT Petição 870250104513, de 14 / 11 / 2025, pág. 170 / 242 163 / 212 GGTTTGGGTTCTACAGATCTGGCCAGGCCAAGGAGACCATCCCACTTCAAGAGACCAGCCTGTATACCCA GGACAGATTAGGCCTGAAGGAGATGGACAATGCTGGCCAGCTTGTCTTCCTGGCTACAGAGGGGGACCAC CTCCAGCTGAGTGAAGAGTGGTTTTATGCCCACATCATACCCTTCCTGGGTTGA 125 sp7_PPT1co19 ATGGCCTTCCTGTGGCTGCTCTCCTGCTGGGCCCTGCTGGGCACCACCTTTGGAGGCCCCCCAGCCCCTC TGCCCCTGGTCATCTGGCATGGCATGGGAGACAGCTGCTGCAACCCTCTCTCCATGGGAGCCATCAAGAA GATGGTGGAGAAGAAGATCCCTGGAATCTATGTCCTCAGCCTGGAGATTGGGAAGACCCTGATGGAGGAT GTGGAGAACTCCTTCTTCCTGAATGTGAACAGCCAGGTGACCACAGTGTGCCAGGCCCTGGCCAAGGACC CCAAGCTGCAGCAGGGCTACAATGCCATGGGCTTCTCCCAGGGAGGCCAGTTCCTGAGGGCTGTGGCCCA GAGATGCCCCTCACCTCCCATGATCAACCTCATCTCTGTGGGAGGCCAGCACCAAGGGGTCTTTGGCCTG CCCAGGTGTCCTGGGGAGAGCAGCCACATCTGTGACTTCATCAGGAAGACCCTGAATGCTGGTGCCTACA GCAAGGTGGTGCAGGAGAGGCTGGTGCAGGCTGAATACTGGCATGACCCCATCAAGGAGGATGTGTACAG GAACCACAGCATCTTCCTGGCAGACATCAACCAGGAGAGAGGCATCAATGAGAGCTACAAGAAGAACCTG ATGGCCCTGAAGAAGTTTGTGATGGTGAAGTTCCTCAATGACTCCATTGTGGACCCTGTGGACTCTGAGT GGTTTGGCTTCTACAGGAGTGGCCAGGCCAAGGAGACCATCCCCCTGCAGGAGACCAGCCTGTACACACAGGACAGACTGGGACTGAAGGAGATGGACAATGCTGGGCAGCTGGTGTTCCTGGCCACAGAGGGAGACCAC CTGCAGCTCTCAGAGGAGTGGTTTTATGCCCACATCATCCCCTTCCTGGGCTGA 126 spSPARC_S-PPT1co1 ATGAGGGCCTGGATCTTTTTTCTGCTTTGCCTGGCAGGAAGGGCCCTAGCAGGACCTCCTGCCCCCTTGC CTCTGGTGATCTGGCATGGCATGGGAGACAGCTGTTGCAACCCCCTCAGCATGGGTGCCATTAAGAAGAT GGTAGAGAAGAAGATACCTGGTATCTATGTGCTCTCCCTAGAGATTGGGAAAACTTTGATGGAGGATGTG GAAAATTCCTTCTTCCTGAATGTCAATTCCCAGGTCACCACAGTGTGCCAGGCTCTGGCAAAGGACCCAA AGCTACAGCAGGGCTATAATGCCATGGGCTTCAGCCAGGGTGGCCAATTCTTGAGGGCAGTGGCTCAGAG GTGTCCATCACCCCCCATGATTAATCTAATATCTGTGGGTGGCCAACACCAAGGTGTCTTTGGTCTCCCC AGGTGTCCTGGGGAGTCCTCACACATATGTGACTTCATCAGGAAGACTCTAAATGCAGGGGCTTATAGCA AGGTGGTTCAAGAAAGGCTGGTTCAAGCTGAGTATTGGCATGACCCCATCAAGGAAGATGTGTACAGAAA CCACTCAATTTTCCTGGCTGACATCAACCAGGAGAGGGGTATCAATGAGAGTTACAAGAAGAACCTCATG GCACTGAAGAAATTTGTGATGGTGAAATTCCTTAATGACTCCATTGTGGATCCTGTGGACTCAGAATGGT TTGGCTTCTACAGGAGTGGCCAAGCCAAAGAGACCATCCCCCTGCAGGAGACTAGCCTGTACACCCAGGA CAGGCTTGGTCTGAAGGAAATGGACAATGCTGGGCAGCTGGTCTTTCTGGCCACAGAAGGGGACCACCTTCAATTATCAGAGGAGTGGTTCTATGCCCACATCATACCTTTCCTGGGCTGA 127 spSPARC_S-PPT1co2 ATGAGGGCCTGGATCTTCTTCCTTCTTTGCTTGGCTGGCAGAGCTTTGGCAGGGCCCCCTGCCCCTCTTC CCTTGGTCATATGGCATGGGATGGGAGATTCCTGCTGCAACCCTCTGTCCATGGGAGCCATTAAGAAGAT GGTGGAAAAGAAGATCCCTGGAATTTATGTCCTAAGCCTGGAAATTGGGAAAACACTCATGGAAGATGTT GAAAATTCCTTCTTCCTCAATGTCAATAGTCAGGTAACTACAGTTTGTCAGGCTCTGGCAAAGGACCCCA AGCTGCAGCAGGGCTACAATGCCATGGGCTTCTCTCAGGGAGGACAATTCTTAAGGGCAGTAGCTCAGAG ATGCCCATCTCCTCCAATGATCAACCTCATCTCTGTTGGAGGGCAGCACCAAGGGGTTTTTGGCCTCCCC AGATGTCCTGGAGAGAGCAGCCATATCTGTGACTTCATCAGGAAGACTCTAAATGCTGGAGCCTACAGTA AGGTTGTACAGGAGAGGCTTGTTCAGGCTGAGTACTGGCATGACCCCATTAAGGAGGATGTGTATAGGAA TCATAGCATATTCTTGGCTGATATAAACCAAGAAAGGGGAATCAATGAAAGCTACAAGAAGAACCTCATG GCCCTAAAGAAGTTTGTGATGGTGAAGTTTCTCAATGACTCCATTGTTGACCCTGTGGACTCTGAATGGT TTGGCTTCTACAGGTCTGGCCAAGCCAAGGAGACAATTCCTCTCCAGGAGACTTCTCTGTACACACAAGA TAGGCTGGGACTAAAGGAAATGGACAATGCAGGTCAGCTGGTGTTCTTGGCCACAGAGGGGGACCACCTG CAGCTTTCTGAGGAGTGGTTCTATGCCCATATTATACCCTTTCTTGGTTGA 128 spSPARC_S-PPT1co3ATGAGAGCCTGGATCTTCTTCCTGCTTTGCCTTGCAGGCAGAGCCTTAGCAGGTCCCCCAGCTCCTCTCC CTCTTGTCATCTGGCATGGAATGGGTGACAGCTGCTGCAATCCATTATCCATGGGAGCCATTAAGAAGAT GGTGGAGAAGAAGATCCCAGGCATCTATGTATTGTCTTTGGAAATTGGGAAGACACTGATGGAGGATGTG GAGAACTCCTTCTTCTTAAATGTCAACTCACAGGTTACCACAGTGTGCCAAGCCCTGGCCAAGGACCCCA AGCTGCAACAGGGTTACAATGCTATGGGGTTCTCTCAAGGTGGCCAGTTCCTCAGGGCTGTGGCACAGAG GTGTCCCTCACCACCTATGATTAATCTCATCAGTGTTGGAGGACAGCATCAAGGTGTCTTTGGCCTCCCA AGATGTCCAGGGGAAAGTTCTCACATCTGTGATTTCATAAGGAAGACCCTCAATGCTGGAGCTTACAGTA AAGTGGTCCAGGAGAGGCTGGTCCAGGCTGAATACTGGCATGACCCAATCAAGGAGGATGTTTATAGAAA TCATTCCATCTTCCTGGCAGACATCAACCAGGAGAGGGGCATCAATGAGAGCTACAAGAAAAATCTCATG GCCCTGAAGAAGTTTGTGATGGTGAAATTTCTAAATGATAGTATTGTGGACCCTGTAGACTCTGAGTGGT TTGGCTTCTACAGGAGTGGGCAGGCCAAGGAAACCATCCCTCTGCAGGAAACTAGCCTTTACACACAGGA CAGGTTGGGCTTGAAGGAAATGGATAATGCTGGGCAGCTTGTCTTCCTTGCCACAGAGGGGGACCACTTG CAGCTCAGTGAGGAGTGGTTTTATGCCCACATCATCCCCTTCCTTGGCTGA Petição 870250104513, de 14 / 11 / 2025, pág. 171 / 242 164 / 212 129 spSPARC_PPT1co20 ATGAGGGCCTGGATATTCTTCCTGCTTTGTCTAGCTGGAAGAGCTCTGGCAGGGCCCCCAGCACCCCTGC CTCTGGTCATCTGGCATGGGATGGGAGATTCCTGCTGCAACCCTCTCAGCATGGGGGCCATTAAGAAAAT GGTGGAGAAGAAGATCCCTGGCATTTATGTCTTGTCCTTGGAGATAGGCAAAACACTAATGGAAGATGTG GAGAACAGCTTCTTCTTAAATGTGAACAGCCAGGTCACCACAGTATGTCAGGCCTTGGCCAAGGACCCCA AGCTCCAGCAGGGCTACAATGCCATGGGTTTTTCTCAGGGAGGTCAGTTCCTCAGGGCTGTGGCTCAGAG ATGCCCCTCACCACCTATGATCAATCTGATCTCTGTGGGAGGGCAGCATCAAGGTGTCTTTGGTCTTCCT AGGTGCCCTGGGGAGTCATCCCACATCTGTGACTTCATCAGGAAAACTTTAAATGCTGGAGCCTACAGCA AGGTTGTCCAAGAGAGGCTTGTCCAAGCAGAGTACTGGCATGATCCCATCAAAGAGGATGTTTACAGAAA CCACAGCATCTTCCTGGCAGACATCAATCAAGAGAGGGGCATTAATGAGTCCTACAAGAAAAACCTCATG GCCCTAAAGAAATTTGTGATGGTGAAATTCTTGAATGACTCCATTGTTGACCCTGTAGACTCTGAGTGGT TTGGCTTCTATAGATCAGGCCAGGCCAAGGAAACCATTCCTCTCCAAGAAACCTCCCTGTACACACAAGA TAGGCTGGGGTTGAAAGAGATGGATAATGCTGGGCAACTGGTGTTCTTGGCCACTGAGGGTGACCATTTA CAGCTTTCAGAGGAATGGTTCTATGCCCACATCATACCCTTTCTTGGATGA 130 spSPARC_S-PPT1co5ATGAGAGCCTGGATCTTCTTTCTCCTTTGCCTTGCTGGAAGAGCTTTGGCAGGGCCTCCAGCCCCCTTAC CTTTGGTCATATGGCATGGAATGGGAGACAGTTGTTGCAACCCCCTCTCTATGGGTGCTATTAAGAAAAT GGTGGAGAAGAAGATACCTGGCATTTATGTCCTCTCCCTGGAAATAGGCAAAACACTGATGGAAGATGTA GAAAACAGCTTTTTCCTCAATGTCAATTCCCAGGTAACAACTGTGTGCCAGGCCCTGGCCAAGGATCCCA AATTGCAGCAAGGTTATAATGCAATGGGATTCTCCCAAGGAGGCCAATTTCTGAGGGCTGTGGCCCAGAG GTGTCCATCTCCTCCCATGATCAACCTCATCAGTGTGGGGGGGCAGCACCAAGGAGTTTTTGGACTTCCA AGGTGCCCTGGGGAATCCAGCCACATTTGTGACTTCATTAGAAAGACACTCAATGCTGGTGCTTATTCCA AAGTTGTTCAGGAGAGGCTTGTGCAGGCTGAGTATTGGCATGACCCCATCAAGGAGGATGTGTACAGGAA TCATTCAATCTTCTTGGCTGACATCAACCAGGAGAGAGGCATCAATGAGAGCTACAAGAAAAACCTCATG GCCTTAAAGAAGTTTGTGATGGTGAAGTTCCTAAATGATAGCATAGTTGACCCAGTGGATTCTGAGTGGT TTGGTTTCTATAGGAGTGGCCAAGCCAAGGAGACCATTCCCCTGCAGGAGACCTCCCTGTACACCCAGGA CAGGCTTGGTCTCAAGGAGATGGACAATGCAGGACAGCTAGTTTTCTTGGCCACTGAGGGGGATCACCTC CAACTCAGTGAAGAATGGTTCTATGCACACATCATCCCCTTCTTGGGCTGA 131 spSPARC_S-PPT1co6 ATGAGGGCCTGGATCTTCTTCCTCCTGTGCCTGGCAGGGAGAGCCTTGGCTGGGCCCCCAGCACCCCTTCCTTTGGTGATATGGCATGGCATGGGTGATAGCTGTTGCAACCCCCTGAGCATGGGGGCCATCAAGAAAAT GGTGGAGAAAAAGATTCCAGGCATATATGTGCTCTCCCTGGAGATTGGAAAAACCCTCATGGAAGATGTG GAGAACAGCTTCTTCTTAAATGTGAATAGTCAAGTTACCACAGTGTGCCAGGCACTGGCCAAGGACCCCA AGCTCCAACAGGGGTACAATGCCATGGGCTTCTCTCAGGGAGGGCAGTTTCTCAGAGCAGTGGCCCAGAG ATGCCCTTCACCCCCCATGATCAATCTCATTTCTGTTGGAGGGCAACACCAGGGGGTATTTGGTCTACCC AGGTGCCCAGGTGAATCCAGCCACATCTGTGACTTCATCAGGAAGACACTGAATGCAGGAGCCTACAGCA AAGTGGTGCAAGAGAGGCTGGTGCAGGCAGAGTACTGGCATGACCCCATCAAGGAGGATGTCTACAGAAA CCATTCCATCTTCCTGGCAGACATCAACCAGGAAAGAGGAATCAATGAGTCCTACAAGAAGAACTTGATG GCCCTCAAGAAGTTTGTGATGGTGAAATTCCTGAATGATTCCATTGTTGACCCTGTGGATTCTGAGTGGT TTGGATTTTACAGAAGTGGCCAGGCCAAGGAAACAATTCCACTACAAGAGACCTCCCTCTACACCCAGGA CAGGCTGGGCCTCAAAGAAATGGACAATGCTGGCCAGCTGGTGTTTCTGGCTACAGAGGGAGACCATCTG CAGCTGTCAGAGGAGTGGTTCTATGCTCACATCATACCTTTCTTAGGATGA 132 spSPARC_S-PPT1co7 ATGAGAGCCTGGATCTTCTTCCTCTTGTGTCTGGCTGGGAGGGCCTTGGCTGGCCCTCCTGCTCCCCTGC CTTTGGTTATCTGGCATGGAATGGGTGACAGCTGTTGCAACCCCTTAAGCATGGGAGCTATTAAGAAAATGGTTGAGAAGAAGATCCCTGGGATCTATGTCCTGAGCTTGGAAATTGGGAAGACACTCATGGAAGATGTG GAGAACTCCTTCTTCCTGAATGTGAATAGCCAAGTGACTACAGTGTGTCAAGCCTTGGCCAAGGACCCCA AGCTGCAGCAGGGCTACAATGCCATGGGCTTCTCCCAGGGAGGACAGTTTCTGAGAGCAGTAGCTCAGAG GTGCCCTTCACCTCCCATGATCAACCTCATCAGTGTGGGGGGCCAGCACCAGGGAGTGTTTGGGCTGCCC AGGTGCCCTGGGGAGTCATCTCACATCTGTGACTTCATCAGGAAAACCCTCAATGCTGGGGCCTACAGCA AGGTGGTCCAGGAGAGACTGGTGCAGGCAGAGTATTGGCATGACCCCATCAAGGAGGATGTCTATAGGAA CCACAGCATTTTCTTAGCTGACATCAATCAAGAGAGAGGCATCAATGAGTCCTACAAGAAGAACCTGATG GCCCTGAAGAAGTTTGTGATGGTGAAGTTCCTCAATGATTCTATTGTGGATCCTGTGGACTCAGAGTGGT TTGGCTTTTACAGATCTGGGCAAGCAAAGGAGACCATTCCCCTGCAGGAAACATCCCTGTACACCCAGGA TAGGCTGGGTCTGAAAGAGATGGACAATGCTGGCCAGCTTGTTTTCCTGGCTACAGAAGGGGACCATTTA CAGCTATCTGAAGAATGGTTTTATGCTCACATTATCCCTTTCCTTGGATGA 133 spSPARC_S-PPT1co8 ATGAGGGCCTGGATCTTCTTTCTGTTGTGTTTGGCAGGAAGGGCCTTGGCTGGGCCCCCTGCACCTCTGC CCCTGGTCATTTGGCATGGCATGGGTGACTCCTGTTGCAATCCCCTGAGCATGGGGGCCATCAAGAAGAT Petição 870250104513, de 14 / 11 / 2025, pág. 172 / 242 165 / 212 GGTGGAGAAGAAGATCCCAGGAATCTATGTTCTGTCCTTAGAAATTGGGAAGACTCTGATGGAAGATGTG GAAAACAGCTTCTTCCTGAATGTGAATTCCCAGGTGACCACAGTCTGCCAGGCTCTGGCTAAGGACCCCA AACTCCAGCAGGGCTACAATGCTATGGGATTCTCCCAGGGTGGGCAGTTCCTCAGAGCAGTGGCTCAGAG ATGCCCATCACCCCCAATGATCAACCTCATCTCTGTTGGTGGTCAGCATCAAGGTGTCTTTGGACTCCCC AGGTGCCCTGGGGAGTCCTCTCACATCTGTGACTTTATCAGAAAAACCTTAAATGCTGGGGCCTACAGCA AGGTGGTCCAGGAAAGGCTGGTCCAGGCTGAGTACTGGCATGATCCCATCAAGGAAGATGTGTACAGGAA CCACTCCATTTTTCTGGCTGACATAAACCAAGAGAGGGGCATCAATGAGTCATATAAGAAAAACCTGATG GCTCTGAAAAAGTTTGTCATGGTTAAATTCCTCAATGACTCTATTGTGGACCCTGTTGACTCTGAGTGGT TTGGCTTCTACAGGTCAGGCCAAGCTAAAGAGACCATCCCCCTGCAGGAGACATCCCTGTACACACAGGA CAGGTTAGGACTGAAGGAGATGGACAATGCTGGACAGCTGGTGTTCCTGGCCACAGAGGGTGACCACCTA CAGTTGTCAGAAGAATGGTTCTATGCTCACATCATACCCTTCCTTGGTTGA 134 spSPARC_S-PPT1co9 ATGAGGGCCTGGATCTTCTTTCTCCTGTGCCTGGCTGGAAGGGCCTTGGCAGGCCCACCTGCTCCCCTCC CCTTGGTGATATGGCATGGCATGGGAGATAGCTGTTGTAATCCCCTCTCCATGGGTGCCATTAAGAAGAT GGTGGAAAAGAAGATTCCTGGAATCTATGTGCTGTCCCTGGAGATAGGGAAGACTCTGATGGAAGATGTGGAAAATTCCTTCTTCTTGAATGTCAACTCCCAGGTGACAACTGTATGCCAGGCCTTGGCAAAGGACCCCA AGCTGCAGCAGGGATACAATGCCATGGGATTCAGCCAAGGTGGACAGTTTCTGAGAGCAGTAGCCCAGAG ATGCCCAAGTCCCCCCATGATCAACCTCATCTCTGTGGGTGGACAGCACCAGGGAGTGTTTGGCCTGCCC AGATGTCCAGGGGAGAGCAGCCACATTTGTGACTTCATCAGGAAAACACTGAATGCTGGGGCCTACAGCA AGGTGGTGCAGGAGAGGCTAGTGCAGGCAGAGTACTGGCATGACCCAATCAAAGAGGATGTTTATAGGAA CCACAGTATCTTTTTGGCAGATATTAACCAGGAAAGAGGCATCAATGAGTCCTACAAGAAGAACCTAATG GCCTTGAAGAAATTTGTCATGGTGAAGTTCCTCAATGATTCCATTGTGGATCCTGTTGACTCAGAATGGT TTGGATTTTATAGATCAGGCCAGGCCAAAGAAACCATACCACTGCAGGAAACATCCCTCTACACTCAAGA TAGGCTGGGGCTGAAGGAAATGGATAATGCTGGGCAGCTGGTATTCCTGGCTACTGAAGGGGATCACCTC CAGCTAAGTGAGGAGTGGTTCTATGCTCACATCATCCCATTTCTTGGCTGA 135 spSPARC_S-PPT1co10 ATGAGGGCCTGGATATTCTTTCTCCTCTGTCTGGCTGGGAGAGCCTTGGCAGGACCCCCTGCCCCTTTGC CCCTGGTCATTTGGCATGGGATGGGTGACAGCTGCTGCAATCCCCTAAGCATGGGAGCCATCAAGAAGAT GGTGGAAAAGAAGATTCCTGGCATTTATGTCCTCTCCCTGGAGATTGGGAAGACCCTGATGGAGGATGTG GAGAACAGCTTCTTCCTGAATGTGAACTCCCAGGTTACAACAGTTTGCCAGGCCTTAGCCAAGGACCCTAAACTCCAGCAAGGCTACAATGCAATGGGCTTCTCTCAGGGTGGGCAGTTTCTGAGGGCTGTGGCACAGAG GTGCCCCAGTCCTCCCATGATCAACCTCATCTCAGTGGGAGGCCAGCACCAGGGTGTTTTTGGGTTGCCA AGATGTCCTGGAGAGAGCTCTCATATCTGTGACTTCATCAGGAAGACACTGAATGCTGGGGCTTATAGCA AGGTGGTACAGGAGAGGCTGGTGCAGGCTGAGTACTGGCATGACCCCATCAAGGAAGATGTGTACAGGAA CCATTCAATCTTCTTGGCAGATATTAACCAGGAGAGGGGCATCAATGAAAGCTACAAGAAGAACCTGATG GCCTTGAAGAAATTTGTCATGGTAAAGTTTCTGAATGACTCCATTGTGGATCCTGTAGACTCTGAGTGGT TTGGCTTTTACAGAAGTGGCCAAGCCAAGGAAACCATCCCCCTGCAGGAGACATCTCTGTACACTCAGGA CAGGTTGGGACTGAAGGAGATGGACAATGCAGGACAGCTGGTCTTTCTGGCCACAGAGGGAGACCACCTG CAGCTCTCAGAAGAGTGGTTTTATGCCCACATCATTCCCTTCTTAGGGTGA 136 spSPARC_S-PPT1co11 ATGAGAGCCTGGATATTCTTTCTCCTCTGTCTTGCTGGAAGAGCCCTGGCTGGACCCCCTGCACCTCTGC CCCTTGTTATATGGCATGGGATGGGAGACAGCTGCTGCAATCCCCTCAGCATGGGTGCCATCAAGAAGAT GGTGGAGAAAAAAATTCCTGGAATTTATGTCCTCAGCTTGGAGATAGGGAAGACACTTATGGAAGATGTG GAAAACAGTTTCTTCCTGAATGTGAACTCCCAGGTGACCACTGTGTGCCAGGCACTGGCCAAAGACCCTA AGCTGCAGCAAGGCTACAATGCTATGGGCTTCAGCCAGGGGGGTCAGTTTCTGAGAGCAGTGGCTCAGAGATGCCCCTCACCTCCCATGATCAACCTGATCTCTGTGGGAGGCCAGCACCAAGGGGTTTTTGGGCTACCA AGGTGTCCTGGAGAGTCTTCACATATGTGACTTCATCAGAAAGACCTTAAATGCAGGGGCCTATAGCA AAGTGGTTCAGGAGAGGCTTGTTCAGGCTGAATACTGGCATGACCCCATCAAAAGAGGATGTCTACAGGAA CCATTCAATCTTCTTAGCTGACATCAATCAGGAGGGGGATAAATGAAAGCTACAAGAAAAATCTCATG GCCCTGAAGAAGTTTGTCATGGTGAAGTTCCATCAGTTGATTGTTGATT TTGGCTTTTCAGGTCAGGCCAAGCTAAAGAGACCATCCCCCTCCAGGAGACCTCCCTCTACACACAGGA CAGACTGGGATTGAAAGAGATGGACAATGCTGGGCAGCTAGTTTTTTTGGCCACAGAGGGACCACCTG CAGCTCAGTGAGGAATGGTTTTATGCTCACCTTGTTGTTGATTGTTGATTGTT spSPARC_S-PPT1co12 ATGAGAGCCTGGATCTTCTTTCTTCTGTGCCTTGCTGGGAGGGCCCTTGCTGGGCCACCTGCTCCCCTGC CCCTTGTCATCTGGCATGGGATGGGAGACAGCTGCAACCCCCTGTCCATGGGGGCCATCAAGAAGAT GGTGGAGAAGAAAATACCTGGAATATATGTCCTCTCTCTGGAGATTGGCAAGACACTGATGGAAGATGTG GGAATTCATTTTCCTGAATGTCAACTCCCAAGTGACCACAGGTGCCAGGCCTTAGCCAAGGACCCCA AGCTTCAGCAGGGCTACAATGCAATGGGGATCAGGCCAGGCCAGGCCAGTT Petition 870250104513, of 14 / 11 / 2025, p. 173 / 242 166 / 212 ATGCCCATCTCCACCTATGATCAATTTGATCTCTGTGGGTGGACAGCATCAAGGTGTGTTTGGGCTACCC AGATGCCCTGGGGAGTCTAGCCACATCTGTGACTTCATCAGGAAGACTCTGAATGCTGGAGCCTACTCAA AGGTGGTGCAGGAGAGGCTGGTGCAAGCTGAGTACTGGCATGATCCCATAAAGGAGGATGTGTACAGGAA CCACAGCATCTTCTTAGCAGACATCAACCAAGAGAGAGGCATCAATGAGTCCTACAAGAAGAACCTCATG GCTCTGAAGAAGTTTGTGATGGTCAAGTTCCTAAATGATTCTATTGTGGATCCTGTGGACTCTGAATGGT TTGGATTTTACAGATCAGGCCAAGCCAAGGAGACCATCCCTCTGCAGGAGACCTCTCTGTACACACAAGA CAGGCTGGGACTCAAGGAGATGGACAATGCTGGACAGCTTGTCTTTCTGGCCACAGAAGGGGACCACCTG CAGCTGTCAGAAGAATGGTTCTATGCTCACATCATACCATTCCTTGGTTGA 138 spSPARC_S-PPT1co13 ATGAGAGCCTGGATCTTCTTCCTGCTGTGTCTTGCTGGCAGAGCCCTGGCAGGGCCCCCTGCACCTCTCC CCCTTGTCATCTGGCATGGGATGGGAGACTCCTGCTGTAACCCTTTATCAATGGGGGCCATCAAGAAGAT GGTAGAGAAGAAAATTCCAGGAATTTATGTCCTCAGCTTGGAAATAGGCAAGACTCTCATGGAAGATGTG GAAAACAGCTTCTTCCTGAATGTGAATAGCCAGGTCACAACAGTGTGCCAGGCCTTAGCTAAAGATCCCA AATTGCAGCAGGGCTACAATGCCATGGGATTTTCCCAGGGAGGGCAATTCCTCAGGGCAGTGGCACAGAG ATGCCCTAGCCCTCCAATGATCAACCTTATCAGTGTGGGTGGGCAGCATCAAGGGGTTTTTGGCTTGCCCAGGTGCCCTGGGGAATCTAGCCACATCTGTGACTTTATAAGGAAAACCCTGAATGCAGGAGCCTACTCAA AAGTGGTCCAGGAGAGGCTGGTGCAAGCTGAATATTGGCATGATCCCATCAAAGAGGATGTGTATAGGAA CCACAGCATCTTTTTAGCTGACATCAATCAAGAAAGGGGTATCAATGAAAGCTACAAGAAAAATTTAATG GCTCTGAAGAAGTTTGTCATGGTAAAGTTTCTCAATGACTCCATTGTGGACCCTGTGGATTCTGAGTGGT TTGGATTCTATAGAAGTGGACAAGCCAAAGAAACCATCCCACTGCAGGAGACCAGCCTCTACACACAAGA CAGATTGGGACTCAAAGAGATGGACAATGCTGGACAGCTTGTTTTCCTGGCTACAGAGGGTGACCATCTG CAGCTGAGTGAAGAATGGTTTTATGCTCACATCATACCATTCCTGGGGTGA 139 spSPARC_S-PPT1co14 ATGAGGGCTTGGATCTTCTTCCTCCTGTGTCTTGCAGGGAGAGCCTTGGCTGGGCCACCTGCCCCTCTGC CATTGGTGATTTGGCATGGCATGGGAGATAGCTGCTGCAATCCTCTCTCCATGGGGGCCATTAAGAAAAT GGTGGAAAAAAAGATTCCAGGGATTTATGTGTTGTCTTTAGAGATTGGGAAGACTCTCATGGAAGATGTG GAGAACAGCTTCTTCCTGAATGTCAACTCACAGGTCACTACTGTCTGTCAGGCTTTAGCTAAGGACCCCA AACTCCAGCAGGGATACAATGCTATGGGCTTCTCTCAGGGAGGGCAATTTCTGAGAGCAGTGGCCCAGAG GTGCCCCAGCCCTCCCATGATCAATCTTATCTCTGTGGGTGGACAGCACCAAGGTGTTTTTGGCTTGCCC AGGTGTCCTGGGGAGAGCTCTCACATCTGTGATTTCATCAGGAAGACACTCAATGCAGGAGCTTACTCCAAAGTGGTCCAAGAGAGGCTGGTCCAAGCAGAATACTGGCATGATCCAATTAAAGAAGATGTTTATAGGAA CCACAGCATCTTCCTGGCAGACATCAATCAGGAAAGAGGGATAAATGAGTCCTACAAGAAAAACTTAATG GCCCTGAAGAAGTTTGTGATGGTCAAATTCCTTAATGACTCCATTGTGGACCCTGTAGATTCAGAGTGGT TTGGTTTTTATAGAAGTGGCCAGGCTAAAGAGACAATTCCCCTGCAAGAGACCAGCCTCTACACCCAAGA CAGGCTAGGCCTGAAAGAAATGGACAATGCTGGACAACTGGTCTTTCTTGCCACTGAAGGTGACCATCTA CAGCTGTCAGAAGAATGGTTCTATGCTCACATCATCCCCTTCCTGGGGTGA 140 spSPARC_S-PPT1co16 ATGAGGGCCTGGATATTCTTCCTCCTCTGCCTGGCAGGGAGAGCCCTGGCAGGCCCTCCAGCCCCTCTGC CCCTGGTCATCTGGCATGGCATGGGAGACAGCTGCTGTAACCCTCTGTCCATGGGAGCCATTAAGAAGAT GGTGGAGAAGAAGATCCCTGGAATCTATGTCCTGTCCCTGGAGATTGGGAAGACACTGATGGAGGATGTG GAGAATTCCTTCTTCTTAAATGTGAACAGCCAGGTCACCACAGTTTGCCAGGCATTGGCCAAGGACCCCA AGCTGCAGCAGGGCTACAATGCCATGGGCTTCTCCCAGGGAGGCCAGTTCCTGAGGGCTGTGGCCCAGAG GTGCCCCTCACCTCCCATGATCAACCTGATCTCTGTGGGAGGCCAGCACCAAGGTGTGTTTGGCCTGCCC AGGTGCCCTGGGGAGTCCAGCCACATCTGTGACTTCATCAGGAAGACTTTAAATGCTGGAGCCTACAGCA AGGTGGTCCAGGAGAGGCTGGTGCAGGCAGAATACTGGCATGATCCCATCAAGGAGGATGTGTACAGGAACCACAGCATCTTCCTGGCAGACATCAACCAAGAGAGAGGGATCAATGAGAGCTACAAGAAGAACCTGATG GCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGACTCCATTGTGGACCCTGTGGATTCTGAGTGGT TTGGCTTTTACAGGTCTGGCCAGGCCAAGGAGACCATCCCTCTGCAGGAGACCAGCCTGTACACACAGGA CAGACTGGGACTGAAGGAGATGGACAATGCTGGGCAGCTGGTGTTCCTGGCCACAGAGGGAGACCATCTG CAGCTGAGTGAGGAGTGGTTTTATGCTCACATCATCCCCTTCCTGGGGTGA Cassetes de expressão 141 Cassete de expressão (Sp7F) GGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCG GCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCG CCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAAC GGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATG GCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGG AAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGG CCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGT Petição 870250104513, de 14 / 11 / 2025, pág. 174 / 242 167 / 212 CTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGC GGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAG CGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTG GCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCG GTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGG ACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCG TCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTGGAGCTTTTGGAG TACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACT GAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGT TCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACGCGTGCCACC ATGGCCTTTCTGTGGCTGCTGTCCTGCTGGGCCCTGCTGGGGACCACCTTTGGCGGGCCGCCGGCGCCGC TGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAA AATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTGATGGAGGAC GTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCA GAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTC CCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGTACT CCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCG CAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTG ATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGT GGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACA GGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCAT CTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAAAAGATCTAGAGCTGAA TTCCTGCAGCCAGGGGGATCAGCCTCTACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCC CCTTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATC ACATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGG GAAGACAATAGCAGGCATGCTGGGGATGCAGTGGGCTCTATGG 142 Cassete de expressão (SPARC) GGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCG CCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAAC GGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATG GCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGG AAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGG CCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGT CTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGC GGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAG CGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTG GCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCG GTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGG ACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCG TCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTGGAGCTTTTGGAG TACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGT TCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACGCGTGCCACC ATGAGGGCCTGGATCTTCTTTCTCCTTTGCCTGGCCGGGAGGGCCTTGGCAGGGCCGCCGGCGCCGCTGC CGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAAAAT GGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTGATGGAGGACGTG GAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATCCTA AATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCAGAG ATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTCCCT CGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGTACTCCA AAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCGCAA CCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTGATG GCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGTGGT TTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACAGGA CCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCCACATCATACCATTCCTTGGATAAAAGATCTAGAGCTGAATTC CTGCAGCCAGGGGGATCAGCCTCTACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCCT Petition 870250104513, dated 11 / 14 / 2025, pp. 175 / 242 168 / 212 TGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCACA TTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAA GACAATAGCAGGCATGCTGGGGATGCAGTGGGCTCTATGG 143 Cassete de expressão tPA GGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCG GCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCG CCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAAC GGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATG GCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGG AAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGG CCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGT CTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGC GGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAG CGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTG GCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCGGCCCTGCTGCAGGAGCTCAAAATGGAGG ACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCCACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCG TCGCTTCATGTGACTCCACGGAGTACCGGGCGCGCTCCAGGCACCTCGATTAGTTCTGGAGCTTTTGGAG TACGTCGTCTTTAGGTTGGGGGGGGTTTTTATGCGATGGAGTTCCCCACACTGAGTGGGTGGAGACT GAAGTTAGGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGT TCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTCTTCCATTTCAGGTGTCGTCGACGCGTCCACC ATGGATGCAATGGAAGAGGGCTCTGCTGTGTGCTGCTGCTGTGGAGCAGTCTTCGTTTCGCCCAGGCCCCAGCCCTGCAGCACCTGGACCCGCCGGCGCCGCTGCCGTGGTGATCTGGCATGGGATGGAGACAAG. CTGTTGCAATCCCTTAAGCGGTGCTATTAAAAAAATGGTGGAGAAGAAAATACCTGGAATTTACGTC TTATCTTTAGAGATTGGGAAGACCCTGATGGAGGACGTGGAGAACAGCTTCTTCTGAATGTCAATTCCC AAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATCTCTAATTGCCAGCAAGGCTACAATGCTATGGATT CTCCCAGGGAGGCCAATTTCTGGAGGCAGTGGCTCAGAGATGCCCTTCACCTCCCATGATCAAATCTGATC TCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTCCCTCAGAGAGAGAGCTCTCCACATCTGTG ACTTCATCCGAAAACACTGAATGCTGGGCGCTACTCCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCGCAACCACAGCATCTTCTTGGCAGATATAAATCAG GAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTGATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCC TCAATGATTCCATTGTGGACCCTGTAGATTCGGAGTGGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGA AACCATTCCCTTACAGGAGACCTCCCTGTACACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCA GGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCACA TCATACCATTCCTTGGATAAAAGATCTAGAGCTGAATTCCTGCAGCCAGGGGGATCAGCCTCTACTGTGC CTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCTTGCCTTCCTTGACCCTGGAAGGTGCCACTCC CACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCACATTGTCTGAGTAGGTGTCATTCTATTCTGGGG GGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCAGTGG GCTCTATGG Ácido nucleico de vetor viral (designação de sequência sinal) 144 Sp7-F de Vetor viral CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTT TGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCC TGCGGCCGCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTA CTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTT TTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTA CGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCT TCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTT GAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTT TCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCT TGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGT GCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGT CTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAG GCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCA AAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGT CCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTGGAG CTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTG Petition 870250104513, dated 11 / 14 / 2025, pp. 176 / 242 169 / 212 GATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACG CGTGCCACCATGGCCTTTCTGTGGCTGCTGTCCTGCTGGGCCCTGCTGGGGACCACCTTTGGCGGGCCGC CGGCGCCGCTGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGC TATTAAAAAAATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTG ATGGAGGACGTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTG CTAAGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGC AGTGGCTCAGAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTT TTTGGACTCCCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTG GGGCGTACTCCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGA TGTGTATCGCAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAG AAAAACCTGATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAG ATTCGGAGTGGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCT GTACACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAA GGGGACCATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAAAAGATCTAGAGCTGAATTCCTGCAGCCAGGGGGATCAGCCTCTACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTT GCCCCTCCCCCTTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGA AATTGCATCACATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGG GAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCAGTGGGCTCTATGGGGTGGTCAATCTAGATCC CATCAAAGGTCACCTAGTCATGTAAGTGAGCCACTATCTCCTCCTACAAGGCCAGGGCTATGGGGTTGGT GAAGTCTAGTTAGGCAGTGGTGCCAGGTCACACCTCACTCATCAGGGGGTGGCCTGACTCAGTGGTGATC TCTACTCACCTCCTCAGGCCCTCATCATTTAGCCTGTAAGACCCAGCAGGGCCTAAGGTGCTAATAGCAG GGTCCACTCACATCATGTAGCTCCTTCCCCCCTGGTGGAGCTCCTGCACTAAGGTAGGGAAATCCCTGAA GCTATCCTAATTAAAAGTAAAGTCTCTCCTAGAATCTATCTAGTCCAGGTTATTCCACTATATATCCAGT GAGAAGTGGGCCCTGGTTATGTAGTCCACCACCTGCCTGGTTAGGGTAGTGCTGCTGTAGCCTCACCTGC ACAGGTGATTACCCACTCCCCAGTAGGGGGGTATGTAGGGATACCCTTACACTACCAGATAGTGGTGCAC CACTCACTTGGGCTGAGGCCCCAGGAATAAGTAGATAGTGAGGGTGCCCCTAGTGCTCCTTCAGCTCAGG GCTTAGCTAGGCTGGAGCACCATATCTAATTAATTGCTGTAAAGCAGGAACACCCTATGTGAAGAGCCCC CTCACTCCAGGGCCAGGTAGAAGGGAGGGCTCCTATAGAGGTTTTCCTTAGGAGTGGGTCACAGATCCCTGTTCCACAGATTATATTAAGTCCATCAGGTGCTCAGTATCAGGGGTCACAGATACTCAGCCAGCCCAGTG GTGTACTAGCTGGGCAGTTAGGTAGACAGCTTCAGGAACTGGTCAGCAAAGAATAGGGGAGCTTAAGTAG TGTTCAGCAGCACCCTCCCATCTAGGTGTCTCCTCTCAGTGACCCCTCAGGGCTCCTCTAAGAACTCCAC AGAATATAGGGGGCTGGGAGCCCTGCTAAGCACTTAGGGGGTCTCCAGAGGCACCTAATTACTCCAATTG GGAGGGAATGAGTATGGTGTCAAGCCTCTTAATTCACACAAAAAACCAACACACAGATGTAATGAAAATA AAGATCCTTTATTCTCGAGATCCACTAGGGCCGCAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTC TGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGC CTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 145 SPARC de Vetor viral CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTT TGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCC TGCGGCCGCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGG GAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTA CTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTT TTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCT TCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTT GAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTT TCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCT TGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGT GCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGT CTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAG GCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCA AAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGT CCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTGGAG CTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGG GTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTG GATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACG CGTGCCACCATGAGGGCCTGGATCTTCTTTCTCCTTTGCCTGGCCGGGAGGGCCTTGGCAGGGCCGCCGGCGCCGCTGCCGTTGGTGATCTGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTCTAT TAAAAAAATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTTAGAGATTGGGAAGACCCTGAT Petition 870250104513, de 14 / 11 / 2025, pág. 177 / 242 170 / 212 GAGGACGTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTA AGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGT GGCTCAGAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTT GGACTCCCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGG CGTACTCCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGT GTATCGCAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAA AACCTGATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATT CGGAGTGGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTA CACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGG GACCATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAAAAGATCTAGA GCTGAATTCCTGCAGCCAGGGGGATCAGCCTCTACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCC CCTCCCCCTTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAAT TGCATCACATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAG GATTGGGAAGACAATAGCAGGCATGCTGGGGATGCAGTGGGCTCTATGGGGTGGTCAATCTAGATCCCATCAAAGGTCACCTAGTCATGTAAGTGAGCCACTATCTCCTCCTACAAGGCCAGGGCTATGGGGTTGGTGAA GTCTAGTTAGGCAGTGGTGCCAGGTCACACCTCACTCATCAGGGGGTGGCCTGACTCAGTGGTGATCTCT ACTCACCTCCTCAGGCCCTCATCATTTAGCCTGTAAGACCCAGCAGGGCCTAAGGTGCTAATAGCAGGGT CCACTCACATCATGTAGCTCCTTCCCCCCTGGTGGAGCTCCTGCACTAAGGTAGGGAAATCCCTGAAGCT ATCCTAATTAAAAGTAAAGTCTCTCCTAGAATCTATCTAGTCCAGGTTATTCCACTATATATCCAGTGAG AAGTGGGCCCTGGTTATGTAGTCCACCACCTGCCTGGTTAGGGTAGTGCTGCTGTAGCCTCACCTGCACA GGTGATTACCCACTCCCCAGTAGGGGGGTATGTAGGGATACCCTTACACTACCAGATAGTGGTGCACCAC TCACTTGGGCTGAGGCCCCAGGAATAAGTAGATAGTGAGGGTGCCCCTAGTGCTCCTTCAGCTCAGGGCT TAGCTAGGCTGGAGCACCATATCTAATTAATTGCTGTAAAGCAGGAACACCCTATGTGAAGAGCCCCCTC ACTCCAGGGCCAGGTAGAAGGGAGGGCTCCTATAGAGGTTTTCCTTAGGAGTGGGTCACAGATCCCTGTT CCACAGATTATATTAAGTCCATCAGGTGCTCAGTATCAGGGGTCACAGATACTCAGCCAGCCCAGTGGTG TACTAGCTGGGCAGTTAGGTAGACAGCTTCAGGAACTGGTCAGCAAAGAATAGGGGAGCTTAAGTAGTGT TCAGCAGCACCCTCCCATCTAGGTGTCTCCTCTCAGTGACCCCTCAGGGCTCCTCTAAGAACTCCACAGA ATATAGGGGGCTGGGAGCCCTGCTAAGCACTTAGGGGGTCTCCAGAGGCACCTAATTACTCCAATTGGGAGGGAATGAGTATGGTGTCAAGCCTCTTAATTCACACAAAAAACCAACACACAGATGTAATGAAAATAAAG ATCCTTTATTCTCGAGATCCACTAGGGCCGCAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGC GCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTC AGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 146 tPA de Vetor viral CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTT TGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCC TGCGGCCGCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGG GAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTA CTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTT TTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTA CGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCT TCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTT GAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTT TCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGT GCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGT CTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAG GCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCA AAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGT CCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTGGAG CTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGG GTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTG GATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACG CGTGCCACCATGGATGCAATGAAGAGAGGGCTCTGCTGTGTGCTGCTGCTGTGTGGAGCAGTCTTCGTTT CGCCCAGCGCCAGAGCCCTGCAGCACCTGGACCCGCCGGCGCCGCTGCCGTTGGTGATCTGGCATGGGAT GGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGCTATTAAAAAAATGGTGGAGAAGAAAATACCTGGA ATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTGATGGAGGACGTGGAGAACAGCTTCTTCTTGAATG TCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTGCTAAGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGCAGTGGCTCAGAGATGCCCTTCACCTCCCATGATC AATCTGATCTCGGTTGGGGGACAACATCAAGGTGTTTTTGGACTCCCTCGATGCCCAGGAGAGAGCTCTC Petition 870250104513, dated 11 / 14 / 2025, pp. 178 / 242 171 / 212 ACATCTGTGACTTCATCCGAAAAACACTGAATGCTGGGGCGTACTCCAAAGTTGTTCAGGAACGCCTCGT GCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCGCAACCACAGCATCTTCTTGGCAGAT ATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAGAAAAACCTGATGGCCCTGAAGAAGTTTGTGATGG TGAAATTCCTCAATGATTCCATTGTGGACCCTGTAGATTCGGAGTGGTTTGGATTTTACAGAAGTGGCCA AGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCTGTACACACAGGACCGCCTGGGGCTAAAGGAAATG GACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCATCTTCAGTTGTCTGAAGAATGGTTTT ATGCCCACATCATACCATTCCTTGGATAAAAGATCTAGAGCTGAATTCCTGCAGCCAGGGGGATCAGCCT CTACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCTTGCCTTCCTTGACCCTGGAAGG TGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCACATTGTCTGAGTAGGTGTCATTCT ATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGG ATGCAGTGGGCTCTATGGGGTGGTCAATCTAGATCCCATCAAAGGTCACCTAGTCATGTAAGTGAGCCAC TATCTCCTCCTACAAGGCCAGGGCTATGGGGTTGGTGAAGTCTAGTTAGGCAGTGGTGCCAGGTCACACC TCACTCATCAGGGGGTGGCCTGACTCAGTGGTGATCTCTACTCACCTCCTCAGGCCCTCATCATTTAGCC TGTAAGACCCAGCAGGGCCTAAGGTGCTAATAGCAGGGTCCACTCACATCATGTAGCTCCTTCCCCCCTGGTGGAGCTCCTGCACTAAGGTAGGGAAATCCCTGAAGCTATCCTAATTAAAAGTAAAGTCTCTCCTAGAA TCTATCTAGTCCAGGTTATTCCACTATATCCAGTGAGAAGTGGGCCCTGGTTATGTAGTCCACCACCT GCCTGGTTAGGGTAGTGCTGCTGTAGCCTCACCTGCACAGGTGATTACCCACTCCCCAGTAGGGGGGTAT GTAGGGATACCCTTACACTACCAGATAGTGCACCACTCACTTGGCTGAGGCCCCAGGAATAAGTAG ATAGTGAGGGTGCCCCTAGTGCTCCTTCAGCTCAGGGCTTAGCTAGGCTGGAGCACCATATCTAATTAAT TGCTGTAAAGCAGGAACACCCTATGTGAAGCCCCCTCACTCCAGGGCCAGGTAGAAGGGAGGGCTCCT AGTATCAGGGGTCACAGATACTCAGCCAGCCCAGTGGTGTACTAGCTGGGCAGTTAGGTAGACAGCTTCA GGAACTGGTCAGCAAAGAATAGGGGAGCTTAAGTAGTTCAGCAGCACCCTCCCATCTAGGTGTCTCCT CTCAGTGACCCCTCAGGGCTCCTCTAAGAACTCCACAGAATAGGGGGCTGGGAGCCCTGCTAAGCACT TAGGGGGTCTCCAGAGGCACCTAATTACTCCAATTGGGAGGGAATGAGTATGGTCAAGCCTCTTAATT CACACAAAAAACCAACACACAGATGTAATGAATGACCTAGTCGATCGATCGATCGATT AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACC AAAGGTCGCCCGACGCCCGGGCTTTGCCCGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGCTGCAG G 147NGF-1 de Vetor viral CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTT TGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCC TGCGGCCGCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGG GAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTA CTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTT TTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTA CGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCT TCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTT GAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTT TCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCT TGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGT GCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGT CTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCA AAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGT CCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTGGAG CTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGG GTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTG GATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACG CGTGCCACCATGTCCATGTTGTTCTACACTCTGATCACAGCTTTTCTGATCGGCATACAGGCGGGGCCGC CGGCGCCGCTGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGC TATTAAAAAAATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTG ATGGAGGACGTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTG CTAAGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGC AGTGGCTCAGAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTT TTTGGACTCCCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTG GGGCGTACTCCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGATGTGTATCGCAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAG AAAAACCTGATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAG Petition 870250104513, dated 11 / 14 / 2025, pp. 179 / 242 172 / 212 ATTCGGAGTGGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCT GTACACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAA GGGGACCATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAAAAGATCT AGAGCTGAATTCCTGCAGCCAGGGGGATCAGCCTCTACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTT GCCCCTCCCCCTTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGA AATTGCATCACATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGG GAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCAGTGGGCTCTATGGGGTGGTCAATCTAGATCC CATCAAAGGTCACCTAGTCATGTAAGTGAGCCACTATCTCCTCCTACAAGGCCAGGGCTATGGGGTTGGT GAAGTCTAGTTAGGCAGTGGTGCCAGGTCACACCTCACTCATCAGGGGGTGGCCTGACTCAGTGGTGATC TCTACTCACCTCCTCAGGCCCTCATCATTTAGCCTGTAAGACCCAGCAGGGCCTAAGGTGCTAATAGCAG GGTCCACTCACATCATGTAGCTCCTTCCCCCCTGGTGGAGCTCCTGCACTAAGGTAGGGAAATCCCTGAA GCTATCCTAATTAAAAGTAAAGTCTCTCCTAGAATCTATCTAGTCCAGGTTATTCCACTATATATCCAGT GAGAAGTGGGCCCTGGTTATGTAGTCCACCACCTGCCTGGTTAGGGTAGTGCTGCTGTAGCCTCACCTGC ACAGGTGATTACCCACTCCCCAGTAGGGGGGTATGTAGGGATACCCTTACACTACCAGATAGTGGTGCACCACTCACTTGGGCTGAGGCCCCAGGAATAAGTAGATAGTGAGGGTGCCCCTAGTGCTCCTTCAGCTCAGG GCTTAGCTAGGCTGGAGCACCATATCTAATTAATTGCTGTAAAGCAGGAACACCCTATGTGAAGAGCCCC CTCACTCCAGGGCCAGGTAGAAGGGAGGGCTCCTATAGAGGTTTTCCTTAGGAGTGGGTCACAGATCCCT GTTCCACAGATTATATTAAGTCCATCAGGTGCTCAGTATCAGGGGTCACAGATACTCAGCCAGCCCAGTG GTGTACTAGCTGGGCAGTTAGGTAGACAGCTTCAGGAACTGGTCAGCAAAGAATAGGGGAGCTTAAGTAG TGTTCAGCAGCACCCTCCCATCTAGGTGTCTCCTCTCAGTGACCCCTCAGGGCTCCTCTAAGAACTCCAC AGAATATAGGGGGCTGGGAGCCCTGCTAAGCACTTAGGGGGTCTCCAGAGGCACCTAATTACTCCAATTG GGAGGGAATGAGTATGGTGTCAAGCCTCTTAATTCACACAAAAAACCAACACACAGATGTAATGAAAATA AAGATCCTTTATTCTCGAGATCCACTAGGGCCGCAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTC TGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGC CTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 148 NGF-2 de Vetor viral CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTT TGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCC TGCGGCCGCGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTA CTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTT TTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTA CGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCT TCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTT GAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTT TCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCT TGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGT GCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGT CTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAG GCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCA AAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGT CCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTGGAG CTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTG GATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGACG CGTGCCACCATGTCCATGTTGTTCTACACTCTGATCACAGCTTTTCTGATCGGCATACAGGCGGTGCCGC CGGCGCCGCTGCCGTTGGTGATCTGGCATGGGATGGGAGACAGCTGTTGCAATCCCTTAAGCATGGGTGC TATTAAAAAAATGGTGGAGAAGAAAATACCTGGAATTTACGTCTTATCTTTAGAGATTGGGAAGACCCTG ATGGAGGACGTGGAGAACAGCTTCTTCTTGAATGTCAATTCCCAAGTAACAACAGTGTGTCAGGCACTTG CTAAGGATCCTAAATTGCAGCAAGGCTACAATGCTATGGGATTCTCCCAGGGAGGCCAATTTCTGAGGGC AGTGGCTCAGAGATGCCCTTCACCTCCCATGATCAATCTGATCTCGGTTGGGGGACAACATCAAGGTGTT TTTGGACTCCCTCGATGCCCAGGAGAGAGCTCTCACATCTGTGACTTCATCCGAAAAACACTGAATGCTG GGGCGTACTCCAAAGTTGTTCAGGAACGCCTCGTGCAAGCCGAATACTGGCATGACCCCATAAAGGAGGA TGTGTATCGCAACCACAGCATCTTCTTGGCAGATATAAATCAGGAGCGGGGTATCAATGAGTCCTACAAG AAAAACCTGATGGCCCTGAAGAAGTTTGTGATGGTGAAATTCCTCAATGATTCCATTGTGGACCCTGTAG ATTCGGAGTGGTTTGGATTTTACAGAAGTGGCCAAGCCAAGGAAACCATTCCCTTACAGGAGACCTCCCT GTACACACAGGACCGCCTGGGGCTAAAGGAAATGGACAATGCAGGACAGCTAGTGTTTCTGGCTACAGAAGGGGACCATCTTCAGTTGTCTGAAGAATGGTTTTATGCCCACATCATACCATTCCTTGGATAAAAGATCT AGAGCTGAATTCCTGCAGCCAGGGGGATCACCTCCTACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTT Petition 870250104513, dated 11 / 14 / 2025, pages 180 / 242 173 / 212 GCCCCTCCCCCTTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGA AATTGCATCACATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGG GAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCAGTGGGCTCTATGGGGTGGTCAATCTAGATCC CATCAAAGGTCACCTAGTCATGTAAGTGAGCCACTATCTCCTCCTACAAGGCCAGGGCTATGGGGTTGGT GAAGTCTAGTTAGGCAGTGGTGCCAGGTCACACCTCACTCATCAGGGGGTGGCCTGACTCAGTGGTGATC TCTACTCACCTCCTCAGGCCCTCATCATTTAGCCTGTAAGACCCAGCAGGGCCTAAGGTGCTAATAGCAG GGTCCACTCACATCATGTAGCTCCTTCCCCCCTGGTGGAGCTCCTGCACTAAGGTAGGGAAATCCCTGAA GCTATCCTAATTAAAAGTAAAGTCTCTCCTAGAATCTATCTAGTCCAGGTTATTCCACTATATATCCAGT GAGAAGTGGGCCCTGGTTATGTAGTCCACCACCTGCCTGGTTAGGGTAGTGCTGCTGTAGCCTCACCTGC ACAGGTGATTACCCACTCCCCAGTAGGGGGGTATGTAGGGATACCCTTACACTACCAGATAGTGGTGCAC CACTCACTTGGGCTGAGGCCCCAGGAATAAGTAGATAGTGAGGGTGCCCCTAGTGCTCCTTCAGCTCAGG GCTTAGCTAGGCTGGAGCACCATATCTAATTAATTGCTGTAAAGCAGGAACACCCTATGTGAAGAGCCCC CTCACTCCAGGGCCAGGTAGAAGGGAGGGCTCCTATAGAGGTTTTCCTTAGGAGTGGGTCACAGATCCCT GTTCCACAGATTATATTAAGTCCATCAGGTGCTCAGTATCAGGGGTCACAGATACTCAGCCAGCCCAGTGGTGTACTAGCTGGGCAGTTAGGTAGACAGCTTCAGGAACTGGTCAGCAAAGAATAGGGGAGCTTAAGTAG TGTTCAGCAGCACCCTCCCATCTAGGTGTCTCCTCTCAGTGACCCCTCAGGGCTCCTCTAAGAACTCCAC AGAATATAGGGGGCTGGGAGCCCTGCTAAGCACTTAGGGGGTCTCCAGAGGCACCTAATTACTCCAATTG GGAGGGAATGAGTATGGTGTCAAGCCTCTTAATTCACACAAAAAACCAACACACAGATGTAATGAAAATA AAGATCCTTTATTCTCGAGATCCACTAGGGCCGCAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTC TGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGC CTCAGTGAGCGAGCGAGCGCGCAGCTGCCTGCAGG 149 Insulina de vetor viral CCTGCAGGCAGCTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTT TGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCC TGCGGCCGCGGCTCCGGTGCCCGT...

Claims

1. A polynucleotide, characterized in that it comprises a nucleic acid sequence encoding a palmitoyl-protein thioesterase-1 (PPT1) polypeptide, said PPT1 polypeptide comprising a PPT1 amino acid sequence with at least 95% identity to the SEQ ID NO: 1 sequence, wherein: (a) said PPT1 polypeptide further comprises a signal sequence of any of the SEQ ID NOs: 16-27 or a variant thereof with an amino acid substitution, deletion or insertion; and / or (b) said PPT1 amino acid sequence comprises a substitution of glycine (G), valine (V) or leucine (L) for aspartic acid (D) at its amino terminus; and / or (c) said PPT1 sequence comprises the leucine-glutamine-histidine-leucine amino acid sequence at its N terminus; and / or (d) the so-called nucleic acid sequence comprises a sequence encoding PPT1 with at least 85% identity to any of the SEQ ID Nos: 61 to 94.

2. Polynucleotide, according to claim 1, characterized in that said polypeptide PPT1 further comprises said signal sequence comprising the sequence of any one of the SEQ ID Nos: 16 to 27. Petition 870250084116, dated 09 / 18 / 2025, p. 58 / 75 2 / 16 3. Polynucleotide, according to claim 2, characterized in that said nucleic acid comprises a signal coding sequence of any one of the SEQ ID NOS: 43 to 58.

4. Polynucleotide, according to claim 2, characterized in that said polypeptide comprises a signal sequence of any of the SEQ ID NOS: 16-21 and 24 to 27.

5. Polynucleotide, according to claim 4, characterized in that said signal sequence comprises the sequence of either of the SEQ ID NOS: 16 or 19.

6. Polynucleotide, according to claim 5, characterized in that said signal sequence comprises the sequence with SEQ ID NO: 16 and said nucleic acid sequence comprises the signal coding sequence with SEQ ID NO: 43; or said signal peptide comprises the sequence with SEQ ID NO: 19 and said nucleic acid sequence comprises the signal coding sequence with SEQ ID NO:

50.

7. Polynucleotide, according to claim 2, characterized in that said polypeptide comprises the signal sequence SEQ ID NO:

23.

8. Polynucleotide, according to claim 7, characterized in that said nucleic acid sequence comprises the signal coding sequence of SEQ ID NO:

54.

9. Polynucleotide, according to any one of claims 1 to 6, characterized in that said amino acid sequence of PPT1 comprises a substitution of G, V, or L for aspartic acid D at its amino terminus and said amino acid sequence of PPT1 has at least 97% identity with the sequence of SEQ ID NO:

1.

10. Polynucleotide, according to claim 9, characterized in that said amino acid sequence of PPT1 comprises the sequence SEQ ID NO: 2, wherein X is G.

11. Polynucleotide, according to any one of claims 1 to 3, 7 or 8, characterized in that said PPT1 sequence comprises the amino acid sequence leucine-glutamine-histidine-leucine at its N-terminus and said PPT1 amino acid sequence has at least 97% identity with the sequence of SEQ ID NO:

1.

12. Polynucleotide, according to claim 11, characterized in that said PPT1 sequence comprises the sequence with SEQ ID NO:

4.

13. Polynucleotide, according to any one of claims 1 to 12, characterized in that said nucleic acid comprises a sequence with at least 85% identity with any one of the SEQ ID Nos: 61 to 94.

14. Polynucleotide, according to claim 1, characterized in that said polypeptide PPT1 comprises a sequence with at least 99% identity to any of the SEQ IDs 31-42.

15. Polynucleotide, according to claim 14, characterized in that said polypeptide PPT1 comprises the sequence SEQ ID NO: 31 or SEQ ID NO:

34.

16. Polynucleotide, according to claim 15, characterized in that said polypeptide PPT1 comprises the sequence SEQ ID NO: 31 wherein X is G and said nucleic acid comprises a sequence with at least 85% identity to the sequence of any of the SEQ ID NOs: 107 to 125 and 168.

17. Polynucleotide, according to claim 16, characterized in that said nucleic acid comprises a sequence with at least 95% identity to the sequence of any of the SEQ ID Nos: 107 to 125 and 168.

18. Polynucleotide, according to claim 17, characterized in that said nucleic acid comprises the sequence of any one of the SEQ ID NOS: 107 to 125 and 168.

19. Polynucleotide, according to claim 15, characterized in that said polypeptide PPT1 Petition 870250084116, dated 09 / 18 / 2025, page 61 / 75 5 / 16 comprises the sequence SEQ ID NO: 34 wherein X is G and said nucleic acid comprises a sequence with 85% identity to the sequence of any of the SEQ ID NOs: 126 to 140 and 161 to 167.

20. Polynucleotide, according to claim 19, characterized in that said nucleic acid comprises a sequence with 95% identity to the sequence of any of the SEQ ID NOs: 126 to 140 and 161 to 167.

21. Polynucleotide, according to claim 20, characterized in that said sequence encoding PPT1 comprises any of the SEQ ID NOs: 126 to 140 and 161 to 167.

22. Polynucleotide, according to claim 1, characterized in that said polypeptide PPT1 comprises the sequence SEQ ID NO:

38.

23. Polypeptide palmitoyl-protein thioesterase-1 (PPT1), characterized in that it comprises an amino acid sequence of PPT1 with at least 95% identity to the sequence of SEQ ID NO: 1, wherein: (a) said polypeptide PPT1 further comprises a signal sequence of any of the SEQ ID NOs: 16 to 27 or a variant thereof with an amino acid substitution, deletion or insertion; and / or (b) said amino acid sequence of PPT1 comprises Petition 870250084116, dated 09 / 18 / 2025, page 62 / 75 6 / 16 a substitution of glycine (G), valine (V) or leucine (L) for aspartic acid (D) at its amino terminus; and / or (c) said PPT1 sequence comprises the amino acid sequence leucine-glutamine-histidine-leucine at its N terminus.

24. Polypeptide, according to claim 23, characterized in that said polypeptide PPT1 further comprises a signal sequence comprising the sequence of any one of the SEQ ID NOS: 16 to 27.

25. Polypeptide, according to claim 24, characterized in that said polypeptide comprises a signal sequence of any one of the SEQ ID NOS: 16 to 21 and 24 to 27.

26. Polypeptide, according to claim 25, characterized in that said signal sequence comprises the sequence of either of the SEQ ID NOS: 16 or 19.

27. Polypeptide, according to claim 24, characterized in that said polypeptide comprises a signal sequence with SEQ ID NO:

23.

28. Polypeptide, according to any one of claims 23 to 27, characterized in that said amino acid sequence of PPT1 comprises a substitution of G, V, or L for aspartic acid D at its amino terminus and said amino acid sequence of PPT1 Petition 870250084116, dated 09 / 18 / 2025, page 63 / 75 7 / 16 exhibits at least 97% identity with the sequence of SEQ ID NO:

1.

29. Polypeptide, according to claim 28, characterized in that said amino acid sequence of PPT1 comprises the sequence SEQ ID NO: 2, wherein X is G.

30. Polypeptide, according to claim 23, characterized in that said PPT1 sequence comprises the amino acid sequence leucine-glutaminehistidine-leucine at its N-terminus and said PPT1 amino acid sequence exhibits at least 97% identity with the sequence of SEQ ID NO:

1.

31. Polypeptide, according to claim 30, characterized in that said PPT1 sequence comprises SEQ ID NO:

4.

32. Polypeptide, according to claim 23, characterized in that said polypeptide PPT1 comprises a sequence with at least 99% identity to any of the SEQ ID Nos: 31-42.

33. Polypeptide, according to claim 32, characterized in that said polypeptide PPT1 comprises the sequence SEQ ID NO: 31 wherein X is G, SEQ ID NO: 34 wherein X is G, or SEQ ID NO:

38.

34. Polynucleotide, characterized in that it comprises a nucleic acid sequence encoding PPT1 polypeptide, wherein said PPT1-coding nucleic acid sequence encodes PPT1 polypeptide as defined in any one of claims 23 to 33.

35. Polynucleotide, characterized in that it comprises two or more exons that together encode the polypeptide PPT1 as defined in any one of claims 23 to 34, and one or more introns.

36. Polynucleotide, according to any one of claims 1 to 22, 34 or 35, characterized in that said polynucleotide is an expression cassette comprising one or more expression control elements operationally linked to said nucleic acid encoding said polypeptide PPT1.

37. Polynucleotide, according to claim 36, characterized in that said nucleic acid encoding said polypeptide PPT1 is operationally linked to an upstream promoter and a downstream polyadenylation signal.

38. Polynucleotide, according to claim 36, characterized in that said expression cassette comprises 5' to 3', operationally linked to said nucleic acid encoding said polypeptide PPT1, a promoter, a kozak sequence, said nucleic acid sequence encoding polypeptide PPT1, and a polyadenylation signal.

39. Polynucleotide, according to any of the Petition 870250084116, dated 09 / 18 / 2025, page 65 / 75 9 / 16 claims 37 or 38, characterized in that said promoter comprises a sequence with at least 95% identity to the sequence with SEQ ID NOS: 5 or 173.

40. Polynucleotide, according to any one of claims 37 to 39, characterized in that said polyadenylation signal operationally linked to the nucleotide sequence encoding PPT1 comprises a sequence with at least 95% identity to the sequence of SEQ ID NO:

6.

41. Polynucleotide, according to any one of claims 36 to 40, characterized in that said expression cassette comprises a nucleotide sequence with at least 95% identity to the sequence of any one of the SEQ ID Nos: 141-143, 169 and 170.

42. Polynucleotide, according to any one of claims 1 to 22 and 34 to 41, characterized in that said polynucleotide is DNA.

43. Recombinant viral vector nucleic acid, characterized in that it comprises the polynucleotide as defined in any one of claims 1 to 22 and 34 to 42, and 5' and / or 3' viral elements providing viral packaging and replication.

44. Recombinant viral vector nucleic acid, according to claim 43, characterized in that said recombinant viral vector nucleic acid is DNA Petition 870250084116, dated 09 / 18 / 2025, page 66 / 75 10 / 16 and comprises an adeno-associated virus (AAV) repeat unit (ITR) flanking the 5' terminus of said polynucleotide and an AAV ITR flanking the 3' terminus of said polynucleotide.

45. Recombinant viral vector nucleic acid, according to claim 44, characterized in that said recombinant viral vector nucleic acid comprises the 5' ITR and the 3' ITR of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.10, AAVrh.74 or AAV3B.

46. ​​Recombinant viral vector nucleic acid, according to claim 44, characterized in that said ITR 5' comprises a sequence with at least 95% identity to the sequence of SEQ ID NO: 8, and said ITR 3' comprises a sequence with at least 95% identity to the sequence of SEQ ID NO:

9.

47. Recombinant viral vector nucleic acid, according to any one of claims 43 to 46, characterized in that it further comprises a polyadenylation sequence operationally linked to said ITR 3'.

48. Recombinant viral vector nucleic acid, according to any one of claims 43 to 47, characterized in that it additionally comprises one or more filler sequences. Petition 870250084116, dated 09 / 18 / 2025, pp. 67 / 75 11 / 16 49. Recombinant viral vector nucleic acid, according to any one of claims 43 to 48, characterized in that said recombinant viral vector nucleic acid comprises a sequence with at least 95% identity to the sequence of any one of the SEQ ID Nos: 144 to 154, 171 and 172.

50. Gene delivery vehicle, characterized in that it comprises a viral or non-viral vector and the polynucleotide, as defined in any one of claims 1 to 22 and 34 to 42, or the recombinant viral vector nucleic acid, as defined in any one of claims 43 to 49.

51. Gene delivery vehicle according to claim 50, characterized in that said gene delivery vehicle is a viral vector.

52. Gene delivery vehicle, according to claim 51, characterized in that said viral vector is a recombinant AAV vector, a recombinant lentiviral vector, or a recombinant adenoviral vector.

53. Gene delivery vehicle, according to claim 52, characterized in that said viral vector is a recombinant AAV vector, and said recombinant AAV vector comprises a capsid comprising a VP1, VP2 or VP3 with at least 90% identity to a VP1, VP2 or VP3 sequence of any of AAV1, AAV2, AAV3, AAV4, Petition 870250084116, dated 09 / 18 / 2025, p. 68 / 75 12 / 16 AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.74, AAV3B, AAV-2i8, AAVrh.10, AAVrh.8, AAVHSC, AAV-B1, AAV-AS, AAV1 / rh.10, SEQ ID NO: 12 or SEQ ID NO:

15.

54. Gene delivery vehicle, according to claim 53, characterized in that said capsid is a capsid of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAVrh.74, AAV3B, AAV2i8, AAVrh.10, AAVrh.8, AAVHSC, AAV-B1, AAV-AS, or AAV1 / rh.10; or said capsid comprises VP1 of SEQ ID NO: 12 or SEQ ID NO:

15.

55. Gene delivery vehicle, according to claim 54, characterized in that the capsid comprises VP1 comprising a sequence with SEQ ID NO: 12, VP2 comprising a sequence with SEQ ID NO: 13, and VP3 comprising a sequence with SEQ ID NO:

14.

56. Gene delivery vehicle, according to claim 50, characterized in that said gene delivery vehicle is a non-viral vector.

57. Gene delivery vehicle, according to claim 56, characterized in that said non-viral vector is a nanoparticle selected from the group consisting of a lipid nanoparticle (LNP), a polymeric nanoparticle, a lipid polymer nanoparticle (LPNP), a protein or peptide-based nanoparticle, a DNA dendrimer or DNA-based nanocarrier, a carbon nanotube, a microparticle, a microcapsule, an inorganic nanoparticle, a peptide cage nanoparticle, and an exosome.

58. Gene delivery vehicle, according to claim 56, characterized in that said non-viral vector is an LNP or LPNP.

59. Pharmaceutical composition, characterized in that it comprises the polynucleotide as defined in any one of claims 1 to 22 and 34 to 42, the PPT1 polypeptide as defined in any one of claims 23 to 33, the recombinant viral vector nucleic acid as defined in any one of claims 43 to 49, or the gene delivery vehicle as defined in any one of claims 50 to 58, and a pharmaceutically acceptable carrier.

60. Method for increasing PPT1 in an individual, characterized in that it comprises administering to the individual the polynucleotide as defined in any one of claims 1 to 22 and 34 to 42, the PPT1 polypeptide as defined in any one of claims 23 to 33, the recombinant viral vector nucleic acid as defined in any one of claims 43 to 49, the gene delivery vehicle as defined in any one of claims 50 to 58, or the pharmaceutical composition as defined in claim 59. Petition 870250084116, dated 09 / 18 / 2025, pp. 70 / 75 14 / 16 61. Method for treating neuronal ceroid lipofuscinosis 1 in an individual, characterized in that it comprises administering to the individual the polynucleotide as defined in any one of claims 1 to 22 and 34 to 42, the PPT1 polypeptide as defined in any one of claims 23 to 33, the recombinant viral vector nucleic acid as defined in any one of claims 43 to 49, the gene delivery vehicle as defined in any one of claims 50 to 58, or the pharmaceutical composition as defined in claim 59.

62. Method, according to claim 60 or 61, characterized in that the administration comprises intraparenchymal, intracisternal or intraventricular administration.

63. Method according to claim 62, characterized in that said administration is intraventricular and results in significant release of rAAV at least in the frontal cortex, parietal cortex, temporal cortex, occipital cortex, thalamus, cerebellar cortex, hippocampus, corpus callosum, spinal cord, caudate nucleus, choroid plexus, optic chiasm, fornix, periaqueductal gray matter, olfactory bulb, and optic nerve.

64. Method, according to claim 60 or 61, characterized in that said administration Petition 870250084116, dated 09 / 18 / 2025, pp. 71 / 75 15 / 16 comprises initial administration outside the central nervous system (CNS).

65. Method according to claim 63, characterized in that said individual is a sheep.

66. Method, according to any one of claims 60 to 62, characterized in that said administration is systemic.

67. A method, according to any one of claims 60 to 63, characterized in that said individual is a human being.

68. AAV vector genome plasmid, characterized in that it comprises recombinant viral vector nucleic acid as defined in any one of claims 43 to 49.

69. AAV genome plasmid according to claim 68, characterized in that said plasmid does not possess the rep and cap genes.

70. Method for producing an rAAV vector, characterized in that it comprises the step of cultivating an rAAV-producing cell line comprising rAAV helper virus activity, wherein the genome of said producing cell comprises recombinant viral vector nucleic acid as defined in any one of claims 43 to 49, a rep gene and a cap gene, wherein said rAAV vector is produced. Petition 870250084116, dated 09 / 18 / 2025, pp. 72 / 75 16 / 16 71. Method for producing rAAV vector, characterized in that it comprises the step of culturing an rAAV-permissive cell comprising the AAV genome plasmid as defined in claim 68 or 69, wherein said rAAV-permissive cell further comprises (a) rep and cap genes provided as part of the cell genome and / or by one or more separate plasmids, and (b) helper virus activity provided by the cell genome and / or by one or more separate plasmids.

72. Method according to claim 71, characterized in that said rAAV-permissive cell is a packaging cell, wherein the genome of said packaging comprises a cap gene and a rep gene.

73. Method according to claim 71, characterized in that both (a) said rep gene, said cap gene and said auxiliary activity are provided in a single plasmid and (b) said rep gene and said cap gene are provided by a rep / cap plasmid, and said auxiliary activity is provided by an auxiliary plasmid.

74. Method for obtaining an rAAV vector, characterized in that it comprises the steps of (a) producing the rAAV using the method as defined in any one of claims 70 to 73 and (b) purifying the rAAV.

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