RNAi agent for inhibiting the expression of an alpha-1 antitrypsin (AAT) gene, composition comprising the same and uses thereof to inhibit AAT expression and treat alpha-1 antitrypsin deficiency.

Abstract

This refers to RNAI agents for inhibiting the expression of the alpha-1 antitrypsin (aat) gene, compositions including Aat RNAI agents, and methods of use. Pharmaceutical compositions including one or more Aat RNAI agents together with one or more excipients capable of delivering the RNAI agents to a liver cell in vivo are also disclosed. Delivery of Aat RNAI agents to liver cells in vivo inhibits Aat gene expression and treats diseases associated with Aat deficiency such as chronic hepatitis, cirrhosis, hepatocellular carcinoma, transaminitis, cholestasis, fibrosis, and fulminant hepatic failure.

Description

"RNAi AGENT TO INHIBIT THE EXPRESSION OF AN ALPHA-1 ANTITRYPSIN (AAT) GENE, COMPOSITION COMPRISING THE SAME AND USES THEREOF TO INHIBIT AAT EXPRESSION AND TREAT ALPHA-1 DEFICIENCY" "ANTITRYPSIN" REFERENCE TO RELATED DEPOSIT REQUESTS

[001] This application claims priority to U.S. Provisional Patent Application Serial Number 62 / 444,452, filed January 10, 2017, U.S. Provisional Patent Application Serial Number 62 / 486,720, filed April 18, 2017, and U.S. Provisional Patent Application Serial Number 62 / 596,232, filed December 8, 2017, the contents of which are incorporated herein in their entirety by reference. FIELD OF THE INVENTION

[002] RNA interference agents (RNAi) for inhibiting alpha-1 antitrypsin gene expression, compositions including alpha-1 antitrypsin RNAi agents, and methods of using them are disclosed in this document. FUNDAMENTALS

[003] Alpha-1 antitrypsin deficiency (AAT, antitrypsin a1, or A1AT) is an inherited autosomal dominant genetic disorder that causes misfolding of the AAT protein and poor secretion of the misfolded protein, leading to lung and liver disease. AAT deficiency (AATD) occurs with a frequency of about 1 in 1,500 to 3,500 individuals and predominantly affects people with European ancestry.

[004] Alpha-1 antitrypsin is a protease inhibitor belonging to the serpin superfamily. Normal AAT protein is a circulating glycoprotein protease inhibitor primarily synthesized in the liver by hepatocytes and secreted into the blood. The known physiological function of AAT is to inhibit Petition 870260038067, dated 04 / 24 / 2026, page 17 / 191 2 / 160 neutrophil proteases, which serve to protect host tissues from nonspecific injury during periods of inflammation.

[005] The most clinically significant form of AATD, a genetic disorder associated with liver disease in children and adults, and lung disease in adults, is caused by the Z mutation. The mutant Z allele (PiZ), through a single point mutation, produces a mutant Z-shaped AAT protein (the “Z-AAT” protein) prone to abnormal folding causing intracellular retention. The mutant Z-AAT protein monomers are capable of forming polymer chains that accumulate into aggregates, which are sometimes referred to as “globules.” The misfolded Z-AAT protein is ineffective at traversing the secretory pathway, and instead polymerizes and accumulates in the endoplasmic reticulum (ER) of hepatocytes. The masses of polymeric globules accentuate the ER and trigger continuous hepatocyte lesions, leading to fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma.Furthermore, the absence of circulating anti-protease activity leaves the lung vulnerable to neutrophil elastase damage, resulting in the development of respiratory complications such as emphysema.

[006] Individuals with the homozygous PiZZ genotype have severe functional AAT deficiency, leading to lung disease. Weekly use of AAT booster therapy, using purified human AAT, results in near-normal plasma AAT levels in individuals with AATD and helps prevent lung damage in affected individuals. However, while administration of purified AAT may improve or help prevent lung damage caused by the absence of endogenously secreted AAT, patients with AATD remain vulnerable to endoplasmic reticulum liver storage diseases caused by the deposition and accumulation of excessive abnormally folded AAT protein. Accumulated Z-AAT protein in the globule conformation in hepatocytes is a well-known feature of AATD liver disease and is believed to lead to proteotoxic effects that are Petition 870260038067, dated 04 / 24 / 2026, page 18 / 191 3 / 160 responsible for inducing liver injury, including damage and death of liver cells and chronic liver injury, in individuals with AATD (see, for example, D. Lindblad et al., Hepatology 2007, 46: 1228-1235). Patients with AATD commonly develop liver diseases, which can be severe or fatal, even in childhood. Clinical presentations of liver injury include chronic hepatitis, cirrhosis, hepatocellular carcinoma, transaminitis, cholestasis, fibrosis, and uniform fulminant hepatic failure.

[007] Currently, there is no clinically approved treatment to prevent the onset or slow the progression of liver disease due to AATD. Furthermore, although US Patent Application Publication 2015 / 0361427 discloses certain RNAi agents capable of inhibiting the expression of an AAT gene, there is still a need for innovative and effective AAT RNAi agents with improved potency that can selectively, efficiently, and safely inhibit the expression of an AAT gene, thus preventing and potentially reversing liver damage related to Z-AAT accumulation and fibrosis. Similarly, although US Patent Application Publication 2015 / 0011607 by Brown et al.(“Brown '607”) discloses several sequences to inhibit the expression of an AAT gene. Brown teaches the use of longer double-stranded constructs (referred to by Brown as DsiRNAs), which according to Brown have been found to provide “unexpectedly effective results in terms of potency and duration of action” as compared to 19-23mer siRNA agents. (See, for example, Brown '607 in paragraph

[0376] ). Furthermore, any of the sequences disclosed in Brown '607 are designed to be used in DsiRNA constructs that are designed to target different sites of an AAT mRNA as compared to the sequences disclosed in the present invention. These differences lead to a different binding affinity to the AAT mRNA and produce a different cleavage site, which can impact the inhibitory effect of the compound, while also potentially leading to off-target issues. Petition 870260038067, dated 04 / 24 / 2026, p. 19 / 191 4 / 160 additional (see, for example, Piotr J. Kamola et al., PLoS Comput Biol, 2015, 11(12):e1004656 in Figure 1 (illustrating the siRNA-mediated Gene Silencing mechanism)). For example, no part in Brown '607 teaches or suggests the design of an RNAi agent (or any length) where the 5'-terminal nucleobase or nucleotide of the antisense strand would be aligned to the position that is 19 nucleotides downstream (towards the 3' end) from position 1000 in an AAT gene (SEQ ID NO: 1). Alternatively, and again only as an example involving a potential AAT RNAi agent sequence, no part in Brown '607 teaches or suggests the design of an RNAi gene where the 5' terminal nucleobase of the antisense strand of an RNAi agent corresponds to position 1018 in an AAT gene (SEQ ID NO: 1). Furthermore, no part in Brown '607 teaches or suggests the modified AAT RNAi agent constructs disclosed in this paper. SUMMARY

[008] There is a need for innovative AAT-specific RNA interference (RNAi) agents (also referred to as RNAi agents, RNAi activators, or activators) that are capable of selectively and effectively inhibiting the expression of an AAT gene. Furthermore, there is a need for innovative AAT-specific RNAi agent compositions for the treatment of diseases associated with AAT deficiency.

[009] Because liver damage resulting from AATD occurs through a gain-of-function mechanism, inhibition of AAT gene expression is useful in preventing the accumulation of Z-AAT protein in the liver. Furthermore, reducing or removing Z-AAT polymer aggregates reduces the emphasis on ER in hepatocytes, and offers additional advantages in reducing the likelihood of liver cell damage and assisting in the treatment of liver cell damage and chronic liver lesions such as fibrosis, cirrhosis, hepatocellular carcinoma, and others. Petition 870260038067, dated 04 / 24 / 2026, p. 20 / 191 5 / 160 conditions and diseases caused by AATD. Reducing inflammatory Z-AAT protein, which has been clearly defined as the cause of progressive liver disease in patients with AATD, is important as it can slow or stop the progression of liver disease and allow for the repair of fibrotic tissue.

[010] In general, the disclosure presents innovative AAT RNAi agents, compositions comprising AAT RNAi agents, and methods for inhibiting the expression of an AAT gene in vivo and / or in vitro using AAT RNAi agents and compositions including AAT RNAi agents. Furthermore, methods for treating AATD-related diseases using the AAT RNAi agents described herein and compositions including AAT RNAi agents are described.

[011] The AAT RNAi agents and methods disclosed herein may provide treatment for AATD, including treatment of conditions and diseases caused by AATD, such as chronic hepatitis, cirrhosis, hepatocellular carcinoma, and fulminant hepatic failure. The AAT RNAi agents disclosed herein, when administered to an individual, may prevent and / or reverse liver damage related to Z-AAT accumulation and fibrosis. The AAT RNAi agents described herein may be administered to an individual, for example, a human or animal individual, by any suitable methods known in the art, such as subcutaneous injection or intravenous administration.

[012] In one aspect, the disclosure provides RNAi agents for inhibiting the expression of an alpha-1 antitrypsin (AAT) gene, wherein the RNAi agent comprises a sense strand and an antisense strand. Compositions are also disclosed comprising an RNAi agent capable of inhibiting the expression of an alpha-1 antitrypsin gene, wherein the RNAi agent comprises a sense strand and an antisense strand, and at least one pharmaceutically acceptable excipient. Petition 870260038067, dated 04 / 24 / 2026, p. 21 / 191 6 / 160

[013] Each AAT RNAi agent described herein includes a sense strand and an antisense strand. The sense strand and the antisense strand may be partially, substantially, or completely complementary to each other. The length of the sense and antisense strands of the RNAi agent described herein may be 16 to 30 nucleotides long. In some embodiments, the sense and antisense strands are independently 17 to 26 nucleotides long. In some embodiments, the sense and antisense strands are independently 21 to 26 nucleotides long. In some embodiments, the sense and antisense strands are independently 21 to 24 nucleotides long. In some embodiments, the sense and / or antisense strands independently have lengths of 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. The sense and antisense strands may have the same length or different lengths.The RNAi agents described in this document, upon delivery to a cell expressing AAT, inhibit the expression of one or more AAT genes in vivo or in vitro.

[014] An AAT RNAi agent includes a sense strand (also referred to as a passenger strand), and an antisense strand (also referred to as a guide strand). A sense strand of AAT RNAi agents described herein includes a nucleotide sequence having at least 85% identity to a core extension of at least 16 consecutive nucleotides to a sequence in an AAT mRNA. In some embodiments, the sense strand core extension having at least 85% identity to a sequence in an AAT mRNA is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides long. An antisense strand of an AAT RNAi agent includes a nucleotide sequence having at least 85% complementarity by a core extension of at least 16 consecutive nucleotides to a sequence in an AAT mRNA and the corresponding sense strand. In some forms, the antisense tape core extension having at least Petition 870260038067, dated 04 / 24 / 2026, p. 22 / 191 7 / 160 85% complementarity to a sequence in an AAT mRNA or the corresponding sense strand is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides in length.

[015] In some embodiments, the AAT RNAi agents disclosed in this document target a portion of an AAT gene having the sequence of any of the sequences in Table 1.

[016] Examples of AAT RNAi agent sense and antisense strands that can be used in AAT RNAi agents are provided in Tables 2, 3, 4, and 5. Examples of duplexes that include an AAT RNAi agent are provided in Table 6. Examples of 19-nucleotide core extension sequences that may consist of or be included in the sense and antisense strands of certain AAT RNAi agents disclosed herein are provided in Table 2.

[017] In another aspect, the disclosure presents methods for delivering AAT RNAi agents to liver cells in an individual, such as a mammal, in vivo. In some embodiments, one or more AAT RNAi agents are delivered to target cells or tissues using any oligonucleotide delivery technology known in the art. Nucleic acid delivery methods include, but are not limited to, encapsulation in liposomes, iontophoresis, or incorporation into other vehicles such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres, proteinaceous vectors, or Dynamic Polyconjugates™ (DPCs) (see, for example, WO 2000 / 053722, WO 2008 / 0022309, WO 2011 / 104169 and WO 2012 / 083185, each of which is incorporated herein by reference).In some embodiments, a delivery vehicle, such as a polymer, an amphipathic polymer, a membrane-active polymer, a peptide such as melittin or melittin-like peptide, a reversibly modified polymer or peptide, or a lipid, may be used with the AAT RNAi agents disclosed herein. Petition 870260038067, dated 04 / 24 / 2026, page 23 / 191 8 / 160

[018] In some embodiments, an AAT RNAi agent is delivered to target cells or tissues by covalently linking or conjugating the RNAi agent to a targeting group such as an asialoglycoprotein receptor ligand. In some embodiments, an asialoglycoprotein receptor ligand includes, consists of, or consists essentially of, a galactose or galactose-derived group. In some embodiments, an AAT RNAi agent is linked to a targeting ligand comprising galactose-derived N-acetylgalactosamine. In some embodiments, a galactose-derived group includes an N-acetylgalactosamine trimer or an N-acetylgalactosamine tetramer. In some embodiments, a galactose-derived group is an N-acetylgalactosamine trimer or an N-acetylgalactosamine tetramer. Useful exemplary targeting groups for delivering RNAi agents are disclosed, for example, in US Patent Application No. 15 / 452.324 and WO 2017 / 156012, which are incorporated herein by reference in their entirety.

[019] A targeting group can be attached to the 3' or 5' end of a sense strand or an antisense strand of an AAT RNAi agent. In some embodiments, a targeting group is attached to the 3' or 5' end of the sense strand. In some embodiments, a targeting group is attached to the 5' end of the sense strand. In some embodiments, a targeting group is internally linked to a nucleotide in the sense and / or antisense strand of the RNAi agent. In some embodiments, a targeting group is linked to the RNAi agent via a linker.

[020] A targeting group, with or without a linker, may be connected to the 5' to 3' end of any of the sense and / or antisense tapes disclosed in Tables 2, 3, 4 and 5. A linker, with or without a targeting group, may be connected to the 5' or 3' end of any of the sense and / or antisense tapes disclosed. Petition 870260038067, dated 04 / 24 / 2026, p. 24 / 191 9 / 160 in Tables 2, 3, 4 and 5.

[021] In another aspect, the revelation presents compositions that include one or more AAT RNAi agents that have the duplex structures revealed in Table 6.

[022] In some embodiments, compositions are described that include a combination or cocktail of at least two AAT RNAi agents having different nucleotide sequences. In some embodiments, the two or more different AAT RNAi agents are each separately and independently linked to targeting groups. In some embodiments, the two or more different AAT RNAi agents are each linked to targeting groups that include or consist of targeting ligands that include one or more moieties targeting an asialoglycoprotein receptor. In some embodiments, the two or more different AAT RNAi agents are each linked to targeting groups that include or consist of targeting ligands that include one or more galactose derivatives.In some embodiments, the two or more different AAT RNAi agents are each linked to targeting groups that include or consist of targeting ligands that include one or more N-acetylgalactosamines. In some embodiments, when two or more RNAi agents are included in a composition, each RNAi agent is independently linked to the same targeting group. In some embodiments, when two or more RNAi agents are included in a composition, each RNAi agent is independently linked to a different targeting group, such as targeting groups having different chemical structures.

[023] In some embodiments, targeting groups are linked to AAT RNAi agents without the use of an additional linker. In some embodiments, the targeting group is designed to have a readily available linker. Petition 870260038067, dated 04 / 24 / 2026, page 25 / 191 10 / 160 present to facilitate binding to an AAT RNAi agent. In some embodiments, when two or more RNAi agents are included in a composition, the two or more RNAi agents may be linked to their respective targeting groups using the same linkers. In some embodiments, when two or more RNAi agents are included in a composition, the two or more RNAi agents are linked to their respective targeting groups using different linkers.

[024] In another aspect, the disclosure presents methods for inhibiting alpha-1 antitrypsin gene expression in an individual, wherein the methods comprise administering to the individual an amount of an AAT RNAi agent capable of inhibiting the expression of an AAT gene, wherein the AAT RNAi agent comprises a sense strand and an antisense strand.

[025] Methods for treating an AATD-induced condition or disease are also described, comprising administering to an individual a therapeutically effective amount of an RNAi agent described in this document. Methods for inhibiting the expression of an AAT gene are further described, wherein the methods include administering to a cell an AAT RNAi agent described in this document.

[026] In some embodiments, methods for the treatment of AATD are disclosed (including the treatment of a condition or disease caused by AATD), and the methods comprise administering to an individual a therapeutically effective amount of an RNAi agent having an antisense strand comprising the sequence of any of the sequences in Tables 2, 3 or 4.

[027] In some embodiments, methods for inhibiting the expression of an AAT gene are disclosed, and the methods comprise administering to a cell an AAT RNAi agent that includes an antisense strand comprising the sequence of any of the sequences in Tables 2, 3 or 4. Petition 870260038067, dated 04 / 24 / 2026, p. 26 / 191 11 / 160

[028] In some embodiments, methods for the treatment of AATD are disclosed (including the treatment of a condition or disease caused by AATD), and the methods comprise administering to an individual a therapeutically effective amount of an RNAi agent that includes a sense strand comprising the sequence of any of the sequences in Tables 2, 3, or 5.

[029] In some embodiments, methods are disclosed for inhibiting the expression of an AAT gene, wherein the methods include administering to a cell an AAT RNAi agent that includes a sense strand comprising the sequence of any of the sequences in Tables 2, 3 or 5.

[030] In some embodiments, methods are disclosed for the treatment of AATD (including the treatment of a condition or disease caused by AATD), wherein the methods include administering to an individual a therapeutically effective amount of an RNAi agent that includes a sense strand comprising any of the sequences in Table 5, and an antisense strand comprising any of the sequences in Table 4.

[031] In some embodiments, methods are disclosed for inhibiting the expression of an AAT gene, wherein the methods include administering to an individual a therapeutically effective amount of an RNAi agent that includes a sense strand comprising any of the sequences in Table 5, and an antisense strand comprising any of the sequences in Table 4.

[032] In some embodiments, methods for inhibiting the expression of an AAT gene are disclosed, wherein the methods include administering to an individual an AAT RNAi agent that includes a sense strand consisting of a nucleobase sequence from any of the sequences in Table 5, and an antisense strand consisting of a nucleobase sequence from any of the sequences in Table 4. In other embodiments, methods for inhibiting the expression of an AAT gene are disclosed, wherein the methods include administering to an individual an agent of Petition 870260038067, dated 04 / 24 / 2026, p. 27 / 191 12 / 160 RNAi from AAT that includes a sense strand consisting of a modified sequence from any of the modified sequences in Table 5, and an antisense strand consisting of a modified sequence from any of the modified sequences in Table 4.

[033] In some embodiments, methods are revealed for inhibiting the expression of an AAT gene in a cell, wherein the methods include administering one or more AAT RNAi agents having the duplex structure presented in Table 6.

[034] In some embodiments, the AAT RNAi agents disclosed herein have structures that include, consist of, or consist essentially of, a structure shown in any one of Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, or Figure 8.

[035] The AAT RNAi agents disclosed herein are designed to target specific positions in an AAT gene (SEQ ID NO:1). As defined herein, an antisense strand sequence is designed to target an AAT gene at a given position in the gene when the 5'-terminal nucleobase of the antisense strand is aligned to the position that is 19 nucleotides downstream (toward the 3' end) from the position in the gene when base-pairing to the gene. For example, as illustrated in Tables 1, 2, and 3, an antisense strand sequence designed to target an AAT gene at position 1000 requires that when base-pairing to the gene, the 5'-terminal nucleobase of the antisense strand is aligned to position 1018 of the AAT gene.As provided in this document, an AAT RNAi agent does not require that the nucleobase at position 1 (5'^3') of the antisense strand be complementary to the gene, provided there is at least 85% complementarity (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% complementarity) of the antisense strand and the gene along a core extension sequence of at least 16 consecutive nucleotides. Petition 870260038067, dated 04 / 24 / 2026, p. 28 / 191 13 / 160 For example, for an AAT RNAi agent disclosed in this document that is designed to target position 1000 of an AAT gene, the 5'-terminal nucleobase of the antisense strand of the AAT RNAi agent must be aligned to position 1018 of the gene; however, the 5'-terminal nucleobase of the antisense strand may, but is not required to, be complementary to position 1018 of an AAT gene, provided there is at least 85% complementarity (e.g., at least 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% complementarity) of the antisense strand and the gene along a core extension sequence of at least 16 consecutive nucleotides.As shown, among other things, by the various examples revealed in this document, the specific gene binding site of the AAT RNAi agent's antisense strand (for example, whether the AAT RNAi agent is designed to target an AAT gene at position 1000, at position 1142, or at some other position) is highly important to the level of inhibition achieved by the AAT RNAi agent.

[036] In some embodiments, the antisense strand sequence is designed to have a target sequence position 1000 of an AAT gene (SEQ ID NO: 1).

[037] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCU (SEQ ID NO: 801), wherein at least one or more nucleotides consist of a modified nucleotide. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCU (SEQ ID NO: 801), wherein all or substantially all nucleotides are modified nucleotides.

[038] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGUU (SEQ ID NO: 794), wherein at least one or more nucleotides consist of a modified nucleotide. In some embodiments, the strand Petition 870260038067, dated 04 / 24 / 2026, p. 29 / 191 14 / 160 antisense of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGUU (SEQ ID NO: 794), in which all or substantially all nucleotides are modified nucleotides.

[039] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCUU (SEQ ID NO: 839), wherein at least one or more nucleotides consist of a modified nucleotide. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCUU (SEQ ID NO: 839), wherein all or substantially all nucleotides are modified nucleotides.

[040] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCG (SEQ ID NO: 800), wherein at least one or more nucleotides consist of a modified nucleotide. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCG (SEQ ID NO: 800), wherein all or substantially all nucleotides are modified nucleotides.

[041] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACG (SEQ ID NO: 80), wherein one or more nucleotides consist of a modified nucleotide. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACG (SEQ ID NO: 80), wherein all or substantially all nucleotides are modified nucleotides.

[042] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of Petition 870260038067, dated 04 / 24 / 2026, p. 30 / 191 15 / 160 AGUUAAACAUGCCUAAACG (SEQ ID NO: 81), wherein one or more nucleotides consist of a modified nucleotide. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of AGUUAAACAUGCCUAAACG (SEQ ID NO: 81), wherein all or substantially all nucleotides are modified nucleotides.

[043] In some embodiments, the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUAACA (SEQ ID NO: 429), wherein one or more nucleotides consist of a modified nucleotide. In some embodiments, the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUAACA (SEQ ID NO: 429), wherein all or substantially all nucleotides are modified nucleotides.

[044] In some embodiments, the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUUAACU (SEQ ID NO: 430), wherein one or more nucleotides consist of a modified nucleotide. In some embodiments, the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUUAACU (SEQ ID NO: 430), wherein all or substantially all nucleotides are modified nucleotides.

[045] In some embodiments, the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUAACA (SEQ ID NO: 429), wherein one or more nucleotides consist of a modified nucleotide, and the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACG (SEQ ID NO: 80), wherein one or more nucleotides consist of a modified nucleotide.

[046] In some embodiments, the sense strand of an AAT RNAi agent Petition 870260038067, dated 04 / 24 / 2026, page 31 / 191 16 / 160 comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUUAACU (SEQ ID NO: 430), wherein one or more nucleotides consist of a modified nucleotide, and the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of AGUUAAACAUGCCUAAACG (SEQ ID NO: 81), wherein one or more nucleotides consist of a modified nucleotide.

[047] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGUU (SEQ ID NO: 794), wherein at least one or more nucleotides consist of a modified nucleotide, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUAACAUU (SEQ ID NO: 857).

[048] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCUU (SEQ ID NO: 839), wherein at least one or more nucleotides consist of a modified nucleotide, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of GCGUUUAGGCAUGUUAACAUU (SEQ ID NO: 885).

[049] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCG (SEQ ID NO: 800), wherein at least one or more nucleotides consist of a modified nucleotide, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGCGUUUAGGCAUGUUAACA (SEQ ID NO: 864).

[050] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCU (SEQ ID NO: 801), wherein at least one or more Petition 870260038067, dated 04 / 24 / 2026, p. 32 / 191 17 / 160 nucleotides consists of a modified nucleotide, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of AGCGUUUAGGCAUGUUAACA (SEQ ID NO: 866).

[051] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGUU (SEQ ID NO: 794) differing by 0, 1, 2, or 3 nucleotides, wherein at least one or more nucleotides consist of a modified nucleotide, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUUAACAUU (SEQ ID NO: 857) differing by 0, 1, 2, or 3 nucleotides.

[052] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCUU (SEQ ID NO: 839) differing by 0, 1, 2, or 3 nucleotides, wherein at least one or more nucleotides consists of a modified nucleotide, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of GCGUUUAGGCAUGUUUAACAUU (SEQ ID NO: 885) differing by 0, 1, 2, or 3 nucleotides.

[053] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCG (SEQ ID NO: 800) differing by 0, 1, 2, or 3 nucleotides, wherein at least one or more nucleotides consists of a modified nucleotide, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGCGUUUAGGCAUGUUUAACA (SEQ ID NO: 864) differing by 0, 1, 2, or 3 nucleotides.

[054] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCU (SEQ ID NO: 801) differing by 0, 1, 2 or 3 Petition 870260038067, dated 04 / 24 / 2026, p. 33 / 191 18 / 160 nucleotides, wherein at least one or more nucleotides consist of a modified nucleotide, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of AGCGUUUAGGCAUGUUAACA (SEQ ID NO: 866) differing by 0, 1, 2, or 3 nucleotides.

[055] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04824 duplex structure.

[056] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04825 duplex structure.

[057] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04826 duplex structure.

[058] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04827 duplex structure.

[059] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04828 duplex structure.

[060] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04829 duplex structure.

[061] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04830 duplex structure.

[062] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04831 duplex structure.

[063] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04832 duplex.

[064] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04833 duplex structure.

[065] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04834 duplex structure.

[066] In some embodiments, the AAT RNAi agent comprises, Petition 870260038067, dated 04 / 24 / 2026, page 34 / 191 19 / 160 consists of, or essentially consists of, a duplex structure of AD04835.

[067] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04836 duplex structure.

[068] In some embodiments, the AAT RNAi agent comprises, consists of, or essentially consists of an AD04837 duplex structure.

[069] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACG (SEQ ID NO: 80), wherein one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 80 is located at positions 1 to 19 (5' ^ 3') of the antisense strand. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACG (SEQ ID NO: 80), wherein all or substantially all nucleotides are modified nucleotides, and wherein SEQ ID NO: 80 is located at positions 1 to 19 (5' ^ 3') of the antisense strand.

[070] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of AGUUAAACAUGCCUAAACG (SEQ ID NO: 81), wherein one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 81 is located at positions 1 to 19 (5' ^ 3') of the antisense strand. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of AGUUAAACAUGCCUAAACG (SEQ ID NO: 81), wherein all or substantially all nucleotides are modified nucleotides, and wherein SEQ ID NO: 81 is located at positions 1 to 19 (5' ^ 3') of the antisense strand.

[071] In some embodiments, the sense strand of an AAT RNAi agent comprises the nucleobase sequence CGUUUAGGCAUGUUAACA (SEQ ID NO: 429), wherein one or more nucleotides consist of a modified nucleotide, and wherein position 19 of SEQ ID NO: 429 forms a base pair with the nucleotide Petition 870260038067, dated 04 / 24 / 2026, page 35 / 191 20 / 160 located at the 5' terminal end of the antisense strand. In some embodiments, the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUUAACA (SEQ ID NO: 429), wherein all or substantially all nucleotides are modified nucleotides, and wherein position 19 of SEQ ID NO: 429 forms a base pair with the nucleotide located at the 5' terminal end of the antisense strand.

[072] In some embodiments, the sense strand of an AAT RNAi agent comprises the nucleobase sequence CGUUUAGGCAUGUUUAACU (SEQ ID NO: 430), wherein one or more nucleotides consist of a modified nucleotide, and wherein position 19 of SEQ ID NO: 430 forms a base pair with the nucleotide located at the 5' terminal end of the antisense strand. In some embodiments, the sense strand of an AAT RNAi agent comprises the nucleobase sequence CGUUUAGGCAUGUUUAACU (SEQ ID NO: 430), wherein all or substantially all nucleotides are modified nucleotides, and wherein position 19 of SEQ ID NO: 430 forms a base pair with the nucleotide located at the 5' terminal end of the antisense strand.

[073] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGUU (SEQ ID NO: 794), wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 794 is located at positions 1 to 21 (5' ^ 3') of the antisense strand. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGUU (SEQ ID NO: 794), wherein all or substantially all nucleotides are modified nucleotides, and wherein SEQ ID NO: 794 is located at positions 1 to 21 (5' ^ 3') of the antisense strand.

[074] In some embodiments, the antisense strand of an RNAi agent of Petition 870260038067, dated 04 / 24 / 2026, p. 36 / 191 21 / 160 AAT comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCUU (SEQ ID NO: 839), wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 839 is located at positions 1 to 22 (5' ^ 3') of the antisense strand. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCUU (SEQ ID NO: 839), wherein all or substantially all nucleotides are modified nucleotides, and wherein SEQ ID NO: 839 is located at positions 1 to 22 (5' ^ 3') of the antisense strand.

[075] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCG (SEQ ID NO: 800), wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 800 is located at positions 1 to 21 (5' ^ 3') of the antisense strand. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCG (SEQ ID NO: 800), wherein all or substantially all nucleotides are modified nucleotides, and wherein SEQ ID NO: 800 is located at positions 1 to 21 (5' ^ 3') of the antisense strand.

[076] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCU (SEQ ID NO: 801), wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 801 is located at positions 1 to 21 (5' ^ 3') of the antisense strand. In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCU (SEQ ID NO: 801), wherein all or substantially all nucleotides are modified nucleotides, Petition 870260038067, dated 04 / 24 / 2026, p. 37 / 191 22 / 160 and where SEQ ID NO: 801 is located in positions 1 to 21 (5' > 3') of the antisense tape.

[077] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGUU (SEQ ID NO: 794), wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 794 is located at the 5' terminal end of the antisense strand, and wherein the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUAACAUU (SEQ ID NO: 857).

[078] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCUU (SEQ ID NO: 839), wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 839 is located at the 5' terminal end of the antisense strand, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of GCGUUUAGGCAUGUUUAACAUU (SEQ ID NO: 885).

[079] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCG (SEQ ID NO: 800), wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 800 is located at the 5' terminal end of the antisense strand, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGCGUUUAGGCAUGUUAACA (SEQ ID NO: 864).

[080] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCU (SEQ ID NO: 801), wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 801 is Petition 870260038067, dated 04 / 24 / 2026, p. 38 / 191 23 / 160 located at the 5' terminal end of the antisense strand, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of AGCGUUUAGGCAUGUUAACA (SEQ ID NO: 866).

[081] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGUU (SEQ ID NO: 794) differing by 0, 1, 2, or 3 nucleotides, wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 794 is located at the 5' terminal end of the antisense strand, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGUUUAGGCAUGUUUAACAUU (SEQ ID NO: 857) differing by 0, 1, 2, or 3 nucleotides.

[082] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCUU (SEQ ID NO: 839) differing by 0, 1, 2, or 3 nucleotides, wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 839 is located at the 5' terminal end of the antisense strand, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of GCGUUUAGGCAUGUUUAACAUU (SEQ ID NO: 885) differing by 0, 1, 2, or 3 nucleotides.

[083] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCG (SEQ ID NO: 800) differing by 0, 1, 2, or 3 nucleotides, wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 800 is located at the 5' terminal end of the antisense strand, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of CGCGUUUAGGCAUGUUUAACA (SEQ ID NO: 864) differing by 0, 1, 2, or 3 nucleotides. Petition 870260038067, dated 04 / 24 / 2026, page 39 / 191 24 / 160

[084] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of UGUUAAACAUGCCUAAACGCU (SEQ ID NO: 801) differing by 0, 1, 2, or 3 nucleotides, wherein at least one or more nucleotides consist of a modified nucleotide, and wherein SEQ ID NO: 801 is located at the 5' terminal end of the antisense strand, and the sense strand of an AAT RNAi agent comprises or consists of a nucleobase sequence of AGCGUUUAGGCAUGUUUAACA (SEQ ID NO: 866) differing by 0, 1, 2, or 3 nucleotides.

[085] The AAT RNAi agents described herein may include one or more modified nucleotides. The AAT RNAi agents described herein may also include one or more phosphorothioate internucleoside linkages.

[086] The AAT RNAi agents described in this document may also include one or more targeting groups or linking groups. In some embodiments, the AAT RNAi agents disclosed in this document include one or more targeting groups. In some embodiments, the targeting groups are composed of an asialoglycoprotein receptor linker. In some embodiments, the asialoglycoprotein receptor linker comprises a galactose or galactose-derived group. In some embodiments, the galactose-derived group comprises N-acetylgalactosamine. In some embodiments, the targeting linker comprises an N-acetylgalactosamine trimer. In some embodiments, a targeting group is conjugated to the sense strand of the AAT RNAi agents disclosed in this document.

[087] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a (5' 3') usGfsusUfaAfaCfallfgCfcUfaAfaCfgusu sequence (SEQ ID NO: 913), wherein a, c, g and u are 2' Petition 870260038067, dated 04 / 24 / 2026, p. 40 / 191 25 / 160 O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; es is a phosphorothioate linkage, and the sense strand is at least substantially complementary to the antisense strand.

[088] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a sequence (5' ^ 3') usGfsusUfaAfaCfaUfgCfcUfaAfaCfgcusu (SEQ ID NO: 958), wherein a, c, gf are 2'O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; es is a phosphorothioate linkage, and the sense strand is at least substantially complementary to the antisense strand.

[089] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a sequence (5' ^ 3') usGfsuUfaAfaCfaUfgCfcUfaAfaCfgsCfsg (SEQ ID NO: 959), wherein a, c, g are 2'O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; es is a phosphorothioate linkage, and the sense strand is at least substantially complementary to the antisense strand.

[090] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a sequence (5' ^ 3') usGfsuUfaAfacaugCfcUfaAfaCfgCfsu (SEQ ID NO: 960), wherein a, c, gf are 2'-Omethyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; es is a phosphorothioate linkage, and the sense strand is at least substantially complementary to the antisense strand.

[091] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a (5' ^ 3') sequence Petition 870260038067, dated 04 / 24 / 2026, p. 41 / 191 26 / 160 usGfsusUfaAfaCfaUfgCfcUfaAfaCfgusu (SEQ ID NO: 913) and the sense strand of an AAT RNAi agent comprises or consists of a sequence (5'^3') cguuuaGfGfCfauguuuaacausu (SEQ ID NO: 1276), wherein a, c, g are 2'-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; s is a phosphorothioate linkage; wherein optionally present in the sense strand is one, two, or more inverted abasic deoxyribose (invAb); and wherein optionally attached to the 5' terminal end of the sense strand is a targeting ligand that includes N-acetylgalactosamine.

[092] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a (5'^3') usGfsusUfaAfaCfaUfgCfcUfaAfaCfgcusu sequence (SEQ ID NO: 958) and the sense strand of an AAT RNAi agent comprises or consists of a (5'^3') gcguuuaGfGfCfauguuuaacausu sequence (SEQ ID NO: 1277), wherein a, c, gf are 2'-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; s is a phosphorothioate linkage; wherein optionally present in the sense strand is one, two, or more inverted abasic deoxyribose (invAb); and optionally attached to the 5' terminal end of the sense strand is a targeting ligand that includes N-acetylgalactosamine.

[093] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a (5'^3') usGfsuUfaAfaCfaUfgCfcUfaAfaCfgsCfsg sequence (SEQ ID NO: 959) and the sense strand of an AAT RNAi agent comprises or consists of a (5'^3') cgcguuuaGfGfCfauguuuaaca sequence (SEQ ID NO: 1278), where a, c, g are 2'-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; s is a connection of Petition 870260038067, dated 04 / 24 / 2026, p. 42 / 191 27 / 160 phosphorothioate; wherein optionally present in the sense strand is one, two, or more inverted abasic deoxyribose (invAb); and wherein optionally attached to the 5' terminal end of the sense strand is a targeting ligand that includes N-acetylgalactosamine.

[094] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a (5'^3') usGfsuUfaAfacaugCfcUfaAfaCfgCfsu sequence (SEQ ID NO: 960) and the sense strand of an AAT RNAi agent comprises or consists of a (5'^3') agcguuuaGfGfCfauguuuaaca sequence (SEQ ID NO: 1279), wherein a, c, g are 2'-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; s is a phosphorothioate linkage; wherein optionally present in the sense strand is one, two, or more inverted abasic deoxyribose (invAb); and optionally attached to the 5' terminal end of the sense strand is a targeting ligand that includes N-acetylgalactosamine.

[095] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a sequence (5'^3') usGfsusUfaAfaCfaUfgCfcUfaAfaCfgusu (SEQ ID NO: 913) and the sense strand of an AAT RNAi agent comprises or consists of (5'^3')(NAG37)s(invAb)scguuuaGfGfCfauguuuaacausu(invAb) (SEQ ID NO: 1028), where a, c, g are 2'-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; s is a phosphorothioate linkage; (invAb) is inverted abasic deoxyribose (invAb); and (NAG37) is the targeting ligand that includes N-acetylgalactosamine having the structure shown in Table 7.

[096] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a (5' ^ 3') sequence Petition 870260038067, dated 04 / 24 / 2026, p. 43 / 191 28 / 160 usGfsusUfaAfaCfaUfgCfcUfaAfaCfgcusu (SEQ ID NO: 958) and the sense strand of an AAT RNAi agent comprises or consists of a sequence (5' ^ 3') (NAG37)s(invAb)sgcguuuaGfGfCfauguuuaacausu(invAb) (SEQ ID NO: 1030), wherein a, c, g are 2'-O-methyl adenosine, cytidine, guanosine or uridine, respectively; Af, Cf, Gf and Uf are 2'-fluoro adenosine, cytidine, guanosine or uridine, respectively; s is a phosphorothioate linkage; (invAb) is inverted abasic deoxyribose (invAb); and (NAG37) is the targeting ligand that includes N-acetylgalactosamine having the structure shown in Table 7.

[097] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a (5'^3') usGfsuUfaAfaCfaUfgCfcUfaAfaCfgsCfsg sequence (SEQ ID NO: 959) and the sense strand of an AAT RNAi agent comprises or consists of a (5'^3') (NAG37)s(invAb)scgcguuuaGfGfCfauguuuaacas(invAb) sequence (SEQ ID NO: 1024), where a, c, g are 2'-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; s is a phosphorothioate linkage; (invAb) is inverted basic deoxyribose (invAb); and (NAG37) is the targeting ligand that includes N-acetylgalactosamine having the structure shown in Table 7.

[098] In some embodiments, the antisense strand of an AAT RNAi agent comprises or consists of a (5'^3') usGfsuUfaAfacaugCfcUfaAfaCfgCfsu sequence (SEQ ID NO: 960) and the sense strand of an AAT RNAi agent comprises or consists of a (5'^3') (NAG37)s(invAb)sagcguuuaGfGfCfauguuuaacas(invAb) sequence (SEQ ID NO: 1033), where a, c, g are 2'-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and Uf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; s is a phosphorothioate linkage; (invAb) is inverted abasic deoxyribose (invAb); and (NAG37) is the targeting ligand that includes N-acetylgalactosamine having the Petition 870260038067, dated 04 / 24 / 2026, p. 44 / 191 29 / 160 structure shown in Table 7.

[099] In some embodiments, the described AAT RNAi agents may include one or more targeting groups having the structure of (PAZ), (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), (NAG39)s, as defined in Table 7.

[0100] In some embodiments, the AAT RNAi agents described herein include a targeting group at the 5' end of the sense strand having the structure of (PAZ), (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), (NAG39)s, as defined in this document in Table 7.

[0101] The AAT RNAi agents disclosed herein may be incorporated into a composition comprising one or more disclosed AAT RNAi agents and at least one pharmaceutically acceptable excipient. In some embodiments, the compositions disclosed herein comprising one or more disclosed AAT RNAi agents and at least one pharmaceutically acceptable excipient is a pharmaceutical composition.

[0102] The pharmaceutical compositions comprising one or more AAT RNAi agents can be administered in a number of ways depending on whether local or systemic treatment is desired. Administration may be, but is not limited to, intravenous, intra-arterial, subcutaneous, intraperitoneal, subdermal (e.g., via an implanted device), and intraparenchymal administration. In some embodiments, the pharmaceutical compositions described in this document are Petition 870260038067, dated 04 / 24 / 2026, p. 45 / 191 30 / 160 administered by subcutaneous injection.

[0103] In some embodiments, the compositions comprise one or more disclosed AAT RNAi agents and at least one pharmaceutically acceptable excipient may further comprise one or more therapeutics or treatments.

[0104] In some embodiments, the compositions described in this document comprising one or more AAT RNAi agents are packaged in a kit, container, package, dispenser, pre-filled syringes or vials. In some embodiments, the compositions described in this document are administered parenterally.

[0105] AAT RNAi agents and compositions comprising the same that are disclosed herein may be administered to an individual to inhibit alpha-1 antitrypsin gene expression in the individual. In some embodiments, the individual is a human being. In some embodiments, the individual is a human being who has been diagnosed with AATD.

[0106] In some embodiments, methods for inhibiting the expression of an AAT gene in a cell are disclosed in this document, wherein the methods comprise administering an AAT RNAi agent that has an antisense strand that is at least partially complementary to the portion of an AAT mRNA having any of the sequences listed in Table 1.

[0107] AAT RNAi agents and compositions comprising the same disclosed herein may be administered to an individual for the treatment of AATD (including a condition or disease caused by alpha-1 antitrypsin deficiency). The condition or disease that may be treated, prevented and / or managed by administration of AAT RNAi agents and compositions comprising the same include chronic hepatitis, cirrhosis, hepatocellular carcinoma, transaminitis, cholestasis, fibrosis or fulminant hepatic failure. Petition 870260038067, dated 04 / 24 / 2026, p. 46 / 191 31 / 160

[0108] Depending on the usage in question, the terms “oligonucleotide” and “polynucleotide” mean a polymer of linked nucleosides, each of which may be independently modified or unmodified.

[0109] As used herein, an “RNAi agent” or “RNAi activator” means a composition containing an RNA oligonucleotide or RNA-like molecule (e.g., chemically modified RNA) that is capable of degrading or inhibiting the translation of messenger RNA (mRNA) transcripts of a target mRNA in a sequence-specific manner. As used herein, RNAi agents may operate via an RNA interference mechanism (i.e., inducing RNA interference through interaction with the RNA interference pathway machinery (RNA-induced silencing complex or RISC) of mammalian cells), or via any alternative mechanisms or pathways. Although RNAi agents, as used herein, are believed to operate primarily via an RNA interference mechanism, the RNAi agents disclosed are not bound, or limited, by any particular pathway or mechanism of action.The RNAi agents disclosed herein are composed of a sense strand and an antisense strand, and include, without limitation: short interfering RNAs (siRNAs), double-stranded RNAs (dsRNAs), microRNAs (miRNAs), short hairpin RNAs (shRNAs), and dicer substrates. The antisense strand of the RNAi agents described herein is at least partially complementary to the mRNA being targeted (e.g., AAT mRNA). The RNAi agents may include one or more modified nucleotides and / or one or more non-phosphodiester linkages.

[0110] As used here, the terms “silence,” “reduce,” “inhibit,” “downward regulate,” or “knock out” when referring to the expression of a given gene, mean that the expression of the gene, as measured by the level of RNA transcribed from the gene or the level of polypeptide, protein, or protein subunit translated from mRNA in a cell, group of cells, tissue, organ, or Petition 870260038067, dated 04 / 24 / 2026, page 47 / 191 32 / 160 individual in whom the gene is transcribed, is reduced when the cell, group of cells, tissue, organ, or individual is treated with the RNAi agents described herein as compared to a second cell, group of cells, tissue, organ, or individual that has not been or is not being treated in this way.

[0111] As used here, the terms “sequence” and “nucleotide sequence” mean an ordered succession of nucleobases or nucleotides, described with a succession of letters using standard nomenclature.

[0112] Depending on the usage in question, a “base,” “nucleotide base,” or “nucleobase,” is a heterocyclic pyrimidine or purine compound that is a standard constituent of all nucleic acids and includes the bases that form the nucleotides adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U). A nucleobase may be further modified to include, without limitation, universal bases, hydrophobic bases, promiscuous bases, extended-size bases, and fluorinated bases. Depending on the usage in question, the term “nucleotide” may include a modified nucleotide (such as, for example, a nucleotide mimic, abasic residue (Ab), or a substituent moiety).

[0113] As used herein, and except where otherwise indicated, the term “complementary,” when used to describe a first nucleobase or nucleotide sequence (e.g., sense strand of RNAi agent or targeted mRNA) in relation to a second nucleobase or nucleotide sequence (e.g., antisense strand of RNAi agent or a single-stranded antisense oligonucleotide), means the ability of an oligonucleotide or polynucleotide including the first nucleotide sequence to hybridize (form base-paired hydrogen bonds under mammalian physiological conditions (or similar conditions in vitro)) and form a duplex or double helical structure under certain standard conditions with an oligonucleotide or polynucleotide including the second nucleotide sequence. Complementary sequences include Watson base pairs. Petition 870260038067, dated 04 / 24 / 2026, page 48 / 191 33 / 160 Crick or non-Watson-Crick base pairs and include natural or modified nucleotides or nucleotide imitations, at least to the extent that the previous hybridization requirements are satisfied. Sequence identity or complementarity is independent of modification. For example, ae Af, as defined herein, are complementary to U (or T) and identical to A for the purposes of determining identity or complementarity.

[0114] Depending on the usage in question, “perfectly complementary” or “fully complementary” means that all (100%) nucleobases or nucleotides in a contiguous sequence of a first polynucleotide will hybridize with the same number of nucleobases or nucleotides in a contiguous sequence of a second polynucleotide. The contiguous sequence may comprise all or part of a first or second nucleotide sequence.

[0115] As used here, “partially complementary” means that in a hybridized pair of nucleobase sequences, at least 70%, but not all, of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide.

[0116] As used here, “substantially complementary” means that in a hybridized pair of nucleobase sequences, at least 85%, but not all, of the bases in a contiguous sequence of a first polynucleotide will hybridize with the same number of bases in a contiguous sequence of a second polynucleotide. The terms “complementary,” “fully complementary,” “partially complementary,” and “substantially complementary” are used in relation to the nucleobase or nucleotide correspondence between the sense strand and the antisense strand of an RNAi agent, or between the antisense strand of an RNAi agent and a sequence of an AAT mRNA.

[0117] Depending on the usage in question, the term “substantially identical” or Petition 870260038067, dated 04 / 24 / 2026, page 49 / 191 34 / 160 “substantial identity” as applied to nucleic acid sequences means that a nucleic acid sequence comprises a sequence that has at least about 85% sequence identity or more, for example, at least 90%, at least 95%, or at least 99% identity, compared to a reference sequence. The percentage of sequence identity is determined by comparing two ideally aligned sequences by a comparison window. The percentage is calculated by determining the number of positions where the identical nucleic acid base occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to yield the percentage of sequence identity.The inventions disclosed herein encompass nucleotide sequences substantially identical to those disclosed herein.

[0118] As used herein, the terms “treat,” “treatment,” and the like, mean the methods or steps taken to provide action or relief from the number, severity, and / or frequency of one or more symptoms of a disease in an individual. As used herein, “treat” and “treatment” may include the prevention, management, prophylactic treatment, and / or inhibition of the number, severity, and / or frequency of one or more symptoms of a disease in an individual.

[0119] As used here, the phrase “introduce into a cell,” when referring to an RNAi agent, means to functionally deliver the RNAi agent into a cell. The phrase “functional delivery” means delivering the RNAi agent to the cell in such a way that it allows the RNAi agent to have the expected biological activity, for example, specific inhibition of gene expression sequence.

[0120] Except where stated otherwise, the use of the symbol as used herein means that any group or groups may be linked to Petition 870260038067, dated 04 / 24 / 2026, page 50 / 191 35 / 160 even if it is in accordance with the scope of the inventions described in this document.

[0121] Depending on the usage in question, the term “isomers” refers to compounds that have identical molecular formulas but differ in the nature or sequence of their atoms’ bonding or in the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called “stereoisomers.” Stereoisomers that are not mirror images of each other are called “diastereomers,” and stereoisomers that are non-superimposable mirror images are called “enantiomers,” or sometimes optical isomers. A carbon atom bonded to four non-identical substituents is called a “chiral center.”

[0122] According to the intended use, except where specifically identified in a structure as having a particular conformation, for each structure where asymmetric centers are present and thus give rise to enantiomers, diastereomers, or other stereoisomeric configurations, each structure disclosed herein is intended to represent all possible isomers, including their optically pure and racemic forms. For example, the structures disclosed herein are intended to encompass mixtures of diastereomers as well as single stereoisomers.

[0123] As used in a claim, the phrase “consists of” excludes any element, step, or ingredient not specified in the claim. When used in a claim, the phrase “consists essentially of” limits the scope of a claim to specific materials or steps and those that do not materially affect the basic and innovative features of the claimed invention.

[0124] An individual with common knowledge of the art would readily understand and assess that the compounds and compositions of the present document Petition 870260038067, dated 04 / 24 / 2026, page 51 / 191 36 / 160 may have certain atoms (e.g., N, O, or S atoms) in a protonated or deprotonated state, depending on the environment in which the compound or composition is placed. Correspondingly, as the use in question applies, the structures disclosed herein consider that certain functional groups, such as OH, SH, or NH, may be protonated or deprotonated. The disclosure herein is intended to cover the disclosed compounds and compositions regardless of their protonation state based on the environment (such as pH), as would be readily understood by an individual with common knowledge of the art.

[0125] Except where otherwise defined, all technical and scientific terms used herein have the same meaning commonly understood by an individual with common knowledge of the art. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, suitable methods and materials will be described below. All publications, patent applications, patents, and other references mentioned are incorporated by reference in their entirety. In case of conflict, this descriptive report, including definitions, shall prevail. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0126] Other objectives, features, aspects and advantages of the invention will become apparent from the detailed description below, attached figures, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0127] Figures 1A to 1E represent the duplex chemical structure of AD04828 shown as a sodium salt.

[0128] Figures 2A to 2E represent the duplex chemical structure of AD04828 shown as a free acid. Petition 870260038067, dated 04 / 24 / 2026, page 52 / 191 37 / 160

[0129] Figures 3A to 3E represent the chemical structure of duplexes AD04831 is shown as a sodium salt.

[0130] Figures 4A to 4E represent the chemical structure of duplexes AD04831 is shown as a free acid.

[0131] Figures 5A to 5E represent the chemical structure of duplexes AD04836 is shown as a sodium salt.

[0132] Figures 6A to 6E represent the chemical structure of duplexes AD04836 is shown as a free acid.

[0133] Figures 7A to 7E represent the chemical structure of duplexes AD04837 is shown as a sodium salt.

[0134] Figures 8A to 8E represent the chemical structure of duplexes AD04837 is shown as a free acid.

[0135] Figure 9 is a bar graph showing mean normalized serum AAT (cAAT) levels in cynomolgus monkeys (cynos) (n=3) following a subcutaneous administration of 3 mg / kg of AD04824, AD04825, AD04826, or AD04827, according to Example 4. Serum AAT levels were normalized to mean pretreatment values. An experimental error is shown as the standard deviation.

[0136] Figure 10 is a bar graph showing mean normalized serum cAAT levels in cynos (n=2 or n=3) following a single subcutaneous administration of 3 mg / kg of AD04828, AD04836, AD04831, or AD04837, as per Example 5. Serum AAT levels were normalized to mean pretreatment values. Experimental error is shown as standard deviation.

[0137] Figure 11 is a bar graph showing the results of a western blot analysis of the soluble fractions (Z-AAT monomer) of PiZ mouse livers dosed with saline solution or RNAi agents of NAG-conjugated AAT having the AD04837 duplex structure, dosed for 8 weeks q2w, Petition 870260038067, dated 04 / 24 / 2026, page 53 / 191 38 / 160 normalized to baseline control, according to Example 7. Individual mouse measurements are shown grouped by treatment group, and experimental error is shown as standard deviation.

[0138] Figure 12 is a bar graph showing the results of a western blot analysis of the insoluble fractions (Z-AAT polymer) of livers from PiZ mice dosed with saline or RNAi agents of NAG-conjugated AAT having the duplex structure AD04837, according to Example 7. Individual mouse measurements are shown grouped by treatment group, and experimental error is shown as standard deviation. DETAILED DESCRIPTION RNAi agents

[0139] RNAi agents to inhibit the expression of an AAT gene (referred to in this document as AAT RNAi agents or AAT RNAi triggers) are described. Each AAT RNAi agent comprises a sense strand and an antisense strand. The sense strand and the antisense strand may be 16 to 30 nucleotides long. In some embodiments, the sense and antisense strands may be 17 to 26 nucleotides long. The sense and antisense strands may be the same length or may be different lengths. In some embodiments, the sense and antisense strands are each independently 17 to 21 nucleotides long. In some embodiments, the sense and antisense strands are each 21 to 26 nucleotides long. In some forms, the sense and antisense strands are each 21 to 24 nucleotides long.In some embodiments, the sense strand is about 19 nucleotides long while the antisense strand is about 21 nucleotides long. In some embodiments, the sense strand is about 21 nucleotides long while the antisense strand is about 23 nucleotides long. In some embodiments, the sense strand is 23 nucleotides long. Petition 870260038067, dated 04 / 24 / 2026, page 54 / 191 39 / 160 length and an antisense strand is 21 nucleotides long. In some embodiments, both the sense and antisense strands are each 21 nucleotides long. In some embodiments, the sense strand is 22 nucleotides long and an antisense strand is 21 nucleotides long. In some embodiments, the sense strand is 19 nucleotides long and an antisense strand is 21 nucleotides long. In some embodiments, the sense and antisense strands of RNAi agents are each independently 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotides long. In some embodiments, a double-stranded RNAi agent has a duplex length of approximately 16, 17, 18, 19, 20, 21, 22, 23, or 24 nucleotides.

[0140] In some embodiments, the region of perfect or substantial complementarity between the sense strand and the antisense strand is 16 to 26 nucleotides long (e.g., 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26) and occurs at or near the 5' end of the antisense strand (e.g., this region may be separated from the 5' end of the antisense strand by 0, 1, 2, 3, or 4 nucleotides that are not perfectly or substantially complementary).

[0141] The sense strand and the antisense strand contain a core extension sequence that is 16 to 23 nucleobases long. An antisense strand core extension sequence is 100% (perfectly) complementary or at least about 85% (substantially) complementary to a nucleotide sequence (sometimes referred to, for example, as a target sequence) present in an AAT mRNA target. The sense strand core extension sequence is 100% (perfectly) complementary or at least about 85% (substantially) complementary to a core extension sequence on the antisense strand, and therefore the sense strand core extension sequence is perfectly identical or at least about 85% identical to a nucleotide sequence (target sequence) present in the AAT mRNA target. A sense strand core extension sequence Petition 870260038067, dated 04 / 24 / 2026, p. 55 / 191 The 40 / 160 sense strand core may have the same length as a corresponding antisense core sequence or it may have a different length. In some embodiments, the antisense strand core extension sequence is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides long. In some embodiments, the sense strand core extension sequence is 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides long.

[0142] Examples of nucleotide sequences used in the formation of AAT RNAi agents are provided in Tables 2, 3, 4, and 5. Examples of AAT RNAi agent duplexes, which include the sense and antisense strand sequences in Tables 2, 3, 4, and 5, are shown in Table 6.

[0143] The sense and antisense strands of AAT RNAi agents anneal to form a duplex. A sense strand and an antisense strand of an AAT RNAi agent may be partially, substantially, or fully complementary to each other. Within the complementary duplex region, the sense strand core extension sequence is at least 85% complementary or 100% complementary to the antisense strand core extension sequence.In some embodiments, the sense strand core extension sequence contains a sequence of at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 nucleotides that is at least 85% or 100% complementary to a corresponding 16, 17, 18, 19, 20, 21, 22, or 23 nucleotide sequence of the antisense strand core extension sequence (i.e., the sense and antisense core extension sequences of an AAT RNAi agent have a region of at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 nucleotides that is at least 85% base paired or 100% base paired).

[0144] In some embodiments, the antisense strand of an AAT RNAi agent disclosed herein differs by 0, 1, 2, or 3 nucleotides from any Petition 870260038067, dated 04 / 24 / 2026, p. 56 / 191 41 / 160 one of the antisense strand sequences in Table 2, Table 3, or Table 4. In some embodiments, the sense strand of an AAT RNAi agent disclosed herein differs by 0, 1, 2, or 3 nucleotides from any of the sense strand sequences in Table 2, Table 3, or Table 5.

[0145] The sense strand and / or the antisense strand may optionally and independently contain 1, 2, 3, 4, 5, or 6 additional nucleotides (extension) at the 3' end, at the 5' end, or at both the 3' and 5' ends of the core extension sequences. The additional antisense strand nucleotides, if present, may or may not be complementary to the corresponding sequence in an AAT mRNA. The additional sense strand nucleotides, if present, may or may not be identical to the corresponding sequence in an AAT mRNA. The additional antisense strand nucleotides, if present, may or may not be complementary to the additional nucleotides of the corresponding sense strand, if present.

[0146] Depending on the use in question, an extension comprises 1, 2, 3, 4, 5, or 6 nucleotides at the 5' and / or 3' end of the sense strand core extension sequence and / or antisense strand core extension sequence. Extension nucleotides on a sense strand may or may not be complementary to nucleotides, whether core extension sequence nucleotides or extension nucleotides, on the corresponding antisense strand. Conversely, extension nucleotides on an antisense strand may or may not be complementary to nucleotides, whether core extension nucleotides or extension nucleotides, on the corresponding sense strand. In some embodiments, the sense strand and the antisense strand of an RNAi agent contain 3' and 5' extensions. In some embodiments, one or more of the 3' nucleotides pair in the base of one strand with one or more 5' nucleotides of the other strand.In other forms, one or more of the 3' extension nucleotides of a strand do not base pair with one or more others. Petition 870260038067, dated 04 / 24 / 2026, page 57 / 191 42 / 160 nucleotides of 5' extension from the other strand. In some embodiments, an AAT RNAi agent has an antisense strand having a 3' extension and a sense strand having a 5' extension.

[0147] In some embodiments, an AAT RNAi agent comprises an antisense strand having a 3' extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. In other embodiments, an AAT RNAi agent comprises an antisense strand having a 3' extension of 1, 2, or 3 nucleotides in length. In some embodiments, one or more antisense strand extension nucleotides comprise uracil or thymidine nucleotides or nucleotides that are complementary to the corresponding AAT mRNA sequence. In some embodiments, a 3' antisense tape extension includes or consists of one or more of the following sequences, but is not limited to: AUA, UGCUU, CUG, UG, UGCC, CUGCC, CGU, CUU, UGCCUA, CUGCCU, UGCCU, UGAUU, GCCUAU, T, TT, U, UU (each listed 5'^3').

[0148] In some embodiments, the 3' end of the antisense strand may include additional abasic residues (Ab). An “abasic residue” or “abasic site” is a nucleotide or nucleoside lacking a nucleobase at the 1' position of the sugar. In some embodiments, Ab or AbAb may be added to the 3' end of the antisense strand. In some embodiments, abasic residues may be added as inverted abasic residues (invAb) (see Table 7). (See, for example, F Czauderna, Nucleic Acids Res., 2003, 31(11), 2705-16).

[0149] In some embodiments, an AAT RNAi agent comprises a sense strand having a 3' extension of 1, 2, 3, 4, or 5 nucleotides in length. In some embodiments, one or more sense strand extension nucleotides comprise adenosine, uracil, or thymidine nucleotides, AT dinucleotide, or nucleotides that correspond to nucleotides in the AAT mRNA sequence. In some embodiments, the 3' sense strand extension includes or consists of one of the Petition 870260038067, dated 04 / 24 / 2026, p. 58 / 191 43 / 160 sequences to follow, but not limited to: T, UT, TT, UU, UUT, TTT, or TTTT (each listed 5' to 3').

[0150] In some embodiments, the 3' end of the sense strand may include additional abasic residues. In some embodiments, UUAb, UAb, or Ab are added to the 3' end of the sense strand. In some embodiments, the one or more abasic residues added to the 3' end of the sense strand are inverted (invAb). In some embodiments, one or more inverted abasic residues or abasic sites may be inserted between the targeting ligand and the nucleobase sequence of the RNAi agent's sense strand. In some embodiments, the inclusion of one or more inverted abasic residues or abasic sites at or near the terminal end or ends of the sense strand of an RNAi agent allows for enhanced activity or other desired properties of an RNAi agent.

[0151] In some embodiments, an AAT RNAi agent comprises a sense strand having a 5' extension of 1, 2, 3, 4, 5, or 6 nucleotides in length. In some embodiments, one or more of the sense strand extension nucleotides comprise uracil or adenosine nucleotides or nucleotides that correspond to nucleotides in the AAT mRNA sequence. In some embodiments, the 5' sense strand extension is one of, but not limited to, the following sequences: CA, AUAGGC, AUAGG, AUAG, AUA, A, AA, AC, GCA, GGCA, GGC, UAUCA, UAUC, UCA, UAU, U, UU (each listed 5' to 3'). A sense strand may have a 3' extension and / or a 5' extension.

[0152] In some embodiments, the 5' end of the sense strand may include one or more additional abasic residues (e.g., (Ab) or (AbAb)). In some embodiments, the one or more abasic residues added to the 5' end of the sense strand may be inverted (e.g., invAb). In some embodiments, one or more inverted abasic residues may be inserted between the targeting ligand and the nucleobase sequence of the RNAi agent's sense strand. In Petition 870260038067, dated 04 / 24 / 2026, p. 59 / 191 44 / 160 In some embodiments, the inclusion of one or more inverted abasic residues at or near the terminal end or ends of the sense strand of an RNAi agent may allow for enhanced activity or other desired properties of an RNAi agent. In some embodiments, an abasic residue (deoxyribose) may be replaced by a ribitol residue (abasic ribose).

[0153] In some embodiments, the 3' end of the antisense tape core extension sequence, or the 3' end of the antisense tape sequence, may include an inverted abasic residue (invAb (see Table 7)).

[0154] Examples of sequences used in the formation of AAT RNAi agents are provided in Tables 2, 3, 4, and 5. In some embodiments, an antisense strand of an AAT RNAi agent includes a sequence from any of the sequences in Tables 2, 3, or 4. In some embodiments, an antisense strand of an AAT RNAi agent includes the nucleotide sequence (from the 5' end to the 3' end) 1-17, 2-15, 2-17, 1-18, 2-18, 1-19, 2-19, 1-20, 2-20, 1-21, 2-21, 1-22, 2-22, 1-23, 2-23, 1-24, or 2-24, from any of the sequences in Table 2, Table 3, or Table 4. In certain embodiments In some embodiments, an AAT RNAi agent antisense strand comprises or consists of a modified sequence of any of the modified sequences in Table 4. In some embodiments, an AAT RNAi agent sense strand includes the sequence of any of the sequences in Tables 2, 3, or 5.In some embodiments, an AAT RNAi agent sense strand includes the nucleotide sequence (from the 5' end to the 3' end) 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 2-19, 2-20, 2-21, 2-22, 2-23, 2-24, 3-20, 3-21, 3-22, 3-23, 3-24, 4-21, 4-22, 4-23, 4-24, 5-22, 5-23, 5-24, 6-23, 6-24, 7-24, from any of the sequences in Tables 2, 3, or 5. In certain embodiments, an AAT RNAi agent sense strand comprises or consists of a modified sequence of any of the modified sequences in Table 5.

[0155] In some modalities, the sense and nonsense tapes of the agents of Petition 870260038067, dated 04 / 24 / 2026, p. 60 / 191 45 / 160 The RNAi described herein contain the same number of nucleotides. In some embodiments, the sense and antisense strands of the RNAi agents described herein contain different numbers of nucleotides. In some embodiments, the 5' end and the 3' end of the antisense strand of an RNAi agent form a blunt end. In some embodiments, the 3' end of the sense strand and the 5' end of the antisense strand of an RNAi agent form a blunt end. In some embodiments, both ends of an RNAi agent form blunt ends. In some embodiments, neither end of an RNAi agent has a blunt end. As used herein, a blunt end refers to an end of a double-stranded RNAi agent in which the terminal nucleotides of the two annealed strands are complementary (form a complementary base pair).

[0156] In some embodiments, the 5' sense end and the 3' antisense end of an RNAi agent form a frayed end. In some embodiments, the 3' sense end and the 5' antisense end of an RNAi agent form a frayed end. In some embodiments, both ends of an RNAi agent form a frayed end. In some embodiments, neither end of an RNAi agent is a frayed end. As used in this context, a frayed end refers to an end of a double-stranded RNAi agent in which the terminal nucleotides of the two annealed strands form a pair (i.e., do not form an overhang) but are not complementary (i.e., form a non-complementary pair). As used in this context, an overhang is an extension of one or more unpaired nucleotides at the end of a strand of a double-stranded RNAi agent.Unpaired nucleotides can be on the sense strand or the antisense strand, creating 3' or 5' overhangs. In some embodiments, the RNAi agent contains: a blunt end and a frayed end. Petition 870260038067, dated 04 / 24 / 2026, page 61 / 191 46 / 160 blind end and one 5' overhang end, one blind end and one 3' overhang end, one worn end and one 5' overhang end, one worn end and one 3' overhang end, two 5' overhang ends, two 3' overhang ends, one 5' overhang end and one 3' overhang end, two worn ends, or two blind ends.

[0157] Modified nucleotides, when used in various polynucleotide or oligonucleotide constructs, can preserve the activity of the compound in cells while simultaneously increasing the serum stability of these compounds, and can also minimize the possibility of activating interferon activity in humans upon administration of the polynucleotide or oligonucleotide construct.

[0158] In some embodiments, an AAT RNAi agent is prepared or provided as a salt, mixed salt, or a free acid. In some embodiments, an AAT RNAi agent is prepared as a sodium salt. These forms are within the scope of the inventions disclosed herein. Modified nucleotides

[0159] In some embodiments, an AAT RNAi agent contains one or more modified nucleotides. Depending on the use in question, a “modified nucleotide” is a nucleotide other than a ribonucleotide (2'-hydroxyl nucleotide). In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100%) of the nucleotides are modified nucleotides. Depending on the application, modified nucleotides include, but are not limited to, deoxyribonucleotides, nucleotide imitations, abasic nucleotides (represented as Ab), 2'-modified nucleotides, 3' to 3' (inverted) linkage nucleotides (represented herein as invdN, invN, Petition 870260038067, dated 04 / 24 / 2026, page 62 / 191 47 / 160 invn), nucleotides comprising modified nucleobase, bridging nucleotides, peptide nucleic acids (PNAs), 2',3'-dry nucleotide imitations (unlocked nucleobase analogs, represented herein as Nuna or NUNA), locked nucleotides (represented herein as Nlna or NLNA), 3-O-methoxy nucleotides (2'-linked internucleoside) (represented herein as 3'-OMen), 2'-F-Arabino nucleotides (represented herein as NfANA or Níana), 5'-Me, 2'-fluoro nucleotide (represented herein as 5Me-Nf), morpholino nucleotides, vinyl phosphonate deoxyribonucleotides (represented herein as vpdN), nucleotides containing vinyl phosphonate, and nucleotides containing cyclopropyl phosphonate (cPrpN).Modified 2'-nucleotides (i.e., a nucleotide with a group other than a hydroxyl group in the 2' position of the five-membered sugar ring) include, but are not limited to, 2'-O-methyl nucleotides (represented herein as a lowercase 'n' in a nucleotide sequence), 2'-deoxy-2'-fluoro nucleotides (represented herein as Nf, also represented herein as 2'-fluoro nucleotide), 2'-deoxy nucleotides (represented herein as dN), 2'-methoxyethyl (2'-O-2-methoxyethyl) nucleotides (represented herein as NM or 2'-MOE), 2'-amino nucleotides, and 2'-alkyl nucleotides. It is not necessary that all positions in a given compound be uniformly modified. Conversely, more than one modification can be incorporated into a single AAT RNAi agent or even into a single nucleotide of the same.The sense and antisense strands of AAT RNAi agents can be synthesized and / or modified by methods known in the art. Modification to one nucleotide is independent of modification to another nucleotide.

[0160] Modified nucleobases include synthetic and natural nucleobases, such as 5-substituted pyrimidines, 6-azapyrimidines, and N-2, N-6, and O-6 purines. Petition 870260038067, dated 04 / 24 / 2026, page 63 / 191 48 / 160 substituted, (e.g., 2-aminopropyladenine, 5-propynyluracil, or 5-propynylcytosine), 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, inosine, xanthine, hypoxanthine, 2-aminoadenine, 6-alkyl derivatives (e.g., 6-methyl, 6-ethyl, 6-isopropyl, or 6-n-butyl) of adenine and guanine, 2-alkyl derivatives (e.g., 2-methyl, 2-ethyl, 2-isopropyl, or 2-n-butyl) and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine, 2-thiocytosine, 5-halouracil, cytosine, 5-propynyl uracil, 5-propynyl cytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-sulfhydryl, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo (e.g., 5-bromo), 5-trifluoromethyl, and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

[0161] In some embodiments, all or substantially all of the nucleotides of an RNAi agent are modified nucleotides. Depending on the usage in question, an RNAi agent where substantially all the nucleotides present are modified nucleotides is an RNAi agent having four or fewer (i.e., 0, 1, 2, 3, or 4) nucleotides in the sense strand and the antisense strand being ribonucleotides (i.e., unmodified). Depending on the usage in question, a sense strand where substantially all the nucleotides present are modified nucleotides is a sense strand having two or fewer (i.e., 0, 1, or 2) nucleotides in the sense strand being ribonucleotides. Depending on the use in question, an antisense strand where substantially all the nucleotides present are modified nucleotides is an antisense strand having two or fewer (i.e., 0, 1, or 2) nucleotides in the sense strand being ribonucleotides. In some embodiments, one or more nucleotides of an RNAi agent consist of a ribonucleotide. Modified internucleoside linkages

[0162] In some embodiments, one or more nucleotides of an AAT RNAi agent are linked by non-standard linkages or backbones (i.e., linkages of Petition 870260038067, dated 04 / 24 / 2026, page 64 / 191 49 / 160 modified internucleoside or modified backbones). Modified internucleoside linkages or backbones include, but are not limited to, 5'-phosphorothioate groups (represented herein as a lowercase "s"), chiral phosphorothioates, thiophosphates, phosphorodithioates, phosphotriesters, aminoalkyl-phosphotriesters, alkyl phosphonates (e.g., methyl phosphonates or 3'-alkylene phosphonates), chiral phosphonates, phosphinates, phosphoramidates (e.g., 3-amino phosphoramidate, aminoalkylphosphoramidates, or thionophosphoramidates), thionoalkyl-phosphonates, thionoalkylphosphotriesters, morpholino linkages, boranophosphates having normal 3'-5' linkages, 2-5' linked analogs of boranophosphates, or boranophosphates having inverted polarity where adjacent pairs of nucleoside units are linked 3'-5' to 5'3' or 2'-5' to 5'-2'. In some embodiments, a modified internucleoside linkage or backbone is devoid of a phosphorus atom.Modified internucleoside linkages lacking a phosphorus atom include, but are not limited to, short-chain alkyl or cycloalkyl intersugar linkages, mixed heteroatomic and alkyl or cycloalkyl intersugar linkages, or one or more short-chain heteroatomic or heterocyclic intersugar linkages. In some embodiments, the modified internucleoside backbones include, but are not limited to, siloxane backbones, sulfide backbones, sulfoxide backbones, sulfone backbones, formacetyl and thioformacetyl backbones, methylene formacetyl and thioformacetyl backbones, alkene-containing backbones, sulfamate backbones, methylenediamine and methylenehydrazine backbones, sulfonate and sulfonamide backbones, amide backbones, and other backbones having mixed N, O, S, and CH2 components.

[0163] In some embodiments, the sense strand of an AAT RNAi agent may contain 1, 2, 3, 4, 5, or 6 phosphorothioate linkages, an antisense strand of an AAT RNAi agent may contain 1, 2, 3, 4, 5, or 6 phosphorothioate linkages, or both the sense strand and the antisense strand independently may contain 1, 2, 3, 4, Petition 870260038067, dated 04 / 24 / 2026, p. 65 / 191 50 / 160 or 6 phosphorothioate linkages. In some embodiments, the sense strand of an AAT RNAi agent may contain 1, 2, 3, or 4 phosphorothioate linkages, an antisense strand of an AAT RNAi agent may contain 1, 2, 3, or 4 phosphorothioate linkages, or both the sense and antisense strands independently may contain 1, 2, 3, or 4 phosphorothioate linkages.

[0164] In some embodiments, an AAT RNAi agent sense strand contains at least two phosphorothioate internucleoside bonds. In some embodiments, the at least two phosphorothioate internucleoside bonds are between nucleotides at positions 1 to 3 from the 3' end of the sense strand. In some embodiments, the at least two phosphorothioate internucleoside bonds are between nucleotides at positions 1-3, 2-4, 3-5, 4-6, 4-5, or 6-8 from the 5' end of the sense strand. In some embodiments, an AAT RNAi agent antisense strand contains four phosphorothioate internucleoside bonds. In some embodiments, the four phosphorothioate internucleoside linkages are between nucleotides at positions 1 to 3 from the 5' end of the antisense strand and between nucleotides at positions 19-21, 20-22, 21-23, 22-24, 23-25, or 24-26 from the 5' end.In some embodiments, an AAT RNAi agent contains at least two phosphorothioate internucleoside bonds on the sense strand and three or four phosphorothioate internucleoside bonds on the antisense strand.

[0165] In some embodiments, an AAT RNAi agent contains one or more modified nucleotides and one or more modified internucleoside linkages. In some embodiments, a 2'-modified nucleoside is combined with a modified internucleoside linkage. AAT RNAi Agents

[0166] In some embodiments, the disclosed AAT RNAi agents target an AAT gene at or near the AAT genome positions shown in Table 1. In some embodiments, the antisense strand of an AAT RNAi agent Petition 870260038067, dated 04 / 24 / 2026, p. 66 / 191 The 51 / 160 sequence disclosed in this document includes a core extension sequence that is complete, substantial, or at least partially complementary to a target AAT 19-mer sequence disclosed in Table 1. Table 1. Target mRNA sequence AAT 19-mer (cDNA take-up of Human AAT, GenBank NM_000295.4 (SEQ ID NO:1)) SEQ ID NO: Target sequences AAT 19-mer (5' —> 3') Corresponding genome position (taken from SEQ ID NO: 1) 2 CGUUUAGGCAUGUUAACA 1000-1018 3 AACAGCACCAAUAUCUUCU 469-487 4 AUAUCAUCACCAAGUUCCU 1142-1160 5 AGAUGCUGCCCAGAAGACA 348-366 6 CUGGCACACCAGUCCAACA 454-472 7 UGGCACACCAGUCCAACAG 455-473 8 GCACACCAGUCCAACAGCA 457-475 9 CAGUCCAACAGCACCAAUA 463-481 10 AGUCCAACAGCACCAAUAU 464-482 11 GUCCAACAGCACCAAUAUC 465-483 12 CCAACAGCACCAAUAUC UU 467-485 13 CCCCAGUGAGCAUCGCUAC 491-509 14 GAGCAUCGCUACAGCCUUU 498-516 15 GCAUCGCUACAGCCUUUGC 500-518 16 CAUCGCUACAGCCUUUGCA 501-519 17 UCGCUACAGCCUUGCAAU 503-521 UGUACCACUCAGAAGCCUU 28 GCCAAGAAACAGAUCAACG 790-808 29 UACUCAAGGGAAAAUUGUG 825-843 30CUCAAGGGAAAAUUGUGGA 827-845 31 UCAAGGGAAAAUUGUGGAU 828-846 32 UUGGUCAAGGAGCUUGACA 847-865 33 AGGAGCUUGACAGAGACAC 854-872 Petition 870260038067, dated 04 / 24 / 2026, page 67 / 191 52 / 160 SEQ ID NO: AAT target sequences 19-mer (5' —> 3') Corresponding genome position (taken from SEQ ID NO: 1) 34 AG CUU GACAGAGACACAG U 857-875 35 UUUGCUCUGGUGAAUUACA 877-8985AGUUAGUAGUAGUACA 998-1016 37 GCGUUUAGGCAUGUUUAAC 999-1017 38 UUAGGCAUGUUUAACAUCC 1003-1021 39 UGGGUGCUGCUGAUGAAAU 1045-1063 40 UGCCACCCAUCUU-1094-1094 CCUGGAAAAUGAACUCACC 1119-1137 42 CGAUAUCAUCACCAAGUUC 1140-1158 43 ACCAAGUUCCUGGAAAAUG 1150-1168 44 UCCAAUUACUGGAACCUAUG 1207-1225 CCAUGAUGAUGAUGA45 1208-1226 46 AC U GGAAC C UAU GAU CU GA 1213-1231 47 GG AAC CU AU G AU CU GAAG A 1216-1234 48 GAAC C UAU GAU CU GAAGAG 1217-1217-1235GAUCCUGGCUG 1269-1287 50 GCAAUGGGGCUGACCUCUC 1271-1289 51 AGAGGAGGCACCCCUGAAG 1299-1317 52 AGGCACCCCUGAAGCUCUC 1304-1322 53 UCUCCAAGGCCGUGCAUAA-1313174 UCCAAGGCCGUGCAUAAGG 1321-1339 55 CCAAGGCCGUGCAUAAGGC 1322-1340 56 CAAGGCCGUGCAUAAGGCU 1323-1341 57 AAGGCUGUGCUGACCAUCG 1336-1354 5GUGCCGACCAGGCAUCG 1338-1356 59 CUGCUGGGGCCAUGUUUUU 1373-1391 60GCUGGGGCCAUGUUUUUAG 1375-1393 61 CUGGGGCCAUGUUUUUAGA 1376-1394 62 GGGGCCAUGUUUUUAGAGG 1378-1396 63 GGGCCAUGUUUUUAGAGGC 1379-1397 64 GAGGCCAUACCCAUGUCUA 1393-1411 65 GGCCAUACCCAUGUCUAUC 1395-1413 66 CCCGAGGUCAAGUUCAACA 1417-1435 67 AG GUC AAG UU CAACAAAC C 1421-1439 68 CAAGUUCAACAAACCCUUU 1425-1443 69 AGUUCAACAAACCCUUUGU 1427-1445 70 GUUCAACAAACCCUUUGUC 1428-1446 71 UCAACAAACCCUUUGUCUU 1430-1448 72 ACCCUUUGUCUUCUUAAUG 1437-1455 Petition 870260038067, dated 04 / 24 / 2026, page 68 / 191 53 / 160 SEQ ID NO: Target sequences AAT 19-mer (5' —> 3') Corresponding genome position (taken from SEQ ID NO: 1) 73 CCUUUGUCUUCUUAAUGAU 1439-1457 74 UACCAAGUCUCCCCUCUUC 1467-1485 75 AAGUCUCCCCUCUUCAUGG 1471-1489 76 AGUCUCCCCUCUUCAUGGG 1472-1490 77 UCUCCCCUCUUCAUGGGAA 1474-1492 78 CUCCCCUCUUCAUGGGAAA 1475-1493 79 AUGACAUUAAAGAAGGGUU 1569-1587

[0167] In some embodiments, an AAT RNAi agent includes an antisense strand wherein position 19 of the antisense strand (5'^3') is capable of forming a base pair with position 1 of a 19-mer target sequence revealed in Table 1. In some embodiments, an AAT RNAi agent includes an antisense strand wherein position 1 of the antisense strand (5'^3') is capable of forming a base pair with position 19 of the 19-mer target sequence revealed in Table 1.

[0168] In some embodiments, an AAT RNAi agent includes an antisense strand wherein position 2 of the antisense strand (5'^3') is capable of forming a base pair with position 18 of the 19-mer target sequence revealed in Table 1. In some embodiments, an AAT RNAi agent includes an antisense strand wherein positions 2 to 18 of the antisense strand (5'^3') are capable of forming base pairs at each of the respective complementary bases located at positions 18 to 2 of the 19-mer target sequence revealed in Table 1.

[0169] For the RNAi agents disclosed in this document, the nucleotide at position 1 of the antisense strand (from the 5' end ^ 3' end) may be perfectly complementary to the AAT gene, or it may be non-complementary to the AAT gene. In some embodiments, the nucleotide at position 1 of the antisense strand (from the 5' end ^ 3' end) is a U, A, or dT. In some embodiments, the nucleotide at position 1 of the antisense strand (from the 5' end ^ 3' end) forms an A:U or U:A base pair with the sense strand. Petition 870260038067, dated 04 / 24 / 2026, p. 69 / 191 54 / 160

[0170] In some embodiments, an AAT RNAi agent antisense strand comprises nucleotide sequence (from the 5' end to the 3' end) 2-18 or 2-19 of any of the antisense strand sequences in Table 2, Table 3, or Table 4. In some embodiments, an AAT RNAi sense strand comprises nucleotide sequence (from the 5' end to the 3' end) 1-17, 1-18, or 2-18 of any of the sense strand sequences in Table 2, Table 3, or Table 5.

[0171] In some embodiments, an AAT RNAi agent is composed of (i) an antisense strand comprising nucleotide sequence (from the 5' end to the 3' end) 2-18 or 2-19 of any of the antisense strand sequences in Table 2, Table 3, or Table 4, and (ii) a sense strand comprising nucleotide sequence (from the 5' end to the 3' end) 1-17 or 1-18 of any of the sense strand sequences in Table 2, Table 3, or Table 5.

[0172] In some embodiments, AAT RNAi agents include core 19-mer nucleotide sequences shown in Table 2 below. Petition 870260038067, dated 04 / 24 / 2026, p. 70 / 191 Table 2. Exemplary AAT RNAi agent antisense and sense strand core extension base sequences (N = any nucleobase) SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: AGUUAAACAUGCCUAAACG 430 CGUUUAGGCAUGUUUAACU 1000-1018 82 NGUUAAACAUGCCUAAACG 431 CGUUUAGGCAUGUUUAACN 1000-1018 83 NGUUAAACAUGCCUAAACN 432 NGUUAAGCAUUUUUUAG 1000-1018 84 AGAAGAUAUUGGUGCUGUU 433 AACAGCACCAAUAUCUUCU 469-487 85 UGAAGAUAUUGGUGCUUCUU 434 AACAGCACCAAUAUCUUCA 469-487 86 NGAAGAUAUUGUACUCACUACUACUACUAG453 469-487 87 NGAAGAUAUUGGUGCUGUN 436 NACAGCACCAAUAUCUUCN 469-487 88 AGGAACUUGGUGAUGAUAU 437 AUAUCAUCACCAAGUUCCU 1142-1160 89 UGGAACUUGGUAGUACUAUCAUCAUCAUAUCAUCAUCAUCAUCAUCAUCAUCAUCAUAU 1142-1160 1142-1160 90 NGGAACUUGGUGAUGAUAU 439 AUAUCAUCACCAAGUUCCN 1142-1160 91 NGGAACUUGGUGAUGAUAN 440 NUAUCAUCACCAAGUUCCN 1142-1160 92 UGUGCUAGCUAGCUGCU4141 AGAUGCUGCCCAGAAGACA 348-366 93 AGUCUUCUGGGCAGCAUCU 442 AGAUGCUGCCCAGAAGACU 348-366 94 NGUCUUCUGGGCAGCAUCU 443 AGAUGCUGCCCAGAAGACN 348-366 95INSTALLATION 444 INSTALLATION 348-366 96 INSTALLATION 445 INSTALLATION 454-472 97 INSTALLATION-INSTALLATION 446 INSTALLATION4AC95CUGCCAA CUSTOMING 447 CUSTOMING 454-472 99 CUSTOMING 448 CUSTOMIZING 454-472 100 CUSTOMIZATION-CUSING-5AC35AC349 U 450 UP 455-473 102 UP 451 455-473 103 NEW-HEAD-4552 452 UGCCAN PRESENTATION 453 CHANGES 455-473 55 / 160 Petition 870260038067, dated 4 / 24 / 2026, p. 71 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1 105 UGCUGUUGGACUGGUGUGC 454 GCACACCAGUCCAACAGCA 457-475 106 AGCUGUUGGACUGGUGUGC 455 GCACACCAGUCCAACAGCU 457-475 107 NGCUGUUGGACUGGUGUGC 456 GCACACCAGUCCAACAGCN 457-475 108 NGCUGUUGGACUGGUGUGN 457 NCACACCAGUCCAACAGCN 457-475 109 UAUUGGUGCUGUUGGACUG 458 CAGUCCAACAGCACCAAUA 463-481 110 AAUUGGUGCUGUUGGACUG 459 CAGUCCAACAGCACCAAUU 463-481 111 NAUUGGUGCUGUUGGACUG 460 CAGUCCAACAGCACCAAUN 463-481 112 NAUUGGUGCUGUUGGACUN 461 NAGUCCAACAGCACCAAUN 463-481 113 AUAUUGGUGCUGUUGGACU 462 AGUCCAACAGCACCAAUAU 464-482 114 UUAUUGGUGCUGUUGGACU 463 AGUCCAACAGCACCAAUAA 464-482 115 NUAUUGGUGCUGUUGGACU 464 AGUCCAACAGCACCAAUAN 464-482 116 NUAUUGGUGCUGUUGGACN 465 NGUCCAACAGCACCAAUAN 464-482 117 GAUAUUGGUGCUGUUGGAC 466 GUCCAACAGCACCAAUAUC 465-483 118 UAUAUUGGUGCUGUUGGAC 467 GUCCAACAGCACCAAUAUA 465-483 119 AAUAUUGGUGCUGUUGGAC 468 GUCCAACAGCACCAAUAUU 465-483 120NAUAUUGGUGCUGUUGGAC 469 GUCCAACAGCACCAAUAUN 465-483 121 NAUAUUGGUGCUGUUGGAN 470 NUCCAACAGCACCAAUAUN 465-483 122 AAGAUAUUGGUGCUGUUGG 471 CCAACAGCACCAAUAUCUU 467-485 123 472 GUAGCGAUGCUCACUGGGG 475 CCCCAGUGAGCAUCGCUAC 491-509 127 UUAGCGAUGCUCACUGGGG 476 CCCCAGUGAGCAUCGCUAA 491-509 128 AUAGCGAUGCUCACUGGGG 477 CCCCAGUGAGCAUCGCUAU 491-509 129 NUAGCGAUGCUCACUGGGG 478 CCCCAGUGAGCAUCGCUAN 491-509 130 NUAGCGAUGCUCACUGGGN 479 NCCCAGUGAGCAUCGCUAN 491-509 131 AAAGGCUGUAGCGAUGCUC 480 GAGCAUCGCUACAGCCUUU 498-516 132 UAAGGCUGUAGCGAUGCUC 481 GAGCAUCGCUACAGCCUUA 498-516 56 / 160 Petition 870260038067, dated 04 / 24 / 2026, page 72 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1 133 NAAGGCUGUAGCGAUGCUC 482 GAGCAUCGCUACAGCCUUN 498-516 134 NAAGGCUGUAGCGAUGCUN 483 NAGCAUCGCUACAGCCUUN 498-516 135 GCAAAGGCUGUAGCGAUGC 484 GCAUCGCUACAGCCUUUGC 500-518 136 UCAAAGGCUGUAGCGAUGC 485 GCAUCGCUACAGCCUUUGA 500-518 137 ACAAAGGCUGUAGCGAUGC 486 GCAUCGCUACAGCCUUUGU 500-518 141 AGCAAAGGCUGUAGCGAUG 490 CAUCGCUACAGCCUUUGCU 501-519 142 NGCAAAGGCUGUAGCGAUG 491 NAUCGCUACAGCCUUUGCN 501-519 143 NGCAAAGGCUGUAGCGAUN 492 NAUCGCUACAGCCUUUGCN 501-519 144 AUUGCAAAGGCUGUAGCGA 493 UCGCUACAGCCUUUGCAAU 503-521 145 UUUGCAAAGGCUGUAGCGA 494 UCGCUACAGCCUUUGCAAA 503-521 146 NUUGCAAAGGCUGUAGCGA 495 UCGCUACAGCCUUUGCAAN 503-521 147 NUUGCAAAGGCUGUAGCGN 496 NCGCUACAGCCUUUGCAAN 503-521 148AGCAUUGCAAAGGCUGUAG 497 CUACAGCCUUUGCAAUGCU 506-524 149 UGCAUUGCAAAGGCUGUAG 498 CUACAGCCUUUGCAAUGCA 506-524 150 NGCAUUGCAAAGGCUGUAG 499 CUACAAAGCUUGCU506-506-524 151 NGCAUUGCAAAGGCUGUAN 500 NUACAGCCUUUGCAAUGCN 506-524 152 AGAGCAUUGCAAAGGCUGU 501 ACAGCCUUUGCAAUGCUCU 508-526 153 UGAGCAUUGCAAAGGCUGU ACAUGCAUGCAUGCUGU 508-526 154 NGAGCAUUGCAAAGGCUGU 503 ACAGCCUUUGCAAUGCUCN 508-526 155 NGAGCAUUGCAAAGGCUGU 504 NCAGCCUUUGCAAUGCUCN 508-526 156 GGAGUUCCUGGACCAGGAGCACUGCUGCUGA 613-631 157 UGAGUUCCUGGAAGCCUUC 506 GAAGGCUUCCAGGAACCUCA 613-631 158 AGAGUUCCUGGAAGCCUUC 507 GAAGGCUUCCAGGAACUCU 613-631 159 NGAGUUCGGAAGCCU8 613-631 160 NGAGUUCCUGGAAGCCUUN 509 NAAGGCUUCCAGGAACUCN 613-631 57 / 160 Petition 870260038067, of 24 / 04 / 2026, p. 73 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1 161 UCCAAAAACUUAUCCACUA ACCAAAAACUUAUCCACUA 511 UAGUGGAUAAGUUUUUGGU 710-728 163 NCCAAAAACUUAUCCACUA 512 UAGUGGAUAAGUUUUUGGN 710-728 164 NCCAAAAACUUAUCCACUN 513 NAGUAGUUUGUUGGU 710-728 165 AAGGCUUCUGAGUGGUACA 514 UG UAC CAC U CAGAAGC CUU 743-761 166 UAGGCUUCUGAGUGGUACA 515 UG UAC CAC U CAGAAGC C UA 743-761 167 NAGGCUUCUGAGUGGUACA U CAGAAGC CUN 743-761 168 NAGGCUUCUGAGUGGUACN 517 NG UAC CAC U CAGAAGC CUN 743-761 169 GAAGGCUUCUGAGUGGUAC 518 GUACCACUCACAGAAGCCUUC 744-762 170 GUACCACUCAGAAGCCUUA 744-762 171 AAAGGCUUCUGAGUGGUAC 520 GUACCACUCAGAAGCCUUU 744-762 172 NAAGGCUUCUGAGUGGUAC 521 GUACCACUCACAGAAGCCUUN 744-762 173 NUACCACUCAGAAGCCUUN 744-762 174 UUCUUGGCCUCUUCGGUGU 523 ACACCGAAGAGGCCAAGAA 779-797 175 AUCUUGGCCUCUUCGGUGU 524ACACCGAAGAGGCCAAGAU 779-797 176 NUCUUGGCCUCUUCGGUGU 525 ACACCGAAGAGGCCAAGAN 779-797 177 NUCUUGGCCUCUUCGGUGN 526 NCACCGAAGAGGCCAAGAN 779-797 178 GUUUCUUGGCCUCUUCGGU 527 ACCGAAGAGGCCAAGAAAC 781-799 179 UUUUCUUGGCCUCUUCGGU 528 ACCGAAGAGGCCAAGAAAA 781-799 180 AUUUCUUGGCCUCUUCGGU 529 ACCGAAGAGGCCAAGAAAU 781-799 181 NUUUCUUGGCCUCUUCGGU 530 ACCGAAGAGGCCAAGAAAN 781-799 182 NUUUCUUGGCCUCUUCGGN 531 NCCGAAGAGGCCAAGAAAN 781-799 183 UUGAUCUGUUUCUUGGCCU 532 AGGCCAAGAAACAGAUCAA 788-806 184 AUGAUCUGUUUCUUGGCCU 533 AGGCCAAGAAACAGAUCAU 788-806 185 NUGAUCUGUUUCUUGGCCU 534 AGGCCAAGAAACAGAUCAN 788-806 186 NUGAUCUGUUUCUUGGCCN 535 NGGCCAAGAAACAGAUCAN 788-806 187 GUUGAUCUGUUUCUUGGCC 536 GGCCAAGAAACAGAUCAAC 789-807 188 UUUGAUCUGUUUCUUGGCC 537 GGCCAAGAAACAGAUCAAA 789-807 58 / 160 Petition 870260038067, dated 04 / 24 / 2026, page 74 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1 190 HOUSEHOLDING 539 GGCCAGAACAGGCCAN 789-807 191 HOUSINGHOUSINGGGCN 540 NGCCAHOUSING 789-807 192 HOUSEHOLDING5HOUSE4HOUSING1 790-808 193 MAINTENANCEGGC 542 MAINTENANCE 790-808 194 MAINTENANCEGGC 543 MAINTENANCE4MAINTENANCE 790-808 196 WATER WATER 545 NC CAAC N 790-808 197 COCOA 546 U AC UC AAG G FIVE 825-843 CCCU7 WATER 198 UGUGN G GAAAAU UGUA 825-843 199 AACAAUUUUCCCUGAGUA 548 U AC UC AAG G GAAAAU UGUU 825-843 200 NACAUUUCCCUUGAGUA 549 U AC UC AAG G GAAAAUUCCUCCUCCUCA325 550 N AC UC AAG G GAAAAU UGUN 825-843 202 UCCACAAUUUUCCUUGAG 551 CUCAAGGGAAAAUUGUGGA 827-845 203ACCACAAUUUUCCCUUGAG 552 CUCAAGGGAAAAUUGUGGU 827-845 204 NCCACAAUUUUCCCUUGAG 553 CUCAAGGGAAAAUUGUGGN 827-845 205 NCCACAAUUUUCCCUUGAN 554 NUCAAGGGAAAAUUGUGGN 827-845 206 AUCCACAAUUUUCCCUUGA 555 UCAAGGGAAAAUUGUGGAU 828-846 207 UUCCACAAUUUUCCCUUGA 556 UCAAGGGAAAAUUGUGGAA 828-846 208 NUCCACAAUUUUCCCUUGA 557 UCAAGGGAAAAUUGUGGAN 828-846 209 NUCCACAAUUUUCCCUUGN 558 NCAAGGGAAAAUUGUGGAN 828-846 210 UGUCAAGCUCCUUGACCAA 559 UUGGUCAAGGAGCUUGACA 847-865 211 AGUCAAGCUCCUUGACCAA 560 UUGGUCAAGGAGCUUGACU 847-865 212 NGUCAAGCUCCUUGACCAA 561 NUGGUCAAGGAGCUUGACA 847-865 213 NGUCAAGCUCCUUGACCAA 562 NUGGUCAAGGAGCUUGACN 847-865 214 GUGUCUCUGUCAAGCUCCU 563 AGGAGCUUGACAGAGACAC 854-872 215 UUGUCUCUGUCAAGCUCCU 564 AGGAGCUUGACAGAGAGACAA 854-872 216 AUGUCCUGUCAAGCUCCU 565 AGGAGCUUGACAGAGACAU 854-872 59 / 160 Petition 870260038067, dated 04 / 24 / 2026, page 75 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO-1 218 GAG 567 NG GAG 854-872 219 GAG 568 AGC U GAG 857-875 220 GAG 527 U 758 U 568 REPLACEMENT 570 AGC U RECOVERY 857-875 222 AGC RECOVERY 571 AGC RECOVERY N 857-875 223 UG UAAU U CAC RECOVERY 570-557 224 AG UAAU 573 877-895 225 NG UAAU U CAC 574 877-895 226 NG UAAU U CAU5 CAAC 877-895 227 UUAAACAUGCCUAAAACGCU 576 AGCGUUUAGGCAUGUUAA 998-1016 228 AUAAACAUGCCUAAAACGCU 577 AGCGUUUAGGCAUGUUUAU 998-1016 229 GCCU8AACUACAU AGCGUUUAGGCAUGUUUAN 998-1016 230 NUAAACAUGCCUAAACGCN 579 NGCGUUUAGGCAUGUUUAN 998-1016 231 GUUAAACAUGCCUAAACGC580 GCGUUUAGGCAUGUUUAAC 999-1017 232 UUUAAACAUGCCUAACGC 581 GCGUUUAGGCAUGUUUAAA 999-1017 233 AUUAAACAUGCCUAACGC 582 GCGUUUAGGCAUGUUUAAUAU 999-1017 234 NUUAAACAUGCCUAACGC 583 GCGUUUAGGCAUGUUUAAN 999-1017 235 NUUAAACAUGCCUAACGN 584 NCGUUUAGGCAUGUUUAAN 999-1017 236 GGAUGUUAAACAUGCCUAA 585 UUAGGCAUGUUUAACAUCC 1003-1021 237 UGAUGUUAAACAUGCCUA 586 UUAGGCAUGUUUAACAUCA 1003-1021 238 AGAUGUUAAACAUGCCUA 587 UUAGGCAUGUUUAACAUCU 1003-1021 239 NGAUGUUAAACAUGCCUAA 588 UUAGGCAUGUUUAACAUCN 1003-1021 240 NGAUGUUAAACAUGCCUAN 589 NUAGGCAUGUUUAACAUCN 1003-1021 241 AUUUCAUCAGCAGCACCCA 590 UGGGUGCUGCUGAUGAAAU 1045-1063 242 UUUUCAUCAGCAGCACCCA 591 UGGGUGCUGCUGAUGAAAA 1045-1063 243 NUUUCAUCAGCAGCACCCA 592 UGGGUGCUGCUGAUGAAAN 1045-1063 244 NUUUCAUCAGCAGCACCCN 593 NGGGUGCUGCUGAUGAAAN 1045-1063 60 / 160 Petition 870260038067, dated 24 / 04 / 2026, p. 76 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1 1074-1092 246 UAAGAAGAUGGCGGUGGCA 595 UGCCACCGCCAUCUUUA 1074-1092 247 AAAGAAGAUGGCGGUGGCA 596 UGCCACCGCCAUCUUCUUUU 1074-1092 NA UGCCACCGCCAUCUUCUN 1074-1092 249 NAAGAAGAUGGCGGUGGCN 598 NGCCACCGCCAUCUUCUN 1074-1092 250 GGUGAGUUCAUUUUCCAGG 599 CCUGGAAAAUGAACUCACC279-1111 STORAGE 600 STORAGE 1119-1137 252 STORAGE 601 STORAGE 1119-1137 253 STORAGE2STORAGE 60 1119-1137 254 NGUGAGUAUUUUCCAGN 603 NCUGG AAAAU G AAC UC AC N 1119-1137 255 GAACUUGGUGAUGAUAUCG 604 CGAUAUCAUCCACAUGUUC 1140-156 U6158 UCCAG CAUAUCACACACAAGUUA 1140-1158 257 AAACUUGGUGAUGAUAUCG 606 CAUAUCACACCAAGUUUU 1140-1158 258 NAACUUGGUGAUGAAUCG 607 CGAUUCAUCAUC1802-15-1 WORKING 608NGAUAUCAUCACCAAGUUN 1140-1158 260 CAUUUUCCAGGAACUUGGU 609 ACCAAGUUCCCUGGAAAAU 1150-1168 261 UAUUUUCCAGGAACUUGGU 610 ACCAAGUUCCUGGAAAUA 1150-1168 262 AAUUUUCCAGGAACUUGGU 611 ACCAAGUUCCCUGGAAAAUU 1150-1168 263 NAUUUUCCAGGAACUUGGU 612 ACCAAGUUCCUGGAAAAUN 1150-1168 264 NAUUUUCCAGGAACUUGGN 613 NCCAAGUUCCUGGAAAAUN 1150-1168 265 CAUAGGUUCCAGUAAUGGA 614 UCCAUUACUGGAACCUAUG 1207-1225 266 UAUAGGUUCCAGUAAUGGA 615 UCCAUUACUGGAACCUAUA 1207-1225 267 AAUAGGUUCCAGUAUGGA 616 UCCAUUACUGGGAACCUAUU 1207-1225 268 NAUAGGUUCCAGUAAUGGA 617 UCCAUUACUGGAACCUAUN 1207-1225 269 NAUAGGUUCCAGUAAUGGN 618 NCCAUUACUGGAACCUAUN 1207-1225 270 UCAUAGGUUCCAGUAUAUGG 619 CCAUAUACUGGAACCUAUGA 1208-1226 271 ACAUAGGUUCCAGUAUAUGG 620 CCAUAUACUGGAACCUAUGU 1208-1226 272 NCAUAGGUUCCAGUAUAUGG 621 CCAUUACUGGAACCUAUGN 1208-1226 61 / 160 Petition 870260038067, dated 24 / 04 / 2026, p. 77 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1 273 NCAUAGGUUCCAGUAAUGN 622 NCAUUACUGGAACCUAUGN 1208-1226 274 UCAGAUCAUAGGUUCCAGU 623 ACUGGAACCUAUGAUCUGA 1213-1231 275 ACAGAUCAUAGGUUCCAGU 624 ACUGGAACCUAUGAUCUGU 1213-1231 276 NCAGAUCAUAGGUUCCAGU 625 ACUGGAACCUAUGAUCUGN 1213-1231 277 NCAGAUCAUAGGUUCCAGN 626 NCUGGAACCUAUGAUCUGN 1213-1231 278 UCUUCAGAUCAUAGGUUCC 627 GGAACCUAUGAUCUGAAGA 1216-1234 279 AC UU CAGAU CAUAGG UUCC 628 GGAACCUAUGAUCUGAAGU 1216-1234 280 NCUUCAGAUCAUAGGUUCC 629 GGAACCUAUGAUCUGAAGN 1216-1234 281 NCUUCAGAUCAUAGGUUCN 630 NG AAC CU AU G AU CUG AAG N 1216-1234 282 CUCUUCAGAUCAUAGGUUC 631 GAAC C UAU GAU CU GAAGAG 1217-1235 283 UUCUUCAGAUCAUAGGUUC 632 G AAC CU AU G AU CUG AAG AA 1217-1235 284 AUCUUCAGAUCAUAGGUUC 633 G AAC CU AU G AU CUG AAG AU 1217-1235 285 NUCUUCAGAUCAUAGGUUC 634 GAAC C UAU GAU CU GAAGAG 1217-1235 286 NUCUUCAGAUCAUAGGUUN 635NACCAUGAUCUGAAGAN 1217-1235 287 GAGGUCAGCCCCAUUGCUG 636 CAGCAAUGGGGCUGACCUC 1269-1287 288 UAGGUCAGCCCCAUUGCUG 637 CAGCAAUGGGGCUGACCUA 281 AAGGUCAGCCAUUGCUG 638 CAUTION 1269-1287 290 CAPACITY 639 CAPACITY 1269-1287 291 CAPACITY 630 CAUTION 1269-1287 1269-1287 292 GAGAGGUCAGCCCCAUUGC 641 GCAAUGGGGCUGACCUCUC 1271-1289 293 UAGAGGUCAGCCCCAUUGC 642 GCAAUGGGGCUGACCUCUA 1271-6G489 ACCAUGUCA 29 GCAAUGGGGCUGACCAU 1271-1289 295 NAGAGGUCAGCCCCAUUGC 644 GCAAUGGGGCUGACCAUUGN 1271-1289 296 NAGAGGUCAGCCAUUGN 645 NCAAUGGGGCUGACCAUUGN 2972871-11 LOADING 646 CHARGE 646 1299-1317 298 LOADING 647 LOADING 649-1317 1299-1317 300 ANSWER 649 GAGGAGGCCCCCUCH 1299-1317 62 / 160 Petition 870260038067, dated 4 / 24 / 2026, p. 78 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1 301 NUUCAGGGGUGCCUCCUCN GAGAGCUUCAGGGGUGCCU 651 AGGCACCCCUGAAGCUCUC 1304-1322 303 UAGAGCUUCAGGGGUGCCU 652 AGGCACCCCUGAAGCUCUA 1304-1322 304 AAGGCCUUCAGGGGUGCCU 305 NAGAGCUUCAGGGGUGCCU 654 AGGCACCCCUGAAGCUCUN 1304-1322 306 NAGAGCUUCAGGGGUGCCN 655 NGGCACCCCUGAAGCUCUN 1304-1322 307 UUAUGCACCGGCCUGGAGA 654AGCCAGCAGUAGCAGUAGCAGUGCUN 1319-1337 308 AUAUGCACGGCCUUGGAGA 657 UCUCCAAGGCCGUGCAUAU 1319-1337 309 NUAUGCACGGCCUUGGAGA 658 UCUCCAAGGCCGUGCAUAN 1319-1337 31ACGGGGGNGCU656 NCUCCAAGGCCGUGCAUAN 1319-1337 311 CCUUAUGCACGGCCUUGGA 660 UCCAAGGCCGUGCAUAAGG 1321-1339 312 UCUUAUGCACGGCCUUGGA 661 UCAAGGCCGUGCUAAGA 13131339 ACUUAUGCACGGCCUUGGA 662 UCCAAGGCCGUGCAUAAGU 1321-1339 314 NCUUAUGCACGGCCUUGGA 663 UCCAAGGCCGUGCAUAAGN 1321-1339 315 NCUUAUGCACGGCCUGGN 664NCCAAGGCCGUGCAUAAGN 1321-1339 316 GCCUUAUGCACGGCCUUGG 665 CCAAGGCCGUGCAUAAGGC 1322-1340 317 UCCUUAUGCACGGCCUUGG 666 CCAAGGCCGUGCAUAAGGA 1322-1340 318 ACCUUAUGCACGGCCUUGG 667 CCAAGGCCGUGCAUAAGGU 1322-1340 319 NCCUUAUGCACGGCCUUGG 668 CCAAGGCCGUGCAUAAGGN 1322-1340 320 NCCUUAUGCACGGCCUUGN 669 NCAAGGCCGUGCAUAAGGN 1322-1340 321 AGCCUUAUGCACGGCCUUG 670 CAAGGCCGUGCAUAAGGCU 1323-1341 322 UGCCUUAUGCACGGCCUUG 671 CAAGGCCGUGCAUAAGGCA 1323-1341 323 NGCCUUAUGCACGGCCUUG 672 CAAGGCCGUGCAUAAGGCN 1323-1341 324 NGCCUUAUGCACGGCCUUN 673 NAAGGCCGUGCAUAAGGCN 1323-1341 325 CGAUGGUCAGCACAGCCUU 674 AAGGCUGUGCUGACCAUCG 1336-1354 326 UGAUGGUCAGCACAGCCUU 675 AAGGCUGUGCUGACCAUCA 1336-1354 327 AGAUGGUCAGCACAGCCUU 676 AAGGCUGUGCUGACCAUCU 1336-1354 328 NGAUGGUCAGCACAGCCUU 677 AAGGCUGUGCUGACCAUCN 1336-1354 63 / 160 Petition 870260038067, dated 04 / 24 / 2026, page 79 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: GUCGAUGGUCAGCACAGCC 679 GGCUGUGCUGACCAUCGAC 1338-1356 331 UUCGAUGGUCAGCACAGCC 680 GGCUGUGCUGACCAUCCAUCGAA 1338-1356 332 AUCGAUGGUCAGCACAGCC 681 GGCUGUGCCAGCCAGCC 1338-1356 333 NUCGAUGGUCAGCACAGCC 682 GGCUGUGCUGACCAUCGAN 1338-1356 334 NUCGAUGGUCAGCACAGCN 683 NGCUGUGCUGACCAUCGAN 1338-1356 335 AAAACAGCAGCCAGGAN 684 CUGCUGGGGCCAUGUUUUU 1373-1391 336 UAAAACAUGGCCCCAGCAG 685 CUGCUGGGGCCAUGUUUUA 1373-1391 337 NAAAACAUGGCCCCAGCAG 686 CUGCUGGGGCAUGUU-13931391 NAAAACAUGGCCCCAGCAN 687 NUGCUGGGGCCAUGUUUUN 1373-1391 339 CUAAAAACAUGGCCCCAGC 688 GCUGGGGCCAUGUUUUUAG 1375-1393 340 UUAAAACAUGGCCCCAGUGGUGCAUGGUGGUGGUGUGUGUG 688 1375-1393 341 AUAAAAACAUGGCCCCAGC 690 GCUGGGGCCAUGUUUUUAU 1375-1393 342 NUAAAAACAUGGCCCCAGC 691 GCUGGGGCCAUGUUUUUAN 1375-1393 3393 AUAAACAUGGCCCAGGAG696NCUGGGGCCAUGUUUUUAN 1375-1393 344 UCUAAAAACAUGGCCCCAG 693 CUGGGGCCAUGUUUUUAGA 1376-1394 345 ACUAAAAACAUGGCCCCAG 694 CUGGGGCCAUGUUUUUAGU 1376-1394 346 NCUAAAAACAUGGCCCCAG 695 CUGGGGCCAUGUUUUUAGN 1376-1394 347 NCUAAAAACAUGGCCCCAN 696 NUGGGGCCAUGUUUUUAGN 1376-1394 348 CCUCUAAAAACAUGGCCCC 697 GGGGCCAUGUUUUUAGAGG 1378-1396 349 UCUCUAAAAACAUGGCCCC 698 GGGGCCAUGUUUUUAGAGA 1378-1396 350 ACUCUAAAAACAUGGCCCC 699 GGGGCCAUGUUUUUAGAGU 1378-1396 351 NCUCUAAAAACAUGGCCCC 700 GGGGCCAUGUUUUUAGAGN 1378-1396 352 NCUCUAAAAACAUGGCCCN 701 NGGGCCAUGUUUUUAGAGN 1378-1396 353 GCCUCUAAAAACAUGGCCC 702 GGGCCAUGUUUUUAGAGGC 1379-1397 354 UCCUCUAAAAACAUGGCCC 703 GGGCCAUGUUUUUAGAGGA 1379-1397 355 ACCUCUAAAAAACAUGGCCC 704 GGGCCAUGUUUUUAGAGGU 1379-1397 356 NCCUCUAAAAACAUGGCCC 705 GGGCCAUGUUUUUAGAGGN 1379-1397 64 / 160 Petition 870260038067, dated 04 / 24 / 2026, page 80 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1379-1397 358 UAGCAUGGUAUGGCCUC 707 GAGGCCAUACCCAUGUCUA 1393-1411 359 AAGACAUGGUAUGGCCUCUCUC 708 GAGGCAUACCCAUGUCUU 1393-1411 NAGAGAUGCCAUGUCUU 360 GAGGCAUACCCAUGUCUN 1393-1411 361 NAGCAUGGGUAUGCCUN 710 NAGGCCAUACCCAUGUCUN 1393-1411 362 GAUAGACAUGGGUAUGCC 711 GGCCAUACCCAUGUGUUGU3614139 UAUAGACAUGGGUAUGGCC 712 GGCCAUACCCAUGUCUAUA 1395-1413 364 AAUAGACAUGGGUAUGGCC 713 GGCCAUACCAUGUGUCUAUU 1395-1413 365 NAUAGACAUGGUAUGAUCCAUCCAUCCAUCCAU 71 1395-1413 366 NAUAGACAUGGGUAUGGCN 715 NGCCAUACCCAUGUCUAUN 1395-1413 367 UGUUCACUGACCUCGGG 716 CCCGAGGUCAGUCAGUCAUCACA 1417-1435 ACCGAUCGAUCAUCA 368 CCCGAGGREATING 1417-1435 369 CHARACTERISTICS CCUGGGG 718 CCCGGGGGGN 1417-1435 370 COGGGGGN 719 NCCGAGGU7141414CYCLE INTRODUCTION 720 AGUU CACAAC C 1421-1439 372 HOUSEHOLD 721 AUGUST A 1421-1439 373 HOUSEHOLD 722 AUGUST 37341 37-144 CHAPTER 723 AD 1421-1439 375 CHAPTER 724 AD 1421-1439 376 AD75 1425-1443 377 WATER 726 HOUSEHOLD 1425-1443 378 HOUSE HOUSEHOLD 727 HOUSEHOLD HOUSE 1425-1443 CHAPTER 1425-1443 380 CHAPTER 729 CHAPTER 1427-1445 381 CHAPTER 1427-1445 730 CHAPTER3-CHAPTER5-821 414 731 AGUUCAACAACCUUUGN 1427-1445 383 NCAAAGGGGUUUGUUGAACN 732 STUDENTS 1427-1445 384 G AC AAAGG AAC 733 464CC-14 65 / 160 Petition 870260038067, dated 4 / 24 / 2026, p. 81 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1428-1446 386 YEAR 735 REPLACEMENT 1428-1446 387 REPLACEMENT 736 RESEARCH 1428-1446 38 ANSWER 1428-1446 389 WATER 738 WATER 1430-1448 390 WATER 739 WATER 739 WATER 39141483 GOODBYE 740 HOME 1430-1448 392 GOODBYE 741 HOME 1430-1448 393 CAU HOUSEHOLD 744 1437-1455 394 UAUUAAGAGACAAAAGG GU 743 ACCUUCUUCUUAAUA 1437-1455 395 ACCUAAGACAAAAGGGU 744 ACCUUGUCUUCUUAUUAU 1437-17ACAU455 ACCUUGUCUUAAUN 1437-1455 397 NAUUAAGAGACAAAAGG GN 746 NCCUUGUCUUAAUN 1437-1455 398 AU CAU UAAGAGACAAAAG G 747 CCUUUGUCUU99454AAUGA UUCAUUAAGAGAAAAGG748 CCUUUGUCUUCUUAAUGAA 1439-1457 400 NUCAUUAAGAAGACAAAGG 749 CCUUUGUCUUCUUAAUGAN 1439-1457 401 NUCAUUAAGAAGACAAAGN 750 NCUUUGUCUUCUUAAUGAN 1439-1457 402 GAAGAGGGGAGACUUGGUA 751 UACCAAGUCCCUCUUC 1467-1485 403 UAAGAGGGGAGACUUGGUA 752 UACCAAGUCUCCCCUUA 1467-1485 404 AAAGAGGGAGACUUGGUA 753 UACCAAGUCUCCCCUUU 1467-1485 405 NAAGAGGGGAGACUUGGUA 754 UACCAAGUCUCCCCUUN 1467-1485 406 NAAGAGGGGAGACUUGGUN 755 NACCAAGUCUCCCCUUN 1467-1485 407 CCAUGAAGAGGGGAGACUU 756 AAGUCUCCCCUCUUCAUGG 1471-1489 408 UCAUGAAGAGGGGAGACUU 757 AAGUCUCCCCUCUUCAUGA 1471-1489 409 ACAUGAAGAGGGGAGACUU 758 AAGUCUCCCCUCUUCAUGU 1471-1489 410 NCAUGAAGAGGGGAGACUU 759 AAGUCUCCCCUCUUCAUGN 1471-1489 411 NCAUGAAGAGGGGAGACUN 760 NAGUCUCCCCCUUCAUGN 1471-1489 412 CCCAUGAAGAGGGGGAGACU 761 AGUCUCCCCUCUUCAUGGG 1472-1490 66 / 160 Petition 870260038067, dated 24 / 04 / 2026, p. 82 / 191 SEQ ID NO: Antisense base sequence (5' - 3') (19-mers) SEQ ID NO: Sense base sequence (5' - 3') (19-mers) Genome position of SEQ ID NO: 1 413 UCCAUGAAGAGGGGAGACU 762 AGUCUCCCCUCUUCAUGGA 1472-1490 414 ACCAUGAAGAGGGGAGACU 763 AGUCUCCCCUCUUCAUGGU 1472-1490 415 NCCAUGAAGAGGGGAGACU 764 AGUCUCCCCUCUUCAUGGN 1472-1490 416 NCCAUGAAGAGGGGAGACN 765 NGUCUCCCCUCUUCAUGGN 1472-1490 417 UUCCCAUGAAGAGGGGAGA 766 UCUCCCCUCUUCAUGGGAA 1474-1492 418 AUCCCAUGAAGAGGGGAGA 767 UCUCCCCUCUUCAUGGGAU 1474-1492 419 NUCCCAUGAAGAGGGGAGA 768 UCUCCCCUCUUCAUGGGAN 1474-1492 420 NUCCCAUGAAGAGGGGAGN 769 NCUCCCCUCUUCAUGGGAN 1474-1492 421 UUUCCCAUGAAGAGGGGAG 770 CUCCCCUCUUCAUGGGAAA 1475-1493 422 AUUCCCAUGAAGAGGGGAG 771 CUCCCCUCUUCAUGGGAAU 1475-1493 423 NUUCCCAUGAAGAGGGGAG 772 CUCCCCUCUUCAUGGGAAN 1475-1493 424 NUUCCCAUGAAGAGGGGAN 773 NUCCCCUCUUCAUGGGAAN 1475-1493 425 AACCCUUCUUUAAUGUCAU 774 AUGACAUUAAAGAAGGGUU 1569-1587 426 UACCCUUCUUUAAUGUCAU 775 AUGACAUUAAAGAAGGGUA 1569-1587 427 NACCCUUCUUUAAUGUCAU 776AUGACAUUAAAGAAGGGUN 1569-1587 428 NACCCUUCUUUAAUGUCAN 777 NUGACAUUAAAGAAGGGUN 1569-1587 67 / 160 Petition 870260038067, dated 04 / 24 / 2026, p. 83 / 191 Table 3. Antisense and sense strand base sequences of AAT RNAi exemplifying SEQ ID NO: Antisense base sequence (5' ^ 3') 778 779 780 781 782 783 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 791 792 799 800 801 GGAACUUGGUGAUGAUAU GAUCAUAGGUUCCAGUAA ACAGCCUUAUGCACGGCC UCGAUGGUCAGCACAGCC CAAAGGGUUUGUUGAACU TGGAACUUGGUGAUGAUAUTT TGGAACUUGGUGAUGAUAUTT TGGAACUUGGUGAUGAUAUCGUG ACUUGGUGAUGAUAUTT TGGAACTTGGTGATGATATTT UUUAAACAUGCCUAAACGCUU UGCAUUGCCCAGGUAUUUCUU UGGAACUUGGUGAUGAUAUUU UGAUCAUAGGUUCCAGUAAUU UACAGCCUUAUGCACGGCCUU UUCGAUGGUCAGCACAGCCUU UCAAAGGGUUUGUUGAACUUU UGUUAAACAUGCCUAAACGUU UUUAAACGUGCCUAAACGCUG UGCAUUGCCCAGGUAUUUCAG UGGAACUUGGUGAUGAUAUCG UGAUCAUAGGUUCCAGUAAUG UACAGCCUUAUGCACGGCCUU UUCGAUGGUCAGCACAGCCUU UCAAAGGGUUUGUUGAACUUG UGUUAAACAUGCCUAAACGCG UGUUAAACAUGCCUAAACGCU Petition 870260038067, dated 04 / 24 / 2026, page 84 / 191 SEQ ID NO: Sense base sequence (5' ^ 3') 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 847 860 861 862 863 864 857 AUAUCAUCACCAAGUUCC UUACUGGAACCUAUGAUC GGCCGUGCAUAAGGCUGU GGCUGUGCUGACCAUCGA AGUUCAACAAACCCUUUG UAUAUAUCAUCACCAAGUUCCAT AUAUCAUCACCAAGUUCCAT CGAUAUCAUCACCAAGUUCCA UAUCAUCACCAAGUUCCAT TATATATCATCACCAAGTTCCAT GCGUUUAGGCAUGUUUAAAUU GAAAUACCUGGGCAAUGCAUU AUAUCAUCACCAAGUUCCAUU UUACUGGAACCUAUGAUCAUU GGCCGUGCAUAAGGCUGUAUU GGCUGUGCUGACCAUCGAAUU AGUUCAACAAACCCUUUGAUU CGUUUAGGCAUGUUUAACAUU CAGCGUUUAGGCAUGUUUAAA CUGAAAUACCUGGGCAAUGCA CGAUAUCAUCACCAAGUUCCA CAUUACUGGAACCUAUGAUCA AAGGCCGUGCAUAAGGCUGUA AAGGCUGUGCUGACCAUCGAA CAAGUUCAACAAACCCUUUGA CGCGUUUAGGCAUGUUUAACA CGUUUAGGCAUGUUUAACAUU 68 / 160 SEQ ID NO: Antisense base sequence (5'^3') 794 801 794 801 802 803 804 804 803 805 806 807 808 808 809 810 811 812 812 813 814 815 816 816 817 818 818 UGCUGUUGGACUGGUGUGCUU UGCUGUUGGACUGGUGUGCCAUU UGCUGUUGGACUGGUGUGCCAGC UAAGGCUUCUGAGUGGUACUU UAAGGCUUCUGAGUGGUACAA UAAGGCUUCUGAGUGGUACAA UAAGGCUUCUGAGUGGUACAACU GAAGGCUUCUGAGUGGUACUU AAGACAAAGGGUUUGUUGAUU AAGACAAAGGGUUUGUUGAAC AAGACAAAGGGUUUGUUGAAC UAGACAAAGGGUUUGUUGAAC AAGACAAAGGGUUUGUUGAACUU UAGACAUGGGUAUGGCCUCUU UAGACAUGGGUAUGGCCUCUA UAGACAUGGGUAUGGCCUCUA UAGACAUGGGUAUGGCCUCUAAA UAGACAUGGGUAUGGCCUCUAUU UUUGAUCUGUUUCUUGGCCUU UUUGAUCUGUUUCUUGGCCUC UUUGAUCUGUUUCUUGGCCUC Petition 870260038067, dated 04 / 24 / 2026, page 85 / 191 SEQ ID NO: Sense base sequence (5' ^ 3') 1265 1265 865 866 866 1266 1266 867 868 867 867 1267 1267 869 869 1268 1269 1269 870 871 870 1270 1270 872 872 872 1271 1271 873 CGUUUAGGCAUGUUAACA CGUUUAGGCAUGUUAACA AACGUUUAGGCAUGUUAACA AGCGUUUAGGCAUGUUAACA AGCGUUUAGGCAUGUUAACA GCACACCAGUCCAACAGCA GCACACCAGUCCAACAGCA UGGCACACCAGUCCAACAGCA AAGCACACCAGUCCAACAGCA UGGCACACCAGUCCAACAGCA UGGCACACCAGUCCAACAGCA GUACCACUCAGAAGCCUUA GUACCACUCAGAAGCCUUA UUGUACCACUCAGAAGCCUUA UUGUACCACUCAGAAGCCUUA GUACCACUCAGAAGCCUUC UCAACAAACCCUUUGUCUU UCAACAAACCCUUUGUCUU GUUCAACAAACCCUUUGUCUU GUUCAACAAACCCUUUGUCUA GUUCAACAAACCCUUUGUCUU GAGGCCAUACCCAUGUCUA GAGGCCAUACCCAUGUCUA UAGAGGCCAUACCCAUGUCUA UAGAGGCCAUACCCAUGUCUA UAGAGGCCAUACCCAUGUCUA GGCCAAGAAACAGAUCAAA GGCCAAGAAACAGAUCAAA GAGGCCAAGAAACAGAUCAAA 69 / 160 SEQ ID NO: Antisense base sequence (5' ^ 3') 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 835 836 836 837 838 839 839 800 801 838 UUUGAUCUGUUUCUUGGCCUCUU UGUUGGACUGGUGUGCCAGUU UGUUGGACUGGUGUGCCAGCU UGUUGGACUGGUGUGCCAGCUGG UGUUGGACUGGUGUGCCAGCUG AAAGGGUUUGUUGAACUUGUU AAAGGGUUUGUUGAACUUGAC UAAGGGUUUGUUGAACUUGACCU UAAGGGUUUGUUGAACUUGAC UAUUGGUGCUGUUGGACUGUU UAUUGGUGCUGUUGGACUGGU UAUUGGUGCUGUUGGACUGGUU UUGUUGGACUGGUGUGCCAG UUGUUGGACUGGUGUGCCAGCU UAUAGACAUGGGUAUGGCCUC UAUAGACAUGGGUAUGGCCUC UCAAAGGGUUUGUUGAACUUGAC UCAAAGGGUUUGUUGAACUUGAC UUAUUGGUGCUGUUGGACUGG UGUUAAACAUGCCUAAACGC UGUUAAACAUGCCUAAACGCUU UGUUAAACAUGCCUAAACGCUU UGUUAAACAUGCCUAAACGCG UGUUAAACAUGCCUAAACGCU UGUUAAACAUGCCUAAACGC Petition 870260038067, dated 04 / 24 / 2026, page 86 / 191 SEQ ID NO: Sense base sequence (5' ^ 3') 873 1272 874 874 875 1273 876 877 877 1274 878 879 880 880 1275 881 882 863 883 884 884 885 886 887 885 GAGGCCAAGAAACAGAUCAAA CUGGCACACCAGUCCAACA AGCUGGCACACCAGUCCAACA AGCUGGCACACCAGUCCAACA GCUGGCACACCAGUCCAACA CAAGUUCAACAAACCCUUU GUCAAGUUCAACAAACCCUUU GUCAAGUUCAACAAACCCUUA GUCAAGUUCAACAAACCCUUA CAGUCCAACAGCACCAAUA ACCAGUCCAACAGCACCAAUA CCAGUCCAACAGCACCAAUA CUGGCACACCAGUCCAACAA CUGGCACACCAGUCCAACAA GGCCAUACCCAUGUCUAUA GAGGCCAUACCCAUGUCUAUA GUCAAGUUCAACAAACCCUUUGA CAAGUUCAACAAACCCUUUGA CCAGUCCAACAGCACCAAUAA GCGUUUAGGCAUGUUUAACA GCGUUUAGGCAUGUUUAACA GCGUUUAGGCAUGUUUAACAUU CGCGUUUAGGCAUGUUUAACAUU AGCGUUUAGGCAUGUUUAACAUU GCGUUUAGGCAUGUUUAACAUU 70 / 160 71 / 160

[0173] The sense and antisense strands of AAT RNAi agents comprising or consisting of nucleotide sequences in Table 2 or Table 3 may be modified or unmodified nucleotides. In some embodiments, AAT RNAi agents having sense and antisense strand sequences comprising or consisting of any of the nucleotide sequences in Table 2 or Table 3 are all or substantially all modified nucleotides.

[0174] In some embodiments, the antisense strand of an AAT RNAi agent disclosed herein differs by 0, 1, 2, or 3 nucleotides from any of the antisense strand sequences in Table 2 or Table 3. In some embodiments, the sense strand of an AAT RNAi agent disclosed herein differs by 0, 1, 2, or 3 nucleotides from any of the sense strand sequences in Table 2 or Table 3.

[0175] Depending on the use in question, each N listed in a sequence disclosed in Table 2 can be independently selected. In some embodiments, an N nucleotide listed in a sequence disclosed in Table 2 has a nucleobase that is complementary to the N nucleotide at the corresponding position on the other strand. In some embodiments, an N nucleotide listed in a sequence disclosed in Table 2 has a nucleobase that is not complementary to the N nucleotide at the corresponding position on the other strand. In some embodiments, an N nucleotide listed in a sequence disclosed in Table 2 has a nucleobase that is the same as the N nucleotide at the corresponding position on the other strand. In some embodiments, an N nucleotide listed in a sequence disclosed in Table 2 has a nucleobase that is different from the N nucleotide at the corresponding position on the other strand.

[0176] Certain modified AAT RNAi agent sense and antisense strands are provided in Table 4 and Table 5. The modified AAT RNAi agent antisense strands, as well as their underlying unmodified nucleobase sequences, are provided in Table 4. The modified AAT RNAi agent sense strands, as well as their unmodified sequences Petition 870260038067, dated 04 / 24 / 2026, page 87 / 191 72 / 160 underlying, are provided in Table 5. In the formation of AAT RNAi agents, each of the nucleotides in each of the unmodified sequences listed in Tables 4 and 5, as well as in Table 2 and Table 3 above, may be a modified nucleotide.

[0177] The AAT RNAi agents described in this document are formed by annealing an antisense strand to a sense strand. A sense strand containing a sequence listed in Table 2, Table 3, or Table 5 can be hybridized to any antisense strand containing a sequence listed in Table 2, Table 3, or Table 4, provided that the two sequences have a region of at least 85% complementarity by a contiguous sequence of 16, 17, 18, 19, 20, or 21 nucleotides.

[0178] In some embodiments, an AAT RNAi agent antisense strand comprises a nucleotide sequence from any of the sequences in Table 2, Table 3, or Table 4.

[0179] In some embodiments, an AAT RNAi agent comprises or consists of a duplex having the nucleobase sequence of the sense strand and the antisense strand of any of the sequences in Table 2 or Table 3.

[0180] Examples of modified nucleotides containing antisense strands are provided in Table 4. Examples of modified nucleotides containing sense strands are provided in Table 5.

[0181] As used in Tables 4 and 5, the following notations are used to indicate modified nucleotides, targeting groups, and linking groups. As an individual with common knowledge of the art would readily understand, except where otherwise indicated by the sequence, that when present in an oligonucleotide, the monomers are mutually linked by 5'-3' phosphodiester bonds: A = adenosine-3'-phosphate; C = cytidine-3'-phosphate; G = guanosine-3'-phosphate; Petition 870260038067, dated 04 / 24 / 2026, page 88 / 191 73 / 160 U = uridine-3'-phosphate n = any modified 2-OMe nucleotide a = 2'-O-methyladenosine-3'-phosphate as = 2'-O-methyladenosine-3'-phosphorothioate c = 2'-O-methylcytidine-3'-phosphate cs = 2'-O-methylcytidine-3'-phosphorothioate g = 2'-O-methylguanosine-3'-phosphate gs = 2'-O-methylguanosine-3'-phosphorothioate t = 2'-O-methyl-5-methyluridine-3'-phosphate ts = 2'-O-methyl-5-methyluridine-3'-phosphorothioate u = 2'-O-methyluridine-3'-phosphate us = 2'-O-methyluridine-3'-phosphorothioate Nf = any modified 2'-fluoronucleotide Af = 2'-fluoroadenosine-3'-phosphate Afs = 2'-fluoroadenosine-3'-phosporothioate Cf = 2'-fluorocytidine-3'-phosphate Cfs = 2'-fluorocytidine-3'-phosphorothioate Gf = 2'-fluoroguanosine-3'-phosphate Gfs = 2'-fluoroguanosine-3'-phosphorothioate Tf = 2'-fluoro-5'-methyluridine-3'-phosphate Tfs = 2'-fluoro-5'-methyluridine-3'-phosphorothioate Uf = 2'-fluorouridine-3'-phosphate Ufs = 2'-fluorouridine-3'-phosphorothioate dN = any 2-deoxymbonucleotide dT = 2'-deoxythymidine-3'-phosphate Nuna = 2',3'-Dried nucleotide imitations (unlocked nucleobase analogs)-3'-Phosphate Nunas = nucleotide imitations 2',3'-dry (unlocked nucleobase analogs)-3'-phosphorothioate Petition 870260038067, dated 04 / 24 / 2026, page 89 / 191 74 / 160 Uuna = 2',3'-seco-uridine-3'-phosphate Uunas = 2',3'-seco-uridine-3'-phosphorothioate a_2N = see Table 7 a_2Ns = see Table 7 pu_2N = see Table 7 pu_2Ns = see Table 7 Npu = see Table 7 Nus = see Table 7 Nlna = locked nucleotide Niana = nucleotide 2'-F-Arabino NM = 2'-methoxyethyl nucleotide AM = 2'-methoxyethyladenosine-3'-phosphate AMs = 2'-methoxyethyladenosine-3'-phosphorothioate TM = 2'-methoxyethylthymidine-3'-phosphate TMs = 2'-methoxyethylthymidine-3'-phosphorothioate R = ribitol (invdN) = any inverted deoxyribonucleotide (3'-3' linked nucleotide) (invAb) = inverted abasic deoxyribonucleotide (3'-3' linked), see Table 7 (invAb)s = inverted abasic deoxyribonucleotide-5'-phosphorothioate (3'-3' linked), see Table 7 (invn) = any inverted 2'-OMe nucleotide (3'-3' linked nucleotide) s = phosphorothioate linkage vpdN = vinyl phosphonate deoxyribonucleotide (5Me-Nf) = 2'-fluoronucleotide 5'-Me cPrp = cyclopropyl phosphonate, see Table 7 epTcPr = see Table 7 epTM = see Table 7 (Chol-TEG) ​​= see Table 7 Petition 870260038067, dated 04 / 24 / 2026, pp. 90 / 191 75 / 160 (TEG-Biotin) = see Table 7 (PEG-C3-SS) = see Table 7 (Alk-SS-C6) = see Table 7 (C6-SS-Alk) = see Table 7 (C6-SS-Alk-Me) = see Table 7

[0182] A person with ordinary skill in the art would readily understand that the terminal nucleotide at the 3' end of a given oligonucleotide sequence would typically have a hydroxyl group (-OH) at the respective 3' position of the given monomer rather than an ex vivo phosphate moiety. Except where expressly stated otherwise, such understandings of a person with ordinary skill in the art are used in describing the AAT RNAi agents and AAT RNAi agent compositions disclosed herein.

[0183] Directing groups and linking groups include the following, whose chemical structures are provided below in Table 7: (PAZ), (NAG13), (NAG13)s, (NAG18), (NAG18)s, (NAG24), (NAG24)s, (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), (NAG39)s. Each sense tape and / or antisense tape may have any of the above-listed direction groups or link groups, as well as other direction or link groups, attached to the 5' and / or 3' end of the sequence. Petition 870260038067, dated 04 / 24 / 2026, pp. 91 / 191 Table 4. Antisense strand sequences of AAT RNAi agent Antisense ID: tape SEQ NO. ID Antisense sequence (modified) (5' - 3') SEQ NO. ID Underlying base sequence (5' - 3') AM00516-AS 888 dTGfgAfaCfUunaUfgGfuGfaUfgAfuAfudTsdT 783 TGGAACUUGGUGAUGAUAUTT AM02129-AS 889 dTsGfsgAfaCfUunaUfgGfuGfaUfgAfuAfudTsdT 783 TGGAACUUGGUGAUGAUAUTT AM02130-AS 890 dTsGfsgAfaCfUunaUfgGfuGfallfgAfuAfuCfgsus g 784 TGGAACUUGGUGAUGAUAUCGUG AM04786-AS 891 aCfUunaUfgGfuGfaUfgAfuAfudTsdT 785 ACUUGGUGAUGAUAUTT AM05303-AS 892 dTdGdGdAdAdCdTdTdGdGdTdGdAdTdGdAdT dAdTdTsdT 786 TGGAACTTGGTGATGATAI II AM05643-AS 893 usUfsusAfaAfcAfllfGfcCfuAfaAfcGfcusu 787 UUUAAACAUGCCUAAACGCUU AM05645-AS 894 usGfscsAfu UfgCfCfCfaGfg Ufallfu llfcusu 788 UGCAUUGCCCAGGUAUUUCUU AM05647-AS 895 usGfsgsAfaCfuUfGfGfuGfallfgAfuAfuusu 789 UGGAACUUGGUGAUGAUAUUU AM05649-AS 896 usGfsaslIfcAfuAfGfGfuucCfaGfuAfausu 790 UGAUCAUAGGUUCCAGUAAUU AM05651-AS 897 usAfscsAfgCfcUfllfAfuGfcAfcGfgCfcusu 791 UACAGCCUUAUGCACGGCCUU AM05653-AS 898 us U fscs Gf a U fg Gf llf Cf aGf cAf cAf g Cf cu su 792UUCGAUGGUCAGCACAGCCUU AM05655-AS 899 usCfsasAfaGfgGfUfllfuGfuUfgAfaCfuusu 793 UCAAAGGGUUUGUUGAACUUU AM05657-AS 900 usGfsusUfaAfaCfAfllfgCfcUfaAfaCfgusu 794 UGUUAAACAUGCCUAAACGUU AM05659-AS 901 usUfuAfaAfcgugcCfuAfaAfcGfcslIfsg 795 UUUAAACGUGCCUAAACGCUG AM05661-AS 902 usGfscAfuUfgcccaGfgUfallfuUfcsAfsg 796 UGCAUUGCCCAGGUAUUUCAG AM05663-AS 903 usGfsgAfaCfuugguGfallfgAfuAfusCfsg 797 UGGAACUUGGUGAUGAUAUCG AM05665-AS 904 usGfsallfcAfuagguUfcCfaGfuAfasUfsg 798 UGAUCAUAGGUUCCAGUAAUG AM05667-AS 905 usAfscAfg Cfcuua uGfcAfcGfg Cfcs llfsu 791 UACAGCCUUAUGCACGGCCUU AM05669-AS 906 usUfscGfallfggucaGfcAfcAfgCfcsUfsu 792 UUCGAUGGUCAGCACAGCCUU AM05671-AS 907 usCfsaAfaGfgguuuGfuUfgAfaCfuslIfsg 799 UCAAAGGGUUUGUUGAACUUG AM05673-AS 908 usGfsuUfaAfacaugCfclIfaAfaCfgsCfsg 800 UGUUAAACAUGCCUAAACGCG AM05677-AS 909 usUfsuAfaAfcgugcCfuAfaAfcGfcslIfsg 795 UUUAAACGUGCCUAAACGCUG AM05884-AS 910 vpusGfsusUfaAfaCfAfllfgCfcUfaAfaCfgusu 794 UGUUAAACAUGCCUAAACGUU 76 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 92 / 191 Antisense ID: tape SEQ NO. ID Antisense sequence (modified) (5' - 3') SEQ NO. ID Underlying base sequence (5' > 3) AM05885-AS 911 cPrpusGfsusUfaAfaCfAfUfgCfclIfaAfaCfgusu 794 UGUUAAACAUGCCUAAACGUU AM05886-AS 912 usGfsusUfaAfaCfAfUfgCfclIfaAfaCfgcsu 801 UGUUAAACAUGCCUAAACGCU AM05887-AS 913 usGfsusUfaAfaCfaUfgCfclIfaAfaCfgusu 794 UGUUAAACAUGCCUAAAACGUU AM05888-AS 914 usGfsusUfaAfaCfaUfgCfclIfaAfaCfgcsu 801 UGUUAAACAUGCCUAAACGCU AM05889-AS 915 usGfsusUfaAfaCfAfUfgCfcUfaAfaCfgCfsu 801 UGUUAAACAUGCCUAAACGCU AM05890-AS 916 usGfsusUfaAfaCfAfUfgCfcUfaAfaCfgCfuusc 802 UGUUAAACAUGCCUAAACGCUUC AM05891-AS 917 usGfsusUfaAfaCfaUfgCfcUfaAfaCfgCfsu 801 UGUUAAACAUGCCUAAACGCU AM05892-AS 918 usGfsusUfaAfaCfaUfgCfclIfaAfaCfgCfuusc 802 UGUUAAACAUGCCUAAACGCUUC AM05900-AS 919 cPrpusGfsullfaAfacaugCfcUfaAfaCfgsCfsg 800 UGUUAAACAUGCCUAAACGCG AM05901-AS 920 usGfsgsAfaCfUunaUfGfGfuGfallfgAfuAfuusu 789 UGGAACUUGGUGAUGAUAUUU AM05954-AS 921 usGfscsUfgUfuggaclIfgGfuGfuGfcusu 803 UGCUGUUGGACUGGUGUGCUUAM05955-AS 922 usGfscsUfgUfuggaclIfgGfuGfuGfccsa 804 UGCUGUUGGACUGGUGUGCCA AM05956-AS 923 usGfscsUfgUfuggaclIfgGfuGfuGfccausu 805 UGCUGUUGGACUGGUGUGCCAUU AM05957-AS 924 usGfscsUfgUfuggaclIfgGfuGfuGfccagsc 806 UGCUGUUGGACUGGUGUGCCAGC AM05961-AS 925 usAfsasGfgCfuUfcUfgAfgllfgGfuAfcusu 807 UAAGGCUUCUGAGUGGUACUU AM05962-AS 926 usAfsasGfgCfuUfcUfgAfgllfgGfuAfcasa 808 UAAGGCUUCUGAGUGGUACAA AM05963-AS 927 usAfsasGfgCfuUfcUfgAfgllfgGfuAfcaacsu 809 UAAGGCUUCUGAGUGGUACAACU AM05964-AS 928 gsAfsasGfgCfuUfcUfgAfgllfgGfuAfcusu 810 GAAGGCUUCUGAGUGGUACUU AM05969-AS 929 asAfsgsAfcAfaAfgGfgUfuUfgllfuGfausu 811 AAGACAAAGGGUUUGUUGAUU AM05970-AS 930 asAfsgsAfcAfcAfgGfgUfuUfgllfuGfaasc 812 AAGACAAAGGGUUUGUUGAAC AM05973-AS 931 usAfsgsAfcAfcAfgGfgUfuUfgllfuGfaasc 813 UAGACAAAGGGUUUGUUGAAC AM05974-AS 932 asAfsgsAfcAfcAfgGfgUfuUfgllfuGfaacusu 814 AAGACAAAGGGUUUGUUGAACUU AM05976-AS 933 usAfsgsAfcAfcAfuGfgGfuAfuGfgCfclIfcusu 815 UAGACAUGGGUAUGGCCUCUU AM05977-AS 934 usAfsgsAfcAf u Gfg Gfu Af u Gfg Cfcllfcusa 816UAGACAUGGGUAUGGCCUCUA AM05979-AS 935 usAfsgsAfcAfuGfgGfuAfuGfgCfclIfcuaasa 817 UAGACAUGGGUAUGGCCUCUAAA AM05980-AS 936 usAfsgsAfcAfuGfgGfuAfuGfgCfcUfcuausu 818 UAGACAUGGGUAUGGCCUCUAUU 09L / ZZ Petition 870260038067, dated 04 / 24 / 2026, page 93 / 191 Antisense ID: tape SEQ NO. ID Antisense sequence (modified) (5' - 3') SEQ NO. ID Underlying base sequence (5' > 3) AM05982-AS 937 usUfsusGfaUfcUfgUfullfcUfuGfgCfcusu 819 UUUGAUCUGUUUCUUGGCCUU AM05983-AS 938 usUfsusGfaUfcUfgUfullfcUfuGfgCfcusc 820 UUUGAUCUGUUUCUUGGCCUC AM05985-AS 939 usUfsusGfaUfcUfgUfullfcUfuGfgCfcucusu 821 UUUGAUCUGUUUCUUGGCCUCUU AM05987-AS 940 usGfsusUfgGfacuggUfgllfgCfcAfgusu 822 UGUUGGACUGGUGUGCCAGUU AM05989-AS 941 usGfsusUfgGfacuggUfgllfgCfcAfgcsu 823 UGUUGGACUGGUGUGCCAGCU AM05990-AS 942 usGfsusUfgGfacuggUfgllfgCfcAfgcugsg 824 UGUUGGACUGGUGUGCCAGCUGG AM05992-AS 943 usGfsusUfgGfacuggUfgllfgCfcAfgcusg 825 UGUUGGACUGGUGUGCCAGCUG AM05994-AS 944 asAfsasGfgGfuUfuGfuUfgAfaCfullfgusu 826 AAAGGGUUUGUUGAACUUGUU AM05996-AS 945 asAfsasGfg Gfu Uf u Gf u Ufg Af aCfu Ufgasc 827 AAAGGGUUUGUUGAACUUGAC AM05998-AS 946 usAfsasGfgGfuUfuGfuUfgAfaCfullfgaccsu 828 UAAGGGUUUGUUGAACUUGACCU AM05999-AS 947 usAfsasGfg Gfu Uf u Gfu Ufg Af aCfu Ufgasc 829 UAAGGGUUUGUUGAACUUGACAM06124-AS 948 usAfsusUfgGfuGfcUfgUfuGfgAfcUfgusu 830 UAUUGGUGCUGUUGGACUGUU AM06125-AS 949 usAfsusUfgGfuGfcUfgUfuGfgAfcUfggsu 831 UAUUGGUGCUGUUGGACUGGU AM06126-AS 950 usAfsusUfgGfuGfcUfgUfuGfgAfcUfggusu 832 UAUUGGUGCUGUUGGACUGGUU AM06130-AS 951 usUfsgsUfuGfgacugGfuGfuGfcCfasg 833 UUGUUGGACUGGUGUGCCAG AM06131-AS 952 usUfsgsUfuGfgacugGfuGfuGfcCfagcsu 834 UUGUUGGACUGGUGUGCCAGCU AM06133-AS 953 usAfsusAfgAfcAfuGfgGfuAfuGfgCfcusc 835 UAUAGACAUGGGUAUGGCCUC AM06134-AS 954 usAfsusAfgAfcauggGfuAfuGfgCfcusc 835 UAUAGACAUGGGUAUGGCCUC AM06137-AS 955 usCfsasAfaGfgGfuUfuGfuUfgAfaCfuugasc 836 UCAAAGGGUUUGUUGAACUUGAC AM06140-AS 956 usUfsasUfuGfgugcuGfuUfgGfaCfugsg 837 UUAUUGGUGCUGUUGGACUGG AM06227-AS 957 usGfsusUfaAfaCfaUfgCfcUfaAfaCfgsc 838 UGUUAAACAUGCCUAAACGC AM06228-AS 958 usGfsusUfaAfaCfaUfgCfcUfaAfaCfgcusu 839 UGUUAAACAUGCCUAAACGCUU AM06234-AS 959 usGfsuUfaAfaCfaUfgCfcUfaAfaCfgsCfsg 800 UGUUAAACAUGCCUAAACGCG AM06235-AS 960 usGfsuUfaAfacaugCfcUfaAfaCfgCfsu 801 UGUUAAACAUGCCUAAACGCU AM06237-AS 961usGfsuUfaAfaCfAfUfgCfcUfaAfaCfgsCfsg 800 UGUUAAACAUGCCUAAACGCG AM06238-AS 962 NpusGfsusUfaAfaCfaUfgCfcUfaAfaCfgusu 794 UGUUAAACAUGCCUAAACGUU 78 / 160 Petition 870260038067, dated 04 / 24 / 2026, p. 94 / 191 Antisense ID: tape SEQ NO. ID Antisense sequence (modified) (5' - 3') SEQ NO. ID Underlying base sequence (5' > 3') AM06261-AS 963 NusGfsusUfaAfaCfallfgCfcUfaAfaCfgusu 794 UGUUAAACAUGCCUAAACGUU Table 5. Agent sense strand sequences and RNAi of AAT Tape ID SEQ sense: ID NO. Sequence sense (modified) (5' - 3') SEQ ID NO.Underlying base sequence (5' - 3') AM01887SS 964 (Chol-TEG)uAuAfuAfuCfaUfcAfcCfaAfgUfuCfcAf(invdT)(TEGBiotin) 845 UAUAUCAUCACCASSAM0965GUUCC88 (Chol-TEG)uAuAfuAfuCfaUfcAfcCfaAfgUfuCfcAf(invdT)(PEGC3-SS) 845 UAUAUCAUCACCAAGUUCCAT AM01855SS 966 (Alk-SS-C6)AfuAfuCfuCfaUfcAfcAfcAf 846 AUAUCAUCACCAAGUUCCA AM02132SS 967 CfsgsAfuAfuCfaUfcAfcCfaAfgUfuCfcAf(C6-SS-Alk) 847 CGAUCAUCACCAAGUUCCA AM02390SS 968 CfsgsAfuAfuCfaUfcAfcCfaAfgUfuCfcAf(C6-SS-Alk-Me) 847 CGAUCAUCACCAAGUUCCA AM04785SS 969 uAfuCfaUfcAfcCfaAfg UfuCfcAf( 84ACAT8UCAGUCA) AM05304SS 970 (Chol- TEG)dTdAdTdAdTdAdTdCdAdTdCdCdCdCdCdAdAdGdTdTdCdC sdA(invdT)(TEG-Biotin) 849 TATATATCATCACCA7-95AGTT599AT TEG)dTdAdTdAdTdAdTdCdAdTdCdCdCdCdCdCdAdAdGdTdTdCdC sdA(invdT) 849 TATATATCATCACCAAGTTCCAT AM05642SS 972 (NAG25)(invAb)GfcGfuUfuAfGfGfcAfuGfullfuAfausu(invAb) 850 GCGUUUAGGCAUGUUUAAAUU AM05644- 973 (NAG25)(invAb)GfaAfallfaCfuCfgCfCfUfg 851 GAAAUACCUGGGCAAUGCAUU. 79 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 95 / 191 ID de fita SEQ Sequência senso (modificada) SEQ Sequência de base subjacente senso: ID NO. (5' - 3') ID NO. (5' - 3') SS AM05646SS 974 (NAG25)(invAb)AfuAfuCfaUfCfAfcCfaAfgUfuCfcausu(invAb) 852 AUAUCAUCACCAAGUUCCAUU AM05648SS 975 (NAG25)(invAb)UfuAfuCfaUfCfAfcCfaAfgUfuCfcausu(invAb) 853 UUACUGGAAACCUAUGAUCAUU AM05650SS 976 (NAG25)(invAb)GfgCfcGfuGfCfAfuAfaGfgCfuGfuausu(invAb) 854 GGCCGUGCAUAAGGCUGUAUU AM05652SS 977 (NAG25)(invAb)GfgCfuGfuGfCfUfgAfcCfaUfcGfaausu(invAb) 855 GGCUGUGCUGACCAUCGAAUU AM05654SS 978 (NAG25)(invAb)AfgUfuCfaAfCfAfaAfcCfcUfuUfgausu(invAb) 856 AGUUCAACAAACCCUUUGAUU AM05656SS 979 (NAG25)(invAb)AfgUfuCfaAfCfAfaAfcCfcUfuUfgausu(invAb) 857 CGUUUAGGCAUGUUUAACAUU AM05658SS 980 (NAG25)scsagcguuuAfGfGfcauguuuuaasa(invAb) 858 CAGCGUUUAGGCAUGUUUAAA AM05660SS 981 (NAG25)scsugaaauaCfCfllfgggcaaugcsa(invAb) 859 CUGAAAUACCUGGGGCAAUGCA AM05662SS 982 (NAG25)scsgauaucallfCfAfccaaguuccsa(invAb) 847 CGAAUAUCAUCACCAAGUUCCA AM05664SS 983 (NAG25)scsauuacugGfAfAfccuaugaucsa(invAb) 860CAUUACUG GAAC C UAUGAUCA AM05666SS 984 (NAG25)sasaggccguGfCfAfuaaggcugusa(invAb) 861 AAGGCCGUGCAUAAGGCUGUA AM05668SS 985 (NAG25)sasaggcuguGfCfllfgaccaucgasa(invAb) 862 AAGGCUGUGCUGACCAUCGAA AM05670SS 986 (NAG25)scsaaguucaAfCfAfaacccuuugsa(invAb) 863 CAAGUUCAACAAACCCUUUGA 80 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 96 / 191 ID of the strand SEQ Sequência senso (modified) SEQ Sequência de base subjacente senso: ID NO. (5' - 3') ID NO. (5' - 3') AM05672SS 987 (NAG25)scsgcguuuaGfGfCfauguuuaacsa(invAb) 864 CGCGUUUAGGCAUGUUUAACA AM05658SS 988 (NAG25)scsagcguuuAfGfGfcauguuuuaasa(invAb) 858 CAGCGUUUAGGCAUGUUUAAA AM05893SS 989 (NAG25)s(invAb)scguuuaGfGfCfauguuuuaacausu(invAb) 857 CGUUUAGGCAUGUUUAACAUU AM05894SS 990 (NAG25)s(invAb)sCfgUfuUfaGfGfCfaUfgUfuUfaAfcas(invAb) 429 CGUUUAGGCAUGUUUAACA AM05895SS 991 (NAG25)s(invAb)scguuuaGfGfCfauguuuuaacas(invAb) 429 CGUUUAGGCAUGUUUAACA AM05896SS 992 (NAG25)s(invAb)saaCfgUfuUfaGfGfCfaUfgUfuUfaAfcas(invAb) 865 AACGUUUAGGCAUGUUUAACA AM05897SS 993 (NAG25)s(invAb)sagCfgUfuUfaGfGfCfaUfgUfuUfaAfcas(invAb) 866 AGCGUUUAGGCAUGUUUAACA AM05898SS 994 (NAG25)s(invAb)saacguuuaGfGfCfauguuuaacas(invAb) 865 AACGUUUAGGCAUGUUUAACA AM05899SS 995 (NAG25)s(invAb)sagcguuuaGfGfCfauguuuuaacas(invAb) 866 AGCGUUUAGGCAUGUUUAACA AM05958SS 996 (NAG37)s(invAb)sgcacacCfAfGfuccaacagcas(invAb) 454GCACACCAGUCCAACAGCA AM05959SS 997 (NAG37)s(invAb)suggcacacCfAfGfuccaacagcas(invAb) 867 UGGCACACCAGUCCAACAGCA AM05960SS 998 (NAG37)s(invAb)saagcacacCfAfGfuccaacagcas(invAb) 868 AAGCACACCAGUCCAACAGCA AM05965SS 999 (NAG37)s(invAb)sguaccaCfllfCfagaagccuuas(invAb) 519 GUACCACUCAGAAGCCUUA AM05966SS 1000 (NAG37)s(invAb)suuguaccaCfllfCfagaagccuuas(invAb) 869 UUGUACCACUCAGAAGCCUUA 81 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 97 / 191 Tape ID SEQ Sense sequence (modified) SEQ Underlying base sense sequence: ID NO. (5' - 3') ID NO. (5' - 3') AM05967SS 1001 (NAG37)s(invAb)sguaccaCfllfCfagaagccuucs(invAb) 518 GUACCACUCAGAAGCCUUC AM05968SS 1002 (NAG37)s(invAb)sucaacaAfAfCfccuuugucuus(invAb) 738 UCAACAAACCCUUUGUCUU AM05971SS 1003 (NAG37)s(invAb)sguucaacaAfAfCfccuuugucuus(invAb) 870 GUUCAACAAACCCUUUGUCUU AM05972SS 1004 (NAG37)s(invAb)sguucaacaAfAfCfccuuugucuas(invAb) 871 GUUCAACAAACCCUUUGUCUA AM05975SS 1005 (NAG37)s(invAb)sgaggccAfllfAfcccaugucuas(invAb) 707 GAGGCCAUACCCAUGUCUA AM05978SS 1006 (NAG37)s(invAb)suagaggccAfllfAfcccaugucuas(invAb) 872 UAGAGGCCAUACCCAUGUCUA AM05981SS 1007 (NAG37)s(invAb)sggccaaGfAfAfacagaucaaas(invAb) 537 GGCCAAGAAACAGAUCAAA AM05984SS 1008 (NAG37)s(invAb)sgaggccaaGfAfAfacagaucaaas(invAb) 873 GAGGCCAAGAAACAGAUCAAA AM05986SS 1009 (NAG37)s(invAb)scuggcaCfAfCfcaguccaacas(invAb) 445 CUGGCACACCAGUCCAACA AM05988SS 1010 (NAG37)s(invAb)sagcuggcaCfAfCfcaguccaacas(invAb) 874 AGCUGGCACACCAGUCCAACAAM05991SS 1011 (NAG37)s(invAb)sgcuggcaCfAfCfcaguccaacas(invAb) 875 GCUGGCACACCAGUCCAACA AM05993SS 1012 (NAG37)s(invAb)scaaguuCfAfAfcaaacccuuus(invAb) 725 CAAGUUCAACAAACCCUUU AM05995SS 1013 (NAG37)s(invAb)sgucaaguuCfAfAfcaaacccuuus(invAb) 876 GUCAAGUUCAACAAACCCUUU AM05997SS 1014 (NAG37)s(invAb)sgucaaguuCfAfAfcaaacccuuas(invAb) 877 GUCAAGUUCAACAAACCCUUA 82 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 98 / 191 ID of the strand SEQ Sequência senso (modified) SEQ Sequência de base subjacente senso: ID NO. (5' - 3') ID NO. (5' - 3') AM06127SS 1015 (NAG37)s(invAb)scaguccAfAfCfagcaccaauas(invAb) 458 CAGUCCAACAGCACCAAUA AM06128SS 1016 (NAG37)s(invAb)saccaguccAfAfCfagcaccaauas(invAb) 878 ACCAGUCCAACAGCACCAAUA AM06129SS 1017 (NAG37)s(invAb)sccaguccAfAfCfagcaccaauas(invAb) 879 CCAGUCCAACAGCACCAAUA AM06132SS 1018 (NAG37)s(invAb)scuggcacAfCfCfaguccaacaas(invAb) 880 CUGGCACACCAGUCCAACAA AM06135SS 1019 712 (NAG37)s(invAb)sgucaaguucaAfCfAfaacccuuugas(invAb) 882 GUCAAGUUCAACAAACCCUUUGA AM06139SS 1022 (NAG37)s(invAb)scaaguucaAfCfAfaacccuuugas(invAb) 863 CAAGUUCAACAAACCCUUUGA AM06141SS 1023 (NAG37)s(invAb)sccaguccaAfCfAfgcaccaauaas(invAb) 883 CCAGUCCAACAGCACCAAUAA AM06195SS 1024 (NAG37)s(invAb)scgcguuuaGfGfCfauguuuaacas(invAb) 864CGCGUUUAGGCAUGUUUAACA AM06223SS 1025 (NAG37)s(invAb)scguuuaGfGfCfauguuuaacas(invAb) 429 CGUUUAGGCAUGUUUAACA AM06224SS 1026 (NAG37)s(invAb)scsgcguuuaGfGfCfauguuuaacsa(invAb) 864 CGCGUUUAGGCAUGUUUAACA AM06225SS 1027 (NAG37)s(invAb)sagCfgUfuUfaGfGfCfaUfgUfuUfaAfcas(invAb) 866 AGCGUUUAGGCAUGUUUAACA AM06226SS 1028 (NAG37)s(invAb)scguuuaGfGfCfauguuuuaacausu(invAb) 857 CGUUUAGGCAUGUUUAACAUU 83 / 160 Petition 870260038067, dated 24 / 04 / 2026, p. 99 / 191 Tape ID SEQ sense: ID NO. Sense sequence (modified) (5' - 3') SEQ ID NO. Underlying base sequence (5' - 3') AM06229SS 1029 (NAG37)s(invAb)sgcguuuaGfGfCfauguuuaacas(invAb) 884 GCGUUUAGGCAUGUUUAACA AM06230SS 1030 (NAG37)s(invAb)sgcguuuaGfGfCfauguuuaacausu(invAb) 885 GCGUUUAGGCAUGUUUAACAUU AM06231SS 1031 (NAG37)s(invAb)scgcguuuaGfGfCfauguuua(86Ab) CGCGUUUAGGCAUGUUUAACAUU AM06232SS 1032 (NAG37)s(invAb)sagCfgUfuUfaGfGfCfaUfgUfuUfaAfcausu(invA b) 887 AGCGUUUAGGCAUGUUUAACAUU SS1062336 (NAG37)s(invAb)sagcguuuaGfGfCfauguuuaacas(invAb) 866 AGCGUUUAGGCAUGUUUAACA AM06239SS 1034 (NAG37)s(invAb)scgcguuuaGfGfCfauguuuaacsas(864Absas) CGCGUUUAGGCAUGUUUAACA 84 / 160 Petition 870260038067, of 24 / 04 / 2026, p. 100 / 191 85 / 160

[0184] The AAT RNAi agents described in this document are formed by annealing an antisense strand to a sense strand. A sense strand containing a sequence listed in Table 2, Table 3, or Table 5 can be hybridized to any antisense strand containing a sequence listed in Table 2, Table 3, or Table 4, provided that the two sequences have a region of at least 85% complementarity by a contiguous sequence of 16, 17, 18, 19, 20, or 21 nucleotides.

[0185] In some embodiments, the antisense strand of an AAT RNAi agent disclosed in this document differs by 0, 1, 2, or 3 nucleotides from any of the antisense strand sequences in Table 4. In some embodiments, the sense strand of an AAT RNAi agent disclosed in this document differs by 0, 1, 2, or 3 nucleotides from any of the sense strand sequences in Table 5.

[0186] In some embodiments, an AAT RNAi agent antisense strand comprises a nucleotide sequence from any of the sequences in Table 2, Table 3, or Table 4. In some embodiments, an AAT RNAi agent antisense strand comprises the nucleotide sequences (from the 5' end to the 3' end) 1-17, 2-17, 1-18, 2-18, 1-19, 2-19, 1-20, 2-20, 1-21, 2-21, 1-22, 2-22, 1-23, 2-23, 1-24, or 2-24 from any of the sequences in Table 2, Table 3, or Table 4. In certain embodiments, an AAT RNAi agent antisense strand comprises or consists of a modified sequence from any of the modified sequences in Table 4. 4.

[0187] In some embodiments, an AAT RNAi agent sense strand comprises the nucleotide sequence of any of the sequences in Table 2, Table 3, or Table 5. In some embodiments, an AAT RNAi agent sense strand comprises the nucleotide sequences (from the 5' end to the 3' end) 1-17, 2-17, 3-17, 4-17, 1-18, 2-18, 3-18, 4-18, 1-19, 2-19, 3-19, 4-19, Petition 870260038067, dated 04 / 24 / 2026, pp. 101 / 191 86 / 160 1-20, 2-20, 3-20, 4-20, 1-21, 2-21, 3-21, 4-21, 1-22, 2-22, 3-22, 4-22, 1-23, 2-23, 3-23, 4-23, 1-24, 2-24, 3-24, or 4-24 of any of the sequences in Table 2, Table 3, or Table 5. In certain embodiments, an AAT RNAi agent sense strand comprises or consists of a modified sequence of any of the modified sequences in Table 5.

[0188] For the AAT RNAi agents disclosed in this document, the nucleotide at position 1 of the antisense strand (from the 5' end to the 3' end) may be perfectly complementary to an AAT gene, or it may be non-complementary to an AAT gene. In some embodiments, the nucleotide at position 1 of the antisense strand (from the 5' end to the 3' end) is a U, A, or dT (or a modified version of U, A, or dT). In some embodiments, the nucleotide at position 1 of the antisense strand (from the 5' end to the 3' end) forms an A:ll or U:A base pair with the sense strand.

[0189] In some embodiments, an AAT RNAi agent antisense strand comprises nucleotide sequences (from the 5' end to the 3' end) 2-18 or 2-19 of any of the antisense strand sequences in Table 2, Table 3, or Table 4. In some embodiments, an AAT RNAi sense strand comprises nucleotide sequences (from the 5' end to the 3' end) 1-17 or 1-18 of any of the sense strand sequences in Table 2, Table 3, or Table 5.

[0190] In some embodiments, an AAT RNAi agent includes (i) an antisense strand comprising nucleotide sequences (from the 5' end to the 3' end) 2-18 or 2-19 of any of the antisense strand sequences in Table 2, Table 3, or Table 4, and (ii) a sense strand comprising nucleotide sequences (from the 5' end to the 3' end) 1-17 or 1-18 of any of the sense strand sequences in Table 2, Table 3, or Table 5. Petition 870260038067, dated 04 / 24 / 2026, pp. 102 / 191 87 / 160

[0191] A sense strand containing a sequence listed in Table 2, Table 3, or Table 5 may be hybridized to any antisense strand containing a sequence listed in Table 2, Table 3, or Table 5, provided that the two sequences have a region of at least 85% complementarity by a sequence of 16, 17, 18, 19, 20, or 21 nucleotides. In some embodiments, the AAT RNAi agent has a sense strand consisting of a modified sequence of any of the modified sequences in Table 5, and an antisense strand consisting of a modified sequence of any of the modified sequences in Table 4. Representative sequence pairings are exemplified by the Duplex ID nodes shown in Table 6.

[0192] In some embodiments, an AAT RNAi agent comprises any of the duplexes represented by any of the Duplex ID nodes presented in this document. In some embodiments, an AAT RNAi agent consists of any of the duplexes represented by any of the Duplex ID nodes presented in this document. In some embodiments, an AAT RNAi agent comprises the sense and antisense strand nucleotide sequences of any of the duplexes represented by any of the Duplex ID nodes presented in this document.In some embodiments, an AAT RNAi agent includes the sense-strand and antisense-strand nucleotide sequences of any of the duplexes represented by any of the Duplex ID nodes presented herein and a targeting group and / or linking group, wherein the targeting group and / or linking group is covalently linked (i.e., conjugated) to the sense strand or the antisense strand. In some embodiments, an AAT RNAi agent includes the modified sense-strand and antisense-strand nucleotide sequences of any of the duplexes represented by any of the Duplex ID nodes presented herein. In some embodiments, an AAT RNAi agent comprises... Petition 870260038067, dated 04 / 24 / 2026, pp. 103 / 191 88 / 160 modified nucleotide sequences of sense and antisense strands from any of the duplexes represented by any of the Duplex ID nodes presented in this document and a targeting group and / or linking group, wherein the targeting group and / or linking group is covalently linked to the sense strand or the antisense strand.

[0193] In some embodiments, an AAT RNAi agent comprises an antisense strand and a sense strand having nucleotide sequences of any of the antisense strand / sense strand duplexes in Table 2, Table 3, or Table 6, and comprises an asialoglycoprotein receptor ligand targeting group.

[0194] In some embodiments, an AAT RNAi agent comprises an antisense strand and a sense strand having the nucleotide sequences of any of the antisense / sense strand duplexes in Table 2 or Table 5, and further comprises a targeting group selected from the group consisting of (PAZ), (NAG13), (NAG13)s, (NAG18), (NAG18)s, (NAG24), (NAG24)s, (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), (NAG39)s. In some modes, the targeting group is (NAG25) or (NAG25)s as defined in Table 7. In other modes, the targeting group is (NAG37) or (NAG37)s as defined in Table 7.

[0195] In some embodiments, an AAT RNAi agent comprises an antisense strand and a sense strand having the modified nucleotide sequence of any of the antisense strand and / or sense strand nucleotide sequences of any of the duplexes in Table 6.

[0196] In some embodiments, an AAT RNAi agent comprises Petition 870260038067, dated 04 / 24 / 2026, pp. 104 / 191 89 / 160 an antisense strand and a sense strand having a modified nucleotide sequence from either of the antisense strand and / or sense strand nucleotide sequences of either of the duplexes in Table 6, and comprises an asialoglycoprotein receptor ligand targeting group.

[0197] In some embodiments, an AAT RNAi agent comprises the duplex structure of any of the duplexes in Table 6.

[0198] In some embodiments, an AAT RNAi agent consists of a duplex structure of any of the duplexes in Table 6. Table 6. AAT RNAi agents identified by Duplex ID number with corresponding sense and antisense strands. Petition 870260038067, dated 04 / 24 / 2026, pp. 105 / 191 90 / 160 Ribbon ID Ribbon ID Duplex Antisense Sense AD01131 AM00516AS AM01887SS AD01132 AM00516AS AM01888SS AD01174 AM00516AS AM01855SS AD01286 AM028555SS AD01286 AM02130AS AM02132SS AD01442 AM02130AS AM02390SS AD03752 AM04786- AS AM04785SS AD04156 AM05303AS AM05304SS AD04406 AM05303AS AM05304SS AD04406 AM05303ASSS595454 AM05643AS AM05642SS AD04445 AM05645AS AM05644SS AD04446 AM05647AS AM05646SS AD04447 AM05649AS AM05648SS AD04448 AM05651ASSS AD04448 AM05653AS AM05652SS AD04450 AM05655AS AM05654SS AD04451 AM05657- AS AM05656SS AD04452 AM05659AS AM05658SS AD04453 AM05652ASSS AD04453 AM05663AS AM05662SS AD04455 AM05665AS AM05664SS AD04456 AM05667- AS AM05666SS AD04457 AM05669AS AM05668SS AD04458 AM05670-AM05670-5671 Tape ID Duplex Tape ID Antisense Sense AS SS AD04459 AM05673- AS AM05672SS AD04464 AM05677- AS AM05658SS AD04601 AM05884AS AM05656SS AD04602 AM05885AS AM05656SS AD04603 AM05886AS AM05656SS AD04604 AM05887AS AM05893SS AD04605 AM05888AS AM05893SS AD04606 AM05657- AS AM05894SS AD04607 AM05886AS AM05894SS AD04608 AM05887AS AM05895SS AD04609 AM05888AS AM05895SS AD04610 AM05657- AS AM05896SS AD04611 AM05889AS AM05897SS AD04612 AM05890AS AM05897SS AD04613 AM05887AS AM05898SS AD04614 AM05891AS AM05899SS AD04615 AM05892AS AM05899SS AD04616 AM05900AS AM05672SS AD04617 AM05901AS AM05646SS AD04652 AM05954AS AM05958SS AD04653 AM05955AS AM05958SS AD04654 AM05955AS AM05959SS AD04655 AM05954AS AM05960SS Petition 870260038067, dated 04 / 24 / 2026, pp. 106 / 191 91 / 160 Tape ID Duplex Tape ID Antisense Sense AD04656 AM05956AS AM05959SS AD04657 AM05957- AS AM05959SS AD04658 AM05961AS AM05965SS AD04659 AM05962AS AM05965SS AD04660 AM05962AS AM05966SS AD04661 AM05963AS AM05966SS AD04662 AM05964AS AM05967SS AD04663 AM05969AS AM05968SS AD04664 AM05970AS AM05968SS AD04665 AM05970AS AM05971SS AD04666 AM05973- AS AM05972SS AD04667 AM05974AS AM05971SS AD04668 AM05976- AS AM05975SS AD04669 AM05977- AS AM05975SS AD04670 AM05977- AS AM05978SS AD04671 AM05979- AS AM05978SS AD04672 AM05980AS AM05978SS AD04673 AM05982AS AM05981SS AD04674 AM05983AS AM05981SS AD04675 AM05983AS AM05984SS AD04676 AM05985AS AM05984SS AD04677 AM05987AS AM05986SS AD04678 AM05989AS AM05988SS AD04679 AM05990- AM05988- Tape ID Duplex Tape ID Antisense Sense AS SS AD04680 AM05992AS AM05991SS AD04681 AM05994AS AM05993SS AD04682 AM05996AS AM05995SS AD04683 AM05998AS AM05997SS AD04684 AM05999AS AM05997SS AD04761 AM06124AS ​​AM06127SS AD04762 AM06125AS AM06128SS AD04763 AM06126AS AM06129SS AD04764 AM06130AS AM06132SS AD04765 AM 06131- AS AM06132SS AD04766 AM06133AS AM06135SS AD04767 AM06134AS AM06136SS AD04768 AM06137- AS AM06138SS AD04769 AM06137- AS AM06139SS AD04770 AM06140AS AM06141SS AD04805 AM05673- AS AM06195SS AD04824 AM05887AS AM06223SS AD04825 AM05900AS AM06224SS AD04826 AM05889AS AM06225SS AD04827 AM05888AS AM06223SS AD04828 AM05887AS AM06226SS AD04829 AM06227- AS AM06229SS AD04830 AM06228AS AM06229SS Petition 870260038067, dated 04 / 24 / 2026, pp. 107 / 191 92 / 160 Tape ID Tape ID Sense Antisense Duplex Tape ID AD04831 AM06228- AS AM06230SS AD04832 AM05673- AS AM06231SS AD04833 AM05889AS AM06232SS AD04834 AM06227- AS AM06230SS AD04836 AM06234- AS AM06195SS AD04837 AM06235- AS AM06236SS AD04838 AM06237- AS AM06239SS AD04839 AM05673- AS AM06239SS AD04840 AM06238- AS AM06223SS AD04857 AM06261- AS AM06223SS Petition 870260038067, dated 04 / 24 / 2026, pp. 108 / 191 93 / 160

[0199] In some embodiments, an AAT RNAi agent is prepared or delivered as a salt, mixed salt, or free acid. The RNAi agents described in this document, upon delivery to a cell expressing an AAT gene, inhibit or knock out the expression of one or more AAT genes in vivo. Steering groups, linking groups and delivery vehicles

[0200] In some embodiments, an AAT RNAi agent is conjugated to one or more non-nucleotide groups including, without limitation, a targeting group, linking group, delivery polymer, or a delivery vehicle. The non-nucleotide group may enhance the targeting, delivery, or binding of the RNAi agent. Examples of targeting groups and linking groups are provided in Table 7. The non-nucleotide group may be covalently linked to the 3' and / or 5' end of the sense strand and / or antisense strand. In some embodiments, an AAT RNAi agent contains a non-nucleotide group linked to the 3' and / or 5' end of the sense strand. In some embodiments, a non-nucleotide group is linked to the 5' end of an AAT RNAi agent sense strand. A non-nucleotide group may be directly or indirectly linked to the RNAi agent via a linker / linking group.In some embodiments, a non-nucleotide group is attached to the RNAi agent via a labile, cleavable, or reversible linker or ligand.

[0201] In some embodiments, a non-nucleotide group enhances the pharmacokinetic or biodistribution properties of an RNAi agent or conjugate to which it is attached in order to enhance cell-specific or tissue-specific distribution and cell-specific uptake of the RNAi agent or conjugate. In some embodiments, a non-nucleotide group enhances the endocytosis of the RNAi agent.

[0202] Targeting groups or targeting moieties can enhance the pharmacokinetic or biodistribution properties of an RNAi conjugate or agent to which they are attached to improve cell distribution. Petition 870260038067, dated 04 / 24 / 2026, pp. 109 / 191 94 / 160 specific and cell-specific uptake of the conjugate or RNAi agent. A targeting group may be monovalent, divalent, trivalent, tetravalent, or have a higher valence for the target to which it is directed. Representative targeting groups include, without limitation, compounds with affinity for cell surface molecules, cell receptor ligands, haptens, antibodies, monoclonal antibodies, antibody fragments, and antibody mimics with affinity for cell surface molecules. In some embodiments, a targeting group is linked to an RNAi agent using a linker, such as a PEG linker or one, two, or three abasic residues and / or ribitol (basic ribose), which, in some cases, may serve as linkers. In some embodiments, a targeting group comprises a galactose derivative group.

[0203] The AAT RNAi agents described in this document can be synthesized by having a reactive group, such as an amine group, at the 5' end. The reactive group can be used to subsequently link a targeting group using methods typical in the art.

[0204] In some embodiments, a targeting group comprises an asialoglycoprotein receptor ligand. In some embodiments, an asialoglycoprotein receptor ligand includes or consists of one or more galactose derivatives. As used herein, the term galactose derivative includes galactose and galactose derivatives with an affinity for the asialoglycoprotein receptor that is equal to or greater than that of galactose. Galactose derivatives include, but are not limited to: galactose, galactosamine, N-formylgalactosamine, N-acetylgalactosamine, N-propionyl-galactosamine, Nn-butanoyl-galactosamine, and N-isobutanoylgalactosamine (see, for example: ST lobst and K. Drickamer, JBC, 1996, 271, 6686). Galactose derivatives, and groups of galactose derivatives, that are useful for in vivo targeting of oligonucleotides and other molecules to the liver are known in the art (see, for example, Baenziger and Fiete, 1980, Cell, Petition 870260038067, dated 04 / 24 / 2026, pp. 110 / 191 95 / 160 22, 611-620; Connolly et al., 1982, J. Biol. Chem., 257, 939-945).

[0205] Galactose derivatives have been used to target molecules to hepatocytes in vivo through their binding to the asialoglycoprotein receptor expressed on the surface of hepatocytes. The binding of asialoglycoprotein receptor ligands to asialoglycoprotein receptors facilitates cell-specific targeting to hepatocytes and endocytosis of the molecule into hepatocytes. Asialoglycoprotein receptor ligands can be monomeric (e.g., having a single galactose derivative) or multimeric (e.g., having multiple galactose derivatives). The galactose derivative or galactose derivative cluster can be attached to the 3' or 5' end of the sense or antisense strand of the RNAi agent using methods known in the art. The preparation of targeting groups, such as galactose derivative groups, is described, for example, in Patent Application Serial Number US 15 / 452,324 and Patent Publication in the US.2017 / 0253875, the contents of both being incorporated into this document in their entirety by reference.

[0206] Depending on the usage in question, a galactose derivative group comprises a molecule having two to four terminal galactose derivatives. A terminal galactose derivative is linked to a molecule through its C-1 carbon. In some embodiments, the galactose derivative group is a galactose derivative trimer (also referred to as a tri-antennary galactose derivative or trivalent galactose derivative). In some embodiments, the galactose derivative group comprises N-acetylgalactosamines. In some embodiments, the galactose derivative group comprises three N-acetylgalactosamines. In some embodiments, the galactose derivative group is a galactose derivative tetramer (also referred to as a tetra-antennary galactose derivative or tetravalent galactose derivative). In some embodiments, the galactose derivative group comprises four N-acetyl Petition 870260038067, dated 04 / 24 / 2026, pp. 111 / 191 96 / 160 galactosamines.

[0207] Depending on the use in question, a galactose derivative trimer contains three galactose derivatives, each linked to a central branching point. Depending on the use in question, a galactose derivative tetramer contains four galactose derivatives, each linked to a central branching point. The galactose derivatives may be linked to the central branching point through the C-1 carbons of the saccharides. In some embodiments, the galactose derivatives are linked to the branching point through linkers or spacers. In some embodiments, the linker or spacer is a flexible hydrophilic spacer, such as a PEG group (see, for example, US Patent No. 5,885,968; Biessen et al. J. Med. Chem. 1995 Vol. 39 p. 1538-1546). In some embodiments, the PEG spacer is a PEG3 spacer.The branching point can be any small molecule that allows the binding of three galactose derivatives and additionally allows the branching point to bind to the RNAi agent. An example of a branching point group is di-lysine or di-glutamate. The binding of the branching point to the RNAi agent can occur through a linker or spacer. In some embodiments, the linker or spacer comprises a flexible hydrophilic spacer, such as, without limitation, a PEG spacer. In some embodiments, the linker comprises a rigid linker, such as a cyclic group. In some embodiments, a galactose derivative comprises or consists of N-acetylgalactosamine. In some embodiments, the galactose derivative group is composed of a galactose derivative tetramer, which may be, for example, an N-acetylgalactosamine tetramer.

[0208] The embodiments of the present disclosure include pharmaceutical compositions for delivering an AAT RNAi agent to a liver cell in vivo. These pharmaceutical compositions may include, for example, an AAT RNAi agent conjugated to a galactose derivative group. In some Petition 870260038067, dated 04 / 24 / 2026, pp. 112 / 191 In 97 / 160 embodiments, the galactose derivative group consists of a galactose derivative trimer, which may be, for example, an N-acetylgalactosamine trimer, or a galactose derivative tetramer, which may be, for example, an N-acetylgalactosamine tetramer.

[0209] Targeting groups include, but are not limited to, (PAZ), (NAG13), (NAG13)s, (NAG18), (NAG18)s, (NAG24), (NAG24)s, (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), and (NAG39)s as defined in Table 7. Other targeting groups, including galactose group targeting ligands, are known in the art.

[0210] In some embodiments, a linking group is conjugated to the RNAi agent. The linking group facilitates the covalent attachment of the agent to a targeting group or delivery polymer or delivery vehicle. The linking group may be attached to the 3' or 5' end of the sense or antisense strand of the RNAi agent. In some embodiments, the linking group is attached to the sense strand of the RNAi agent. In some embodiments, the linking group is conjugated to the 5' or 3' end of a sense strand of the RNAi agent. In some embodiments, a linking group is conjugated to the 5' end of a sense strand of the RNAi agent. Examples of linking groups may include, but are not limited to: reactive groups such as primary amines and alkynes, alkyl groups, abasic nucleotides, ribitol (basic ribose), and / or PEG groups.

[0211] A linker or linking group is a connection between two atoms that binds a chemical group (such as an RNAi agent) or segment of interest to another chemical group (such as a targeting group or polymer delivery group) or segment of interest through one or more covalent bonds. A labile bond Petition 870260038067, dated 04 / 24 / 2026, pp. 113 / 191 98 / 160 contains a labile bond. A bond may optionally include a spacer that increases the distance between the two bonded atoms. A spacer may also add flexibility and / or length to the bond. Spacers may include, but are not limited to, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, aralkyl groups, aralkenyl groups, and aralkinyl groups; each of which may contain one or more heteroatoms, heterocycles, amino acids, nucleotides, and saccharides. Spacer groups are well known in the art and the preceding list is not intended to limit the scope of the description.

[0212] Any of the AAT RNAi agent nucleotide sequences listed in Tables 2, 3, 4, or 5, whether modified or unmodified, may contain targeting groups or 3' or 5' linking groups. Any of the AAT RNAi agent sequences listed in Tables 4 or 5 that contains a targeting group or 3' or 5' linking group may alternatively not contain a targeting group or 3' or 5' linking group, or may contain a different targeting group or 3' or 5' linking group including, without limitation, those described in Table 7.Any of the AAT RNAi agent duplexes listed in Table 2, Table 3, or Table 6, whether modified or unmodified, may further comprise a targeting group or linking group, which includes, but is not limited to, that described in Table 7, and the targeting group or linking group may be attached to the 3' or 5' end of the sense strand or antisense strand of the AAT RNAi agent duplex.

[0213] Examples of targeting groups and linking groups are provided in Table 7. Table 5 provides various embodiments of AAT RNAi agent sense strands having a targeting group or linking group attached to the 5' or 3' end. Table 7. Structures representing various modified nucleotides, targeting groups, and linking groups. Petition 870260038067, dated 04 / 24 / 2026, pp. 114 / 191 99 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 115 / 191 100 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 116 / 191 101 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 117 / 191 102 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 118 / 191 103 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 119 / 191 104 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 120 / 191 105 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 121 / 191 106 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 122 / 191 107 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 123 / 191 108 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 124 / 191 109 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 125 / 191 110 / 160 (NAG30) (NAG30)s NAG—O HN NAG O. NAG THE THE H N THE THE NH THE NH (NAG31) Petition 870260038067, dated 04 / 24 / 2026, pp. 126 / 191 111 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 127 / 191 112 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 128 / 191 113 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 129 / 191 114 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 130 / 191 115 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 131 / 191 116 / 160

[0214] In each of the preceding structures in Table 7, NAG comprises an N-acetylgalactosamine or other asialoglycoprotein receptor ligand, as would be understood by an individual with common knowledge of the art to be ligated in view of the preceding structures and the description provided in this document. For example, in some embodiments, NAG in the structures provided in Table 7 is represented by the following structure: (N-acetylgalactosamine) Petition 870260038067, dated 04 / 24 / 2026, pp. 132 / 191 117 / 160 iOP—i < I s

[0215] Each (NAGx) can be linked to an AAT RNAi agent via a phosphate group (as in (NAG25), (NAG30), and (NAG31)), or a phosphorothioate group (as in (NAG25)s, (NAG29)s, (NAG30)s, (NAG31)s, or (NAG37)s), or another linking group. OO II -OP— .- I s Phosphate Group Phosphorothioate Group

[0216] Other linking groups known in the art may be used.

[0217] In some embodiments, a delivery vehicle may be used to deliver an RNAi agent to a cell or tissue. A delivery vehicle is a compound that enhances the delivery of the RNAi agent to a cell or tissue. A delivery vehicle may include, or consist of, without limitation: a polymer, such as an amphipathic polymer, a membrane-active polymer, a peptide, a melittin peptide, a melittin-like peptide (MLP), a lipid, a reversibly modified polymer or peptide, or a reversibly modified membrane-active polyamine. In some embodiments, RNAi agents may be combined with lipids, nanoparticles, polymers, liposomes, micelles, DPCs, or other delivery systems available in the art.RNAi agents can also be chemically conjugated to targeting groups, lipids (including, without limitation, cholesterol and cholesteryl derivatives), nanoparticles, polymers, liposomes, micelles, DPCs (see, for example, WO 2000 / 053722, WO 2008 / 0022309, WO 2011 / 104169 and WO 2012 / 083185, WO 2013 / 032829, WO 2013 / 158141, each of which is incorporated herein by reference), or other delivery systems available in the art. Pharmaceutical compositions and formulations

[0218] The AAT RNAi agents disclosed herein may be prepared as pharmaceutical compositions or formulations. In some Petition 870260038067, dated 04 / 24 / 2026, pp. 133 / 191 In embodiments 118 / 160, the pharmaceutical compositions include at least one AAT RNAi agent. These pharmaceutical compositions are particularly useful in inhibiting the expression of target mRNA in a target cell, a group of cells, a tissue, or an organism. The pharmaceutical compositions can be used to treat an individual with a disease or disorder that would benefit from a reduction in the level of target mRNA, or inhibition of target gene expression. The pharmaceutical compositions can be used to treat an individual at risk of developing a disease or disorder that would benefit from a reduction in the level of target mRNA or inhibition of target gene expression. In one embodiment, the method includes administering an AAT RNAi agent linked to a targeting ligand as described herein to an individual to be treated.In some embodiments, one or more pharmaceutically acceptable excipients (including vehicles, carriers, diluents, and / or delivery polymers) are added to pharmaceutical compositions including an AAT RNAi agent, thereby forming a pharmaceutical formulation suitable for in vivo delivery to an individual, including a human being.

[0219] The pharmaceutical compositions that include an AAT RNAi agent and methods disclosed herein reduce the level of target mRNA in a cell, group of cells, tissue, or individual, including: administering to the individual a therapeutically effective amount of an AAT RNAi agent described herein, thereby inhibiting AAT mRNA expression in the individual.

[0220] In some embodiments, the described pharmaceutical compositions including an AAT RNAi agent are used to treat or manage clinical presentations in an individual with AATD, such as chronic hepatitis, cirrhosis, hepatocellular carcinoma, transaminitis, cholestasis, fibrosis, and uniform fulminant hepatic failure. In some embodiments, a therapeutically or prophylactically effective amount of one or more pharmaceutical compositions is administered to Petition 870260038067, dated 04 / 24 / 2026, pp. 134 / 191 119 / 160 an individual in need of this treatment. In some modalities, administration of any of the AAT RNAi agents disclosed may be used to reduce the number, severity, and / or frequency of symptoms of a disease in an individual.

[0221] The pharmaceutical compositions described, including an AAT RNAi agent, can be used to treat at least one symptom in an individual having a disease or disorder that would benefit from reduction or inhibition in AAT mRNA expression. In some embodiments, the individual is administered a therapeutically effective amount of one or more pharmaceutical compositions including an AAT RNAi agent, thus treating the symptom. In other embodiments, the individual is administered a prophylactically effective amount of one or more AAT RNAi agents, thus preventing at least one symptom.

[0222] The delivery route is the path by which an AAT RNAi agent comes into contact with the body. In general, methods of administering drugs and nucleic acids from a mammal are well known in the art and can be applied to the administration of the compositions described in this document. The AAT RNAi agents disclosed in this document can be administered via any suitable route in a preparation appropriately adapted to the particular route. Therefore, the pharmaceutical compositions described in this document can be administered by injection, for example, intravenously, intramuscularly, intracutaneously, subcutaneously, intra-articularly, or intraperitoneally. In some embodiments, the pharmaceutical compositions described in this document are administered by subcutaneous injection.

[0223] The pharmaceutical compositions including an AAT RNAi agent described herein may be delivered to a cell, group of cells, tissue, or individual using oligonucleotide delivery technologies. Petition 870260038067, dated 04 / 24 / 2026, pp. 135 / 191 120 / 160 known in the art. In general, any suitable method recognized in the art for delivering a nucleic acid molecule (in vitro or in vivo) can be adapted for use with the compositions described herein. For example, delivery can be by local administration (e.g., direct injection, implant, or topical administration), systemic administration, or subcutaneous, intravenous, intraperitoneal, or parenteral routes, including intracranial administration (e.g., intraventricular, intraparenchymal, and intrathecal), intramuscular, transdermal, airway (aerosol), nasal, oral, rectal, or topical (including buccal and sublingual). In certain embodiments, the compositions are administered by infusion or subcutaneous or intravenous injection.

[0224] Correspondingly, in some embodiments, the pharmaceutical compositions described herein comprise one or more pharmaceutically acceptable excipients. The pharmaceutical compositions described herein are formulated for administration to an individual.

[0225] Depending on the intended use, the pharmaceutical composition or drug product includes a pharmacologically effective amount of at least one of the described AAT RNAi agents and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances other than the Active Pharmaceutical Ingredient (API, therapeutic product, e.g., AAT RNAi agent) that are intentionally included in the drug delivery system. Excipients do not exert, nor are they intended to exert, a therapeutic effect at the intended dosage. Excipients may act to a) assist in the processing of the drug delivery system during manufacturing, b) protect, support, or enhance the stability, bioavailability, or patient acceptability of the API, c) assist in product identification, and / or d) enhance any other attribute of the overall safety, efficacy, or deliverability of the API during storage or use.A pharmaceutically acceptable excipient may or may not be a substance. Petition 870260038067, dated 04 / 24 / 2026, pp. 136 / 191 121 / 160 inert.

[0226] Excipients include, but are not limited to: absorption enhancers, anti-adherents, anti-foaming agents, antioxidants, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, delivery polymers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavorings, glidants, humectants, lubricants, oils, polymers, preservatives, saline solution, salts, solvents, sugars, suspending agents, sustained-release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repellent agents, and humectants.

[0227] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water-soluble) or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline solution, bacteriostatic water, Cremophor® EL™ (BASF, Parsippany, NJ, USA) or phosphate-buffered saline (PBS). They must be stable under manufacturing and storage conditions and must be preserved against contaminating action by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Appropriate fluidity may be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants.In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including an agent that delays absorption, for example, aluminum monostearate and gelatin. Petition 870260038067, dated 04 / 24 / 2026, pp. 137 / 191 122 / 160

[0228] Sterile injectable solutions can be prepared by incorporating the active compound in the required quantity into an appropriate solvent with one or a combination of ingredients listed above, as needed, followed by sterilization by filtration. In general, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the other necessary ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preparation methods include vacuum drying and freeze-drying, which produces a powder of the active ingredient plus any desired additional ingredient from a previously sterile filtered solution thereof.

[0229] Suitable formulations for intra-articular administration may be in the form of a sterile aqueous preparation of the drug which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the drug for intra-articular and ophthalmic administration.

[0230] The active compounds may be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing these formulations will become apparent to those skilled in the art. Liposomal suspensions may also be used as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0231] AAT RNAi agents can be formulated in compositions Petition 870260038067, dated 04 / 24 / 2026, pp. 138 / 191 123 / 160 in unit dosage form for ease of administration and dosage uniformity. The unit dosage form refers to physically discrete units suitable as unit dosages for the individual to be treated; each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the necessary pharmaceutical carrier. The specification for the unit dosage forms of the development is dictated by, and directly dependent on, the unique characteristics of the active compound and the therapeutic effect to be achieved, and the inherent limitations in the technique of compounding that active compound for the treatment of individuals.

[0232] A pharmaceutical composition may contain other additional components commonly found in pharmaceutical compositions. These additional components include, but are not limited to: antipruritics, astringents, local anesthetics, or anti-inflammatory agents (e.g., antihistamine, diphenhydramine, etc.). It is also conceivable that isolated cells, tissues, or organs expressing or comprising the RNAi agents defined herein may also be used as “pharmaceutical compositions.” Depending on the use in question, “pharmacologically effective amount,” “therapeutically effective amount,” or simply “effective amount” refers to the amount of an RNAi agent to produce a pharmacological, therapeutic, or preventive result.

[0233] In general, an effective amount of an active compound will be in the range of about 0.1 to about 100 mg / kg of body weight / day, for example, about 1.0 to about 50 mg / kg of body weight / day. In some embodiments, an effective amount of an active compound will be in the range of about 0.25 to about 5 mg / kg of body weight per dose. In some embodiments, an effective amount of an active ingredient will be in the range of about 0.5 to about 4 mg / kg of body weight per dose. The amount administered will also likely depend on variables such as the patient's overall health status, biological efficacy Petition 870260038067, dated 04 / 24 / 2026, pp. 139 / 191 124 / 160 relative to the delivered compound, the drug formulation, the presence and types of excipients in the formulation, and the route of administration. Similarly, it should be understood that the initial dosage administered may, in some cases, be increased beyond the upper limit to rapidly achieve the desired blood or tissue level, or the initial dosage may, in some cases, be lower than ideal.

[0234] For the treatment of a disease or for the formation of a medicament or composition for the treatment of a disease, the pharmaceutical compositions described herein including an AAT RNAi agent may be combined with an excipient or with a second therapeutic agent or treatment including, without limitation: a second or other RNAi agent, a small molecule drug, an antibody, an antibody fragment, peptide and / or aptamer.

[0235] The described AAT RNAi agents, when added to pharmaceutically acceptable excipients or adjuvants, may be packaged in kits, containers, packets or dispensers. The pharmaceutical compositions described in this document may be packaged in pre-filled syringes or vials. Treatment methods and inhibition of expression

[0236] The AAT RNAi agents disclosed herein may be used to treat an individual (e.g., a human or other mammal) having a disease or disorder that would benefit from administration of the compound. In some embodiments, the RNAi agents disclosed herein may be used to treat an individual (e.g., a human) having AATD, or symptoms, diseases, or disorders that would benefit from reduction or inhibition in AAT mRNA expression, such as AATD liver disease. The individual is administered a therapeutically effective amount of one or more of the Petition 870260038067, dated 04 / 24 / 2026, pp. 140 / 191 125 / 160 AAT RNAi agents described in this document. The individual may be a human being, patient, or human patient. The individual may be an adult, adolescent, child, or infant. The pharmaceutical compositions described, including an AAT RNAi agent, may be used to provide methods for the therapeutic treatment of diseases such as AATD. These methods include administering a pharmaceutical composition described in this document to a human being or animal.

[0237] In some embodiments, the AATD RNAi agents described herein are used to treat an individual with AATD, including symptoms, diseases, or disorders related to AATD. AATD liver diseases or disorders include, but are not limited to, chronic hepatitis, cirrhosis, hepatocellular carcinoma, transaminitis, cholestasis, fibrosis, and fulminant hepatic failure. In some embodiments, the described AATD RNAi agents are used to treat at least one symptom in an individual having AATD. The individual is administered a therapeutically effective amount of any one or more of the described RNAi agents.

[0238] In certain embodiments, the present invention provides methods for treating AATD in a patient in need thereof, comprising administering to the patient any of the AAT RNAi agents described herein.

[0239] In some embodiments, AAT RNAi agents are used to treat or manage a clinical presentation of an individual with an AATD liver disease or disorder. The individual is administered a therapeutically effective amount of one or more of the AAT RNAi agents or compositions containing an AAT RNAi agent described in this document. In some embodiments, the method comprises administering a composition comprising an AAT RNAi agent described in this document to an individual to be Petition 870260038067, dated 04 / 24 / 2026, pp. 141 / 191 126 / 160 treaty.

[0240] In some embodiments, the gene expression level and / or mRNA level of an AAT gene in an individual to whom a described AAT RNAi agent is administered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, 96%, 97%, 98%, 99%, or more than 99% relative to the individual before being administered with an AAT RNAi agent or to an individual who does not receive the AAT RNAi agent. The gene expression level and / or mRNA level in the individual is reduced in a cell, group of cells, and / or tissue of the individual.

[0241] In some embodiments, the AAT protein level in an individual to whom a described AAT RNAi agent has been administered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% relative to the individual before the AAT RNAi agent is administered or to an individual who does not receive the AAT RNAi agent. The protein level in the individual is reduced in a cell, group of cells, tissue, blood, and / or other fluid of the individual.

[0242] In some embodiments, the Z-AAT polymer protein level in an individual having AATD to whom a described AAT RNAi agent has been administered is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% relative to the individual before the AAT RNAi agent was administered or to an individual who did not receive the AAT RNAi agent. In some embodiments, the level of Z-AAT polymer protein in an individual to whom a described AAT RNAi agent has been administered is reduced by at least approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more than 99% relative to Petition 870260038067, dated 04 / 24 / 2026, pp. 142 / 191 127 / 160 individual before the AAT RNAi agent is administered or to an individual who does not receive the AAT RNAi agent.

[0243] A reduction in AAT gene expression, AAT mRNA, or AAT protein levels can be assessed and quantified by general methods known in the art. The examples disclosed in this document present generally known methods for assessing the inhibition of AAT gene expression and reduction in AAT protein levels. The reduction or decrease in AAT mRNA level and / or protein level (including Z-AAT polymer and / or monomer) are collectively referred to in this document as a reduction or decrease in AAT or inhibition or reduction of AAT expression. Non-human cells and tissues and organisms

[0244] Non-human cells, tissues and organisms that include at least one of the AAT RNAi agents described in this document are contemplated. The non-human cell, tissue or organism is produced by delivering the RNAi agent to the non-human cell, tissue or organism.

[0245] The modalities and items provided above will now be illustrated in the following non-limiting examples. Examples Example 1. Identification of RNAi agent sequences and synthesis of RNAi agents.

[0246] A selection process to identify leader sequences to inhibit AAT gene expression begins with in silico methods to identify sequences conserved by variants of an AAT gene (SEQ ID NO: 1). The AAT sequence was initially screened using bioinformatics for a 19-nucleotide sequence having a complementary sequence in known variants of human AAT. Sequences known to have manufacturing challenges and those predicted to have weak RNAi activity based on parameters were also screened. Petition 870260038067, dated 04 / 24 / 2026, pp. 143 / 191 128 / 160 known sequences were eliminated. The sequences were then subjected to a cross-species reactivity analysis to select candidates that would cross-react with cynomolgus monkey AAT. The sequences were also evaluated for specificity to avoid off-target effects against human and cynomolgus monkey genomes. One hundred and fifteen (115) 19mer sequence families were selected as candidates.

[0247] The duplexes in Table 6 were synthesized according to the following procedures: Synthesis

[0248] The sense and antisense strands of AAT RNAi agents were synthesized according to the solid-phase phosphoramidite technology used in oligonucleotide synthesis. Depending on the scale, MerMade96E® (Bioautomation) or MerMade12® (Bioautomation) was used. The syntheses were performed on a solid support made of controlled porous glass (CPG, 500 A or 600 A, obtained from Prime Synthesis, Aston, PA, USA). All RNA and 2'-modified RNA phosphoramidites were acquired from Thermo Fisher Scientific (Milwaukee, WI, USA).Specifically, the following 2'-O-methyl phosphoramidites were used: (5'-O-dimethoxytrityl-N6-(benzoyl)-2'-O-methyladenosine-3'-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite, 5'-O-dimethoxytrityl-N4-(acetyl)-2'-O-methylcytidine-3'-O(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite, (5'-O-dimethoxytrityl-N2-(isobutyryl)-2'O-methylguanosine-3'-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite, and 5'-O-dimethoxy-trityl-2'-O-methyl-uridine-3'-O-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite. The 2'-deoxy-2'-fluoro-phosphoramidites carried the same protecting groups as the 2'-O-methyl RNA amidites. The following UNA phosphoramidites were used: 5'-(4,4'Dimethoxytrityl)-N-benzoyl-2',3'-seco-adenosine, 2'-benzoyl-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-(4,4'-Dimethoxytrityl)-N-acetyl-2',3'-seco-cytosine, 2'benzoyl-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-(4,4'-Dimethoxytritil)-NPetition 870260038067, dated 04 / 24 / 2026, page 144 / 191. 129 / 160 isobutyryl-2',3'-seco-guanosine, 2'-benzoyl-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]phosphoramidite, and 5'-(4,4'-Dimethoxy-trityl)-2',3'-seco-uridine, 2'-benzoyl-3'-[(2-cyanoethyl)(N,N-diisopropyl)]-phosphoramidite.

[0249] Phosphoramidites containing targeting ligand in anhydrous dichloromethane or anhydrous acetonitrile (50 mM), while all other amidites were dissolved in anhydrous acetonitrile (50 mM) and molecular sieves (3A) were added. 5-Benzylthio-1H-tetrazole (BTT, 250 mM in acetonitrile) or 5-Ethylthio-1H-tetrazole (ETT, 250 mM in acetonitrile) was used as activating solution. The coupling times were 10 min (RNA), 15 min (targeting ligand), 90 s (2'OMe), and 60 s (2'F). In order to introduce phosphorothioate linkages, a 100 mM solution of 3-phenyl 1,2,4-dithiazolin-5-one (POS, obtained from PolyOrg, Inc., Leominster, MA, USA) in anhydrous acetonitrile was employed. Cleavage and deprotection of support-linking oligomers.

[0250] After completion of the solid phase synthesis, the dry solid support was treated with a 1:1 volume solution of 40% by weight of methylamine in water and 28% ammonium hydroxide solution (Aldrich) for two hours at 30°C. The solution was evaporated and the solid residue was reconstituted in water (see below). Purification

[0251] Crude oligomers were purified by anion-exchange HPLC using a TKSgel SuperQ-5PW 13u column and a Shimadzu LC-8 system. Buffer A was 20 mM Tris, 5 mM EDTA, pH 9.0 and contained 20% Acetonitrile, and buffer B was the same as buffer A with the addition of 1.5 M sodium chloride. Trace UV at 260 nm was recorded. Appropriate fractions were pooled and then run HPLC by size exclusion using a GE Healthcare XK 16 / 40 column packed with Sephadex G-25 medium with a buffer running 100 mM ammonium bicarbonate, pH 6.7 and 20% Acetonitrile. Ringing Petition 870260038067, dated 04 / 24 / 2026, pp. 145 / 191 130 / 160

[0252] Complementary strands were mixed by combining equimolar RNA solutions (sense and antisense) in 0.2χ PBS (phosphate-buffered saline, 1χ, Corning, Cellgro) to form the RNAi agents. This solution was placed in a thermomixer at 70°C, heated to 95°C, held at 95°C for 5 minutes, and cooled slowly to room temperature. Some RNAi agents were lyophilized and stored at -15 to -25°C. The duplex concentration was determined by measuring the solution absorbance in a UV-Vis spectrometer in 0.2χ PBS. The solution absorbance at 260 nm was then multiplied by a conversion factor and the dilution factor to determine the duplex concentration. Except where stated otherwise, all conversion factors were 0.037 mg / (mL^cm). For some experiments, a conversion factor was calculated from an experimentally determined extinction coefficient. Example 2. In vitro testing of AAT RNAi agents.

[0253] Candidate sequence duplexes were tested in vitro. Antisense strand sequences and sense strand sequences were annealed to form 21-mer strand duplexes (having 19 base pairs and a UU dinucleotide overhang at each 3' end) for in vitro testing, as shown in Table 8 below: Petition 870260038067, dated 04 / 24 / 2026, pp. 146 / 191 Table 8. RNAi agent sequences of AAT in Example 2 SEQ NO: Antisense Sequence ID (5' - 3') SEQ NO: Sense Sequence ID (5' - 3') Duplex ID No. AUAUCACACACACCACCAUGHT D2 1037 CLEAR 1152 CLEAR D3 1038 CLEAR CLEAN D4 CLEAR D4 CLEAR 1039 UGGCACQUESTION D5 1040 UGCACHACQUE D5 1155 UGCACHACQUIRED6 1041 UAUUQUEQUAKAUU D7 U1042UGQUAUCAUUU AGUCACAGCACCAAUUUU D8 1043 GAUUGGUGCUGUGGACUUU 1158 GAUUGGUGCUGUGGACUUU D9 1044 AAGAUAUUGGUGCUUUUUUU 1159 CCAACACAGCCAAUCUGUUUUUU0 D10101045 CCCCAWATER D11 1046 AAAGGWATERWATER 1161 WATERWATER D12 1047 GCAWATERWATER1162 WATERWATER16013 D8GC CAUGCWACAGCCUUUGCAUUU D14 1049 AUUGCAAAGGCUUAGCAAUUU 1164 UCGWACACAGCCUUUGCAAUUUU D15 1050 ACCAUUGCAAAGGCUUGUAGUUUU 1165CUACAGCCUUUGCAAUGCUUU D16 1051 AGAGCAUUGCAAAGGCUGUUU 1166 ACAGCCUUUGCAAUGCUCUUUU D17 1052 GGAGUUCCUGGAAGCCUUCUU 1167 GAAGGCUUCCAGGAACUCCUUU 135 1168 UAGUGGAUAAGUUUUUGGAUU D19 1054 AAGGCUUCUGAGUGGUACAUU 1169 UG UAC CAC U CAGAAGC CUUUU D20 1055 GAAGGCUUCUGAGUGGUACUU 1170 GUACCACUCAGAA D19106 UUCUUGGCCUCUUCGGUGUUUU 1171 ACACCGAAGAGGCCAAGAAUU D22 1057 GUUUCUUGGCCUCUUCGGUUUU 1172 ACCGAAGAGGCCAAGAAACUU D23 1058 UUGAUCUGUUUUCUUGGCCUUUU 1177AAGAAGAAAGAAGAAGAAUUU24 1059 GUUGAUCUGUUUCUUGGCCUU 1174 GGCCAAGAAACAGAUCAACUU D25 1060 CGUUGAUCUGUUUCUUGGCUU 1175 GCCAAGAAACAGAUCAACGUU D26 131 / 160 Petition 870260038067, of 24 / 04 / 2026, p. 147 / 191 SEQ NO: Anti-sense Sequence ID (5' - 3') SEQ NO: Sense Sequence ID (5' - 3') Duplex ID No. CUCAAGGGAAAAUUUGGAUU D28 1063 AUCCACAAUUUCCCUUUUU 1178 UCAAGGGAAAAUUUCCAUUUUUU D29 1064 CUT 1179 UUGGUCAAGGAGCUUGCAUUUU65D 1180 HOLDING D31 1066 1181 AGC U HOUSING UU D32 1067 UG UAAU U CAC HOUSING U 1182 1183 AGCGUUUAGGCAUGUUAAUU D34 1069 GUUAAACAUGCAUAACCGCUU 1184 GCGUUUAGGCAUGUUAACUU D35 1070 UGUUAAACAUGCCUAAACCUU 1185 CGUUUAGGCAUGUU716D3UUAACU GGAUGUUAAACAUGCCUAUU 1186 UUAGGCAUGUUUAACAUCCUU D37 1072 AUUUCAUCAGCAGCACCCAUU 1187 UGGGUGCUGCUGAUGAAUUU D38 1073 GAAUGAAGAUGGCGGUGCCAUUU3 CUCCAUGC CA11 1074 HOLDING 1189 HOLDING D40 1075 HOLDING D41 1076CAUUUCCAGGAACUUGGUUU 1191 ACCAAGUUCCUGGAAAAUGUUU D42 1077 CAUAGGUUCCAGUAAUGGAUU 1192 UCCAUUACUGGAACCUAUGUU D43 1078 UCAUAGGUUCCAGUAAUGGUU 1193 CACUACUUUGA 1079 UCAGAUCAUAGGUUCCAGUUU 1194 ACUGGAACCUAUGAUCUGAUU D45 1080 UCUUCAGAUCAUAGGUUCCUU 1195 GGAACCUAUGAUCUGAAGAUU D46 1081 CUCUCAGAUCAUAGGUUCUUGAU 1196 ACCUUGAUGAUU GAAGAG UU D47 1082 GAGGUCAGCCCCAUUGCUGUU 1197 CAGCAAUGGGGCUGACCCUCUU D48 1083 GAGAGGUCAGCCCCAUUGCUUU 1198 GCAAUGGGGCUGACCCUCUUU D49 1084 CUAGGUGUCCUGCUCUCUU191084 AGAGGAGGCACCCCUGAAGUU D50 1085 GAGAGCUUCAGGGGUGCCUUU 1200 AGGCACCCCUGAAGCUCUCUUU D51 1086 UUAUGCACGGCCUUGGAGAUU 1201 UCUCCAAGGCCGUGCAUAUU D52 1202 UCCAAGGCCGUGCAUAAGGUU D53 1088 GCCUUAUGCACGGCCUUGGUU 1203 CCAAGGCCGUGCAUAAGGCUU D54 132 / 160 Petition 870260038067, of 24 / 04 / 2026, p. 148 / 191 SEQ NO: Antisense Sequence ID (5' - 3') SEQ NO: Sense Sequence ID (5' - 3') Duplex ID No. AAGGSTORAGE D56 1091 STORAGE WATER 1206 STORAGE WATER D57 1092 AAAAACAUGGCCCCAWAY D57 1207 STORAGE3CCAUUUAU5 WATER9 1208 GCUGGGCCAUGUUUUUAGUU D59 1094 UCUAAAAACAUGGCCCCAGUU 1209 CUGGGGCCAUGUUUUUUUUAGUUU D60 1095 CCUCUAAAAACAUGCCCCCUUU 1210 GGGGAGCCAUGUUU09 GCCUCUAAAAACAUGGCCCUU 1211 GGGCCAUGUUUUUUAGGGCCUU D62 1097 UAGCAUGGCAUGCCAUUU D63 1098 GAUGACCAUGGUUGGCCUUU D63904GCCAU13 STORAGE 1214 CCCGGRAPPING D65 1100 STORAGE 1215 AG GU CAAG UU CAACAAAC CUU D66 1101 AAAGGGUSTAKING1CACAUS1 D67 1102 REPAIR 1217 REPAIR D68 1103 REPAIR 1218 REPLACEMENT D69 1104AAGACAAAGGGUUGUUGAUUUU 1219 UCACAACCUUUGUUUUU D70 1105 C AU U AAG AAGAC AAAG GGUUUU 1220 ACCAUUAAGAGUUCUUUUUUUUUUUU1 D72 1107 HOUSEHOLD 1222 UACCAGGGGHOUSEHOUSE D73 1108 HOUSEHOLD D74 1109 HOUSEHOUSE2HOUSEHOUSE12 D75 1110 PUPPY 1225 PUPPY D76 1111 PUPPY D77 1112 PUPPY27 PUPPY AUGACAUAAAAGGGGUUUU D78 1113 UUGUUGGACUGGUGGUGCCAUU 1228 UGGCACACCAGUCCAUU D79 1114 UAUAUUGGGCUUUUU 1229 GUCACAGCACCAAUAUGAGGAUUU1 U50 1230 CCCCAGCAUGCAUGCUAUUU D81 1116 UCAAAGGCUUGAUUUU 1231 CCCACCACACCUUUGAUUU D82 133 / 160 Petition 870260038067, dated 4 / 24 / 2026, p. 149 / 191 SEQ NO: Anti-sense Sequence ID (5' - 3') SEQ NO: Sense Sequence ID (5' - 3') Duplex ID No. GUACCACUCAGAAGCUAUUU D84 1119 UUUUCUGGCCUCUUUUU 1234 ACCGAAGGCCAAAAAAUU D85 1120 UUUGAAGAGCUUCUUUUUUUGGCCUUUU1235 UU1U1D86 1236 GCCAAGAAACAGAUCAUU D87 1122 UACAAUUUCCCUUGAGUAUU 1237 U AC UC AAG G GAAAAU UGU AU U D88 1123 UUGUCUCUCUUUGUACCAUUUU 1238 AGGAGCUUGACACACAAUU19D48 UUUAAACAUGCCUAAAACGCUU 1239 GCGUUUAGGCAUGUUUAAAUU D90 1125 UGAUGUUAAACAUGCAUAUU 1240 UAAGAAGAUGGCGGUGGCAUU1UCUGCAUCA1241 UGUGAGUUCAUUUUCCAGGUU 1242 CCUGGAAAAUGAACAUUCACAUU D93 1128 UAACUUGGUGAUCCAUAUUCAUUU 1243 CAUUCAUCCACAGUAUUUU D94 1129 UAUUUUCCAGGAACUUGGUU149AUCCAAGUUU 124 UAUAGGUUCCAGUAAUGGAUUU 1245 YOUTH D96 1131 YOUR CHILDREN 1246 YOUR D97 1132UAGGUCAGCCCCAUUGCUGUUU 1247 CAGCAAUGGGGCUGACCUAUU D98 1133 UAGAGGUCAGCCCCAUUGCUUU 1248 GCAAUGGGGCUGACCUCUAUU D99 1134 UUUCAGGGGUGCCUCCUCUAG 1249GACUGCUGAUGCUGAUGCUUUU 1135 UAGAGCUUCAGGGGUGCCUUU 1250 AGGCACCCCUGAAGCUCUAUU D101 1136 UCUUAUGCACGGCCUUGGAUU 1251 UCCAAGGCCGUGCAUAAGAUU D102 1137 UCCUUAUGCACGGCCUUGGUGGUG101 CCAAGGCCGUGCAUAAGGAUU D103 1138 UGAUGGUCAGCACAGCCUUUU 1253 AAGGCUGUGCUGACCACAUCAUU D104 1139 UUCGAUGGUCAGCACAGCCUU 1254 GGCUGUGCUGACCAUCGAAUU D11050 1255 GCUGGGGCCAUGUUUUAAUU D106 1141 UCUCUAAAAACAUGGCCCCUU 1256 GGGGCCAUGUUUUUAGAGAUU D107 1142 UCCUCUAAAAACAUGGCCCUU 1257 GGCAUGUUUUGAUGUU14013 UAUAGACAUGGGUAUGGCCUU 1258 GGCCAUACCCAUGUCUAUAUU D109 1144 UGUUUGUUGAACUUGACCUUU 1259 AG GU CAAG UU CAACAAAC AU U D110 134 / 160 Petition 870260038067, of 24 / 04 / 2026, p. 150 / 191 SEQ NO: ID Sequence antisense (5' - 3') SEQ NO: ID Sequence sense (5' - 3') Duplex ID No. 1145 UACAAAGGGUUUGUUGAACUU 1260 GUUCAACAAACCCUUUGUAUU D111 1146 U AU U AAG AAGAC AAAG GGUUU 1261 ACCCUUUGUCUUCUUAAUAUU D112 1147 UAAGAGGGGAGACUUGGUAUU 1262 UACCAAGUCUCCCCUCUUAUU D113 1148 UCAUGAAGAGGGGAGACUUUU 1263 AAGUCUCCCCUCUUCAUGAUU D114 1149 UCCAUGAAGAGGGGAGACUUU 1264 AGUCUCCCCUCUUCAUGGAUU D115 135 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 151 / 191 136 / 160

[0254] AAT RNAi agents were evaluated by transfecting Hep3B cells, a human hepatocellular carcinoma cell line. Cells were plated at ~10,000 cells per 96-well plate, and each of the 115 AAT RNAi agent duplexes was transfected at three concentrations (10 nM, 1 nM, and 0.1 nM) using the transfection reagent. LipoFectamine RNAiMax (Thermo Fisher). The relative expression of each of the 115 AAT RNAi agents was determined by qRT-PCR by comparing AAT mRNA expression levels to an endogenous control, and normalized to untreated Hep3B cells (ΔΔ^γ analysis), as shown in Table 9. Table 9. In vitro Duplex Data from Example 2 Duplex ID number (from Table 8) Average Exp. nM Rei. 10 Average Exp. 1 Rei. nM Average Exp. nM Rel. 0.1 D1 1.037 0.896 0.709 D2 0.068 0.089 0.381 D3 0.046 0.064 0.403 D4 0.075 0.090 0.391 D5 0.408 0.424 0.743 D6 0.018 0.032 0.347 D7 0.069 0.125 0.666 D8 0.092 0.193 0.794 D9 0.206 0.228 0.839 D10 0.023 0.032 0.235 D11 0.309 0.522 0.894 D12 0.049 0.092 0.732 D13 0.549 0.665 0.955 D14 0.531 0.654 0.934 D15 0.108 0.197 0.820 D16 0.558 0.516 0.834 D17 0.626 0.606 0.841 D18 0.668 0.703 0.778 D19 0.624 0.803 0.785 D20 0.071 0.080 0.506 D21 0.022 0.037 0.345 D22 0.086 0.127 0.588 D23 0.175 0.238 0.893 D24 0.134 0.078 0.368 D25 0.056 0.075 0.687 D26 0.122 0.196 0.756 D27 0.517 0.560 0.846 Petition 870260038067, dated 04 / 24 / 2026, pp. 152 / 191 137 / 160 Duplex ID number (from Table 8) Average Exp. nM King. 10 Average Exp. 1 King. nM Average Exp. nM Rel.0.1 D28 0.801 0.838 0.884 D29 0.820 0.870 0.903 D30 0.558 0.632 0.879 D31 1.112 1.110 0.922 D32 0.246 0.359 1.041 D33 0.107 0.355 0.967 D34 0.096 0.170 0.962 D35 0.317 0.552 0.949 D36 0.064 0.134 0.873 D37 0.463 1.005 1.006 D38 0.428 0.688 0.486 D39 0.730 0,918 1,258 D40 0,059 0,067 0,912 D41 0,093 0,095 0,952 D42 0,582 0,665 0,944 D43 0,196 0,283 1,004 D44 0,195 0,278 0,860 D45 0.053 0.103 0.817 D46 0.082 0.127 1.034 D47 0.089 0.156 0.821 D48 0.735 0.695 0.838 D49 0.604 0.610 0.838 D50 0.543 0.633 0.806 D51 D52 0.108 0.203 0.836 D53 1.062 0.836 0.931 0.884 D57 0.049 0.126 0.797 D58 0.198 0.302 0.917 D59 0.732 0.745 0.953 D60 0.389 0.580 0.897 D61 0.585 0.624 1.802 D62 0.174 0.215 1,115 D63 0,093 0,074 0,917 D64 0,133 0,133 1,055 D65 0,395 0,362 0,986 D66 0,054 0,055 1,083 D67 0,105 0,118 1,018 D68 0.106 0.122 1.290 D69 0.201 0.194 1.062 D70 0.050 0.048 0.709 D71 0.231 0.216 0.767. Petition 870260038067, dated 04 / 24 / 2026, pp. 153 / 191 138 / 160 Duplex ID number (from Table 8) Average Exp. nM King. 10 Average Exp. 1 King. nM Average Exp. nM Rel.0,1 D72 0,046 0,030 0,737 D73 0,521 0,423 0,782 D74 0,479 0,467 0,694 D75 0,531 0,583 0,794 D76 0,210 0,285 0,924 D77 0,152 0,181 0,803 D78 0,425 0,485 0,703 D79 0,120 0,127 0,711 D80 0,203 0,167 0,672 D81 0,477 0,402 0,611 D82 0,540 0,489 0,661 D83 0,315 0,316 0,838 D84 0,135 0,118 0,375 D85 0,209 0,270 1,050 D86 0,120 0,136 0,928 D87 0,172 0,207 1,056 D88 0,218 0,308 1,006 D89 0,605 0,643 0,925 D90 0,205 0,259 0,927 D91 0,594 1,097 1,052 D92 0,337 0,887 1,015 D93 0,068 0,503 0,864 D94 0,067 0,475 0,811 D95 0,186 0,770 0,931 D96 0,062 0,389 0,550 D97 0,066 0,470 0,896 D98 0,567 0,998 1,044 D99 0,451 1,092 1,359 D100 0,292 0,745 0,875 D101 0,049 0,320 0,659 D102 0,313 0,799 0,732 D103 0,068 0,541 0,630 D104 0,077 0,552 0,682 D105 0,071 0,355 0,459 D106 1,179 1,117 1,076 D107 0,328 0,597 0,876 D108 0,125 0,467 0,573 D109 0,141 0,545 0,753 D110 0,076 0,497 0,778 D111 0,132 0,511 0,634 D112 0,216 0,586 0,784 D113 0,462 0,687 1,021 D114 0,507 0,792 1,170 D115 0,259 0,797 1,027. Petition 870260038067, dated 04 / 24 / 2026, pp. 154 / 191 139 / 160 Example 3. In vivo testing of AAT NAG-conjugated RNAi agents in PiZ mice.

[0255] A transgenic PiZ mouse model (PiZ mice) was used to evaluate AAT RNAi agents in vivo. PiZ mice harbor the human AAT mutant allele of PiZ and the human AATD model (Carlson et al., Journal of Clinical Investigation 1989).

[0256] NAG-conjugated AAT RNAi agents were prepared in a pharmaceutically acceptable saline buffer and administered to PiZ mice to evaluate the knockout of AAT gene expression. On day 1, each mouse received a single subcutaneous (SQ) dose in the flabby skin on the back between the shoulders of 5.0 mg / kg (mpk) of AD04446, AD04447, AD04448, AD04449, AD04450, AD04451, AD04454, AD04455, AD04456, AD04457, AD04458, or AD04459. (See Tables 47 for modified AAT RNAi agents and NAG linker structures). The AAT RNAi agents AD04451 and AD04459 included a modified nucleotide antisense strand sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1000; the AAT RNAi agents AD04446 and AD04454 included a modified nucleotide antisense strand sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1142;The AAT RNAi agents AD04447 and AD04455 included a modified nucleotide antisense strand sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1211; the AAT RNAi agents AD04448 and AD04456 included a modified nucleotide antisense strand sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1326; the AAT RNAi agents AD04449 and AD04457 included a modified nucleotide antisense strand sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1338; and the AAT RNAi agents AD04450 and AD04458 included a nucleotide antisense strand sequence. Petition 870260038067, dated 04 / 24 / 2026, pp. 155 / 191 A modified 140 / 160 antibody was designed to target an AAT gene (SEQ ID NO: 1) at position 1427. (See also Tables 1 and 2). Three mice were dosed with each AAT RNAi agent (n = 3).

[0257] Plasma samples were collected and analyzed to determine AAT protein (Z-AAT) levels on day 1 (pre-dose), day 8, day 15, day 22, day 29, and day 36. AAT levels were normalized to the plasma AAT levels of day 1 (pre-dose). Protein levels were measured by quantifying circulating human ZAAT levels in plasma using a commercially available ELISA kit according to the manufacturer's recommendations. The mean normalized AAT (Z-AAT) levels for each RNAi agent are reported in Table 10 below: Petition 870260038067, dated 04 / 24 / 2026, pp. 156 / 191 Table 10. Mean normalized ATT protein (normalized to pretreatment) from Example 3 Day 8 Day 15 Day 22 Day 29 Day 36 Group ID Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Group 1 mg / kg AD04447) (5.0 1.010 0.256 1.050 0.108 1.451 0.137 1.145 0.154 1.117 0.080 Group 2 mg / kg AD04448) (5.0 0.884 0.262 0.866 0.276 1.306 0.112 1.147 0.119 1.076 0.172 Group 3 mg / kg AD04449) (5.0 0.909 0.060 0.969 0.152 1.290 0.185 1.290 0.201 1.245 0.106 Group 4 mg / kg AD04450) (5.0 0.595 0.083 0.799 0.131 1.099 0.256 1.090 0.346 1.229 0.444 Group 5 mg / kg AD04451) (5.0 0.282 0.006 0.525 0.020 1.358 0.188 1.767 0.325 1.586 0.297 Group 6 mg / kg AD04455) (5.0 0.656 0.126 0.639 0.039 0.741 0.089 0.738 0.235 0.819 0.156 Group 7 mg / kg AD04456) (5.0 0.605 0.129 0.469 0.036 0.717 0.105 0.662 0.097 0.875 0.195 Group 8 mg / kg AD04457) (5.0 0.501 0.108 0.663 0.091 1.031 0.324 1.176 0.368 1.603 0.597 Group 9 (5.0 0.308 0.081 0.174 0.031 0.177 0.010 0.211 0.010 0.345 0.041 141 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 157 / 191 Day 8 Day 15 Day 22 Day 29 Day 36 Group ID Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) mg / kg AD04458) Group 10 mg / kg AD04459) (5.0 0.256 0.021 0.134 0.045 0.174 0.084 0.234 0.174 0.315 0.336 Group 11 mg / kg AD04446) (5.0 0.686 0.178 0.739 0.130 0.973 0.263 0.955 0.107 0.885 0.119 Group 12 mg / kg AD04454) (5.0 0.338 0.014 0.361 0.105 0.602 0.252 0.729 0.266 0.970 0.245 142 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 158 / 191 143 / 160

[0258] As shown from the data in Table 10 above, while the AAT RNAi agent AD04447 showed essentially no reduction in AAT protein, the AAT RNAi agents AD04458 (which included a modified nucleotide sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1427) and AD04459 (which included a modified nucleotide sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1000) showed a substantial reduction in AAT protein at all time points. For example, AD04458 showed approximately 69% knockout on day 8 (0.308); approximately 83% on day 15 (0.174), and approximately 82% on day 22 (0.177). Additionally, for example, AD04459 showed a knockout rate of approximately 74% on day 8 (0.256), approximately 87% on day 15 (0.134), and approximately 83% on day 22 (0.174). Example 4. In vivo testing of NAG-conjugated AAT RNAi agents in cynomolgus monkeys.

[0259] NAG-conjugated AAT RNAi agents were manufactured and combined in a pharmaceutically acceptable saline buffer as known in the art for subcutaneous (SC) injection. On day 1, cynomolgus macaques (Macaca fascicularis) (referred to herein as “cynos” or “macacos”) were injected subcutaneously with 3 mg / kg of AD04824, AD04825, AD04826, or AD04827 (see Tables 4 to 7 for the modified AAT RNAi agents and NAG linker structures). Each of these AAT RNAi agents included a modified nucleotide sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1000, and was cross-reactive with cynos. Three macaques in each group were tested (n=3).

[0260] Serum samples from treated cynomolgus monkeys were collected on day 7 and day 1 (pre-dose), and on days 8, 15, 22, and 29 to monitor for knockout. On day 36, serum was also measured for cynos that were injected with AD04825 and AD04826. Petition 870260038067, dated 04 / 24 / 2026, pp. 159 / 191 144 / 160 At the indicated time points, blood samples were collected and analyzed for cynomolgus monkey AAT (cAAT). Blood was collected from the femoral vein. cAAT levels were determined on a Cobas Integra 400 Plus (Roche Diagnostics) according to the manufacturer's recommendations. AAT levels for each animal at a respective time point were divided by the pretreatment level (average of day -7 and day 1 (pre-dose)) of expression in that animal to determine the “normalized to pre-dose” expression ratio.

[0261] Normalized cynomolgus monkey AAT protein (cAAT) levels after treatment with each respective AAT RNAi agent are reported in Table 11 below: Petition 870260038067, dated 04 / 24 / 2026, pp. 160 / 191 Table 11. Normalized cAAT protein (between normalized and pre-treatment) from Example 4 in cynomolgus monkeys Day 8 Day 15 Day 22 Day 29 Day 36 Group ID cAAT cAAT cAAT cAAT cAAT Group 1, Cyno A (3.0 mg / kg AD04824) 0.62 0.52 0.45 0.52 Group 1, Cyno B (3.0 mg / kg AD04824) 0.60 0.36 0.32 0.32 Group 1, Cyno C (3.0 mg / kg AD04824) 0.62 0.44 0.41 0.41 Group 2, Cyno A (3.0 mg / kg AD04825) 0.58 0.33 0.24 0.24 0.22 Group 2, Cyno B (3.0 mg / kg AD04825) 0.58 0.38 0.27 0.25 0.27 Group 2, Cyno C (3.0 mg / kg AD04825) 0.79 0.58 0.43 0.43 0.44 Group 3, Cyno A (3.0 mg / kg AD04826) 0.75 0.59 0.44 0.42 0.38 Group 3, Cyno B (3.0 mg / kg AD04826) 0.66 0.43 0.30 0.26 0.24 Group 3, Cyno C (3.0 mg / kg AD04826) 0.62 0.36 0.27 0.25 0.25 Group 4, Cyno A (3.0 mg / kg AD04827) 0.57 0.38 0.26 0.26 Group 4, Cyno B (3.0 mg / kg AD04827) 0.61 0.37 0.34 0.34 Group 4, Cyno C (3.0 mg / kg AD04827) 0.66 0.43 0.41 0.39 145 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 161 / 191 146 / 160

[0262] The mean normalized cAAT levels for each of the respective treatment groups are shown in the bar graph in Figure 9. As illustrated in Table 11 above and Figure 9, each of the tested AAT RNAi agents showed a substantial knockout of cAAT in cynomolgus monkeys at all measured time points. Example 5. In vivo testing of NAG-conjugated AAT RNAi agents in cynomolgus monkeys.

[0263] NAG-conjugated AAT RNAi agents were produced and combined in a pharmaceutically acceptable saline buffer as known in the art for subcutaneous (SC) injection. On day 1, cynomolgus macaque primates (Macaca fascicularis) were injected subcutaneously with 3 mg / kg of AD04828, AD04831, AD04836, or AD04837 (see Tables 4 to 7 for the modified AAT RNAi agents and NAG linker structures). Each of these AAT RNAi agents included a modified nucleotide sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1000, and was cross-reactive with cynos. Three monkeys in each group were tested (n=3) for AD04828 and AD04831, and two monkeys in each group were tested (n=2) for AD04836 and AD04837.

[0264] Serum samples from treated cynos were collected on day -35 and day 1 (pre-dose), and on days 8, 15, 21, and 29 to monitor for knockout. At the indicated time points, blood samples were collected and analyzed for cAAT. Blood was collected from the femoral vein. cAAT levels were determined on a Cobas Integra 400 Plus (Roche Diagnostics) according to the manufacturer's recommendations. The cAAT levels for each animal at a respective time point were divided by the pre-treatment level (average of day -35 and day 1 (pre-dose)) of expression in that animal to determine the “normalized to pre-treatment” expression ratio.

[0265] The normalized levels of cynomolgus monkey AAT protein (cAAT) after treatment with each respective AAT RNAi agent are Petition 870260038067, dated 04 / 24 / 2026, pp. 162 / 191 147 / 160 reported in Table 12 below: Petition 870260038067, dated 04 / 24 / 2026, pp. 163 / 191 Table 12. Normalized AAT protein (between normalized and pretreatment) from Example 5 in cynomolgus monkeys. Day 8 Day 15 Day 22 Day 29 Group ID cAAT cAAT cAAT cAAT Group 1, Cyno A (3.0 mg / kg AD04828) 0.60 0.32 0.25 0.23 Group 1, Cyno B (3.0 mg / kg AD04828) 0.67 0.59 0.61 0.76 Group 1, Cyno C (3.0 mg / kg AD04828) 0.51 0.35 0.29 0.29 Group 2, Cyno A (3.0 mg / kg AD04831) 0.68 0.43 0.32 0.28 Group 2, Cyno B (3.0 mg / kg AD04831) 0.71 0.49 0.47 0.44 Group 2, Cyno C (3.0 mg / kg AD04831) 0.61 0.43 0.34 0.30 Group 3, Cyno A (3.0 mg / kg AD04836) 0.61 0.37 0.27 0.23 Group 3, Cyno B (3.0 mg / kg AD04836) 0.67 0.43 0.32 0.27 Group 4, Cyno A (3.0 mg / kg AD04837) 0.65 0.40 0.28 0.24 Group 4, Cyno B (3.0 mg / kg AD04837) 0.55 0.29 0.20 0.17 148 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 164 / 191 149 / 160

[0266] The mean normalized cAAT levels for each of the respective treatment groups are shown in the bar graph in Figure 10. As shown earlier in Table 12, as well as in the bar graph in Figure 10, each of the tested AAT RNAi agents showed a substantial knockout of cAAT in cynomolgus monkeys at all measured time points. Example 6. In vivo testing of NAG-conjugated AAT RNAi agents in sPiZ mice.

[0267] The transgenic PiZ mouse model (PiZ mice) as presented in Example 3 was used to evaluate AAT RNAi agents in vivo. NAG-conjugated AAT RNAi agents were prepared in a pharmaceutically acceptable saline buffer and administered to PiZ mice to evaluate an AAT gene expression knockout. On day 1, each mouse received a single subcutaneous (SQ) dose in the flabby skin of the back between the shoulders of 2.0 mg / kg (mpk) of AD04824, AD04828, AD04829, AD04830, AD04831, AD04832, AD04833, AD04834, AD04836, AD04837, AD04838, AD04839, or AD04857. (See Tables 4 to 7 for the modified AAT RNAi agents and NAG linker structures). Each of the AAT RNAi agents in this study included a modified nucleotide antisense strand sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1000. (See also Tables 1 and 2). Three mice were dosed with each AAT RNAi agent (n = 3).

[0268] Plasma samples were collected and analyzed to determine AAT protein levels (Z-AAT) on days -2, day 1 (pre-dose), day 8, day 15, day 22, day 29, and day 36. AAT levels were normalized to the day 1 pre-dose plasma AAT levels. Protein levels were measured by quantifying circulating human Z-AAT levels in plasma using a commercially available ELISA kit according to the manufacturer's recommendations. The mean normalized AAT levels (Z-AAT) for each RNAi agent are reported in Table 13 below: Petition 870260038067, dated 04 / 24 / 2026, pp. 165 / 191 Table 13. Average normalized AAT protein (between normalized and pre-treatment) from Example 6 Day 8 Day 15 Day 22 Day 29 Day 36 Group ID Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Group 1 mg / kg AD04824) (2.0 0.105 0.036 0.140 0.067 0.204 0.108 0.313 0.104 0.437 0.229 Group 2 mg / kg AD04828) (2.0 0.141 0.055 0.236 0.111 0.304 0.138 0.624 0.289 0.814 0.139 Group 3 mg / kg AD04829) (2.0 0.109 0.072 0.119 0.102 0.140 0.119 0.141 0.116 0.179 0.145 Group 4 mg / kg AD04830) (2.0 0.147 0.095 0.190 0.148 0.307 0.192 0.521 0.424 0.547 0.202 Group 5 mg / kg AD04831) (2.0 0.154 0.104 0.215 0.171 0.449 0.375 0.701 0.519 0.584 0.418 Group 6 mg / kg AD04832) (2.0 0.088 0.032 0.089 0.048 0.090 0.046 0.117 0.071 0.193 0.131 Group 7 mg / kg AD04833) (2.0 0.168 0.029 0.282 0.047 0.448 0.048 0.748 0.223 1.361 0.346 Group 8 mg / kg AD04834) (2.0 0.159 0.037 0.255 0.159 0.470 0.315 0.662 0.346 0.728 0.141 Group 9 (2.0 0.108 0.035 0.070 0.024 0.083 0.032 0.090 0.035 0.168 0.078 150 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 166 / 191 Day 8 Day 15 Day 22 Day 29 Day 36 Group ID Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) mg / kg AD04836) Group 10 mg / kg AD04837) (2.0 0.157 0.071 0.209 0.104 0.242 0.097 0.417 0.198 0.550 0.193 Group 11 mg / kg AD04838) (2.0 0.106 0.017 0.099 0.022 0.108 0.039 0.158 0.072 0.188 0.050 Group 12 mg / kg AD04839) (2.0 0.096 0.026 0.069 0.019 0.089 0.036 0.120 0.038 0.186 0.083 Group 12 mg / kg AD04857) (2.0 0.272 0.130 0.302 0.145 0.478 0.187 0.815 0.436 1.772 1.412 151 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 167 / 191 152 / 160

[0269] As shown from the data in Table 13 above, each of the AAT RNAi agents showed a substantial reduction in AAT protein over at least day 29. For example, on day 15, each of the tested AAT RNAi agents achieved at least approximately 70% protein knockout compared to pretreatment levels, with multiple groups achieving 90% or better knockout. Example 7. In vivo testing of NAG-conjugated AAT RNAi agents in PiZ mice.

[0270] The transgenic PiZ mouse model described in Example 3 was used. Each mouse was 5 weeks old at baseline. NAG-conjugated AAT RNAi agents were prepared in a pharmaceutically acceptable saline buffer and administered to PiZ mice to assess an AAT gene expression knockout. Beginning on day 1, each mouse received a q2w subcutaneous (SQ) dose (i.e., one injection every two weeks, for a total of 4 injections) into the flabby skin of the back between the shoulders of 4.0 mg / kg (mpk) of: (1) saline vehicle; (2) AD04837 (see Tables 4 to 7 for the modified AAT RNAi agent and NAG ligand structures), which as previously noted included a modified nucleotide antisense strand sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1000; or (3) a NAG-conjugated RNAi agent that included a nucleotide sequence targeting the HBV gene, to be used as a negative control.Single subcutaneous injections for the saline vehicle group, AAT RNAi agent group, and HBV RNAi agent group were performed on days 1, 15, 29, and 43. Seven (7) mice were dosed q2w with the saline vehicle (Group 1); nine (9) mice were dosed q2w with the AAT RNAi agent (Group 2); and six (6) mice were dosed with the HBV RNAi agent (Group 3). Mice in all three treatment groups were sacrificed on day 57 (13 weeks of age). In addition to the treatment groups, Petition 870260038067, dated 04 / 24 / 2026, pp. 168 / 191 153 / 160 seven (7) mice were sacrificed in week 1 of the study (i.e., 5 weeks of age) to serve as a baseline control.

[0271] Plasma samples were collected and analyzed for AAT protein (Z-AAT) levels on day 1 (pre-dose), day 8, day 15, day 22, day 29, and day 36 for all groups. Additional samples for the AAT RNAi agent group and the saline vehicle group were collected on day 43, day 50, and day 57. AAT levels were normalized to day 1 AAT plasma levels (pre-dose). Protein levels were measured by quantifying circulating human Z-AAT levels in plasma using a commercially available ELISA kit according to the manufacturer's recommendations. The mean normalized AAT (Z-AAT) levels for the saline vehicle and each RNAi agent are reported in Table 14 below: Petition 870260038067, dated 04 / 24 / 2026, pp. 169 / 191 Table 14. Mean normalized AAT protein (between normalized and pre-treatment) from Example 7 Day 8 Day 15 Day 22 Day 29 Group ID Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Group 1 (saline vehicle) (n=7) 0.876 0.172 1.264 0.386 1.234 0.457 1.319 0.453 Group 2 (AD04837) (n=9) 0.139 0.050 0.146 0.064 0.067 0.029 0.072 0.038 Group 3 (HBV RNAi negative control agent) (n=6) 1.212 0.360 1.019 0.201 1.540 0.155 1.585 0.640 Day 36 Day 43 Day 50 Day 57 Group ID Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Group 1 (saline vehicle) (n=7) 1.267 0.491 1.441 0.416 1.172 0.340 1.058 0.299 Group 2 (AD04837) (n=9) 0.040 0.011 0.051 0.020 0.034 0.007 0.038 0.009 Group 3 (HBV RNAi negative control agent) (n=6) 1.665 0.476 1.943 0.221 1.580 0.491 2.001 0.770 154 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 170 / 191 155 / 160

[0272] As shown from the data in Table 14 above, the HBV RNAi agent was successfully performed as a negative control showing essentially no inhibition of AAT. Furthermore, the NAG-conjugated AAT RNAi agent (AD04837) achieved a significant knockout of expression compared to the saline and negative control HBV RNAi agent at all time points. At q2w dosing, the AAT RNAi agent in Example 7 showed approximately 96% knockout of AAT protein on day 36 (0.040) and maintained a similar knockout level until day 57.

[0273] In addition to monitoring serum AAT levels, homogenized liver tissue from PiZ mice treated with NAG-conjugated AAT RNAi agent (AD04837) was further analyzed to determine whether soluble ZAAT polymers (expected to be predominantly monomeric protein) and insoluble Z-AAT polymers (expected to be polymeric protein) were effectively reduced. A modified western blot protocol was used to separate the soluble and insoluble Z-AAT fractions under non-denaturation conditions as previously described and known in the art (see, for example, Mueller et al., Molecular Therapy, March 2012, 20(3): 590-600).

[0274] A western blot was prepared to examine certain livers from sacrificed mice. Specifically, livers were examined from (i) 6 baseline mice; (ii) 5 AAT RNAi agent mice; and (iii) 4 saline mice. (The gels used for the western blot analysis included 15 wells). Samples for the animals used for this western blot were randomly selected from several groups. Figures 11 and 12 show bar graphs reflecting the levels of Z-AAT polymer and ZAAT monomer quantified from the western blot analysis.

[0275] As observed from the bar graph in Figure 11, which reports the levels of monomeric protein when compared to the baseline each Petition 870260038067, dated 04 / 24 / 2026, pp. 171 / 191 One of the mice dosed with AAT RNAi agent (156 / 160) showed a significant reduction in monomeric AAT protein at all time points, indicating significant gene inhibition. Furthermore, as shown in Figure 12, which reports polymeric protein levels, animals treated with the saline vehicle continued to have an increased polymeric AAT burden after 8 weeks. Conversely, animals treated with the AAT RNAi agent showed a reduction in polymeric burden of approximately 50% over the course of 8 weeks compared to baseline mice (5 weeks old), indicating that administration of NAG-conjugated AAT RNAi agent (AD04837) is capable of preventing and potentially reversing polymeric AAT protein production. Example 8. In vivo testing of NAG-conjugated AAT RNAi agents in PiZ mice.

[0276] The transgenic PiZ mouse model described in Example 3 was used to evaluate RNAi agents in vivo. Each mouse received a single subcutaneous (SQ) dose on day 1 in the flabby skin of the back between the shoulders of: (1) saline solution; (2) 1.0 mg / kg of the AD04837 NAG-conjugated AAT RNAi agent (which includes a modified nucleotide antisense strand sequence designed to target an AAT gene (SEQ ID NO: 1) at position 1000); (3) 2.0 mg / kg of AD04837; (4) 4.0 mg / kg of AD04837; or (5) 8.0 mg / kg of AD04837. Four animals were dosed in group 1 (saline solution), and all four were sacrificed on day 43. Fifteen (15) animals were dosed in each of groups 2, 3, 4 and 5, and 3 animals from each group were sacrificed on day 8, day 15, day 22, day 29 and day 43, respectively.

[0277] Plasma samples were collected and analyzed for AAT protein (Z-AAT) levels on day 1 (pre-dose), day 8, day 15, day 22, day 29, day 36, and day 43 for all groups. For sacrificed mice, cardiac rods were Petition 870260038067, dated 04 / 24 / 2026, pp. 172 / 191 157 / 160 samples were performed for serum isolation to assess Z-AAT protein levels (200 μL of plasma). AAT levels were normalized to day 1 plasma AAT (predose) levels. Protein levels were measured by quantifying circulating human ZAAT levels in plasma using a commercially available ELISA kit according to the manufacturer's recommendations. Mean normalized AAT (Z-AAT) levels for the saline vehicle and each RNAi agent dosage group are reported in Table 15 below: Petition 870260038067, dated 04 / 24 / 2026, pp. 173 / 191 Table 15. Mean normalized AAT protein (between normalized and pretreatment) from Example 8. Day 8 Day 15 Day 22 Day 29 Group ID Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Average AAT Standard Deviation (+ / -) Group 1 (saline vehicle) 1.240 0.633 1.037 0.256 0.884 0.229 0.857 0.286 Group 2 (1.0 mg / kg AD04837) 0.266 0.100 0.250 0.107 0.259 0.060 0.412 0.191 Group 3 (2.0 mg / kg AD04837) 0.170 0.102 0.162 0.132 0.199 0.161 0.511 0.514 Group 4 (4.0 mg / kg AD04837) 0.051 0.015 0.038 0.010 0.051 0.021 0.110 0.045 Group 5 (8.0 mg / kg AD04837) 0.030 0.011 0.025 0.010 0.040 0.024 0.063 0.030 Day 36 Day 43 Group 1 (saline vehicle) 1.485 0.431 0.932 0.243 Group 2 (1.0 mg / kg AD04837) 0.791 0.207 0.560 0.111 Group 3 (2.0 mg / kg AD04837) 0.600 0.140 0.595 0.217 Group 4 (4.0 mg / kg AD04837) 0.156 0.008 0.148 0.022 Group 5 (8.0 mg / kg AD04837) 0.239 0.183 0.202 0.119 158 / 160 Petition 870260038067, dated 04 / 24 / 2026, pp. 174 / 191 159 / 160

[0278] As shown from the data in Table 15 above, the AAT NAG-conjugated RNAi agent achieved a significant knockout of expression compared to saline solution at all time points measured at all dosage levels tested.

[0279] In addition, AAT mRNA levels were also assessed for mice sacrificed at each respective time point. As described previously, for Groups 2 to 5 (i.e., the RNAi agent groups), 3 mice were sacrificed on each of days 8, 15, 22, 29, and 43; and for Group 1, all 4 mice were sacrificed on day 43. Half of the left lateral lobe of the liver was collected and flash-frozen in liquid nitrogen for RNA isolation. Table 16. Relative AAT mRNA levels in PiZ mice following administration of a single SQ injection of saline solution or AAT RNAi agent. Treatment Group Day Animals Mean Relative mRNA Expression Low Variance High Variance Group 1 (saline vehicle) 43 n=4 1.000 0.071 0.076 Group 2 (1.0 mg / kg AD04837) 8 n=3 0.412 0.080 0.099 15 n=3 0.419 0.037 0.040 22 n=3 0.483 0.066 0.076 29 n=3 0.696 0.069 0.076 43 n=3 0.813 0.103 0.118 Group 3 (2.0 mg / kg AD04837) 8 n=3 0.272 0.101 0.160 15 n=3 0.235 0.039 0.046 22 n=3 0.327 0.099 0.141 29 n=3 0.587 0.155 0.210 43 n=3 0.845 0.123 0.145 Group 4 (4.0 mg / kg AD04837) 8 n=3 0.129 0.025 0.031 15 n=3 0.161 0.017 0.020 22 n=3 0.222 0.048 0.061 29 n=3 0.247 0.067 0.093 Petition 870260038067, dated 04 / 24 / 2026, pp. 175 / 191 160 / 160 Treatment Group Day Animals Mean Relative mRNA Expression Low Variance High Variance 43 n=3 0.454 0.051 0.057 Group 5 (8.0 mg / kg AD04837) 8 n=3 0.078 0.013 0.015 15 n=3 0.055 0.014 0.019 22 n=3 0.077 0.009 0.010 29 n=3 0.116 0.038 0.056 43 n=3 0.332 0.122 0.193

[0280] As shown in Table 16 above, relative AAT mRNA expression levels were significantly reduced at all measured time points compared to the saline vehicle. For example, on day 15, Group 2 (1.0 mg / kg AAT RNAi agent) showed approximately a 58% reduction in AAT mRNA levels (0.419); Group 3 (2.0 mg / kg AAT RNAi agent) showed approximately a 67% reduction in AAT mRNA levels (0.327); Group 4 (4.0 mg / kg AAT RNAi agent) showed approximately an 84% reduction in AAT mRNA levels (0.161); and Group 5 (8.0 mg / kg AAT RNAi agent) showed approximately a 94% reduction in ZAAT mRNA levels (0.055) following a single SQ dose on day 1. Other modalities

[0281] It should be understood that although the invention has been described in conjunction with the detailed description, the preceding description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims

1. RNAi agent for inhibiting the expression of an alpha-1 antitrypsin (AAT) gene CHARACTERIZED in that it comprises a sense strand and an antisense strand, wherein nucleotides 2 to 18 of the antisense strand comprise the nucleotides 2 to 18 NGUUAAACAUGCCUAAACN (SEQ ID NO: 83), wherein the sense strand is at least substantially complementary to the antisense strand, and wherein the antisense strand comprises (i) 2 or 3 phosphorothioate linkages at its 5' end, (ii) at least 8 nucleotides selected from 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoroguanosine and 2'-fluorouridine, (iii) at least 11 nucleotides selected from 2'-O-methyladenosine, 2'-O-methylcytidine, 2'-O-methylguanosine and 2'-O-methyl uridine, or (iv) any combination thereof.

2. RNAi agent, according to claim 1, CHARACTERIZED in that the antisense strand comprises a nucleotide sequence selected from (5'—>3'): (i) UGUUAAACAUGCCUAAACGUU (SEQ ID NO: 794); (ii) UGUUAAACAUGCCUAAACGCUU (SEQ ID NO: 839); (iii) UGUUAAACAUGCCUAAACGCG (SEQ ID NO: 800); (iv) UGUUAAACAUGCCUAAACGCU (SEQ ID NO: 801); and wherein the sense strand comprises a nucleotide sequence selected from (5'—>3'): (i) AGCGUUUAGGCAUGUUAACA (SEQ ID NO: 866); (ii) CGUUUAGGCAUGUUAACAUU (SEQ ID NO: 857); (iii) GCGUUUAGGCAUGUUAACAUU (SEQ ID NO: 885); (iv) CGCGUUUAGGCAUGUUAACA (SEQ ID NO: 864). Petition 870260038067, dated 04 / 24 / 2026, page 177 / 191 2 / 6 3. RNAi agent, according to claim 1 or 2, CHARACTERIZED in that the RNAi agent comprises a targeting group, wherein the targeting group is conjugated to the 5' terminal end of the sense strand; wherein the targeting group comprises an asialoglycoprotein receptor ligand, wherein the asialoglycoprotein receptor ligand comprises an N-acetylgalactosamine trimer.

4. RNAi agent, according to any one of claims 1 to 3, CHARACTERIZED in that the RNAi agent further comprises one or more targeting groups, and wherein the targeting group has a structure selected from the group consisting of: (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), (NAG39)s.

5. RNAi agent, according to claim 4, CHARACTERIZED in that the targeting group is (NAG37)s, and (NAG37)s has the following chemical structure:

6. RNAi agent, according to any one of claims 1 to 5, CHARACTERIZED in that the RNAi agent has two blunt ends. Petition 870260038067, dated 04 / 24 / 2026, p. 178 / 191 3 / 6 7. RNAi agent, according to any one of claims 1 to 6, CHARACTERIZED in that all nucleotides are modified nucleotides.

8. RNAi agent, according to any one of claims 1 to 7, CHARACTERIZED in that it is selected from the group consisting of: - the antisense strand comprises the nucleotide sequence (5' 3') usGfsuUfaAfacaugCfclIfaAfaCfgCfsu (SEQ ID NO: 960), wherein a, c, g are 2'-O-methyl adenosine, cytidine, guanosine or uridine, respectively; Af, Cf, Gf and llf are 2'-fluoro-adenosine, cytidine, guanosine or uridine, respectively; es is a phosphorothioate linkage; and - the sense strand comprises the sequence (5' 3') agcguuuaGfGfCfauguuuaaca (SEQ ID NO: 1279), where a, c, gf are 2'-O-methyl adenosine, cytidine, guanosine or uridine, respectively; Af, Cf, Gf and llf are 2'-fluoro adenosine, cytidine, guanosine or uridine, respectively; s is a phosphorothioate linkage; wherein optionally present in the sense strand is one or two inverted abasic deoxyribose (invAb) residues and / or one, two, three or four phosphorothioate internucleoside linkages;and wherein optionally attached to the 5' terminal end of the sense strand is a targeting ligand comprising N-acetylgalactosamine; and / or - the antisense strand comprises the nucleotide sequence (5' 3') usGfsusUfaAfaCfallfgCfcUfaAfaCfgusu (SEQ ID NO: 913), wherein a, c, geu are 2'-O-methyl adenosine, cytidine, guanosine or uridine, respectively; Af, Cf, Gf and llf are 2'-fluoro adenosine, cytidine, guanosine or uridine, respectively; es is a phosphorothioate linkage; and the sense strand comprises the sequence (5' 3') cguuuaGfGfCfauguuuaacausu (SEQ ID NO: 1276), wherein a, c, geu are 2'-O-methyl adenosine, cytidine, guanosine or uridine, respectively; Af, Cf, Gf and llf are 2'-fluoro Petition 870260038067, dated 04 / 24 / 2026, p. 179 / 191 4 / 6 adenosine, cytidine, guanosine or uridine, respectively; s is a phosphorothioate linkage;wherein optionally present in the sense strand is one or two inverted abasic deoxyribose (invAb) residues and / or one, two, three or four phosphorothioate internucleoside linkages; and wherein optionally attached to the 5' terminal end of the sense strand is a targeting linker comprising N-acetylgalactosamine; and / or - the antisense strand comprises the nucleotide sequence (5'^3') usGfsusUfaAfaCfaUfgCfcUfaAfaCfgcusu (SEQ ID NO: 958), where a, c, g and u are 2'O-methyl adenosine, cytidine, guanosine or uridine, respectively; Af, Cf, Gf and Uf are 2'-fluoro adenosine, cytidine, guanosine or uridine, respectively; es is a phosphorothioate linkage; and - the sense ribbon comprises the sequence (5' ^ 3') gcguuuaGfGfCfauguuuaacausu (SEQ ID NO: 1277), where a, c, gf are 2'-O-methyl adenosine, cytidine, guanosine or uridine, respectively; Af, Cf, Gf and Uf are 2'-fluoro adenosine, cytidine, guanosine or uridine, respectively; s is a phosphorothioate linkage;wherein optionally present in the sense strand is one or two inverted abasic deoxyribose (invAb) residues and / or one, two, three or four phosphorothioate internucleoside linkages; and wherein optionally attached to the 5' terminal end of the sense strand is a targeting linker comprising N-acetylgalactosamine; and / or - the antisense strand comprises the nucleotide sequence (5'^3') usGfsuUfaAfaCfaUfgCfcUfaAfaCfgsCfsg (SEQ ID NO: 959), where a, c, g and u are 2'O-methyl adenosine, cytidine, guanosine or uridine, respectively; Af, Cf, Gf and Uf are 2'-fluoro adenosine, cytidine, guanosine or uridine, respectively; es is a phosphorothioate linkage; - the sense ribbon comprises the sequence (5' ^ 3') cgcguuuaGfGfCfauguuuaaca (SEQ ID NO: 1278), where a, c, g and e are 2'-O-methyl adenosine, cytidine, guanosine or uridine, respectively;Af, Cf, Gf and llf are 2'-fluoroadenosine, cytidine, guanosine or uridine, respectively; s is a phosphorothioate linkage; wherein optionally present in the sense strand is one or two inverted abasic deoxyribose (invAb) residues and / or one, two, three or four phosphorothioate internucleoside linkages; and wherein optionally attached to the 5' terminal end of the sense strand is a targeting ligand comprising N-acetylgalactosamine.

9. RNAi agent, according to any one of claims 1 to 8, CHARACTERIZED in that the antisense strand is 21 or 22 nucleotides long.

10. RNAi agent, according to claim 1, CHARACTERIZED in that it comprises: (a) an antisense strand comprising the nucleotide sequence selected from the group consisting of (5' 3'): (i) usGfsusUfaAfaCfaUfgCfcUfaAfaCfgusu (SEQ ID NO: 913); (ii) usGfsusUfaAfaCfaUfgCfcUfaAfaCfgcusu (SEQ ID NO: 958); (iii) usGfsuUfaAfaCfaUfgCfcUfaAfaCfgsCfsg (SEQ ID NO: 959); and (iv) usGfsulIfaAfacaugCfcUfaAfaCfgCfsu (SEQ ID NO: 960); where a, c, gf are 2'-O-methyl adenosine, cytidine, guanosine, or uridine, respectively; Af, Cf, Gf, and llf are 2'-fluoro adenosine, cytidine, guanosine, or uridine, respectively; es is a phosphorothioate linkage; and (b) the sense strand is at least substantially complementary to the antisense strand, wherein all or substantially all nucleotides in the sense strand are modified nucleotides; and wherein the sense strand is linked to a directing group comprising N-acetylgalactosamine.

11. RNAi agent, according to claim 10, CHARACTERIZED in that the RNAi agent has the duplex structure of AD04828 (SEQ ID Petition 870260038067, dated 04 / 24 / 2026, pp. 181 / 191 6 / 6 PAIR Nos: 913 / 1028).

12. RNAi agent, according to claim 10, CHARACTERIZED in that the RNAi agent has the duplex structure of AD04831 (SEQ ID PAIR NOS: 958 / 1030).

13. RNAi agent, according to claim 10, CHARACTERIZED in that the RNAi agent has the duplex structure of AD04836 (SEQ ID PAIR NOS: 959 / 1024).

14. RNAi agent, according to claim 10, CHARACTERIZED in that the RNAi agent has the duplex structure of AD04837 (SEQ ID PAIR NOS: 960 / 1033).

15. Composition CHARACTERIZED in that it comprises the RNAi agent, as defined in any one of claims 1 to 13, and at least one pharmaceutically acceptable excipient.

16. Composition according to claim 15, CHARACTERIZED in that the composition is formulated for administration by subcutaneous injection.

17. Use of the composition, as defined in claim 15 or 16, CHARACTERIZED in that it is in the preparation of a medicament to inhibit the expression of AAT in a cell, tissue or individual.

18. Use of the composition, as defined in claim 15 or 16, CHARACTERIZED in that it is in the preparation of a medicament for treating alpha-1 antitrypsin deficiency (AATD) in an individual, wherein the condition or disease caused by AATD is a liver disease, wherein the liver disease is chronic hepatitis, cirrhosis, hepatocellular carcinoma, transaminitis, cholestasis, fibrosis or fulminant hepatic failure.

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