Granted Patent B2

US 12,516,322 · App. 18/532,300 · Granted Jan 6, 2026

Inventors: Jonathan Edward Farley (Boston, MA); Mark K. Schlegel (Lexington, MA); James D. McIninch (Burlington, MA); Jeffrey Zuber (Somerville, MA); Adam Castoreno (Framingham, MA); Stephen Abbott (Lexington, MA); Joseph Barry (Arlington, MA)

Assignee: Alnylam Pharmaceuticals, Inc.

C12N15/113A61K48/005C12N15/85C12N2310/14C12N2310/315

Abstract

Claims (54)

1 . A double-stranded ribonucleic acid (dsRNA) agent, or a pharmaceutically acceptable salt thereof, comprising a sense strand and an antisense strand forming a double-stranded region, wherein the antisense strand comprises the nucleotide sequence,

5′-VPusAfsccdAudAcgagcuUfgGfgucacsgsu-3′ (SEQ ID. NO: 1011),

wherein

VP is a 5′-vinyl phosphonate;

s is a phosphorothioate linkage;

a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;

dA is 2′-deoxy A; and

Af, Gf, Uf are 2′-deoxy-2′-fluoro (2′-F) A, G, and U, respectively.

2 . The dsRNA agent of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the sense strand comprises the nucleotide sequence,

5′-gsusgac (Chd) caAfGfCfucguauggsusa-3′ (SEQ ID. NO: 1007),

wherein

(Chd) is 2′-O-hexadecyl-cytidine-3′-phosphate;

s is a phosphorothioate linkage;

a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively; and

Af, Cf, and Gf are 2′-deoxy-2′-fluoro (2′-F) A, C, and G, respectively.

3 . A double-stranded ribonucleic acid (dsRNA) agent, or a pharmaceutically acceptable salt thereof, comprising a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand consists of the nucleotide sequence,

5′-gsusgac (Chd) caAfGfCfucguauggsusa-3′ (SEQ ID. NO: 1007), and the antisense strand consists of the nucleotide sequence,

5′-VPusAfsccdAudAcgagcuUfgGfgucacsgsu-3′ (SEQ ID. NO: 1011),

wherein

VP is a 5′-vinyl phosphonate;

s is a phosphorothioate linkage;

a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;

dA is 2′-deoxy A;

Af, Cf, Gf, Uf are 2′-deoxy-2′-fluoro (2′-F) A, C, G, and U, respectively; and

(Chd) is 2′-O-hexadecyl-cytidine-3′-phosphate.

4 . A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of MAPT , wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,

wherein the antisense strand comprises a region of complementarity to an mRNA encoding Tau, and wherein the region of complementarity comprises at least nucleotides 2-18 of the antisense sequence, counting from the 5′-end of the antisense sequence,

(SEQ ID NO: 1003)

UACCAU A CGAGCUUGGGUCACGU.

5 . The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 4 , wherein the region of complementarity comprises at least 19 contiguous nucleotides of the antisense sequence.

6 . The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 4 , wherein the sense strand comprises the nucleotide sequence SEQ ID NO: 999.

7 . The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 4 , wherein the antisense strand comprises the nucleotide sequence SEQ ID NO: 1003.

8 . The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 7 , wherein the sense strand comprises the nucleotide sequence SEQ ID NO: 999.

9 . The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 4 , wherein the sense strand consists of the nucleotide sequence SEQ ID NO: 999, and the antisense strand consists of the nucleotide sequence SEQ ID NO: 1003.

10 . The dsRNA agent of claim 4 , wherein the dsRNA agent comprises at least one modified nucleotide.

11 . The dsRNA agent of claim 10 , wherein the at least one modified nucleotide is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxythymidine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural nucleotide base, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a nucleotide comprising a 5′-methylphosphonate group, a nucleotide comprising a 5′ phosphate or 5′ phosphate mimic, a nucleotide comprising vinyl phosphonate, a glycol nucleic acid (GNA), a glycol nucleic acid S-Isomer (S-GNA), a 2′-5′-linked ribonucleotides (“3′-RNA”), nucleotide comprising 2-hydroxymethyl-tetrahydrofuran-5-phosphate, a nucleotide comprising 2′-deoxythymidine-3′phosphate, a nucleotide comprising 2′-deoxyguanosine-3′-phosphate, and a terminal nucleotide linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group; and combinations thereof.

12 . The dsRNA agent of claim 4 , wherein at least one strand comprises a 3′ overhang of 1 or 2 nucleotides.

13 . The dsRNA agent of claim 4 , wherein each strand has 19-23 nucleotides and the double-stranded region is 17-23 in length.

14 . The dsRNA agent of claim 4 , wherein the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides.

15 . The dsRNA agent of claim 4 , further comprising at least one phosphorothioate internucleotide linkage.

16 . The dsRNA agent of claim 15 , wherein the dsRNA agent comprises 6-8 phosphorothioate internucleotide linkages.

17 . The dsRNA agent of claim 4 , further comprising a phosphate or phosphate mimic at the 5′-end of the antisense strand.

18 . The dsRNA agent of claim 17 , wherein the phosphate mimic is a 5′-vinyl phosphonate (VP).

19 . The dsRNA agent of claim 4 , wherein the base pair at the 1 position of the 5′-end of the antisense strand of the double-stranded region is an AU base pair.

20 . The dsRNA agent of claim 4 , wherein the sense strand, the antisense strand, or both the sense strand and the antisense strand is conjugated to one or more lipophilic moieties.

21 . The dsRNA agent of claim 20 , wherein the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 4-8 and 13-18 on the sense strand, and positions 6-10 and 15-18 on the antisense strand, counting from the 5′end of each strand.

22 . The dsRNA agent of claim 20 , wherein the one or more lipophilic moieties contain a saturated or unsaturated C4-C30 hydrocarbon chain, and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne.

23 . The dsRNA agent of claim 20 , wherein the one or more lipophilic moieties are conjugated to a nucleobase, sugar moiety, or internucleosidic linkage.

24 . The dsRNA agent of claim 20 , wherein the one or more lipophilic moieties contain a saturated or unsaturated C16 hydrocarbon chain.

25 . The dsRNA agent of claim 24 , wherein the saturated or unsaturated C16 hydrocarbon chain is conjugated to position 6 or 7 of the sense strand, counting from the 5′-end of the sense strand.

26 . The dsRNA agent of claim 2 that is a pharmaceutically acceptable salt.

27 . The dsRNA agent of claim 26 that is the sodium salt.

28 . The dsRNA agent of claim 3 that is a pharmaceutically acceptable salt.

29 . The dsRNA agent of claim 28 that is the sodium salt.

Assignments (2)

Continuity (5)

References Cited (400)