# US 12,110,491 B2 · Selective reduction of allelic variants

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- Number: US 12,110,491 B2
- Document ID: US12110491B2
- Status: Granted
- Kind: B2
- Application number: 17/577,832
- Filed: 2022-01-18
- Published: 2022-12-22
- Granted: 2024-10-08
- Earliest claimed: 2010-02-08
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: C. Frank Bennett; Susan M. Freier; Sarah Greenlee; Eric E. Swayze
- Web page: https://patentgrep.com/patent/US12110491B2

## CPC

- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2320/34: Allele or polymorphism specific uses
- C12N 2320/35: based on a specific dosage / administration regimen
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are antisense compounds and methods for selectively reducing expression of an allelic variant of a gene containing a single nucleotide polymorphism (SNP). Such methods, compounds, and composition are useful to treat, prevent, or ameliorate diseases, including neurodegenerative diseases, such as Huntington's Disease (HD).

## Claims

### Claim 1

A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides and comprising a nucleobase sequence having at least 95% sequence identity to the nucleobase sequence of SEQ ID NO: 274, wherein the modified oligonucleotide comprises at least one nucleoside comprising a modified sugar and at least one modified internucleoside linkage, wherein each T in SEQ ID NO: 274 is independently a T or a U, and wherein the modified oligonucleotide is a gapmer.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the modified oligonucleotide comprises a nucleobase sequence having 100% sequence identity to the nucleobase sequence of SEQ ID NO: 274, wherein each T in SEQ ID NO: 274 is independently a T or a U.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the modified sugar is a 2′MOE sugar.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the modified sugar is a 2′-OMe sugar.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 6 (depends on 1)

The compound of claim 1, wherein at least one nucleoside comprises a modified nucleobase.

### Claim 7 (depends on 6)

The compound of claim 6, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the gapmer has a 5-10-5 wing-gap-wing motif.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable diluent or carrier.

### Claim 10

A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides, wherein the modified oligonucleotide is complementary to a differentiating polymorphism site, wherein the modified oligonucleotide comprises at least a 16 contiguous nucleobase portion of the nucleobase sequence of any of SEQ ID NOs: 274-276, wherein position 8, 9, or 10 of the modified oligonucleotide, as counted from the 5′ terminus of the modified oligonucleotide, aligns with the differentiating polymorphism site, wherein the modified oligonucleotide comprises at least one nucleoside comprising a modified sugar and at least one modified internucleoside linkage, and wherein each T in SEQ ID NO: 274, 275, or 276 is independently a T or a U, and wherein the modified oligonucleotide is a gapmer.

### Claim 11 (depends on 10)

The compound of claim 10, wherein the modified oligonucleotide comprises a 17 contiguous nucleobase portion of the nucleobase sequence of any of SEQ ID NOs: 274-276, wherein each Tin SEQ ID NO: 274, 275, and 276 is independently a T or a U.

### Claim 12 (depends on 10)

The compound of claim 10, wherein the modified sugar is a 2′MOE sugar.

### Claim 13 (depends on 10)

The compound of claim 10, wherein the modified sugar is a 2′-OMe sugar.

### Claim 14 (depends on 10)

The compound of claim 10, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 15 (depends on 10)

The compound of claim 10, wherein at least one nucleoside comprises a modified nucleobase.

### Claim 16 (depends on 15)

The compound of claim 15, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 17 (depends on 10)

The compound of claim 10, wherein the gapmer has a 5-10-5 wing-gap-wing motif.

### Claim 18 (depends on 10)

A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable diluent or carrier.

### Claim 19

A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides and having a nucleobase sequence comprising a portion that is complementary to at least 16 contiguous nucleobases of nucleobases 167062-167080 or nucleobases 167063-167081 of SEQ ID NO: 1, wherein the modified oligonucleotide comprises at least one nucleoside comprising a modified sugar and at least one modified internucleoside linkage, and wherein the modified oligonucleotide is a gapmer.

### Claim 20 (depends on 19)

The compound of claim 19, wherein the modified oligonucleotide has a nucleobase sequence comprising a portion that is complementary to at least 17 contiguous nucleobases of nucleobases 167062 to 167080 of SEQ ID NO: 1.

### Claim 21 (depends on 19)

The compound of claim 19, wherein the modified oligonucleotide has a nucleobase sequence comprising a portion that is complementary to at least 18 contiguous nucleobases of nucleobases 167062 to 167080 of SEQ ID NO: 1.

### Claim 22 (depends on 19)

The compound of claim 19, wherein the modified oligonucleotide has a nucleobase sequence comprising a portion that is complementary to at least 19 contiguous nucleobases of nucleobases 167062 to 167080 of SEQ ID NO: 1.

### Claim 23 (depends on 19)

The compound of claim 19, wherein the modified oligonucleotide has a nucleobase sequence comprising a portion that is complementary to at least 17 contiguous nucleobases of nucleobases 167063 to 167081 of SEQ ID NO: 1.

### Claim 24 (depends on 19)

The compound of claim 19, wherein the modified oligonucleotide has a nucleobase sequence comprising a portion that is complementary to at least 18 contiguous nucleobases of nucleobases 167063 to 167081 of SEQ ID NO: 1.

### Claim 25 (depends on 19)

The compound of claim 19, wherein the modified oligonucleotide has a nucleobase sequence comprising a portion that is complementary to at least 19 contiguous nucleobases of nucleobases 167063 to 167081 of SEQ ID NO: 1.

### Claim 26 (depends on 19)

The compound of claim 19, wherein the modified sugar is a 2′MOE sugar.

### Claim 27 (depends on 19)

The compound of claim 19, wherein the modified sugar is a 2′-OMe sugar.

### Claim 28 (depends on 19)

The compound of claim 19, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 29 (depends on 19)

The compound of claim 19, wherein at least one nucleoside comprises a modified nucleobase.

### Claim 30 (depends on 29)

The compound of claim 29, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 31 (depends on 19)

The compound of claim 19, wherein the gapmer has a 5-10-5 wing-gap-wing motif.

### Claim 32 (depends on 19)

A pharmaceutical composition comprising the compound of claim 19 and a pharmaceutically acceptable diluent or carrier.

### Claim 33

A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides and comprising the nucleobase sequence of SEQ ID NO: 275, wherein the modified oligonucleotide comprises at least one nucleoside comprising a modified sugar and at least one modified internucleoside linkage, wherein each T in SEQ ID NO: 275 is independently a T or a U, and wherein the modified oligonucleotide is a gapmer.

### Claim 34 (depends on 33)

The compound of claim 33, wherein the modified sugar is a 2′MOE sugar.

### Claim 35 (depends on 33)

The compound of claim 33, wherein the modified sugar is a 2′-OMe sugar.

### Claim 36 (depends on 33)

The compound of claim 33, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 37 (depends on 33)

The compound of claim 33, wherein at least one nucleoside comprises a modified nucleobase.

### Claim 38 (depends on 37)

The compound of claim 37, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 39 (depends on 33)

The compound of claim 33, wherein the gapmer has a 5-10-5 wing-gap-wing motif.

### Claim 40 (depends on 33)

A pharmaceutical composition comprising the compound of claim 33 and a pharmaceutically acceptable diluent or carrier.

### Claim 41

A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides and comprising the nucleobase sequence of SEQ ID NO: 276, wherein the modified oligonucleotide comprises at least one nucleoside comprising a modified sugar and at least one modified internucleoside linkage, wherein each T in SEQ ID NO: 276 is independently a T or a U, and wherein the modified oligonucleotide is a gapmer.

### Claim 42 (depends on 41)

The compound of claim 41, wherein the modified sugar is a 2′MOE sugar.

### Claim 43 (depends on 41)

The compound of claim 41, wherein the modified sugar is a 2′-OMe sugar.

### Claim 44 (depends on 41)

The compound of claim 41, wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 45 (depends on 41)

The compound of claim 41, wherein at least one nucleoside comprises a modified nucleobase.

### Claim 46 (depends on 45)

The compound of claim 45, wherein the modified nucleobase is a 5-methylcytosine.

### Claim 47 (depends on 41)

The compound of claim 41, wherein the gapmer has a 5-10-5 wing-gap-wing motif.

### Claim 48 (depends on 41)

A pharmaceutical composition comprising the compound of claim 41 and a pharmaceutically acceptable diluent or carrier.

### Claim 49 (depends on 10)

The compound of claim 10, wherein the modified oligonucleotide comprises an 18 contiguous nucleobase portion of the nucleobase sequence of any of SEQ ID NOs: 274-276, wherein each Tin SEQ ID NO: 274, 275, and 276 is independently a T or a U.

### Claim 50 (depends on 10)

The compound of claim 10, wherein the modified oligonucleotide comprises a 19 contiguous nucleobase portion of the nucleobase sequence of any of SEQ ID NOs: 274-276, wherein each Tin SEQ ID NO: 274, 275, and 276 is independently a T or a U.