# US 12,767,948 B2 · Oligomeric compounds comprising bicyclic nucleotides and uses thereof

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- Number: US 12,767,948 B2
- Document ID: US12767948B2
- Status: Granted
- Kind: B2
- Application number: 18/067,574
- Filed: 2022-12-16
- Published: 2023-09-07
- Granted: 2026-10-20
- Earliest claimed: 2012-04-20
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Susan M. Freier; Eric E. Swayze
- Web page: https://patentgrep.com/patent/US12767948B2

## 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)}
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- C12Y 301/03016: Phosphoprotein phosphatase (3.1.3.16), i.e. calcineurin
- C12Y 301/03048: Protein-tyrosine-phosphatase (3.1.3.48)
- C12Y 301/03067: Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (3.1.3.67)
- C12N 2310/11: Antisense
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/343: having patterns, e.g. ==--==--==--
- C12N 2310/3525: MOE, methoxyethoxy
- C12N 2320/51: modulating the chemical stability, e.g. nuclease-resistance
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

## Claims

### Claim 1

A compound comprising:
a modified oligonucleotide consisting of 16-18 linked nucleosides, wherein the modified oligonucleotide consists of:
a 5′-wing consisting of 4 linked nucleosides and having the sugar motif B-B-A-A;
a 3′-wing consisting of 4 linked nucleosides and having the sugar motif A-A-B-B; and
a gap between the 5′-wing and the 3′-wing consisting of 8-10 linked 2′-deoxynucleosides;
wherein each B is a bicyclic nucleoside and each A is a 2′-substituted nucleoside comprising a substituent at the 2′-position other than H or OH; and
wherein the nucleobase sequence of the modified oligonucleotide is complementary to the nucleobase sequence of a target nucleic acid.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the gap between the 5′-wing and the 3′-wing consists of 8 linked 2′-deoxynucleosides.

### Claim 3 (depends on 1)

The compound of claim 1, wherein each bicyclic nucleoside is a locked nucleic acid (LNA) nucleoside or a constrained ethyl (cEt) nucleoside.

### Claim 4 (depends on 1)

The compound of claim 1, wherein each bicyclic nucleoside is a LNA nucleoside.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the substituent at the 2′-position of each 2′-substituted nucleoside is selected from 2′-OMe, 2′-O-methoxyethyl, and 2′-F.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the substituent at the 2′-position of each 2′-substituted nucleoside is a 2′-O-methoxyethyl group.

### Claim 7 (depends on 1)

The compound of claim 1, wherein each bicyclic nucleoside is a LNA nucleoside and the substituent at the 2′-position of each 2′-substituted nucleoside is a 2′-O-methoxyethyl group.

### Claim 8 (depends on 2)

The compound of claim 2, wherein each bicyclic nucleoside is a LNA nucleoside and the substituent at the 2′-position of each 2′-substituted nucleoside is a 2′-O-methoxyethyl group.

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 8)

A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable diluent.

### Claim 11 (depends on 8)

The compound of claim 8, comprising a conjugate group.

### Claim 12 (depends on 1)

A method of modulating expression of a target nucleic acid in a cell comprising contacting the cell with the compound of claim 1.

### Claim 13 (depends on 8)

A method of modulating expression of a target nucleic acid in a cell comprising contacting the cell with the compound of claim 8.

### Claim 14

A modified oligonucleotide consisting of 16 linked nucleosides, wherein the modified oligonucleotide comprises:
a 5′-wing consisting of 4 linked nucleosides and having the sugar motif B-B-A-A;
a 3′-wing consisting of 4 linked nucleosides and having the sugar motif A-A-B-B; and
a gap between the 5′-wing and the 3′-wing consisting of 8 linked 2′-deoxynucleosides;
wherein each B is a LNA nucleoside and each A is a 2′-O-methoxyethyl nucleoside; and
wherein the nucleobase sequence of the modified oligonucleotide is complementary to the nucleobase sequence of a target nucleic acid.

### Claim 15 (depends on 14)

A pharmaceutical composition comprising the modified oligonucleotide of claim 14 and a pharmaceutically acceptable diluent.

### Claim 16 (depends on 14)

A method of modulating expression of a target nucleic acid in a cell comprising contacting the cell with the modified oligonucleotide of claim 14.