# US 12,760,308 B2 · Compositions and methods for silencing SCN9A expression

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- Number: US 12,760,308 B2
- Document ID: US12760308B2
- Status: Granted
- Kind: B2
- Application number: 17/995,699
- Filed: 2021-04-06
- Published: 2023-05-25
- Granted: 2026-10-13
- Earliest claimed: 2020-04-07
- Assignees: Alnylam Pharmaceuticals, Inc.
- Applicants: Alnylam Pharmaceuticals, Inc.
- Inventors: William Cantley; James D. McIninch; Adam Castoreno; Charalambos Kaittanis; Mark K. Schlegel
- Web page: https://patentgrep.com/patent/US12760308B2

## CPC

- C12N 15/1138: {against receptors or cell surface proteins}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/3125: Methylphosphonates
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2310/3525: MOE, methoxyethoxy
- C12N 2320/31: Combination therapy
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The disclosure relates to double-stranded ribonucleic acid (dsRNA) compositions targeting SCN9A, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of SCN9A.

## Claims

### Claim 1

A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of sodium channel, voltage gated, type IX alpha subunit (SCN9A), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides, with 0 or 1 mismatch, from the antisense sequence set forth as SEQ ID NO: 5093 and wherein the sense strand comprises a nucleotide sequence comprising at least 17 contiguous nucleotides, with 0 or 1 mismatch, from a sense sequence set forth as SEQ ID NO: 4827.

### Claim 2 (depends on 1)

The dsRNA of claim 1, wherein the sense strand comprises the nucleotide sequence set forth as SEQ ID NO: 4827 and the antisense strand comprises the nucleotide sequence set forth as SEQ ID NO: 5093.

### Claim 3 (depends on 1)

The dsRNA agent of claim 1, wherein at least one of the sense strand and the antisense strand is conjugated to one or more lipophilic moieties.

### Claim 4 (depends on 3)

The dsRNA agent of claim 3, wherein the lipophilic moiety is conjugated to the dsRNA agent (i) via a carrier that replaces one or more nucleotide(s) in the internal position(s) or the double stranded region; or (ii) via a linker containing an ether, thioether, urea, carbonate, amine, amide, maleimide-thioether, disulfide, phosphodiester, sulfonamide linkage, a product of a click reaction, or carbamate.

### Claim 5 (depends on 1)

The dsRNA agent of claim 1, wherein
(a) the dsRNA agent comprises at least one modified nucleotide;
(b) no more than five of the sense strand nucleotides and not more than five of the nucleotides of the antisense strand are unmodified nucleotides; or
(c) all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides.

### Claim 6 (depends on 5)

The dsRNA agent of claim 5, wherein at least one of the modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxythimidine (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, 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 phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, a nucleotide comprising a 5′-phosphate mimic, a glycol modified nucleotide, and a 2-O-(N-methylacetamide) modified nucleotide; and combinations thereof.

### Claim 7 (depends on 1)

The dsRNA agent of claim 1, wherein
(a) at least one strand comprises a 3′ overhang of at least 2 nucleotides;
(b) the double stranded region is 15-30 nucleotide pairs in length;
(c) the double stranded region is 17-23 nucleotide pairs in length;
(d) each strand has 19-30 nucleotides; and/or
(e) the dsRNA agent comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

### Claim 8 (depends on 3)

The dsRNA agent of claim 3, wherein the dsRNA agent further comprises
(a) a targeting ligand;
(b) a targeting ligand that targets a CNS tissue; or
(c) a targeting ligand that targets a CNS tissue, wherein the CNS tissue is a brain tissue or a spinal tissue.

### Claim 9 (depends on 1)

The dsRNA agent of claim 1, wherein the dsRNA agent comprises
(a) a phosphate or phosphate mimic at the 5′-end of the antisense strand; or
(b) a 5′-vinyl phosphonate (VP) at the 5′-end of the antisense strand.

### Claim 10 (depends on 1)

The dsRNA agent of claim 1, wherein
the sense strand comprises the modified sequence 5′-usgsucgaguAfCfAfcuuu(Uhd)acugaL96-3′ (SEQ ID NO: 4029), and the antisense strand comprises the modified sequence 5′-VPusCfsagdTadAaagudGuAfcdTegacasusu-3′ (SEQ ID NO: 4295),
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;
Af and Cf is 2′-deoxy-2′-fluoro (2′-F) A and U, respectively;
s is a phosphorothioate linkage;
dT, dA, and dG is 2′-deoxythymidine, 2′-deoxyadenosine-3′-phosphate, and 2′-deoxyguanosine-3′-phosphate, respectively;
Uhd is 2′-O-hexadecyl-uridine-3′-phosphate;
VP is vinyl phosphonate; and
L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol Hyp-(GalNAc-alkyl) 3.

### Claim 11 (depends on 1)

An isolated cell containing the dsRNA agent of claim 1.

### Claim 12 (depends on 1)

A pharmaceutical composition for inhibiting expression of a SCN9A, comprising the dsRNA agent of claim 1.

### Claim 13 (depends on 1)

A method of inhibiting expression of SCN9A in a cell, the method comprising:
(a) introducing into the cell the dsRNA agent of claim 1; and
(b) maintaining the cell produced in step (a) for a time sufficient to reduce levels of SCN9A mRNA, SCN9A protein, or both of SCN9A mRNA and protein, thereby inhibiting expression of SCN9A in the cell.

### Claim 14 (depends on 1)

A method of treating a subject having or diagnosed with having a SCN9A-associated disorder, wherein the SCN9A-associated disorder is pain associated with primary erythromelalgia (PE) or paroxysmal extreme pain disorder (PEPD), comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1, thereby treating the disorder.

### Claim 15 (depends on 14)

The method of claim 14, wherein treating comprises amelioration of at least one sign or symptom of the disorder PE or PEPD in the subject; and/or the treating comprises (a) reducing pain in the subject; or (b) inhibiting or reducing the expression or activity of SCN9A in the subject.

### Claim 16 (depends on 14)

The method of claim 14 wherein
(a) the dsRNA agent is administered to the subject intracranially, intrathecally, intraventricularly, or intracerebrally; and/or
(b) the method further comprises administering to the subject an additional agent or therapy suitable for treatment or prevention of PE or PEPD.

### Claim 17 (depends on 3)

The dsRNA agent of claim 3, wherein
(a) the one or more lipophilic moieties are conjugated via a linker or carrier;
(b) the one or more lipophilic moieties are conjugated to one or more internal positions on at least one strand;
(c) the one or more lipophilic moieties are conjugated to one or more internal positions on at least one strand via a linker or carrier;
(d) the one or more lipophilic moieties are an aliphatic, alicyclic, or polyalicyclic compound;
(e) the one or more lipophilic moieties contain a saturated or unsaturated C16 hydrocarbon chain; and/or
(f) the one or more lipophilic moieties are conjugated to a nucleobase, sugar moiety, or internucleosidic linkage.

### Claim 18 (depends on 13)

The method of claim 13, wherein
(a) the cell is within a non-human subject; or
(b) the cell is within a human subject.