# US 11,299,737 B1 · Compounds and methods for modulating SMN2

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- Number: US 11,299,737 B1
- Document ID: US11299737B1
- Status: Granted
- Kind: B1
- Application number: 17/356,961
- Filed: 2021-06-24
- Granted: 2022-04-12
- Earliest claimed: 2020-02-28
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Frank Rigo
- Web page: https://patentgrep.com/patent/US11299737B1

## CPC

- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- 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)}
- A61K 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/345: having at least two different backbone modifications
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2320/33: Alteration of splicing
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Provided are compounds, methods, and pharmaceutical compositions for modulating SMN2 RNA and/or protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a neurodegenerative disorder. Such symptoms include reduced muscle strength; inability or reduced ability to sit upright, to stand, and/or walk; reduced neuromuscular activity; reduced electrical activity in one or more muscles; reduced respiration; inability or reduced ability to eat, drink, and/or breathe without assistance; loss of weight or reduced weight gain; and/or decreased survival.

## Claims

### Claim 1

A modified oligonucleotide according to the following chemical structure:
(SEQ ID NO: 21), or a salt thereof.

### Claim 2 (depends on 1)

The modified oligonucleotide of claim 1, which is the sodium salt or the potassium salt.

### Claim 3

A modified oligonucleotide according to the following chemical structure:
(SEQ ID NO: 21).

### Claim 4

An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: mCns Ano mCns Tno Tns Tns mCns Ans Tns Ans Ans Tns Gns mCns Tns Gns Gns mCn (SEQ ID NO: 21),
wherein:
A=an adenine nucleobase,
mC=a 5-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
n=a 2′-NMA sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.

### Claim 5 (depends on 1)

A population of modified oligonucleotides of claim 1, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

### Claim 6 (depends on 3)

A population of modified oligonucleotides of claim 3, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

### Claim 7 (depends on 4)

A population of oligomeric compounds of claim 4, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 8)

The pharmaceutical composition of claim 8, wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial CSF (aCSF) or PBS.

### Claim 11 (depends on 3)

A pharmaceutical composition comprising the modified oligonucleotide of claim 3 and a pharmaceutically acceptable diluent.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS.

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial CSF (aCSF) or PBS.

### Claim 14 (depends on 4)

A pharmaceutical composition comprising the oligomeric compound of claim 4 and a pharmaceutically acceptable diluent.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS.

### Claim 16 (depends on 15)

The pharmaceutical composition of claim 15, wherein the pharmaceutical composition consists essentially of the oligomeric compound and artificial CSF (aCSF) or PBS.

### Claim 17 (depends on 5)

A pharmaceutical composition comprising the population of modified oligonucleotides of claim 5 and a pharmaceutically acceptable diluent.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS.

### Claim 19 (depends on 18)

The pharmaceutical composition of claim 18, wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and artificial CSF (aCSF) or PBS.

### Claim 20 (depends on 6)

A pharmaceutical composition comprising the population of modified oligonucleotides of claim 6 and a pharmaceutically acceptable diluent.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS.

### Claim 22 (depends on 21)

The pharmaceutical composition of claim 21, wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and artificial CSF (aCSF) or PBS.

### Claim 23 (depends on 7)

A pharmaceutical composition comprising the population of oligomeric compounds of claim 7 and a pharmaceutically acceptable diluent.

### Claim 24 (depends on 23)

The pharmaceutical composition of claim 23, wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS.

### Claim 25 (depends on 24)

The pharmaceutical composition of claim 24, wherein the pharmaceutical composition consists essentially of the population of oligomeric compounds and artificial CSF (aCSF) or PBS.

### Claim 26 (depends on 2)

A pharmaceutical composition comprising the modified oligonucleotide of claim 2 and a pharmaceutically acceptable diluent.

### Claim 27 (depends on 26)

The pharmaceutical composition of claim 26, wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS.

### Claim 28 (depends on 27)

The pharmaceutical composition of claim 27, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial CSF (aCSF) or PBS.

### Claim 29 (depends on 2)

A population of modified oligonucleotides of claim 2, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

### Claim 30 (depends on 29)

A pharmaceutical composition comprising the population of modified oligonucleotides of claim 29 and a pharmaceutically acceptable diluent.

### Claim 31 (depends on 30)

The pharmaceutical composition of claim 30, wherein the pharmaceutically acceptable diluent is artificial CSF (aCSF) or PBS.

### Claim 32 (depends on 31)

The pharmaceutical composition of claim 31, wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and artificial CSF (aCSF) or PBS.