# US 11,078,486 B2 · Compounds and methods for reducing ATXN2 expression

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- Number: US 11,078,486 B2
- Document ID: US11078486B2
- Status: Granted
- Kind: B2
- Application number: 16/522,133
- Filed: 2019-07-25
- Published: 2020-02-20
- Granted: 2021-08-03
- Earliest claimed: 2018-07-25
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Paymaan Jafar-nejad
- Web page: https://patentgrep.com/patent/US11078486B2

## 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)}
- A61K 47/02: Inorganic compounds
- A61K 47/46: Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
- C12N 2310/11: Antisense
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/322: 2'-R Modification
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/351: Conjugate
- 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

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN2 RNA in a cell or animal, and in certain instances reducing the amount of Ataxin-2 protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. Such neurodegenerative diseases include spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and parkinsonism.

## Claims

### Claim 1

A modified oligonucleotide according to the following formula:
or a salt thereof.

### Claim 2 (depends on 1)

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

### Claim 3

A modified oligonucleotide according to the following formula:

### Claim 4 (depends on 1)

A chirally enriched population of modified oligonucleotides of claim 1, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.

### Claim 5 (depends on 4)

The chirally enriched population of claim 4, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration.

### Claim 6 (depends on 4)

The chirally enriched population of claim 4, wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration.

### Claim 7 (depends on 4)

The chirally enriched population of claim 4, wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage.

### Claim 8 (depends on 7)

The chirally enriched population of claim 7, wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each phosphorothioate internucleoside linkage.

### Claim 9 (depends on 7)

The chirally enriched population of claim 7, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at each phosphorothioate internucleoside linkage.

### Claim 10 (depends on 4)

The chirally enriched population of claim 4, wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp-Sp-Rp configuration, in the 5′ to 3′ direction.

### Claim 11 (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 12 (depends on 1)

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

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12, comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 14 (depends on 12)

The pharmaceutical composition of claim 12, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 15

An oligomeric compound comprising a modified oligonucleotide according to the following formula:
TesGeoGeoAeoTeoTeomCdsTdsGdsTdsAdsmCdsTdsTdsTdsTdsmCeoTesmCes Ae (SEQ ID NO: 3235);
wherein,
A=an adenine nucleobase,
mC=a 5′-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-MOE modified sugar,
d=a 2′-deoxyribose sugar,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.

### Claim 16 (depends on 4)

A pharmaceutical composition comprising the chirally enriched population of modified oligonucleotides of claim 4, and a pharmaceutically acceptable diluent or carrier.

### Claim 17 (depends on 15)

The oligomeric compound of claim 15, wherein the modified oligonucleotide is covalently linked to a conjugate group.

### Claim 18 (depends on 1)

An oligomeric duplex comprising the modified oligonucleotide of claim 1.

### Claim 19 (depends on 15)

An oligomeric duplex comprising the oligomeric compound of claim 15.

### Claim 20 (depends on 15)

A pharmaceutical composition comprising the oligomeric compound of claim 15 and a pharmaceutically acceptable carrier or diluent.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 22 (depends on 20)

The pharmaceutical composition of claim 20, wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 23 (depends on 17)

A pharmaceutical composition comprising the oligomeric compound of claim 17 and a pharmaceutically acceptable carrier or diluent.

### Claim 24 (depends on 23)

The pharmaceutical composition of claim 23, comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 25 (depends on 23)

The pharmaceutical composition of claim 23, wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 26 (depends on 7)

The chirally enriched population of claim 7, wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages.

### Claim 27 (depends on 1)

The modified oligonucleotide of claim 1, which is a potassium salt of the formula.

### Claim 28 (depends on 3)

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

### Claim 29 (depends on 28)

The pharmaceutical composition of claim 28, comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 30 (depends on 28)

The pharmaceutical composition of claim 28, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and phosphate-buffered saline (PBC) or artificial cerebrospinal fluid (aCSF).

### Claim 31 (depends on 27)

A pharmaceutical composition comprising the modified oligonucleotide of claim 27 and a pharmaceutically acceptable carrier or diluent.

### Claim 32 (depends on 31)

The pharmaceutical composition of claim 31, comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 33 (depends on 31)

The pharmaceutical composition of claim 31, wherein the pharmaceutical composition consists essentially of the oligomeric compound and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 34 (depends on 18)

A pharmaceutical composition comprising the oligomeric duplex of claim 18 and a pharmaceutically acceptable carrier or diluent.

### Claim 35 (depends on 34)

The pharmaceutical composition of claim 34, comprising a pharmaceutically acceptable diluent, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).

### Claim 36 (depends on 34)

The pharmaceutical composition of claim 34, wherein the pharmaceutical composition consists essentially of the oligomeric duplex and phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (aCSF).