# US 2023/0057718 A1 · Compositions and methods for modulating complement factor b expression

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- Number: US 2023/0057718 A1
- Document ID: US20230057718A1
- Status: Published application
- Kind: A1
- Application number: 17/314,537
- Filed: 2021-05-07
- Published: 2023-02-23
- Earliest claimed: 2014-05-01
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Thazha P. Prakash; Punit P. Seth; Eric E. Swayze; Tamar R. Grossman; Michael L. McCaleb; Andrew T. Watt; Susan M. Freier
- Web page: https://patentgrep.com/patent/US20230057718A1

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61P 13/12: of the kidneys
- A61P 27/02: Ophthalmic agents
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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)}
- C12Y 304/21047: Alternative-complement-pathway C3/C5 convertase (3.4.21.47), i.e. properdin factor B
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- 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 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Y: ENZYMES

## Abstract

The present embodiments provide methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway by administering a Complement Factor B (CFB) specific inhibitor to a subject.

## Claims

### Claim at position 1

1-263. (canceled)

### Claim 264

A modified single-stranded oligonucleotide covalently attached to a conjugate group, wherein the modified single-stranded oligonucleotide consists of 10 to 30 linked nucleosides and has a nucleobase sequence comprising at least 8 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 455, and wherein the conjugate group covalently attached to the modified single-stranded oligonucleotide comprises:

### Claim 265

A modified single-stranded oligonucleotide covalently attached to a conjugate group, wherein the modified single-stranded oligonucleotide consists of 20 to 30 linked nucleosides and has a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO: 455, and wherein the conjugate group covalently attached to the modified single-stranded oligonucleotide comprises:

### Claim 266 (depends on 265)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 265, wherein the modified single-stranded oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 455.

### Claim 267 (depends on 264)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 264, wherein the modified single-stranded oligonucleotide has:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides; and
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

### Claim 268 (depends on 265)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 265, wherein the modified single-stranded oligonucleotide consists of 20 linked nucleosides and has a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 455, and wherein the modified single-stranded oligonucleotide has:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides; and
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; wherein each internucleoside linkage of the modified single-stranded oligonucleotide is a phosphorothioate linkage, and wherein each cytosine is 5-methylcytosine.

### Claim 269 (depends on 268)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 268, wherein the modified single-stranded oligonucleotide has a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NO: 455.

### Claim 270 (depends on 264)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 264, wherein the modified single-stranded oligonucleotide is at least 85% complementary to SEQ ID NO: 1.

### Claim 271 (depends on 264)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 264, wherein the modified single-stranded oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase.

### Claim 272 (depends on 271)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 271, wherein the modified single-stranded oligonucleotide comprises at least one modified internucleoside linkage.

### Claim 273 (depends on 272)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 272, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

### Claim 274 (depends on 273)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 273, wherein the modified single-stranded oligonucleotide comprises at least 1 phosphodiester internucleoside linkage.

### Claim 275 (depends on 274)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 274, wherein each internucleoside linkage of the modified single-stranded oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.

### Claim 276 (depends on 271)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 271, wherein each internucleoside linkage of the modified single-stranded oligonucleotide comprises a phosphorothioate internucleoside linkage.

### Claim 277 (depends on 271)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 271, wherein the modified sugar is a bicyclic sugar.

### Claim 278 (depends on 277)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 277, wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH2)—O-2′ (LNA); 4′-(CH2)2—O-2′ (ENA); and 4′-CH(CH3)—O-2′ (cEt).

### Claim 279 (depends on 271)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 271, wherein the modified sugar is 2′-O-methoxyethyl.

### Claim 280 (depends on 271)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 271, wherein the modified nucleobase is 5-methylcytosine.

### Claim 281 (depends on 264)

A modified double-stranded oligonucleotide comprising the modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 264, and a second single stranded oligonucleotide hybridized to said modified single stranded oligonucleotide.

### Claim 282 (depends on 264)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 264, wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide.

### Claim 283 (depends on 264)

The modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 264, wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide.

### Claim 284 (depends on 264)

A method of treating a disease associated with dysregulation of the complement alternative pathway in a subject comprising administering to the subject the modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 264, or a pharmaceutically acceptable salt thereof, thereby treating the disease.

### Claim 285 (depends on 284)

The method of claim 284, wherein the disease is macular degeneration, age related macular degeneration (AMD), wet AMD, dry AMD, or Geographic Atrophy.

### Claim 286 (depends on 284)

The method of claim 284, wherein the disease is a kidney disease.

### Claim 287 (depends on 286)

The method of claim 286, wherein the kidney disease is lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, IgA nephropathy, or atypical hemolytic uremic syndrome (aHUS).

### Claim 288 (depends on 268)

A method of treating a disease associated with dysregulation of the complement alternative pathway in a subject comprising administering to the subject the modified single-stranded oligonucleotide covalently attached to a conjugate group of claim 268, or a pharmaceutically acceptable salt thereof, thereby treating the disease.

### Claim 289 (depends on 288)

The method of claim 288, wherein the disease is macular degeneration, age related macular degeneration (AMD), wet AMD, dry AMD, or Geographic Atrophy.

### Claim 290 (depends on 289)

The method of claim 289, wherein the disease is a kidney disease.

### Claim 291 (depends on 290)

The method of claim 290, wherein the kidney disease is lupus nephritis, systemic lupus erythematosus (SLE), dense deposit disease (DDD), C3 glomerulonephritis (C3GN), CFHR5 nephropathy, IgA nephropathy, or atypical hemolytic uremic syndrome (aHUS).