# US 11,306,315 B2 · Angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use thereof

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- Number: US 11,306,315 B2
- Document ID: US11306315B2
- Status: Granted
- Kind: B2
- Application number: 17/531,888
- Filed: 2021-11-22
- Published: 2022-03-10
- Granted: 2022-04-19
- Earliest claimed: 2011-06-21
- Assignees: Alnylam Pharmaceuticals, Inc.
- Applicants: Alnylam Pharmaceuticals, Inc.
- Inventors: Brian Bettencourt; William Querbes; Kevin Fitzgerald; Maria Frank-Kamenetsky; Stuart Milstein; Svetlana Shulga Morskaya
- Web page: https://patentgrep.com/patent/US11306315B2

## CPC

- C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones}
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 3/06: Antihyperlipidemics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- 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)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/351: Conjugate
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ANGPTL3 gene, as well as methods of inhibiting expression of ANGPTL3 and methods of treating subjects having a disorder of lipid metabolism, such as hyperlipidemia or hypertriglyceridemia, using such dsRNA compositions.

## Claims

### Claim 1

A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), comprising a sense strand and an antisense strand,
wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from the complement of nucleotides 244-307 of SEQ ID NO:1,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,
wherein at least one of the modified nucleotides is selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, an abasic nucleotide, and a 2′-amino modified nucleotide, and
wherein a ligand comprising an N-acetylgalactosamine (GalNAc) derivative is conjugated to at least one strand of the dsRNA agent.

### Claim 2

A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), wherein the dsRNA agent comprises a sense strand and an antisense strand,
wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from the complement of nucleotides 256-306 of SEQ ID NO:1,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,
wherein at least one of the modified nucleotides is selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, an abasic nucleotide, and a 2′-amino modified nucleotide, and
wherein a ligand comprising an N-acetylgalactosamine (GalNAc) derivative is conjugated to at least one strand of the dsRNA agent.

### Claim 3

A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), wherein the dsRNA agent comprises a sense strand and an antisense strand,
wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from the complement of nucleotides 266-299 of SEQ ID NO:1,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides,
wherein at least one of the modified nucleotides is selected from the group consisting of a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, an abasic nucleotide, and a 2′-amino modified nucleotide, and
wherein a ligand comprising an N-acetylgalactosamine (GalNAc) derivative is conjugated to at least one strand of the dsRNA agent.

### Claim 4 (depends on 1)

The dsRNA agent of claim 1, wherein each strand is independently 19-25 nucleotides in length.

### Claim 5 (depends on 1)

The dsRNA agent of claim 1, wherein the dsRNA agent comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

### Claim 6 (depends on 1)

The dsRNA of claim 1, wherein the GalNAc (N-acetylgalactosamine) derivative is attached through a bivalent or trivalent branched linker.

### Claim 7 (depends on 1)

The dsRNA agent of claim 1, wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of
(SEQ ID NO: 312)
5′-AUCAGUCUUUUUAUGAUCUAU-3′
and
(SEQ ID NO: 497)
5′-AUAGAUCAUAAAAAGACUGAUCA-3′;
(SEQ ID NO: 403)
5′-GAUCAGUCUUUUUAUGAUCUA-3′
and
(SEQ ID NO: 588)
5′-UAGAUCAUAAAAAGACUGAUCAA-3′;
(SEQ ID NO: 61)
5′-AUUUGAUCAGUCUUUUUAU-3′
and
(SEQ ID NO: 123)
5′-AUAAAAAGACUGAUCAAAU-3′;
(SEQ ID NO: 16)
5′-UAUUUGAUCAGUCUUUUUA-3′
and
(SEQ ID NO: 78)
5′-UAAAAAGACUGAUCAAAUA-3′;
(SEQ ID NO: 387)
5′-CAUAUUUGAUCAGUCUUUUUA-3′
and
(SEQ ID NO: 572)
5′-UAAAAAGACUGAUCAAAUAUGUU-3′;
(SEQ ID NO: 287)
5′-ACAUAUUUGAUCAGUCUUUUU-3′
and
(SEQ ID NO: 472)
5′-AAAAAGACUGAUCAAAUAUGUUG-3′;
(SEQ ID NO: 303)
5′-AACAUAUUUGAUCAGUCUUUU-3′
and
(SEQ ID NO: 488)
5′-AAAAGACUGAUCAAAUAUGUUGA-3′;
(SEQ ID NO: 39)
5′-ACAUAUUUGAUCAGUCUUU-3′
and
(SEQ ID NO: 101)
5′-AAAGACUGAUCAAAUAUGU -3′;
(SEQ ID NO: 294)
5′-CAACAUAUUUGAUCAGUCUUU-3′
and
(SEQ ID NO: 479)
5′-AAAGACUGAUCAAAUAUGUUGAG-3′;
(SEQ ID NO: 358)
5′-UCAACAUAUUUGAUCAGUCUU-3′
and
(SEQ ID NO: 543)
5′-AAGACUGAUCAAAUAUGUUGAGU-3′;
(SEQ ID NO: 64)
5′-CAACAUAUUUGAUCAGUCU-3′
and
(SEQ ID NO: 126)
5′-AGACUGAUCAAAUAUGUUG-3′;
(SEQ ID NO: 321)
5′-CAAAAACUCAACAUAUUUGAU-3′
and
(SEQ ID NO: 506)
5′-AUCAAAUAUGUUGAGUUUUUGAA-3′;
(SEQ ID NO: 351)
5′-UGACAUAUUUCAAAAACUCAA-3′
and
(SEQ ID NO: 536)
5′-UUGAGUUUUUGAAAUAUGUCAUU-3′;
(SEQ ID NO: 352)
5′-AAAUUAAUGACAUAUUUCAAA-3′
and
(SEQ ID NO: 537)
5′-UUUGAAAUAUGUCAUUAAUUUGG-3′;
(SEQ ID NO: 285)
5′-GGCCAAAUUAAUGACAUAUUU-3′
and
(SEQ ID NO: 470)
5′-AAAUAUGUCAUUAAUUUGGCCCU-3′;
and
(SEQ ID NO: 417)
5′-GGGCCAAAUUAAUGACAUAUU-3′
and
(SEQ ID NO: 602)
5′-AAUAUGUCAUUAAUUUGGCCCUU-3′.

### Claim 8 (depends on 1)

A cell containing the dsRNA agent of claim 1.

### Claim 9 (depends on 1)

A pharmaceutical composition for inhibiting expression of an ANGPTL3 gene, comprising the dsRNA agent of claim 1.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, wherein the dsRNA agent is present in a buffered solution.

### Claim 11 (depends on 1)

A method of inhibiting ANGPTL3 expression in a cell, the method comprising:
(a) contacting the cell with the dsRNA agent of claim 1; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of an ANGPTL3 gene, thereby inhibiting expression of the ANGPTL3 gene in the cell.

### Claim 12 (depends on 11)

The method of claim 11, wherein the cell is within a subject.

### Claim 13 (depends on 1)

A method of inhibiting the expression of ANGPTL3 in a subject, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1, thereby inhibiting the expression of ANGPTL3 in the subject.

### Claim 14 (depends on 1)

A method of treating a subject having a disorder that would benefit from reduction in ANGPTL3 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1, thereby treating the subject.

### Claim 15 (depends on 14)

The method of claim 14, wherein the disorder is a disorder of lipid metabolism.

### Claim 16 (depends on 14)

The method of claim 14, wherein the disorder is selected from the group consisting of hypertriglyceridemia, obesity, hyperlipidemia, atherosclerosis, diabetes, cardiovascular disease, and coronary artery disease.

### Claim 17 (depends on 14)

The method of claim 14, further comprising administering an additional therapeutic to the subject.

### Claim 18 (depends on 17)

The method of claim 17, wherein the additional therapeutic is a statin.

### Claim 19 (depends on 14)

The method of claim 14, wherein the dsRNA agent is administered at a dose of about 0.5 mg/kg to about 50 mg/kg.

### Claim 20 (depends on 14)

The method of claim 14, wherein the administration of the dsRNA agent to the subject causes a decrease in one or more serum lipid and/or a decrease in ANGPTL3 protein accumulation.