# US 10,308,941 B2 · Compositions and methods for inhibiting gene expression of factor XII

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- Number: US 10,308,941 B2
- Document ID: US10308941B2
- Status: Granted
- Kind: B2
- Application number: 15/715,765
- Filed: 2017-09-26
- Published: 2018-01-25
- Granted: 2019-06-04
- Earliest claimed: 2015-03-17
- Assignees: Arrowhead Pharmaceuticals, Inc.
- Applicants: Arrowhead Pharmaceuticals, Inc.
- Inventors: Steven B. Kanner; David L. Lewis; Darren H. Wakefield; Lauren J. Almeida
- Web page: https://patentgrep.com/patent/US10308941B2

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/322: 2'-R Modification
- C12N 2310/351: Conjugate
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2320/30: Special therapeutic applications
- 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

RNA interference (RNAi) triggers for inhibiting the expression of Factor XII (F12) gene through the mechanism of RNA interference are described. Pharmaceutical compositions comprising one or more F12 RNAi triggers together with one or more excipients capable of delivering the RNAi trigger(s) to a liver cell in vivo are also described. Delivery of the F12 RNAi trigger(s) to liver cells in vivo provides for inhibition of F12 gene expression and treatment of angioedema, including hereditary angioedema (HAE) and venous thromboembolism (VTE), and diseases associated with angioedema.

## Claims

### Claim 1

A method for inhibiting Factor XII gene expression in a subject, the method comprising: administering to the subject a therapeutically effective amount of a composition comprising an RNA interference (RNAi) trigger capable of inhibiting the expression of an F12 gene, wherein the RNAi trigger comprises a sense strand and an antisense strand, wherein the antisense strand comprises the nucleotide sequence of nucleotides 2 to 19 (5′ to 3′) of SEQ ID NO: 1417 (GGUCUUUCACUUUCUUGG) and all of the nucleotides of the antisense strand are modified nucleotides, and wherein the sense strand is at least substantially complementary to the antisense strand and all of the nucleotides of the sense strand are modified nucleotides.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
(i) the modified nucleotides of the antisense strand of the RNAi trigger are independently selected from the group consisting of: 2′-O-methyl nucleotide and 2′-Fluoro nucleotide; and
(ii) the modified nucleotides of the sense strand of the RNAi trigger are independently selected from the group consisting of 2′-O-methyl nucleotide and 2′-Fluoro nucleotide.

### Claim 3 (depends on 1)

The method of claim 1, wherein the sense strand or the antisense strand of the RNAi trigger comprises one or more phosphorothioate internucleotide linkages.

### Claim 4 (depends on 3)

The method of claim 3, wherein the sense strand of the RNAi agent comprises one or two phosphorothioate internucleotide linkages.

### Claim 5 (depends on 3)

The method of claim 3, wherein the antisense strand of the RNAi agent comprises one, two, three, or four phosphorothioate internucleotide linkages.

### Claim 6 (depends on 1)

The method of claim 1, wherein the RNAi agent comprises a targeting group conjugated to the sense strand.

### Claim 7 (depends on 6)

The method of claim 6, wherein the targeting group comprises a cholesterol or cholesteryl derivative.

### Claim 8 (depends on 6)

The method of claim 6, wherein the targeting group comprises an asialoglycoprotein receptor ligand.

### Claim 9 (depends on 8)

The method of claim 8, wherein the asialoglycoprotein receptor ligand comprises a galactose cluster.

### Claim 10 (depends on 9)

The method of claim 9, wherein the galactose cluster comprises an N-acetyl-galactosamine trimer.

### Claim 11 (depends on 1)

The method of claim 1, wherein the sense strand of the RNAi agent comprises the nucleotide sequence of SEQ ID NO: 1385 (CCAAGAAAGUGAAAGACCA).

### Claim 12 (depends on 11)

The method of claim 11, wherein the RNAi trigger comprises ADO 1520 (SEQ ID NO: 1064 and SEQ ID NO:693), AD02023 (SEQ ID NO: 1146 and SEQ ID NO:791), AD00900 (SEQ ID NO:986 and SEQ ID NO:461), AD01001 (SEQ ID NO:986 and SEQ ID NO:604), AD02562 (SEQ ID NO: 1211 and SEQ ID NO:772), AD02639 (SEQ ID NO: 1228 and SEQ ID NO:791), AD02640 (SEQ ID NO: 1229 and SEQ ID NO:791), AD02642 (SEQ ID NO: 1232 and SEQ ID NO:791), AD02708 (SEQ ID NO: 1232 and SEQ ID NO:827), AD02807 (SEQ ID NO: 1296 and SEQ ID NO:791), AD02822 (SEQ ID NO: 1359 and SEQ ID NO:830), AD02867 (SEQ ID NO: 1363 and SEQ ID NO:791), or AD02868 (SEQ ID NO:1364 and SEQ ID NO:791).

### Claim 13 (depends on 12)

The method of claim 12, wherein the composition is administered to the subject by subcutaneous injection or intravenous infusion or injection.

### Claim 14

A method for the treatment of diseases or conditions associated with angioedema, including hereditary angioedema and venous thromboembolism, in a human subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a composition comprising an RNA interference (RNAi) trigger capable of inhibiting the expression of an F12 gene, wherein the RNAi trigger comprises a sense strand and an antisense strand, wherein said antisense strand comprises nucleotides 2 to 19 (5′ to 3′) of SEQ ID NO: 1417 (GGUCUUUCACUUUCUUGG) and all of the nucleotides of the antisense strand are modified nucleotides, and wherein the sense strand is at least substantially complementary to the antisense strand and all of the nucleotides of the sense strand are modified nucleotides.

### Claim 15 (depends on 14)

The method of claim 14, wherein:
(i) the modified nucleotides of the antisense strand of the RNAi trigger are independently selected from the group consisting of: 2′-O-methyl nucleotide and 2′-Fluoro nucleotide; and
(ii) the modified nucleotides of the sense strand of the RNAi trigger are independently selected from the group consisting of: 2′-O-methyl nucleotide and 2′-Fluoro nucleotide.

### Claim 16 (depends on 14)

The method of claim 14, wherein the sense strand or the antisense strand of the RNAi trigger comprises one or more phosphorothioate internucleotide linkages.

### Claim 17 (depends on 16)

The method of claim 16, wherein the sense strand of the RNAi agent comprises one or two phosphorothioate internucleotide linkages.

### Claim 18 (depends on 16)

The method of claim 16, wherein the antisense strand of the RNAi agent comprises one, two, three, or four phosphorothioate internucleotide linkages.

### Claim 19 (depends on 14)

The method of claim 14, wherein the RNAi agent comprises a targeting group conjugated to the sense strand.

### Claim 20 (depends on 19)

The method of claim 19, wherein the targeting group comprises a cholesterol or cholesteryl derivative.

### Claim 21 (depends on 19)

The method of claim 19, wherein the targeting group comprises an asialoglycoprotein receptor ligand.

### Claim 22 (depends on 21)

The method of claim 21, wherein the asialoglycoprotein receptor ligand comprises a galactose cluster.

### Claim 23 (depends on 22)

The method of claim 22, wherein the galactose cluster comprises an N-acetyl-galactosamine trimer.

### Claim 24 (depends on 14)

The method of claim 14, wherein the sense strand of the RNAi agent comprises SEQ ID NO: 1385 (CCAAGAAAGUGAAAGACCA).

### Claim 25 (depends on 24)

The method of claim 24, wherein the RNAi trigger comprises AD01520 (SEQ ID NO: 1064 and SEQ ID NO:693), AD02023 (SEQ ID NO: 1146 and SEQ ID NO:791), AD00900 (SEQ ID NO:986 and SEQ ID NO:461), AD01001 (SEQ ID NO:986 and SEQ ID NO:604), AD02562 (SEQ ID NO: 1211 and SEQ ID NO:772), AD02639 (SEQ ID NO:1228 and SEQ ID NO:791), AD02640 (SEQ ID NO: 1229 and SEQ ID NO:791), AD02642 (SEQ ID NO: 1232 and SEQ ID NO:791), AD02708 (SEQ ID NO: 1232 and SEQ ID NO:827), AD02807 (SEQ ID NO: 1296 and SEQ ID NO:791), AD02822 (SEQ ID NO:1359 and SEQ ID NO:830), AD02867 (SEQ ID NO:1363 and SEQ ID NO:791), or AD02868 (SEQ ID NO:1364 and SEQ ID NO:791).

### Claim 26 (depends on 25)

The method of claim 25, wherein the composition is administered to the subject by subcutaneous injection or intravenous infusion or injection.