# US 2018/0023086 A1 · Compositions and Methods for Inhibiting Gene Expression of Factor XII

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- Number: US 2018/0023086 A1
- Document ID: US20180023086A1
- Status: Published application
- Kind: A1
- Application number: 15/715,765
- Filed: 2017-09-26
- Published: 2018-01-25
- 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/US20180023086A1

## 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

An RNA interference (RNAi) trigger capable of inhibiting the expression of an Factor XII (F12) gene wherein said RNAi trigger comprises a sense strand and an antisense strand, and wherein said antisense strand comprises any of the antisense sequences in Table 1 and Table 2.

### Claim 2 (depends on 1)

The RNAi trigger of claim 1, wherein the RNAi trigger comprises at least one modified nucleotide.

### Claim 3 (depends on 2)

The RNAi trigger of claim 2, wherein the at least one modified nucleotide is selected from the group consisting of: 2′-O-methyl nucleotide, 2′-Fluoro nucleotide, 2′-deoxy nucleotide, 2′,3′-seco nucleotide mimic, locked nucleotide, 2′-F-Arabino nucleotide, 2′-methoxyethyl nucleotide, abasic ribose, ribitol, inverted nucleotide, inverted abasic nucleotide, inverted 2′-OMe nucleotide, inverted 2′-deoxy nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, vinyl phosphonate deoxyribonucleotide, and 3′-OMe nucleotide.

### Claim 4 (depends on 1)

The RNAi trigger of claim 1, wherein the sense strand contains one, two, or three 2′-F nucleotides at positions 11, 12, and/or 13 from the 3′ end.

### Claim 5 (depends on 1)

The RNAi trigger of claim 1, wherein the antisense strand contains a 2′-F nucleotide at position 2 from the 5′ end.

### Claim 6 (depends on 1)

The RNAi trigger of claim 1, wherein the antisense strand contains a 2′-F nucleotide at position 14 from the 5′ end.

### Claim 7 (depends on 1)

The RNAi trigger of claim 1, wherein the antisense strand contains one, two, three, or four 2′-F nucleotides at positions 4, 6, 8, 10, and 12 from the 5′ end.

### Claim 8 (depends on 1)

The RNAi trigger of claim 1, wherein the RNAi trigger comprises one or more phosphorothioate intemucleotide linkages.

### Claim 9 (depends on 1)

The RNAi trigger of claim 1, wherein the sense strand comprises one or two phosphorothioate intemucleotide linkages.

### Claim 10 (depends on 1)

The RNAi trigger of claim 1, wherein the antisense strand contains one, two, three, or four phosphorothioate intemucleotide linkages.

### Claim 11 (depends on 1)

The RNAi trigger of claim 1, further comprising a targeting group conjugated to the sense strand.

### Claim 12 (depends on 11)

The RNAi trigger molecule of claim 11, wherein the targeting group comprises a cholesterol or cholesteryl derivative.

### Claim 13 (depends on 11)

The RNAi trigger of claim 11, wherein a targeting group comprises an asialoglycoprotein receptor ligand.

### Claim 14 (depends on 13)

The RNAi trigger of claim 13, wherein the asialoglycoprotein receptor ligand comprises a galactose cluster.

### Claim 15 (depends on 14)

The RNAi trigger of claim 14, wherein the galactose cluster comprises an N-acetyl-galactosamine trimer.

### Claim 16 (depends on 15)

The RNAi trigger of claim 15, wherein the N-acetyl-galactosamine trimer has a structure selected from the group consisting of: NAG3, NAG13, NAG14, NAG15, NAG16, NAG17, NAG18, NAG19, NAG20, NAG21, NAG23, and NAG4.

### Claim 17 (depends on 1)

The RNAi trigger of claim 1, wherein the RNAi trigger comprises AD01520, AD02023, AD00900, AD01001, AD02639, AD02640, AD02642, AD02708, AD02807, AD02822, AD02867, or AD02868.

### Claim 18 (depends on 1)

The RNAi trigger of claim 1, wherein antisense strand comprises the nucleotide sequence of SEQ ID No. 177, SEQ ID No. 150, or SEQ ID No. 11.

### Claim 19 (depends on 1)

The RNAi trigger of claim 1, wherein sense strand comprises the nucleotide sequence of SEQ ID No. 374 or SEQ ID No. 379.

### Claim 20

A composition comprising: RNA interference (RNAi) trigger molecule capable of inhibiting the expression of an Factor XII gene, wherein said RNAi trigger molecule comprises a sense strand and an antisense strand, wherein said antisense strand comprises any of the antisense sequences in Table 1 and Table 2, and at least one pharmaceutically acceptable excipient.

### Claim 21 (depends on 20)

The composition of claim 20, wherein the at least one pharmaceutically acceptable excipient includes a delivery polymer.

### Claim 22 (depends on 21)

The composition of claim 21, wherein the delivery polymer comprises a melittin-like peptide.

### Claim 23 (depends on 20)

The composition of claim 20, further comprising a second therapeutic or treatment.

### Claim 24 (depends on 20)

The composition of claim 20, wherein said composition is packaged in a kit, container, pack, dispenser, pre-filled syringes, or vials.

### Claim 25 (depends on 20)

The composition of claim 20, wherein said composition is administered parenterally.

### Claim 26

A method for inhibiting Factor XII expression in a subject comprising: administering to said subject a therapeutically effective amount of an RNA interference (RNAi) trigger capable of inhibiting the expression of an F12 gene wherein said RNAi trigger comprises a sense strand and an antisense strand, wherein said antisense strand comprises any of the antisense sequences in Table 1 and Table 2.

### Claim 27 (depends on 1)

A method for the treatment of angioedema, including hereditary angioedema and venous thromboembolism, comprising administering to a patient in need of such treatment the composition of claim 1.

### Claim 28 (depends on 17)

A method for the treatment of angioedema, including hereditary angioedema and venous thromboembolism, comprising administering to a patient in need of such treatment the composition of claim 17.