# US 10,246,713 B2 · TMPRSS6 iRNA compositions and methods of use thereof

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- Number: US 10,246,713 B2
- Document ID: US10246713B2
- Status: Granted
- Kind: B2
- Application number: 15/603,560
- Filed: 2017-05-24
- Published: 2017-12-21
- Granted: 2019-04-02
- Earliest claimed: 2014-11-24
- Assignees: Alnylam Pharmaceuticals, Inc.
- Applicants: Alnylam Pharmaceuticals, Inc.
- Inventors: James Butler; Martin Maier; Kevin Fitzgerald; Shannon Fishman; Donald Foster; Vasant Jadhav; Stuart Milstein
- Web page: https://patentgrep.com/patent/US10246713B2

## 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
- A61P 7/06: Antianaemics
- C12N 15/1138: {against receptors or cell surface proteins}
- C12Y 304/21: Serine endopeptidases (3.4.21)
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/322: 2'-R Modification
- C12N 2310/351: Conjugate
- C12N 2310/353: linked to the nucleic acid via an atom other than carbon
- C12N 2310/3533: Halogen
- C12N 2320/31: Combination therapy
- 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
- C12Y: ENZYMES

## Abstract

The invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the TMPRSS6 gene, and methods of using such RNAi agents to inhibit expression of TMPRSS6 and methods of treating subjects having a TMPRSS6 associated disorder, e.g., an iron overload associated disorder, such as β-thalassemia or hemochromatosis.

## Claims

### Claim 1

A double stranded RNAi agent for inhibiting expression of TMPRSS6 in a cell, wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a duplex, wherein the sense strand comprises any one of the modified nucleotide sequences selected from the group consisting of SEQ ID NOS: 62-86, 112-127, and 144-147, and the antisense strand comprises any one of the modified nucleotide sequences selected from the group consisting of SEQ ID NOS: 87-111, 128-143, and 148-151, and wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

### Claim 2 (depends on 1)

The double stranded RNAi agent of claim 1, wherein the sense strand and the antisense strand comprise the sense and antisense strand nucleotide sequences of a duplex selected from the group consisting of AD-63202, AD-64372, AD-64373, AD-64374, AD-64375, AD-64376, AD-64377, AD-64378, AD-64380, AD-64381, AD-64382, AD-64384, AD-64385, AD-64386, AD-64387, AD-64389, AD-64601, AD-64569, AD-64604, AD-64567, AD-60940, AD-65105, AD-65106, AD-65107, AD-65108, AD-65109, AD-65110, AD-65111, AD-65112, AD-61002, AD-66014, AD-66015, and AD-65189.

### Claim 3 (depends on 1)

The double stranded RNAi agent of claim 1, further comprising a ligand.

### Claim 4 (depends on 3)

The double stranded RNAi agent of claim 3, wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

### Claim 5 (depends on 3)

The double stranded RNAi agent of claim 3, wherein the ligand is

### Claim 6 (depends on 3)

The double stranded RNAi agent of claim 3, wherein the ligand is attached to the 3′ end of the sense strand.

### Claim 7 (depends on 6)

The double stranded RNAi agent of claim 6, wherein the RNAi agent is conjugated to the ligand as shown in the following schematic
wherein X is O or S.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising the double stranded RNAi agent of claim 1.

### Claim 9 (depends on 1)

The double stranded RNAi agent of claim 1, wherein
the sense strand comprises the nucleotide sequence 5′-csusggudAuuucdCuaggg(Tgn)acaa-3′ (SEQ ID NO: 120) and the antisense strand comprises the nucleotide sequence 5′-usUsguacccudAggadAauaccagsasg-3′ (SEQ ID NO: 136),
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U; U is uridine-3′-phosphate; s is a phosphorothioate linkage; dA is 2′-deoxyadenosine; dC is 2′-deoxycytosine; and (Tgn) is thymidine-glycol nucleic acid (GNA)S-Isomer.

### Claim 10 (depends on 9)

The double stranded RNAi agent of claim 9, further comprising a ligand.

### Claim 11 (depends on 10)

The double stranded RNAi agent of claim 10, wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

### Claim 12 (depends on 10)

The double stranded RNAi agent of claim 10, wherein the ligand is

### Claim 13 (depends on 10)

The double stranded RNAi agent of claim 10, wherein the ligand is attached to the 3′ end of the sense strand.

### Claim 14 (depends on 13)

The double stranded RNAi agent of claim 13, wherein the RNAi agent is conjugated to the ligand as shown in the following schematic
wherein X is O or S.