# US 10,370,655 B2 · Methods and compositions for the specific inhibition of alpha-1 antitrypsin by double-stranded RNA

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- Number: US 10,370,655 B2
- Document ID: US10370655B2
- Status: Granted
- Kind: B2
- Application number: 15/247,201
- Filed: 2016-08-25
- Published: 2017-05-11
- Granted: 2019-08-06
- Earliest claimed: 2013-07-03
- Assignees: Dicerna Pharmaceuticals, Inc.
- Applicants: Dicerna Pharmaceuticals, Inc.
- Inventors: Bob D. Brown; Henryk T. Dudek
- Web page: https://patentgrep.com/patent/US10370655B2

## CPC

- 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)}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 35/00: Antineoplastic agents
- C12N 2310/11: Antisense
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/3233: Morpholino-type ring
- C12N 2310/343: having patterns, e.g. ==--==--==--
- 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

## Abstract

This invention relates to compounds, compositions, and methods useful for reducing α-1 antitrypsin target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.

## Claims

### Claim 1

A nucleic acid comprising an oligonucleotide strand consisting of 22 nucleotides in length, wherein said oligonucleotide strand has a region that is perfectly complementary to a contiguous sequence of α-1 antitrypsin mRNA consisting of 20 nucleotides in length, which contiguous sequence comprises a target α-1 antitrypsin mRNA sequence as set forth in SEQ ID NO: 1547, and wherein the nucleic acid comprises one or more modified nucleotides.

### Claim 2 (depends on 1)

A mammalian cell containing the nucleic acid of claim 1.

### Claim 3 (depends on 1)

A pharmaceutical composition comprising the nucleic acid of claim 1 and a pharmaceutically acceptable carrier.

### Claim 4 (depends on 1)

A kit comprising the nucleic acid of claim 1 and instructions for its use.

### Claim 5 (depends on 1)

The nucleic acid of claim 1, further comprising one or more phosphorothioate linkages.

### Claim 6

A double stranded nucleic acid (dsNA) comprising a sense strand and an antisense strand, wherein the antisense strand is 22 nucleotides in length, wherein the antisense strand has a region that is perfectly complementary to a contiguous sequence of α-1 antitrypsin mRNA consisting of 20 nucleotides in length, which contiguous sequence comprises a target α-1 antitrypsin mRNA sequence as set forth in SEQ ID NO: 1547, and wherein the dsNA comprises one or more modified nucleotides.

### Claim 7 (depends on 6)

The dsNA of claim 6, wherein the sense strand and antisense strand form a duplex such that the antisense strand comprises a two nucleotide overhang at its 3′ end.

### Claim 8 (depends on 6)

The dsNA of claim 6, wherein the dsNA comprises a duplex of 20 to 25 base pairs in length.

### Claim 9 (depends on 7)

The dsNA of claim 7, wherein the sense strand is 25 to 53 nucleotides in length.

### Claim 10 (depends on 7)

The dsNA of claim 7, wherein the sense strand is 36 nucleotides in length.

### Claim 11 (depends on 7)

The dsNA of claim 7, wherein the 3′ terminus of the sense strand and the 5′ terminus of the antisense strand form a blunt end.

### Claim 12 (depends on 6)

The dsNA of claim 6, wherein the sense strand comprises a tetraloop at its 3′ end.

### Claim 13 (depends on 10)

The dsNA of claim 10, wherein the sense strand comprises a tetraloop at its 3′ end.

### Claim 14 (depends on 13)

The dsNA of claim 13, wherein the tetraloop comprises a single stranded loop having a sequence of GAAA.

### Claim 15 (depends on 6)

The dsNA of claim 6, wherein the dsNA comprises at least one phosphorothioate linkage.

### Claim 16 (depends on 14)

The dsNA of claim 14, wherein the dsNA comprises at least one phosphorothioate linkage.

### Claim 17 (depends on 6)

The dsNA of claim 6, wherein the one or more modified nucleotides contains a 2′ modification.

### Claim 18 (depends on 17)

The dsNA of claim 17, wherein the one or more modified nucleotides are selected from a 2′-O-methyl nucleotide and a 2′-fluoro nucleotide.

### Claim 19 (depends on 18)

The dsNA of claim 18, wherein the dsNA comprises at least one 2′-fluoro nucleotide and at least one 2′-O-methyl nucleotide.

### Claim 20 (depends on 6)

The dsNA of claim 6, wherein the dsNA is attached to a moiety selected from the group consisting of a GalNAc moiety, a cholesterol moiety, and a cholesterol targeting ligand.

### Claim 21 (depends on 18)

The dsNA of claim 18, wherein the dsNA is attached to a GalNAc moiety.

### Claim 22 (depends on 21)

A pharmaceutical composition comprising the dsNA of claim 21 and a pharmaceutically acceptable carrier.