# US 10,246,709 B2 · Targeting ligands for therapeutic compounds

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- Number: US 10,246,709 B2
- Document ID: US10246709B2
- Status: Granted
- Kind: B2
- Application number: 15/452,423
- Filed: 2017-03-07
- Published: 2017-09-07
- Granted: 2019-04-02
- Earliest claimed: 2016-03-07
- Assignees: Arrowhead Pharmaceuticals, Inc.
- Applicants: Arrowhead Pharmaceuticals, Inc.
- Inventors: David B. Rozema; Darren H. Wakefield; Andrei V. Blokhin; Jonathan D. Benson; Zhen Li; Tao Pei; Fred Fleitz
- Web page: https://patentgrep.com/patent/US10246709B2

## 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)}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 15/04: attached to an oxygen atom of the saccharide radical
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/317: with an inverted bond, e.g. a cap structure
- C12N 2310/32: of the sugar
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

Described are novel targeting ligands that may be linked to compounds, such therapeutic compounds, that are useful in directing the compounds to the target in vivo. The targeting ligands disclosed herein can serve to target expression-inhibiting oligomeric compounds, such as RNAi agents, to liver cells to modulate gene expression. The targeting ligands disclosed herein, when conjugated to an expression-inhibiting oligomeric compound, may be used in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Compositions including the targeting ligands disclosed herein when linked to expression-inhibiting oligomeric compounds are capable of mediating expression of target nucleic acid sequences in liver cells, such as hepatocytes, which may be useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism.

## Claims

### Claim 1

A targeting ligand comprising the structure of Formula B:
wherein n is an integer from 1 to 20; X is O, S, or NH; and Targeting Moiety is selected from the group consisting of: N-acetyl-galactosamine, galactose, galactosamine, N-formyl-galactosamine, N-propionyl-galactosamine, N-n-butanoylgalactosamine, and N-iso-butanoylgalactosamine.

### Claim 2 (depends on 1)

The targeting ligand of claim 1, comprising the following structure:
wherein n is an integer from 1 to 20 (Structure 1).

### Claim 3 (depends on 1)

The targeting ligand of claim 1, wherein the targeting ligand comprises the structure selected from:

### Claim 4 (depends on 1)

The targeting ligand of claim 1, wherein the Targeting Moiety is

### Claim 5 (depends on 1)

The targeting ligand of claim 1, wherein n is 6.

### Claim 6 (depends on 1)

The targeting ligand of claim 1, wherein the targeting ligand is linked to an expression-inhibiting oligomeric compound.

### Claim 7 (depends on 6)

The targeting ligand of claim 6, wherein the expression-inhibiting oligomeric compound is an RNAi agent.

### Claim 8 (depends on 7)

The targeting ligand of claim 7, wherein the RNAi agent is double stranded.

### Claim 9 (depends on 8)

The targeting ligand of claim 8, wherein the RNAi agent comprises one or more modified nucleotides.

### Claim 10 (depends on 7)

The targeting ligand claim 7, wherein the targeting ligand is linked at the 3′ or 5′ terminal end of the RNAi agent.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 11)

The targeting ligand of claim 11, wherein the double-stranded RNAi agent is linked to the targeting ligand at the 5′ terminal end of the sense strand of the RNAi agent.

### Claim 13 (depends on 7)

The targeting ligand of claim 7, wherein the RNAi agent is linked to targeting ligand via a phosphate group, phosphorothioate group, or a phosphonate group.

### Claim 14 (depends on 1)

A composition comprising the targeting ligand of claim 1, wherein the targeting ligand is linked to an expression-inhibiting oligomeric compound, wherein the structure of the targeting ligand and expression-inhibiting oligomeric compound is represented by the structure selected from the group consisting of:
wherein Z includes or consists of an expression-inhibiting oligomeric compound (Structure 101a);
wherein Z includes or consists of an expression-inhibiting oligomeric compound (Structure 102a); and
wherein Z includes or consists of an expression-inhibiting oligomeric compound (Structure 103a).

### Claim 15 (depends on 14)

The composition of claim 14, wherein the expression-inhibiting oligomeric compound is a double-stranded RNAi agent.

### Claim 16 (depends on 15)

The composition of claim 15, wherein the double-stranded RNAi agent is attached to the targeting ligand at the 5′ end of the sense strand of the RNAi agent.

### Claim 17

A compound having the structure of:
wherein n is an integer from 1 to 20 (Structure 1d).

### Claim 18 (depends on 17)

The compound of claim 17, having the structure selected from the group consisting of:

### Claim 19 (depends on 18)

The compound of claim 18, wherein the compound is:

### Claim 20 (depends on 1)

A method of inhibiting expression of a target nucleic acid in a subject, the method comprising administering a therapeutic amount of an expression-inhibiting oligomeric compound conjugated to the targeting ligand of claim 1.

### Claim 21 (depends on 1)

A method of introducing an expression-inhibiting oligomeric compound into a mammalian cell, the method comprising contacting a mammalian cell with the targeting ligand of claim 1, linked to the expression-inhibiting oligomeric compound.

### Claim 22 (depends on 21)

The method of claim 21, wherein the cell is present in a subject.

### Claim 23 (depends on 22)

The method of claim 22, wherein the subject is a human.

### Claim 24 (depends on 21)

The method of claim 21, wherein the expression-inhibiting oligomeric compound is an RNAi agent.

### Claim 25 (depends on 1)

A method of treating a disease or disorder that would benefit from administration of an expression-inhibiting oligomeric compound, the method comprising administering a therapeutic amount of the targeting ligand of claim 1 linked to an expression-inhibiting oligomeric compound to a subject in need of treatment thereof.

### Claim 26 (depends on 25)

The method of claim 25, wherein the expression-inhibiting oligomeric compound is an RNAi agent.

### Claim 27 (depends on 14)

A method of treating a disease or disorder that would benefit from administration of an expression-inhibiting oligomeric compound, the method comprising administering a therapeutic amount of the composition of claim 14 to a subject in need of treatment thereof.