# US 11,299,736 B1 · Conjugated antisense compounds and their use

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- Number: US 11,299,736 B1
- Document ID: US11299736B1
- Status: Granted
- Kind: B1
- Application number: 17/070,287
- Filed: 2020-10-14
- Granted: 2022-04-12
- Earliest claimed: 2013-05-01
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Thazha P. Prakash; Punit P. Seth; Eric E. Swayze
- Web page: https://patentgrep.com/patent/US11299736B1

## 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 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 21/04: with deoxyribosyl as saccharide radical
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12Y 301/03048: Protein-tyrosine-phosphatase (3.1.3.48)
- C12N 2310/11: Antisense
- C12N 2310/113: targeting other non-coding nucleic acids, e.g. antagomirs
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/17: Immunomodulatory nucleic acids
- C12N 2310/31: of the backbone
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2310/351: Conjugate
- C12N 2310/3511: intercalating or cleaving agent
- C12N 2310/3513: Protein; Peptide
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2310/3525: MOE, methoxyethoxy
- C12N 2310/353: linked to the nucleic acid via an atom other than carbon
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- 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)
- C12Y: ENZYMES

## Abstract

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.

## Claims

### Claim 1

A compound comprising a conjugate having the formula:

### Claim 2 (depends on 1)

The compound of claim 1, further comprising a linker joined to the conjugate.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the linker comprises an amine, an amide, an ester, an ether, a pyrrolidine, PEG, a polyamide, or a disulfide bond.

### Claim 4 (depends on 2)

The compound of claim 2, wherein the linker does not comprise a pyrrolidine.

### Claim 5 (depends on 2)

The compound of claim 2, wherein the linker has the formula:

### Claim 6 (depends on 2)

The compound of claim 2, wherein the linker has the formula:
wherein:
CM is a cleavable moiety and T3 is a nucleoside, a nucleotide, a monomeric subunit, or an oligomeric compound.

### Claim 7 (depends on 2)

The compound of claim 2, wherein the linker has the formula:
wherein:
T3 is a nucleoside, a nucleotide, a monomeric subunit, or an oligomeric compound.

### Claim 8 (depends on 7)

The compound of claim 7, wherein T3 is a group comprising an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide.

### Claim 9 (depends on 8)

The compound of claim 8, wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides wherein at least one nucleoside is a modified nucleoside.

### Claim 10 (depends on 8)

The compound of claim 8, wherein the modified oligonucleotide comprises at least one modified nucleoside selected from among: a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a (4′-CH2—O-2′) bicyclic nucleoside, a (4′-(CH2)2—O-2′) bicyclic nucleoside, a (4′-C(CH3)H—O-2′) bicyclic nucleoside; and a morpholino.

### Claim 11 (depends on 8)

The compound of claim 8, wherein the modified oligonucleotide has a gapmer sugar motif comprising:
a 5′-region consisting of 2-8 linked 5′-region nucleosides, wherein at least two 5′-region nucleosides are modified nucleosides and wherein the 3′-most 5′-region nucleoside is a modified nucleoside;
a 3′-region consisting of 2-8 linked 3′-region nucleosides, wherein at least two 3′-region nucleosides are modified nucleosides and wherein the 5′-most 3′-region nucleoside is a modified nucleoside; and
a central region between the 5′-region and the 3′-region consisting of 5-10 linked central region nucleosides, each independently selected from among: a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′-most central region nucleoside is an unmodified deoxynucleoside and the 3′-most central region nucleoside is an unmodified deoxynucleoside.

### Claim 12 (depends on 11)

The compound of claim 11, wherein each 5′-region nucleoside is a modified nucleoside; each 3′-region nucleoside is a modified nucleoside; and each central region nucleoside is an unmodified deoxynucleoside.

### Claim 13 (depends on 12)

The compound of claim 12, wherein the 5′-region consists of 2-5 linked 5′-region nucleosides; the 3′-region consists of 2-5 linked 3′-region nucleosides; and the central region consists of 8-10 central region nucleosides.

### Claim 14 (depends on 8)

The compound of claim 8, wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.

### Claim 15 (depends on 14)

The compound of claim 14, wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.

### Claim 16 (depends on 15)

The compound of claim 15, wherein each internucleoside linkage of the modified oligonucleotide is either phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage.

### Claim 17 (depends on 8)

The compound of claim 8, wherein the modified oligonucleotide is an antisense oligonucleotide.

### Claim 18 (depends on 17)

The compound of claim 17, wherein the modified oligonucleotide is complementary to a target nucleic acid.

### Claim 19 (depends on 18)

The compound of claim 18, wherein the modified oligonucleotide is single-stranded.

### Claim 20 (depends on 18)

The compound of claim 18, wherein the modified oligonucleotide is double-stranded.

### Claim 21 (depends on 20)

The compound of claim 20, wherein the modified oligonucleotide activates the RISC pathway.