# US 11,299,738 B2 · Further novel oligonucleotide-ligand conjugates

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- Number: US 11,299,738 B2
- Document ID: US11299738B2
- Status: Granted
- Kind: B2
- Application number: 16/603,211
- Filed: 2018-04-05
- Published: 2021-03-25
- Granted: 2022-04-12
- Earliest claimed: 2017-04-05
- Assignees: Silence Therapeutics GmbH
- Applicants: Silence Therapeutics GmbH
- Inventors: Dmitry Samarsky; Christian Frauendorf
- Web page: https://patentgrep.com/patent/US11299738B2

## CPC

- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C12N 15/1138: {against receptors or cell surface proteins}
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61K 47/605: {the macromolecule containing phosphorus in the main chain, e.g. poly-phosphazene}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/06: Antihyperlipidemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/351: Conjugate
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- 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)
- 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

The present invention relates to a compound comprising a modified saccharide moiety conjugated to a nucleic acid. The compound is useful in medicine for RNA interference therapy or for research and diagnostic purposes. In particular, the compound is useful in treating liver disease.

## Claims

### Claim 1

A compound having the formula I:
[S—X1—P—X2]3-A-X3—Z (I)
wherein:
S represents a saccharide;
X1 represents C3-C6 alkylene or (—CH2—CH2—O)m(—CH2)2— wherein m is 1, 2, or 3;
P is a modified phosphate;
X2 is C1-C8 alkylene;
X3 represents a bridging unit;
Z is a nucleic acid;
the linkage between X3 and Z is a phosphate or thiophosphate;
and A is a branching unit selected from:
wherein:
R1 is hydrogen or C1-C10 alkylene;
and R2 is C1-C10 alkylene.

### Claim 2 (depends on 1)

The compound of claim 1, wherein A has the structure:
wherein:
R1 is hydrogen or C1-C10 alkylene; and
R2 is C1-C10 alkylene.

### Claim 3 (depends on 2)

The compound of claim 2, wherein A has a structure selected from:
wherein in each case
X3 is attached to the nitrogen atom.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X3 may be selected from —C1-C20 alkylene-, —C2-C20 alkenylene-, an alkylene ether of formula —(C1-C20 alkylene)-O—(C1-C20 alkylene)-, —C0-C4 alkylene(Cy)C0-C4 alkylene- wherein Cy represents a substituted or unsubstituted 5 or 6 membered cycloalkylene, arylene, heterocyclylene or heteroarylene ring, —C1-C4 alkylene-NHC(O)—C1-C4 alkylene-, —C1-C4 alkylene-C(O)NH—C1-C4 alkylene-, —C1-C4 alkylene-SC(O)—C1-C4 alkylene-, —C1-C4 alkylene-C(O)S—C1-C4 alkylene-, —C1-C4 alkylene-OC(O)—C1-C4 alkylene-, —C1-C4 alkylene-C(O)O—C1-C4 alkylene-, and —C1-C6 alkylene-S—S—C1-C6 alkylene-.

### Claim 5 (depends on 4)

The compound of claim 4, wherein X3 is:
a. —C1-C20 alkylene-;
b. selected from the group consisting of —C3H6—, —C6H12— and —C8H16—; or,
c. —C3H6—.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the modified phosphate is a thiophosphate.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the saccharide is:
a. selected from N-acetyl galactosamine, mannose, galactose, glucose, glucosamine and fructose; or
b. N-acetyl galactosamine.

### Claim 8 (depends on 1)

The compound of claim 1, wherein X1 is:
a. (—CH2—CH2—O)m(—CH2)2— wherein m is 1, 2, or 3; or
b. C3-C6 alkylene.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound has one of the following formulas:
wherein Z is a nucleic acid.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the nucleic acid is selected from RNAi, siRNA, siNA, antisense nucleic acid, ribozymes, aptamers and spiegelmers.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the nucleic acid is modified.

### Claim 12 (depends on 11)

The compound of claim 11 wherein the modification is selected from substitutions or insertions with analogues of nucleic acids or bases and chemical modification of the base, sugar or phosphate moieties.

### Claim 13 (depends on 1)

A composition comprising a compound as defined in claim 1 and a pharmaceutically suitable carrier or excipient.

### Claim 14 (depends on 1)

A method for treating a subject in need thereof, comprising a step of administering the compound of claim 1 to the subject.

### Claim 15 (depends on 14)

The method of claim 14, wherein the subject is suffering from a liver disease, a genetic disease, hemophilia or bleeding disorder, liver fibrosis, non-alcoholic steotohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), viral hepatitis, a rare disease, a metabolic disease, a cardiovascular disease, obesity, thalassemia, liver injury, hemochromatosis, alcoholic liver disease, alcohol dependence, anemia, or anemia of chronic disease.

### Claim 16 (depends on 1)

A method of delivering nucleic acids to a hepatocyte, the method comprising contacting the hepatocyte with a compound of claim 1.

### Claim 17 (depends on 15)

The method of claim 15, wherein the rare disease is acromegaly; the metabolic disease is hypercholesterolemia, dyslipidemia, or hypertriglyceridemia; or the liver injury is drug induced liver injury.

### Claim 18 (depends on 10)

A method of treating a subject in need thereof, the method comprising a step of administering a composition of claim 10 to the subject.

### Claim 19 (depends on 17)

The method of claim 17, wherein the subject is suffering from a liver disease, a genetic disease, hemophilia or bleeding disorder, liver fibrosis, non-alcoholic steotohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), viral hepatitis, a rare diseases, a metabolic diseases, a cardiovascular disease, obesity, thalassemia, liver injury, hemochromatosis, alcoholic liver disease, alcohol dependence, anemia, or anemia of chronic diseases.

### Claim 20 (depends on 19)

The method of claim 19, wherein the rare disease is acromegaly; the metabolic disease is hypercholesterolemia, dyslipidemia, or hypertriglyceridemia; or the liver injury is drug induced liver injury.

### Claim 21 (depends on 10)

The compound of claim 10, wherein the nucleic acid is a siRNA and wherein the siRNA comprises:
a. 1-5 2′-O-CH3 modified nucleotides;
b. 5-10 2′-O-CH3 modified nucleotides;
c. 15-20 2′-O-CH3 modified nucleotides;
d. 20-25 2′-O-CH3 modified nucleotides; or
e. 25-30 2′-O-CH3 modified nucleotides.

### Claim 22 (depends on 10)

The compound of claim 10, wherein the nucleic acid is a siRNA and wherein the siRNA comprises an antisense strand of 19 nucleotides in length and a sense strand 19 nucleotides in length, wherein said antisense strand comprises 2′-O-CH3 modifications at nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19, and wherein said sense strand comprises 2′-O-CH3 modifications at nucleotides 2, 4, 6, 8, 10, 12 ,14, 16 and 18, wherein said antisense strand is numbered from 5′-3′ and said sense strand is numbered from 3′-5′.

### Claim 23 (depends on 10)

The compound of claim 10, wherein the nucleic acid is a siRNA, wherein the siRNA is blunt-ended on both ends and wherein the siRNA has a length of 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 consecutive nucleotides.