# US 9,517,245 B2 · Sorafenib-microRNA combination therapy for liver cancer

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,517,245 B2
- Document ID: US9517245B2
- Status: Granted
- Kind: B2
- Application number: 14/634,243
- Filed: 2015-02-27
- Published: 2015-09-03
- Granted: 2016-12-13
- Earliest claimed: 2014-02-28
- Assignees: Mirna Therapeutics, Inc.
- Applicants: Mirna Therapeutics, Inc.
- Inventors: Andreas Bader; Jane Zhao
- Web page: https://patentgrep.com/patent/US9517245B2

## CPC

- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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)}
- C12N 2320/31: Combination therapy
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

A method of treating a subject having liver cancer can include administering a synthetic oligonucleotide to a subject having liver cancer, the oligonucleotide comprising a sequence that is at least 80% identical to at least one of SEQ ID NO:1-12 (e.g., a miR-34 or miR-215 mimic); and administering sorafenib to the subject, wherein the molar ratio of sorafenib:oligonucleotide administered to the subject is in the range of about 10-2000 (e.g., a ratio that provides a superior, for example synergistic or greater than additive, effect).

## Claims

### Claim 1

A synergistic compound combination comprising a synergistically effective amount of: (a) sorafenib; and (b) a 17-30 basepair synthetic oligonucleotide comprising:
(i) a guide strand comprising a sequence according to SEQ ID NO:9;
(ii) a separate passenger strand that is at least 60% complementary to the guide strand; and
(iii) a 5′ end nucleotide modification on the passenger strand, wherein the 5′ end nucleotide modification is: a 5′ end terminal nucleotide cap; a mismatch at the first nucleotide at the 5′ end of the passenger strand; a mismatch at the second nucleotide at the 5′ end of the passenger strand; or any combinations thereof.

### Claim 2 (depends on 1)

The synergistic compound combination of claim 1, wherein the synthetic oligonucleotide is 20-23 basepairs in length.

### Claim 3 (depends on 2)

The synergistic compound combination of claim 2, wherein the synthetic oligonucleotide comprises a sequence according to SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3.

### Claim 4 (depends on 2)

The synergistic compound combination of claim 2, wherein the synthetic oligonucleotide comprises a sequence according to SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7.

### Claim 5 (depends on 1)

The synergistic compound combination of claim 1, wherein the 5′ end terminal nucleotide cap on the passenger strand is a C6 alkylamine group.

### Claim 6 (depends on 1)

A method of treating a liver cancer in a subject in need thereof, comprising:
administering to the subject the synergistic combination of claim 1.

### Claim 7 (depends on 6)

The method of claim 6, wherein the liver cancer is primary liver cancer.

### Claim 8 (depends on 7)

The method of claim 7, wherein the liver cancer is hepatocellular carcinoma (HCC).

### Claim 9 (depends on 6)

The method of claim 6, wherein the synergy is quantified as (a) a level of cancer cell inhibition greater than about 70%; (b) a combination index (CI) of less than about; and (c) a dose reduction index (DRI) greater than about 2.0 for both sorafenib and the oligonucleotide.

### Claim 10 (depends on 6)

The method of claim 6, wherein the molar ratio of sorafenib:oligonucleotide administered to the subject is in the range of about 15:1 to 2032:1.

### Claim 11 (depends on 6)

The method of claim 6, wherein the molar ratio of sorafenib:oligonucleotide administered to the subject is in the range of about 15:1 to 1723:1.

### Claim 12 (depends on 6)

The method of claim 6, wherein the molar ratio is based on the amount of sorafenib:oligonucleotide administered to the subject in a single day, a single week, 14 days, 21 days, or 28 days.

### Claim 13 (depends on 6)

The method of claim 6, wherein the oligonucleotide is administered to the subject prior to the sorafenib, concurrently with the sorafenib, or after the sorafenib.

### Claim 14 (depends on 6)

The method of claim 6, wherein the liver cancer has primary or secondary resistance to sorafenib.

### Claim 15 (depends on 1)

A method of inhibiting proliferation of liver cancer cells, the method comprising administering the synergistic combination of claim 1.

### Claim 16 (depends on 1)

A method of treating a hepatocellular carcinoma (HCC) in a subject in need thereof, comprising:
administering to the subject the synergistic combination of claim 1, wherein the synthetic oligonucleotide comprises a sequence according to SEQ ID NO:1.

### Claim 17 (depends on 16)

The method of claim 16, wherein the synergy is quantified as (a) a level of cancer cell inhibition greater than about 70%; (b) a combination index (CI) of less than about 0.60; and (c) a dose reduction index (DRI) greater than about 2.0 for both sorafenib and the oligonucleotide.

### Claim 18 (depends on 16)

The method of claim 16, wherein the molar ratio of sorafenib:oligonucleotide is in the range of about 15:1 to 2032:1.

### Claim 19 (depends on 16)

The method of claim 16,
wherein the oligonucleotide is administered to the subject in an amount of about 10, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, or 250 mg/m2 per day;
wherein the sorafenib is administered to the subject in an amount of about 800, 600, 400, or 200 mg/day;
wherein the molar ratio of sorafenib:oligonucleotide administered to the subject is in the range of about 15:1 to 2032:1 based on the amount of sorafenib:oligonucleotide administered to the subject in a single day, a single week, 14 days, 21 days, or 28 days.