# US 9,752,146 B2 · Oligomeric compounds and compositions for use in modulation of small non-coding RNAs

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- Number: US 9,752,146 B2
- Document ID: US9752146B2
- Status: Granted
- Kind: B2
- Application number: 15/234,487
- Filed: 2016-08-11
- Published: 2017-02-09
- Granted: 2017-09-05
- Earliest claimed: 2003-07-31
- Assignees: Regulus Therapeutics Inc.
- Applicants: Regulus Therapeutics Inc.
- Inventors: C. Frank Bennett; Susan M. Freier; Richard H. Griffey
- Web page: https://patentgrep.com/patent/US9752146B2

## 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 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 37/00: Drugs for immunological or allergic disorders
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 2310/11: Antisense
- C12N 2310/113: targeting other non-coding nucleic acids, e.g. antagomirs
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2310/31: of the backbone
- C12N 2310/315: Phosphorothioates
- C12N 2310/317: with an inverted bond, e.g. a cap structure
- C12N 2310/3181: Peptide nucleic acid, PNA
- C12N 2310/32: of the sugar
- C12N 2310/321: 2'-O-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 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2320/11: for the determination of target sites, i.e. of active nucleic acids
- C12N 2320/30: Special therapeutic applications
- C12N 2320/50: Methods for regulating/modulating their activity
- 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

Compounds, compositions and methods are provided for modulating the expression and function of small non-coding RNAs. The compositions comprise oligomeric compounds, targeted to small non-coding RNAs. Methods of using these compounds for modulation of small non-coding RNAs as well as downstream targets of these RNAs and for diagnosis and treatment of disease associated with small non-coding RNAs are also provided.

## Claims

### Claim 1

A method of inhibiting the activity, function, or amount of miR-17 (SEQ ID NO: 204), comprising contacting a cell with a compound comprising a modified oligonucleotide, wherein:
the modified oligonucleotide consists of 8, 9, 10, 11, or 12 linked monomeric subunits;
each monomeric subunit of the modified oligonucleotide comprises a modified sugar moiety; and
the modified oligonucleotide is complementary to miR-17 with no more than one mismatch.

### Claim 2 (depends on 1)

The method of claim 1 wherein the modified oligonucleotide consists of 8 monomeric subunits.

### Claim 3 (depends on 1)

The method of claim 1 wherein the modified oligonucleotide consists of 9 monomeric subunits.

### Claim 4 (depends on 1)

The method of claim 1 wherein the modified oligonucleotide consists of 10 monomeric subunits.

### Claim 5 (depends on 1)

The method of claim 1 wherein the modified oligonucleotide consists of 11 monomeric subunits.

### Claim 6 (depends on 1)

The method of claim 1 wherein the modified oligonucleotide consists of 12 monomeric subunits.

### Claim 7 (depends on 1)

The method of claim 1, wherein each modified sugar moiety is independently selected from a 2′-F sugar moiety, a 2′-O-methyl sugar moiety, a 2′-O-methoxyethyl sugar moiety, and a bicyclic sugar moiety.

### Claim 8 (depends on 7)

The method of claim 7, wherein the bicyclic sugar moiety has a 4′-CH2—O-2′ bridge.

### Claim 9 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

### Claim 10 (depends on 9)

The method of claim 9, wherein the modified internucleoside linkage is a phosphorothioate linkage.

### Claim 11 (depends on 1)

The method of claim 1, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.

### Claim 12 (depends on 1)

The method of claim 1, wherein the oligonucleotide comprises two or more chemically distinct regions.

### Claim 13 (depends on 12)

The method of claim 12, wherein the sugar moiety of each nucleoside of a first chemically distinct region is the same and is selected from a 2′-fluoro nucleoside, a 2′-O-methyl nucleoside, a 2′-O-methoxyethyl nucleoside, and a bicyclic sugar nucleoside.

### Claim 14 (depends on 13)

The method of claim 13, wherein the bicyclic nucleoside has a 4′-CH2—O-2′ bridge.

### Claim 15 (depends on 1)

The method of claim 1, wherein the oligonucleotide comprises at least one 5-methylcytosine.

### Claim 16 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide is attached to a conjugate group.

### Claim 17 (depends on 16)

The method of claim 16, wherein the conjugate group is cholesterol.

### Claim 18 (depends on 16)

The method of claim 16, wherein the conjugate group comprises a carbohydrate.

### Claim 19 (depends on 1)

The method of claim 1, wherein each modified sugar moiety is a bicyclic sugar moiety.

### Claim 20 (depends on 19)

The method of claim 19, wherein each bicyclic sugar moiety has a 4′-CH2—O-2′ bridge.

### Claim 21 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide is complementary to a target region comprising nucleobases 1 to 8 of miR-17.

### Claim 22 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide is complementary to a target region comprising nucleobases 2 to 9 of miR-17.

### Claim 23 (depends on 1)

The method of claim 1, wherein the modified oligonucleotide is complementary to a target region comprising nucleobases 3 to 10 of miR-17.

### Claim 24 (depends on 1)

The method of claim 1, wherein the contacting comprises administering the compound to a subject.