# US 10,870,676 B2 · Antisense nucleic acids

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- Number: US 10,870,676 B2
- Document ID: US10870676B2
- Status: Granted
- Kind: B2
- Application number: 16/408,529
- Filed: 2019-05-10
- Published: 2020-04-16
- Granted: 2020-12-22
- Earliest claimed: 2010-09-01
- Assignees: Nippon Shinyaku Co., Ltd.; National Center of Neurology and Psychiatry
- Applicants: Nippon Shinyaku Co., Ltd.; National Center of Neurology and Psychiatry
- Inventors: Naoki Watanabe; Youhei Satou; Shin'ichi Takeda; Tetsuya Nagata
- Web page: https://patentgrep.com/patent/US10870676B2

## CPC

- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- C07H 21/04: with deoxyribosyl as saccharide radical
- 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
- C07K 14/4708: {Duchenne dystrophy}
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- 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 2310/11: Antisense
- C12N 2310/3145: with the nitrogen in 3' or 5'-position
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/3525: MOE, methoxyethoxy
- C12N 2320/33: Alteration of splicing
- 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)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention provides an oligomer which efficiently enables to cause skipping of the 53rd exon in the human dystrophin gene. Also provided is a pharmaceutical composition which causes skipping of the 53rd exon in the human dystrophin gene with a high efficiency.

## Claims

### Claim 1

A method of treating Duchenne muscular dystrophy (DMD) in a patient in need thereof comprising administering an antisense oligomer, or a pharmaceutically acceptable salt or hydrate thereof, wherein the antisense oligomer consists of a nucleotide sequence complementary to the sequence consisting of the 36th to the 56th nucleotides from the 5′ end of the 53rd exon in a human dystrophin pre-mRNA, and wherein the 53rd exon in the human dystrophin pre-mRNA consists of a nucleotide sequence corresponding to SEQ ID NO: 1.

### Claim 2

A method of treating Duchenne muscular dystrophy (DMD) in a patient in need thereof comprising administering a pharmaceutical composition comprising as an active ingredient an antisense oligomer, or a pharmaceutically acceptable salt or hydrate thereof, wherein the antisense oligomer consists of a nucleotide sequence complementary to the sequence consisting of the 36th to the 56th nucleotides from the 5′ end of the 53rd exon in a human dystrophin pre-mRNA, and wherein the 53rd exon in the human dystrophin pre-mRNA consists of a nucleotide sequence corresponding to SEQ ID NO: 1.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the antisense oligomer is an oligonucleotide.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the oligonucleotide comprises at least one nucleotide having a modified sugar moiety or having a modified phosphate-binding region.

### Claim 5 (depends on 4)

The method according to claim 4, wherein the modified sugar moiety is a ribose in which the 2′-OH group is replaced by any one selected from the group consisting of: OR, R, R′OR, SH, SR, NH2, NHR, NR2, N3, CN, F, Cl, Br, and I (wherein R is an alkyl or an aryl and R′ is an alkylene).

### Claim 6 (depends on 4)

The method according to claim 4, wherein the modified phosphate-binding region is any one selected from the group consisting of: a phosphorothioate bond, a phosphorodithioate bond, an alkylphosphonate bond, a phosphoramidate bond, and a boranophosphate bond.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the antisense oligomer is a morpholino oligomer.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer.

### Claim 9 (depends on 8)

The method according to claim 8, wherein the 5′ end of the antisense oligomer is any one of the groups of chemical formulae (1) to (3) below:

### Claim 10 (depends on 1)

The method according to claim 1, wherein the antisense oligomer, or the pharmaceutically acceptable salt or hydrate thereof, is administered intravenously.

### Claim 11 (depends on 2)

The method according to claim 2, wherein the antisense oligomer is an oligonucleotide.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the oligonucleotide comprises at least one nucleotide having a modified sugar moiety or having a modified phosphate-binding region.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the modified sugar moiety is a ribose in which the 2′-OH group is replaced by any one selected from the group consisting of: OR, R, R′OR, SH, SR, NH2, NHR, NR2, N3, CN, F, Cl, Br, and I (wherein R is an alkyl or an aryl and R′ is an alkylene).

### Claim 14 (depends on 12)

The method according to claim 12, wherein the modified phosphate-binding region is any one selected from the group consisting of: a phosphorothioate bond, a phosphorodithioate bond, an alkylphosphonate bond, a phosphoramidate bond, and a boranophosphate bond.

### Claim 15 (depends on 2)

The method according to claim 2, wherein the antisense oligomer is a morpholino oligomer.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the 5′ end of the antisense oligomer is any one of the groups of chemical formulae (1) to (3) below:

### Claim 18 (depends on 2)

The method according to claim 2, wherein the pharmaceutical composition is administered intravenously.