# US 10,865,413 B2 · Oligomeric compounds comprising α-β-constrained nucleic acid

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- Number: US 10,865,413 B2
- Document ID: US10865413B2
- Status: Granted
- Kind: B2
- Application number: 16/239,781
- Filed: 2019-01-04
- Published: 2019-11-28
- Granted: 2020-12-15
- Earliest claimed: 2014-04-24
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Michael Oestergaard; Eric E. Swayze; Punit P. Seth
- Web page: https://patentgrep.com/patent/US10865413B2

## 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)}
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 2310/11: Antisense
- C12N 2310/31: of the backbone
- C12N 2310/314: Phosphoramidates
- C12N 2310/315: Phosphorothioates
- C12N 2310/322: 2'-R Modification
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/345: having at least two different backbone modifications
- C12N 2320/30: Special therapeutic applications
- C12N 2320/34: Allele or polymorphism specific uses
- C12N 2330/30: chemically synthesised
- 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 disclosure provides oligomeric compounds comprising at least one α-β-constrained nucleic acid as provided herein. More particularly, the α-β-constrained nucleic acid provided herein comprise an optionally modified nucleoside with a phosphorus containing constrained internucleoside linkage such as for example a cyclic phosphate internucleoside linkage. The α-β-constrained nucleic acid provided herein are expected to be useful for enhancing one or more properties of oligomeric compounds they are incorporated into such as for example nuclease resistance. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

## Claims

### Claim 1

An antisense gapped oligomeric compound comprising:
a first region of from 1 to about 5 contiguous monomer subunits;
a second region of from 1 to about 5 contiguous monomer subunits; and
a third region located between the first and second region comprising from 6 to about 14 monomer subunits;
wherein each monomer subunit in the first and second region is, independently, a modified nucleoside and each monomer subunit in the third region is, independently, a nucleoside or a modified nucleoside other than the modified nucleosides in the first and second region and wherein the third region comprises at least one modified nucleotide having Formula III:
wherein independently for each modified nucleotide having Formula III:
T5 is one of the monomer subunits;
T6 is an internucleoside linking group attached to one of the monomer subunits;
each Bx is a heterocyclic base moiety;
each G1 and G2 is, independently, H, OH or a 2′-sugar substituent group;
each X or each Z is CJ1J2, NJ1, S or O and the other of each X or each Z is O;
each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; and
n is from 1 to about 3.

### Claim 2 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each X is O.

### Claim 3 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each X is CJ1J2.

### Claim 4 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each X is CH2.

### Claim 5 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each X is S.

### Claim 6 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each X is NJ1.

### Claim 7 (depends on 6)

The gapped oligomeric compound of claim 6 wherein each J1 is H or CH3.

### Claim 8 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each Z is O.

### Claim 9 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each Z is CJ1J2.

### Claim 10 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each Z is CH2.

### Claim 11 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each Z is S.

### Claim 12 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each Z is NJ1.

### Claim 13 (depends on 12)

The gapped oligomeric compound of claim 12 wherein each J1 is H or CH3.

### Claim 14 (depends on 1)

The gapped oligomeric compound of claim 1 wherein for each modified nucleotide of Formula III, one of G1 and G2 is H and the other of G1 and G2 is, independently, selected from halogen and O—[C(R1)(R2)]i—[(C═O)m-A]j-T;
each R1 and R2 is, independently, H, C1-C6 alkyl or halogen;
A is O, S or N(E1);
T is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl or N(E2)(E3);
E1, E2 and E3 are each, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl;
i is from 1 to about 6;
m is 0 or 1;
j is 0 or 1;
wherein each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ3, N(J3)(J4), =NJ3, SJ3, N3, CN, OC(=L2)J3, OC(=L2)N(J3)(J4) and C(=L2)N(J3)(J4);
L2 is O, S or NJ5;
each J3, J4 and J5 is, independently, H or C1-C6 alkyl; and
when j is 1 then T is other than halogen.

### Claim 15 (depends on 1)

The gapped oligomeric compound of claim 1 wherein for each modified nucleotide of Formula III, one of G1 and G2 is H and the other of G1 and G2 is, independently, selected from F, OCH3, O(CH2)2—OCH3 or OCH2C(═O)—N(H)CH3.

### Claim 16 (depends on 1)

The gapped oligomeric compound of any of claim 1 wherein each G2 is H.

### Claim 17 (depends on 1)

The gapped oligomeric compound of claim 1 wherein for each modified nucleotide of Formula III, G1 is O(CH2)2—OCH3 and G2 is H.

### Claim 18 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each G1 and G2 is H.

### Claim 19 (depends on 1)

The gapped oligomeric compound of claim 1 wherein for each modified nucleotide of Formula III, X and Z are each O and G1 and G2 are each H.

### Claim 20 (depends on 1)

The gapped oligomeric compound of claim 1 wherein each Bx is, independently, an optionally protected pyrimidine, substituted pyrimidine, purine or substituted purine.