IP Library › Granted Patent US 12,596,118
Granted Patent B2
US 12,596,118 · App. 19/258,035 · Granted Apr 7, 2026

Oligonucleotides for inducing paternal UBE3A expression

Inventors: Veronica Costa (Basel, CH); Maj Hedtjärn (Hørsholm, DK); Marius Hoener (Basel, CH); Ravi Jagasia (Basel, CH); Mads Aaboe Jensen (Hørsholm, DK); Christoph Patsch (Basel, CH); Lykke Pedersen (Hørsholm, DK); Søren Vestergaard Rasmussen (Hørsholm, DK)
Assignee: Hoffmann-La Roche Inc.
G01N33/5014C12N5/0018C12N5/0619C12N5/0623C12N5/0696C12N15/11C12N15/111C12N15/113C12N15/1137G01N33/5058C12N2310/11C12N2310/20C12N2310/315C12N2310/321C12N2310/322C12N2310/3231C12N2310/33C12N2310/3341C12N2310/341C12N2310/346C12N2310/351C12N2320/34C12N2500/38C12N2500/44C12N2501/01C12N2501/11C12N2501/115C12N2501/119C12N2501/13C12N2501/41C12N2501/60C12N2501/727C12N2501/999C12N2503/02C12N2506/45C12N2533/52
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Quick Facts
Patent No.
US 12,596,118
App. No.
19/258,035
Granted
Apr 7, 2026
Kind
B2
Abstract

The present invention relates to oligonucleotides that are capable of inducing expression of ubiquitin-protein ligase E3A (UBE3A) from the paternal allele in animal or human neurons. The oligonucleotides target the suppressor of the UBE3A paternal allele by hybridization to SNHG14 long non-coding RNA downstream of SNORD109B. The present invention further relates to pharmaceutical compositions and methods for treatment of Angelman syndrome.

Claims (34)

1 . An antisense oligonucleotide comprising a contiguous nucleotide sequence of about 10 to about 30 nucleotides in length with at least 98% complementarity to position 12,179 to 12,256 of SEQ ID NO: 1, wherein the antisense oligonucleotide comprises one or more modified nucleosides.

2 . The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is about 15 to about 24 nucleotides in length.

3 . The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is about 17 to about 22 nucleotides in length.

4 . The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is about 20 nucleotides in length.

5 . The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide comprises a contiguous nucleotide sequence with 100% complementarity to position 12,179 to 12,256 of SEQ ID NO: 1.

6 . The antisense oligonucleotide of claim 1 , wherein the one or more modified nucleosides comprise one or more 2′ sugar modified nucleosides.

7 . The antisense oligonucleotide of claim 6 , wherein the one or more 2′ sugar modified nucleosides are independently selected from the group consisting of 2′-O-alkyl nucleoside, 2′-O-methyl nucleoside, 2′-alkoxy nucleoside, 2′-O-methoxyethyl nucleoside, 2′-amino nucleoside, 2′-fluoro nucleoside, arabino nucleic acid (ANA), 2′-fluoro-ANA, and LNA nucleosides.

8 . The antisense oligonucleotide of claim 6 , wherein the one or more 2′ sugar modified nucleosides are 2′-O-methoxyethyl nucleosides.

9 . The antisense oligonucleotide of claim 1 , wherein the one or more modified nucleosides comprise modified purines or pyrimidines.

10 . The antisense oligonucleotide of claim 9 , wherein the modified pyrimidine comprises isocytosine, pseudoisocytosine, 5-methyl cytosine, 5-thiozolo-cytosine, 5-propynyl-cytosine, 5-propynyl-uracil, 5-bromouracil, 5-thiazolo-uracil, 2-thio-uracil, 2′thio-thymine, inosine, diaminopurine, 6-aminopurine, 2-aminopurine, 2,6-diaminopurine, and 2-chloro-6-aminopurine.

11 . The antisense oligonucleotide of claim 10 , wherein the modified pyrimidine comprises 5-methyl cytosine.

12 . The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage within the contiguous nucleotide sequence.

13 . The antisense oligonucleotide of claim 12 , wherein the at least one modified internucleoside linkage within the contiguous nucleotide sequence is at least one phosphorothioate internucleoside linkage.

14 . The antisense oligonucleotide of claim 13 , wherein at least 50% of internucleoside linkages in the antisense oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate linkages.

15 . The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is a gapmer.

16 . The antisense oligonucleotide of claim 15 , wherein the gapmer has a formula of 5′-F-G-F′-3′, wherein region F and F′ independently comprise between about 1 and about 7 modified nucleosides and G is a region comprising between about 6 and about 16 nucleosides.

17 . The antisense oligonucleotide of claim 16 , wherein the regions F and F′ each comprise 5 modified nucleosides and G is a region comprising 10 nucleosides.

18 . The antisense oligonucleotide of claim 16 , wherein the modified nucleosides of region F and F′ comprise 2′-O-methoxyethyl nucleosides.

19 . The antisense oligonucleotide of claim 16 , wherein the nucleosides of region G comprise deoxynucleosides.

20 . The antisense oligonucleotide of claim 16 , wherein the nucleosides of region G comprise phosphorothioate internucleoside linkages.

21 . An antisense oligonucleotide gapmer comprising a contiguous nucleotide sequence of about 10 to about 30 nucleotides in length with at least 98% complementarity to position 12,179 to 12,256 of SEQ ID NO: 1,

wherein the gapmer has a formula of 5′-F-G-F′-3′, wherein region F and F′ independently comprise 5 nucleosides and region G comprises 10 nucleosides,

wherein the antisense oligonucleotide gapmer comprises at least one modified internucleoside linkage and at least one modified nucleoside,

wherein the modified nucleosides comprise 2′-O-methoxyethyl nucleosides, modified pyrimidines, or a combination thereof, wherein the modified pyrimidines comprise 5-methyl cytosine, and

wherein at least one modified internucleoside linkage comprises a phosphorothioate internucleoside linkage.

22 . The antisense oligonucleotide of claim 21 , wherein all nucleosides in region G comprise phosphorothioate internucleoside linkages.

23 . A method for treating a disease in a subject comprising administering a therapeutically effective amount of an antisense oligonucleotide comprising a contiguous nucleotide sequence of about 10 to about 30 nucleotides in length with at least 98% complementarity to position 12,179 to 12,256 of SEQ ID NO: 1, wherein the antisense oligonucleotide comprises one or more modified nucleosides.

24 . The method of claim 23 , wherein the subject suffers from or is susceptible to Angelman syndrome.

25 . The method of claim 23 , wherein the subject is an infant or a juvenile.

26 . The method of claim 23 , wherein the one or more modified nucleosides comprise one or more of 2′ sugar modified nucleosides, modified purines or pyrimidines, and modified internucleoside linkages.

27 . The method of claim 26 , wherein the one or more 2′ sugar modified nucleosides are 2′-O-methoxyethyl nucleosides.

28 . The method of claim 23 , wherein the antisense oligonucleotide is a gapmer.

29 . The method of claim 28 , wherein the gapmer has a formula of 5′-F-G-F′-3′, wherein region F and F′ independently comprise between about 1 and about 7 modified nucleosides and G is a region comprising between about 6 and about 16 nucleosides.

30 . The method of claim 29 , wherein the regions F and F′ each comprise 5 modified nucleosides and G is a region comprising 10 nucleosides.

Assignments (8)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 16, 2026
From: HOFFMANN-LA ROCHE INC.
To: OHB PEDIATRICS LTD.
Reel/Frame 075293/0160 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2025
From: COSTA, VERONICA; HOENER, MARIUS; JAGASIA, RAVI; PATSCH, CHRISTOPH
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 073088/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2025
From: HEDTJÄRN, MAJ; JENSEN, MADS AABOE; PEDERSEN, LYKKE
To: ROCHE INNOVATION CENTER COPENHAGEN A/S
Reel/Frame 073088/0203 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2025
From: HEDTJÄRN, MAJ; JENSEN, MADS AABOE; PEDERSEN, LYKKE; RASMUSSEN, SØREN VESTERGAARD
To: ROCHE INNOVATION CENTER COPENHAGEN A/S
Reel/Frame 073088/0469 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2025
From: COSTA, VERONICA; HOENER, MARIUS; JAGASIA, RAVI; PATSCH, CHRISTOPH
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 073088/0097 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2025
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 073088/0903 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2025
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 073089/0063 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2025
From: ROCHE INNOVATION CENTER COPENHAGEN A/S
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 073088/0763 →
Priority Claims (2)
EP 15194367 · Nov 12, 2015 · regional
EP 16189502 · Sep 19, 2016 · regional
Continuity (8)
Continuation 18491513 · Oct 20, 2023
Continuation 17581089 · Jan 21, 2022
Continuation 16933445 · Jul 20, 2020
Continuation 16663024 · Oct 24, 2019
Continuation 16388714 · Apr 18, 2019
Continuation 15351113 · Nov 14, 2016
Continuation PCTEP2016077383 · Nov 11, 2016
Related Publication 20250389713A1 · Dec 25, 2025
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