IP Library › Granted Patent US 12,566,172
Granted Patent B2
US 12,566,172 · App. 18/491,513 · Granted Mar 3, 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 12,566,172
App. No.
18/491,513
Granted
Mar 3, 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 (14)

1 . A method for preventing or ameliorating one or more characteristics associated with a disease, wherein the disease is Angelman syndrome, the method comprising administering to a subject susceptible to or having the disease an effective amount of an antisense oligonucleotide, a pharmaceutically acceptable salt of the antisense oligonucleotide, or a pharmaceutical composition comprising the antisense oligonucleotide and a pharmaceutically acceptable diluent, solvent, carrier, salt, and/or adjuvant, wherein the antisense oligonucleotide is the oligonucleotide compound TTAcActtaattatactTCC (SEQ ID NO: 626), wherein capital letters represent beta-D-oxy LNA nucleosides and lowercase letters represent DNA nucleosides, wherein all LNA C are 5-methyl cytosine, and wherein all internucleoside linkages are phosphorothioate internucleoside linkages.

2 . The method of claim 1 , wherein the pharmaceutically acceptable salt of the antisense oligonucleotide is a sodium salt.

3 . The method of claim 1 , wherein the pharmaceutically acceptable salt of the antisense oligonucleotide is a potassium salt.

4 . The method of claim 1 , wherein the pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS).

5 . The method of claim 1 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable sodium salt.

6 . The method of claim 1 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable potassium salt.

7 . The method of claim 1 , wherein the one or more characteristics associated with the disease comprise severe intellectual and/or development disability, sleep disturbance, seizure, jerky movement, EEG abnormality, frequent laughter or smiling, or profound language impairment.

8 . The method of claim 1 , wherein administering prevents the one or more characteristics associated with the disease.

9 . The method of claim 1 , wherein administering ameliorates the one or more characteristics associated with the disease.

10 . The method of claim 1 , wherein the antisense oligonucleotide induces expression of a paternal UBE3A gene.

11 . The method of claim 1 , wherein the antisense oligonucleotide induces increased expression of UBE3A protein.

12 . The method of claim 11 , wherein the expression of UBE3A protein is increased by at least 40% as compared to expression of UBE3A in a control.

13 . The method of claim 11 , wherein the increased expression of UBE3A protein prevents the one or more characteristics associated with the disease.

14 . The method of claim 11 , wherein the increased expression of UBE3A protein ameliorates the one or more characteristics associated with the disease.

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 Mar 7, 2024
From: COSTA, VERONICA; HOENER, MARIUS; JAGASIA, RAVI; PATSCH, CHRISTOPH
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 066684/0735 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2024
From: HEDTJÄRN, MAJ; JENSEN, MADS AABOE; PEDERSEN, LYKKE
To: ROCHE INNOVATION CENTER COPENHAGEN A/S
Reel/Frame 066684/0761 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2024
From: HEDTJÄRN, MAJ; JENSEN, MADS AABOE; PEDERSEN, LYKKE; RASMUSSEN, SØREN VESTERGAARD
To: ROCHE INNOVATION CENTER COPENHAGEN A/S
Reel/Frame 066684/0766 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2024
From: COSTA, VERONICA; HOENER, MARIUS; JAGASIA, RAVI; PATSCH, CHRISTOPH
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 066684/0730 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2024
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 066684/0786 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2024
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 066684/0790 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2024
From: ROCHE INNOVATION CENTER COPENHAGEN A/S
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 066684/0780 →
Priority Claims (2)
EP 15194367 · Nov 12, 2015 · regional
EP 16189502 · Sep 19, 2016 · regional
Continuity (8)
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 20240085402A1 · Mar 14, 2024
Related Publication 20250116656A2 · Apr 10, 2025
References Cited (183)
US 4373084A · Robinson · 1983 [cited by applicant]
US 6184212B1 · Miraglia et al. · 2001 [cited by applicant]
US 6300132B1 · Monia et al. · 2001 [cited by applicant]
US 6617162B2 · Dobie et al. · 2003 [cited by applicant]
US 8067173B2 · Liew · 2011 [cited by applicant]
US 9617539B2 · Rigo et al. · 2017 [cited by applicant]
US 10494633B2 · Costa et al. · 2019 [cited by applicant]
US 10718753B2 · Costa et al. · 2020 [cited by applicant]
US 10739332B2 · Costa et al. · 2020 [cited by applicant]
US 11320421B2 · Costa et al. · 2022 [cited by applicant]
US 11852627B2 · Costa et al. · 2023 [cited by applicant]
US 12259380B2 · Costa et al. · 2025 [cited by applicant]
US 20020098511A1 · Heichman et al. · 2002 [cited by applicant]
US 20030087855A1 · Ward et al. · 2003 [cited by applicant]
US 20130225659A1 · Bennett · 2013 [cited by applicant]
US 20150191723A1 · Rigo et al. · 2015 [cited by applicant]
US 20170191064A1 · Costa et al. · 2017 [cited by applicant]
US 20190310244A1 · Costa et al. · 2019 [cited by applicant]
US 20200057052A1 · Costa et al. · 2020 [cited by applicant]
US 20200348286A1 · Costa et al. · 2020 [cited by applicant]
US 20220146496A1 · Costa et al. · 2022 [cited by applicant]
US 20230296587A1 · Costa et al. · 2023 [cited by applicant]
CL 2008000857A1 · 2008 [cited by applicant]
CL 2020000889A1 · 2020 [cited by applicant]
CL 2021002159A1 · 2022 [cited by applicant]
CO 2020000679A2 · 2020 [cited by applicant]
EP 2864479B1 · 2015 [cited by applicant]
EP 2640853B1 · 2018 [cited by applicant]
EP 3374509B1 · 2020 [cited by applicant]
JP 2015529635A · 2015 [cited by applicant]
WO WO9307883A1 · 1993 [cited by applicant]
WO WO98039352A1 · 1998 [cited by applicant]
WO WO9914226A2 · 1999 [cited by applicant]
WO WO00047599A1 · 2000 [cited by applicant]
WO WO0066604A2 · 2000 [cited by applicant]
WO WO0123613A1 · 2001 [cited by applicant]
WO WO2001092582A1 · 2001 [cited by applicant]
WO WO2004016754A2 · 2004 [cited by applicant]
WO WO2004046160A2 · 2004 [cited by applicant]
WO WO2007031091A2 · 2007 [cited by applicant]
WO WO2007087113A2 · 2007 [cited by applicant]
WO WO2007090071A2 · 2007 [cited by applicant]
WO WO2007134181A2 · 2007 [cited by applicant]
WO WO2007146511A2 · 2007 [cited by applicant]
WO WO2008113832A2 · 2008 [cited by applicant]
WO WO2008116860A2 · 2008 [cited by applicant]
WO WO2008150729A2 · 2008 [cited by applicant]
WO WO2008154401A2 · 2008 [cited by applicant]
WO WO2009006478A2 · 2009 [cited by applicant]
WO WO2009067647A1 · 2009 [cited by applicant]
WO WO2009090182A1 · 2009 [cited by applicant]
WO WO2009124238A1 · 2009 [cited by applicant]
WO WO2010036698A1 · 2010 [cited by applicant]
WO WO2010077578A1 · 2010 [cited by applicant]
WO WO2011017521A2 · 2011 [cited by applicant]
WO WO2011079261A2 · 2011 [cited by applicant]
WO WO2011156202A1 · 2011 [cited by applicant]
WO WO2012009402A2 · 2012 [cited by applicant]
WO WO2012012467A2 · 2012 [cited by applicant]
WO WO2012064806A2 · 2012 [cited by applicant]
WO WO2012143379A1 · 2012 [cited by applicant]
WO WO2013033230A1 · 2013 [cited by applicant]
WO WO2013036868A1 · 2013 [cited by applicant]
WO WO2013154798A1 · 2013 [cited by applicant]
WO WO2014004572A2 · 2014 [cited by applicant]
WO WO2014076195A1 · 2014 [cited by applicant]
WO WO2014077693A1 · 2014 [cited by applicant]
WO WO2017081223A1 · 2017 [cited by applicant]
WO WO2017081250A1 · 2017 [cited by applicant]
WO WO2017081254A1 · 2017 [cited by applicant]
WO WO2019006107A1 · 2019 [cited by applicant]
WO WO2019109001A1 · 2019 [cited by applicant]
WO WO2019145384A1 · 2019 [cited by applicant]
WO WO2020205463A1 · 2020 [cited by examiner]
Cleveland Clinic, downloaded from Angelman Syndrome: What It Is, Symptoms & Treatment on Jan. 10, 2025. [cited by examiner]
The Mayo Clinic—Angelman Syndrome downloaded from Angelman syndrome—Diagnosis and treatment—Mayo Clinic on Apr. 22, 2025. [cited by examiner]
Milazzo et al. (JCI Insight. 2021;6(15):e145991). [cited by examiner]
Ionis downloaded from lonis Announces Pivotal Phase 3 Trial Design for ION582 in Angelman Syndrome on Apr. 22, 2025. [cited by examiner]
“Angelman Syndrome,” Cleveland Clinic, <https://my.clevelandclinic.org/health/diseases/17978-angelman-syndrome>, Last reviewed on Dec. 11, 2018, Retrieved on Mar. 31, 2021 (7 pages). [cited by applicant]
“Angelman Syndrome,” Natural Living Center. Retrieved from <http://www.naturallivingcenter.net/ns/DisplayMonograph.asp?StoreID=b571dewxvcs92jj200akhmccqa7w8v75&DocID=condition-angelman#PREVENTION> on Feb. 11, 2019 (1 pa… [cited by applicant]
Abaturov et al., “Angelman Syndrome. part 3, (Differential diagnosis and treatment),” Child's Health, Nov. 2015, 7(67):86-92 (English Abstract). [cited by applicant]
Bauman, “Uconn Stem Cell Lines Go Global,” Health and Wellness Research, dated Feb. 2014 [ retrieved Mar. 31, 2021], retreived from URL <https://today .uconn.edu/2014/02/uconn-stem-cell-lines-go-global/#>, 6 pages. [cited by applicant]
Beaudet, “Drugs to awaken a paternal gene,” Nature, 2012, 481(7380):150-152. [cited by applicant]
Bergstrom, “Unnatural Nucleosides with Unusual Base Pairing Properties,” Current Protocols in Nucleic Acid Chemistry, Jun. 2009, 1:Unit 1.4-Unit 1.4.32(Supplement 37) 32 pages. [cited by applicant]
Biological Material transfer agreements relating to the iPSC cells in 029, retrieved on Aug. 11, 2022, 8 pages (2011). [cited by applicant]
Blaydes et al., “Analysis of murine Snrpn and human SNRPN gene imprinting in transgenic mice,” Mamm Genome. 10(6):549-55 (1999). [cited by applicant]
Boissart et al., “Differentiation from human pluripotent stem cells of cortical neurons of the superficial layers amenable to psychiatric disease modeling and high-throughput drug screening,” Transl Psychiatry. 3(e294):… [cited by applicant]
Caruthers et al., “[15] Chemical synthesis of deoxyoligonucleotides by the phosphoramidite method,” Methods in Enzvmology, 1987, 154:287-313. [cited by applicant]
Cavaillé et al., “Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization,” Proc Natl Acad Sci U S A. 97(26):14311-6 (Dec. 19, 2000). [cited by applicant]
Cellbank.mcgill.ca, [ online] “The Repository for Mutant Human Cell Strains,” available on or before Apr. 2008, Wayback Machine URL <Cellbank.mcgill.ca/?Topic=Order>, 2 pages. [cited by applicant]
Chamberlain et al., “Angelman Syndrome, A genomic Imprinting Disorder of the Brain,” The Journal of Neuroscience, 2010, 30(30):9958-9963. [cited by applicant]
Chamberlain et al., “Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes,” Proc Natl Academy Science USA, 2010, 107(41):17668-17673. [cited by applicant]
Chamberlain, “Declaration of Dr Stormy J. Chamberlain,” dated Apr. 8, 2021, 9 pages. [cited by applicant]
Chung et al., “Prader-Willi syndrome: reflections on seminal studies and future therapies,” Open Bioi., 2020, 10(9):2300195 (17 pages). [cited by applicant]
Cleveland Clinic, “Angelman Syndrome Prevention,” [retrieved on Feb. 11, 2019] retrieved from URL<https://my.clevelandclinic.org/health/diseases/17978-angelman-syndrome/prevention> (1 page). [cited by applicant]
Conference program for Keystone Symposium on MicroRNAs and Huma Disease, Banff, Alberta, Feb. 11-16, 2011, retrieved on Oct. 5, 2019, retrieved from URL <http://www.keystonesymposia.org/11J6>, 7 pages. [cited by applicant]
Connecticut Stem Cell Research program grant agreement, Dec. 2008, 4 pages. [cited by applicant]
Crooke, “Basic Principles of Antisense Technology,” Antisense Drug Technology: Principles, Strategies and Applications, 2001, 1: 1-18. [cited by applicant]
CV of Dr Stormy J. Chamberlain, No. Date, 9 pages. [cited by applicant]
Danckwardt et al., “3′ end mRNA processing; molecular mechanisms and implications for health and disease,” The EMBO Journal, Feb. 6, 2008, 27:482-498. [cited by applicant]
Declaration of Dr Frank Rigo, Apr. 10, 2019, 21 pages. [cited by applicant]
Declaration of Lykke Pedersen, Jun. 8, 2020, 24 pages. [cited by applicant]
Declaration of Professor Claes Wahlestedt, May 10, 2019, 45 pages. [cited by applicant]
Deleavey et al., “Designing Chemically Modified Oligonucleotides for Targeted Gene Silencing,” Chemistry & Biology. 19(8):937-54 (2012). [cited by applicant]
DeVos et al., “Antisense Oligonucleotides: Treating Neurodegeneration at the Level of RNA,” Neurotherapeutics. 10(3):486-97 (2013). [cited by applicant]
Dunkley et al., “Characterization of a human pluripotent stem cell-derived model of neuronal development using multiplexed targeted proteomics,” Proteomics Clin Appl., Aug. 2015, 9(7-8):684-694. [cited by applicant]
Efthymiou et al., “Functional Screening Assays with Neurons Generated from Pluripotent Stem Cell-Derived Neural Stem Cells,” J. Biomol. Screen, 2014, 19(1):32-43. [cited by applicant]
Entrez gene summary for SNORD109B, dated Mar. 29, 2020, retrieved from URL <https://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=338429>, 1 page. [cited by applicant]
Extracts of information from U.S. Pat. No. 20030087855 Sequence ID No. 87, May 8, 2003, 1 page. [cited by applicant]
Extracts of information from U.S. Pat. No. 6184212 Sequence ID No. 261, Feb. 6, 2001, 2 pages. [cited by applicant]
Extracts of information from U.S. Pat. No. 6300132 Sequence ID No. 71, Oct. 9, 2001, 1 page. [cited by applicant]
Extracts of information from U.S. Pat. No. 6617162 Sequence ID No. 43, Sep. 9, 2003, 1 page. [cited by applicant]
Extracts of information from WO2004016754 Sequence ID No. 7124, Feb. 26, 2004, 1 page. [cited by applicant]
Faghihi et al., “Regulatory roles of natural antisense transcripts,” Nature Rev Mol Cell Biol., 2009, 10(9):637-643. [cited by applicant]
Faghihi, “RNAi Screen Indicates Widespread Biological Function for Human Natural Antisense Transcripts,” PLoS One, 2010, 5:e13177 10 pages. [cited by applicant]
Fluiter et al., “Filling the gap in LNA antisense oligo gapmers: the effects of unlocked nucleic acid (UNA) and 4′-C-hydroxymethyl-DNA modifications on RNase H recruitment and efficacy of an LNA gapmer,” Mol BioSyst. 5(… [cited by applicant]
Freier et al., “Methods of Selecting Sites in RNA for Antisense Targeting,” Antisense Drug Technology: Principles, Strategies and Applications, 2001, 5: 107-119. [cited by applicant]
Freier et al., “The ups and downs of nucleic acid duplex stability: structure-stability studies on chemically-modified DNA:RNA duplexes,” Nucleic Acids Res. 25(22):4429-43 (1997). [cited by applicant]
GenBank entry NM_130838.1 “ [cited by applicant]
Germain et al., “Antisense oligonucleotides targeting UBE3A-ATS restore expression of UBE3A by relieving transcriptional interference,” bioRxiv preprint, https://doi.org/10.1101/2021.07.09.451826, (2021) (33 pages). [cited by applicant]
Hagedorn et al., “Locked nucleic acid: Modality, diversity, and drug discovery,” Drug Discovery Todav, 2018, 23(1):101-114. [cited by applicant]
Hansen et al., “Entropy titration. A calorimetric method for the determination of deltaGº(K) , deltaHº and deltaSº,” Chem Comm., 1965, 3:36-38. [cited by applicant]
Hirao et al., “Natural versus Artificial Creation of Base Pairs in DNA: Origin of Nucleobases from the Perspectives of Unnatural Base Pair Studies,” Accounts of Chemical Research, Dec. 18, 2012, 45(12):2055-2065. [cited by applicant]
Holdgate et al., “Measurements of binding thermodynamics in drug discovery,” Drug Discov Today., Nov. 15, 2005, 10(22):1543-1550. [cited by applicant]
Huang et al., “Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons,” Nature, 2012, 481(7380):185-189. [cited by applicant]
Hélène C, et al., “Specific regulation of gene expression by antisense, sense and antigene nucleic acids,” Biochimica et Biophysica Acta, 1049, pp. 99-125, (1990). [cited by applicant]
Johnstone et al., “A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects,” Human Molecular Genetics. 15(3):393-404 … [cited by applicant]
King et al., “Topoisomerases facilitate transcription of long genes linked to autism,” Nature, 2013, 501(7456):58-62. [cited by applicant]
Koch et al., “Quantum Mechanical Studies on DNA and LNA, Nucleic Acid Therapeutics,” 2014, 24(2):139-148. [cited by applicant]
Landers et al., “Regulation of the large (˜1000 kb) imprinted murine Ube3a antisense transcript by alternative exons upstream of Snurf/Snrpn,” Nucleic Acids Res. 32(11):3480-92 (2004). [cited by applicant]
Luo et al., “A Ribonucleolytic Rat Torpedoes RNA Polymerase II,” Cell, Dec. 29, 2004, 119(7):911-914. [cited by applicant]
Mangos et al., “Efficient RNase H-Directed Cleavage of RNA Promoted by Antisense DNA or 2′F-ANA Constructs Containing Acyclic Nucleotide Inserts” J Am Chem Soc. 125(3):654-61 (2003). [cited by applicant]
Manoharan, “Chapter 16: Oligonucleotide Conjugates in Antisense Technology.” [cited by applicant]
Manoharan, “Oligonucleotide Conjugates as Potential Antisense Drugs with Improved Uptake, Biodistribution, Targeted Delivery, and Mechanism of Action,” Antisense and Nucleic Acid Drug Development, Jul. 2004, 12(2):103-1… [cited by applicant]
McTigue et al., “Sequence-dependent thermodynamic parameters for locked nucleic acid (LNA)-DNA duplex formation,” Biochemistry, May 11, 2004, 43(18):5388-5405. [cited by applicant]
Meng et al., “Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a,” Human Molecular Genetics, 2012, 21(13):3001-3012. [cited by applicant]
Meng et al., “Towards a therapy for Angelman syndrome by reduction of a long non-coding RNA,” Nature. 518(7539):409-12 (Feb. 2015). [cited by applicant]
Mergny and Lacroix, “Analysis of thermal melting curves,” Oligonucleotides, Dec. 2003, 13(6):515-537. [cited by applicant]
Mitsuoka et al., “A bridged nucleic acid, 2′,4′-BNA [cited by applicant]
Modarresi et al., “Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation,” Nature Biotechnology, 2012, vol. 30(5):Supporting Online Material: 33 pages. [cited by applicant]
Modarresi et al., “Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation,” Nature Biotechnology, Mar. 25, 2012, 30(5):453-459. [cited by applicant]
Morita et al., “2′-O,4′-C-ethylene-bridged nucleic acids (ENA): highly nuclease-resistant and thermodynamically stable oligonucleotides for antisense drug,” Bioorganic & Med Chem Lett., Jan. 7, 2002, 12(1):73-76. [cited by applicant]
Morris et al., “Bidirectional Transcription Directs Both Transcriptional Gene Activation and Suppression in Human Cells,” PLoS Genetics, Nov. 2008, 4(11):e1000258 9 pages. [cited by applicant]
NCBI.nlm.nih.gov Gene ID: 338429, “SNORD109B small nucleolar RNA, C/D box 109B [ [cited by applicant]
NCBI.nlm.nih.gov, “SNORD109A small nucleolar RNA, C/D box 109A [ [cited by applicant]
Papargyri et al., “Chemical Diversity of Locked Nucelic Acid-Modified Antisense Oligonucleotides allos Optimization of Pharmaceutical Properties,” Molecular Therapy Nucleic Acids., Mar. 2020, (19):706-717. [cited by applicant]
Petrov, “Chemistry Guide for Schoolchildren,” M List, 1998, p. 321. [cited by applicant]
Phillips M., et al., “In vivo applications of antisense oligonucleotides for peptide research,” Regulatory Peptides 59 pp. 131-141 (1995). [cited by applicant]
Philpot et al., “Angelman syndrome: advancing the research frontier of neurodevelopmental disorders,” J Neurodevelop Disord, 2011, 3:50-56. [cited by applicant]
PNAS, “Information for Authors,” revised Jan. 2020, 117 :xi-xviii. [cited by applicant]
Rougelle et al., “The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain,” Nature Genetics, 1997, 17:14-15. [cited by applicant]
Rougeulle et al., “An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript,” Nature Genetics, 1998, 19:15-16. [cited by applicant]
SantaLucia, John Jr., “A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics,” Proc Natl Acad Sci. 95:1460-5 (1998). [cited by applicant]
Search overview of documents teaching the targeting of non-overlapping regions, Feb. 17, 2020, 29 pages. [cited by applicant]
Second Declaration of Claes Wahlestedt, dated Jun. 15, 2020, 50 pages. [cited by applicant]
Seth at al., “Synthesis and Biophysical Evaluation of 2′,4′-Constrained 2′O-Methoxyethyl and 2′,4′-Constrained 2′O-Ethyl Nucleic Acid Analogues,” J Org Chem., Mar. 5, 2010, 75(5):1569-1581. [cited by applicant]
Sharma et al., “Antisense oligonucleotides: modifications and clinical trials,” MedChemComm. 5(10):1454-1471 (2014). [cited by applicant]
Shi et al., “In situ entry of oligonucleotides into brain cells can occur through a nucleic acid channel,” Oligonucleotides, 2007, 17(1):122-133. [cited by applicant]
Smith et al., “Transcription is required to establish maternal imprinting at the Prader-Willi syndrome and Angelman syndrome locus,” PLoS Genetics, 2011, 7(12):e1002422 10 pages. [cited by applicant]
Sugimoto et al., “Thermodynamic Parameters To Predict Stability of RNA/DNA Hybrid Duplexes,” Biochemistry, Sep. 1995, 34(35): 11211-11216. [cited by applicant]
Swayze et al., “The Medicinal Chemistry of Oligonucleotides,” Antisense Drug Technology, CRC Press, 2nd edition, chapter 6, 23 pages (Jul. 24, 2007). [cited by applicant]
UCSC Genome Browser on Human Dec. 2013 (GRCh38/hg38) Assembly, Dec. 2013, 1 page. [cited by applicant]
Uhlmann, “Recent Advances in the medicinal chemistry of antisense oligonucleotides,” Current Opinion in Drug Development, 2000, 3(2):203-213. [cited by applicant]
Vester et al., “Chemically modified oligonucleotides with efficient RNase H response,” Bioorg Med Chem Lett., Apr. 1, 2008, 18(7):2296-2300. [cited by applicant]
Wahlestedt , “Natural antisense and noncoding RNA transcripts as potential drug targets,” Drug Discovery Today, 2006, 11(11/12):503-508. [cited by applicant]
Wahlestedt et al., “Presentation: Regulatory Natural Antisense Transcripts,” Keystone Symposium on MicroRNAs and Human Disease, Banff, Alberta, Feb. 11-16, 2011, 41 pages. [cited by applicant]
www.uniprot.org, “UniProtKB—Q05086,” Last updated Dec. 11, 2019, retrieved on Feb. 4, 2020, retrieved from URL <httos://www.uniprot.org/uniprot/Q05086>, 23 pages. [cited by applicant]
Yang D. et al., “Gene targets of antisense therapies in breast cancer,” Expert Opinion on Therapeutic Targets, 6:3, pp. 375-385, (2005) (12 pages). [cited by applicant]
Boards of Appeal of the European Patent Office, Datasheet for the decision of Apr. 2, 2020 for European Application No. 06772386.6 (14 pages). [cited by applicant]
Brief Communication for European Patent Application No. 11840796.4, dated Oct. 18, 2021 (11 pages). [cited by applicant]
Colombian Office Action with Colombian Application No. NC20180004550, dated Apr. 14, 2020, 23 pages. [cited by applicant]
European Grounds of Appeal for European Patent No. 2864479, dated Apr. 29, 2022 (69 pages). [cited by applicant]
European Opposition in European Patent No. 2864479, dated Jun. 17, 2020, 17 pages. [cited by applicant]
European Revision of the EPC: Article 54(5), CA/PL4/00, dated Jan. 24, 2000, 4 pages. [cited by applicant]
European Revision of the European Patent Convention: CA/100/00, dated Aug. 9, 2000, 5 pages. [cited by applicant]
European Search Report for European Patent Application No. 23152543, dated Jul. 26, 2023 (7 pages). [cited by applicant]
Interlocutory decision in Opposition proceedings for European Patent Application No. 11840796.4, dated Jun. 21, 2022 (22 pages). [cited by applicant]
International Search Report and Written Opinion for International Patent Application No. PCT/EP2016/077383, dated Feb. 23, 2017 (12 pages). [cited by applicant]
U.S. Appl. No. 61/664,083, Rigo et al., filed Jun. 25, 2012, 90 pages. [cited by applicant]
U.S. Appl. No. 61/738,959, Rigo et al., filed Dec. 18, 2012, 102 pages. [cited by applicant]
U.S. Appl. No. 61/750,939, Rigo et al., filed Jan. 10, 2013, 105 pages. [cited by applicant]
U.S. Appl. No. 61/755,617, Rigo et al., filed Jan. 23, 2013, 108 pages. [cited by applicant]
U.S. Appl. No. 61/772,925, Rigo et al., filed Mar. 5, 2013, 109 pages. [cited by applicant]