`
`Filed on behalf of: Sarepta Therapeutics, Inc.
`
`
`
`
`
`
`Filed: June 21, 2021
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`SAREPTA THERAPEUTICS, INC.
`Petitioner
`v.
`NIPPON SHINYAKU CO., LTD.
`&
`NATIONAL CENTER OF NEUROLOGY AND PSYCHIATRY
`Patent Owners
`______________________
`
`Case No. IPR2021-01139
`Patent No. 10,662,217
`______________________
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`EXHIBIT LIST
`
`Exhibit
`
`Description
`
`EX1004
`
`EX1001 U.S. Patent No. 10,662,217
`EX1002 PCT Patent Application No. PCT/JP2011/070318 (published as
`WO2012029986)
`EX1003
`Japanese Provisional Application No. 2010-196032
`Certified translation of Japanese Provisional Application No.
`2010-196032
`Certified translation of PCT Application No. PCT/JP2011/070318
`EX1005
`EX1006 Affidavit (translation declaration Japanese Provisional Application
`No. 2010-196032)
`EX1007 Affidavit (translation of PCT Application No.
`PCT/JP2011/070318)
`EX1008
`Reserved
`
`EX1009
`
`Reserved
`
`EX1010
`
`Reserved
`
`EX1011
`
`Excerpts of file history of U.S. Patent No. 9,708,361
`
`EX1012
`
`Reserved
`
`EX1013
`
`Reserved
`
`EX1014
`
`Reserved
`
`EX1015
`
`Reserved
`
`EX1016
`
`Excerpts of file history of U.S. Patent No. 10,662,217
`
`EX1017
`
`Reserved
`
`EX1018
`
`Reserved
`
`EX1019
`
`Reserved
`
`
`
`i
`
`

`

`
`
`Exhibit
`
`Description
`
`EX1020
`
`EX1021
`
`Reserved
`Popplewell et al., “Comparative Analysis of Antisense
`Oligonucleotide Sequences Targeting Exon 53 of the Human
`DMD Gene: Implications for Future Clinical Trials,”
`Neuromuscul. Disord. (2010) 20:102-110
`Sazani et al., “Safety Pharmacology and Genotoxicity Evaluation
`of AVI-4658,” Int. J. Toxicol. (2010) 29(2):143-156
`EX1023 U.S. Patent Application Publication No. 2010/0168212
`
`EX1022
`
`EX1024 U.S. Patent Application Publication No. 2010/0130591
`EX1025 U.S. Patent Application Publication No. 2013/0109091
`
`EX1026 U.S. Patent Application Publication No. 2012/0190728
`
`EX1027
`
`EX1028
`
`Bushby et al., “Diagnosis and Management of Duchenne Muscular
`Dystrophy, Part 1: Diagnosis, and Pharmacological and
`Psychosocial Management,” Lancet Neurol. (2010) 9(1): 77-93
`Kinali et al., “Local Restoration of Dystrophin Expression with the
`Morpholino Oligomer AVI-4658 in Duchenne Muscular
`Dystrophy: A Single-Blind, Placebo-Controlled, Dose-Escalation,
`Proof-of-Concept Study,” Lancet Neurol. (2009) 8(10): 918-928
`EX1029 Hoffman et al., “Skipping Toward Personalized Molecular
`Medicine,” N. Engl. J. Med. (2007) 357(26): 2719-2722
`Wilton et al., “Exon Skipping and Duchenne Muscular Dystrophy:
`Hope, Hype and How Feasible?” Neurol. India (2008) 56(3): 254-
`262
`Arechavala-Gomeza et al., “Comparative Analysis of Antisense
`Oligonucleotide Sequences for Targeted Skipping of Exon 51
`During Dystrophin Pre-mRNA Splicing in Human Muscle,” Hum.
`Gene. Ther. (2007) 18(9): 798-810
`Ginjaar et al., “Dystrophin Nonsense Mutation Induces Different
`Levels of Exon 29 Skipping and Leads to Variable Phenotypes
`Within One BMD Family,” Eur. J. Hum. Genet. (2000) 8(10):
`793-796
`
`EX1030
`
`EX1031
`
`EX1032
`
`
`
`ii
`
`

`

`
`
`Description
`Exhibit
`EX1033 Wilton et al., “Antisense Oligonucleotides, Exon Skipping and the
`Dystrophin Gene Transcript,” Acta Myol. (2005) 24(3): 222-229
`
`EX1034
`
`EX1035
`
`EX1036
`
`EX1037
`
`EX1038
`
`Reserved
`Wilton et al., “Antisense Oligonucleotide-Induced Exon Skipping
`Across the Human Dystrophin Gene Transcript,” Mol. Ther.
`(2007) 15(7): 1288-1296
`Muntoni et al., “The Development of Antisense Oligonucleotide
`Therapies for Duchenne Muscular Dystrophy: Report on a
`TREAT-NMD Workshop Hosted by the European Medicines
`Agency (EMA), on September 25th 2009,” Neuromuscul. Disord.
`(2010) 20(5): 355-362
`van Deutekom et al., “Local Dystrophin Restoration with
`Antisense Oligonucleotide PRO051,” N. Engl. J. Med. (2007)
`357(26): 2677-2686
`Goemans et al., “Systemic Administration of PRO051 in
`Duchenne's Muscular Dystrophy,” N. Engl. J. Med. (2011)
`364(16): 1513-1522
`Cirak et al., “Exon Skipping and Dystrophin Restoration in
`Patients with Duchenne Muscular Dystrophy After Systemic
`Phosphorodiamidate Morpholino Oligomer Treatment: An Open-
`Label, Phase 2, Dose-Escalation Study,” Lancet (2011) 378(9791):
`595-605
`EX1040 Nakamura et al., “Exon-Skipping Therapy for Duchenne Muscular
`Dystrophy,” Neuropathology (2009) 29(4): 494-501
`EX1041 Yokota et al., “A Renaissance for Antisense Oligonucleotide
`Drugs in Neurology,” Arch. Neurol. (2009) 66(1): 32-38
`Aartsma-Rus et al., “Guidelines for Antisense Oligonucleotide
`Design and Insight into Splice-Modulating Mechanisms,” Mol.
`Ther. (2009) 17(3): 548-553
`Aartsma-Rus et al., “Less is More: Therapeutic Exon Skipping for
`Duchenne Muscular Dystrophy,” Lancet Neurol. (2009) 8(10):
`873-875
`Chan et al., “Antisense Oligonucleotides: From Design to
`Therapeutic Application,” Clin. Exp. Pharmacol. Physiol. (2006)
`33(5-6): 533-540
`
`EX1039
`
`EX1042
`
`EX1043
`
`EX1044
`
`
`
`iii
`
`

`

`
`
`Exhibit
`
`EX1045
`
`EX1046
`
`Description
`Summerton et al., “Morpholino Antisense Oligomers: Design,
`Preparation, and Properties,” Antisense Nucleic Acid Drug Dev.
`(1997) 7(3): 187-195
`Adams et al., “Antisense Oligonucleotide Induced Exon Skipping
`and the Dystrophin Gene Transcript: Cocktails and Chemistries,”
`BMC Mol. Biol. (2007) 8:57
`EX1047 U.S. Patent Application Publication No. 2003/0166588
`Aartsma-Rus et al., “Functional Analysis of 114 Exon-Internal
`AONs for Targeted DMD Exon Skipping: Indication for Steric
`Hindrance of SR Protein Binding Sites,” Oligonucleotides (2005)
`15(4): 284-297
`PCT Patent Application Publication No. WO 2004/083432
`
`EX1048
`
`EX1049
`
`EX1050
`
`PCT Patent Application Publication No. WO 2006/000057
`
`EX1052
`
`EX1051 U.S. Patent Application Publication No. 2007/0082861
`Popplewell et al., “Design of Phosphorodiamidate Morpholino
`Oligomers (PMOs) for the Induction of Exon Skipping of the
`Human DMD Gene,” Mol. Ther. (2009) 17(3): 554-561
`EX1053 Moulton et al., “Gene Knockdowns in Adult Animals: PPMOs and
`Vivo-Morpholinos,” Molecules (2009) 14(3): 1304-1323
`PCT Patent Application Publication No. WO 2011/057350
`Summerton, “Morpholino Antisense Oligomers: The Case for an
`RNase H-independent Structural Type,” Biochim. Biophys. Acta
`(1999) 1489(1): 141-158
`Muntoni et al., “149th ENMC International Workshop and 1st
`TREAT-NMD Workshop on: “Planning Phase I/II Clinical Trials
`Using Systemically Delivered Antisense Oligonucleotides in
`Duchenne Muscular Dystrophy,” Neuromuscul. Disord. (2008)
`18(3): 268-275
`Aartsma-Rus et al., “Antisense-Mediated Exon Slipping: A
`Versatile Tool with Therapeutic and Research Applications,” RNA
`(2007) 13(10): 1609-1624
`
`EX1054
`
`EX1055
`
`EX1056
`
`EX1057
`
`
`
`iv
`
`

`

`
`
`Exhibit
`
`EX1058
`
`Description
`Trollet et al., “Gene Therapy for Muscular Dystrophy: Current
`Progress and Future Prospects,” Expert Opin. Biol. Ther. (2009)
`9(7): 849-866
`“Prosensa and GlaxoSmithKline Initiate Development of Four
`Additional Products under Existing Alliance in Duchenne
`Muscular Dystrophy; Broadened Program Marks Key Inflexion in
`Prosensa’s Progress to a Fully Integrated Specialty-Pharma
`Company,” Business Wire (June 23, 2010)
`EX1060 Vickers et al., “Effects of RNA Secondary Structure on Cellular
`Antisense Activity,” Nucleic Acids Res. (2000) 28(6): 1340-1347
`
`EX1059
`
`EX1061
`
`Reserved
`
`EX1062
`
`Excerpt of File History of U.S. Application No. 14/776,533
`
`EX1063
`
`Excerpt of File History of U.S. Application No. 14/776,533
`
`EX1064
`
`EX1065
`
`EX1067
`
`Interference No. 106,007, Paper No. 476, May 12, 2016
`McClorey et al., “Induced Dystrophin Exon Skipping in Human
`Muscle Explants,” Neuromuscul. Disord. (2006) 16(9-10): 583-
`590
`EX1066 U.S. Provisional Application No. 61/591,354
`Mann et al., “Improved Antisense Oligonucleotide Induced Exon
`Skipping in the Mdx Mouse Model of Muscular Dystrophy,” J.
`Gene Med. (2002) 4(6): 644-654
`EX1068 Albert et al., Molecular Biology of the Cell 191-234, 299-374 (4th
`ed. 2002)
`EX1069 Wood and Douglas, “Splicing therapy for neuromuscular disease,”
`Mol. and Cellular Neuroscience (2013) 56: 169-185
`Dominski and Kole, “Restoration of Correct Splicing in
`Thalassemic pre-mRNA by Antisense Oligonucleotides,” Proc.
`Natl. Acad. Sci. U.S.A. (1993) 90: 8673-8677
`Dominski and Kole, “Identification and Characterization by
`Antisense Oligonucleotides of Exon and Intron Sequences
`Required for Splicing,” Mol. Cell. Biol. (1994) 14(11): 7445-7454
`v
`
`EX1070
`
`EX1071
`
`
`
`

`

`
`
`Exhibit
`
`EX1072
`
`Description
`Sierakowska et al., “Repair of Thalassemic Human beta-Globin
`mRNA in Mammalian Cells by Antisense Oligonucleotides,”
`Proc. Natl. Acad. Sci. U.S.A. (1996) 93: 12840-12844
`Aartsma-Rus et al., “Targeted Exon Skipping as a Potential Gene
`Correction Therapy for Duchenne Muscular Dystrophy,”
`Neuromuscul. Disord. (2002) 12: S71-S77
`Bremmer-Bout et al., “Targeted Exon Skipping in Transgenic
`hDMD Mice: A Model for Direct Preclinical Screening of Human-
`Specific Antisense Oligonucleotides,” Mol. Ther. (2004) 10(2):
`232-240
`EX1075 U.S. Patent Application Publication No. 2009/0131624
`
`EX1073
`
`EX1074
`
`EX1076 U.S. Patent Application Publication No. 2009/0088562
`
`EX1077 U.S. Patent No. 5,185,444
`
`EX1078
`
`Reserved
`
`EX1079
`
`Reserved
`
`EX1080
`
`Reserved
`
`EX1081
`
`Reserved
`
`EX1082
`
`Reserved
`
`EX1083
`
`Reserved
`
`EX1084
`
`Experimental Report filed in EP 3018211 B1
`
`EX1085 Declaration of Dr. Ueda filed in EP 3018211 B1
`Preliminary Opinion of the European Opposition Division issued
`in EP 3018211 B1
`Reserved
`
`EX1086
`
`EX1087
`
`EX1088
`
`Reserved
`
`EX1089
`
`Reserved
`
`
`
`vi
`
`

`

`
`
`Description
`
`Exhibit
`
`EX1090
`
`Reserved
`
`EX1091
`
`Reserved
`
`Reserved
`EX1092
`EX1093 Declaration of Kelley M. Hayes Greenhill (U.S. Patent No.
`10,662,217)
`EX1094
`Reserved
`
`EX1095
`
`Reserved
`
`EX1096
`
`Reserved
`
`EX1097
`
`Reserved
`
`EX1098
`
`Reserved
`
`Reserved
`EX1099
`EX1100 Declaration of Dr. David R. Corey in Support of Petition for Inter
`Partes Review of U.S. Patent No. 10,662,217
`EX1101
`Reserved
`
`
`
`
`
`vii
`
`
`
`
`
`

`

`
`
`I.
`
`TABLE OF CONTENTS
`Statement of Precise Relief Requested and Reasons Therefor (37
`C.F.R. § 42.22(A)) ........................................................................................... 1
`Introduction ...................................................................................................... 1
`II.
`III. Grounds for Standing ....................................................................................... 4
`IV.
`Identification of Challenge .............................................................................. 4
`V.
`The Alleged Invention of the ’217 Patent ....................................................... 5
`A.
`The Challenged Claims ......................................................................... 6
`B.
`Claim Construction..............................................................................11
`1.
`“A method of treating a DMD patient” ....................................11
`2.
`“causes skipping of the 53rd exon in a human dystrophin
`pre-mRNA”’ ..............................................................................11
`The Effective Filing Date of the ’217 Patent ......................................12
`C.
`Summary of Relevant Prosecution History of the ’217 Patent ...........13
`D.
`Summary of Relevant Prosecution History of the ’361 Patent ...........14
`E.
`VI. State of the Art Before August 31, 2011 .......................................................17
`A. DMD ....................................................................................................17
`B.
`AOs in Exon Skipping Therapy in DMD ............................................18
`C.
`Prior Art AOs Targeting Exon 53 of Dystrophin ................................24
`D.
`The Asserted Prior Art ........................................................................29
`1.
`Popplewell .................................................................................29
`2.
`Sazani ........................................................................................32
`VII. Level of Ordinary Skill in the Art .................................................................33
` Detailed Explanation of Ground ....................................................................33
`
`
`
`viii
`
`

`

`
`
`b)
`
`c)
`
`A. Ground 1: Claims 1–4 Are Obvious Over Popplewell and
`Sazani ..................................................................................................33
`1.
`A POSA Would Have Been Motivated, with a
`Reasonable Expectation of Success, to Administer a
`PMO According to the Methods Recited in Claims 1–4 ..........34
`a)
`The Prior Art Recommended AOs Targeting Exon
`53 as a Promising Treatment for DMD ..........................35
`The Prior Art Identified an Effective Target
`Region of Exon 53 that Encompasses the Target
`Sequence of the Claimed AOs ........................................38
`A POSA Would Have Been Motivated, with a
`Reasonable Expectation of Success, to Administer
`a to a Patient with DMD a 25-mer PMO 100%
`Complementary to the +36+60 Sequence of Exon
`53 with a 5’ TEG Group .................................................40
`Popplewell Does Not Teach Away from AOs that Are 25
`Bases in Length .........................................................................49
`The Methods of Claims 1–4 Would Have Been Obvious ........51
`3.
`Secondary Considerations Do Not Support Nonobviousness .............53
`1.
`There Is No Evidence of Unexpected Results as NS
`Incorrectly Argued During Prosecution ....................................53
`Near-Simultaneous Development Precludes a Holding of
`Nonobviousness ........................................................................59
` The Same or Substantially the Same Arguments and Evidence Were
`Not Previously Presented to the Office .........................................................60
`X. Mandatory Notices Under 37 C.F.R. § 42.8 ..................................................66
`A.
`Real Parties-in-Interest ........................................................................66
`B.
`Related Matters ....................................................................................66
`C.
`Lead and Backup Counsel ....................................................................66
`
`B.
`
`2.
`
`2.
`
`
`
`ix
`
`

`

`
`
`D.
`Service Information .............................................................................67
`XI. Payment of Fees .............................................................................................67
`XII. Conclusion .....................................................................................................67
`
`
`
`
`x
`
`

`

`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott Vascular, Inc. v. FlexStent, LLC, IPR2019-00882, Paper 11 (PTAB
`Oct. 7, 2019) .......................................................................................... 62, 63, 65
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte GmbH,
`IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) (precedential) ........... 61, 62, 63
`Becton Dickinson & Co. v. B. Braun Melsungen AG, IPR2017-01586, Paper
`8 (PTAB Dec. 15, 2017) (precedential) ........................................... 61, 63, 64, 65
`Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc., 246 F.3d 1368
`(Fed. Cir. 2001) ...................................................................................................11
`Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 752 F.3d 967 (Fed. Cir.
`2014) ...................................................................................................................58
`Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801 (Fed. Cir.
`2002) ...................................................................................................................11
`Ecolochem, Inc. v. S. Cal. Edison Co., 227 F.3d 1361, 1376 (Fed. Cir. 2000) .......59
`Geo. M. Martin Co. v. Alliance Mach. Sys. Int’l LLC, 618 F.3d 1294 (Fed.
`Cir. 2010) ............................................................................................................59
`In re Baxter Travenol Labs., 952 F.2d 388 (Fed. Cir. 1991) (same) .......................58
`In re Gurley, 27 F.3d 551 (Fed. Cir. 1994) ..............................................................49
`In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003) ......................................................41
`In re Susi, 440 F.2d 442 (C.C.P.A. 1971) ................................................................49
`Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804 (Fed. Cir. 1989) ......................49
`Navistar, Inc. v. Fatigue Fracture Tech., LLC, IPR2018-00853, Paper 13
`(PTAB Sept. 12, 2018 .........................................................................................62
`Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) ....................................46
`
`xi
`
`

`

`
`
`Prollenium US Inc. v. Allergan Indus., SAS, IPR2019-01617, Paper 17
`(PTAB Mar. 20, 2020) ........................................................................................65
`University of Western Australia v. Academisch Ziekenhuis Leiden,
`Interference No. 106,007, Paper No. 476 (May 12, 2016) .................................47
`Statutes
`35 U.S.C. § 102 ....................................................................................................4, 13
`35 U.S.C. § 103 ............................................................................................... 1, 5, 15
`Rules
`M.P.E.P. § 2152.01 ..................................................................................................13
`Regulations
`37 C.F.R. § 42.103(a) ...............................................................................................67
`37 C.F.R. § 42.15(a) .................................................................................................67
`37 C.F.R. § 42.22(A).................................................................................................. 1
`37 C.F.R. § 42.8 .......................................................................................................66
`
`
`
`xii
`
`

`

`
`
`GLOSSARY
`
`AO
`BMD
`DMD
`exon 53
`FDA
`IPR
`Italicized text
`
`NS or Patent Owners
`
`Sarepta or Petitioner
`PMO
`2’-OMePS
`TEG
`POSA
`Japanese Application
`USPTO or Office
`’217 patent
`’361 patent
`’092 patent
`’461 patent
`’106 patent
`’741 patent
`
`Antisense oligomer
`Becker muscular dystrophy
`Duchenne muscular dystrophy
`the 53rd exon of the human dystrophin (or DMD) gene
`U.S. Food and Drug Administration
`Inter partes review
`Emphasis added unless otherwise indicated
`Nippon Shinyaku Co., Ltd.
`National Center of Neurology and Psychiatry
`Sarepta Therapeutics, Inc.
`phosphorodiamidate morpholino oligomer
`phosphorothioate-linked 2’-O-methyl oligomer
`triethylene glycol
`Person of ordinary skill in the art
`Japanese Priority Application No. 2010-196032
`U.S. Patent and Trademark Office
`U.S. Patent No. 10,662,217
`U.S. Patent No. 9,708,361
`U.S. Patent No. 10,385,092
`U.S. Patent No. 10,407,461
`U.S. Patent No. 10,487,106
`U.S. Patent No. 10,647,741
`
`xiii
`
`

`

`
`
`
`
`
`U.S. Patent No. 10,683,322
`’322 patent
`US. Patent No. 10,683,322
`’322 patent
`
`
`
`
`
`
`xiv
`
`XiV
`
`

`

`
`
`I.
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`Statement of Precise Relief Requested and Reasons Therefor (37 C.F.R.
`§ 42.22(A))
`Sarepta hereby submits this petition for inter partes review (“Petition”)
`
`seeking cancellation of claims 1–4 of U.S. Patent No. 10,662,217 (“the ’217 patent”)
`
`(EX1001), assigned to Nippon Shinyaku Co., Ltd. and National Center of Neurology
`
`and Psychiatry (collectively, “NS” or “Patent Owners”). The challenged claims are
`
`unpatentable under 35 U.S.C. § 103(a). This Petition is supported by the declaration
`
`of Dr. David R. Corey, an expert in the design and evaluation of antisense oligomers
`
`for therapeutic purposes. This Petition is being filed concurrently with Petitions for
`
`related U.S. Patent Nos. 10,385,092 (“the ’092 patent”), 9,708,361 (“the ’361
`
`patent”), 10,487,106 (“the ’106 patent”), 10,407,461 (“the ’461 patent”), 10,647,741
`
`(“the ’741 patent”), and 10,683,322 (“the ’322 patent”), all of which have claims
`
`substantially similar to the claims challenged in this Petition.
`
`II.
`
`Introduction
`The challenged claims encompass methods of intravenously administering to
`
`patients with Duchenne Muscular Dystrophy (DMD) antisense oligomers (“AOs”)
`
`that are 100% complementary to positions 36 to 60 (+36+60) of exon 53 of the
`
`human dystrophin pre-mRNA.
`
`The challenged claims are obvious over the prior art. By August 31, 2011,
`
`AO-induced exon skipping was a promising therapeutic approach for restoring
`
`1
`
`
`

`

`
`
`functional dystrophin in DMD patients, with proof-of-principle clinical trials
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`providing encouraging results. Moreover, scientists had identified numerous AOs
`
`that effectively skipped exon 53: testing of AOs by multiple research groups had
`
`identified positions 30 to 65 (+30+65) within exon 53 as a hotspot target region for
`
`AOs causing exon 53 skipping. One of the AOs binding to this hotspot (PMO-A),
`
`described in the prior art as a “viable” candidate for upcoming exon 53 clinical trials,
`
`targeted and was perfectly complementary to positions 35 to 59 of exon 53
`
`(+35+59)—just one position shifted from the claimed 36–60 (+36+60) target
`
`sequence.
`
`
`
`A POSA would have been motivated to generate a 25-mer AO targeting the
`
`+36+60 sequence of exon 53 as part of a conventional screen to optimize the prior
`
`art AOs. Such screens were well-established and routine by August 31, 2011.
`
`Further, a POSA would have reasonably expected that an AO targeting the +36+60
`
`sequence of exon 53 could be administered to a DMD patient and would successfully
`
`induce skipping of exon 53, as numerous prior art AOs targeting this region had
`
`2
`
`
`

`

`
`
`already exhibited skipping, including PMO-A targeting positions +35+59 of exon
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`53.
`
`The objective evidence supports a conclusion of obviousness. Indeed, the
`
`claimed subject matter was published independently within months of the effective
`
`filing date for the ’217 patent. Moreover, while NS secured allowance of a parent
`
`application to the ’217 patent—which is also directed to an AO targeting the +36+60
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`sequence of exon 53—by alleging unexpected results, those results are illusory. As
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`described below, a direct comparison disclosed in NS’s own patent specification,
`
`overlooked by the Examiner, shows that an AO targeting the +36+60 sequence
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`recited in the claimed methods resulted in similar (and perhaps less) skipping
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`efficacy than a prior art AO targeting the +35+59 sequence of exon 53.
`
`Because challenged claims 1–4 offer nothing inventive over what was well
`
`known as of August 31, 2011, Sarepta requests inter partes review.
`
`Notably, the ’217 patent is one of several related patents obtained by NS with
`
`substantially similar claims. For instance, the ’361, ’106, ’092, and ’461 patents are
`
`directed to 25-mers targeting the same +36+60 sequence of exon 53 as the AOs
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`encompassed by the challenged claims. The ’741 patent is similarly directed to
`
`methods of administering AOs targeting the +36+60 sequence. The ’322 patent is
`
`directed to methods of making AOs targeting the +36+60 sequence. During
`
`prosecution of the ’217 patent, NS filed terminal disclaimers over, inter alia, the
`3
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`

`

`
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`’361, ’092, ’461, and ’106 patents, as well as the application leading to the ’741
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`
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`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`patent. Petitions challenging the ’361, ’092, ’461, ’106, ’741, and ’322 patents are
`
`being filed concurrently.
`
`III. Grounds for Standing
`Petitioner certifies that the ’217 patent is available for IPR and that Petitioner
`
`is not barred or estopped from requesting review on the ground identified. (EX1016,
`
`1–11 (December 12, 2019, Application Data Sheet listing priority chain and
`
`declining to designate as a transition application); EX1001, 1:6–17, title page, items
`
`(63) & (30).)
`
`IV.
`
`Identification of Challenge
`Sarepta requests that claims 1–4 of the ’217 patent be found unpatentable and
`
`cancelled in view of the following references:
`
`Reference 1: Popplewell et al., Neuromuscul. Disord. (2010) 20:102–110
`
`(“Popplewell”) (EX1021), published in February 2010. Popplewell is prior art to the
`
`’217 patent under 35 U.S.C. § 102(b). See EX1093 (declaration confirming public
`
`accessibility of Popplewell prior to August 31, 2011).
`
`Reference 2: Sazani et al., Int’l J. of Toxicology (2010) 29(2):143–156
`
`(“Sazani”) (EX1022), published in March 2010. Sazani is prior art to the ’217 patent
`
`under 35 U.S.C. § 102(b). See EX1093 (declaration confirming public accessibility
`
`of Sazani prior to August 31, 2011.)
`
`4
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`

`

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`
`
`The specific ground is:
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`Claims
`1–4
`
`Description
`Obvious under 35 U.S.C. § 103(a) over Popplewell
`and Sazani
`
`Ground
`1
`
`V. The Alleged Invention of the ’217 Patent
`The ’217 patent issued on May 26, 2020, from U.S. Application No.
`
`16/712,686, and claims priority to PCT/JP2011/070318 (EX1002), filed August 31,
`
`2011, and Japanese Provisional Application No. 2010-196032 (EX1003), filed on
`
`September 1, 2010. (EX1100, ¶¶81–83.) Certified English translations of Japanese
`
`Provisional Application No. 2010-196032 (EX1004) and PCT/JP2011/070318
`
`(EX1005), along with accompanying translation declarations (EX1006; EX1007)
`
`are submitted with this Petition.
`
`The ’217 patent is entitled “Antisense Nucleic Acids.” (EX1001, title page,
`
`item (54); see EX1100, ¶¶93–97.) It states that the alleged invention “relates to an
`
`antisense oligomer which causes skipping of exon 53 in the human dystrophin gene,
`
`and a pharmaceutical composition comprising the oligomer.” (EX1001, 1:30–33.)
`
`The specification describes the “present invention” as an AO which induces skipping
`
`of exon 53, consisting of an oligomer sequence complementary to one of 36 listed
`
`5
`
`
`

`

`
`
`sequences within the 31st and 58th nucleotides of exon 53.1 (Id., 3:26–44; see also
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`id., Table 1 (listing AOs of SEQ ID NOs. 2–37).) Additional AOs complementary to
`
`exon 53 are provided in Tables 2 and 7, including the AO identified as H53_36-60,
`
`which targets the 36th to 60th nucleotides of exon 53 of the human dystrophin pre-
`
`mRNA. (Id., Table 2, Table 7 (listing SEQ ID NOs. 49–123).)
`
`Based on the in vitro test data described in the patent specification, the patent
`
`concludes: “Consequently, the oligomers of the present invention can induce exon
`
`53 skipping with a high efficiency, when DMD patients are administered. Therefore,
`
`the oligomers of the present invention are extremely useful for the treatment of
`
`DMD.” (Id., 42:23–27.)
`
`The patent contains no clinical data and no studies in humans.
`
`A. The Challenged Claims
`The ’217 patent contains four claims, all of which are independent claims.
`
`Claim 1 is directed to a method of intravenously administering to a DMD patient an
`
`AO comprising a 25-mer PMO targeting the (+36+60) sequence of exon 53. Claim
`
`1 states:
`
`1. A method of treating a DMD patient comprising
`
`
`1 Unless indicated otherwise, target regions of exon 53 discussed herein are counted
`
`from the 5’-end of exon 53.
`
`6
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`

`

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`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`intravenously administering to said patient an oligomer
`comprising:
`
`a) a phosphorodiamidate morpholino oligomer (PMO) that
`is 100% complementary to the 36th to the 60th nucleotides
`from the 5' end of the 53rd exon in a human dystrophin
`pre-mRNA, wherein the 53rd exon in said human
`dystrophin pre-mRNA consists of a nucleotide sequence
`corresponding to SEQ ID NO: 1, wherein said PMO
`hybridizes to said human dystrophin pre-mRNA with
`Watson-Crick
`base
`pairing,
`wherein
`the
`phosphorodiamidate morpholino monomers of said PMO
`have the formula:
`
`
`
`wherein each of R2 and R3 represents a methyl; and
`wherein Base is a nucleobase selected from the group
`consisting of: uracil, cytosine, thymine, adenine, and
`guanine; and
`
`b) a group at the 5' end of said PMO with the formula:
`
`7
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`

`

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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`
`
`
`
`(EX1001, claim 1.) SEQ ID NO:1 is identical to exon 53 of the human dystrophin
`
`gene, the sequence of which was known in the prior art before the ’217 patent was
`
`filed. (EX1001, 6:47–52; EX1100, ¶84.) Claim 1 contains no efficacy limitations
`
`and does not require that the recited PMOs induce skipping of exon 53.
`
`Independent claim 2 is identical to claim 1 except that claim 2 recites the target
`
`sequence of the human dystrophin pre-mRNA, stating that the recited PMO is 100%
`
`complementary
`
`to
`
`the
`
`“target
`
`sequence
`
`5’-
`
`GAACACCUUCAGAACCGGAGGCAAC-3’ (SEQ ID NO: 124).” (EX1001,
`
`claim 2; EX1100, ¶85.) SEQ ID NO:124 is identical to the pre-mRNA corresponding
`
`to the 36th to 60th nucleotides of exon 53 of the human dystrophin gene, the
`
`sequence of which was known in the prior art before the ’217 patent was filed.
`
`(EX1001, 6:47–49; EX1100, ¶85.) Despite their slightly different language, claims
`
`1 and 2 cover subject matter of the same scope. (EX1100, ¶85.)
`
`Independent claim 3 is similarly directed to a method of intravenously
`
`administering a PMO to a DMD patient. Claim 3 states that the recited PMO “causes
`
`8
`
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`

`

`
`
`skipping of the 53rd exon in a human dystrophin pre-mRNA” and that the PMO
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`consists of a 25-mer oligomer as follows:
`
`3. A method of treating a DMD patient comprising
`
`a
`patient
`said
`to
`administering
`intravenously
`phosphorodiamidate morpholino oligomer (PMO) that
`causes skipping of the 53rd exon in a human dystrophin
`pre-mRNA, consisting of a 25-mer oligomer that is 100%
`complementary to the 36th to the 60th nucleotides from
`the 5' end of the 53rd exon in said human dystrophin pre-
`mRNA, wherein the 53rd exon in said human dystrophin
`pre-mRNA
`consists
`of
`a
`nucleotide
`sequence
`corresponding to SEQ ID NO: 1, wherein said morpholino
`oligomer hybridizes to said pre-mRNA with Watson-
`Crick base pairing, wherein each morpholino monomer
`has the formula:
`
`
`
`wherein each of R2 and R3 are methyl;
`
`wherein Base is a nucleobase selected from the group
`consisting of: uracil, cytosine, thymine, adenine, and
`guanine; and
`
`9
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`

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`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`wherein the 5' end of said PMO has the formula:
`
`
`
`(EX1001, claim 3.) Claim 3 does not require that the 25-mer PMO induce skipping
`
`of exon 53 in a DMD patient. (EX1100, ¶¶86–88.) Nor does claim 3 require
`
`inducement of a particular level of exon 53 skipping. (Id.) Thus, demonstration that
`
`the recited AO induces any measurable level of exon 53 skipping in in vitro testing
`
`in human cells—as exemplified in the specification of the ’217 patent—satisfies the
`
`claim. (Id.)
`
`Independent claim 4 is identical to claim 3 except that claim 4 recites the target
`
`sequence of the human dystrophin pre-mRNA, stating that the recited 25-mer PMO
`
`is
`
`100%
`
`complementary
`
`to
`
`the
`
`“target
`
`sequence
`
`5’-
`
`GAACACCUUCAGAACCGGAGGCAAC-3’ [SEQ ID NO:124].” (EX1001,
`
`claim 4; EX1100, ¶87.) Despite their slightly different language, claims 3 and 4
`
`cover subject matter of the same scope. (EX1100, ¶87.)
`
`Both claims 1 and 2 recite an AO of an unspecified length comprising a 25-
`
`mer PMO targeting the (+36+60) sequence of exon 53, while claims 3 and 4 recite
`
`an AO consisting of such a 25-mer PMO.
`10
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`

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`
`
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 10,662,217
`
`B. Claim Construction
`Solely for purposes of this proceeding, Petitioner provides the following
`
`constructions.
`
`“A method of treating a DMD patient”
`1.
`Each of claims 1–4 of the ’217 patent contains a preamble reciting “[a] method
`
`of treating a DMD patient,” which identifies the patient population to which the
`
`claimed methods are directed. The body of each of claims 1–4 defines a complete
`
`method and none is missing an essential step or structure. Moreover, as described
`
`below, the preamble was not relied upon by either the applicants or the Office durin