`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`ONCUSP THERAPEUTICS, INC,
`Petitioner,
`
`v.
`
`DAIICHI SANKYO COMPANY, LTD,
`Patent Owner.
`_______________
`
`Case PGR2023-00037
`
`U.S. Patent 11,446,386
`
`Title: Anti-CDH6 Antibody and
`Method of Producing an Anti-CDH6 Antibody-Drug Conjugate
`
`_______________
`
`
`PETITION FOR POST-GRANT REVIEW
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`U.S. Patent No. 11,446,386
`
`TABLE OF CONTENTS
`
`Page
`TABLE OF AUTHORITIES ................................................................................... xi
`I.
`INTRODUCTION .......................................................................................... 1
`II. Mandatory notices .......................................................................................... 6
`A.
`Real Party-in-Interest (37 C.F.R. § 42.8(b)(1)) .................................... 6
`B.
`Related Matters (37 C.F.R. § 42.8(b)(2)) ............................................. 6
`C.
`Counsel and Service Information (37 C.F.R. §§ 42.8(b)(3) and
`(4)) ........................................................................................................ 6
`III. ADDITIONAL REQUIREMENTS ............................................................... 7
`A.
`Payment of Fees ................................................................................... 7
`B.
`Time for Filing Petition ........................................................................ 8
`C. Grounds for Standing ........................................................................... 8
`D.
`Identification of Challenge Under 37 C.F.R. § 42.204(b) and
`Relief Requested ................................................................................... 8
`IV. BACKGROUND AND SUMMARY OF THE ’386 PATENT ..................... 9
`V.
`PROSECUTION OF THE ’386 PATENT AND RELATED
`APPLICATIONS .......................................................................................... 18
`A. U.S. Application No. 16/613,203 (“’203 Application”) .................... 18
`B. U.S. Application No. 17/010,162 (“’162 Application”) .................... 23
`VI. LEVEL OF ORDINARY SKILL IN THE ART .......................................... 26
`VII. CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3) ................. 26
`VIII. SUMMARY OF THE PRIOR ART ............................................................. 28
`A.
`Int’l Application PCT/IB2015056032 (“Novartis”) .......................... 28
`B. U.S. Patent Application No. 15/027,489 (“Urano”) .......................... 28
`C. U.S. Patent Application No. 14/927,007 (“Sato”) ............................. 29
`IT IS MORE LIKELY THAN NOT THAT AT LEAST ONE OF THE
`CHALLENGED CLAIMS OF THE ’386 PATENT IS
`UNPATENTABLE ....................................................................................... 29
`
`IX.
`
`i
`
`

`

`U.S. Patent No. 11,446,386
`
`2.
`
`3.
`
`2.
`
`b.
`
`A. Ground 1: Lack of Written Description of Claims 1-18 of the ’386
`patent .................................................................................................. 29
`1.
`The Very Broad Claims (Claims 1-6 and 13-18) Cover A
`Vast Number of Antibodies That Are Not Supported By
`Any Common Structural Features ........................................... 32
`The Limited Number Of Working Examples In The Patent
`Are All Nearly Identical And Are Therefore An Extremely
`Narrow Subset That Is Not Representative Of The Diverse
`Genus Of The Challenged Claims ........................................... 42
`The Narrower Dependent Claims (Claims 7-12) Also Lack
`Written Description Because They Still Claim A
`“Functional Fragment” Of The Claimed Genus ...................... 48
`B. Ground 2: Lack of Enablement of Claims 1-18 of the ’386 Patent ... 50
`1.
`The Make-and-Screen Approach Of the Invention Renders
`The Challenged Claims Invalid For Lack of Enablement ....... 51
`The Application of the Wands Factors Compels A Finding
`Of Undue Experimentation ...................................................... 56
`a.
`The Nature of the Invention and Breadth of the
`Claims ............................................................................ 56
`The State of the Art, Predictability in the Field, and
`the Level of Ordinary Skill ............................................ 57
`The Knowledge Of One Of Ordinary Skill ................... 58
`The Amount of Direction or Guidance Provided And
`The Lack of Representative Examples .......................... 59
`The Quantity of Experimentation Required To
`Practice The Full Scope of the Claims .......................... 61
`C. Ground 3: Anticipation of Claims 1, 5, 13-16, and 18 By Novartis .. 62
`1.
`Claim 1: “A human or humanized monoclonal antibody that
`specifically binds to the amino acid sequence shown of
`SEQ ID NO: 4 and possesses an ability to internalize that
`permits cellular uptake, or a functional fragment of the
`antibody that binds to the amino acid sequence of SEO ID
`NO: 4 and possesses an ability to internalize that permits
`cellular uptake.” ....................................................................... 63
`
`c.
`d.
`
`e.
`
`ii
`
`

`

`4.
`
`5.
`
`6.
`
`7.
`
`2.
`
`U.S. Patent No. 11,446,386
`
`3.
`
`Claim 5: “The antibody or the functional fragment of the
`antibody according to claim 1, which is humanized.” ............. 64
`Claim 13: “The functional fragment of the antibody
`according to claim 1, wherein the functional fragment is
`selected from the group consisting of Fab, F(ab′)2, Fab′ and
`Fv.” ........................................................................................... 65
`Claim 14: “The antibody or the functional fragment of the
`antibody according to claim 1, wherein the heavy chain or
`the light chain has undergone one or two or more
`modifications selected from the group consisting of N-
`linked glycosylation, O-linked glycosylation, N-terminal
`processing, C-terminal processing, deamidation,
`isomerization of aspartic acid, oxidation of methionine,
`addition of a methionine residue to the N-terminus,
`amidation of a proline residue, conversion of N-terminal
`glutamine or N-terminal glutamic acid to pyroglutamic acid,
`and a deletion of one or two amino acids from the carboxyl
`terminus.” ................................................................................. 65
`Claim 15: “The antibody according to claim 14, wherein
`one or two amino acids are deleted from the carboxyl
`terminus of a heavy chain thereof.” ......................................... 66
`Claim 16: “The antibody according to claim 15, wherein
`one amino acid is deleted from each of the carboxyl termini
`of both of the heavy chains thereof.” ....................................... 67
`Claim 18: “The antibody or the functional fragment of the
`antibody according to claim 1, wherein sugar chain
`modification is regulated in order to enhance antibody-
`dependent cellular cytotoxic activity.” .................................... 67
`D. Ground 4: Obviousness of Claims 1, 5, and 13-18 Over Novartis
`or Novartis in Combination with Urano and or Sato As To Claims
`14-17 ................................................................................................... 68
`1.
`Claim 14: “The antibody or the functional fragment of the
`antibody according to claim 1, wherein the heavy chain or
`the light chain has undergone one or two or more
`modifications selected from the group consisting of N-
`linked glycosylation, O-linked glycosylation, N-terminal
`processing, C-terminal processing, deamidation,
`
`iii
`
`

`

`U.S. Patent No. 11,446,386
`
`2.
`
`3.
`
`isomerization of aspartic acid, oxidation of methionine,
`addition of a methionine residue to the N-terminus,
`amidation of a proline residue, conversion of N-terminal
`glutamine or N-terminal glutamic acid to pyroglutamic acid,
`and a deletion of one or two amino acids from the carboxyl
`terminus.” ................................................................................. 70
`Claim 15: “The antibody according to claim 14, wherein
`one or two amino acids are deleted from the carboxyl
`terminus of a heavy chain thereof.” ......................................... 71
`Claim 16: The antibody according to claim 15, wherein one
`amino acid is deleted from each of the carboxyl termini of
`both of the heavy chains thereof. ............................................. 71
`Claim 17: “The antibody according to claim 14, wherein a
`proline residue at the carboxyl terminus of a heavy chain
`thereof is further amidated.” .................................................... 72
`Ground 5: At Least Claims 1-5 and 14-18 Are Patent-Ineligible
`Under 35 U.S.C. § 101 ....................................................................... 73
`1.
`Legal Standard For 35 U.S.C. § 101 Patent Ineligibility ......... 73
`2.
`At Least Claims 1-5 and 14-18 Are Patent-Ineligible Under
`The Two-Step Framework of Mayo and Alice......................... 76
`Institution of Trial Should Not Be Discretionarily Denied Under Becton
`and Advanced Bionics ................................................................................... 79
`XI. CONCLUSION ............................................................................................. 82
`
`
`X.
`
`4.
`
`E.
`
`iv
`
`

`

`U.S. Patent No. 11,446,386
`
`LIST OF EXHIBITS
`
`Exhibit No.
`1001
`
`Description
`US Patent No. 11,446,386 to Atsuko Saito, et al., issued
`
`1002
`
`1003
`
`1004
`
`1005
`
`September 20, 2022 (“the ’386 Patent”)
`
`Prosecution History of the ’386 Patent
`
`Declaration of Stylianos Bournazos, Ph.D.
`
`Curriculum Vitae of Stylianos Bournazos, Ph.D.
`
`International PCT Application WO2016/024195A1 to Carl
`
`Bialucha, et al., published February 18, 2016
`
`1006
`
`U.S. Application Publication No. 2016/0317656A1 to Atsushi
`
`Urano et al., published November 3, 2016
`
`1007
`
`U.S. Application Publication No. 2016/0046720A1 to Hiromu
`
`Sato, et al., published February 18, 2016
`
`1008
`
`Mark L. Chiu, et al., Antibody Structure and Function: The Basis
`
`for Engineering Therapeutics, 8 ANTIBODIES 55 (2019)
`
`1009
`
`Inbal Sela-Culang, et al., The Structural Basis of Antibody-
`
`Antigen Recognition, 4 FRONTIERS IN IMMUNOLOGY, Oct. 8, 2013,
`
`at 1
`
`v
`
`

`

`U.S. Patent No. 11,446,386
`
`Exhibit No.
`1010
`
`Description
`Charles A. Janeway et al., IMMUNOBIOLOGY: THE IMMUNE
`
`SYSTEM IN HEALTH AND DISEASE (Garland Publishing, 5th ed.
`
`2001)
`
`1011
`
`Cristina Caldas, et al., Humanization of the Anti-CD18 Antibody
`
`6.7: An Unexpected Effect of a Framework Residue in Binding to
`
`Antigen, 39 MOLECULAR IMMUNOLOGY 941 (2003)
`
`1012
`
`Vered Kunik, et al., Structural Consensus Among Antibodies
`
`Defines the Antigen Binding Site, 8 PLOS COMPUTATIONAL
`
`BIOLOGY, Feb. 2012, at 1
`
`1013
`
`Sanjib Bhattacharyya, et al., Nanoconjugation Modulates the
`
`Trafficking and Mechanism of Antibody Induced Receptor
`
`Endocytosis, 107 PROC. NAT. ACAD. SCI. USA 14541 (2010)
`
`1014
`
`Cecile Chalouni & Sophia Doll, Fate of Antibody-Drug
`
`Conjugates in Cancer Cells, 37 J. EXP. & CLINICAL CANCER
`
`RESEARCH, no. 20, 2018, at 1
`
`1015
`
`Christina Peters & Stuart Brown, Antibody-Drug Candidates as
`
`Novel Anti-Cancer Chemotherapuetics, 35 BIOSCIENCE REP. 4
`
`(2015)
`
`vi
`
`

`

`U.S. Patent No. 11,446,386
`
`Exhibit No.
`1016
`
`Description
`Madeleine K. Ramos, et al., Valency of HER2 Targeting
`
`Antibodies Influences Tumor Cell Internalization and
`
`Penetration, 20 MOLECULAR CANCER THERAPEUTICS 1956 (2021)
`
`1017
`
`Stephen A. Beers, et al., Antigenic Modulation Limits the Efficacy
`
`of Anti-CD20 Antibodies: Implications for Antibody Selection,
`
`115 BLOOD 5191 (2010)
`
`1018
`
`Hilal A. Parray, et al., Hybridoma Technology a Versatile Method
`
`for Isolation of Monoclonal Antibodies, its Applicability Across
`
`Species, Limitations, Advancement, and Future Perspectives, 85
`
`INT’L IMMUNOPHARMACOLOGY, May 27, 2020, at 1
`
`1019
`
`Phei Er Saw & Er-Wei Song, Phage Display Screening of
`
`Therapeutic Peptide for Cancer Targeting and Therapy, 10
`
`PROTEIN & CELL 787 (2019)
`
`1020
`
`Thilo Riedl, et al., High-Throughput Screening for Internalizing
`
`Antibodies by Homogeneous Fluorescence Imaging of a pH-
`
`Activated Probe, 21 J. BIOMOLECULAR. SCREENING 12 (2016)
`
`1021
`
`Yutaka Shimoyama, et al., Isolation and Sequence Analysis of
`
`Human Cadherin-6 Complementary DNA for the Full coding
`
`vii
`
`

`

`U.S. Patent No. 11,446,386
`
`Exhibit No.
`
`Description
`Sequence and Its Expression in Human Carcinoma Cells, 55
`
`CANCER RESEARCH 2206 (1995)
`
`1022
`
`Fabian Sievers, et al., Fast, Scalable Generation of High-Quality
`
`Protein Multiple Sequence Alignments Using Clustal Omega, 7
`
`MOLECULAR SYSTEMS BIOLOGY, Oct. 11, 2011, at 1
`
`1023
`
`Veronique Giudicelli, et al., IMGT/V-QUEST: IMGT
`
`Standardized Analysis of the Immunoglobulin (IG) and T Cell
`
`Receptor (TR) Nucleotide Sequences, 6 COLD SPRING HARBOR
`
`PROTOCOLS, June 1, 2011, at 1
`
`1024
`
`Carien M. Niessen, et al., Tissue Organization by Cadherin
`
`Adhesion Molecules: Dynamic Molecular and Cellular
`
`Mechanisms of Morphogenetic Regulation, 91 PHYSIOLOGY REV.
`
`691 (2011)
`
`1025
`
`Roger Paul, et al., Cadherin-6: A New Prognostic Marker for
`
`Renal Cell Carcinoma, 171 J. UROLOGY 97 (2004)
`
`1026
`
`Toru Shimazui, et al., Expression of Cadherin-6 as a Novel
`
`Diagnostic Tool to Predict Prognosis of Patients with E-
`
`Cadherin-Absent Renal Cell Carcinoma, 4 CLINICAL CANCER
`
`RESEARCH 2419 (1998)
`
`viii
`
`

`

`U.S. Patent No. 11,446,386
`
`Exhibit No.
`1027
`
`Description
`Valentina Sancisi, et al., Cadherin 6 is a New RUNX2 Target in
`
`TGF-β Signalling Pathway, 8 PLOS ONE, Sept. 12, 2013, at 1
`
`1028
`
`Martin Kobel, et al., Ovarian Carcinoma Subtypes are Different
`
`Diseases: Implications for Biomarker Studies, 5 PLOS MEDICINE,
`
`Dec. 2, 2008, at 1
`
`1029
`
`Ming Meng, et al., CDH6 as a Prognostic Indicator and Marker
`
`for Chemotherapy in Gliomas, 13 FRONTIERS IN GENETICS, July.
`
`22, 2022, at 1
`
`1030
`
`Brent A. Kochert, et al., Hydrogen-Deuterium Exchange Mass
`
`Spectrometry to Study Protein Complexes, in METHODS IN
`
`MOLECULAR BIOLOGY 1764 (Joseph A. Marsh ed., 2018)
`
`1031
`
`Jeffrey G. Mandell, et al., Identification of Protein-Protein
`
`Interfaces by Decreased Amide Proton Solvent Accessibility, 95
`
`PROC. NAT. ACAD. SCI. USA 14705 (1998)
`
`1032
`
`Carl U. Bialucha, et al., Discovery and Optimization of HKT288,
`
`a Cadherin-6-Targeting ADC for the Treatment of Ovarian and
`
`Renal Cancers, 7 CANCER DISCOVERY 1030 (2017)
`
`ix
`
`

`

`U.S. Patent No. 11,446,386
`
`Exhibit No.
`1033
`
`Description
`Ruth Muchekehu, et al., The Effect of Molecular Weight, PK, and
`
`Valency on Tumor Biodistribution and Efficacy of Antibody-
`
`Based Drugs, 6 TRANSLATIONAL ONCOLOGY 562 (2013)
`
`1034
`
`Ben T. Ruddle, et al., Characterization of Disulfide Bond
`
`Rebridged Fab-Drug Conjugates Prepared Using a Dual
`
`Maleimide Pyrrolobenzodiazepine Cytotoxic Payload, 14
`
`CHEMMEDCHEM 1185 (2019)
`
`1035
`
`Lutz Riechmann, et al., Reshaping Human Antibodies for
`
`Therapy, 332 NATURE 323 (1988)
`
`1036
`
`Josee Golay, et al., Role of Fc Core Fucosylation in the Effector
`
`Function of IgG1 Antibodies, 13 FRONTIERS IN IMMUNOLOGY,
`
`June 30, 2022, at 1
`
`1037
`
`Christian Klein, et al., Epitope Interactions of Monoclonal
`
`Antibodies Targeting CD20 and Their Relationship to Functional
`
`Properties, 5 MABS 22 (2013)
`
`1038
`
`Prosecution History of U.S. Application No. 17/010,162
`
`
`
`
`
`
`
`x
`
`

`

`U.S. Patent No. 11,446,386
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc.,
`759 F.3d 1285 (Fed. Cir. 2014) ...................................................................passim
`
`Advanced Bionics LLC v. MED-EL Elektromedizinische Gerate
`GmbH, IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) ................. 79, 80, 81, 82
`Alice Corp. v. CLS Bank Int’l,
`573 U.S. 208 (2014) .......................................................................... 73, 74, 75, 76
`Alza Corp. v. Mylan Labs., Inc.,
`464 F.3d 1286 (Fed. Cir. 2006) .......................................................................... 69
`Amgen Inc. v. Sanofi,
`2019 WL 4058927 (D. Del. 2019) ...................................................................... 53
`Amgen Inc. v. Sanofi,
`872 F.3d 1367 (Fed. Cir. 2017), cert. denied, 139 S. Ct. 787 (2019) .......... 31, 32
`Amgen Inc. v. Sanofi, Aventisub LLC,
`987 F.3d 1080 (Fed. Cir. 2021) .......................................................... 3, 51, 52, 53
`Ariad Pharm., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) (en banc) ...................................................passim
`Ass’n for Molecular Pathology v. Myriad Genetics, Inc.,
`569 U.S. 576 (2013) ............................................................................................ 74
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017) ......................................... 79, 80
`BSG Tech LLC v. Buyseasons, Inc.,
`899 F.3d 1281 (Fed. Cir. 2018) .......................................................................... 75
`Carnegie Mellon Univ. v. Hoffmann-La Roche Inc.,
`541 F.3d 1115 (Fed. Cir. 2008) .......................................................................... 30
`ChargePoint, Inc. v. SemaConnect, Inc.,
`920 F.3d 759 (Fed. Cir. 2019) ............................................................................ 74
`
`xi
`
`

`

`U.S. Patent No. 11,446,386
`
`Diamond v. Chakrabarty,
`44 U.S. 303 (1980) .............................................................................................. 74
`Enzo BioChem, Inc. v. Calgene, Inc.,
`188 F.3d 1362 (Fed. Cir. 1999) .......................................................................... 51
`Enzo Life Scis., Inc. v. Roche Molecular Sys., Inc.,
`928 F.3d 1340 (Fed. Cir. 2019) .......................................................................... 51
`Funk Bros. Seed Co. v. Kalo Inoculant Co.,
`333 U.S. 127 (1948) ............................................................................................ 74
`Genentech v. Novo Nordisk,
`108 F.3d 1361 (Fed. Cir. 1997) .......................................................................... 59
`Genetic Techs. Ltd. v. Merial L.L.C.,
`818 F.3d 1369 (Fed. Cir. 2016) .......................................................................... 75
`Idenix Pharms. LLC v. Gilead Scis. Inc.,
`941 F.3d 1149 (Fed. Cir. 2019) .............................................................. 51, 53, 55
`Invitrogen Corp. v. Clontech Labs., Inc.,
`429 F.3d 1052 (Fed. Cir. 2005) .......................................................................... 50
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ............................................................................ 68
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 68, 69
`Lockwood v. Am. Airlines, Inc.,
`107 F.3d 1565 (Fed. Cir. 1997) .......................................................................... 30
`Mayo Collaborative Servs. v. Prometheus Labs., Inc.,
`566 U.S. 66 (2012) .................................................................................. 73, 75, 76
`Oticon Medical AB v. Cochlear Limited,
`IPR2019-00975, Paper 15 (PTAB Oct. 16, 2019) .............................................. 81
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .................................................................... 26, 27
`
`xii
`
`

`

`U.S. Patent No. 11,446,386
`
`Realtime Data, LLC v. Iancu,
`912 F.3d 1368 (Fed. Cir. 2019) .......................................................................... 69
`Regents of the Univ. of California v. Eli Lilly & Co.,
`119 F.3d 1559 (Fed. Cir. 1997) .................................................................... 31, 38
`In re Roslin Institute (Edinburgh),
`750 F.3d 1333 (Fed. Cir. 2014) .......................................................................... 74
`Schering Corp. v. Geneva Pharms., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) .................................................................... 62, 63
`Senju Pharm. Co. Ltd., v. Apotex Inc.,
`717 F.Supp 2d 404 (D. Del. 2010) ...................................................................... 68
`Stored Value Solutions, Inc. v. Card Activation Technologies, Inc.,
`796 F.Supp. 2d 520 (D. Del. 2011) ..................................................................... 68
`Tokai Corp. v. Easton Enterprises,
`632 F.3d 1358 (Fed. Cir. 2011) .......................................................................... 69
`Univ. of Utah Rsch. Found. v. Ambry Genetics,
`774 F.3d 755 (Fed. Cir. 2014) ............................................................................ 74
`University of Rochester v. Searle,
`358 F.3d 916 (Fed. Cir. 2004) ............................................................................ 38
`Vas-Cath Inc. v. Mahurkar,
`935 F.2d 1555 (Fed. Cir. 1991) .......................................................................... 30
`In re Wands,
`858 F.2d 731 (Fed. Cir. 1988) .....................................................................passim
`Wyeth & Cordis Corp. v. Abbott Labs.,
`720 F.3d 1380 (Fed. Cir. 2013) .............................................................. 51, 55, 56
`Statutes
`35 U.S.C. § 101 .................................................................................................passim
`35 U.S.C. § 102 .................................................................................................passim
`35 U.S.C. § 103 .................................................................................................passim
`
`xiii
`
`

`

`U.S. Patent No. 11,446,386
`
`35 U.S.C. § 112 .................................................................................................passim
`35 U.S.C. § 321 .......................................................................................................... 1
`35 U.S.C. § 322 .......................................................................................................... 1
`35 U.S.C. § 323 .......................................................................................................... 1
`35 U.S.C. § 324 .......................................................................................................... 1
`35 U.S.C. § 325 .............................................................................................. 1, 79, 82
`35 U.S.C. § 326 .......................................................................................................... 1
`Other Authorities
`37 C.F.R. § 42.8 ......................................................................................................... 6
`37 C.F.R. § 42.15 ....................................................................................................... 7
`37 C.F.R. § 42.104 ................................................................................................... 26
`37 C.F.R. § 42.200 et seq. .......................................................................................... 1
`37 C.F.R. § 42.202 ..................................................................................................... 8
`37 C.F.R. § 42.203 ..................................................................................................... 7
`37 C.F.R. § 42.204 ..................................................................................................... 8
`
`
`
`xiv
`
`

`

`U.S. Patent No. 11,446,386
`
`I.
`
`INTRODUCTION
`Petitioner OnCusp Therapeutics, Inc. (“OnCusp” or “Petitioner”) requests
`
`post-grant review (“PGR”) in accordance with 35 U.S.C. §§ 321-326 and 37
`
`C.F.R. § 42.200 et seq. of claims 1-18 of U.S. Patent 11,446,386 (the ’386 patent)
`
`(Ex. 1001), which issued on September 20, 2022, and is owned by Daiichi Sankyo
`
`Company, Limited (“Patent Owner,” “PO,” or “Daiichi”).
`
`Claims 1-18 of the ’386 patent (the “Challenged Claims”) are directed to
`
`human or humanized monoclonal antibodies, or a functional fragment thereof, that
`
`binds to the EC3 domain of CDH6 and possesses an ability to internalize that
`
`permits cellular uptake.
`
`Among these Challenged Claims is a group of very broad claims which
`
`classically represent unsupported genus claims to antibodies that Courts, including
`
`as recently as last month, the Supreme Court, have consistently invalidated for
`
`lack of written description and/or lack of enablement. This is based on the fact that
`
`these genus antibody claims are directed to not what the inventions are, but rather
`
`what they do functionally, which fails to adequately describe the scope of the
`
`invention and enable others to reasonably practice the claimed invention. The
`
`inventors of the ’386 patent only made four (4) antibodies satisfying the claims,
`
`which all share about 98% or more sequence identity, and are in fact clones of each
`
`other. (Ex. 1003, ¶99.) They were created only by first screening vast amounts
`
`1
`
`

`

`U.S. Patent No. 11,446,386
`
`(millions) of antibodies that could potentially bind to the EC3 domain of CDH6,
`
`and then by running assay after assay to randomly determine whether any actually
`
`could bind to EC3 and then internalize into cells. But the inventors did not
`
`determine anything about these antibodies that allowed them to function as claimed
`
`in terms of their structure or sequence.1 The only way the inventors knew that
`
`these four antibodies would actually bind and internalize, compared to those that
`
`would not, was by actually making and screening for them. Despite this, Patent
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`Owner obtained broad genus claims that cover all human or humanized antibodies
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`from any species of origin, from any germline, in any format, of any isotype or
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`subtype, that bind to any part of EC3, and have the ability to internalize.2 However,
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`1 While the Challenged Claims contain SEQ ID NO; 4 as an element, this is not a
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`sequence within the claimed antibodies, but rather the 115 amino acid length EC3
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`region of the target CDH6 antigen. The inventors never identified in their
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`functionally defined claims any specific amino acids within this EC3 region that
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`any of the claimed antibodies bind to (i.e., epitopes).
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`2 In fact, the ’386 patent itself makes the critical admission that one cannot predict
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`the claimed antibody’s functional ability to internalize based on the structure of the
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`antibody. (Ex. 1001, 2:49-52 (“It is difficult to predict an antigen-binding site
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`suitable for internalization from the molecular structure of a target or to predict an
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`2
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`U.S. Patent No. 11,446,386
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`this make-and-screen approach of claiming a broad genus of antibodies claimed
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`solely by function has repeatedly been struck down over and over again as invalid
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`for lack of written description and/or lack of enablement.
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`To satisfy the written description requirement, an inventor seeking patent
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`protection for broad functional antibody genus claims, like the Challenged Claims,
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`must either identify structural features that are common to all antibodies within the
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`genus or must provide a representative number of species of antibodies within the
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`genus. Here, because Patent Owner has failed to describe either requirement, these
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`claims lack written description. See AbbVie Deutschland GmbH & Co., KG v.
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`Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014).
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`Moreover, where, as here, the claims are directed to a genus of antibodies
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`claimed broadly by function, and there are only a handful of working examples
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`disclosed in the patent without any guidance in the specification as to how to
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`practice the full scope of the invention except through random trial-and-error
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`screening and experimentation, the claims are not enabled. See Amgen Inc. v.
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`Sanofi, Aventisub LLC, 987 F.3d 1080, 1087 (Fed. Cir. 2021), aff’d 598 U.S. __,
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`143 S.Ct. 1243 (2023) (“Amgen I”).
`
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`antibody having high internalization ability based on binding strength, physical
`
`properties, and the like of the antibody.”)).
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`
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`3
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`U.S. Patent No. 11,446,386
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`Even though some of the dependent claims of the Challenged Claims are
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`limited to certain structural features, these claims still lack written description and
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`enablement, because like all the Challenged Claims, these claims still cover not
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`only the claimed human or humanized antibody, but any “functional fragment” of
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`the antibody, which the ’386 patent broadly defines as any “partial fragment of the
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`antibody having binding activity against an antigen.” (Ex. 1001 at 17:40-43.)
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`Clearly, by disclosing just four exemplified antibodies that are mere clones of each
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`other, the inventors did not show that they possessed all claimed functional
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`fragments that have binding activity to EC3 and possess an ability to internalize,
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`and did not teach one of ordinary skill in the art to practice all such claimed
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`functional fragments. Thus, all the Challenged Claims, including these narrower
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`dependent claims, are invalid under 35 U.S.C. § 112 based on this fatal defect of
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`claiming “functional fragment[s].”
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`In addition, the very broad claims are anticipated or rendered obvious by
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`PCT/IB2015/056032, filed on August 7, 2015, and which published on February
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`18, 2016, as WO 2016/024195 A1 (“Novartis”) (Ex. 1005). Novartis’s prior art
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`patent application actually disclosed - more than one year prior to the effective
`
`filing date of the Challenged Claims - the claimed humanized monoclonal
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`antibodies that bind to the EC3 domain of CDH6 and possess an ability to
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`internalize. While Patent Owner overcame a similar rejection under 35 U.S.C. §
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`4
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`U.S. Patent No. 11,446,386
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`102(a)(1) over the Novartis prior art during prosecution of the Challenged Claims,
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`this was based on Patent Owner’s clear misrepresentation that this reference did
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`not disclose binding to EC3 and internalization.3 As shown herein, the Novartis
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`reference does disclose this.
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`Finally, at least claims 1-5 and 14-18 are invalid under 35 U.S.C. § 101 for
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`claiming patent-ineligible subject matter. For example, claim 1 covers a “human”
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`monoclonal antibody that specifically binds to EC3 and internalizes, and as such,
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`covers naturally occurring anti-CDH6 antibodies that exist naturally in human
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`cancer patients, or antibodies that are not markedly different from these naturally
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`occurring antibodies. Since these claims do not add significantly more to the
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`covered natural product that could transform them into patent-eligible subject
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`matter, these claims are invalid under 35 U.S.C. § 101.
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`As this Petition shows, along with the Declaration of Dr. Stylianos
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`Bournazos in support of this Petition (“Bournazos Decl.”) (Ex. 1003), the
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`Challenged Claims are invalid for lack of written description, lack of enablement,
`
`
`3 Notably, when confronted with a prior art rejection based on this Novartis
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`reference in a related application, Patent Owner was forced to amend the broad
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`claims to overcome the rejection. See infra at § IV.B.
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`5
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`U.S. Patent No. 11,446,386
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`for being anticipated and/or obvious over the prior art, and for claiming patent-
`
`ineligible subject matter.
`
`II. MANDATORY NOTICES
`A. Real Party-in-Interest (37 C.F.R. § 42.8(b)(1))
`Petitioner OnCusp Therapeutics, Inc., as well as OnCusp Therapeutics and
`
`
`
`Multitude Therapeutics Inc. are real parties-in-interest.
`
`B. Related Matters (37 C.F.R. § 42.8(b)(2))
`Petitioner is unaware of any judicial or administrative proceedings that
`
`would either affect or be affected by a decision regarding this Petition.
`
`C. Counsel and Service Information (37 C.F.R. §§ 42.8(b)(3) and (4))
`Petitioner identifies its lead and backup counsel as shown below:
`
`Lead Counsel
`Gerard P. Norton, Ph.D.
`USPTO Registration 36,621
`FOX ROTHSCHILD LLP
`Princeton Pike Corporate Center
`997 Lenox Drive
`Lawrenceville NJ 08648-2311
`(609) 844-3020
`gnorton@foxrothschild.com
`
`
`
`Backup Counsel
`Ryan N. Miller
`USPTO Registration 68,262
`FOX ROTHSCHILD LLP
`2000 Market St.
`20th Floor
`Philadelphia PA 19103-3222
`(215) 299-2901
`rmiller@foxrothschild.com
`
`Howard S. Suh (pro hac vice to be filed)
`FOX ROTHSCHILD LLP
`101 Park Avenue, 17th Floor
`New York, NY 10178
`(212) 878-7914
`hsuh@foxrothschild.com
`
`Jianming Jimmy Hao
`
`6
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`

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`U.S. Patent No. 11,446,386
`
`USPTO Registration 54,694
`Fox Rothschild LLP
`997 Lenox Drive
`Lawrenceville, NJ 08648
`Telephone: (609) 895-7065
`Facsimile: (609) 896-1469
`JHao@foxrothschild.com
`
`Joe G. Chen (Reg. No. 70,066)
`Fox Rothschild L