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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ONCUSP THERAPEUTICS INC,
`Petitioner,
`
`v.
`
`DAIICHI SANKYO CO LTD,
`Patent Owner.
`____________
`Case No. PGR2023-00037
`Patent No. 11,446,386
`____________
`
`
`EXPERT DECLARATION OF
`STYLIANOS BOURNAZOS, Ph.D.
`
`
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`I.
`II.
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`Table of Contents
`QUALIFICATIONS....................................................................................... 5
`RELEVANT FIELD AND LEVEL OF ORDINARY SKILL IN THE
`ART ................................................................................................................ 7
`III. MATERIALS REVIEWED ........................................................................... 8
`IV.
`SUMMARY OF MY OPINIONS ................................................................ 14
`V.
`THE UNDERSTANDING APPLIED TO MY ANALYSIS....................... 16
`VI. BACKGROUND AND STATE OF THE ART........................................... 23
`A.
`Introduction to Antibodies and Overview of the State of Art............ 23
`Antibody Structures ................................................................. 24
`Antibodies Comprise Diverse Amino Acid Sequences that
`Influence Functionality and Antigen Binding Affinity ........... 27
`The Substantial Diversity of Antibody Sequences is
`Essential for the Immune Response to Novel Antigens .......... 28
`Antibody Interactions with Target Antigens Focus on
`Specific Antigen Segments...................................................... 31
`Antibody-Antigen Binding: Structure Drives Function .......... 31
`Antibodies or Fragments Capable of Internalization............... 33
`Antibody Identification and Production for Testing................ 35
`VII. THE ’386 PATENT...................................................................................... 41
`A.
`Claims of the ’386 Patent................................................................... 41
`B.
`The ’386 Patent’s Disclosure ............................................................. 51
`C.
`Antibodies Described by the ’386 Patent........................................... 54
`VIII. OVERVIEW OF PRIOR ART..................................................................... 62
`A. WO2016024195A1 (“Novartis”) ....................................................... 62
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`B.
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`IX.
`X.
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`U.S. Patent Application No. 15/027,489 (“Urano”) .......................... 72
`B.
`U.S. Patent Application No. 14/927,007 (“Sato”) ............................. 73
`C.
`LEVEL OF ORDINARY SKILL IN THE ART.......................................... 74
`THE ’386 PATENT DOES NOT SUPPORT OR ENABLE ANY OF
`CLAIMS 1-18............................................................................................... 75
`A.
`The ’386 Patent Lack of Written Description for Any of Claims 1-
`18 ........................................................................................................ 75
`The exemplary humanized anti-CDH6 antibodies at best are
`Narrow and Unrepresentative Subset ...................................... 78
`The Claims of the ’386 Patent Do Not Specify Structural
`Features Common to the Members of the Claimed Invention
`That are Required for Binding hCDH6 EC3 and
`Internalization .......................................................................... 89
`The ’386 Patent Lack of Enablement for Any of Claims 1-18.......... 97
`The Nature of the Invention and Breadth of the Claims........ 100
`The State of the Art, Predictability in the Field, and the
`Level of Ordinary Skill .......................................................... 101
`The Amount of Direction or Guidance Provided .................. 103
`The Amount of Experimentation Required ........................... 104
`XI. CLAIMS 1, 5, 13-16, and 18 ARE ANTICIPATED BY PRIOR ART..... 106
`A.
`Claim 1 ............................................................................................. 106
`B.
`Claim 5 ............................................................................................. 108
`C.
`Claim 13 ........................................................................................... 109
`D.
`Claim 14 ........................................................................................... 109
`E.
`Claim 15 ........................................................................................... 110
`F.
`Claim 16 ........................................................................................... 111
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`Claim 18 ........................................................................................... 111(cid:3)
`G.(cid:3)
`XII.(cid:3) CLAIMS 1, 5, AND 13-18 ARE OBVIOUS OVER THE PRIOR ART .. 112(cid:3)
`A.(cid:3)
`Claim 1 ............................................................................................. 113(cid:3)
`B.(cid:3)
`Claim 5 ............................................................................................. 114(cid:3)
`C.(cid:3)
`Claim 13 ........................................................................................... 115(cid:3)
`D.(cid:3)
`Claim 14 ........................................................................................... 116(cid:3)
`E.(cid:3)
`Claim 15 ........................................................................................... 119(cid:3)
`F.(cid:3)
`Claim 16 ........................................................................................... 120(cid:3)
`G.(cid:3)
`Claim 17 ........................................................................................... 122(cid:3)
`H.(cid:3)
`Claim 18 ........................................................................................... 123(cid:3)
`XIII.(cid:3) CLAIMS 1-5 AND 14-18 ARE PATENT INELIGIBLE .......................... 124(cid:3)
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`I, Stylianos Bournazos, declare as follows:
`
`1.
`
`I am over the age of 21 years and am fully competent to make this
`
`Declaration. I make the following statements based on personal knowledge and, if
`
`called to testify to them, could and would do so.
`
`I.
`
`QUALIFICATIONS
`
`2.
`
`I received my BS in Genetics and Immunology in 2005 from the
`
`University of Aberdeen, Aberdeen, United Kingdom. I received my MS in Life
`
`Science in 2006 from the University of Edinburgh, Edinburgh, United Kingdom. I
`
`received my Ph.D. in Immunology in 2010 from the University of Edinburgh. I
`
`did my postdoctoral work at the Rockefeller University in the division of virology
`
`and antibody therapeutics.
`
`3.
`
`I am currently employed by the Rockefeller University, where I am a
`
`Research Associate Professor. I was also a member of American Association of
`
`Immunologists, New York Academy of Science, American Heart Association, and
`
`WHO Expert Group for the development of preclinical models of COVID-19
`
`disease.
`
`4.
`
`I have over 15 years of research experience in the study of antibody
`
`and FcR function in health and disease. My studies have demonstrated a critical
`
`role for IgG Fc-FcγR interactions in the protective activity of antibodies against
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`bacterial and viral pathogens, leading to the clinical development of Fc-optimized
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`antibodies with improved effector function. Additionally, my research on the
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`mechanisms by which antibodies contribute to dengue disease pathogenesis
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`identified specific glycan changes at the IgG Fc domain as robust predictive
`
`biomarkers for symptomatic dengue disease. In addition, I have determined the in
`
`vivo immunological mechanisms by which Fc-FcγR interactions drive dengue
`
`pathogenesis.
`
`5.
`
`I have served as a scientific reviewer for peer-reviewed scientific
`
`journals, such as PLoS One, Journal of Experimental Medicine, Lung, Cell
`
`Reports, Cell Host & Microbe, International Archives of Allergy and Immunology,
`
`European Journal of Immunology, The Journal of Immunology, Nature
`
`Microbiology, Nature Communications, Frontiers in Immunology, Immunity, Cell
`
`Reports Medicine, iScience, EBioMedicine, and Scientific Reports.
`
`6.
`
`I have also served as a grant reviewer for the National Cancer
`
`Institute, the National Institute on Aging, the Medical Research Council (MRC)
`
`(United Kingdom), Deutsche Forschung Gemeinschaft (DFG) (Germany), and the
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`Israeli Ministry of Innovation, Science and Technology (Israel).
`
`7.
`
`Since 2012, I have been an invited speaker of various scientific
`
`meetings, including NIAID Workshop on Clinical Development of Broadly
`
`Neutralizing Antibodies (bnAbs) for HIV-1, 2022; EMBO Workshop on
`
`Antibodies and complement: Effector functions, therapies and technologies,
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`Girona, Spain; PEGS Europe: Protein & Antibody Engineering Summit, 2017,
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`Lisbon, Portugal; 2nd Next-Generation Antibodies and Protein Analysis 2017,
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`Gent, Belgium; NIAID Workshop on Mechanisms of Fc-Dependent, Antibody-
`
`Mediated Killing, Rockville, MD; Keystone Biobetters and Next-Generation
`
`Biologics: Innovative Strategies for Optimally Effective Therapies 2017,
`
`Snowbird, UT; and AIDS vaccine 2012 conference, Boston, MA.
`
`A copy of my current CV is enclosed. (Ex. 1004.)
`
`8.
`
`
`
`II. RELEVANT FIELD AND LEVEL OF ORDINARY SKILL IN THE
`
`ART
`
`9.
`
`I have reviewed US Patent No. 11,446,386 (“the ’386 Patent”) (Ex.
`
`1001) and relevant portions of its prosecution history with the United States Patent
`
`and Trademark Office. Specifically, I have reviewed the ’386 Patent and its
`
`prosecution history in relation to the asserted prior art and arguments at issue in the
`
`present post-grant review (PGR).
`
`10. Based on my experience described above and contained in my CV, I
`
`have an established understanding of the relevant field in the relevant timeframe,
`
`and the knowledge that would have been known by a person of ordinary skill in the
`
`art (POSA), as defined above and during the relevant time frame (on or before May
`
`15, 2017 – the claimed priority date of the ’386 Patent).
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`III. MATERIALS REVIEWED
`
`11.
`
`I have reviewed the Petition and supporting evidence. I have also
`
`reviewed all challenged claims of the ’386 Patent (Claims 1-18), as well as the
`
`’386 specification and parts of its file history. I have examined the prior art
`
`references asserted against the ’386 Patent in the Petition. I will use the exhibit
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`numbers listed on the “LIST OF EXHIBITS” the Petition, which I have included
`
`for ease of reference below:
`
`TABLE OF EXHIBITS
`
`Exhibit No. Description
`
`1001
`
`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
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`1007
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`U.S. Application Publication No. 2016/0046720A1to Hiromu
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`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
`
`1010
`
`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)
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`1014
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`Cecile Chalouni & Sophia Doll, Fate of Antibody-Drug
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`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)
`
`1016
`
`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)
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`1020
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`Thilo Riedl, et al., High-Throughput Screening for Internalizing
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`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
`
`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
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`Veronique Giudicelli, et al., IMGT/V-QUEST: IMGT
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`Standardized Analysis of the Immunoglobulin (IG) and T Cell
`
`Receptor (TR) Nucleotide Sequences, 6 COLD SPRING HARBOR
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`PROTOCOLS, June 1, 2011, at 1
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`1024
`
`Carien M. Niessen, et al., Tissue Organization by Cadherin
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`Adhesion Molecules: Dynamic Molecular and Cellular
`
`Mechanisms of Morphogenetic Regulation, 91 PHYSIOLOGY REV.
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`691 (2011)
`
`1025
`
`Roger Paul, et al., Cadherin-6: A New Prognostic Marker for
`
`Renal Cell Carcinoma, 171 J. UROLOGY 97 (2004)
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`1026
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`Toru Shimazui, et al., Expression of Cadherin-6 as a Novel
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`Diagnostic Tool to Predict Prognosis of Patients with E-
`
`Cadherin-Absent Renal Cell Carcinoma, 4 CLINICAL CANCER
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`RESEARCH 2419 (1998)
`
`1027
`
`Valentina Sancisi, et al., Cadherin 6 is a New RUNX2 Target in
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`TGF-β Signalling Pathway, 8 PLOS ONE, Sept. 12, 2013, at 1
`
`1028
`
`Martin Kobel, et al., Ovarian Carcinoma Subtypes are Different
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`Diseases: Implications for Biomarker Studies, 5 PLOS MEDICINE,
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`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
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`Spectrometry to Study Protein Complexes, in METHODS IN
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`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)
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`1032
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`Carl U. Bialucha, et al., Discovery and Optimization of HKT288,
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`a Cadherin-6-Targeting ADC for the Treatment of Ovarian and
`
`Renal Cancers, 7 CANCER DISCOVERY 1030 (2017)
`
`1033
`
`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
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`Josee Golay, et al., Role of Fc Core Fucosylation in the Effector
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`Function of IgG1 Antibodies, 13 FRONTIERS IN IMMUNOLOGY,
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`June 30, 2022, at 1
`
`1037
`
`Christian Klein, et al., Epitope Interactions of Monoclonal
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`Antibodies Targeting CD20 and Their Relationship to Functional
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`Properties, 5 MABS 22 (2013)
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`1038
`
`Prosecution History of U.S. Application No. 17/010,162
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`IV. SUMMARY OF MY OPINIONS
`12.
`I have been asked to consider whether the disclosure in the ’386
`
`Patent demonstrates possession of the full scope of the invention recited in claims
`
`1-18. The ’386 patent claims antibodies and their functional fragments that are
`
`defined solely by their functions (i) an ability to specifically bind to the amino acid
`
`sequence shown of SEQ ID NO: 4 and (ii) an ability to internalize that permits
`
`cellular uptake. The claims cover a diverse genus of antibodies and their functional
`
`fragments having different amino acid sequences, associated higher order
`
`structures, isotypes, subclasses, and corresponding functions. The claims also
`
`cover antibodies and their functional fragments generated by various methods, as
`
`well as antibodies and their functional fragments containing various modifications.
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`13.
`
`In my opinion, none of claims 1-18 are adequately described or
`
`supported. The ’386 Patent not only fails to provide sufficient representative
`
`examples across the claimed genus of antibodies that exhibit the desired binding
`
`and internalization functions, but also fails to identify any common structural
`
`features required or in correlation with the desired binding and internalization
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`functions. Furthermore, based on the limited information provided in the patent, a
`
`skilled artisan could not visualize what other antibody sequences might provide the
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`claimed ability to specifically bind to the amino acid sequence shown of SEQ ID
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`NO: 4 and internalize. As admitted by the ’386 Patent, predicting the sequences of
`
`antibodies that provide the internalization function simply was not possible at the
`
`time this patent was effectively filed, which is the claimed priority date of the ’386
`
`Patent.
`
`14.
`
`I have also considered whether the disclosure in the ’386 patent would
`
`enable a person of ordinary skill in the art to make and use the antibodies and their
`
`functional fragments of claims 1-18. For similar reasons, a skilled artisan at or
`
`around the claimed priority date would not have had sufficient guidance to make
`
`and use the many different antibodies and their functional fragments covered by
`
`the claims, nor would they have such guidance today. The specification offers
`
`testing data for only four highly similar humanized antibodies. The very limited
`
`guidance provided by the ’386 Patent amounts to invitation to carry out a research
`
`plan, which cannot be accomplished without undue experimentation.
`
`15.
`
`I have been asked to consider whether the claims of the ’386 Patent
`
`are anticipated or otherwise obvious in view of the references published before the
`
`claimed priority date. I find that the prior art reference WO2016024195A1
`
`(“Novartis”) (Ex. 1005) discloses all the limitations of at least claims 1, 5, 13-16,
`
`and 18 of the ’386 Patent. I also find that Novartis or a combination of Novartis
`
`and another prior art references U.S. Patent Application No. 15/027,489 (“Urano”)
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`(Ex. 1006) and/or U.S. Patent Application No. 14/927,007 (“Sato”) (Ex. 1007)
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`disclose or suggest all the limitations of at least claims 1, 5, and 13-18 of the ’386
`
`Patent.
`
`16.
`
`I have also been asked to consider whether any of the claims of the
`
`’386 Patent are directed to patent ineligible subject matter. In particular, I have
`
`considered whether the claims are directed to a product of nature or a product that
`
`is not markedly different from what occurs in nature, and if so, whether the claims
`
`include additional features that could add significantly more to the product of
`
`nature. I find that claims 1-5 and 14-18 of the ’386 Patent cover either a naturally
`
`occurring anti-Cadherin 6 (CDH6) antibody or an anti-CDH6 antibody that is not
`
`markedly different from a naturally occurring anti-CDH6 antibody. In addition,
`
`none of claims 1-5 and 14-18 includes additional features that add significantly
`
`more to the product of nature to transform it into patent eligible subject matter.
`
`Therefore, it is my opinion that all the claims of the ’386 Patent are patent
`
`ineligible.
`
`
`
`V. THE UNDERSTANDING APPLIED TO MY ANALYSIS
`
`17.
`
`In preparing this Declaration, certain patent law concepts have been
`
`explained to me, including the legal standard for interpreting claims, as well as
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`those for assessing written description, enablement, anticipation, obviousness, and
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`patent eligibility.
`
`18.
`
`I understand that in a PGR proceeding, claims should be construed as
`
`having their ordinary and customary meaning as understood by a POSA at the time
`
`of the invention. I understand that claims should be read in the context of the
`
`claim language of which they are a part. I further understand that the specification
`
`and file history can also inform the scope of the claims. If, after a review of this
`
`evidence, the construction is not apparent, I understand that extrinsic evidence,
`
`such as dictionary definitions, treatises, and trade journals, may be consulted to
`
`discern the meaning of a term. For terms where no construction is necessary, I
`
`have simply read the terms according to their ordinary and customary meaning.
`
`My understandings herein are made in light of how a person of ordinary skill in the
`
`art in or around 2017 would view the ordinary and customary meaning of the claim
`
`terms. I reserve the right to supplement my Declaration should any claim terms be
`
`given different constructions.
`
`19.
`
`I understand that a claim in a granted patent must be sufficiently
`
`supported by the disclosure in the patent’s specification, read in the context of
`
`what one of ordinary skill in the art would have known at the time of the claimed
`
`invention. I understand that the basic inquiry for written description is whether the
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`specification provides sufficient information for a skilled artisan to recognize that
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`the named inventors possessed the full scope of the claimed invention.
`
`20. The claims of the ’386 Patent recite a human or a humanized
`
`monoclonal antibody that binds to a 115-amino acid region on CDH6 defined by
`
`SEQ ID NO: 4, covering diverse antibodies defined by their function rather than
`
`any particular structure. (Ex. 1001, 181:58-65.) To satisfy the written description
`
`requirement for such claims, I understand that the specification must disclose
`
`either a representative number of species falling within the scope of the claimed
`
`genus or structural features common to the members of the genus such that one
`
`skilled in the art can “visualize or recognize” the members of the claimed genus.
`
`21.
`
`I understand that, in addition to written description, a patent
`
`specification must also enable a person of ordinary skill in the art to make and use
`
`the full scope of the claimed invention without undue experimentation as of its
`
`effective filing date. I understand that multiple factors should be considered when
`
`making this determination. These factors include: (a) the breadth of the claims;
`
`(b) the nature of the claimed invention; (c) the state of the prior art; (d) the level of
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`predictability or unpredictability of the art; (e) the knowledge of one of ordinary
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`skill; (f) the amount of direction provided by the named inventor(s); (g) the
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`presence or absence of working examples; and (h) the quantity of experimentation
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`needed to make or use the claimed invention based on the content of the disclosure.
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`22.
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`I understand that a claim is anticipated if a single prior art reference
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`discloses each and every limitation of the claimed invention. I understand that a
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`limitation can be expressly disclosed by the reference or be inherent. I further
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`understand that for a feature to be inherently disclosed, a POSA would understand
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`the inherent feature would necessarily and inevitably be present when the teaching
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`of the reference is practiced. That is, I understand that if a feature is not
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`necessarily and inevitably present, it is not inherently disclosed.
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`23.
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`I understand that a patent claim may be unpatentable for obviousness
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`if the difference between the claimed subject matter and the prior art is such that
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`the subject matter as a whole would have been obvious at the time the invention
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`was made to a person having ordinary skill in the art. I understand that a finding of
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`obviousness requires a determination of: (1) the scope and content of the prior art;
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`(2) the difference(s) between the claimed invention and the prior art; and (3) the
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`level of skill of the ordinary artisan in the pertinent art. I understand this analysis
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`looks at whether the differences are such that the claimed invention as a whole
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`would have been obvious to one of ordinary skill in the art at the time the invention
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`was made. I further understand that any obviousness analysis must consider
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`objective evidence of non-obviousness, where such evidence is present.
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`24.
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`I understand that objective evidence of non-obviousness includes (1)
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`copying, (2) long felt but unsolved need, (3) failure of others, (4) commercial
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`success of the invention, (5) unexpected results created by the claimed invention,
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`(6) unexpected properties of the claimed invention, (7) licenses showing industry
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`respect for the invention, (8) skepticism of skilled artisans before the invention, (9)
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`recognition of invention’s advancement, and (10) contemporaneous invention by
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`others or absence thereof. In general, there must be a connection between any of
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`the factors and the claimed invention. For instance, the “commercial success” of a
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`product practicing the claimed invention is relevant to the obviousness analysis
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`only if the commercial success is attributable to advantages from the use of the
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`invention that were not available to the purchasing public before the invention was
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`made.
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`25. My understanding is that the obviousness inquiry is not limited to just
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`the prior art references being applied, but includes the knowledge and
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`understanding of one of ordinary skill in the art.
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`26. However, I understand that merely demonstrating that each element,
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`independently, was known in the prior art is, by itself, insufficient to establish a
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`claim was obvious. My understanding is that the test for obviousness is not
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`whether the features of one reference can be incorporated into the structure of
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`another reference, but rather what the combined teachings would have suggested to
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`those of ordinary skill in the art. I further understand that a party seeking to
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`invalidate a patent must show a person of ordinary skill in the art would have been
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`motivated to combine the teachings of the prior art references to achieve the
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`claimed invention.
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`27.
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`It is my understanding that each prior art reference must be considered
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`as a whole, including the portions that would lead away from the claimed
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`invention. I have been informed that some prior art combinations are improper, or
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`not combinable. For instance, the reference cannot be non-analogous art. In order
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`for a reference to be used to show obviousness, the reference must be analogous art
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`to the claimed invention. I understand that to be analogous, the art must be from
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`the same field of endeavor or be reasonably pertinent to the problem – and
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`therefore logically would command the artisan’s attention in considering her/his
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`problem. I also understand that when (1) the combination of prior art references
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`teaches away from the claimed invention or from each other, (2) the combination
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`makes one invention unsatisfactory for its intended purpose, or (3) when the
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`combination would change the principle of operation of prior art reference, such a
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`combination is improper and does not show obviousness.
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`28.
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`I understand that a combination of old, familiar, or known elements
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`according to known methods is likely to be obvious when it does no more than
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`yield predictable results. Predictable variations of a work from one field are likely
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`to be obvious, even if the variation is in another field. For example, where a
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`technique has been used to improve a device, use of the same technique to improve
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`similar devices is a predictable variation and likely obvious. Likewise, if the use
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`of prior art for improvements is simply done according to the prior art’s established
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`functions, a person of ordinary skill in the art has simply implemented a
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`predictable variation. If there existed at the time of invention a known problem for
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`which there was an obvious solution, a patent claim encompassing that solution is
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`not patentable.
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`29.
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`I understand that a claimed invention is patent eligible if it claims a
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`new and useful process, machine, manufacture, or composition of matter, unless
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`the claims are directed to judicial exceptions, such as laws of nature, natural
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`phenomena, and abstract ideas. I understand that a two-step inquiry has been
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`adopted to determine whether a claim is patent eligible. In step one, a
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`determination is made as to whether the claimed invention is directed to one of the
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`four statutory categories. If the claimed invention is directed to a statutory category
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`(e.g., composition of matter), step two requires a determination as to whether the
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`claimed invention is directed to a judicial exception, such as a product of nature. If
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`the claim encompasses a product that does not have markedly different
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`characteristics from any found in nature, the claim is still directed to a “product of
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`nature” exception. If the claim is directed to an exception, it is patent ineligible if
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`the claim does not include additional features that could add significantly more to
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`the exception itself. A feature is not deemed significantly more if it merely adds
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`well-understood, routine, conventional activity already engaged in by the scientific
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`community to the product of nature.
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`30. Although the following analysis cites to particular pages, lines,
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`paragraphs, or figures of many of the references discussed, these citations are
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`intended to assist in understanding the various bases of my conclusions, and prior
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`art teachings used to reach them. These citations are not intended to be an
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`exhaustive recitation of every page, line number, or paragraph in which these
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`teachings may be found. Similar teachings or disclosures may be found at other
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`pages, lines, or paragraphs, as well as in other references, and it is to be understood
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`that my opinions and statements are made in view of all of the references and
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`teachings I have reviewed.
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`
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`VI. BACKGROUND AND STATE OF THE ART
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`A.
`Introduction to Antibodies and Overview of the State of Art
`31. Antibodies are a foundational component of the immune system’s
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`defense against both foreign agents (e.g., viruses, bacteria, fungi, and protozoa)
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`and aberrant self-made components of the body (e.g., cancers and auto-immune
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`diseases). Each antibody can recognize a specific target molecule called an antigen.
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`Through binding to its specific antigen, an antibody can trigger additional
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`biological processes to occur, depending on the biological context in which the
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`binding occurs. (Ex. 1008 at 38.)
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`32.
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`In recent decades, through the painstaking development of unique
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`antibodies targeting specific antigens, scientists have been able to develop
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`prophylactic, diagnostic, and therapeutic antibody-based tools that have
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`collectively transformed modern medicine. Importantly, many different antibody
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`structures may functionally bind to the same target antigen. (Ex. 1010 at 151.)
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`Antibody Structures
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`33.
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`The generic structure of a representative antibody of the IgG class is
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`shown below in Figure 1. (Ex.