UNITED STATES DISTRICT COURT
`CENTRAL DISTRICT OF CALIFORNIA
`WESTERN DIVISION
`
`Case No. 2:13-cv-05400-MRP-JEM
`
`CONFIDENTIAL
`
`EXPERT REPORT OF CARLO M.
`CROCE, M.D.
`
`
`
`Case No. 2:13-cv-07248-MRP-JEM
`
`
`
`Mylan v. Genentech
`IPR2016-00710
`Genentech Exhibit 2072
`Page 1
`
`
`
`
`
`BRISTOL-MYERS SQUIBB COMPANY,
`Plaintiff/Counter-Defendant,
`v.
`GENENTECH, INC., and CITY OF HOPE
`Defendants/Counter-Plaintiffs.
`
`ELI LILLY AND COMPANY and
`IMCLONE SYSTEMS LLC,
`Plaintiffs/Counter-Defendants,
`v.
`GENENTECH, INC. and CITY OF HOPE,
`Defendants/Counter-Plaintiffs.
`
`
`
`
`

`
`
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION ................................................................................................... 1
`
`PROFESSIONAL EXPERIENCE AND QUALIFICATIONS ............................... 1
`
`PRIOR TESTIMONY ............................................................................................. 4
`
`COMPENSATION .................................................................................................. 5
`
`MATERIALS CONSIDERED ................................................................................ 5
`
`QUESTIONS PRESENTED ................................................................................... 5
`
`VII.
`
`SUMMARY OF OPINION ..................................................................................... 7
`
`VIII. RELEVANT LAW .................................................................................................. 8
`A.
`35 U.S.C. § 112—Written Description and Enablement ............................. 8
`
`IX.
`
`THE PERSON OF ORDINARY SKILL IN THE ART ........................................ 10
`
`THE MEANING OF THE CLAIMS OF THE CABILLY II AND III PATENTS
`11
`
`X.
`
`
`XI.
`
`B.
`
`C.
`
`OPINION ............................................................................................................... 14
`The State of the Art of Antibody Production in 1983 Was Focused
`A.
`on Approaches that Did Not Involve Recombinant DNA ......................... 14
`Many Working In the Field In 1983 Were Using Hybridoma
`Technology to Make Monoclonal Antibodies, Including Human
`Ones ........................................................................................................... 17
`Although My Laboratory Worked at the Intersection of Molecular
`Biology, Immunology and Medicine, We Did Not Envisage
`Making Antibodies Recombinantly ........................................................... 23
`The Cabilly II and Cabilly III Patents Adequately Describe How to
`Make a Recombinant Human Antibody that Binds to a Known or
`Desired Antigen ......................................................................................... 26
`The Cabilly II and Cabilly III Patents Adequately Disclose Sources
`1.
`for Obtaining the DNA Sequences of an Antibody Capable of
`Binding a Known or Desired Antigen ........................................... 27
`
`D.
`
`
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`

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`
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`E.
`
`F.
`
`G.
`
`2.
`
`3.
`
`4.
`
`The Cabilly II and Cabilly III Patents Sufficiently Describe How to
`Isolate the mRNA Encoding a Human Antibody that Binds to a
`Known Antigen .............................................................................. 32
`The Cabilly II and Cabilly III Patents Sufficiently Describe How to
`Isolate the mRNA Encoding a Human Antibody that Binds to a
`Desired Antigen ............................................................................. 40
`Phage Display, PCR, and Recombinant Mouse Technology Are
`Not Required to Make a Recombinant Human Antibody That
`Binds to a Known or Desired Antigen ........................................... 42
`The Cabilly II and Cabilly III Patent Show Possession of How to
`Make a Recombinant Human Antibody that Contains the DNA
`Sequence of an Antibody that Binds to a Known or Desired
`Antigen ...................................................................................................... 45
`The Cabilly II and Cabilly III Patents Adequately Describe and
`Enable How to Make a Recombinant Antibody Having a Variable
`Region ........................................................................................................ 46
`The Cabilly II and Cabilly III Patents Adequately Describe and
`Enable How to Make the Full Scope of Recombinant Antibodies ............ 48
`
`XII. CONCLUSION ...................................................................................................... 53
`
`
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`I.
`
`INTRODUCTION
`
`1.
`
`I submit this expert report, pursuant to Federal Rule of Civil Procedure
`
`26(a)(2), on behalf of the defendants, Genentech, Inc. and City of Hope. I expect to
`
`testify at trial concerning the matters set forth in this report.
`
`2.
`
`If called to testify, I may also explain principles and terminology referred
`
`and alluded to in this report as well as the documents referenced herein. I have not
`
`prepared at this time any exhibits that I expect to use to illustrate or summarize my
`
`testimony at trial.
`
`3.
`
`However, I expect to refer to some or all of the information set forth
`
`below, and I will prepare any exhibits in accordance with the Court’s orders. I also
`
`reserve the right to modify, amend and/or supplement the opinions expressed herein –
`
`particularly in response to any additional information cited by or opinions offered on
`
`behalf of Lilly or BMS.
`
`II.
`
`PROFESSIONAL EXPERIENCE AND QUALIFICATIONS
`
`4.
`
`I am the John W. Wolfe Chair in Human Cancer Genetics; Professor and
`
`Chairman of the Department of Molecular Virology, Immunology and Medical Genetics;
`
`Professor of Medicine; and Director of the Institute of Genetics and of the Human Cancer
`
`Genetics Program at Ohio State University in Columbus, OH.
`
`5.
`
`My expertise is in the field of genetic mechanisms implicated in the
`
`pathogenesis of human cancer. Research performed in my laboratory has resulted in
`
`several significant scientific discoveries, including: a) demonstrating the juxtaposition of
`
`the human immunoglobulin genes to the myc oncogene and the deregulation of myc in
`
`Burkitt’s lymphoma; and b) the discovery of the ALL1 gene (involved in acute
`
`leukemias) and the TLC 1 gene (associated with T-cell leukemias). My laboratory was
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`also the first to clone and characterize the Bc12 gene which is involved in follicular
`
`lymphoma and many other malignancies.
`
`6.
`
`My research also focuses on the early events involved in the pathogenesis
`
`of lung, nasopharyngeal, head and neck, esophageal, gastro-intestinal and breast cancers.
`
`Recently, my laboratory discovered the involvement of microRNA genes in human
`
`cancer.
`
`7.
`
`I received my M.D. degree, summa cum laude, from the University of
`
`Rome in 1969. I joined the faculty of the Wistar Institute in Philadelphia, Pennsylvania
`
`in 1970 and became a Professor in 1976. From 1980 to 1991, I was an Institute Professor
`
`and Associate Director at the Wistar Institute, and from 1980 to 1988 I was the Wistar
`
`Professor of Human Genetics at the University of Pennsylvania School of Medicine.
`
`8.
`
`From 1988 to 1991, I also held the following positions at Temple
`
`University: a) Professor in the Departments of Pathology and Medicine at the School of
`
`Medicine; b) Chairman of the Graduate Program in Molecular Biology and Genetics, at
`
`the School of Medicine; and c) Director of the Fels Institute for Cancer Research and
`
`Molecular Biology.
`
`9.
`
`From 1991-2004, I was the Director of the Kimmel Cancer
`
`Institute/Kimmel Cancer Center, and the Pugh Professor within and Chairman of the
`
`Department of Microbiology/Immunology at Jefferson Medical College of the Thomas
`
`Jefferson University, Philadelphia, Pennsylvania.
`
`10.
`
`During the span of my career I have received over 20 awards from various
`
`institutions and foundations for cancer research, including: a) the Outstanding
`
`Investigator Award, from the National Cancer Institute of the National Institutes of
`
`
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`2
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`Health (1985 and 1992); b) the Leukemia Lifetime Achievement Award (1992); c) the
`
`GM Cancer Foundation Mott Prize (1993); d) the John Scott Award (1992); e) the
`
`Pasarow Foundation Cancer Award (1994); f) the Pezcoller International Award for
`
`Cancer Research, from the American Association for Cancer Research (1999); g) the
`
`H.A. Clowes Memorial Award, from the American Association for Cancer Research
`
`(2006); h) The Henry M. Stratton Medal, American Society of Hematology (2007); i) the
`
`Albert Szent-Gyôrgyi Prize (2008); j) the ARC Leopold Griffuel Prize for a Major
`
`Breakthrough in the Field of Cancer (2008); k) The Ernst W. Berthner Memorial Award
`
`(2010); and l) the Health Prize of the Fund InBev-Baillet Latour (2013).
`
`11.
`
`In 1996, I was elected a member of the National Academy of Sciences,
`
`USA. I have also been elected to the American Academy of Arts and Sciences, the
`
`American Association of Physicians, the Institute of Medicine, and the National
`
`Academy of Inventors.
`
`12.
`
`I have also received the following awards and appointments: a) the
`
`Clavius Award for Achievement in Science and Research (2001); b) the Italian Gold
`
`Medal for Public Health and the President of the Republic Prize, Accademia di Lincei,
`
`both of which were presented by President Ciampi (2003); c) election as a Foreign
`
`Member of the Accademia Nazionale delle Scienze, della dei XL (2003); and d) Premio
`
`Beccaria, A. Serra Foundation for Cancer Research (2004).
`
`13.
`
`In 2000, I was the recipient of an honorary doctorate in Medicine from the
`
`Uppsala University in Sweden and the recipient of the Honor of Merit of the Italian
`
`Republic.
`
`
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`14.
`
`I have served on the editorial boards of Cancer Research (Editor-in-Chief,
`
`1990-1999) and the British Journal of Cancer (Subject Editor — Genetics and Genomics,
`
`2001-2003).
`
`15.
`
`Over my career, I have been a member of various scientific organizations.
`
`From 1983 to 1986, I was a member of the American Cancer Society Advisory
`
`Committee on Cell and Developmental Biology. From 1985 to 1989, I was a member of
`
`the National Cancer Institute Advisory Committee of the Frederick Cancer Research
`
`Facility. From 1991 to 1995, I was a member of the Board of Scientific Counselors,
`
`Division of Cancer Treatment, at the National Cancer Institute. From 1998 to 2000, I
`
`was a member of the National Advisory Board, Environmental Health Sciences Council
`
`of the National Institutes of Health.
`
`16.
`
`Currently, I am a member of The Human Genome Organization (HUGO),
`
`the American Association for Cancer Research, the American Society for Microbiology,
`
`the American Association for the Advancement of Science and the American Society of
`
`Hematology.
`
`17.
`
`Over the course of my career I have trained approximately 35 doctoral
`
`students and more than 200 post-doctoral fellows in immunology, molecular biology and
`
`related fields.
`
`18.
`
`I have over 1,000 research publications and have given over 500 invited
`
`and contributed presentations.
`
`19.
`
`A copy of my curriculum vitae is attached as Exhibit A.
`
`III.
`
`PRIOR TESTIMONY
`
`20.
`
` I testified on July 8, 2010, in Centocor Ortho Biotech, Inc. v. Genentech,
`
`Inc., 2:08-cv-03573-MRP -JEM (C.D. Cal.) and on January 6, 2012 in Glaxo Group Ltd.
`
`
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`
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`v. Genentech, Inc., 2:10-cv-02764-MRP-FMOx (C.D. Cal.). I also provided expert
`
`reports in those cases and in MedImmune, Inc. v. Genentech, Inc., 2:03-cv-02567 (C.D.
`
`Cal.).
`
`IV. COMPENSATION
`
`21.
`
`I am being compensated for my work in connection with this litigation at
`
`my customary rate of $2000 per hour. My compensation is in no way dependent on the
`
`outcome of this litigation.
`
`V. MATERIALS CONSIDERED
`
`22.
`
`The materials I have considered in connection with the opinions expressed
`
`in this expert report are listed in Exhibit B.
`
`VI. QUESTIONS PRESENTED
`
`23.
`
`I have been asked to describe the state of the art of antibody production as
`
`of April 1983 and to discuss my own work at the intersection of molecular biology,
`
`immunology and medicine, my interest in the late 1970s and early 1980s in producing
`
`antibodies commercially and my personal reaction when I learned of Cabilly et al.’s
`
`recombinant approach to antibody production. The inventions recited in claims of the
`
`Cabilly II patent (U.S. Patent No. 6,331,415) and Cabilly III patent (U.S. Patent No.
`
`7,923,221) had not occurred to me in 1983, even though I had had a keen interest in
`
`producing antibodies since the mid 1970s.
`
`24.
`
`BMS’s technical expert, Dr. Paolo Casali, has opined that the Cabilly II
`
`patent and the Cabilly III patent do not enable or show possession of a method for
`
`recombinantly producing a human antibody that is capable of binding to a known antigen.
`
`Dr. Casali has also opined that the Cabilly II patent and the Cabilly III patent do not
`
`enable or show possession of a method for recombinantly producing a human antibody
`
`
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`
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`that has specificity for a desired antigen. Dr. Casali further opines that the
`
`Cabilly II patent and the Cabilly III patent do not enable or show possession of a method
`
`for recombinantly producing an immunoglobulin having variable regions for any species,
`
`including humans, for any known antigen. For the reasons discussed below, I believe
`
`that the Cabilly II patent and Cabilly III patent sufficiently enabled a person of ordinary
`
`skill in the art in 1983 to recombinantly produce a human antibody that binds to a known
`
`antigen or to a desired antigen. I also believe that the Cabilly II patent and Cabilly III
`
`show possession of recombinantly producing such an antibody. Further, I believe that the
`
`Cabilly II patent and Cabilly III patent sufficiently enabled a person of ordinary skill in
`
`the art in 1983 to recombinantly produce an immunoglobulin having a variable region for
`
`a number of species, including humans, for any known antigen. I also believe that the
`
`Cabilly II patent and Cabilly III show possession of recombinantly producing such an
`
`antibody.
`
`25.
`
`Lilly’s technical expert, Sir Gregory Winter, also opines that the Cabilly II
`
`patent and the Cabilly III patent do not enable or show possession of a method for
`
`recombinantly producing a recombinant human antibody. Dr. Winter further opines that
`
`the Cabilly II patent and the Cabilly III patent do not enable or show possession of a
`
`method for recombinantly producing the full scope of immunoglobulins or fragments,
`
`including altered antibodies. For the reasons discussed below, I believe that the
`
`Cabilly II patent and Cabilly III patent sufficiently enabled a person of ordinary skill in
`
`the art in 1983 to recombinantly produce a human antibody. I also believe that the
`
`Cabilly II patent and Cabilly III show possession of recombinantly producing such an
`
`antibody. Further, I believe that the Cabilly II patent and Cabilly III patent sufficiently
`
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`enabled a person of ordinary skill in the art in 1983 to recombinantly produce the full
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`scope of immunoglobulins or fragments, including altered antibodies. I also believe that
`
`the Cabilly II patent and Cabilly III show possession of recombinantly producing such
`
`immunoglobulins.
`
`VII. SUMMARY OF OPINION
`
`26.
`
`It is my opinion that the Cabilly II patent and Cabilly III patent
`
`sufficiently enable a person of ordinary skill in the art in 1983 to make a recombinant
`
`antibody that binds to a known or desired antigen, including a recombinant human
`
`antibody that binds to a known or desired antigen (an antigen-specific, human antibody),
`
`because it teaches:
`
`•
`
`•
`
`•
`
`•
`
`different cell types (hybridomas and transformed B-cells) that can serve as
`
`a source for the DNA used to make such an antibody according to the
`
`claimed invention;
`
`specifically, in the disclosed experiments, how to make a recombinant,
`
`antigen-specific antibody using a hybridoma cell;
`
`that the techniques used to make the antibody disclosed in the experiments
`
`can be used to make a recombinant antigen-specific antibody that contains
`
`sequences from any mammal;
`
`that the claimed invention encompasses a wide variety of recombinant
`
`antibodies with changes to any region and including sequences from any
`
`mammal; and
`
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`•
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`the sourcing of human DNA immunoglobulin sequences from cell types
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`extant at the time that expressed antigen-specific, human antibodies at
`
`high levels for long periods.
`
`27.
`
`In addition, those methods that Dr. Casali and Dr. Winter identify as being
`
`required to make an antigen-specific, human monoclonal antibody are not required, and
`
`are merely later improvements on the method taught in the Cabilly II and Cabilly III
`
`patents. The now preferred methods for making therapeutic antibodies employ the
`
`teachings of the Cabilly II patent and Cabilly III patent.
`
`28.
`
`It is my opinion that the broad disclosures of the Cabilly II patent and
`
`Cabilly III patent show possession of recombinant methods for producing antigen
`
`specific antibodies from a variety of species, including humans.
`
`29.
`
`It is my opinion that the Cabilly II patent and Cabilly III patent
`
`sufficiently enable a person of ordinary skill in the art in 1983 to make a wide variety of
`
`recombinant antibodies, including chimeric antibodies and altered antibodies. It is also
`
`my opinion that the broad disclosures of the Cabilly II patent and Cabilly III patent show
`
`possession of recombinantly producing such recombinant antibodies.
`
`VIII. RELEVANT LAW
`
`A.
`
`30.
`
`35 U.S.C. § 112—Written Description and Enablement
`
`I have been informed that Title 35 of the United States Code contains the
`
`statutory patent laws of the United States. I understand that Section 112 of the statute
`
`mandates that certain disclosure requirements be met by applicants for United States
`
`patents and that failure to comply may result in the patent being held invalid by a court of
`
`law. I have been asked to read 35 U.S.C. § 112, which provides in relevant part:
`
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`The specification shall contain a written description of the
`invention, and of the manner and process of making and using it, in
`such full, clear, concise, and exact terms as to enable any person
`skilled in the art to which it pertains, or with which it is most
`nearly connected, to make and use the same[.]
`
`31.
`
`It has been explained to me that compliance with the foregoing
`
`requirements of 35 U.S.C. § 112 are judged based on the disclosure, and as of the filing
`
`date, of the application to which the patent claims priority — which, for both the
`
`Cabilly II patent and Cabilly III patent, is Application No. 06/483,457, filed April 8,
`
`1983.
`
`32.
`
`It has further been explained to me that compliance is assessed from the
`
`standpoint of a person of ordinary skill in the art and in accordance with how such
`
`person, as of the filing date, would understand the teachings of the application. My views
`
`on who the person of ordinary skill would have been in April 1983 are provided below.
`
`33.
`
`Similarly, I have provided my understanding of the Court’s interpretation
`
`of the claims and understand that “the invention” referenced in 35 U.S.C. § 112 means
`
`the invention recited in those claims.
`
`34.
`
`It has been explained to me that the written description requirement is
`
`satisfied if one of ordinary skill in the art at the time of the invention would have
`
`understood, from reading the disclosure of the patent in conjunction with their own
`
`knowledge, that the inventors were in possession of the full scope of the claimed
`
`invention.
`
`35.
`
`I have also been informed that the enablement requirement is satisfied if
`
`one of ordinary skill in the art would be able to practice the full scope of the claimed
`
`invention as of the filing date of the patent application, without undue experimentation. I
`
`understand that eight factors may be considered in determining whether undue
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`experimentation is required for a skilled person to practice the claimed invention. I
`
`understand that those factors are: (1) the quantity of experimentation necessary; (2) the
`
`amount of direction or guidance disclosed in the patent; (3) the presence or absence of
`
`working examples in the patent; (4) the nature of the invention; (5) the state of the prior
`
`art; (6) the relative skill of those in the art; (7) the predictability of the art; and (8) the
`
`breadth of the claim.
`
`IX.
`
`THE PERSON OF ORDINARY SKILL IN THE ART
`
`36. My opinions on the art and the level of skill a person of ordinary skill in
`
`the art would have had in April 1983 are as follows. The Cabilly II patent and Cabilly III
`
`patent relate to recombinant DNA techniques and their application to the design and
`
`production of immunoglobulins. In my opinion, the person of ordinary skill in the art of
`
`protein production by recombinant DNA methods in 1983 would have been an individual
`
`with a Ph.D. in molecular biology (or a comparable biological discipline) and 2-3 years
`
`of post-doctoral experience. In my view, the persons of ordinary skill in the art to which
`
`the Cabilly II patent and Cabilly III patent pertain were so-called “genetic engineers”
`
`interested in using recombinant DNA techniques to make proteins as end products. Such
`
`individuals would include scientists in industry interested in producing proteins, such as
`
`therapeutic proteins, as commercial products and academic scientists who needed to
`
`produce certain proteins for use in their research pursuits.
`
`37.
`
`He or she would have had a basic understanding of antibody structure and
`
`function and some knowledge of the cells involved in the immune response. However, I
`
`do not believe that the person of ordinary skill in the genetic engineering arts would have
`
`been an immunologist, nor a molecular biologist researching immunoglobulin genes,
`
`their regulation or other fundamental aspects of the immune response. Such investigators
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`would have focused on the mechanisms of antibody production and their regulation.
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`Producing antibodies as a protein product was not a pursuit of scientists focused on the
`
`immune response and its underlying genetics.
`
`X.
`
`THE MEANING OF THE CLAIMS OF THE CABILLY II AND III
`PATENTS
`
`38.
`
`Claim 15 of the Cabilly II patent states:
`
`A vector comprising a first DNA sequence encoding at least a
`variable domain of an immunoglobulin heavy chain and a second
`DNA sequence encoding at least a variable domain of an
`immunoglobulin light chain wherein said first DNA sequence and
`said second DNA sequence are located in said vector at different
`insertion sites.
`
`39.
`
`Claim 17 of the Cabilly II patent states:
`
`A host cell transformed with a vector according to claim 15.
`
`40.
`
`Claim 33 of the Cabilly II patent states:
`
`A process for producing an immunoglobulin molecule or an
`immunologically functional immunoglobulin fragment comprising
`at least the variable domains of the immunoglobulin heavy and
`light chains, in a single host cell, comprising:
`independently expressing a first DNA sequence encoding at least
`the variable domain of the immunoglobulin heavy chain and a
`second DNA sequence encoding at least the variable domain of the
`immunoglobulin light chain so that said immunoglobulin heavy
`and light chains are produced as separate molecules in said single
`host cell transformed with said first and second DNA sequences.
`
`41.
`
`Claim 15 of the Cabilly III patent states:
`
`A method for making an antibody or antibody fragment capable of
`specifically binding a desired antigen, wherein the antibody or
`antibody fragment comprises (a) an antibody heavy chain or
`fragment thereof comprising a human constant region sequence
`and a variable region comprising non human mammalian variable
`region sequences and (b) an antibody light chain or fragment
`thereof comprising a human constant region sequence and a
`variable region comprising non human mammalian variable region
`sequences, the method comprising coexpressing the heavy chain or
`
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`fragment thereof and the light chain or fragment thereof in a
`recombinant host cell.
`
`42.
`
`Claim 20 of the Cabilly III patent states:
`
`The method of claim 15 which results in the production of an
`antibody.
`
`43.
`
`Claim 25 of the Cabilly III patent states:
`
`A method for making an antibody heavy chain or fragment thereof
`and an antibody light chain or fragment thereof each having
`specificity for a desired antigen, wherein the heavy chain or
`fragment thereof comprises a variable region sequence and a
`human constant region sequence, the method comprising culturing
`a recombinant host cell comprising DNA encoding the heavy chain
`or fragment thereof and the light chain or fragment thereof and
`recovering the heavy chain or fragment thereof and light chain or
`fragment thereof from the host cell culture.
`
`44.
`
`Claim 27 of the Cabilly III patent states:
`
`The method of claim 25 wherein the host cell comprises a vector
`comprising DNA encoding the heavy chain or fragment thereof
`and DNA encoding the light chain or fragment thereof.
`
`45.
`
`Claim 31 of the Cabilly III patent states:
`
`The method of claim 25 wherein the host cell is a eukaryotic cell.
`
`46.
`
`Claim 32 of the Cabilly III patent states:
`
`The method of claim 31 wherein the eukaryotic cell is a
`mammalian cell.
`
`47.
`
`Claim 34 of the Cabilly III patent states:
`
`The method of claim 32 wherein the mammalian cell is a CHO
`cell.
`
`48.
`
`Claim 38 of the Cabilly III patent states:
`
`A method for making an antibody or antibody fragment capable of
`specifically binding a desired antigen, wherein the antibody or
`antibody fragment comprises (a) an antibody heavy chain or
`fragment thereof comprising a variable region sequence and a
`human constant region sequence and (b) an antibody light chain or
`
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`fragment thereof comprising a variable region sequence and a
`human constant region sequence, the method comprising
`coexpressing the heavy chain or fragment thereof and the light
`chain or fragment thereof in a recombinant host cell.
`
`49.
`
`Claim 43 of the Cabilly III patent states:
`
`The method of claim 38 which results in the production of an
`antibody.
`
`50.
`
`Claim 45 of the Cabilly III patent states:
`
`A replicable expression vector comprising DNA encoding an
`antibody heavy chain or fragment thereof and an antibody light
`chain or fragment thereof each having specificity for a desired
`antigen, the heavy chain or fragment thereof and the light chain or
`fragment thereof each comprising a variable region sequence and a
`human constant region sequence.
`
`51.
`
`Claim 46 of the Cabilly III patent states:
`
`A recombinant host cell comprising the vector of claim 45.
`
`52.
`
`For the method claims, I understand that claim 33 of the Cabilly II patent
`
`covers methods of making recombinant antibodies, including antibodies with human
`
`variable regions, human constant regions, or both.
`
`53.
`
`I understand that claims 27, 34, and 43 of the Cabilly III patent cover
`
`methods of making recombinant antibodies having a human constant region sequence,
`
`and a variable region sequence that includes human variable region sequences.
`
`54.
`
`I understand that claim 20 of the Cabilly III patent covers methods of
`
`making recombinant antibodies having a human constant region sequence, but the
`
`variable region sequence must be a non human mammalian variable region sequence.
`
`Therefore, I understand that Dr. Casali’s and Dr. Winter’s opinions regarding fully
`
`human antibodies, which contain a human variable region sequence, do not apply to
`
`claim 20.
`
`
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`55.
`
`I have read the Court’s April 18, 2014, Claim Construction Order and the
`
`parties’ January 21, 2014 Joint Claim Construction Statement and have been instructed to
`
`follow the constructions for the various claim terms in claims 15, 17 and 33 of the
`
`Cabilly II patent and claims 20, 27, 34, 43, and 46 of the Cabilly III Patent construed by
`
`the Court or agreed upon by the parties.
`
`56.
`
`For the other claim elements that the Court has not expressly defined or
`
`that the parties have not agreed to define, I understand that I am to apply the ordinary
`
`meaning that one of ordinary skill in the art would have assigned to these terms in April
`
`of 1983.
`
`XI. OPINION
`
`A.
`
`The State of the Art of Antibody Production in 1983 Was Focused on
`Approaches that Did Not Involve Recombinant DNA
`
`57.
`
`Antibodies, also called immunoglobulins, are proteins produced by cells
`
`of the immune system to fight foreign antigens by binding to portions of the antigen.
`
`Antibodies are generally Y-shaped molecules composed of four amino acid chains – two
`
`identical heavy chains and two light chains – chemically linked by disulfide bonds.1 The
`
`heavy chain is longer than the light chain and has a higher molecular weight. Each heavy
`
`and light chain is divided into a variable and a constant region. The constant region is
`
`fairly constant between antibodies and signals the immune system. The variable region
`
`varies significantly between different antibodies, and binds to the foreign antigen. The
`
`unique sequence of amino acids in the variable region is what gives each antibody its
`
`
`1 Antibodies can be of the form, or class, IgG, IgM, IgE, IgA, and IgD. Each of these
`forms contain the Y-shaped structure, but they exhibit other structural differences.
`
`
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`
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`specificity for a given antigen. Figure 1 of the Cabilly II patent is of an antibody
`
`annotated to show the heavy and light chains and the variable and constant regions.
`
`58.
`
`In my opinion, the invention of the Cabilly II patent and Cabilly III patent
`
`represents a significant departure from the techniques in use in April 1983 for making
`
`immunoglobulins and antibodies.
`
`59.
`
`In April 1983, one long-practiced approach to making antibodies was by
`
`immunization of an animal (typically, a mammal) with a foreign antigen and subsequent
`
`recovery of the polyclonal antisera. This approach was, and remains, in widespread use
`
`for laboratory research and other purposes, including diagnostics.
`
`60. When a mammal is exposed to a foreign antigen, the antigen induces an
`
`immune response in the mammalian immune system. This response includes a cell-
`
`mediated response and a humoral response. The latter involves the ability of the immune
`
`system to induce the B-lymphocytes in the organism to produce immunoglobulins that
`
`specifically recognize the antigen. Such immunoglobulins are called antibodies. They
`
`are secreted by the B-lymphocytes and are recoverable in the serum fraction of blood.
`
`61.
`
`Antibodies produced as part of the natural mammalian immune response
`
`are called “polyclonal antibodies” because they are secreted by different clonal
`
`populations of B-lymphocytes exposed to the same antigen. Polyclonal antibodies
`
`specific for the same antigen are not identical to one another. They vary as to the
`
`“epitopes” they recognize, i.e., the portions of the three-dimensional antigen molecule to
`
`which they specifically bind. They also vary with respect to the affinity (or strength)
`
`with which they bind to their respective epitopes.
`
`
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`62.
`
`Polyclonal antibodies are limited in their utility because of this lack of
`
`uniformity. While they still serve a purpose in certain laboratory and diagnostic
`
`applications, their heterogeneity can result in cross-reactivities that negatively impact
`
`many diagnostic and therapeutic applications.
`
`63.
`
`There was a major breakthrough in the art of antibody production in 1975:
`
`the invention of hybridoma technology by Georges Kohler and Cesar Milstein, for which
`
`they were subsequently awarded the Nobel Prize in Physiology and Medicine in 1984.
`
`This work appeared in Kohler’s and Milstein’s landmark paper, “Continuous cultures of
`
`fused cells secreting antibody of predefined specificity,” Nature, 256: 495-97 (1975). It
`
`demonstrated that a process of somatic cell fusion, specifically between a B-lymphocyte
`
`and a myeloma cell, could yield hybrid cells that can be expanded into a clonal
`
`population of cells or culture that produces a monoclonal antibody. The monoclonal
`
`antibodies produced by clonal hybridomas are all identical, that is, they all have the same
`
`protein sequence and bind to the same antigen.
`
`64.
`
`In their experiments, Kohler and Milstein injected mice with an antigen
`
`and then f