UNITED STATES DISTRICT COURT
`CENTRAL DISTRICT OF CALIFORNIA
`
`Case No. 2:l3—cv—07248-MRPJEMX
`
`ELI LILLY AND COMPANY, and
`IMCLONE SYSTEMS LLC,
`
`Plaintiffs,
`
`v.
`
`GENENTECH, INC. and CITY OF
`HOPE,
`
`Defendants.
`
`\-/\--/\-—J‘~—/\-—l\-../‘-—-r'\-_/\._/\—/
`
`EXPERT REPORT OF SIR GREGORY WINTER, CBE, FRS
`REGARDING INVALIDITY OF U.S. PATENT NOS. 6 31 415 AND 7 923 21
`
`Mylan v. Genentech
`Mylan v. Genentech
`IPR2016-00710
`Genentech Exhibit 2023
`
`
`
`IPR2016-00710
`
`Genentech Exhibit 2023
`
`
`
`

`

`TABLE OF CONTENTS
`
`Introduction ............................................................................................................ ..
`
`............l
`
`Education and Professional Accomplishments ...................................................... ..
`
`Prior Testimony ..................................................................................................... ..
`
`Compensation ........................................................................................................ ..
`
`.......... ..l
`
`.......... ..3
`
`.......... ..4
`
`4 4
`
`MaterialsConsidered
`
`Person ofOrdinary Skill in the
`
`Law of Written Description, Enablement And Double Patenting ......................... ..
`
`.......... ..4
`
`Summary ofMyOpinions
`
`7
`
`.<
`
`VI.
`
`VII.
`
`VIII.
`
`IX.
`
`The Claimsat
`
`11
`
`Producing Imrnunoglobulins Assembled In Vivo in Mammalian Cells Was
`Unpredictable Given the Immature State ofthe Art in April
`
`A.
`
`B.
`
`C.
`
`D.
`
`Correct Propottions of Heavy and Light Chain Polypeptides
`
`Regulatory Elements .................................................................................. ..
`
`Signal Sequences ....................................................................................... ..
`
`The Cabilly Patents Do Not Describe or Enable Vectors, Host Cells, or
`Methods for Producing lmmunoglobulins Assembled In Vivo in
`Mammalian
`
`The Cabilly Patents Do Not Describe or Enable Vectors, Host Cells, or
`Methods for Producing the Full Scope of Immunoglobulins or Fragments
`
`l 7
`
`24
`
`25
`
`26
`
`28
`
`. . - o . . . . .-
`
`.29
`
`.33
`
`The Cabilly Patents Do Not Describe or Enable Vectors, Host Cells, or
`Methods for Producing Fully Human Immunoglobnlins..................................................
`
`.36
`
`A.
`
`Human Antibodies Are Produced by Phage Display!Antibody
`Repertoire Technology or Transgenic Mouse Technology
`
`.40
`
`The Cabilly Patents Do Not Describe or Enable Vectors, Host Cells, or
`Methods for Producing IgA or IgM Immunoglobulins.....................................................
`
`.44
`
`XI.
`
`XII.
`
`XIII.
`
`XIV.
`
`

`

`XV.
`
`The Assorted Cabilly II and Ill Claims Are Invalid for Double Patenting ........................46
`
`A.
`
`B.
`
`Cabilly I Claims 1 and 2 Cover Three Transformation Options...........................
`
`Cabilly ll Claim 33 Is Not Patentably Distinct from Cabilly I
`Claim 1 ....................................................................................................... ..
`
`Cabilly III Claims 20, 27, and 43 Are Not Patentably Distinct fi'om
`Cabilly I Claim
`_
`..
`
`Cabilly [Claim 6 Covers Three Transformation Options
`
`Cabilly II Claim 15 Is Not Pate-ntably Distinct From Cabilly I
`Claim
`
`Cabilly I Claim 7 Covers Thrcc Transfonnation Options
`
`Cabilly [1 Claim 17 Is Not Patentably Distinct From Cabilly 1
`Claim
`
`Cabilly Ill Claim 46 Is Not Patcntably Distinct From Cabilly I
`Claim
`
`.47
`
`49
`
`54
`
`.54
`
`.56
`
`XVI.
`
`Conclusion
`
`56
`
`

`

`I.
`
`Introduction
`
`].
`
`I have been retained by Eli Lilly and Company and ImClone Systems LLC
`
`(collectively, “Lilly”), to provide expert opinions and testimony concerning the invalidity of U.S.
`
`Patent Nos. 6,331,415 to Cabilly et al. (“the ’4l5 Patent” or “Cabilly II”) and 7,923,221 to
`
`Cabilly et at. (“the ’221 Patent” or “Cabilly III”) (together, “the Cabilly Patents”)-'
`
`2.
`
`I understand that I am submitting this expert report pursuant to United States
`
`Federal Rule of Civil Procedure 26(a){2). If I am called upon to testify at trial, I expect to testify
`
`about the matters and opinions set forth in this report.
`
`3.
`
`I may also present a tutorial to thejudge andforjury concerning the terminology
`
`used in my report and the scientific principles underlying my analyses and opinions.
`
`4.
`
`I understand that Genentech and City of Hope (collectively, “Genentech”) may
`
`submit a rebuttal to my report through its own experts, and that additional discovery may take
`
`place in this case. With that in mind, I may need to supplement or amend my report and my
`
`expected testimony after I have reviewed these additional materials.
`
`I also expect to reply as
`
`needed to any positions, theories, or evidence advanced by Genentech or its experts in their
`
`rebuttals.
`
`II.
`
`Education and Professional Accomplishments
`
`5.
`
`A copy of my current curriculum vitae is attached to my report as Exhibit A.
`
`Below I briefly summarize some of my relevant experience and accomplishments.
`
`I I understand that another Cabilly Patent, U.S. Patent No. 4,816,567 (“Cabilly I”) is now
`expired. Because I understand that all the Cabilly Patents share the same specification apart
`from their claims, I generally refer to Cabilly II and Cabilly Ill collectively as the “Cabilly
`Patents,” and refer to the patents individually only where necessary. For convenience, all
`citations to column and line numbers refer to the Cabilly ll specification.
`
`

`

`6.
`
`I am cunently the Master of Trinity College, University of Cambridge.
`
`I was
`
`previously the Deputy Director of the Laboratory of Molecular Biology, Cambridge, and of the
`
`Centre for Protein Engineering, Cambridge, institutions funded by the UK Medical Research
`
`Council. I have spent my career establishing and working in the field of therapeutic monoclonal
`
`antibodies.
`
`‘.7.
`
`In terms of my professional background, a brief chronology is as follows: I was
`
`awarded a B.A. degree in Natural Sciences at Trinity College, Cambridge University, in 1933.
`
`In 1976, I was awarded a Ph.D., also from Cambridge University.
`
`8.
`
`I was a postdoctoral research fellow at Imperial College, London, fi'om 1976 to
`
`197?.
`
`I was a postdoctoral research fellow at the Laboratory of Molecular Biology (“LMB”) of
`
`the U.K. Medical Research Council (“MRC”), Cambridge, from 1977 to 1980.
`
`I have been a
`
`member of the scientific staff at the LMB since I981 and served as the Deputy Director from
`
`2006 to 201 1.
`
`9.
`
`From 1990 to 2010, I was the Deputy Director ofthe Cambridge Centre for
`
`Protein Engineering. During part of that time (1994-2003), I was Joint Head of Division of
`
`Protein and Nucleic Acid Chemistry at the LMB. Throughout most of that time, I was also a
`
`Senior Research Fellow ofTrinity College (1991-2012). In 2012, I became Master ofTrinity
`
`College.
`
`10.
`
`In 1986, I invented methods to humanize mouse monoclonal antibodies,
`
`commonly called CDR grafting. In the period 1989 to 1991, I invented methods for making fully
`
`human recombinant antibodies by antibody phage display technology using combinatorial gene
`
`rcpertoires.
`
`

`

`I 1.
`
`During the course ofmy career I have received several awards, including the
`
`Novo Biotechnology Award, Denmark, 1986; the Emil von Behring Prize, Federal Republic of
`
`Germany, 1989; the Louis Jeantet Prize for Medicine, Switzerland, 1989; the Scheele Award of
`
`the Swedish Academy of Pharmaceutical Sciences, 1994; the King Faisal International Prize in
`
`Medicine, Saudi Arabia, 1995; the William B. Coley Award, Cancer Research Institute, USA,
`
`1999; the Baly Medal of the Royal College of Physicians, 2005; the Biochemical Society Award,
`
`2006; and the Royal Medal of the Royal Society in 20] 1.
`
`In 2013, I received the Canada
`
`Gairdner International Award for the engineering of humanized monoclonal antibodies and their
`
`widespread use in medical therapy, particularly for treatment of cancer and immune disorders.
`
`12.
`
`In 199?, I received the honor of “Commander of the Order of the British Empire,”
`
`and in 2004 the honor of “Knight Bachelor,” each from Her Majesty the Queen for services to
`
`science.
`
`13.
`
`I have also founded three biotechnology companies: Cambridge Antibody
`
`Technology (1989), Domantis (2000), and Bicycle Therapeutics (2009). Cambridge Antibody
`
`Technology and Domantis both pioneered the use of antibody repertoire technologies to develop
`
`fully human antibody therapeutics. Bicycle Therapeutics is focusing on the development of
`
`bicyclic peptides as small antibody mimics.
`
`In 2006, Cambridge Antibody Technology was
`
`acquired by Astrazeneca, and Domantis was acquired by GlaxoSmithKline-
`
`14.
`
`As shown in Exhibit B, I have authored nearly 200 peer-reviewed papers.
`
`I have
`
`also presented on numerous occasions as an invited lecturer, and am an inventor on numerous
`
`patents issued in the United States and other countries.
`
`III.
`
`Prior Testimony
`
`15.
`
`I have not testified as an expert at deposition or trial in the past four years.
`
`

`

`IV.
`
`Compensation
`
`16.
`
`I am being compensated for my work in connection with this litigation at my
`
`customary consulting rate of $5,000 per day for work done in the UK, and at the rate of $10,000
`
`per day for work that requires me to travel to the United States. My compensation is not
`
`dependent on the outcome of this litigation.
`
`V.
`
`Materials Considered
`
`17.
`
`In teaching my opinions, I considered the materials identified in Exhibit C
`
`(“Materials Considered”).
`
`VI.
`
`Person of Ordinary Skill in the Art
`
`18.
`
`For purposes of this report, I define a person of ordinary skill in the relevant art
`
`(“POSA”) to be an individual with a Ph.D. degree in molecular biology or a related discipline,
`
`such as biochemistry or immunology, and having at least 1-2 years of postdoctoral experience.
`
`The POSA would also have experience in protein chemistry, recombinant DNA technology, and
`
`the expression of recombinant proteins. The POSA would also have knowledge of the protein
`
`structure of antibodies and their genes. This opinion is based on the level of education and
`
`experience of persons working in the field of recombinant DNA technology as of April 1983 (the
`
`date I have been informed is the priority date of the Cabilly Patents).
`
`VII.
`
`Law of Written Description, Enablement And Double Patenting
`
`I9.
`
`Counsel has informed me of certain relevant legal principles that impact whether
`
`the claims ofa patent are valid.
`
`20.
`
`It has been explained to me that for a patent to be valid: (a) the specification must
`
`provide adequate written description of the invention (the “written description requirement”);
`
`

`

`and (b) the specification must explain how to make and use the invention, in such full, clear,
`
`concise, and exact terms to enable a POSA to carry out the invention (the “enablernent
`
`requirement”).
`
`21.
`
`I understand the written description requirement is satisfied when the patent
`
`describes each and every limitation of a patent claim with reasonable clarity so that a POSA at
`
`the time of the invention would understand that the inventors were in possession of the fiill scope
`
`of the claimed invention as of the filing date of the patent- In other words, the specification must
`
`clearly allow a POSA to recognize that the inventors invented what is claimed.
`
`22. Whether a patent complies with the written description requirement varies
`
`depending on the nature and Scope of the claims, the existing knowledge in the particular field,
`
`the extent and content of the prior art, the maturity of the science or technology, and the
`
`predictability of the aspect at issue.
`
`23.
`
`I understand that the enablement requirement is satisfied when a POSA at the
`
`time of the invention would be able to practice the full scope of the claimed invention without
`
`undue experimentation.
`
`I understand a permissible amount of experimentation to be an amount
`
`appropriate for the complexity of the field of the invention, and for the level of expertise and
`
`knowledge of persons skilled in that field.
`
`I also understand that enablement is tested as of the
`
`date the patent application was filed.
`
`24.
`
`l have been informed that the following factors may be considered when
`
`determining whether undue experimentation would be necessary for a POSA to practice the
`
`claimed invention: (1) the breadth ofthe claims; (2) the nature ofthe invention; (3) the state of
`
`the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the
`
`amount of direction provided by the inventor; (7) the existence of working examples; and (8) the
`
`

`

`quantity of experimentation needed to make or use the invention based on the content of the
`
`disclosure.
`
`25.
`
`I further understand that a patent does not need to expressly state information
`
`known to or obtainable by a POSA at the time of the invention, but that such supplementation
`
`cannot cure the patent’s failure to provide information necessary to practice the full scope of the
`
`claimed invention, particularly in an emerging field.
`
`26.
`
`Finally, it has been explained to me that the doctrine of double patenting prevents
`
`an inventor from obtaining more than one patent term on one invention. I understand that a
`
`patent claim is invalid for “obviousness-type double patenting” if it is not patentably distinct
`
`from the subject matter claimed in an earlier commonly owned patent.
`
`I am informed that a
`
`claim in a later patent is not patentably distinct from a claim in an earlier patent if the later claim
`
`is anticipated by, or obvious over, the earlier claim.
`
`2?.
`
`It has also been explained to me that there are two steps to an obviousness~type
`
`double patenting analysis. First, I understand that the earlier and later claims should be
`
`interpreted as they would be understood by a POSA to determine their scope, and that claims
`
`should be interpreted in light of the specification of which they are a part. Second, I understand
`
`that the differences between the coverage of the earlier and later claims should be determined in
`
`order to establish whether the later claim is patentably distinct from the earlier claim.
`
`I have
`
`adopted this analysis in forming my opinions.
`
`28.
`
`It has further been explained to me that anticipation exists if the earlier claim
`
`describes every element of the later claim. And I am informed that an earlier generic claim
`
`(covering a limited set of options) anticipates a later claim to one or more of those options if a
`
`

`

`POSA would “at once envisage,” !'.e., would have before him or her, the limited set of options
`
`covered by the earlier claim.
`
`VIII. Summag of My Opinions
`
`29.
`
`Based on my review of the materials identified in Exhibit C, together with my
`
`background and experience, it is my opinion that:
`
`30.
`
`The claims of the Cabilly Patents are extremely broad.
`
`I understand the method
`
`claims cover the production of any recombinantly-produced imrnunoglobulinz of any type,
`
`whether assembled in vitro or in vivo, in any type of host cell.
`
`l fiirther understand the product
`
`claims cover vectors comprising DNA encoding any immunoglobulin of any type, or any host
`
`cell comprising such a vector. However, I do not believe the Cabilly Patents describe the full
`
`scope of the claims. By contrast with the claims, the disclosure of the Cabilly specification is
`
`narrow; the only experimental data in the specification relates to the expression of IgG heavy and
`
`light chains in E. coli in an insoluble form and the attempted assembly ofthose two chains in
`
`virro using denaturing chemicals and sulfl1ydryl reagents.
`
`31.
`
`The Cabilly Patents do not provide sufficient written description to demonstrate
`
`with reasonable clarity to a POSA in April 1983 that the inventors were in possession of the
`
`extremely broad scope of vectors, host cells, and methods for making immunoglobulins that the
`
`claims cover. Nor would a POSA in April 1983 have been taught how to make the broad scope
`
`of vectors and host cells, or practice the full scope of the claimed methods for making
`
`immunoglobulins, without undue experimentation. This is especially true because the field of
`
`2 For convenience, in this report I will use the word “imrnunoglobulin” to mean assembled
`imrnunoglobulins and fragments thereof, and assembled antibodies and fragments thereof, unless
`there is a reason to use more specific terminology.
`
`

`

`heterologous protein expression (the expression of a protein in cells that do not normally express
`
`the protein) was an emerging and unpredictable field in April 1983, and the Cabilly Patents
`
`provide little or no disclosure. In particular, there are no working or predictive examples
`
`regarding the expression and assembly in viva of immunoglobulins in mammalian cells.
`
`32.
`
`For the purposes ofthis report, I focus my opinions on the issue of expression and
`
`assembly in vivo in mammalian cells.
`
`I am informed that another expert will opine on the issues
`
`of expression and assembly in vivo in bacteria.3 In nature, immunoglobulins are produced in
`
`mammalian lymphoid cells (i.e., cells produced by the immune system) called B cells. As of
`
`April 1933, however, there were several issues that would have been important when considering
`
`the possibility (or impossibility) of expression and assembly of recombinant immunoglobulins in
`
`mammalian cells, including the roles of chaperone proteins, promoters or other regulatory
`
`sequences, and signal sequences. Most of these issues are hardly discussed in the Cabilly
`
`Patents. Given the limited understanding and unpredictability of the field, and the absence of
`
`detailed guidance or a working example in the Cabilly Patents, a POSA in April 1983 would not
`
`have reasonably concluded that the inventors were in possession of vectors, host cells, or
`
`methods for producing immunoglobulins, assembled in vivo, in non- lymphoid mammalian cells.
`
`Additionally, a POSA would not have been taught how to make them or practice those methods
`
`without undue experimentation.
`
`3 I note that functional imrnunoglobulin andior irnmunoglobulin fragment assembly and secretion
`were not published until 1988 in E. coli and yeast, and until 1989 in plants.
`($l<erra, A. &
`Plitckthun, A., Assembly ofafimctiona! immzmogiobulin F12fiagmenr in Escherichia cofi, 240
`SCIENCE I038 (l938); Better, M., er al., Escherichia coli secretion of an active chinicric
`antiboajrfragmeni, 240 SCIENCE 1041 (1983); I-lorwitz, A.H., er ml, Secretion offunctional
`antibody and Fabfiagmemfiom yeast ceiis, 85 PROC. NAT’L. ACAD. SCI. USA 8678 (1988);
`Hiatt, A., at al., Production ofantibodies in transgemb plants, 342 NATURE 76 ( l989).)
`
`

`

`33.
`
`Furthermore, while the Cabilly Patents encompass several immunoglobulin types
`3) CS
`
`and imrnunoglobulin fragments, including “rnamntalian antibodies,
`
`composite
`
`immunoglobulins,” “hybrid antibodies,” “chimeric antibodies,” “univalent antibodies,” and “Fab
`
`protein,” most of these are described only in fimctional terms, with no structural information, and
`
`little or no guidance is provided regarding how to make these types of immunoglobulins and
`
`immunoglobulin fragments. A POSA in April 1983 would thus not have believed that the
`
`Cabilly inventors were in possession of these different immunoglobulin types and
`
`irnmunoglobulin fragments, and would not have been taught how to make them without undue
`
`experimentation.
`
`In particular, although encompassed by the claims, the Cabilly Patents do not
`
`describe and did not provide a specific and useful teaching to a POSA in April 1983 on how to
`
`make humanized and fully human antibodies, both of which were only made possible by
`
`inventions made after the Cabilly Patents were filed. My own group was responsible for the
`
`invention of humanized antibodies, and (in combination with the group of Richard Lerner) was
`
`also responsible for one of the two major methods for making fully human antibodies, namely,
`
`“phage display/antibody repertoire technology.”
`
`34.
`
`Finally, though the claims of the Cabilly Patents also encompass IgA and IgM
`
`immunoglobulins, the patents ignore that IgA and IgM itnmunoglobulins were known by April
`
`1983 to be assembled as higher—order multimeric structures that contain a third polypeptide
`
`chain, the “J chain,” in addition to the heavy and light chains. However, nothing in the Cabilly
`
`Patents would have either convinced a POSA in April 1983 that the inventors were in possession
`
`of vectors, host cells, or methods of making assembled lgA or IgM immunoglobulins, or taught a
`
`POSA how to make such immunoglobulins without undue experimentation.
`
`

`

`35.
`
`It is also my opinion that the asserted claims of the later Cabilly I1 and III patents
`
`are not patentably distinct from claims 1, 2, 6, and 7 ofthe earlier Cabilly I patent.
`
`36.
`
`First, it is my opinion that Cabilly ll process claim 33 and Cabilly III method
`
`claims 20, 27, and 43 are not patentably distinct from method claims I and 2 ofCabilly I.
`
`Cabilly 1 method claim 1 covers a method for making a chimeric imrnunoglobuiin that includes
`
`all three of the transformation options set forth in the patent: (i) transforming separate host cells
`
`with separate vectors each containing either a heavy or light chain DNA sequence, (ii)
`
`transforming a single host cell with separate vectors each containiug either a heavy or light chain
`
`DNA sequence, and (iii) transforming a single host cell with a single vector containing both
`
`heavy and light chain DNA sequences. (Col. 12, lines 24-30.) A POSA would at once envisage
`
`this limited number of options from the claim language, when interpreted in light of the
`
`specification. Cabilly ll process claim 33 and Cabilly III method claims 20, 27, and 43 cover a
`
`method for making a chimeric immunoglobulin (Cabilly II process claim 33) or a chimeric
`
`antibody (Cabilly III method claims 20, 27, and 43) using one or two ofthese same three
`
`transformation options. Therefore, the later claims are anticipated by the earlier claims, and,
`
`thus, are not patentably distinct from the earlier claims.
`
`37.
`
`Second, it is my opinion that Cabilly ll vector claim 15 is not patentably distinct
`
`from Cabilly I vector claim 6. Because Cabilly I vector claim 6 covers vectors that can be used
`
`for all three of the transformation options disclosed in the Cabilly Patents (listed above), a POSA
`
`would at once envisage this limited number of options from the claim language, when interpreted
`
`in light of the specification. Cabilly II vector claim 15 covers a vector that can be used for the
`
`third transformation option, namely, transforming a single host cell with a single vector
`
`-10-
`
`

`

`containing both heavy and light chain DNA sequences. Therefore, the later claim is anticipated
`
`by the earlier claim, and thus is not patentably distinct from the earlier claim.
`
`38.
`
`Third, it is filrther my opinion that Cahilly II host cell claim 1'? and Cabilly III
`
`host cell claim 46 are not patentably distinct fi'oIn Cabilly I host cell claim 7. Because Cabilly I
`
`host cell claim 7 covers a host cell transformed according to all three of the transformation
`
`options disclosed in the Cabilly Patents, a POSA would at once envisage this limited number of
`
`options from the claim language, when interpreted in light of the specification. Cabilly II host
`
`cell claim I? and Cabilly III host cell ciaim 46 cover a host cell transformed according to the
`
`third of the three transformation options. Therefore, the later claims are anticipated by the earlier
`
`claim and thus, are not patentably distinct from the earlier claim.
`
`IX.
`
`The Claims at Issue
`
`39.
`
`I understand that claims 15, 1?, and 33 ofCabilIy II are at issue in this case.
`
`Those claims read as follows:
`
`15. 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.
`
`17. A host cell transformed with a vector according to claim 15.
`
`33. A process for producing an imrnunoglobulin molecule or an
`immunologically fimctional 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
`
`-1]-
`
`

`

`as separate molecules in said single host cell transformed
`
`with said first and second DNA sequences.
`
`40.
`
`I understand that claims 20, 2?, 43, and 46 ofCabilly III are at issue in this case.
`
`Those claims read as follows (including independent claims as necessary for clarity):
`
`15. 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 coexprcssing the heavy
`chain or fragment thereof and the light chain or fragment thereof in
`a recombinant host cell.
`
`20. The method of claim IS which results in the production of an
`antibody.
`
`25. 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.
`
`2?. 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.
`
`38. 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 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.
`
`-12-
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`

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`43. The method of claim 38 which results in the production of an
`antibody.
`
`45. 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.
`
`46. A recombinant host cell comprising the vector of claim 45.
`
`41.
`
`I have been informed that the terms “antibody” and “immunoglobulin” have not
`
`been construed by the Court. (Claim Construction Order (“CC Ord.”), D.I. 158, at 2 n.1.)
`
`Therefore, my understanding of those terms for the purpose of rendering my opinions here is
`
`based on the definitions presented in the Cabilly Patents at col. 6, lines 3-] 1. That is, “antibody”
`
`means a tetrameric assembly, comprising light and heavy polypeptide chains, which has specific
`
`immunoreactive activity (i.e., specifically binds a particular antigen), or multimeric aggregates
`
`thereof. (Col. 6, lines 3—7.) “lmmunoglobulin” means a tetrameric assembly, comprising light
`
`and heavy polypeptide chains, whether or not specific immunoreactive activity is a property, or
`
`multimeric aggregates thereof. (Col. 6, lines 7-1 1.) “Antibodies” are thus a subset of
`
`“immunoglobulins.”
`
`42.
`
`Claim 33 ofCabilly ll claims “[a] process for producing an immunoglobulin
`
`molecule or an immunologically functional immunoglobulin fragment” and thus requires that
`
`practicing the claimed process results in the formation of an assembled immunoglobulin or
`
`fragment thereof.
`
`I have been informed that during prosecution, Genentech stated that the
`
`Cabilly II claims, including claim 33, require assembly. (CC 0rd. at 15-16.)
`
`43.
`
`Claims 20 and 43 ofCabilly III similarly claim a method that “results in the
`
`production ofan antibody” and thus require that practicing the claimed methods results in the
`
`formation ofan assembled antibody. Claim 27 of Cabilly Ill includes a recovery step, which I
`
`..]3-
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`

`

`understand the Court has held covers both recovery of an antibody assembled in vitro from
`
`separate chains and recovery ofan antibody assembled in viva. (CC 0rd. at 17-13.)
`
`44.
`
`An assembled antibody is shown in Figure l ofthe Cabilly Patents, which is
`
`reproduced below.
`
`
`
`Fig. 1: Structure of an Immunoglobulin Tetramer
`
`The assembled antibody is a tetramer (or multimer of tetrarners) that consists of four polypeptide
`
`chains—two heavy chains and two light chains—held together by disulphide bonds (labeled as
`
`“—SS—” in the figure) both within (intrachain) and between (interchain) polypeptide chains.
`
`Assembled immunoglobulins have the same basic structure.
`
`45.
`
`As noted above, the Court found that claim 2? of Cabilly III covers both assembly
`
`in virro (using chemical processes), and in viva (using the host cell’s own protein folding and
`
`assembly machinery). (CC 0rd. at I7-18.) Method claims 33 of Cabilly II and 20 and 43 of
`
`Cabilly III likewise say nothing about how and where the heavy and Ii ght chains are assembled
`
`and therefore are also broad enough to cover immunoglobulin or antibodies, respectively,
`
`assembled in vftro and in viva.
`
`I am informed that in a prior case, Genentech specifically
`
`acknowledged that Cabilly 11 “claim 33 is broad enough to encompass assembly of an
`
`-14-
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`

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`immunoglobulin both inside the host cell and outside the host cell.” (Claim Construction Order,
`
`Centocor Inc., v. Genentech, Inc, et aI., 08-cv-035 73 (C-D. Cal., 2009), D.I. 93 at 17.)
`
`46.
`
`The Cabiliy Patents note that there are different types ofheavy chain, 7 (gamma), [1,
`
`(mu), ct (alpha), 5 (delta), and e (epsilon), as well as two types of light chain, kappa and lambda.
`
`(Col- 3, lines 27-32.) The type of heavy chain determines the immunoglobuiinfantibody class.
`
`(Col. 3, lines 27-31.) The terms “immunoglobnlin” and “antibody” as used in the Cabilly Patents
`
`are not limited to a specific type of heavy or light chain but instead broadly cover all five of the
`
`major immunoglobulinlantibody classes, IgG, IgM, IgA, IgD, and IgE. (Col- 3, lines 60-65.) As
`
`of April 1983, it was known that I gM and IgA are pentamers and dimers of the basic tetrameric
`
`structure, respectively, and the Cabilly Patents expressly state, for example, that
`
`“immunoglobulins” and “antibodies” include these aggregates of tetramers. (Col. 6, lines 3-9.)
`
`47.
`
`In the context of the Cabilly Patents, the broad terms “irnm unoglobulin” and
`
`“antibody” also cover several different immunoglobulin or antibody types, including
`
`“mamrnalian antibodies” (col. 6, lines 12-18; col. 1 1, line 19-col. 12, line 56), “cornposite
`
`immunoglobulins” (col. 6, lines 30-34; col. 14, lines 40-63), “hybrid antibodies” (col. 6, lines 19-
`
`29; col. 14, line 64-col. l5, line 9), “chimeric antibodies” (col. 6, lines 35-56; col. 15, lines 10-
`
`33), and “nnivalent antibodies” (col. 7, lines 25-34; col. 15, line 49-col. 16, line 2).
`
`48. While the term “antibody” requires specific immunoreactive activity (col. 6, lines
`
`3-7), the term “immunoglobulin” does not require specific binding to a particular known antigen
`
`(col. 6, lines 7-9). However, the Cabilly Patents contain no restriction on the types of antigens
`
`that the “antibodies” bind and thus, the term “antibodies” covers antibodies that bind to any
`
`antigen.
`
`-15-
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`

`

`49.
`
`Claim 33 of Cabilly II additionally requires “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.” Claim 15 of Cabilly II
`
`similarly requires “ [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,” and claim 17 requires a host cell
`
`transformed with the vector of claim 15. Because “immunoglobulin” is not limited to a
`
`particular type or species source