UNITED STATES DISTRICT COURT
`
`CENTRAL DISTRICT OF CALIFORNIA
`
`WESTERN DIVISION
`
`BRISTOL-MYERS SQUIBB COMPANY,
`
`Case No. 2: 13-cv-05400-MRP-JEM
`
`Plaintiff and
`
`Counter- Defendant,
`
`V.
`
`GENENTECH, INC ., and CITY OF HOPE
`
`Defendants and
`
`Counter-Plaintiffs.
`
`EXPERT REPORT OF JOHN FIDDES, Ph.D.
`
`Page '1
`
`GENENTECH 2007
`GENZYME V. GENENTECH
`IPRZO16-00383
`
`GENENTECH 2007
`GENZYME V. GENENTECH
`IPR2016-00383
`
`

`
`TABLE OF CONTENTS
`
`INTRODUCTION AND BACKGROUND ...................................................................... ..1
`
`COMPENSATION ............................................................................................................ ..2
`
`PRIOR EXPERT TESTIMONY ........................................................................................ ..2
`
`QUALIFICATIONS AND EXPERIENCE ....................................................................... ..2
`
`QUESTIONS PRESENTED .............................................................................................. ..4
`
`SUMMARY OF MY OPINIONS ...................................................................................... ..5
`
`THE CLAIMS UNDER CONSIDERATION AND THEIR INTERPRETATION .......... ..5
`
`III.
`
`IV.
`
`VI.
`
`VII.
`
`VIII.
`
`RELEVANT LAW .......................................................................................................... .. I 0
`
`A.
`
`B.
`
`C.
`
`35 U.S.C. § 102: Novelty or “Anticipation”..........................................................10
`
`35 U.S.C. § 103: Obviousness ............................................................................. ..11
`
`Obviousness-Type Double Patenting ................................................................... ..12
`
`IX.
`
`THE PERSON OF ORDINARY SKILL IN THE ART .................................................. ..l2
`
`THE STATE OF THE ART OF RECOMBINANT DNA-BASED PRODUCTION
`OF PROTEINS TN APRIL 1983 ...................................................................................... ..]3
`
`A,
`
`B.
`
`C.
`
`In April 1983, Co-expression Was a Novel, Non-Obvious Approach in
`Recombinant DNA Technology .......................................................................... .. I 3
`
`In April 1983, The One-Protein-Of-Interest-Per-Host-Cell Approach Would
`Have Been Followed By A Person of Ordinary Skill in the Art — Even For the
`Recombinant Production of a Multimeric Protein ............................................... .. I 7
`
`Other Trends in the Art in 1983 Would Not Have Suggested Genetically
`Engineering Host Cells to Co-Express Antibody Heavy and Light Chains ........ ..2l
`
`XI.
`
`CLAIMS 15, 17 AND 33 OF CABILLY II ARE NOT ANTICIPATED BY
`COHEN & BOYER ......................................................................................................... ..22
`
`XII.
`
`CLAIM 33 OF CABILLY [I IS NOT OBVIOUS IN VIEW OF
`
`COHEN & BOYER IN COMBINATION VVITH RIGGS & ITAKURA ....................... ..3l
`
`XIII.
`
`CLAIMS 15, 17 AND 33 OF CABILLY II ARE NOT ANTICIPATED BY BU.IARD..33
`
`XIV.
`
`CLAIM 33 OF CABILLY 11 IS NOT OBVIOUS IN VIEW OF BUIARD IN
`
`COMBINATION WITH RIGGS & ITAKURA .............................................................. ..4I
`
`XV.
`
`CLAIMS 20, 27, 43 AND 46 OF CABILLY III ARE NOT INVALID FOR
`OBVIOUSNESS-TYPE DOUBLE PATENTING IN VIEW OF CLAIM 2 OF
`CABILLY I IN COMBINATION WITH EITHER COHEN & BOYER OR BUJARD
`
`ALONE OR IN FURTHER COMBINATION WITH ITAKURA & RIGGS ............... ..42
`
`Page 2
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`I.
`
`INTRODUCTION AND BACKGROUND
`
`1.
`
`Genentech, Inc. and City of Hope have retained me as an expert consultant
`
`in the above-captioned case.
`
`I submit this report on their behalf pursuant to Federal Rule
`
`of Civil Procedure 26(a)(2).
`
`2.
`
`In view of my education, trai.ning, skills, knowledge and experience, I
`
`have been asked to evaluate, and respond to, certain opinions regarding the validity of
`
`Us Patent No. 6,331,415 (“Cabilly II”) and U _s_ Patent No. 7,923,221 (“Cabilly III”)
`
`expressed by Jefferson Foote, Ph.D., in an expert report dated October 13, 2014, filed in
`
`this case on behalf of Bristol-Myers Squibb Co. and Medarex, LLC (collectively,
`
`“BMS”).
`
`I expect to testify about my evaluations and responsive opinions, set forth
`
`herein.
`
`3.
`
`If called to testify, to help make the complex science and the language
`
`associated with it understandable, I may also serve in a teaching capacity, explaining the
`
`basic principles referred to and the terminology used in this report, the report I address
`
`herein, as well as other documents and literature referenced herein. At this point in time,
`
`I have not prepared any demonstrative exhibits, illustrations, prototypes, models,
`
`animations or other such testimonial aids in support of my testimony, although I expect 1
`
`may utilize such and will do so in accordance with the Court’s orders.
`
`4.
`
`I reserve the right to modify, amend and/or supplement the opinions
`
`expressed herein — especially to address any new arguments raised by BMS, directly or
`
`through its experts.
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`Page 3
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`

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`II.
`
`COMPENSATION
`
`5.
`
`I am being compensated for my time spent working on this case at a rate
`
`of $450 per hour plus expenses. My compensation in this case is in no way dependent on
`
`its outcome.
`
`Ill.
`
`PRIOR EXPERT TESTIMONY
`
`6.
`
`I have not testified at a trial or deposition in the preceding four years.
`
`IV.
`
`QUALIFICATIONS AND EXPERIENCE
`
`7.
`
`If called to testify, I expect to describe my qualifications and experience
`
`that are relevant to the issues I address herein. My background is summarized below and
`
`in my currfc'm'um vitae (“C V”), which includes a list of my publications and patents, both
`
`of which are attached as Exhibit A.
`
`8.
`
`I received a Bachelor of Science degree in Biological Sciences (Molecular
`
`Biology) with First Class Honors from the University of Edinburgh, Edinburgh, Scotland
`
`in 1973.
`
`In 1977, I received my Ph.D. in molecular biology from Kings College,
`
`Cambridge University, Cambridge, England. My thesis advisor was Dr. Fred Sanger.
`
`The topic of my thesis was, “Sequencing of the bacteriophage ¢X 1 74 and G4 genomes.”
`
`From 19?? to 1980, I was a Postdoctoral Research Fellow at the University of California,
`
`San Francisco (“UCSF”), in the laboratory of Dr. Howard Goodman, where I worked on
`
`the human growth hormone, human chorionic somatomammotropin and human
`
`glycoprotein hormone genes. While I was focused on cDNA cloning and the cloning and
`
`structural characterization of genes encoding these human hormones, several of my
`
`colleagues focused on gene expression for the production of recombinant proteins, and I
`
`had frequent discussions with them on their research strategies.
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`Page 4
`2
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`

`
`9.
`
`After my post-doc at UCSF, I became a Senior Staff Investigator at Cold
`
`Spring Harbor Laboratory (“CSHL”) in Cold Spring Harbor, New York, a position I held
`
`until January 1983. My research at CSHL focused on the structure, evolution and
`
`expression of the human glycoprotein hormone genes, specifically human chorionic
`
`gonadotropin and human luteinizing hormone, and on methods of making CDNA libraries
`
`suitable for immunological screening of expression products.
`
`I was also an instructor at
`
`the CSHL Advanced Cloning Course in the summers of 1982-1983.
`
`10.
`
`Following my academic career, I entered industry and spent over twenty
`
`years in drug discovery and development in biopharmaceutical companies, as reflected in
`
`my CV. In January 1983, just shortly before the filing date of the Cabilly patents, I took
`
`a position at California Biotechnology Inc. (later called Scios Inc.) in Mountain View
`
`California, a biotechnology company interested in applying recombinant DNA
`
`technologies to the production of therapeutically useful proteins. Among other things, I
`
`was involved in the development of systems for the production of recombinant forms of
`
`basic fibroblast growth factor, and the isolation of CDNA and genomic clones for atrial
`
`natriuretic peptide, vascular endothelial growth factor variant and heparin-binding, EGF-
`
`like growth factor.
`
`1 1.
`
`My last corporate position was at Genencor International Inc. in Palo Alto,
`
`California where I was Vice President Research, Health Care from 2003 to 2005. Since
`
`2005, I have been an independent consultant on biopharmaceutical matters for a variety
`
`of organizations, including the California Antiviral Foundation and the Institute for One
`
`World Health.
`
`Page 5
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`

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`12.
`
`Based on my academic and early industrial experience, I was well aware
`
`of the birth of recombinant DNA technology and experienced as well as followed the
`
`developments that led to the applications of the technology to the production of
`
`recombinant forms of medically and industrially important proteins. This, in my view, is
`
`the art to which the Cabilly patents pertain, and I believe I am well-positioned to
`
`understand and address the skills and mindset of a person of Ordinary skill in this art circa
`
`1 982-83.
`
`V.
`
`QUESTIONS PRESENTED
`
`13.
`
`I have been asked to provide an overview of the state of the art of protein
`
`production using recombinant DNA technology as of April 1983, so as to express my
`
`opinion, responsive to that of Dr. Foote, on whether the inventions claimed in claims 15,
`
`17 and 33 of Cabilly II (collectively, “the asserted claims”) constitute inventive advances
`
`over the prior art Dr. Foote relies on, specifically, Cohen and Boyer, U.S. Patent No.
`
`4,237,224 (“Cohen & Boyer”) and Bujard 9: mi, U.S. Patent No. 4,495,280 (“Bujard"),
`
`alone or in combination with Riggs and ltalcura, Am. J. Hum. Genet. 31:53}-538 (1979)
`
`(“Riggs & ltakura”).
`
`14.
`
`As further discussed herein, my opinion is that the subject matter of the
`
`asserted claims of Cabilly 11 represents inventive advances over the references relied on
`
`by Dr. Foote.
`
`15.
`
`I have also been asked to express my opinion on whether claims 20, 27, 43
`
`and 46 of Cabilly III are obvious over claim 2 of U.S. Patent No. 4,816,567 (“Cabilly I”)
`
`in combination with either Cohen & Boyer or Bujard alone or in further combination with
`
`Riggs & Itakura and thus to assess whether these claims are valid under the doctrine of
`
`obviousness-type double patenting (“ODP”).
`
`Page 6
`4
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`

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`16.
`
`As further discussed herein, my opinion is that claims 20, 27, 43 and 46 of
`
`Cabilly III are not obvious from claim 2 of Cabilly I in combination with the art relied on
`
`by Dr. Foote and thus, not invalid under ODP.
`
`VI.
`
`SUMMARY OF MY OPINIONS
`
`1?.
`
`As explained in detail below, my opinions expressed in this report with
`
`respect to Cabilly Il may be summarized as follows:
`
`I Claims 15, 17 and 33 are not anticipated by Cohen & Boyer.
`
`0 Claims 15, 17 and 33 are not anticipated by Bujard.
`
`0 Claim 33 is not obvious in view of Cohen & Boyer in combination with Riggs
`& Itakura.
`
`0 Claim 33 is not obvious in view of Bujard in combination with Riggs &
`Itakura.
`
`18,
`
`As explained in detail below, my opinions expressed in this report with
`
`respect to Cabilly III may be summarized as follows:
`
`0 Claims 20, 27, 43 and 46 are not invalid under the doctrine of ODP in view of
`
`claim 2 ofCabi1ly I in combination with (1) Cohen & Boyer alone or (2)
`Cohen & Boyer plus Riggs & Itakura.
`
`0 Claims 20, 27, 43 and 46 are not invalid under the doctrine of ODP in View of
`claim 2 o1°Cabilly I in combination with (1) Bujard alone or (2) Bujard plus
`Riggs & Itakura.
`
`19,
`
`A list of materials I have reviewed in preparation of this report is attached
`
`as Exhibit B.
`
`VII.
`
`THE CLAIMS UNDER CONSIDERATION AND THEIR
`
`INTERPRETATION
`
`20.
`
`I understand that before the validity (or infringement) of a patent claim
`
`can be judged, it must first be interpreted by the Court. As reflected in Exhibit B, I have
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`Page 7
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`been provided a copy of the Court’s Claim Construction Order (“Claim Constr. Or.”) in
`
`this case and have reviewed it.
`
`21.
`
`The claims of Cabilly II that I have considered are claims 15, 17 and 33,
`
`which 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.
`
`* * =56
`
`17.
`
`A host cell transformed with a vector according to
`claim 15.
`
`* =l= *
`
`33.
`
`A process for producing an immunoglobulin
`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 as separate molecules in said single host
`cell transformed with said first and second DNA
`
`se ql.l€l'1C CS.
`
`22.
`
`The claims of Cabilly III that I have considered are claims 20, 27, 43 and
`
`46, which are reproduced below. Because all of these claims are dependent claims, the
`
`claims on which they depend (r'.e., claims 15, 25, 38 and 45) are also reproduced below:
`
`15,
`
`A method for making an antibody or antibody
`fragment capable of specifically binding a desired
`
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`6
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`
`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 fragment thereof
`and the light chain or fragment thereof in a
`recombinant host cell.
`
`1:**
`
`20.
`
`The method of claim 15 which results in the
`
`production of an antibody.
`
`**7c
`
`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.
`
`1:**
`
`27.
`
`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.
`
`‘.i'*'k
`
`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
`
`Page 9
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`

`
`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.
`
`**1:
`
`43.
`
`The method of claim 38 which results in the
`
`production of an antibody.
`
`‘kkic
`
`45.
`
`A replicable expression vector comprising DNA
`encoding an antibody heavy chain or fragment
`thereof and an antibody Ii ght 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.
`
`23.
`
`I understand that the Court has construed certain claim terms in Cabilly II.
`
`Specifically, “host cell” was construed to mean “a cell whose heritable DNA has been or
`
`will be altered by the inclusion of foreign DNA; the term includes the progeny of the
`
`originally transformed cell.” Claim Constr. Or. at 18. Also, “transformed” was found to
`
`have its plain and ordinary meaning and that it “does not require a separate step of
`
`transforming.” Id.
`
`24.
`
`I understand that the Court has construed certain claim terms in Cabilly
`
`III. Specifically, “recovering the heavy chain or fragment thereof and light chain or
`
`fragment thereof ’ was found to have its plain and ordinary meaning.
`
`Id.
`
`25.
`
`I further understand that the parties have agreed to the meaning of other
`
`terms within the claims of the Cabilly II and 111 patents. Specifically, the parties have
`
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`8
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`agreed that, in Cabilly II, “transformed host cell” means “a cell whose heritable DNA has
`
`been altered by the inclusion of foreign DNA; the term includes the progeny of the
`
`originally transfonned cell.” Id. at 4. Furthermore, “different insertion sites” was agreed
`
`to mean “in the vector, the DNA sequence encoding for at least the variable domain of
`
`the heavy chain is not contiguous to the DNA sequence encoding for at least the variable
`
`domain of the light chain, the former being separated from the latter by sufficient DNA
`
`sequence to ensure independent expression.” Ia’. Lastly, “vector” was agreed to mean “a
`
`DNA construct comprising DNA foreign to the DNA host cell, which DNA construct is
`
`capable of effecting the expression of the foreign DNA.” Id. at 5.
`
`26.
`
`For Cabilly III, I understand that the parties have agreed that “recombinant
`
`host cell” means “a cell whose heritable DNA has been altered by the inclusion of foreign
`
`DNA; the term includes the progeny of the originally transformed cell.” Claim Constr.
`
`Or. at 4. Furthermore, they have agreed that “coexpressing the heavy chain or fragment
`
`thereof and the light chain or fragment thereof’’ means “independently expressing the
`
`heavy chain or fragment thereof and the light chain or fragment thereof in the same host
`
`cell.” Joint Claim Constr. And Prehearing Statement at 1-2.
`
`It was agreed that “host cell
`
`culture” has its plain and ordinary meaning. Claim Constr. Or. at 5. “Vector” was agreed
`
`to mean “a DNA construct comprising DNA foreign to the DNA host cell, which DNA
`
`construct is capable of effecting the expression of the foreign DNA.” Id. Lastly,
`
`“replicable expression vector” was agreed to mean “a DNA construct comprising DNA
`
`foreign to the DNA host cell, which DNA construct is capable of effecting the expression
`
`of the foreign DNA.” Id.
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`27.
`
`I understand that the Court has taken no position on the construction of the
`
`claim terms “immunoglobulin” (used in Cabilly II) and “antibody” (used in Cabilly III).
`
`Claim Constr. Or. at 2.
`
`I understand that the parties agree on the fact that all antibodies
`
`are also immunoglobulins.
`
`I use the terms interchangeably herein.
`
`28.
`
`Lastly, I understand that the asserted process and method claims require
`
`not only the co-expression of heavy and light chains in a single host cell, but also that
`
`assembled immunoglobulins (in the case of Cabilly II) and assembled antibodies (in the
`
`case of Cabilly III) be produced.
`
`VIII. RELEVANT LAW
`
`A.
`
`35 U.S.C. § 102: Novelty or “Anticipation”
`
`29.
`
`I understand that Title 35 of the United States Code contains the statutory
`
`patent laws of the United States and that § 102 sets forth the novelty requirement.
`
`1 have
`
`been informed that the subject matter of a valid claim must be new and that novelty (and
`
`hence, validity) is destroyed when a single prior art reference discloses, expressly or
`
`inherently, each and every element of the claimed invention.
`
`1 have been further
`
`informed that such a prior art reference must not only disclose in an enabling manner all
`
`elements of a patent claim within its four corners to be novelty-destroying, but that it
`
`must also disclose those elements arranged as in the claim. Such a reference, I
`
`understand, is also said to be “anticipatory.” I understand further that
`
`noveltyfanticipation is judged as of a patent's priority date as understood by a person of
`
`ordinary skill in the art.
`
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`
`B.
`
`35 U.S.C. § 103: Obviousness
`
`30.
`
`I understand that the subject matter of a valid claim, in addition to being
`
`novel, must be non-obvious.
`
`I have been informed that 35 U.S.C. § 103(a) sets forth the
`
`standard for obviousness and states
`
`A patent may not be obtained though the
`(a)
`invention is not identically disclosed or described [in the
`prior art] if the differences between the subject matter
`sought to be patented and the prior art are such that the
`subject matter as a whole would have been obvious at the
`time the invention was made to a person having ordinary
`skill in the art to which said subject matter pertains.
`Patentability shall not be negatived by the manner in which
`the invention was made.
`
`31 ,
`
`I also understand that, when evaluating whether the claims of a patent are
`
`obvious or not, one may (I) consider the inventions claimed in the asserted claims and
`
`the scope and content of the prior art; (2) compare the claimed inventions to the prior art
`
`and assess the differences; and (3) determine whether those differences would have been
`
`considered obvious to a person of ordinary skill in the art as of the priority date of the
`
`patent, which I have been asked to assume is the filing date of the application underlying
`
`Cabilly II, Serial No. 06r’483,457, filed April 8, 1983.
`
`32.
`
`Furthermore, I understand that obviousness is judged from the vantage
`
`point of a person of ordinary skill in the art as of April 1983, whom I have characterized
`
`in Section IX, below.
`
`I have been informed that I should assume that a person of
`
`ordinary skill in the art would have known of the teachings provided in all the relevant
`
`body of art.
`
`33.
`
`I have been advised that the U.S. Supreme Court has commented that a
`
`person of ordinary skill in the art is not an automaton but rather possesses an ordinary
`
`level of creativity for problem-solving. However, I further understand, a person of
`
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`
`ordinary skill in the art is not an inventor and is not expected to solve problems with
`
`innovative approaches.
`
`C.
`
`Obviousness-Type Double Patenting
`
`34.
`
`It has been explained to me that so-called “obviousness-type double
`
`patenting” is a doctrine created by the courts, the purpose of which is to ensure that
`
`claims of commonly owned patents are patentably distinct, 1'. e., that the subject matter
`
`claimed in one patent is not made obvious by the subject matter claimed in another co-
`
`owned patent.
`
`I have been informed that one of the policy concerns addressed by this
`
`doctrine is the prevention of a later-expiring patent, which claims an invention patentably
`
`indistinct from that claimed in an earlier-expiring patent, from, in effect, improperly
`
`extending the term of the patent monopoly.
`
`35.
`
`I understand that the obviousness-type double patenting analysis requires
`
`that the claims of the later-expiring patent be compared to the claims of the earlier-
`
`expiring patent and not to the entirety of the teachings of the specifications, although the
`
`specification of the earlier expiring patent may be consulted, as necessary, for claim
`
`interpretation purposes.
`
`36.
`
`I understand that this analysis includes basically three steps: (I) the
`
`interpretation of the claims of the earlier and later patent; (2) a comparison of the claims
`
`to identify differences, if any and (3) an assessment, in accordance with the principles of
`
`35 U.S.C. §102 (anticipation) and §103 (obviousness) (described above), of whether the
`
`later claims are patentably distinct from the earlier claims.
`
`IX.
`
`THE PERSON OF ORDINARY SKILL IN THE ART
`
`3?.
`
`In my opinion, the art area of the Cabilly II and III patents is the use of
`
`recombinant DNA technology for the production of proteins of interest in host cells, 1'.e.,
`
`Page 14
`I2
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`

`
`those cells engineered to contain, express and propagate genes they naturally do not
`
`harbor. Thus, the person of ordinary skill in this art in early 1983 would have had
`
`training in the then relatively new “genetic engineering” technologies. Such a person, in
`
`my view, would have had a Ph.D. in molecular biology or related discipline, such as
`
`biochemistry, microbiology or cell biology plus two to three years post-doctoral training
`
`and experience (whether in academia or industry) in the application of recombinant DNA
`
`technology to protein production- More often than not, in my view, the person of
`
`ordinary skill in the art in early 1983, whether in an academic setting or in industry,
`
`would have been pursuing the recombinant production of a protein of known or expected
`
`therapeutic or industrial utility.
`
`38.
`
`The person of ordinary skill in the art, in my opinion, would not have been
`
`an immunologist, nor would otherwise have had extensive training about the immune
`
`response in humans and other animals. However, I believe that the person of ordinary
`
`skill in the art would have had a basic course in immunology or at least would have been
`
`knowledgeable about the structure and function of antibodies and would have had some
`
`familiarity with the genetics and other complexities of the immune system.
`
`39.
`
`1 base my ability to so characterize the person of ordinary skill in the art in
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`early 1983 on my own personal experiences in academic and biotechnology industrial
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`research at the relevant time.
`
`X.
`
`THE STATE OF THE ART OF RECOMBINANT DNA-BASED
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`PRODUCTION OF PROTEINS IN APRIL 1983
`
`A.
`
`In April 1983, Co-expression Was a Novel, Non-Obvious Approach in
`Recombinant DNA Technology
`
`40.
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`Based on my personal experience and review of pre-April 1983 original
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`research papers, I am aware of no instance in which the concept of co-expression in a
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`single host cell of two distinct exogenous genes encoding constituent polypeptide chains
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`of a multimeric protein was articulated or implemented as a recombinant DNA (“rDNA”)
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`approach to the production of any multimeric protein, much less one as large and
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`complex as an antibody. Consistent with the claim construction discussion above, by
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`“exogenous genes”, 1 mean genes that do not naturally exist in the host, but rather are
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`heterologous or foreign to the host and have been introduced into it by recombinant
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`means. By “co-expression”, I mean the production in a single recombinantly engineered
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`host cell of the individual polypeptide chains encoded by the introduced genes as separate
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`protein molecules. By my read, the Cabilly patents were the first to have reported the co-
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`expression approach for producing immunoglobulins from recombinant heavy and light
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`chains made in a single host cell and to have demonstrated its successful practice.
`
`41.
`
`To appreciate the ambitiousness of Cabilly er a!. ’s undertaking, and the
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`significant advance in the art represented by their achievement, it is important to bear in
`
`mind the norms of the time.
`
`42.
`
`As depicted in Fig.
`
`I of the Cabilly patents, and as would be known to a
`
`person of ordinary skill in the art in April 1983, an antibody is a multimeric protein
`
`composed of four constituent polypeptide chains.
`
`In a naturally occurring antibody, there
`
`are two identical “heavy” chains (or “H” chains) and two identical “light” chains (or “L”
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`chains) that form what is schematically depicted as a Y-shaped molecule. A disulfide
`
`bond joins each L chain to a respective H chain, forming the “arms” of the Y, and three
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`disulfide bonds join the two H chains at the top of the “stalk” of the Y. The heavy and
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`light chains are so-called because they differ in molecular weight. By way of example, in
`
`antibodies of the immunoglobulin G (“IgG”) isotype, the longer H chains, naturally
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`comprised of about 447 amino acids apiece, each have a molecular weight of about
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`50,000 Daltons, whereas the shorter L chains, naturally comprised of about 214 amino
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`acids apiece, each have a molecular weight of about 25,000 Daltons. Thus, when the four
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`chains are combined into the characteristic tetrameric form of an IgG antibody, the
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`molecular weight of the resulting antibody is about 150,000 Daltons, strikingly larger
`
`than any other protein that had been made by rDNA techniques by April 1983.
`
`43.
`
`Indeed, by April 1983, the vast majority of target recombinant proteins
`
`were relatively small compared to an antibody. The expression of eukaryotic genes in E.
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`coil’, a prokaryote and the best characterized and most widely used host cell of this era,
`
`was reviewed in Harris, Genetic Engineering, 4: 127-84 (1983). See, Table 2 for a
`
`summary of the types and sizes (molecular weights) of recombinant proteins expressed in
`
`coir’ prior to Cabilly er al. '3 filing date. The successful recombinant production of
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`proteins such as human insulin, growth hormone, interferons and B-endorphin, was
`
`widely hailed at the time because recombinant DNA technology had made possible vast
`
`quantities of medically important human proteins that were purer and expected to be safer
`
`and less expensive than their counterparts derived from human tissue (e.g. human growth
`
`hormone derived from the pituitaries of cadavers) or their surrogates derived from
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`animals (e.g. porcine insulin derived from pigs).
`
`In the early 1980s, the recombinant
`
`production of known proteins with medical utility was considered a breakthrough and
`
`patents were regularly awarded for these efforts. See, e.g. US. Patent No. 4,517,294
`
`(recombinant human antithrombin III); U.S. Patent No. 4,563,424 (recombinant
`
`somatostatin); U.S. Patent No. 4,530,901 (recombinant human interferon); U.S. Patent
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`No. 4,710,463 (recombinant hepatitis B viral (“HBV”) antigens); and U.S. Patent No.
`
`4,818,694 (recombinant herpes simplex virus (“HSV”) proteins).
`
`44. While E. cob‘ was the predominant recombinant host cell in use in April
`
`1983, strides were being made in the art to genetically engineer eukaryotic cells,
`
`including mammalian cells, for recombinant production of proteins. Examples of
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`eukaryotic host cells and vectors and regulatory elements for use in them are disclosed in
`
`the Cabilly patents, e.g., in Cabilly II at column 9, line I6-column 10, line 25.
`
`45.
`
`For example, by April 1983, viral vectors had been the subject of
`
`significant study and development for introducing foreign DNA into mammalian host
`
`cells. Simian virus 40 (“SV40”), in particular, was a well-characterized virus at the time.
`
`SV40-derived viral vectors were in use in numerous laboratories world-wide for
`
`introducing and expressing genes encoding such proteins as human growth hormone, rat
`
`preproinsulin and proinsulin, human immune interferon and human fibroblast interferon
`
`in various mammalian host cells, including African Green Monkey Kidney cells, COS
`
`cells and human HeLa cells. See, e.g., Pavlakis er a!., PNAS 78 (12): 7398-7402 (1981);
`
`Pavlakis and Hamer, Recent Progress in Hormone Research, 39: 353-385 (1983); Grass
`
`and Khoury, PNAS 78(1): 133-13? (1981); Horowitz stall, J. Mol. Appl. Gen. 2: 14?-
`
`l59 (1983); Lomedico, PNAS 79: 5798-5802 (1982); Devos er a/., Nucl. Acids Res. I0
`
`(8): 2487-2501 (1982); Fiers er a;’., Phil. Trans. R. Soc. Lond. B 299: 29.33 (1982);
`
`Gheysen and Fiers, J. Molec. App]. Gen. I: 385-394 (I982); and Gray er ar'., Nature 295:
`
`503-508 (1982). Other viral Vectors, such as those derived from bovine papilloma virus
`
`(“BPV”), had been used by early 1983 for expression of human B interferon in C12?
`
`mouse cells. See, Mitrani-Rosenbaum er oi, Molec. Cell. Biol. 3 (2): 233-240 (1983).
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`46.
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`As with the prokaryotic systems then in use, the target proteins in
`
`recombinant eukaryotic (mammalian) host cell systems were small in size relative to an
`
`antibody molecule.
`
`47. What is perhaps more notable about the earliest recombinantly-made
`
`proteins is their lack of structural complexity. With one exception (insulin), discussed
`
`below, by April 1983, the proteins that had been produced in heterologous systems using
`
`recombinant DNA technology were all monomeric, i.e., single chain proteins. In their
`
`native environments, such proteins were encoded by single genes. Not surprisingly, a
`
`“one-protein-oilinterest-per-host-cell” approach was taken to produce these proteins
`
`recombinantly, because only one gene had to be introduced into a host cell to achieve this
`
`goal
`
`B.
`
`In April 1983, The 0ne-Protein—Of-Interest-Per-Host-Cell Approach
`Would Have Been Followed By A Person of Ordinary Skill in the Art
`— Even For the Recombinant Production of a Multimeric Protein
`
`48.
`
`In April 1983, the only multimeric protein that had actually been made in
`
`a heterologous host using recombinant DNA techniques was insulin, a small, dimeric
`
`protein.
`
`49.
`
`Insulin, a polypeptide hormone that regulates glucose metabolism, is made
`
`in mammals in