Petitioners
`
`V.
`
`GENENTECH, INC. AND CITY OF HOPE
`Patent Owners
`
`Case IPR2016-OO'7101
`
`US. Patent No. 6,331,415
`
`REBUTTAL DECLARATION OF ROGER D. KORNBERG
`
`IN SUPPORT OF MERCK’S REPLY TO PATENT OWNERS’ RESPONSE
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS, INC. and
`MERCK SHARP & DOHME CORP.
`
`1 Case IPR2017-00047 has been joined with this proceeding.
`
`Mylan v. Genentech
`IPR2016-00710
`Merck Ex. 1090, Pg. 1
`
`

`

`TABLE OF CONTENTS
`
`INTRODUCTION............................................................................................................ ..1
`
`BACKGROUND AND QUALIFICATIONS .................................................................. ..2
`
`MATERIALS CONSIDERED........................................................................................ ..4
`
`COMPENSATION .......................................................................................................... ..5
`
`INTER PARTESREVIEW OF THE ’415 PATENT ................................................... ..5
`
`A.
`
`Relevant Legal Standards ................................................................................... ..6
`
`1.
`
`2.
`
`Legal Standard for Prior Art ...................................................................... ..6
`
`Legal Standard for Obviousness ................................................................ ..7
`
`B.
`
`C.
`
`Level of Ordinary Skill in the Art ........................................................................ .. 12
`
`Claim Construction .............................................................................................. .. 13
`
`SUMMARY OF OPINIONS ......................................................................................... ..14
`
`THE CHALLENGED CLAIMS ................................................................................... ..16
`
`THE STATE OF THE ART FOR RECOMBINANT PROTEIN
`PRODUCTION IN APRIL 1983 .................................................................................. ..17
`
`Single Gene of Interest............................................................................. ..53
`
`PATENT OWNERS’ AND THEIR EXPERTS’ READING OF BUJARD IS
`OVERLY NARROW AND FAILS TO APPRECIATE THE FULL
`TEACHINGS OF BUJARD .......................................................................................... ..32
`
`A.
`
`B.
`
`Dr. Fiddes and Dr. Gentz Adopt An Unreasonany Narrow View of Bujard ...... ..34
`
`Bujard Teaches the Use of the Co-Expression of Multiple, Distinct
`Eukaryotic Genes of Interest in a Single Host Cell ............................................. ..39
`
`1.
`
`The Structure of the Buj ard Vector Allows for the Co-EXpression
`of Multiple Distinct Genes of Interest in a Single Host Cell ................... ..39
`
`Bujard’s Reference to “Multimers” Does Not Limit Bujard to
`Multiple Copies of the Same Gene .......................................................... ..41
`
`Bujard’s Reference to “More Than One Gene” Does Not Limit
`Bujard to a Single Gene of Interest .......................................................... ..48
`
`Bujard’s Reference to “Stop Codons” Does Not Limit Bujard to a
`
`Merck Ex. 1090, Pg. 2
`
`

`

`C.
`
`D.
`
`Bujard Teaches a Method for Producing Antibodies ........................................... ..55
`
`Bujard Teaches the In Vivo Assembly of a Multimeric Protein Encoded by
`More Than One Gene in a Single Host Cell ........................................................ ..59
`
`A.
`
`Riggs & Itakura Suggests the In Vitro Assembly of Heavy and Light
`Chains .................................................................................................................. ..62
`
`A Person of Skill in the Art Would Have Been Motivated to Combine
`
`Bujard With Riggs & Itakura ................................................................................ ..65
`
`A Person of Skill in the Art Would Have Had a Reasonable Expectation of
`Success in Combining Bujard with Riggs & Itakura ........................................... ..68
`
`IT WOULD HAVE BEEN OBVIOUS TO COMBINE THE TEACHINGS
`OF SOUTHERN AND BUJARD .................................................................................. ..71
`
`THE PATENT OWNERS’ CHALLENGES TO THE BOARD’S
`PRELIMINARY FINDING THAT IT WOULD HAVE BEEN OBVIOUS
`TO COMBINE BUJARD WITH RIGGS & ITAKURA ARE WRONG ................. ..62
`
`CONCLUSION .............................................................................................................. ..83
`
`A.
`
`Southern Discloses a Two-Vector Approach For Expressing More Than
`One Protein of Interest in a Single Host Cell ....................................................... ..72
`
`A Person of Ordinary Skill in the Art Would Have Had Good Reason to
`Combine Buj ard With Southern ........................................................................... ..76
`
`A Person of Ordinary Skill in the Art Would Have Had A Reasonable
`Expectation of Success in Combining Bujard With Southern ............................. ..80
`
`Patent Owners’ Arguments That Southern Cannot Invalidate Claims 1, 2,
`and 33 Are Wrong ................................................................................................ ..82
`
`Merck Ex. 1090, Pg. 3
`
`

`

`INTRODUCTION
`
`1, Roger D. Kornberg, hereby declare and state as follows:
`
`1.
`
`I have been asked by counsel for Merck Sharp & Dohme Corp.
`
`(“Merck”) to provide expert opinions in the above-captioned matter in rebuttal to the
`
`expert declarations offered by John Fiddes, PhD. (Ex. 2019) and Reiner Gentz,
`
`PhD. (Ex. 2021) on behalf of Genentech, Inc. (“Genentech”) and City of Hope
`
`with them.
`
`(collectively, “Patent Owners”) as well as the arguments made in the Patent Owners”
`
`Response (Paper No. 31).
`
`2.
`
`I have prepared this declaration in connection with Petitioners’ Reply
`
`concerning the unpatentability of certain claims of US Patent No. 6,331,415 (“the
`
`’415 patent”), which I understand is being filed by Merck concurrently with this
`
`declaration.
`
`3.
`
`I reserve the right to revise, supplement, and/0r amend my opinions
`
`stated herein based on new information and on my continuing analysis of the
`
`materials already provided, particularly in view of any new arguments raised by
`
`Patent Owners or their experts.
`
`4.
`
`The fact that I do not herein address all of the opinions set forth in Dr.
`
`Fiddes’ declaration or Dr. Gentz’s declaration does not mean that I concede or agree
`
`Merck Ex. 1090, Pg. 4
`
`

`

`II.
`
`BACKGROUND AND QUALIFICATIONS
`
`5.
`
`As further detailed in my CV, attached as Exhibit A to this declaration,
`
`I received a Bachelor of Science degree in Chemistry from Harvard University in
`
`1967 and a PhD. in Chemical Physics from Stanford University in 1972. My thesis
`
`described my discovery of “flip-flop” and lateral diffusion of phospholipids in
`
`bilayer membranes.
`
`6.
`
`I conducted postdoctoral work at the Laboratory of Molecular Biology
`
`in Cambridge, where I studied X-ray diffraction with Nobel Laureates Aaron Klug
`
`(awarded for the development of electron crystallography and studies of nucleic acid
`
`protein complexes) and Francis Crick (awarded for the discovery of the double helix
`
`the process by which genetic
`
`structure of DNA) from 1972-1975. At Cambridge, I discovered the nucleosome,
`
`the basic protein complex responsible for packaging chromosomal DNA in the
`
`nucleus of eukaryotic cells.
`
`7.
`
`Thereafter, I returned to the U. S. as a professor of Biological Chemistry
`
`at Harvard Medical School from 1976-1977, and then a professor of Structural
`
`Biology at Stanford University School of Medicine from 1978-2003. Since 2003, I
`
`have been the Winzer Professor in Medicine in the Department of Structural Biology
`
`at Stanford Medical School.
`
`8.
`
`In 2006, I won the Nobel Prize in Chemistry for my research on the
`
`molecular basis of eukaryotic transcription,
`
`Merck Ex. 1090, Pg. 5
`
`

`

`information from DNA is copied into RNA.
`
`I discovered the structure of RNA
`
`polymerase II, a giant multi-protein (112., multimeric) complex.
`
`I also discovered
`
`additional multimeric complexes required for gene transcription, including the 21 -
`
`protein “Mediator,” which is responsible for all regulation of gene transcription.
`
`9.
`
`My research group at Stanford continues to elucidate the fundamental
`
`basis of gene regulation by studying the molecular machines involved in
`
`transcription, reconstitution of the process with purified components, structure
`
`chromatin, the natural DNA template for transcription.
`
`determination of the transcription machinery, and structure-function relationships in
`
`the US. National Academy of Sciences, and am a member of several academic and
`
`10.
`
`In addition to the Nobel Prize, I have also won over 25 other awards
`
`and honors for my research, including the Eli Lilly Award in Biological Chemistry
`
`in 1981 , the Passano Award in 1982, the Harvey Prize in 1997, the Gairdner
`
`International Award in 2000, the Welch Award in Chemistry in 2001, the Grand
`
`Prize of the French Academy of Sciences in 2003, and the Horwitz Prize in 2006.
`
`1 1.
`
`I have authored over 200 refereed joumal articles, including 150 articles
`
`related to protein structure and folding, gene regulation, and transcription control.
`
`I
`
`have honorary degrees from universities in Europe and Israel, including the Hebrew
`
`University, where I am a Professor.
`
`I am also a Professor at Shanghai Tech
`
`University in China and Konkuk University in Korea.
`
`I have also been elected to
`
`Merck Ex. 1090, Pg. 6
`
`

`

`professional societies throughout
`
`the world,
`
`including the Royal Society,
`
`the
`
`Japanese Biochemical Society, the American Academy of Arts and Sciences, and
`
`the European Molecular Biology Organization.
`
`12.
`
`I have also served, either currently or in the past, on scientific advisory
`
`Discovery, Inc, ChromaDex corporation, Xenetic Biosciences, Inc, OphthaliX Inc,
`
`Protalix BioTherapeutics, Inc, Oplon Ltd., Pacific Biosciences, StemRad, Ltd.,
`
`OPKO Health, Inc, Epiphany Biosciences, Inc, SuperGen Inc, BioCancell Ltd.,
`
`InterX Inc, Predictive Therapeutics Inc, Sensor Kinesis Corp, Cognos Corp,
`
`Aposense Inc, and Teva Pharmaceutical Industries. For several of these companies
`
`boards and boards of directors for various companies and organizations, e.g, Crystal
`
`that may not yet have been provided to me.
`
`I am chief scientist, chairman of the board or executive CEO.
`
`III. MATERIALS CONSIDERED
`
`13.
`
`In forming the opinions set forth herein, I have considered and relied
`
`upon my education, knowledge of the relevant fields, and experience.
`
`I have also
`
`considered the materials identified in this report and those listed in Exhibit B.
`
`14.
`
`I reserve the right to rely upon additional materials to respond to
`
`arguments raised by Patent Owners and their experts. I may also consider additional
`
`documents and information in formng any necessary opinions, including documents
`
`Merck Ex. 1090, Pg. 7
`
`

`

`IV.
`
`CONIPENSATION
`
`15.
`
`I am being compensated by Merck for my work on this case at my
`
`standard consulting rate of $25,000 per quarter. My compensation is not contingent
`
`upon the results of my analysis or the substance of my testimony.
`
`I have no stake in
`
`the outcome of this proceeding or any related litigation or administrative
`
`proceedings.
`
`1 have no financial interest in Merck, and similarly have no financial
`
`interest in the ’41 5 patent or its owner.
`
`V.
`
`INTER PARTES REVIEW OF THE ’415 PATENT
`
`16.
`
`I understand that the Board has instituted the inter partes review of
`
`claims 1-4, 11, 12, 14, 18-20, and 33 (the “Challenged Claims”) of the ’415 patent
`
`on the following grounds:
`
`(EX. 2003,
`
`patent are obvious over the Bujard patent in view of P.J.
`Southern and P. Berg, Transformation ofMammalian Cells to
`Antibiotic Resistance with a Bacterial Gene Under Control of
`the SV40 Early Region Promoter, 1 J. MOLECULAR AND
`APPLIED GENETICS 327-341 (1982) (“Southern”) (EX. 1004).
`
`Ground 1: Whether claims 1, 3, 4, ll, l2, l4, l9, and 33 ofthe
`
`’41 5 patent are obvious over US Patent No. 4,495,280
`(“Bujard”) (EX. 1002) in view of Arthur D. Riggs and Keiichi
`ltakura, Synthetic DNA and Medicine, 31 AM. J. HUM. GENET.,
`531-538 (1979) (“Riggs & ltakura”) (Ex. 1003);
`
`Ground 2: Whether claims 1, 2, 18, 20, and 33 of the ’415
`
`17.
`
`I understand that the Board previously instituted the inter partes review
`
`of the Challenged Claims on the same grounds in a related proceeding.
`
`Merck Ex. 1090, Pg. 8
`
`

`

`lPR2015-01624, Paper 15).
`
`I also understand that the Board adopted the same
`
`reasoning in instituting the instant inter partes review.
`
`18.
`
`I understand that Petitioners have offered the Declaration of Jefferson
`
`Foote, Ph.D. (Ex. 1006) and the Declaration of Kathryn Calame, Ph.D. (EX. 1059)
`
`is not to supplement the opinions rendered by Dr. Foote or Dr. Calame. Rather, the
`
`scope of my opinions herein is limited to responding to certain opinions made by Dr.
`
`Fiddes and Dr. Gentz.
`
`A.
`
`Relevant Legal Standards
`
`in support of their petition for inter partes review. The purpose of this declaration
`
`that a printed publication, such as an article published in a
`
`19.
`
`In this section I briefly describe my understanding of certain legal
`
`standards that are relevant to my opinions in this declaration.
`
`I am not an attorney
`
`and am relying only on my understanding of these standards as they were explained
`
`to me by Merck’s attomeys.
`
`1.
`
`Legal Standard for Prior Art
`
`20.
`
`I understand that a patent or other publication must first qualify as prior
`
`art before it can be used to invalidate a patent claim.
`
`I also understand that:
`
`(l)
`
`a U. S. or foreign patent qualifies as prior art to an asserted patent
`
`under 35 U.S.C. § 102(a) if the date of issuance of the patent is
`
`prior to the invention of the asserted patent. I further understand
`
`Merck Ex. 1090, Pg. 9
`
`

`

`magazine or trade publication, qualifies as prior art under
`
`Section 102(a) to an asserted patent if the date of publication is
`
`prior to the invention of the asserted patent.
`
`a U. S. or foreign patent qualifies as prior art to an asserted patent
`
`under 35 U.S.C. § 102(b) if the date of issuance of the patent is
`
`more than one year before the filing date of the asserted patent.
`
`I further understand that a printed publication, such as an article
`
`published in a magazine or trade publication, constitutes prior art
`
`under 102(b) to an asserted patent if the publication occurs more
`
`than one year before the filing date of the asserted patent.
`
`a U. S. patent qualifies as prior art to an asserted patent under 35
`
`U.S.C. § 102(e) if the application for that patent was filed in the
`
`United States before the invention of the asserted patent claim.
`
`the differences between the prior art and the challenged claims, (3) the level of
`
`consideration of various factors such as (l) the scope and content of the prior art, (2)
`
`21.
`
`I understand that in an inter partes review proceeding, invalidity must
`
`be shown by a preponderance of the evidence.
`
`2.
`
`Legal Standard for Obviousness
`
`22.
`
`I understand that
`
`an obviousness determination includes
`
`the
`
`Merck Ex. 1090, Pg. 10
`
`

`

`ordinary skill in the pertinent art, and (4) the existence of secondary considerations
`
`such as commercial success, long-felt but unresolved needs, failure of others, etc.
`
`23.
`
`I understand that an obviousness evaluation can be based on a
`
`combination of multiple prior art references. I am informed by counsel that the prior
`
`art references themselves may provide a suggestion, motivation, or reason to
`
`combine, but at other times the nexus linking two or more prior art references is
`
`simple common sense.
`
`I am further informed by counsel that obviousness analysis
`
`recognizes that market demand often drives innovation, and that a motivation to
`
`combine references may be supplied by the direction of the marketplace.
`
`24.
`
`I understand that a person of ordinary skill in the art provides a
`
`reference point from which the prior art and claimed invention should be viewed.
`
`I
`
`am informed by counsel
`
`that obviousness cannot be based on the hindsight
`
`combination of components selectively drawn from the prior art.
`
`25.
`
`I understand that if a technique has been used to improve one device,
`
`beyond their primary purposes. I am further informed by counsel that a person of
`
`and a person of ordinary skill in the art would recognize that it would improve similar
`
`devices in the same way, using the technique is obvious unless its actual application
`
`is beyond his or her skill.
`
`26.
`
`I understand that practical and common sense considerations should
`
`guide a proper obviousness analysis because familiar items may have obvious uses
`
`Merck Ex. 1090, Pg. 11
`
`

`

`ordinary skill in the art looking to overcome a problem will often be able to fit the
`
`art need not be like two puzzle pieces that must fit perfectly together. I am informed
`
`by counsel that obviousness analysis therefore takes into account the inferences and
`
`creative steps that a person of ordinary skill in the art would employ under the
`
`circumstances.
`
`27.
`
`I understand that a particular combination may be proven obvious
`
`merely by showing that it was obvious to try the combination. For example, when
`
`there is a design need or market pressure to solve a problem and there are a finite
`
`number of identified, predictable solutions, a person of ordinary skill has good
`
`reason to pursue the known options within his or her technical grasp because the
`
`result is likely the product not of innovation but of ordinary skill and common sense.
`
`I am informed by counsel that the combination of familiar elements according to
`
`known methods is likely to be obvious when it does no more than yield predictable
`
`results. When a work is available in one field of endeavor, design incentives and
`
`other market forces can prompt variations of it, either in the same field or a different
`
`one. If a person of ordinary skill can implement a predictable variation, obviousness
`
`teachings of multiple publications together like pieces of a puzzle, although the prior
`
`known or obvious to a person of ordinary skill in the art, not just the patentee.
`
`likely bars its patentability.
`
`28.
`
`I understand that a proper obviousness analysis focuses on what was
`
`Merck Ex. 1090, Pg. 12
`
`

`

`Accordingly, I am informed by counsel that any need or problem known in the field
`
`of endeavor at the time of invention and addressed by the patent can provide a reason
`
`for combining the elements in the manner claimed.
`
`29.
`
`I understand that a claim can be obvious in light of a single reference,
`
`without the need to combine references, if the elements of the claim that are not
`
`found explicitly or inherently in the reference can be supplied by the common sense
`
`of one of skill in the art.
`
`from the very nature of the problem sought to solved that would lead inventors to
`
`two pieces of prior art and have a reasonable expectation of success. With respect
`
`30.
`
`I understand that a person of ordinary skill could have combined two
`
`pieces of prior art or substituted one prior art element for another if the substitution
`
`can be made with predictable results, even if the swapped-in element is different
`
`from the swapped-out element.
`
`In other words, the prior art need not be like two
`
`puzzle pieces that must fit together perfectly. The relevant question is whether prior
`
`art techniques are interoperable with respect to one another, such that that a person
`
`of skill would view them as a design choice, or whether a person of skill could apply
`
`prior art techniques into a new combined system.
`
`31.
`
`I understand person of ordinary skill must be motivated to combine the
`
`to the motivation to combine, I understand that to combine references may come
`
`from the references themselves, from the knowledge of those skilled in the art, or
`
`Merck Ex. 1090, Pg. 13
`
`

`

`look to references relating to possible solutions to that problem. I further understand
`
`that the motivation need not be expressly stated, but can be inferred.
`
`32. With respect to a respect to a reasonable expectation of success, I
`
`understand that refers to the likelihood of success in combining references to meet
`
`the limitations of the claimed invention.
`
`I have been informed that evaluating
`
`whether there is a reasonable expectation of success, there is no requirement for
`
`ab solute predictability of success—all that is required is a reasonable expectation of
`
`by others is a secondary consideration supporting an obviousness determination.
`
`success.
`
`I understand that where the reference discloses or suggests using its
`
`teachings toward the direction of the challenged patent, this is strong evidence for a
`
`reasonable expectation of success.
`
`33.
`
`I understand that secondary indicia of non-obviousness may include (1)
`
`a long felt but unmet need in the prior art that was satisfied by the invention of the
`
`patent; (2) commercial success or lack of commercial success of processes covered
`
`by the patent; (3) unexpected results achieved by the invention; (4) praise of the
`
`invention by others skilled in the art; (5) taking of licenses under the patent by others;
`
`and (6) deliberate copying of the invention. I am also informed by counsel that there
`
`must be a causal relationship between any such secondary indicia and the invention.
`
`I am further informed by counsel that contemporaneous and independent invention
`
`Merck Ex. 1090, Pg. 14
`
`

`

`34.
`
`Finally, I understand that the legal question of obviousness is resolved
`
`on the basis of underlying factual determinations, as described above, which differ
`
`from a non-statutory “obviousness-type double patenting” determination, which I
`
`have been informed came up in proceedings before the PTO.
`
`B.
`
`Level of Ordinary Skill in the Art
`
`35.
`
`I understand that factors relevant to the level of ordinary skill in the art
`
`include: (1) the educational level of the inventor; (2) type of problems encountered
`
`in the art', (3) prior art solutions to those problems; (4) rapidity with which
`
`definition in forming the opinion expressed herein.
`
`innovations are made', (5) sophistication of the technology; and (6) educational level
`
`of active workers in the field.
`
`I also understand these factors are not exhaustive but
`
`are merely a guide to formulating a definition of a person of ordinary skill in the art
`
`(“person of ordinary skill”).
`
`36.
`
`I understand that Drs. Foote and Calame have previously opined that a
`
`person of ordinary skill would have a PhD. in molecular biology (or a related
`
`discipline, such as biochemistry) with at least 1-2 years of postdoctoral experience,
`
`or an equivalent amount of combined education and laboratory experience. The
`
`person of ordinary skill would also have experience using recombinant DNA
`
`techniques to express proteins and have some familiarity with protein chemistry,
`
`immunology, and antibody production, structure, and function.
`
`I have applied this
`
`Merck Ex. 1090, Pg. 15
`
`

`

`37.
`
`I understand that Patent Owners do not dispute this definition of a
`
`person of ordinary skill in the art. (Paper 31, Patent Owners’ Response at 23).
`
`38. My opinions are from the point of view of this person of ordinary skill
`
`working in the field of heterologous, 1'. e., recombinant, protein expression as of April
`
`1983. Generally, and as used herein, a heterologous protein is one that is foreign to
`
`a host cell and is introduced using recombinant DNA techniques. For convenience,
`
`the produced proteins are sometimes called recombinant proteins, but technically it
`
`is the genes that are recombinant, rather than the protein itself.
`
`39.
`
`I understand that Dr. Fiddes has his own articulation of the level of skill
`
`in the art. (EX. 2019, Fiddes Decl. ml 147-49). 1 do not believe Dr. Fiddes’ definition
`
`the level of skill in the art.
`
`is materially different from my own, and my opinions in this declaration apply
`
`equally under either articulation of the level of skill in the art.2
`
`C.
`
`Claim Construction
`
`Dr. Gentz does not define the level of skill in the art. To the extent that his
`
`references to “a scientist with a PhD. in molecular biology or a related discipline,”
`
`(see, e.g., EX. 2021, Gentz Decl. 1M 30, 36), constitute his articulation of the level
`
`of skill in the art, I do not believe that definition is materially different from my
`
`own, and my opinions in this declaration apply equally under either articulation of
`
`Merck Ex. 1090, Pg. 16
`
`

`

`40.
`
`In responding to Dr. Fiddes and Dr. Gentz below, I have interpreted the
`
`Challenged Claims under the “broadest reasonable interpretation” of the claims
`
`“consistent with the specification,” and have read the claim language in light of the
`
`specification as it would be understood by a person of ordinary skill, which I
`
`understand is the approach taken by the Patent Trial and Appeal Board of the PTO
`
`in an inter partes review.
`
`VI.
`
`SUMMARY OF OPINIONS
`
`regarding the scope and teachings of Riggs & Itakura and Southern, alone and in
`
`use of the co-expression of multiple, distinct eukaryotic genes of interest in a single
`
`41.
`
`I have been asked to provide my expert opinion in response to certain
`
`opinions offered by Dr. Fiddes and Dr. Gentz concerning the state of the art in April
`
`1983, the Buj ard patent, Riggs & Itakura, and Southem.
`
`42.
`
`Dr. Fiddes’ and Dr. Gentz’s opinions are based on an overly narrow and
`
`selective reading of the Bujard patent.
`
`It is my opinion that Bujard (i) teaches the
`
`host cell, (ii) suggests a method for producing antibodies, and (iii) suggests the in
`
`viva assembly of a multimeric protein encoded by more than one gene in a single
`
`host cell. For a person of ordinary skill, the obvious import of applying the teachings
`
`of Bujard to produce the claimed subject matter would have been reinforced by the
`
`contemporaneous market demand to produce antibodies recombinantly.
`
`43.
`
`In addition, I disagree with Dr. Fiddes’ and Dr. Gentz’s opinions
`
`Merck Ex. 1090, Pg. 17
`
`

`

`combination with Buj ard. In my opinion, there was a strong motivation to combine
`
`Bujard with either Riggs & ltakura or Southern.
`
`44.
`
`It is my opinion that a person of ordinary skill would have been
`
`motivated to apply the teachings of either Riggs & Itakura or Southem with Buj ard
`
`to appreciate the feasibility of the co-expression of multiple independent proteins of
`
`skill would have a reasonable expectation of success to use the two different vectors
`
`interest in a single eukaryotic cell to make antibodies. First of all, contrary to Dr.
`
`Fiddes’ opinions, Bujard explicitly teaches that antibodies can be made by its
`
`method. Thus, when Riggs & ltakura disclosed the in vitro assembly of two chains
`
`and expressly noted the application of such technique to antibody production, it is
`
`obvious that such teachings will likewise extend to the explicit teachings of antibody
`
`production referenced in Bujard. Moreover,
`
`I disagree with Dr. Fiddes’
`
`characterization of Southern. Southern’s teaching of double transfection to produce
`
`two or more proteins is likewise equally applicable to, and would be read by a person
`
`of ordinary skill to include, the production of antibodies as taught in Bujard.
`
`45.
`
`In my opinion, a person of ordinary skill would have recognized that
`
`expressing two proteins of interest could have been accomplished by assembling the
`
`proteins in vitro as taught by Riggs & ltakura or, when the two genes are co-
`
`transformed in the cell by separate vectors, to provide for separate expression of the
`
`multiple desired proteins of interest, as taught by Southern. A person of ordinary
`
`Merck Ex. 1090, Pg. 18
`
`

`

`disclosed in Southern to co-transform a mammalian ho st cell with multiple, different
`
`genes of interest to separately express complex, eukaryotic proteins in a single host
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`cell. Similarly, a person of ordinary skill would have been equally motivated to use
`
`these same teachings to co-transform a single host cell with one vector to separately
`
`express multiple, different proteins of interest.
`
`46.
`
`In my opinion, a person of ordinary skill would have been motivated to
`
`use the tools taught by Buj ard to make antibodies using any of the above teachings
`
`relating to the co-transformation of recombinant DNA molecules and co-expression
`
`opinions expressed herein. (Ex. 1006, Foote Decl. W 26-41).
`
`techniques (e.g., as taught in Buj ard, Riggs & Itakura, or Southern) with a reasonable
`
`expectation of success in achieving the subject matter of the Challenged Claims.
`
`47.
`
`It is further my opinion that (i) the combination of Riggs & Itakura and
`
`Bujard renders the Challenged Claims of the ”415 patent obvious, and (ii) the
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`combination of Southem and Bujard renders the Challenged Claims of the ’415
`
`patent obvious.
`
`VII. THE CHALLENGED CLAIMS
`
`48.
`
`I have reviewed Dr. Foote”s description of the Challenged Claims and
`
`his overview of the ’415 patent and have applied that description in forming the
`
`Merck Ex. 1090, Pg. 19
`
`

`

`VIII. THE STATE OF THE ART FOR RECOMBINANT PROTEIN
`
`PRODUCTION IN APRIL 1983
`
`49.
`
`I understand that Patent Owners and Dr. Fiddes have suggested that
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`should be made recombinantly in a single host cell.
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`(See, e.g., Paper 31, Patent
`
`Owners” Response at 10-13; Ex. 2019, Fiddes Decl. W 87, 96).
`
`I disagree.
`
`I was
`
`active in the field in the early 1980s and I held no such View; nor did any other
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`scientist I know sub scribe to such a view. In fact, even in the early 1980 s, scientists
`
`possessed the ability to introduce multiple genes into single host cells for the purpose
`
`of recombinant expression of multiple proteins. At that time, recombinant DNA was
`
`becoming a tool of virtually every laboratory in any field of biology or biochemistry.
`
`Many recombinant DNA techniques had already become standard practice and
`
`scientists understood the practical impact and benefits of being able to manipulate
`
`genes and engineer proteins of interest in a single host cell rather than having to
`
`employ multiple expression systems across multiple host cells. The materials and
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`methods for doing so had developed in a step-wise fashion, and all of the steps had
`
`there was a prevailing mindset in the early 19803 that only one protein of interest
`
`17
`
`been accomplished and disclosed prior to April 1983.
`
`50.
`
`Dr. Fiddes
`
`acknowledges
`
`that
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`“recombinant gene
`
`expression
`
`technology was seen as a promising way to produce proteins of interest” in April
`
`1983, but claims that “many of the biological mechanisms controlling the expression
`
`of foreign DNA and the assembly of the resulting proteins were still poorly
`
`Merck Ex. 1090, Pg. 20
`
`

`

`understood at the time.” (Ex. 2019, Fiddes Decl. 11 57). I disagree. I was personally
`
`familiar with the materials and methods used to recombinantly-produce proteins in
`
`April 1983. As of that date, I was a professor of Structural Biology at Stanford
`
`University School of Medicine. Both myself and the researchers in my lab had been
`
`proteins for years.
`
`Indeed, numerous references describe the widespread use and
`
`application of these techniques and protocols for cloning genes, transforming host
`
`cells and analyzing recombinant protein expression.
`
`(See, e.g., Ex. 1095, Maniatis,
`
`T., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory
`
`(1982)).
`
`In the 1970s, recombinant DNA techniques were being used to produce
`
`proteins by transfecting cells with DNA sequences not already present in those cells,
`
`and then propagating the cells containing the heterologous DNA in vitro under
`
`using recombinant DNA techniques to manipulate and produce a wide variety of
`
`that were successfully co-transfected or co-transformed and have a certain
`
`conditions that cause the cell to produce the protein coded by that DNA. One notable
`
`example is the work of Stanley Cohen and Herbert Boyer, two researchers who
`
`shared the Albert Lasker Basic Medical Research Award with my Stanford
`
`University School of Medicine colleagues, Paul Berg (co-author of Southern, Ex.
`
`1004) and Dale Kaiser, for recombinantly expressing heterologous proteins in cells.
`
`Their work involved co-transfecting a vector with DNA foreign to that host cell (e.g,
`
`DNA coding for eukaryotic proteins in a prokaryotic cell) and selecting for the cells
`
`Merck Ex. 1090, Pg. 21
`
`

`

`“phenotypic property” by virtue of co-expressing a marker protein recombinantly.
`
`Thus, the cells are grown in conditions such that only cells that have acquired the
`
`selectable marker survive. The Cohen & Boyer technique, documented in US.
`
`Patent No. 4,237,224 (Ex. 1005), has been used extensively over the last forty plus
`
`years and remains a common method of expressing eukaryotic proteins in bacterial
`
`cells.
`
`51.
`
`Dr. Fiddes also opines that “[a]s of April 1983, E. coli, a prokaryotic
`
`bacterial organism, was the best characterized and most widely used host cell for
`
`cells lack