UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MERCK SHARP & DOHME CORP.
`Petitioner
`
`v.
`
`GENENTECH, INC. AND CITY OF HOPE
`Patent Owners
`____________
`
`U.S. Patent No. 6,331,415
`
`“Methods of Producing Immunoglobulins, Vectors and
`Transformed Host Cells for Use Therein”
`____________
`
`Inter Partes Review No. 2017-00047
`
`DECLARATION OF MARGARET H. BARON IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF U.S. PATENT NO. 6,331,415
`
`
`
`
`
`
`
`
`
`Merck Ex. 1006, pg 92
`
`

`
`
`
`TABLE OF CONTENTS
`
`I.
`
`BACKGROUND AND QUALIFICATIONS, PRIOR TESTIMONY, AND
`COMPENSATION ................................................................................................... 1
`
`A.
`
`B.
`
`Background and Qualifications ..................................................................... 1
`
`Prior Testimony and Compensation .............................................................. 5
`
`II. MATERIALS CONSIDERED ................................................................................. 5
`
`A.
`
`Anticipation ................................................................................................... 6
`
`B.
`
`C.
`
`Obviousness ................................................................................................... 7
`
`Person of Ordinary Skill in the Art ............................................................... 9
`
`D.
`
`Claim Construction........................................................................................ 9
`
`III.
`
`SUMMARY OF OPINIONS .................................................................................. 10
`
`IV. OVERVIEW OF THE ’415 PATENT AND THE CHALLENGED
`CLAIMS ................................................................................................................. 11
`
`A.
`
`Description of the Technology of the ’415 Patent and the Challenged
`Claims .......................................................................................................... 11
`
`B.
`
`The Prosecution and Reexamination History of the ’415 Patent ................ 19
`
`V.
`
`PRIOR ART RELEVANT TO MY OPINIONS .................................................... 22
`
`A.
`
`Technology Background ............................................................................. 22
`
`1.
`
`2.
`
`3.
`
`The Sophistication of Recombinant DNA Technology Was
`Advanced by April 8, 1983, and Mammalian Proteins Were
`Being Made in Host Cells Transformed with Foreign Genes .......... 22
`
`Prior Art Production of Single Immunoglobulin Chains ................. 25
`
`The Prevailing Mindset by April 1983 Was That One or More
`Proteins of Interest Could be Made in a Single Host Cell ............... 28
`
`B.
`
`References Underlying Merck’s Challenge to the Patentability of
`Claims of the ’415 Patent ............................................................................ 33
`
`
`
`i
`
`Merck Ex. 1006, pg 93
`
`

`
`
`
`1.
`
`2.
`
`3.
`
`4.
`
`The Bujard Patent Discloses Expressing a “Plurality of
`Genes” in Bacterial or Mammalian Host Cells and Identifies
`“Immunoglobulins” as a Protein of Interest ..................................... 33
`
`The Cohen & Boyer Patent Discloses Expressing “One or
`More Genes” in Bacteria and Identifies “Antibodies” as a
`Protein of Interest ............................................................................. 40
`
`Riggs & Itakura Discloses Hybridomas as a Source of
`Antibody Genes and the In Vitro Assemble of Heavy and
`Light Chains ..................................................................................... 46
`
`Southern Discloses One Host Cell Transformed with Two
`Vectors ............................................................................................. 47
`
`VI. ANTICIPATION AND OBVIOUSNESS OF THE CHALLENGED
`CLAIMS ................................................................................................................. 49
`
`A.
`
`Opinions in Support of Merck’s Anticipation and Obviousness
`Arguments Concerning the Challenged Claims Based on the Bujard
`Patent ........................................................................................................... 49
`
`1.
`
`2.
`
`3.
`
`4.
`
`Bujard Discloses Each and Every Limitation of Claims 1, 15,
`17 and 33 .......................................................................................... 49
`
`Bujard Discloses Each and Every Limitation of Claims 3, 4,
`9, 11, 12, 16 and 19 .......................................................................... 53
`
`Claims 1, 3, 4, 11, 12, 14, 19 and 33 in View of Bujard in
`Combination with Riggs & Itakura .................................................. 55
`
`Claims 1, 2, 18, 20 and 33 in View of Bujard in Combination
`with Southern ................................................................................... 58
`
`B.
`
`Opinions in Support of Merck’s Obviousness Arguments
`Concerning Claims 1, 3, 4, 11, 12, 14 and 33 Based on the Cohen &
`Boyer Patent and the Riggs & Itakura Publication ..................................... 60
`
`1.
`
`2.
`
`The Disclosures of Cohen & Boyer ................................................. 60
`
`Claims 1, 3, 4, 11, 12, 14, and 33 in View of Cohen & Boyer
`in Combination with Riggs & Itakura .............................................. 63
`
`VII. CONCLUSION ....................................................................................................... 66
`
`
`
`ii
`
`Merck Ex. 1006, pg 94
`
`

`
`
`
`I, Margaret H. Baron, hereby declare and state as follows:
`
`1.
`
`I have been retained as an expert by counsel for Merck Sharp &
`
`Dohme Corp. (“Merck”). I have prepared this declaration in connection with
`
`Merck’s related petition for Inter Partes Review of U.S. Patent No. 6,331,415 (“the
`
`’415 patent,” Ex. 1001), which I am informed is being filed concurrently with this
`
`declaration. I have been asked to provide certain opinions relating to the
`
`patentability of the ’415 patent. Specifically, I have been asked to provide my
`
`opinion regarding whether claims 1, 2, 3, 4, 9, 11, 12, 14, 15, 16, 17, 18, 19, 20,
`
`and 33 of the ’415 patent would have been obvious in view of the prior art.
`
`I.
`
`BACKGROUND AND QUALIFICATIONS, PRIOR TESTIMONY,
`AND COMPENSATION
`
`A.
`
`2.
`
`Background and Qualifications
`
`As further detailed in my CV, attached as Exhibit A, I received a
`
`bachelor’s degree from Harvard University (Cambridge, MA) in 1976 summa cum
`
`laude in Biochemical Sciences. My senior thesis involved a structural analysis of
`
`the aqueous central cavity (containing the active site) of the enzyme Aspartate
`
`Transcarbamylase (ATCase) of Escherichia coli. The research for this thesis was
`
`performed in the Department of Chemistry under the direction of the late William
`
`N. Lipscomb, Ph.D. (Nobel Laureate, 1976).
`
`3.
`
`In September 1976, I started medical and Ph.D. graduate studies in the
`
`Harvard-M.I.T. Program in Health Sciences and Technology (HST Program) at
`
`
`
`1
`
`Merck Ex. 1006, pg 95
`
`

`
`
`
`Harvard Medical School (Boston, MA) and Massachusetts Institute of Technology
`
`(M.I.T., Cambridge MA). I took medical school courses at Harvard Medical
`
`School and at M.I.T. and graduate courses in Biology at M.I.T. From July 1978
`
`through December 1981, I performed Ph.D. dissertation research in the laboratory
`
`of Nobel Laureate (1975) David Baltimore, Ph.D., in the Department of Biology at
`
`M.I.T. This research focused on the mechanism of replication of poliovirus, using
`
`protein and RNA nucleic acid biochemistry techniques. I received my Ph.D. from
`
`M.I.T. in March, 1982.
`
`4.
`
`From January 1982 through December 1982, I returned to Harvard
`
`Medical School to complete the clinical clerkship requirements for my M.D.
`
`degree, which was awarded in June 1983.
`
`5.
`
`From January 1983 through June 1983, I returned to David
`
`Baltimore’s laboratory at M.I.T. and carried out recombinant DNA studies of
`
`Abelson murine leukemia virus.
`
`6.
`
`From July 1983 through June 1984, I completed an internship in
`
`Internal Medicine at Massachusetts General Hospital. I subsequently became
`
`licensed in medicine and surgery (Diplomate, National Board of Medical
`
`Examiners) in the Commonwealth of Massachusetts.
`
`7.
`
`From August 1984 through March 1989, I was a postdoctoral fellow
`
`in the laboratory of Tom Maniatis, Ph.D., in the Department of Biochemistry and
`
`
`
`2
`
`Merck Ex. 1006, pg 96
`
`

`
`
`
`Molecular Biology at Harvard University (Cambridge, MA), where I analyzed the
`
`plasticity of the differentiated state (i.e., the ability to be reprogrammed) of
`
`mammalian erythroid cells. I was a Postdoctoral Fellow of the Helen Hay Whitney
`
`Foundation (1984-1987) and then a Postdoctoral Scholar of the Lucille P. Markey
`
`Charitable Trust.
`
`8.
`
`Following my postdoctoral training, I started an independent research
`
`laboratory in the Faculty of Arts and Sciences at Harvard University (Cambridge,
`
`MA). From April 1989 through June 1997, I was Assistant Professor (Department
`
`of Cellular and Developmental Biology) and then Associate Professor (Department
`
`of Molecular and Cellular Biology) at Harvard. My research there focused first on
`
`regulation of the human embryonic β-like globin gene (ε) (protein biochemistry
`
`and molecular biology, including recombinant DNA technology) and then on the
`
`mechanism of activation of hematopoiesis in the mouse embryo (embryology, cell
`
`biology, recombinant DNA technology). During this time, I was a Faculty Scholar
`
`of the Lucille P. Markey Charitable Trust.
`
`9.
`
`In July, 1997, I moved my laboratory to the Mount Sinai School of
`
`Medicine (New York, NY) as an Associate Professor with Tenure, in the
`
`Department of Medicine (Division of Hematology). I also held secondary
`
`appointments in three basic science departments. I was named the Irene and Dr.
`
`Arthur M. Fishberg Professor of Medicine in 2001 (as an Associate Professor) and
`
`
`
`3
`
`Merck Ex. 1006, pg 97
`
`

`
`
`
`was promoted to full Professor with Tenure in 2003. My research at Mount Sinai
`
`has covered several areas, including developmental hematopoiesis, stem cell
`
`biology, vascular development, and erythropoiesis. We make use of a wide range
`
`of techniques in cellular, molecular, and developmental biology and genetics.
`
`10. Research in my laboratory has been funded continuously by the
`
`National Institutes of Health since 1989 and by other agencies, including the New
`
`York State Department of Health, the March of Dimes, and the Roche Anemia
`
`Foundation.
`
`11.
`
`I have served as Interim Co-Director of the Black Family Stem Cell
`
`Institute of Mount Sinai, Director of Research in the Division of Hematology and
`
`Medical Oncology, and as Co-Director of two different Ph.D. training programs
`
`(Multidisciplinary Training Areas), one of which I co-founded.
`
`12.
`
`In 2012-2013, I was sponsored by Mount Sinai as a Fellow of the
`
`Executive Leadership in Academic Medicine Program of the Drexel University
`
`College of Medicine.
`
`13.
`
`In January, 2015, I was named Senior Associate Dean for Education
`
`and Director of the M.D./Ph.D. Program at the Icahn School of Medicine at Mount
`
`Sinai (formerly Mount Sinai School of Medicine).
`
`14.
`
`In addition to the fellowships I held while at Harvard and my
`
`endowed professorship at Mount Sinai, I have received numerous other awards and
`
`
`
`4
`
`Merck Ex. 1006, pg 98
`
`

`
`
`
`honors, detailed in my CV. I am an elected member of the American Society for
`
`Clinical Investigation and the Association of American Physicians.
`
`B.
`
`15.
`
`16.
`
`Prior Testimony and Compensation
`
`I have not given trial or deposition testimony in the last four years.
`
`I am being compensated at my normal consulting rate of $750 per
`
`hour and at a daily rate of $7,500. 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.
`
`I have no financial interest in the Petitioner or Merck, and similarly have no
`
`financial interest in the ’415 patent or its owners.
`
`II. MATERIALS CONSIDERED
`
`17.
`
`In forming the opinions that are set forth herein, I have considered and
`
`relied upon the scientific experience and knowledge I had in April 1983 when the
`
`’415 patent was filed, when that particular snapshot in time is relevant to my
`
`analysis. To the extent that the scientific experience and knowledge I have
`
`acquired after April 1983 is relevant to my analysis—e.g., in my analysis of claim
`
`9 of the ’415 patent, discussed below at Paragraph 100—I have relied on that as
`
`well. At all times, my analysis has been from the perspective of a person of
`
`ordinary skill in the art (“POSITA,” defined below).
`
`
`
`5
`
`Merck Ex. 1006, pg 99
`
`

`
`
`
`18.
`
`I also reviewed and considered the Declaration of Jefferson Foote,
`
`Ph.D. in Support of Sanofi-Aventis U.S. LLC and Regeneron’s Petition for Inter
`
`Partes Review of U.S. Patent No. 6,331,415 (IPR 2015-1624, Ex. 1006) as well as
`
`all materials and exhibits referenced therein.
`
`19. Although I am not a lawyer, I have been advised on certain relevant
`
`legal principles that I accept for the purpose of my analysis. Specifically, I am
`
`informed that 35 U.S.C. § 102 governs the determination of anticipation and that
`
`35 U.S.C.§ 103 governs the determination of obviousness. These are outlined
`
`below.
`
`A. Anticipation
`
`20.
`
`It is my understanding that for a patent claim to be invalid as
`
`anticipated in the context of an Inter Partes Review, it must be shown by a
`
`preponderance of the evidence (“more likely than not”) that all limitations of the
`
`claim are disclosed in a single prior art reference, either expressly or inherently.
`
`21. A claim limitation is inherent in the prior art if it is necessarily present
`
`in the prior art reference. This can occur, for example, (1) when the natural result
`
`flowing from an express disclosure in the prior art would result in the performance
`
`of the inherent feature, even if that result would not have been appreciated by a
`
`POSITA at the time; or (2) in situations where the common knowledge of
`
`
`
`6
`
`Merck Ex. 1006, pg 100
`
`

`
`
`
`technologists is not recorded in the reference, such as where technological facts are
`
`known to those in the field of the invention but not to lay persons.
`
`22. A prior art reference does not need to anticipate every possible
`
`embodiment within the scope of the claim: it anticipates if it discloses an
`
`embodiment that is within the scope of the claim.
`
`23. Moreover, anticipation does not require actual performance of the
`
`suggestions contained in a disclosure, nor are the anticipatory disclosures of a prior
`
`art reference limited to the reference’s preferred embodiments. Anticipation
`
`requires only that the reference describe the claimed invention in a manner to have
`
`placed the public in possession of it. Such possession is effected if a POSITA
`
`could have combined the publication’s description of the invention with his own
`
`knowledge to make the claimed invention without undue experimentation.
`
`B. Obviousness
`
`24.
`
`It is my understanding that in order to invalidate a patent claim as
`
`obvious in the context of an Inter Partes Review, it must be shown by a
`
`preponderance of the evidence that the claim would have been obvious to a
`
`POSITA at the time the invention was made. The prior art does not need to render
`
`obvious every possible embodiment within the scope of the claim: the prior art
`
`renders the claim obvious if the combined teachings disclose an embodiment that
`
`is within the scope of the claim. In determining whether a patent claim is invalid
`
`
`
`7
`
`Merck Ex. 1006, pg 101
`
`

`
`
`
`because of obviousness, one must consider the scope and content of the prior art,
`
`the differences between the prior art and the claimed invention, and the level of
`
`ordinary skill in the art.
`
`25.
`
`I am also informed that obviousness can be established by combining
`
`or modifying the teachings of the prior art to produce the claimed invention where
`
`there is some teaching, suggestion, or motivation to do so; and that a reasonable
`
`expectation of success in achieving the subject matter of the claim at issue must
`
`also be shown. Further, I am informed that the teaching, suggestion or motivation
`
`test is flexible and that an explicit suggestion to combine the prior art is not
`
`necessary—the motivation to combine may be implicit and may be found in the
`
`knowledge of one of ordinary skill in the art, from the nature of the problem to be
`
`solved, market demand, or common sense.
`
`26. A prior art reference is pertinent to the obviousness analysis if it
`
`discloses information designed to solve the same problems faced by the patent’s
`
`inventors or if the reference discloses information that has obvious uses beyond its
`
`main purpose that a POSITA would reasonably examine to solve the same
`
`problems faced by the inventors.
`
`27.
`
`In undertaking an obviousness analysis, I also understand that I may
`
`take into account the inferences and creative steps that a POSITA would have
`
`employed in reviewing the prior art at the time of the invention. If the claimed
`
`
`
`8
`
`Merck Ex. 1006, pg 102
`
`

`
`
`
`invention combines elements known in the prior art and the combination yields
`
`results that would have been predictable to a POSITA at the time of the invention,
`
`then this evidence would make it more likely that the claim was obvious.
`
`C.
`
`Person of Ordinary Skill in the Art
`
`28. Some of my opinions refer to the perspective of a POSITA at the time
`
`at which the ’415 patent was filed (April 8, 1983). With respect to the particular
`
`subject matter that is the focus of my opinions below, it is my opinion that a
`
`POSITA would have a Ph.D. in molecular biology (or a related discipline, such as
`
`biochemistry) with 1 or 2 years of post-doctoral experience, or an equivalent
`
`amount of combined education and laboratory experience. The POSITA 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 base this opinion on the level of education
`
`and experience of persons actively working in the field at the time of the invention,
`
`including the inventors of the ’415 patent; the type of problems encountered in the
`
`art and the prior art solutions to those problems; and the sophistication of the
`
`technology in the art at the time of the invention, including the rapidity with which
`
`innovations were made in the art at the time of the invention.
`
`D. Claim Construction
`
`
`
`9
`
`Merck Ex. 1006, pg 103
`
`

`
`
`
`29.
`
`I understand that in the context of an Inter Partes Review, the Patent
`
`Trial and Appeal Board of the U.S. Patent and Trademark Office (“USPTO”) is
`
`charged with applying the “broadest reasonable interpretation” of the claims
`
`“consistent with the specification,” and that the claim language should read in light
`
`of the specification as it would be understood by a POSITA. In reaching my
`
`conclusions expressed below, I have interpreted the challenged claims consistent
`
`with these standards and requirements.
`
`III. SUMMARY OF OPINIONS
`
`30. As set out in further detail below, a summary of my opinions
`
`expressed in this declaration is as follows:
`
`(1) all of the limitations of claims 1, 3, 4, 9, 11, 12, 15, 16, 17, 19 and 33 of
`
`the ’415 patent are disclosed in the Bujard patent (Ex. 1002);
`
`(2) a POSITA would have been motivated to combine the disclosures of the
`
`Bujard patent with the disclosures of Riggs & Itakura (Ex. 1003) with a
`
`reasonable expectation of success in achieving the subject matter of
`
`claims 1, 3, 4, 11, 12, 14, 19 and 33 of the ’415 patent;
`
`(3) a POSITA would have been motivated to combine the disclosures of the
`
`Bujard patent with the disclosures of Southern (Ex. 1004) with a
`
`reasonable expectation of success in achieving the subject matter of
`
`claims 1, 2, 18, 20 and 33 of the ’415 patent; and
`
`
`
`10
`
`Merck Ex. 1006, pg 104
`
`

`
`
`
`(4) a POSITA would have been motivated to combine the disclosures of the
`
`Cohen & Boyer patent (Ex. 1005) with the disclosures of Riggs & Itakura
`
`with a reasonable expectation of success in achieving the subject matter
`
`of claims 1, 3, 4, 11, 12, 14 and 33 of the ’415 patent.
`
`IV. OVERVIEW OF THE ’415 PATENT AND THE CHALLENGED
`CLAIMS
`
`A. Description of the Technology of the ’415 Patent and the
`Challenged Claims
`
`31. The ’415 patent is directed to processes and related compositions for
`
`making immunoglobulins (or fragments thereof) in host cells using recombinant
`
`DNA technology. Ex. 1001 at 1:14-21, 4:53-62. Immunoglobulins are proteins (or
`
`“polypeptides”) having a globular conformation that are produced by and secreted
`
`from cells of the immune system of vertebrates in response to the presence in the
`
`body of a foreign substance, called an “antigen,” often a foreign protein or foreign
`
`cell (such as a bacterium). Id. at 1:23-37; 16:38-39. Immunoglobulins bind to
`
`antigens to rid the body of the foreign invader. Id. at 1:26-31. Most
`
`immunoglobulins are composed of two heavy chain polypeptides and two light
`
`chain polypeptides that are connected via disulfide bonds (represented below as –
`
`SS–) to form a four-chain tetramer with a highly specific and defined Y-shaped
`
`conformation that is required for antigen binding.
`
`
`
`11
`
`Merck Ex. 1006, pg 105
`
`

`
`
`
`
`
`Id. at Fig. 1, 3:17-26.
`
`32. The heavy and light chains comprise segments referred to as the
`
`variable and constant domains (or regions). Id. at 3:42-59. The heavy chain and
`
`light chain are encoded by separate DNA sequences or genes. Id. at 1:48-51. The
`
`nature of immunoglobulin structure and function as described above would have
`
`been well within the common knowledge of a POSITA before April 8, 1983. This
`
`is evidenced by the discussion of the subject under “Background of the Invention”
`
`in the ’415 patent. Id. at 1:22-4:5.
`
`33. The patent identifies a prior art method of making antibodies in
`
`hybridoma cells, which results in the production of a homogeneous antibody
`
`population that specifically binds to a single antigen, so called “monoclonal”
`
`
`
`12
`
`Merck Ex. 1006, pg 106
`
`

`
`
`
`antibodies. Id. at 1:64-2:19. According to the patent, the use of recombinant DNA
`
`technology to make antibodies avoids the drawbacks of hybridoma production. Id.
`
`at 2:40-3:2.
`
`34. The recombinant DNA approach to making antibodies described in
`
`the ’415 patent, in short, proceeds as follows: (1) the genetic material encoding the
`
`heavy and light chain polypeptides is identified and isolated (for example, from a
`
`hybridoma) (id. at 11:28-12:8); (2) the heavy and light chain DNA is introduced
`
`into suitable host cells by a process called “transformation,” which may be
`
`facilitated by first inserting the DNA into an expression vector that acts as a
`
`vehicle to introduce the foreign DNA into the host cell (id. at 12:9-30); and (3) the
`
`host cells transcribe and translate the heavy and light chain DNA, a process called
`
`“expression,” to produce the heavy and light chain polypeptides (id. at 12:31-33,
`
`4:24-29). This process is depicted below:
`
`
`
`13
`
`
`
`Merck Ex. 1006, pg 107
`
`

`
`
`
`Host cells may either be microorganisms (for example, prokaryotic cells, such as
`
`bacteria) or cell lines from multicellular eukaryotic organisms, including
`
`mammalian cells. Id. at 8:41-56, 9:56-10:18.
`
`35.
`
`I understand that Merck is challenging the patentability of claims 1-4,
`
`9, 11, 12, 14-20 and 33. The text of these claims is reproduced below:
`
`1. A process for producing an immunoglobulin molecule or an
`
`immunologically functional immunoglobulin fragment comprising at least
`
`the variable domains of the immunoglobulin heavy and light chains, in a
`
`single host cell, comprising the steps of: (i) transforming said single host cell
`
`with 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, and (ii)
`
`independently expressing said first DNA sequence and said second DNA
`
`sequence so that said immunoglobulin heavy and light chains are produced
`
`as separate molecules in said transformed single host cell.
`
`2. The process according to claim 1 wherein said first and second DNA
`
`sequences are present in different vectors.
`
`3. The process according to claim 1 wherein said first and second DNA
`
`sequences are present in a single vector.
`
`4. A process according to claim 3 wherein the vector is a plasmid.
`
`9. A process according to claim 1 wherein the immunoglobulin heavy and
`
`light chains are expressed in the host cell and secreted therefrom as an
`
`immunologically functional immunoglobulin molecule or immunoglobulin
`
`fragment.
`
`
`
`14
`
`Merck Ex. 1006, pg 108
`
`

`
`
`
`11. A process according to claim 1 wherein the DNA sequences code for the
`
`complete immunoglobulin heavy and light chains.
`
`12. The process according to claim 1 wherein said first or said second DNA
`
`sequence further encodes at least one constant domain, wherein the constant
`
`domain is derived from the same source as the variable domain to which it is
`
`attached.
`
`14. The process according to claim 1 wherein said first and second DNA
`
`sequences are derived from one or more monoclonal antibody producing
`
`hybridomas.
`
`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.
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`16. A vector according to claim 15 which is a plasmid.
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`17. A host cell transformed with a vector according to claim 15.
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`18. A transformed host cell comprising at least two vectors, at least one of
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`said vectors comprising a DNA sequence encoding at least a variable
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`domain of an immunoglobulin heavy chain and at least another one of said
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`vectors comprising a DNA sequence encoding at least the variable domain
`
`of an immunoglobulin light chain.
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`19. The process of claim 1 wherein the host cell is a mammalian cell.
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`20. The transformed host cell of claim 18 wherein the host cell is a
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`mammalian cell.
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`33. A process for producing an immunoglobulin molecule or an
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`immunologically functional immunoglobulin fragment comprising at least
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`the variable domains of the immunoglobulin heavy and light chains, in a
`
`
`
`15
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`Merck Ex. 1006, pg 109
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`
`
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`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
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`immunoglobulin light chain so that said immunoglobulin heavy and light
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`chains are produced as separate molecules in said single host cell
`
`transformed with said first and second DNA sequences.
`36. Generally speaking, independent process claims 1 and 33 are directed
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`to a method for producing an immunoglobulin by expressing at least the variable
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`domains of both the immunoglobulin heavy and light chains inside a single host
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`cell transformed with DNA encoding at least the variable domains of both the
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`immunoglobulin heavy and light chains.
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`37. Claims 2, 3, 4, 9, 11, 12, 14 and 19 are dependent on claim 1 (or on
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`another claim dependent thereon) and therefore incorporate all of the limitations of
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`claim 1. Claim 2 requires that the two DNA sequences of claim 1 “are present in
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`different vectors.” Claim 3 requires that the heavy and light chain DNA sequences
`
`be “present in a single vector.” Claim 4 requires that the “vector” of claim 3 is a
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`“plasmid.” Claim 9 requires that the heavy and light chains of claim 1 “are
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`expressed in the host cell and secreted therefrom as an immunologically functional
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`immunoglobulin molecule or immunoglobulin fragment.” Claim 11 requires that
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`the DNA sequences encode the “complete” heavy and light chain polypeptides.
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`Claim 12 requires that any “constant domain” encoded by the DNA sequences “is
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`derived from the same source as the variable domain to which it is attached.”
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`
`
`16
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`Merck Ex. 1006, pg 110
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`
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`Claim 14 requires that the heavy and light chain DNA sequences “are derived from
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`one or more monoclonal antibody producing hybridomas.” And claim 19 requires
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`that the host cell is a “mammalian cell.”
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`38.
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`Independent claim 15 is directed to a single vector containing DNA
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`encoding at least the variable domains of both the immunoglobulin heavy and light
`
`chains. Claim 16, dependent on claim 15, adds the requirement that the “vector” of
`
`claim 15 is a “plasmid.” Claim 17 is directed to a host cell transformed with the
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`vector of claim 15.
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`39.
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`Independent claim 18 is directed to a host cell comprising at least two
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`vectors, with the first vector containing a DNA sequence encoding at least the
`
`variable domain of the immunoglobulin heavy chain, and the second vector
`
`containing a DNA sequence encoding at least the variable domain of the
`
`immunoglobulin light chain. Claim 20, dependent on claim 18, adds the
`
`requirement that the “host cell” of claim 18 is a “mammalian cell.”
`
`40. All of the challenged claims, by their very language, require two
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`genes: a first DNA sequence encoding the heavy chain and a second DNA
`
`sequence encoding the light chain. Likewise, all of the challenged process claims
`
`require that the host cell express both DNA sequences to produce both heavy chain
`
`and light chain polypeptides (referred to as “co-expression” in the ’415 patent).
`
`Ex. 1001, at 12:50-51; see also Ex. 1009, Owners’ Response (11/25/05), at 46.
`
`
`
`17
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`Merck Ex. 1006, pg 111
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`
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`The challenged process claims also require that the heavy and light chain
`
`polypeptides are produced as “separate molecules” by virtue of their “independent
`
`expression.” Ex. 1001, claims 1, 33; see also Ex. 1022, Owners’ Response
`
`(10/30/06), at 30 (“[T]he ’415 patent requires that the transformed cell produce the
`
`immunoglobulin heavy and light chain polypeptides encoded by the two DNA
`
`sequences as separate molecules. This result stems from the requirement for
`
`independent expression of the introduced DNA sequences. . . .”).
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`41. Furthermore, the process claims also require assembly of the separate
`
`heavy and light chain polypeptides into an immunoglobulin tetramer. Ex. 1009,
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`Owners’ Response (11/25/05), at 46. This can occur inside of the host cell through
`
`its natural cellular machinery (“in vivo” assembly), which could then secrete the
`
`assembled immunoglobulin out of the cell; or, if the host cell is unable to assemble
`
`the chains in vivo, the cell may be lysed and the separate chains assembled by
`
`chemical means (“in vitro” assembly). Ex. 1010, Owners’ Response (5/21/07), at
`
`29 & n. 8; Ex. 1001, 12:50-55, claims 9 & 10; Ex. 1011, Office Action (9/13/05),
`
`at 3. The processes of in vivo and in vitro assembly of the co-expressed chains is
`
`depicted below:
`
`
`
`18
`
`Merck Ex. 1006, pg 112
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`
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`
`
`B.
`
`42.
`
`The Prosecution and Reexamination History of the ’415 Patent
`
`I have reviewed the substantive sections of the prosecution file history
`
`and the reexamination proceedings for the ’415 patent (i.e., arguments between the
`
`USPTO and Genentech and City of Hope’s attorneys and associated expert
`
`declarations) in connection with preparing my declaration.
`
`43.
`
`I understand that during the reexamination proceedings, the PTO
`
`rejected the ’415 patent claims based on a number of prior art patent references. In
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`particular, the PTO rejected the claims over the Axel patent (U.S. Patent No.
`
`4,399,216, Ex. 1018). See, e.g., Ex. 1011, Office Action (9/13/05), at 5; Ex. 1016,
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`Office Action (8/16/06), at 21-24; Ex. 1008, Office Action (2/16/07), at 22-24, 26-
`
`31, 50-51; Ex. 1017, Office Action (2/25/08), at 12-14, 27-31.
`
`
`
`19
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`Merck Ex. 1006, pg 113
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`44. The invention of the Axel patent concerned “the introduction and
`
`expression of genetic informational material, i.e., DNA which includes genes
`
`coding for proteinaceous materials . . . into eucaryotic[sic] cells. . . . Such genetic
`
`intervention is commonly referred to as genetic engineering and in certain aspects
`
`involves the use of recombinant DNA technology.” Ex. 1018, Axel patent, 1:12-
`
`21. Axel disclosed the transformation of eukaryotic (mammalian) h