UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SANOFI-AVENTIS U.S. LLC AND
`
`REGENERON PHARMACEUTICALS, INC,
`Petitioners
`
`V.
`
`GENENTECH, INC. AND CITY OF HOPE,
`Patent Owners
`
`U.S. Patent No. 6,331,415
`Appl. No. 07/205,419, filed June 10, 1988
`Issued: Dec. 18, 2001
`
`Title: Methods of Producing Immunoglobulins, Vectors
`and Transformed Host Cells for Use Therein
`
`IPR Trial No. TBD
`
`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
`
`716732358
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`Sanofi/Regeneron Ex. 1006, pg 92
`
`Mylan Ex. 1006, pg 92
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`

`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`BACKGROUND AND QUALIFICATIONS, PREVIOUS
`
`TESTIMONY, AND COMPENSATION .................................................... ..l
`
`A.
`
`B.
`
`C.
`
`Background and Qualifications .......................................................... ..l
`
`Prior Testimony .................................................................................. ..4
`
`Compensation ..................................................................................... . .4
`
`II. MATERIALS CONSIDERED ..................................................................... ..5
`
`A.
`
`B.
`
`C.
`
`Anticipation ........................................................................................ . .5
`
`Obviousness ........................................................................................ . .6
`
`Person of Ordinary Skill in the Art .................................................... ..8
`
`D.
`
`Claim Construction ............................................................................. ..9
`
`III.
`
`SUI\/[MARY OF OPINIONS ........................................................................ ..9
`
`IV. OVERVIEW OF THE '4l5 PATENT AND THE CHALLENGED
`
`CLAIMS ..................................................................................................... ..lO
`
`A.
`
`Description of the Technology of the '41 5 Patent and the
`Challenged Claims ........................................................................... ..lO
`
`B.
`
`The Prosecution and Reexamination History of the '4l5 Patent ...... ..l9
`
`V.
`
`PRIOR ART RELEVANT TO MY OPINIONS ........................................ ..22
`
`A.
`
`Technology Background .................................................................. ..22
`
`l.
`
`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
`
`2.
`
`Prior Art Production of Single Immunoglobulin Chains ....... ..25
`
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`Sanofi/Regeneron Ex. 1006, pg 93
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`Mylan Ex. 1006, pg 93
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`

`
`TABLE OF CONTENTS
`
`(continued)
`
`Page
`
`3.
`
`The Prevailing Mindset by April 1983 Was That One or
`More Proteins of Interest Could be Made in a Single Host
`Cell ......................................................................................... ..27
`
`B.
`
`References Underlying Petitioners’ Challenge to the
`Patentability of the Claims of the '415 Patent .................................. ..33
`
`1.
`
`2.
`
`3.
`
`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 ................................................................... ..4O
`
`Riggs & Itakura Discloses Hybridomas as a Source of
`Antibody Genes and the In Vitro Assembly of Heavy and
`Light Chains ........................................................................... ..45
`
`4.
`
`Southern Discloses One Host Cell Transformed with
`
`Two Vectors ........................................................................... ..46
`
`VI. ANTICIPATION AND OBVIOUSNESS OF THE CHALLENGED
`
`CLAIMS ..................................................................................................... ..49
`
`A.
`
`Opinions in Support of Petitioners’ Anticipation and
`Obviousness Arguments Concerning the Challenged Claims
`Based on the Bujard Patent .............................................................. ..49
`
`1.
`
`2.
`
`3.
`
`Bujard Discloses Each and Every Limitation of Claims 1,
`15,17 and33 .......................................................................... ..49
`
`Bujard Discloses Each and Every Limitation of Claims 3,
`4, 9, 11, 12, 16 and 19 ............................................................ ..52
`
`Claims 1, 3, 4,11,12,14,19 and 33 in View ofBujard in
`Combination with Riggs & Itakura ........................................ ..54
`
`716732358
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`Sanofi/Regeneron Ex. 1006, pg 94
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`Mylan Ex. 1006, pg 94
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`

`
`TABLE OF CONTENTS
`
`(continued)
`
`Page
`
`4.
`
`Claims 1, 2, 18, 20 and 33 in View of Bujard in
`Combination with Southern ................................................... ..57
`
`B.
`
`Opinions in Support of Petitioners‘ Obviousness Arguments
`Concerning Claims 1, 3, 4, 11, 12, 14 and 33 Based on the
`Cohen & Boyer Patent and the Riggs & Itakura Publication ........... ..6O
`
`1.
`
`The Disclosures of Cohen & Boyer ....................................... ..6O
`
`a.
`
`b.
`
`Cohen & Boyer Disclosures with Respect to
`Independent Claims 1 and 33 ...................................... ..6O
`
`Cohen & Boyer's Disclosures with Respect to
`Dependent Claims 3, 4, 11 and 12 ............................... ..62
`
`2.
`
`Claims 1, 3, 4,11,12,14 and 33 in View of Cohen &
`Boyer in Combination with Riggs & Itakura ......................... ..63
`
`716732358
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`iii
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`Sanofi/Regeneron Ex. 1006, pg 95
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`Mylan Ex. 1006, pg 95
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`

`
`1.
`
`I, Jefferson Foote, Ph.D., have been retained by Mayer Brown LLP,
`
`counsel for sanofi-aventis U.S. LLC and Regeneron Pharmaceuticals, Inc.
`
`I
`
`understand that sanofi-aventis and Regeneron have petitioned for inter partes
`
`review of U.S. Patent No. 6,331,415 ("the '415 patent," Ex. 1001) and requested
`
`that the United States Patent and Trademark Office cancel Claims 1-4, 9, 11, 12,
`
`14-20 and 33 of the '415 patent ("the challenged claims") as unpatentable. The
`
`following discussion and analyses address and are presented in support of the bases
`
`for sanofi-aventis and Regeneron’s petition.
`
`I.
`
`BACKGROUND AND QUALIFICATIONS, PREVIOUS
`
`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 College in 1977 in Biochemical Sciences. My
`
`senior thesis involved structural studies on the enzyme aspartate transcarbamylase
`
`from Escherichia coll" (E. coll") and was performed in the Chemistry Department
`
`under the direction of Professor William N. Lipscomb.
`
`3.
`
`After receiving my undergraduate degree, I worked as a research
`
`assistant in Harvard's Department of Biochemistry and Molecular Biology from
`
`1977-79 in the laboratory of Professor David Dressler. My first research project
`
`716732358
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`
`was an attempt to clone an antibody gene. I subsequently performed studies on the
`
`biochemical basis of genetic recombination in E. coll".
`
`4.
`
`From 1979-1980, I worked as a research assistant in the Chemistry
`
`Department at Boston College, under the direction of Professor Evan Kantrowitz.
`
`The projects I worked on included genetic approaches to studying the structure and
`
`function of aspartate transcarbamylase, which included an attempt to clone the
`
`gene encoding it. I also performed enzyme mechanism studies and briefly
`
`undertook structure-function studies of the beta-lactamase gene cloned in the
`
`plasmid pBR322.
`
`5.
`
`From 1980-1985, I was a graduate student at University of California,
`
`Berkeley.
`
`I received my Ph.D. from the University of California, Berkeley in 1985
`
`in the department of Biochemistry. I did research for my dissertation in the
`
`laboratory of Professor Howard Schachman, focusing on kinetic studies of
`
`recombinant aspartate transcarbamylase.
`
`6.
`
`From 1985-1992, I was a postdoctoral fellow at the Medical Research
`
`Council Laboratory of Molecular Biology, in Cambridge, England, in the
`
`laboratories of Sir Gregory Winter and the late Cesar Milstein and performed
`
`antibody research there. My work at the MRC in Cambridge included
`
`development of the first "humanized" antibodies with Dr. Winter and biophysical
`
`aspects of immune responses with Dr. Milstein.
`
`716732358
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`Sanofi/Regeneron Ex. 1006, pg 97
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`Mylan Ex. 1006, pg 97
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`7.
`
`Following my post-doctoral fellowship, I held faculty positions from
`
`1992-2004 at the Fred Hutchinson Cancer Research Center and at the University of
`
`Washington, both in Seattle. My research group at Fred Hutchinson studied 3-
`
`dimensional structures of humanized antibodies, and developed a new
`
`humanization method (for which I am an inventor of U.S. Patent Nos. 6,881,5 57,
`
`7,709,226; and 7,732,578). My research also focused on developing a drug
`
`delivery method using antibodies. In 2003, I started Arrowsmith Technology
`
`Licensing LLC (originally Arrowsmith Technologies LLC), which was assigned
`
`rights to U.S. Patent No. 6,881,557 from Fred Hutchinson.
`
`8.
`
`To commercialize the aforementioned humanization method, I co-
`
`founded Absalus, Inc., a biotechnology company in Mountain View, CA. Absalus
`
`merged with EvoGenix Ltd, an Australian biotechnology company, which
`
`subsequently merged with Peptech Corp., another Australian biotechnology
`
`company, to form Arana Therapeutics, Ltd. Arana was acquired by Cephalon,
`
`Inc., a Philadelphia-based pharmaceutical company. Teva Pharmaceutical
`
`Industries Ltd (Petah Tikva, Israel) subsequently acquired Cephalon, Teva is the
`
`exclusive licensee of the humanization technology.
`
`9.
`
`In 2004, I left Fred Hutchinson after starting Arrowsmith
`
`Technologies Corporation to commercialize the aforementioned drug delivery
`
`technology (US. Patent Application No. 11/226,05 5), the rights to which were
`
`716732358
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`Mylan Ex. 1006, pg 98
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`

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`acquired from Fred Hutchinson.
`
`I divide my professional time among maintaining
`
`a laboratory, scholarly activities such as peer review, prosecuting the drug delivery
`
`patent, presenting the drug delivery technology to potential investors, and scientific
`
`and legal consulting.
`
`10.
`
`I have received the following awards and accolades during my career:
`
`Jane Coffin Childs Fellow, 1985-88, Merck Fellow, 1989-92, and Beckman Young
`
`Investigator, 1995-97.
`
`B.
`
`Prior Testimony
`
`11.
`
`In the last four years, I have given testimony in Glaxo Group Ltd. et
`
`al. v. Genentech, Inc. et al., Case No. 10-cv-02764-MRP (CD. Cal); Perez-
`
`Melgosa v. State of Washington, Case No. 13-2-36617-7 SEA (Washington
`
`Superior Court), and Bristol-Myers Squibb v. Genentech, Inc. et al., Case No.13-
`
`cv-05400 (CD. Cal.).
`
`C.
`
`Compensation
`
`12.
`
`I am being compensated at my normal consulting rate of $600 per
`
`hour, except for oral testimony, for which I will be compensated at a rate of $800
`
`per hour. I have no personal financial interest in any of the entities involved in this
`
`litigation and my compensation does not depend in any way on my testimony, my
`
`conclusions or the outcome of my analysis.
`
`716732358
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`Sanofi/Regeneron Ex. 1006, pg 99
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`Mylan Ex. 1006, pg 99
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`
`II. MATERIALS CONSIDERED
`
`13.
`
`In reaching my opinions, I have considered the documents identified
`
`in this declaration. I have also 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 95—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).
`
`14. 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
`
`15.
`
`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.
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`Mylan Ex. 1006, pg 100
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`16. 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
`
`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.
`
`17. 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.
`
`18. 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
`
`19.
`
`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
`
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`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
`
`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.
`
`20.
`
`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.
`
`21. A prior art reference is pertinent to the obviousness analysis if it
`
`discloses information designed to solve the same problems faced by the patents
`
`inventors or if the reference discloses information that has obvious uses beyond its
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`main purpose that a POSITA would reasonably examine to solve the same
`
`problems faced by the inventors.
`
`22.
`
`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
`
`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
`
`23.
`
`Some of my opinions refer to the perspective of a POSITA at the time
`
`at which the '4l5 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 l 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 '4l5 patent, the type of problems encountered in the
`
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`Mylan Ex. 1006, pg 103
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`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
`
`24.
`
`I understand that in the context of an Inter Partes Review, the Patent
`
`Trial and Appeal Board of the 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
`
`25. As set out in further detail below, a summary of my opinions
`
`expressed in this declaration is as follows:
`
`°
`
`all ofthe limitations of claims 1, 3, 4, 9, ll, l2, l5, l6, l7, l9 and 33 of
`
`the '4l5 patent are disclosed in the Bujard patent (Ex. 1002),
`
`°
`
`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, ll, l2, l4, l9 and 33 ofthe '4l5 patent;
`
`°
`
`a POSITA would have been motivated to combine the disclosures of the
`
`Bujard patent with the disclosures of Southern (Ex. 1004) with a
`
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`
`reasonable expectation of success in achieving the subject matter of
`
`claims 1, 2, 18, 20 and 33 ofthe '415 patent, and
`
`°
`
`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 ofthe '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
`
`26.
`
`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. Ex. 1001 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
`
`—S S—) to form a four-chain tetramer with a highly specific and defined Y-shaped
`
`conformation that is required for antigen binding.
`
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`Sanofi/Regeneron Ex. 1006, pg 105
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`Mylan Ex. 1006, pg 105
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`

`
`Id. at Fig. l and 3:17-26.
`
`27.
`
`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 '4l5 patent. Id. at 1:22-4:5.
`
`28.
`
`The patent identifies a prior art method of making antibodies in
`
`hybridoma cells, which results in the production of a homogeneous antibody
`
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`Sanofi/Regeneron Ex. 1006, pg 106
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`Mylan Ex. 1006, pg 106
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`

`
`population that specifically binds to a single antigen, so called ”monoclonal”
`
`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 2140-3 :2.
`
`29.
`
`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 129-30), 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:
`
`716732358
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`12
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`Sanofi/Regeneron Ex. 1006, pg 107
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`Mylan Ex. 1006, pg 107
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`

`
`Heavy chain
`
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`
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`
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`
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`
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`
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`
`into vector
`—>
`
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`
`'_
`
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`4
`ii
`0-0
`
`H0
`
`Heavy and Light Chain DNA
`nucleotide sequences
`
`Vector containing
`heavy and light chain DNA
`
`Light chain
`
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`
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`
`V/_»/:"’”‘\\_
`o
`-
`I O
`I
`L
`_
`Expression
`‘‘
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`
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`
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`*4’-,...‘__;;;
`
`Expressed
`_
`_
`heavy and light chains
`
`Transformed host cell
`
`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.
`
`30.
`
`I understand that Petitioners are 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
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`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.
`
`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
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`second DNA sequence are located in said vector at different insertion
`
`sites.
`
`16. A vector according to claim 15 which is a plasmid.
`
`17. A host cell transformed with a vector according to claim 15.
`
`18. A transformed host cell comprising at least two vectors, at least
`
`one of said vectors comprising a DNA sequence encoding at least a
`
`variable domain of an immunoglobulin heavy chain and at least
`
`another one of said vectors comprising a DNA sequence encoding at
`
`least the variable domain of an immunoglobulin light chain.
`
`19. The process of claim 1 wherein the host cell is a mammalian cell.
`
`20. The transformed host cell of claim 18 wherein the host cell is a
`
`mammalian cell.
`
`33. A process for producing an immunoglobulin molecule or an
`
`immunologically functional immunoglobulin fragment comprising at
`
`least the variable domains of the immunoglobulin heavy and light
`
`chains, in a single host cell, comprising: independently expressing a
`
`first DNA sequence encoding at least the variable domain of the
`
`immunoglobulin heavy chain and a second DNA sequence encoding
`
`at least the variable domain of the immunoglobulin light chain so that
`
`said immunoglobulin heavy and light chains are produced as separate
`
`molecules in said single host cell transformed with said first and
`
`second DNA sequences.
`
`31. Generally speaking, independent process claims 1 and 33 are directed
`
`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
`
`cell transformed with DNA encoding for at least the variable domains of both the
`
`immunoglobulin heavy and light chains.
`
`32.
`
`Claims 2, 3, 4, 9, 11, 12, 14 and 19 are dependent on claim 1 (or on
`
`another claim dependent thereon) and therefore incorporate all of the limitations of
`
`claim 1. Claim 2 requires that the two DNA sequences of claim 1 ”are present in
`
`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
`
`"plasmid." Claim 9 requires that the heavy and light chains of claim 1 "are
`
`expressed in the host cell and secreted therefrom as an immunologically functional
`
`immunoglobulin molecule or immunoglobulin fragment." Claim 11 requires that
`
`the DNA sequences encode the "complete" heavy and light chain polypeptides.
`
`Claim 12 requires that any "constant domain” encoded by the DNA sequences "is
`
`derived from the same source as the variable domain to which it is attached."
`
`Claim 14 requires that the heavy and light chain DNA sequences "are derived from
`
`one or more monoclonal antibody producing hybridomas." And claim 19 requires
`
`that the host cell is a "mammalian cell."
`
`33.
`
`Independent claim 15 is directed to a single vector containing DNA
`
`encoding for at least the variable domains of both the immunoglobulin heavy and
`
`light chains. Claim 16, dependent on claim 15, adds the requirement that the
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`"vector" of claim 15 is a "plasmid.” Claim 17 is directed to a host cell transformed
`
`with the vector of claim 15.
`
`34.
`
`Independent claim 18 is directed to a host cell comprising at least two
`
`vectors, with the first vector containing a DNA sequence encoding for at least the
`
`variable domain of the immunoglobulin heavy chain, and the second vector
`
`containing a DNA sequence encoding for 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."
`
`35. All of the challenged claims, by their very language, require two
`
`genes: a first DNA sequence encoding for the heavy chain and a second DNA
`
`sequence encoding for 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
`
`patentl). See also Ex. 1009, Owners’ Response (11/25/05), at 46. 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
`
`1Ex. 1001, at 12:50-51
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`molecules. This result stems from the requirement for independent expression of
`
`the introduced DNA sequences...").
`
`36.
`
`Furthermore, the process claims also require assembly of the separate
`
`heavy and light chain polypeptides into an immunoglobulin tetramer. Ex. 1009,
`
`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 and 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:
`
`_
`
`k _’7
`
`L secells
`I .
`2 \
`
`A I
`J’
`
`‘
`
`_
`
`\ "
`
`J
`
`i 3
`'
`
`-\
`1
`a -\
`‘ A,
`) I
`‘ ’
`
`I
`
`'
`'
`V‘ J
`
`Recovery of separate
`
`heavy chains and
`Iightchains
`
`.»
`
`-*1‘
`
`In vitro assembly
`
`Secretion
`
`C0-expressed
`heavy chains and
`light chains
`
`In vivo
`assembly
`
`fifl
`
`A
`
`‘Y’ 9,;
`
`.
`
`and
`purification
`
`Q
`=
`'
`5 '
`:3 Rmvervof
`antibody
`“MmmMmmW“
`
`/
`
`Assembled
`immunoglobulin
`
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`
`B.
`
`The Prosecution and Reexamination History of the '415 Patent
`
`37.
`
`I have reviewed the substantive sections of the prosecution file history
`
`and the reexamination proceedings for the '415 patent (z'.e., arguments between the
`
`USPTO and Genentech and City of Hope's attorneys and associated expert
`
`declarations) in connection with preparing my declaration.
`
`38.
`
`I understand that during the reexamination proceedings, the PTO
`
`rejected the '415 patent claims based on a number of prior art patent references. In
`
`particular, the PTO rejected the claims over the Axel patent (US. Patent No.
`
`4,399,216, Ex. 1018). See, e.g., Ex. 1011, Office Action (9/13/05), at 5, Ex. 1016,
`
`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.
`
`39.
`
`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 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) host cells using a
`
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`two DNA system: "DNA 1," which coded for a "desired proteinaceous material"2
`
`that is "h