UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`GENZYME CORPORATION,
`Petitioner
`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. IPR2016-00383
`_____________
`
`DECLARATION OF MARGARET H. BARON, M.D., PH.D.,
`IN SUPPORT OF GENZYME'S PETITION FOR
`INTER PARTES REVIEW OF U.S. PATENT NO. 6,331,415
`
`718856478
`
`Genzyme Ex. 1058, pg 1225
`
`

`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`BACKGROUND AND QUALIFICATIONS, PREVIOUS
`TESTIMONY, AND COMPENSATION......................................................1
`
`A.
`
`B.
`
`C.
`
`Background and Qualifications............................................................1
`
`Prior Testimony....................................................................................5
`
`Compensation.......................................................................................5
`
`II. MATERIALS AND INFORMATION CONSIDERED AND RELIED
`UPON..............................................................................................................5
`
`III.
`
`LEGAL FRAMEWORK FOR MY ANALYSIS...........................................6
`
`A.
`
`B.
`
`C.
`
`D.
`
`Anticipation..........................................................................................6
`
`Obviousness..........................................................................................7
`
`Person of Ordinary Skill in the Art ......................................................9
`
`Claim Construction.............................................................................10
`
`SUMMARY OF OPINIONS........................................................................11
`
`OVERVIEW OF THE '415 PATENT TECHNOLOGY AND THE
`CHALLENGED CLAIMS ...........................................................................11
`
`A.
`
`B.
`
`Background of the Technology: Antibody Structure, Function
`and Production....................................................................................11
`
`The Subject Matter of the Challenged Claims ...................................16
`
`IV.
`
`V.
`
`VI.
`
`THE STATE OF PRIOR ART RDNA ANTIBODY EXPRESSION
`IN APRIL 1983 AND OWNERS' ARGUMENTS DURING
`REEXAM .....................................................................................................24
`
`B.
`
`Prior Art Platform Technologies for Expressing Foreign Genes
`in Mammalian Cells ...........................................................................25
`
`1.
`
`The Axel Patent........................................................................25
`
`718856478
`
`i
`
`Genzyme Ex. 1058, pg 1226
`
`

`
`TABLE OF CONTENTS
`(continued)
`
`Page
`
`2.
`
`The Southern Reference...........................................................28
`
`The Prior Art Taught Expression of Single Immunoglobulin
`Chains in Transformed Mammalian Host Cells.................................29
`
`Owners' Arguments During Reexamination Regarding the Axel
`Patent ..................................................................................................30
`
`C.
`
`D.
`
`VII. STATEMENT OF GROUNDS FOR THE UNPATENTABILITY OF
`THE CHALLENGED CLAIMS ..................................................................33
`
`A.
`
`The Salser Patent Anticipates Claims 1-4, 9, 11, 12, 15-20 and
`33 Under 35 U.S.C. § 102(e)..............................................................33
`
`1.
`
`2.
`
`Overview of the Salser Patent Disclosures..............................33
`
`The Salser Patent Anticipates Independent Claims 1, 15,
`17, 18 and 33............................................................................38
`
`a.
`
`b.
`
`c.
`
`d.
`
`Independent Process Claim 1 ........................................38
`
`Independent Process Claim 33 ......................................49
`
`Independent Composition Claims 15 and 17 ................49
`
`Independent Composition Claim 18..............................50
`
`3.
`
`The Salser Patent Anticipates Dependent Claims 2, 3, 4,
`9, 11, 12, 16, 19 and 20............................................................50
`
`B.
`
`All of the Challenged Claims Are Obvious Over Salser in View
`of Ochi (I)...........................................................................................53
`
`1.
`
`2.
`
`Claims 1-4, 9, 11, 12, 15-20 and 33.........................................53
`
`Claim 14...................................................................................54
`
`C.
`
`Claims 2, 18, and 20 Are Also Obvious Based on Salser in
`Combination with Southern ...............................................................55
`
`718856478
`
`ii
`
`Genzyme Ex. 1058, pg 1227
`
`

`
`1.
`
`I, Margaret H. Baron, MD, PhD, have been retained by Mayer Brown
`
`LLP, counsel for Genzyme. I understand that Genzyme has 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 Genzyme'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 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, PhD (Nobel Laureate, 1976).
`
`3.
`
`In September 1976, I started medical and PhD graduate studies in the
`
`Harvard-M.I.T. Program in Health Sciences and Technology (HST Program) at
`
`Harvard Medical School (Boston, MA) and Massachusetts Institute of Technology
`
`718856478
`
`1
`
`Genzyme Ex. 1058, pg 1228
`
`

`
`(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 PhD dissertation research in the laboratory of Nobel
`
`Laureate (1975) David Baltimore, PhD, 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 PhD 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 MD 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, PhD, in the Department of Biochemistry and
`
`Molecular Biology at Harvard University (Cambridge, MA), where I analyzed the
`
`718856478
`
`2
`
`Genzyme Ex. 1058, pg 1229
`
`

`
`plasticity of the differentiated state (i.e. the ability to be reprogrammed) of
`
`mammalian erythroid cells. I was a Predoctoral 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
`
`was promoted to full Professor with Tenure in 2003. My research at Mount Sinai
`
`718856478
`
`3
`
`Genzyme Ex. 1058, pg 1230
`
`

`
`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 (NIGMS, NIDDK, NHLBI, and NIBIB)
`
`and by other agencies, including the New York State Department of Health
`
`(NYSTEM), 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 PhD 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 (ELAM) Program of the Drexel
`
`University College of Medicine.
`
`13.
`
`In January, 2015, I was named Senior Associate Dean for Education
`
`and Director of the MD/PhD 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 honors,
`
`718856478
`
`4
`
`Genzyme Ex. 1058, pg 1231
`
`

`
`detailed in my CV. I am an elected member of the American Society for Clinical
`
`Investigation (ASCI) and the Association of American Physicians (AAP).
`
`B.
`
`15.
`
`C.
`
`16.
`
`Prior Testimony
`
`I have not given trial or deposition testimony in the last four years.
`
`Compensation
`
`I am being compensated at my normal consulting rate of $750 per hour
`
`and at a daily rate of $7,500. I have no personal financial interest in any of the
`
`entities involved in this Petition and my compensation does not depend in any way
`
`on my testimony, my conclusions or the outcome of my analysis.
`
`II. MATERIALS AND INFORMATION
`CONSIDERED AND RELIED UPON
`
`17.
`
`In formulating my opinions, I have considered and relied upon the
`
`Exhibits referred to in this Declaration in light of the general knowledge that a
`
`person of ordinary skill in the art of the '415 patent ("POSITA," defined below)
`
`would have had on April 8, 1983, the filing date of the '415 patent. I have also
`
`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). I
`
`have also relied upon my experience, education and knowledge in the relevant art.
`
`718856478
`
`5
`
`Genzyme Ex. 1058, pg 1232
`
`

`
`III. LEGAL FRAMEWORK FOR MY ANALYSIS
`
`18. Although I am not a lawyer, I have been asked to form conclusions
`
`regarding the "novelty" (i.e., whether a claim is anticipated) and obviousness of the
`
`challenged claims in view of the prior art. In doing so, I have been apprised of and
`
`considered the legal frameworks below.
`
`A.
`
`19.
`
`Anticipation
`
`I have been informed and understand that for a patent claim to be
`
`invalid as anticipated, it must be shown by a preponderance of the evidence ("more
`
`likely than not") that all of limitations of the claim are disclosed in a single piece of
`
`prior art, either expressly or inherently. I understand that a claim element is
`
`inherent in the prior art if it is necessarily present in the prior art reference, even
`
`though a POSITA would not necessarily recognize or appreciate the presence of the
`
`inherent disclosure in the prior art at the time of the filing of the patent.
`
`20.
`
`I have been informed and understand that to determine whether a claim
`
`limitation is present in a prior art reference, the reference must be taken in
`
`conjunction with the knowledge of a POSITA. In other words, even if a prior art
`
`reference does not expressly disclose a limitation, it anticipates if a person of
`
`ordinary skill in the art would understand the prior art to disclose the limitation and
`
`could combine the prior art description with his own knowledge to make the subject
`
`matter of the claim at issue. A POSITA may also employ common sense or simple
`
`718856478
`
`6
`
`Genzyme Ex. 1058, pg 1233
`
`

`
`logic in considering a prior art reference to conclude that it contains a claim
`
`limitation that is not disclosed verbatim.
`
`21.
`
`I have been informed and understand that if a prior art reference
`
`discloses a "genus" of compounds that encompasses a particular compound that is
`
`the subject of a patent claim, the claimed compound is anticipated by the earlier-
`
`disclosed genus if the genus comprises a definite and limited class of compounds
`
`such that a POSITA would be able to at once envision each member of the genus,
`
`including the claimed compound.
`
`22.
`
`I have been informed and understand that 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.
`
`Moreover, it is my understanding that anticipation does not require actual
`
`performance and/or working examples in the prior art reference; it only requires
`
`that a reference teach a person skilled in the art how to implement the disclosure of
`
`a reference without undue experimentation.
`
`B.
`
`23.
`
`Obviousness
`
`I have been informed and understand that if a patent claim is not
`
`anticipated, it can be invalid if it is considered to have been obvious to a person of
`
`ordinary skill in the art at the time the application was filed. This means that, even
`
`if all of the requirements of a claim are not found in a single prior art document, the
`
`718856478
`
`7
`
`Genzyme Ex. 1058, pg 1234
`
`

`
`claim is not patentable if the differences between the subject matter in the prior art
`
`and the subject matter in the claim would have been obvious to a POSITA.
`
`24.
`
`I have been informed and understand that a determination of whether a
`
`claim would have been obvious at the time the application (for patent) was filed is
`
`based upon several factors, including: (a) the level of ordinary skill in the art at the
`
`time the application was filed; (b) the scope and content of the prior art; and (c)
`
`what differences, if any, existed between the claimed invention and the prior art.
`
`25.
`
`I have been informed and understand that the teachings of two or more
`
`references may be combined in the same way as recited in the claims, if such a
`
`combination would have been obvious to one having ordinary skill in the art. In
`
`determining whether a combination or modification based on either a single
`
`reference or multiple references would have been obvious, it is appropriate to
`
`consider, among other factors: (a) whether the teachings of the prior art references
`
`disclose known concepts combined in familiar ways, and when combined, would
`
`yield predictable results; (b) whether a person of ordinary skill in the art could
`
`implement a predictable variation of the disclosures in the prior art, and would see
`
`the benefit of doing so; (c) whether a person of ordinary skill would have
`
`recognized a reason to combine known elements in the prior art in the manner
`
`described in the claim; and (d) whether there is some motivation, teaching or
`
`718856478
`
`8
`
`Genzyme Ex. 1058, pg 1235
`
`

`
`suggestion in the prior art to make the modification or combination of elements
`
`claimed in the patent.
`
`26.
`
`I have been informed and understand that reasons to combine prior art
`
`references can come from a variety of sources, not just the prior art itself or the
`
`specific problem the patentee was trying to solve. I also understand that the prior art
`
`references themselves need not provide a specific hint or suggestion of the
`
`alteration needed to arrive at the claimed invention; the analysis may include
`
`recourse to logic, judgment, and common sense available to a person having
`
`ordinary skill in the art, who has ordinary creativity and is not an automaton.
`
`27.
`
`I have been informed and understand that once some reason or other
`
`basis has been established to combine the prior art, a claim is obvious if a POSITA
`
`would have had a reasonable expectation of success in achieving the subject matter
`
`of the claim.
`
`28.
`
`I understand that in considering obviousness, it is important not to
`
`determine obviousness using the benefit of hindsight derived from the patent being
`
`considered.
`
`C.
`
`29.
`
`Person of Ordinary Skill in the Art
`
`Some of my opinions refer to the perspective of a POSITA when the
`
`'415 patent was filed (April 8, 1983). I have been informed and understand that a
`
`POSITA is a hypothetical person, who is presumed to know the contents of all
`
`718856478
`
`9
`
`Genzyme Ex. 1058, pg 1236
`
`

`
`relevant art at the time, with working experience in the relevant field. I have been
`
`informed and understand that a POSITA is not an automaton but rather thinks along
`
`the lines of conventional wisdom in the art, and is a person of ordinary creativity.
`
`This person may also work as part of a multi-disciplinary team and draw upon not
`
`only his or her own skills, but also take advantage of certain specialized skills of
`
`others in the team, to solve a given problem.
`
`30. As of April 8, 1983, the education and experience level of a POSITA
`
`would have been a PhD 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.
`
`D.
`
`31.
`
`Claim Construction
`
`I have been informed and understand that in interpreting the meaning
`
`of the challenged claims, I should give claim terms the broadest reasonable
`
`interpretation consistent with the '415 patent specification and that I should read the
`
`claim language in light of the specification as it would be understood by a POSITA.
`
`In reaching the conclusions expressed below, I have interpreted the challenged
`
`claims consistent with these standards and requirements.
`
`718856478
`
`10
`
`Genzyme Ex. 1058, pg 1237
`
`

`
`IV.
`
`SUMMARY OF OPINIONS
`
`32. As set out in further detail below, a summary of my opinions expressed
`
`in this declaration is as follows:
`
`•
`
`•
`
`•
`
`•
`
`all of the limitations of claims 1-4, 9, 11, 12, 15-20 and 33 of the '415 patent are
`disclosed either expressly or inherently in the Salser patent (Ex. 1002) and are
`therefore anticipated by the Salser patent;
`
`a POSITA would have been motivated to combine the disclosures of the Salser
`patent with the disclosures of Ochi (I) (Ex. 1003) with a reasonable expectation
`of success in achieving the subject matter of claims 1-4, 9, 11, 12, 15-20 and 33
`of the '415 patent, thus rendering those claims obvious;
`
`a POSITA would have been motivated to combine the disclosures of the Salser
`patent with the disclosures of Ochi (I) (Ex. 1003) with a reasonable expectation
`of success in achieving the subject matter of claim 14 of the '415 patent, thus
`rendering claim 14 obvious; and
`
`a POSITA would have been motivated to combine the disclosures of the Salser
`patent with the disclosures of Southern (Ex. 1004) with a reasonable
`expectation of success in achieving the subject matter of claims 2, 18 and 20 of
`the '415 patent, thus rendering those claims obvious.
`
`V.
`
`OVERVIEW OF THE '415 PATENT TECHNOLOGY AND THE
`CHALLENGED CLAIMS
`
`A.
`
`Background of the Technology: Antibody
`Structure, Function and Production
`
`33.
`
`The '415 patent is titled "Methods of Producing Immunoglobulins,
`
`Vectors and Transformed Host Cells for Use Therein." The disclosed and claimed
`
`718856478
`
`11
`
`Genzyme Ex. 1058, pg 1238
`
`

`
`"methods" of producing immunoglobulins referred to in the title utilize recombinant
`
`DNA ("rDNA") techniques to "genetically engineer" cells to "host" foreign DNA
`
`sequences and make the associated proteins—here, immunoglobulins—that the
`
`cells do not ordinarily make. Ex. 1001, 1:12-21, 4:52-55, 8:26-32. The '415 patent
`
`specification provides an overview of the claimed rDNA production of
`
`immunoglobulins and compares it to the production of immunoglobulins that occurs
`
`in nature in certain types of B lymphocytes (and derivative cell lines, such as
`
`hybridomas1), which naturally contain immunoglobulin DNA sequences. Ex. 1001,
`
`1:43-3:15, 4:6-5:39.
`
`34.
`
`Immunoglobulins, and antibodies in particular,2 are proteins produced
`
`by the mammalian immune system in response to an infection by foreign cells or
`
`other "antigenic" (i.e., antibody generating) substances. Ex. 1001, 1:23-26.
`
`Antibodies specifically bind to the antigen to eliminate the foreign cell or substance
`
`from the body by recruiting other components of the immune system, such as
`
`phagocytic cells that envelop and ingest invading microorganisms. Ex. 1001, 1:26-
`
`1 A hybridoma cell is a fusion of an antibody-producing B lymphocyte or spleen
`
`cell with and an "immortal" cancer cell line. Ex. 1001, 1:64-2:11.
`
`2 For purposes of my opinions in this Declaration, the term immunoglobulin is
`
`interchangeable with antibody, which the '415 patent defines as a specific
`
`immunoglobulin polypeptide. Ex. 1001, 1:23-24.
`
`718856478
`
`12
`
`Genzyme Ex. 1058, pg 1239
`
`

`
`
`
`
`
`35; Ex. 1010, Alberts (1983) at 966. Plasma cells (a type of B lymphocyte) are the35; Ex. 1010, Alberts (1983) at 966. Plasma cells (a type of B lymphocyte) are the35; Ex. 1010, Alberts (1983) at 966. Plasma cells (a type of B lymphocyte) are the
`
`
`
`
`
`primary cells of the immune system that make and secrete antibodies. Ex. 1001,primary cells of the immune system that make and secrete antibodies. Ex. 1001,primary cells of the immune system that make and secrete antibodies. Ex. 1001,
`
`
`
`1:43-48; Ex. 1010, Alberts (1983)48; Ex. 1010, Alberts (1983) at 964.
`
`35.
`
`
`
`
`
`The basic structure of immunoglobulins was well understood by AprilThe basic structure of immunoglobulins was well understood by AprilThe basic structure of immunoglobulins was well understood by April
`
`
`
`
`
`1983. Ex. 1001, 3:16-19. Two identical heavy chain and two identical light chain19. Two identical heavy chain and two identical light chain19. Two identical heavy chain and two identical light chain
`
`
`
`
`
`polypeptides are connected together by disulfide bonds (polypeptides are connected together by disulfide bonds (–SS–, below) inside of, below) inside of
`
`
`
`
`
`plasma cells to form a tetrameric protein that is typically depicted as a Ya tetrameric protein that is typically depicted as a Ya tetrameric protein that is typically depicted as a Y-shaped
`
`molecule:
`
`
`
`
`
`Ex. 1001, Figure 1 (modified), 1:48Ex. 1001, Figure 1 (modified), 1:48-51, 3:16-59. As suggested by the name,59. As suggested by the name,
`
`
`
`
`
`immunoglobulins have globular shaped domains in each chain when they arehave globular shaped domains in each chain when they arehave globular shaped domains in each chain when they are
`
`
`
`properly folded as part of the teproperly folded as part of the tetramer. Ex. 1011, Huber at 1217.
`
`36.
`
`
`
`
`
`The amino acid sequence of the heavy and light chain polypeptidesThe amino acid sequence of the heavy and light chain polypeptidesThe amino acid sequence of the heavy and light chain polypeptides
`
`
`
`begins at the "N-terminal" position atterminal" position at the top of the Y and ends at the "Cthe top of the Y and ends at the "C-terminal"
`
`
`
`718856478
`
`13
`
`Genzyme Ex. 1058, pg 1240
`
`

`
`position at the bottom of each chain. Ex. 1001, 3:42-44. At the N-terminal position
`
`is the variable region, which is the segment of the antibody responsible for
`
`specifically binding to the antigen that elicited it. Ex. 1001, 3:44-45. The variable
`
`region is linked in each chain to a constant region which extends the remaining
`
`length of the chain. Ex. 1001, 3:48-50.
`
`37.
`
`The heavy and light polypeptide chains are produced in plasma cells
`
`according to the genetic instructions found in separate DNA sequences on different
`
`chromosomes: one gene coding for the heavy chain and one for the light chain. Ex.
`
`1001, 1:48-51; Ex. 1014, Malcolm at 4957. Antibody-producing plasma cells
`
`"express"3 each encoding DNA sequence to produce separate heavy and light chain
`
`polypeptides, which are joined together through disulfide bonds into an
`
`immunoglobulin tetramer inside of the plasma cell, which is then secreted from the
`
`cell. Ex. 1001, 1:51-55, 3:33-38; Ex. 1013, Kuby at 130, 133-134. For purposes of
`
`this Declaration, I will refer to this process as "in vivo assembly."
`
`3 Expression of the heavy and light chain polypeptides from their respective genes
`
`is a two-step process: transcription and translation. In short, the DNA is first
`
`transcribed to a corresponding RNA molecule; then, the RNA transcript is
`
`translated into a sequence of amino acids linked by peptide bonds to form the
`
`heavy and light chain polypeptides. Ex. 1001, 4:24-29; Ex. 1013, Kuby at 130.
`
`718856478
`
`14
`
`Genzyme Ex. 1058, pg 1241
`
`

`
`38.
`
`
`
`
`
`The process by which the heavy and light chains are assembledThe process by which the heavy and light chains are assembledThe process by which the heavy and light chains are assembled in vivo
`
`
`
`
`
`in plasma cells and secreted as an immunoglobulin tetramer is facin plasma cells and secreted as an immunoglobulin tetramer is facilitated by anilitated by an
`
`
`
`
`
`amino acid "leader" (or "signal") sequence attached at the Namino acid "leader" (or "signal") sequence attached at the N-terminal end of eachterminal end of each
`
`
`
`
`
`chain and which is encoded by a corresponding DNA sequence that is part of thechain and which is encoded by a corresponding DNA sequence that is part of thechain and which is encoded by a corresponding DNA sequence that is part of the
`
`
`
`
`
`heavy and light chain genes. Ex. 1013, Kuby at 133heavy and light chain genes. Ex. 1013, Kuby at 133-134. Each chain's respective134. Each chain's respective
`
`
`
`
`
`leader sequence guides the chain to the endoplasmic reticulum compartment insideleader sequence guides the chain to the endoplasmic reticulum compartment insideleader sequence guides the chain to the endoplasmic reticulum compartment inside
`
`
`
`
`
`of the plasma cell. Ex. 1013, Kuby at 133of the plasma cell. Ex. 1013, Kuby at 133-134. There, the leader sequences are134. There, the leader sequences are
`
`
`
`
`
`cleaved from the heavy and light chains, and the chains are assembled stepwise intocleaved from the heavy and light chains, and the chains are assembled stepwise intocleaved from the heavy and light chains, and the chains are assembled stepwise into
`
`
`
`
`
`an immunoglobulin, which is then transported to the plasma cell membrane andbulin, which is then transported to the plasma cell membrane andbulin, which is then transported to the plasma cell membrane and
`
`secreted:
`
`718856478
`
`15
`
`Genzyme Ex. 1058, pg 1242
`
`

`
`Ex. 1013, Kuby at 134, Fig. 5-20 (modified).
`
`B.
`
`The Subject Matter of the Challenged Claims
`
`39. By April of 1983, the rDNA technology described in the '415 patent
`
`had already reached "sufficient sophistication" and embraced a "repertoire of
`
`techniques" and molecular tools to permit the kinds of genetic manipulations
`
`utilized in the patent, including the isolation, introduction into and expression in
`
`cells of foreign DNA sequences. Ex. 1001, 4:6-41.4 The challenged claims of the
`
`'415 patent are directed to various aspects and components of these techniques and
`
`tools to produce immunoglobulins by rDNA means. Among the fundamental tools
`
`and techniques of rDNA technology claimed by the '415 patent is the process of
`
`"transforming" "host cells" through the construction of "vectors" capable of
`
`expressing the heavy and light chain DNA, as set out below in the text of the
`
`challenged claims.
`
`4 For example, by April 1983, using the prior art rDNA technologies generally
`
`discussed in the '415 patent, scientists had already produced a few dozen
`
`mammalian proteins in genetically engineered bacteria, as Genentech's expert in
`
`the reexamination, Dr. Timothy Harris, attested. Ex. 1017, Harris, at 163-169
`
`(identifying human insulin and fibroblast interferon, human and bovine growth
`
`hormone, rat preproinsulin, chicken ovalbumin, and rabbit β-globin, among other
`
`proteins); Ex. 1018, Harris Decl., ¶ 16.
`
`718856478
`
`16
`
`Genzyme Ex. 1058, pg 1243
`
`

`
`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.
`
`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
`
`718856478
`
`17
`
`Genzyme Ex. 1058, pg 1244
`
`

`
`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