Filed on behalf of Patent Owner Genentech, Inc. by:
`
`David L. Cavanaugh (Reg. No. 36,476)
`Owen K. Allen (Reg. No. 71,118)
`Robert J. Gunther, Jr. (Pro Hac Vice to be filed)
`Lisa J. Pirozzolo (Pro Hac Vice to be filed)
`Kevin S. Prussia (Pro Hac Vice to be filed)
`Andrew J. Danford (Pro Hac Vice to be filed)
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
`
`Adam R. Brausa (Reg. No.
`60,287)
`Daralyn J. Durie (Pro Hac
`Vice to be filed)
`DURIE TANGRI LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`
`PFIZER, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________________________________________
`
`Case IPR2017-01488
`Patent 6,407,213
`____________________________________________
`
`DECLARATION OF DR. PAUL J. CARTER
`
`Pfizer v. Genentech
`IPR2017-01488
`Genentech Exhibit 2017
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
`
`I, Dr. Paul J. Carter, declare as follows:
`
`I.
`
`Background
`1.
`I am a research scientist with over 30 years of experience working in
`
`the biotechnology field.
`
`2.
`
`I obtained my B.A. degree in Natural Sciences in 1982 from
`
`Cambridge University, with a focus in Biochemistry. I obtained my Ph.D. in
`
`Molecular Biology in 1986 at the Medical Research Council (MRC) Laboratory of
`
`Molecular Biology in Cambridge University, UK. My Ph.D. dissertation research,
`
`which I carried out in the laboratory of Dr. Gregory Winter, related to the site-
`
`directed mutagenesis of a particular enzyme, tyrosyl tRNA synthetase, from the
`
`bacteria, Bacillus stearothermophilus.
`
`3.
`
`I first joined Genentech as a Postdoctoral Fellow in 1986 researching
`
`protein engineering. In the spring of 1989, I started my own laboratory as a
`
`Scientist in the Protein Engineering Department. From 1989 to 1995, I focused on
`
`engineering antibodies for therapy and helped initiate Genentech’s antibody
`
`humanization program.
`
`4.
`
`One of the early projects in my laboratory at Genentech was to
`
`humanize an antibody. Dr. Leonard Presta and I collaborated on this project, and
`
`the specific methodology we used to perform this work involved the creation of
`
`widely-applicable human consensus sequences. We successfully created human
`
`1
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
`
`consensus sequences and humanized the murine 4D5 antibody, which was known
`
`to inhibit proliferation of human tumor cells overexpressing p185HER2 found in
`
`certain breast cancers. For this work, Dr. Presta and I were awarded U.S. Patent
`
`No. 6,407,213 (“the ’213 patent). This work also resulted in Herceptin® and other
`
`humanized antibodies that use the techniques of the ’213 patent, such as Perjeta®,
`
`Xolair®, Avastin®, and Lucentis®. In addition to the ’213 patent, this work is also
`
`described in the research paper, “Humanization of the anti-p185 antibody for
`
`human cancer therapy,” published in Proc. Natl. Acad. Sci., Vol. 89, pp. 4285-
`
`4289, May 1992, which I co-authored. (Ex. 2020.)
`
`5.
`
`In 1995, I was promoted to Senior Scientist in Molecular Oncology,
`
`and from 1995 to 2000, I led teams that focused on developing antibodies for
`
`treating cancer.
`
`6.
`
`From 2000 to 2010, I held antibody research positions at several other
`
`biotechnology companies. For example, from 2000 to 2002, I was the Director of
`
`Protein Engineering at Immunex, Inc. in Seattle, Washington, where I helped
`
`develop and implement strategy to establish human antibody therapeutics as a
`
`major part of the drug pipeline. From 2002 to 2003, I was Associate Director then
`
`Director of Research of Antibody Technologies at Amgen, Inc., in Seattle,
`
`Washington. From 2003 to 2008, I was at Seattle Genetics, Inc., first as Senior
`
`Director of Antibody Technologies, and then as Vice President of Antibody
`
`2
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
`
`Technologies. And from 2008 to 2009, I was Chief Scientific Officer and Senior
`
`Vice President of Research and Development at VLST, Inc.
`
`7.
`
`In 2010, I rejoined Genentech as a Staff Scientist and Senior Director
`
`of Antibody Engineering. Since then, I have led my department’s research
`
`focusing on developing antibody therapeutics.
`
`8.
`
`I have published over 100 scientific articles, with over 14,800 total
`
`citations. I am a listed inventor on 43 issued United States patents and 48
`
`published United States applications, including several related to humanized
`
`antibodies. I have co-organized 13 international conferences on protein or
`
`antibody engineering and therapeutics, and delivered over 100 conference
`
`presentations and invited lectures, including keynote presentations. In 2006, I was
`
`short-listed by the journal Nature Biotechnology as a nominee for the most
`
`significant contributor to biopharmaceuticals in the past decade. In 2013, I was
`
`named as the second-most influential person in the antibody field by Terrapinn.
`
`9.
`
`My curriculum vitae, which has a list of my publications and
`
`presentations, is attached as Appendix A.
`
`II. Overview of Invention and Documentation
`10. Below, I describe my contribution to the invention of the ’213 patent.
`
`In the course of that work, I: (1) proposed, with Dr. Presta, the concept of creating
`
`and using widely-applicable human consensus sequences to humanize an antibody;
`
`3
`
`

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`IPR2017-01488
`Declaration of Dr. Paul J. Carter
`
`(2) created the actual DNA sequences encoding for several different versions of
`
`heavy and light chain variable regions of a humanized 4D5 antibody; (3) created
`
`plasmids and vectors containing these DNA sequences; (4) expressed the DNA
`
`sequences that correlate to the sample referred to in the ’213 patent as huMAb4D5-
`
`5 in E. coli to create fragment antigen-binding, or “Fabs,” and full length IgG1
`
`antibodies; (5) demonstrated that both the Fab and full-length antibody of
`
`huMAb4D5-5 showed binding specificity and affinity to HER2; and (6) supervised
`
`and directed others to create different versions of humanized 4D5 antibodies (also
`
`described in the ’213 patent) and to perform comparative binding analyses. By
`
`, I had expressed the Fab of huMAb4D5-5 and established its
`
`binding specificity and affinity to HER2. By
`
`, I had expressed the
`
`full-length antibody of huMAb4D5-5 and confirmed that it bound to HER2 with
`
`specificity and high affinity. By
`
`, others at my direction produced and
`
`determined binding affinity for other variants of humanized 4D5 antibodies labeled
`
`huMAb4D5-3 to huMAb4D5-8 in the ’213 patent.
`
`11. My work is documented in my laboratory notebooks and records. I
`
`am familiar with Genentech’s practices regarding the creation and maintenance of
`
`laboratory notebooks. Genentech’s library provides Genentech scientists with
`
`laboratory notebooks, each of which is given a unique number and filmed when
`
`completed. As was the general practice with all scientists at Genentech, I
`
`4
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
`
`maintained a laboratory notebook to record my work, including during all of
`
`
`
`when I was working as a Scientist in Protein Engineering. During my regular
`
`course of work in developing and researching technologies, I recorded the
`
`experiments I was doing, including their design, experimental details and results,
`
`and often some interpretation of the results. It was my regular practice to create
`
`such records at or near the time they occurred, and to date and sign such
`
`documents. As a result, the dates recorded in my notebooks reflect my work
`
`performed at or around the time they occurred.
`
`12.
`
`Exhibit 2003 is my laboratory Notebook 11268, which was issued to
`
`me on
`
`. Exhibit 2004 is my laboratory Notebook 11643, which was
`
`issued to me on
`
`. Other than when these notebooks were filmed by
`
`the Genentech library on
`
`, they stayed in my possession during my
`
`employment with Genentech. When I left Genentech in 2000, I provided the
`
`original notebooks to Genentech for its records. As I describe in more detail
`
`below, these notebooks document many of the steps I took to create, express, and
`
`determine binding affinity of the humanized 4D5 antibody.
`
`13. Beyond these notebooks, I generated and/or received additional
`
`records in the ordinary course of my work at Genentech document the invention
`
`described in the ’213 patent. For example, while we were working on the
`
`invention, Dr. Presta and I exchanged emails and/or memos informing each other
`
`5
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
`
`of our progress. These are discussed in more detail below and include: (1) a
`
` email from me to Dr. Presta and Dr. Dennis Henner proposing the
`
`DNA sequences for the humanized 4D5 sequences (Ex. 2010); and (2) an
`
` email from me to Dr. Presta informing him that I had expressed the
`
`humanized 4D5 Fab of one variant, later referred to as huMAb4D5-5 in the ’213
`
`patent (Ex. 2011).
`
`14. Also, once I had established that I could create, express, and show
`
`binding specificity and affinity for a humanized 4D5 variant, others assisted in
`
`testing the various humanized 4D5 variants. For example, Dr. Cornelia Gorman
`
`and a research technician in her laboratory, John Ridgway (who later changed his
`
`name to John Brady), assisted me by expressing at my request several different
`
`humanized 4D5 variants in a mammalian cell line. Mr. Brady, working at my
`
`direction, then provided his samples for assay analysis. Assays to determine
`
`binding affinity and activity were conducted on our humanized 4D5 antibody
`
`samples by a number of individuals, including Dr. Wai Lee Wong and her research
`
`technician, Ann Rowland, as well as Timothy Hotaling and Monique Carver. We
`
`had meetings to coordinate our work humanizing the murine 4D5 antibody, and
`
`these individuals’ roles are detailed in part in a
`
` status memo. (Ex.
`
`2014.)
`
`6
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
`
`15. With our success creating humanized 4D5 antibodies, Genentech
`
`worked on developing and creating human therapeutics using this invention. Some
`
`of this focus is shown in minutes from an
`
`meeting of Genentech’s
`
`Research Review Committee (“RRC”), which I attended.
`
`16.
`
`These documents were created contemporaneous with the events that
`
`they are recording and were kept in the ordinary course of Genentech’s business.
`
`III. Our Design of Humanized Antibodies Using a “Consensus Sequence”
`17.
`I have read Dr. Presta’s December 9, 2016 declaration, and in
`
`particular, his description of basic antibody structure. As Dr. Presta describes,
`
`antibodies include constant domains and variable domains. The variable domains
`
`include “complementarity determining regions,” or CDRs that are primarily
`
`responsible for binding to an antigen, and framework regions, or FRs, that hold the
`
`CDRs into place and are generally conserved across other antibodies with similar
`
`structures. I agree with this description, as well as the general background he
`
`provides regarding scientists’ early efforts to humanize antibodies. As described in
`
`Dr. Presta’s declaration, these early efforts involved grafting murine CDRs into
`
`human variable domains and/or creating a humanized antibody by starting from the
`
`human variable domain sequence that was the most homologous, or “best fit,” to
`
`the original murine antibody.
`
`7
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
`
`18.
`
`I had previously been a graduate student in Dr. Gregory Winter’s
`
`laboratory, which had humanized antibodies by CDR grafting, and was aware of
`
`others’ work, including that activity may require substituting the CDRs as well as
`
`additional FR resides.
`
`, I wanted to humanize an antibody, but I did not want to simply apply
`
`these prior techniques to create a humanized antibody. Instead,
`
`, I
`
`proposed to Dr. Presta that we attempt a new way of creating a humanized
`
`antibody by creating broadly-applicable human “consensus” variable domain
`
`sequences, which would provide a template to humanize almost any antibody.
`
`Consistent with that approach, the ’213 patent defines a consensus sequence as “an
`
`amino acid sequence which comprises the most frequently occurring amino acid
`
`residues at each location in all human immunoglobulins of any particular subclass
`
`or subunit structure.” (Ex. 1001, ’213 patent, 11:32-38.)
`
`19.
`
`I believed this consensus sequence could help solve the problems
`
`researchers found in developing humanized antibodies as therapeutics. At this
`
`time, no one had successfully developed a humanized therapeutic antibody and
`
`obtained regulatory approval for any purpose. Indeed, there were concerns in the
`
`scientific community whether therapeutic antibodies would ever be a viable
`
`treatment given that foreign antibodies could provoke an immunogenic response. I
`
`believed that this novel consensus sequence approach would reduce the possibility
`
`8
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
`
`of an immunogenic response by avoiding the unique variations introduced by
`
`relying on published antibody sequences obtained from a single individual. I also
`
`hoped that this approach would provide a more efficient platform for developing
`
`humanized antibodies by creating a universal sequence for use in humanizing any
`
`antibody.
`
`20.
`
`21.
`
`The murine antibody we chose to humanize using this new method
`
`was muMAb4D5, which is directed against the human epidermal growth factor
`
`receptor 2 (p185HER2) antigen and inhibits proliferation of human tumor cells
`
`overexpressing p185HER2.
`
`1
`
`9
`
`

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`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`22. At the time, Dr. Presta was an experienced protein modeler, which
`
`made him uniquely skilled to take our concept of human consensus sequences, and
`
`to propose an amino acid sequence for a humanized 4D5 antibody. After our
`
`initial planning discussions in
`
`, Dr. Presta developed human consensus
`
`sequences, and then performed extensive molecular modeling to use those
`
`sequences to propose amino acid sequences for humanized 4D5 antibodies. The
`
`steps Dr. Presta took are described in more detail in his December 9, 2016
`
`declaration.
`
`23.
`
`24.
`
`
`
`10
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`11
`
`

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`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`25.
`
`26.
`
`12
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`13
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`27.
`
`28.
`
`14
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`29.
`
`15
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`IV. Constructing and Testing the Binding Specificity and Affinity of the
`First Humanized Antibody FAB for 4D5
`30.
`
`31.
`
`16
`
`

`

`32.
`
`33.
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`34.
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`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`
`
`17
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`35.
`
`36.
`
`18
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`37.
`
`
`
`19
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`38.
`
`20
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`39.
`
`40.
`
`21
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`41.
`
`42.
`
`22
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`
`
`43.
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`44.
`
`
`
`23
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`45.
`
`46.
`
`47.
`
`24
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`48.
`
`49.
`
`
`
`25
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`50.
`
`26
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`51.
`
`52.
`
`27
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`53.
`
`28
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`54.
`
`55.
`
`29
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`
`
`56.
`
`30
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`(cid:120)
`
`57.
`
`V.
`
`Constructing and Testing the Binding Specificity and Affinity of the
`First Humanized Full Length Antibody of 4D5
`58.
`
`31
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`59.
`
`60.
`
`32
`
`

`

`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`61.
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`62.
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`63.
`
`33
`
`

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`Declaration of Dr. Paul J. Carter
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`64.
`
`
`
`34
`
`

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`Declaration of Dr. Paul J. Carter
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`65.
`
`35
`
`

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`Declaration of Dr. Paul J. Carter
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`
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`66.
`
`36
`
`

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`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`VI. Construction and Testing Other Variants of Humanized 4D5
`67.
`
`68.
`
`37
`
`

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`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`69.
`
`70.
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`71.
`
`38
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`

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`Declaration of Dr. Paul J. Carter
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`72.
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`73.
`
`2
`
`
`
`39
`
`

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`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`74.
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`75.
`
`
`
`40
`
`

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`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`76.
`
`41
`
`

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`IPR2017-01488
`Declaration of Dr. Paul J. Carter
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`77. Variant 6, HuMab4D5-8, is humanized 4D5 antibody that we
`
`ultimately chose to put into clinical development and is the active ingredient in the
`
`drug Herceptin®.
`
`78. Our invention and success sparked within Genentech a focus on
`
`humanized antibody therapeutics.
`
`79.
`
`I have reviewed the claims of the ’213 patent. In view of the
`
`information described above and the exhibits submitted herewith, I possessed the
`
`invention recited in claims 1-2, 4, 12, 25, 29-31, 33, 42, 60, 62-67, 69, and 71-81
`
`before July 26, 1990 as confirmed by my development before that date of several
`
`humanized antibodies applying our invention, including HuMAb4D5-5 and
`
`HuMAb4D5-8.
`
`42
`
`

`

`I declare under penalty of perjury of the laws of the United States of
`
`IPR2017—01488
`
`Declaration of Dr. Paul J. Carter
`
`America that the foregoing is true and correct.
`
`Date: August i, 2017 .
`
`1
`
`;
`
`Dr. Paul J. Carter
`
`
`
`
`43
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`

`

`(cid:36)(cid:51)(cid:51)(cid:40)(cid:49)(cid:39)(cid:44)(cid:59)(cid:3)(cid:36)
`
`APPENDIX A
`
`44
`44
`
`

`

`(cid:51)(cid:68)(cid:88)(cid:79)(cid:3)(cid:45)(cid:17)(cid:3)(cid:38)(cid:68)(cid:85)(cid:87)(cid:72)(cid:85)(cid:15)(cid:3)(cid:51)(cid:75)(cid:17)(cid:3)(cid:39)(cid:17)(cid:3)
`(cid:38)(cid:56)(cid:53)(cid:53)(cid:44)(cid:38)(cid:56)(cid:47)(cid:56)(cid:48)(cid:3)(cid:57)(cid:44)(cid:55)(cid:36)(cid:40)(cid:3)
`
`(cid:38)(cid:50)(cid:49)(cid:55)(cid:36)(cid:38)(cid:55)(cid:3)(cid:44)(cid:49)(cid:41)(cid:50)(cid:53)(cid:48)(cid:36)(cid:55)(cid:44)(cid:50)(cid:49)(cid:3)
`
`(cid:42)(cid:72)(cid:81)(cid:72)(cid:81)(cid:87)(cid:72)(cid:70)(cid:75)(cid:15)(cid:3)(cid:44)(cid:81)(cid:70)(cid:17)(cid:3)
`(cid:39)(cid:72)(cid:83)(cid:68)(cid:85)(cid:87)(cid:80)(cid:72)(cid:81)(cid:87)(cid:3)(cid:82)(cid:73)(cid:3)(cid:36)(cid:81)(cid:87)(cid:76)(cid:69)(cid:82)(cid:71)(cid:92)(cid:3)(cid:40)(cid:81)(cid:74)(cid:76)(cid:81)(cid:72)(cid:72)(cid:85)(cid:76)(cid:81)(cid:74)(cid:3)
`(cid:20)(cid:3)(cid:39)(cid:49)(cid:36)(cid:3)(cid:58)(cid:68)(cid:92)(cid:15)(cid:3)(cid:54)(cid:82)(cid:88)(cid:87)(cid:75)(cid:3)(cid:54)(cid:68)(cid:81)(cid:3)(cid:41)(cid:85)(cid:68)(cid:81)(cid:70)(cid:76)(cid:86)(cid:70)(cid:82)(cid:15)(cid:3)(cid:38)(cid:36)(cid:3)(cid:28)(cid:23)(cid:19)(cid:27)(cid:19)(cid:3)
`
`(cid:50)(cid:73)(cid:73)(cid:76)(cid:70)(cid:72)(cid:29)(cid:3)
`(cid:38)(cid:72)(cid:79)(cid:79)(cid:29)(cid:3)
`(cid:40)(cid:80)(cid:68)(cid:76)(cid:79)(cid:29)(cid:3)
`
`(cid:11)(cid:25)(cid:24)(cid:19)(cid:12)(cid:3)(cid:23)(cid:25)(cid:26)(cid:3)(cid:23)(cid:22)(cid:26)(cid:20)(cid:3)
`(cid:11)(cid:25)(cid:24)(cid:19)(cid:12)(cid:3)(cid:22)(cid:28)(cid:21)(cid:3)(cid:24)(cid:23)(cid:26)(cid:20)(cid:3)
`(cid:83)(cid:77)(cid:70)(cid:35)(cid:74)(cid:72)(cid:81)(cid:72)(cid:17)(cid:70)(cid:82)(cid:80)(cid:3)
`
`(cid:54)(cid:56)(cid:48)(cid:48)(cid:36)(cid:53)(cid:60)(cid:3)
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