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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS, INC., and
`MERCK SHARP & DOHME CORP.,
`Petitioners
`
`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. 2016-07101
`____________
`
`DECLARATION OF NOBUMICHI HOZUMI IN SUPPORT OF MERCK’S
`REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
`
`
`
`1 Case IPR2017-00047 has been joined with this proceeding.
`
`
`
`
`
`Mylan v. Genentech
`IPR2016-00710
`Merck Ex. 1094, Pg. 1
`
`
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`
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`I.
`
`INTRODUCTION
`
`I, Nobumichi Hozumi, hereby declare and state as follows:
`
`1.
`
`This declaration is submitted on behalf of Merck Sharp & Dohme
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`Corp. (“Merck”) in IPR No. 2016-00170, regarding U.S. Patent No. 6,331,415,
`
`“Methods of Producing Immunoglobulins, Vectors and Transformed Host Cells for
`
`Use Therein,” owned by Genentech, Inc. and City of Hope (collectively, “Patent
`
`Owners”).
`
`2.
`
`I have been asked to provide information on my scientific work
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`related to recombinant expression of immunoglobulin heavy and light chains in
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`mammalian cells, which took place in the early 1980s in response to statements
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`made in Patent Owners’ Response (Paper 31) and the opinions expressed by Patent
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`Owners’ expert Dr. John Fiddes (Ex. 2019). Specifically, I have been asked to
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`explain how the work I performed prior to April 1983 refutes Patent Owners’ and
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`Dr. Fiddes’ arguments regarding the alleged uncertainties surrounding recombinant
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`expression of antibodies in April 1983 and their arguments that the “prevailing
`
`mindset” in April 1983 was to express only one exogenous protein per host cell.
`
`II. BACKGROUND AND RELEVANT EXPERIENCE
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`3.
`
`As further detailed in my CV, attached as Exhibit A to this
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`declaration, I graduated from the School of Medicine at Keio University in 1967
`
`
`
`1
`
`Merck Ex. 1094, Pg. 2
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`
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`
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`and received my M.D. degree in 1968. In 1972, I obtained a Ph.D. in Medical
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`Science from Keio University, where I majored in Molecular Biology.
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`4.
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`I lectured at the Keio School of Medicine from 1972 until 1975, when
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`I became a member of the Basel Institute for Immunology in Basel, Switzerland.
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`Afterwards, I was a postdoctoral Fellow at the University of Toronto’s Ontario
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`Cancer Institute, part of the Department of Medical Biophysics. In 1979, I became
`
`an assistant professor for the department, then in 1984 an associate professor, and
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`finally in 1988 a professor for the department.
`
`5.
`
`During the time I was a professor, I was also a senior staff member at
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`the Ontario Cancer Institute until 1985. In 1985, I was hired as a Senior Scientist
`
`at the Samuel Lunenfield Research Institute at Mount Sinai Hospital. I continued
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`in that role, as well as becoming a member of the institute in 1998, until 2000.
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`From 1996 through the present, I have been a professor at the Research Institute
`
`for Biological Sciences in the Tokyo University of Sciences.
`
`6.
`
`In 1983, I won the David Pressman Memorial award. In 1984, I won
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`the Boehringer Mannheim Canada Prize of Canadian Biochemical Society.
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`7.
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`Finally,
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`I am a member of
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`the American Association of
`
`Immunologists, the Japanese Society of Immunologists. I was a member of the
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`advisor board for the Journal of Biochemistry from 1997-2001, and from 2005-
`
`
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`2
`
`Merck Ex. 1094, Pg. 3
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`
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`2008 was a member of the advisory board for the Japanese Society of
`
`Immunologists.
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`8.
`
`I am a named inventor on U.S. Patent No. 5,663,481, entitled “Animal
`
`
`
`model of the human immune system.”
`
`III. COMPENSATION
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`9.
`
`I am being compensated for my work on this case at my standard
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`consulting rate of $500/hour. My compensation is not contingent upon the results
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`of my analysis or the substance of my testimony. I have no stake in the outcome of
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`this proceeding or any related litigation or administrative proceedings. I have no
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`financial interest in Merck, and similarly have no financial interest in the ’415
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`patent or its owner.
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`IV. MY WORK ON RECOMBINANT EXPRESSION OF ANTIBODIES
`
`10.
`
`In the early 1980s, I began collaboration with Marc Shulman, one of
`
`my colleagues at the University of Toronto. Among the projects that our labs
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`undertook was the recombinant expression of an antibody molecule. Our initial
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`work focused on transferring and expressing the light () chain of an antibody
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`specific for the hapten TNP; however our ultimate goal was to transfer and express
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`both a heavy and a light chain.
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`11.
`
`In connection with this work, I obtained the pSV2-neo vector from
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`Richard Mulligan, a member of Paul Berg’s lab. I was familiar with the Berg lab’s
`
`
`
`3
`
`Merck Ex. 1094, Pg. 4
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`
`
`
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`prior work describing the pSV2 vector and I chose the pSV2-neo vector because it
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`was well-suited to expressing exogenous genes in mammalian cells. When I
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`selected the pSV2-neo vector, I believed that it would be capable of accepting
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`genes for both the heavy and light chains on a single vector.
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`12. Our work transferring and expressing the antibody light chain was
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`primarily carried out by Atsuo Ochi, one of the researchers in my lab. In
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`particular, Dr. Ochi was responsible for performing protoplast fusion whereby a
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`bacterial cell containing the pSV2-neo vector was fused with a mammalian host
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`cell. Our work expressing the antibody light chain is described in Ochi et al.
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`“Transfer of a cloned immunoglobulin light-chain gene to mutant hybridoma cells
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`restores specific antibody production.” Nature 340-342 (1983) (Ex. 1021 (“Ochi
`
`I”)).
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`13. After we successfully transferred and expressed the antibody light
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`chain, we began work to transfer and express the heavy and light chains together in
`
`a single host cell. This was the clear and natural next step of our recombinant
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`antibody research.
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`14.
`
`I understand that Patent Owners have alleged that the “prevailing
`
`mindset” as of April 1983 was that the antibody heavy and light chains should be
`
`expressed in separate host cells. We never contemplated such an approach. To the
`
`contrary, we determined that expressing the heavy and light chains in a single host
`
`
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`4
`
`Merck Ex. 1094, Pg. 5
`
`
`
`
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`cell was superior approach because it allowed the heavy and light chains to be
`
`assembled into a functional antibody in vivo; as occurs in nature.
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`15. Our work expressing the heavy and light chains was performed in late
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`1982 and early 1983. Similar to our earlier work expressing the light chain, Dr.
`
`Ochi was responsible for performing the protoplast fusion experiments that
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`transferred the pSV2 vector into the mammalian host cell.
`
`16. My co-authors and I disclosed our work expressing the antibody and
`
`light chains in a single host cell in several different ways. I presented this work at
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`the Fifth International Congress of Immunology in Kyoto, Japan from August 21 to
`
`26, 1983. In connection with making that presentation, I submitted an abstract no
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`later than January 31, 1983, the due date for submissions. Attached is a true and
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`correct copy of the abstract that I submitted to the conference organizers. Ex. 1140.
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`17. As indicated in the abstract, our work regarding “the transfer of light
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`chain and heavy chain genes into several other cell lines, including T cells, pre-B
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`cells, and fibroblasts” was still ongoing as of January 31, 1983. Ex. 1140. With
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`our clear research path, which was to express both chains in a single host cell, and
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`our success in having expressed each single chain using the same vectors and
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`genes, I expected it to be successful. This expectation of success is evidenced by
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`my contemporaneous statement to the conference organizers that these results “will
`
`be discussed” at the upcoming conference. Ex. 1140.
`
`
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`5
`
`Merck Ex. 1094, Pg. 6
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`
`
`
`
`18.
`
`I ultimately did present these results at the conference, and published
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`them shortly thereafter. The disclosure of our work expressing the heavy and light
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`chains together as I originally contemplated was in Ochi et al. “Functional
`
`immunoglobulin M production after transfection of cloned immunoglobulin heavy
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`and light chain genes into lymphoid cells.” Proceedings of the National Academy
`
`of Sciences 80.20 (1983): 6351-6355 (Ex. 1040 (“Ochi II”)).
`
`
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`6
`
`Merck Ex. 1094, Pg. 7
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`
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`
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`V. CONCLUSION
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`19.
`
`I declare that all statements made herein of my own knowledge are
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`true and that all statements made on information and belief are believed to be true,
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`and further that these statements were made with the knowledge that willful false
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`statements and the like so made are punishable by fine or imprisonment, or both,
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`under Section 1001 of Title 18 of the United States Code.
`
`Executed this 7th day of April 2017. I declare under penalty of
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`perjury that the foregoing is true and correct.
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`
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`
`
`7
`
`Merck Ex. 1094, Pg. 8
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`
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`Merck Ex. 1094, Pg. 9
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`
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`EXHIBIT A
`
`EXHIBIT A
`
`
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`
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`Merck Ex. 1094, Pg. 9
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`
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`
`
`2
`
`Curriculum Vitae
`NOBUMICHI HOZUMI
`
`DATE OF BIRTH:
`
`February 25, 1943
`
`EDUCATION:
`
`
`
`March 1967
`
`March 1968
`
`March 1968
`
`April 1968
`
`Graduated from the School of Medicine,
`Keio University, Japan
`
`Completed the whole course of the Internship for
`Medical Practitioners at the Keio University Hospital,
`Japan
`
`Passed the National Examination for Medical
`Practitioners.
`Received M.D. degree
`
`Entered the Post-graduate School of Medical Science,
`Keio University, Japan.
`Majored in Molecular Biology
`
`March 1972
`
`Completed Post-graduate studies
`
`September 1972
`
`Received Degree of Doctor of Medical Science
`(Ph.D.), Keio University, Japan
`
`
`
`
`
`EXPERIENCE:
`
`Nov. 1972 - Feb. 1975
`
`Lecturer, School of Medicine, Keio University, Japan
`
`Feb. 1975 - June 1978
`
`Member, Basel Institute for Immunology,
`Basel, Switzerland
`
`July 1978 - June 1979
`
`Postdoctoral Fellow, Ontario Cancer Institute,
`University of Toronto, Dept. of Medical Biophysics
`
`July 1979 - June 1985
`
`Senior Staff Member, Ontario Cancer Institute
`
`July 1979 - June 1984
`
`July 1984 - June 1988
`
`Assistant Professor Dept. of Medical Biophysics,
`University of Toronto
`
`Associate Professor Dept. of Medical Biophysics and
`Immunology, University of Toronto
`
`
`
`
`
`
`Merck Ex. 1094, Pg. 10
`
`
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`
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`3
`
`July 1985 - Oct. 2000
`
`July 1988 - June 1998
`
`Senior Scientist, Samuel Lunenfeld Research
`Institute at Mount Sinai Hospital
`
`Professor, Department of Immunology, University of
`Toronto
`
`Nov. 1998 - July 2000
`
`Adjunct Member, Samuel Lunenfeld Research
`Instituteat Mount Hospital
`
`July 1996 - Mar. 2000
`
`Visiting Professor of the Tsumura Medical
`Foundation, Keio University
`
`Oct. 1996 - Mar. 2008
`
`Professor, Research Institute for Biological Sciences,
`Tokyo University of Science
`
`Apr. 2008 - Present
`
`Adjunct Professor, Tokyo University of Science
`
`Apr. 2000 - Mar. 2001
`
`Invited Professor, Faculty of Medicine, Keio
`University
`
`Apr. 2001- Mar. 2005
`
`Visiting Professor, Faculty of Medicine, Keio
`University
`
`Apr. 2010 - Mar. 2016
`
`Professor, Faculty of Health Sciences, Ryotokuji
`University
`
`Apr 2016 - Mar. 2017
`
`Yomiuri-land Keiyu Hosital (Terminal Care)
`
`Apr. 2017 - Present
`
`Saito Clinic (Psychiatry)
`
`
`
`
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`AWARDS:
`
`1983 The David Pressman Memorial Award
`
`
`
`
`
`1984 The Boehringer Mannheim Canada Prize of
`Canadian Biochemical Society
`
`
`
`PROFESSIONAL
`AFFILIATIONS:
`
`The American Association of Immunologists
`
`
`
`
`
`
`
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`
`
`The Japanese Society of Immunologists
`
`October 1997-December 2001 Member of Advisory
`Board, The Journal of Biochemistry
`
`January 2005-September 2008 Member of Advisory
`
`
`
`Merck Ex. 1094, Pg. 11
`
`
`
`
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`4
`
`Board of The Japanese Society Immunologists
`
`Patent: Us Patent #5663481 Animal model of the
`human immune system
`
`S. Gallinger, N. Hozumi, J. Roder, J. Sandhu, B.
`Schpitz
`
`Sep. 2nd 1997
`
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`Merck Ex. 1094, Pg. 12
`
`
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