`
`
`
`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 ATSUO OCHI 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. 1093, Pg. 1
`
`

`

`I, Atsuo Ochi, hereby declare and state as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been asked by counsel for Merck Sharp & Dohme Corp.
`
`(“Merck”) to submit this declaration in connection with 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
`
`related to recombinant expression of immunoglobulin heavy and light chains in
`
`mammalian cells, which took place in the early 1980s, in response to statements
`
`made in Patent Owners’ Response (Paper 31) and the opinions expressed by Patent
`
`Owners’ expert Dr. John Fiddes (Ex. 2019). Specifically, I have been asked to
`
`explain how the work I performed prior to April 1983 refutes Patent Owners’ and
`
`Dr. Fiddes’ arguments regarding the alleged uncertainties surrounding recombinant
`
`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
`
`3.
`
`As further detailed in my curriculum vitae, attached hereto as Exhibit
`
`A, I graduated from Tokyo Medical and Dental University in 1978 with a degree in
`
`Dentistry. Afterwards, I matriculated to Tokyo University, where I graduated with
`
`
`
`2
`
`Merck Ex. 1093, Pg. 2
`
`

`

`a Ph.D. in Immunology in 1982. I completed Postdoctoral training at the Ontario
`
`Cancer Institute and University of Toronto, in Dr. Nobumichi Hozumi’s lab, in
`
`1986.
`
`4.
`
`After my Postdoctoral training, I was hired as a Staff Scientist and
`
`Assistant Professor at the Mt. Sinai Hospital Research Institute at the University of
`
`Toronto from 1986 to 1994. In 1994, I transferred to the John P. Robarts Research
`
`Institute and the University of Western Ontario, where I was a Staff Scientist and
`
`Assistant Professor until 1999. In 1999, I was promoted to Associate Professor, a
`
`position I held until 2005. My work, through this point, was entirely in the
`
`departments of Microbiology, Medical Genetics, and Immunology.
`
`5.
`
`In 2003, I stopped working as a Staff Scientist at the John P. Robarts
`
`Research Institute, and instead was hired as an Associate Scientist in Research in
`
`2004. I held that position until 2010, when I transferred to the Mt. Sinai Hospital
`
`Research Institute in Toronto, where I had the same title. I continued in that role
`
`until 2011, when I took positions with the New York University Medical Center as
`
`a Scientist in Research and Assistant Professor, both in the Department of Surgery.
`
`6.
`
`I have authored over 50 journal articles and contributed 48 abstracts
`
`and presentations.
`
`7.
`
`I have received multiple grants and an award for my research. I
`
`received the National Institute of Canada Research Scholarship for the term of
`
`
`
`3
`
`Merck Ex. 1093, Pg. 3
`
`

`

`1986 through 1990. I have received over $1.5 million in grant money for my
`
`research.
`
`8.
`
`I am also a member of various professional societies. I was a member
`
`of the Canadian Association of Immunologists from 1994 to 2004 and a member
`
`of the American Association of Immunologists from 1996 to 2004. I served on the
`
`committee for the CIHR senior Investigator Awards committee in 2002 and 2003.
`
`III. COMPENSATION
`
`9.
`
`I am being compensated for my work on this case at my standard
`
`consulting rate of $500 per hour. My compensation is not contingent upon the
`
`results of my analysis or the substance of my testimony. I have no stake in the
`
`outcome of this proceeding or any related litigation or administrative proceedings.
`
`I have no financial interest in Merck, and similarly have no financial interest in the
`
`’415 patent or its owner.
`
`IV. MY WORK EXPRESSING THE ANTIBODY LIGHT CHAIN
`
`10.
`
`I moved to Canada and joined Dr. Hozumi’s lab in June 1982.
`
`Immediately thereafter, I began working to express an antibody light chain using
`
`recombinant DNA techniques. My work on this project and the follow-on project
`
`to express the heavy and light chains is reflected in a series of lab notebooks that I
`
`kept in the ordinary course of my research and that have remained in my
`
`possession since then. True and accurate copies of these notebooks are attached as
`
`
`
`4
`
`Merck Ex. 1093, Pg. 4
`
`

`

`Exhibits 1137, 1138, and 1146. My work expressing an antibody light chain is
`
`also described in Ochi et al. “Transfer of a cloned immunoglobulin light-chain
`
`gene to mutant hybridoma cells restores specific antibody production,” Nature
`
`340-342 (1983) (Ex. 1021 (“Ochi I”)).
`
`11. Upon joining Dr. Hozumi’s lab, my first task was to construct a vector
`
`containing the  gene for a IgM() antibody specific for the hapten TNP. Dr.
`
`Hozumi selected the pSV2-neo vector. Throughout the months of June and July
`
`1982, I worked to insert the  gene into a pSV2-neo vector. By August 1, 1982, I
`
`had successfully created two vectors containing the TNP gene, one containing the 
`
`gene in a tandem orientation and a second containing the gene is a reversed
`
`orientation. Ex. 1137 at 69. These vectors are referred to as PT-T1 and PR-T1,
`
`respectively, in Ochi I. Ex. 1021 at 340.
`
`12. Thereafter, I sought to transform the vectors that I created into a
`
`eukaryotic host cell, specifically a mutant form of the Sp603 hybridoma.
`
`Implementing the techniques needed to transform foreign DNA into a eukaryotic
`
`host cell was the most technically challenging aspect of our work. Dr. Hozumi and
`
`I decided to use a protoplast fusion technique, which requires growing the plasmid
`
`in a bacterial cell and then fusing that bacterial cell with the host cell in this case,
`
`the mutant form of Sp603. The protoplast fusion technique is derived from the
`
`
`
`5
`
`Merck Ex. 1093, Pg. 5
`
`

`

`technique used to make hybridomas, which I was familiar with before joining Dr.
`
`Hozumi’s lab.
`
`13.
`
`I began work on transforming light chain deficient mutant Sp603 with
`
`the PT-T1 and PR-T1 vectors on August 3, 1982. Ex. 1146 at 9. Throughout
`
`August, September, and October 1982, I continued to work on transforming mutant
`
`Sp603 cell lines and to test for recovery of an anti-TNP antibody. By October 3,
`
`1982, I had obtained the results reflected in Table 1 of Ochi I showing that four out
`
`of fourteen transformants expressed detectable levels of an anti-TNP antibody. Id.
`
`at 46; Ex. 1021 at 341.
`
`14.
`
`I understand that Dr. Fiddes opines that this result shows the “the
`
`uncertain and unpredictable state of the art before the Cabilly patent application
`
`was filed in April 1983.” Ex. 2019 at ¶¶ 117-119. I disagree. It was well
`
`understood in April 1983 that protoplast fusion was an inefficient technique, and I
`
`and my colleagues never expected all or nearly all of the transformants to be
`
`successful. By way of comparison, when making hybridomas using a similar
`
`technique as protoplast fusion, a success rate of one in 100 was considered good.
`
`Thus, we considered our result of four out of fourteen successful transformants to
`
`be quite good and far from creating uncertainty, this result gave us strong
`
`reassurance that the protoplast fusion technique was an effective method for
`
`introducing exogenous DNA into a eukaryotic host cell.
`
`
`
`6
`
`Merck Ex. 1093, Pg. 6
`
`

`

`V. MY WORK EXPRESSING THE ANTIBODY HEAVY AND LIGHT
`CHAINS
`
`15. Following our successful experiments, which validated our protoplast
`
`fusion technique and our ability to express an antibody light chain using
`
`recombinant DNA techniques, we immediately began working to express the
`
`antibody heavy chain, both individually and in combination with an antibody light
`
`chain. Given our earlier success in expressing the antibody light chain, I did not
`
`believe that expressing the antibody heavy and light chains was an uncertain
`
`endeavor. To the contrary, I was confident that we would be able successfully
`
`express the heavy and light chains and we expected that we would be able to
`
`achieve our ultimate goal of recovery of a functional recombinant antibody.
`
`16. My work on expression of the heavy and light chains is also reflected
`
`in my laboratory notebooks. It is also reflected in Ochi et al. “Functional
`
`immunoglobulin M production after transfection of cloned immunoglobulin heavy
`
`and light chain genes into lymphoid cells,” Proceedings of the National Academy
`
`of Sciences 80.20 (1983): 6351-6355 (Ex. 1040 (“Ochi II”)).
`
`17. Once again for experiments involving expression of heavy chain,
`
`either by itself or with a light chain, we used an anti-TNP IgM() antibody. In the
`
`case of our experiments expressing the heavy and light chain, the µ gene encoding
`
`the heavy chain was inserted into the pSV2-neo vector containing the  gene
`
`encoding the antibody light chain (PR-T1). I was not personally responsible for
`
`
`
`7
`
`Merck Ex. 1093, Pg. 7
`
`

`

`synthesizing the vector containing the µ and  genes; however, I was responsible
`
`for transforming this vector into a plasmacytoma cell, X63Ag8, and a hybridoma
`
`cell, Sp2/0, and for assessing expression of an anti-TNP antibody. Once again, I
`
`used the protoplast fusion method for the transformation. I assessed expression of
`
`an anti-TNP antibody using ELISA. By January 28, 1983, I had obtained positive
`
`results for expression of an anti-TNP antibody in both the X63Ag8 and Sp2/0 cell
`
`lines. Exhibit 1138 at 6-11.
`
`18.
`
`I understand that Patent Owners and Dr. Fiddes have alleged that the
`
`“prevailing mindset” as of April 1983 was that only one exogenous protein should
`
`be expressed in a single host cell. (See Paper 31 Patent Owners’ Response at 37-
`
`38, 11; Ex. 2019 at ¶ 87). I disagree with this assertion. As my laboratory
`
`notebooks show, by the end of January 1983, we had already acted contrary to this
`
`alleged “prevailing mindset” and successfully expressed the heavy and light chains
`
`in a single host cell. Indeed, I do not recall ever considering making an antibody
`
`by expressing the heavy and light chains in separate host cells.
`
`19.
`
`I disagree with Dr. Fiddes’ opinion there was “enormous uncertainty
`
`that would have been present in any attempt to utilize a host cell’s protein
`
`production machinery to make multiple, distinct proteins.” Ex. 2019 at ¶ 95. My
`
`co-authors and I never had significant concerns that the eukaryotic host cells we
`
`were utilizing could make the heavy and light chains in a single cell. Expressing
`
`
`
`8
`
`Merck Ex. 1093, Pg. 8
`
`

`

`the heavy and light chains in a single cell was what these cells did not naturally
`
`and we correctly expected that the result would not be any different when the
`
`heavy and light chains were expressed recombinantly. Dr. Fiddes appears to be
`
`confusing the difficulty of transfecting eukaryotic cells with expression of proteins
`
`once those cells were transfected. Only the former was a concern for our team. In
`
`1982, gpt and tk were the most common selection markers for use in eukaryotic
`
`host cells. Systems employing these selection markers were known to be toxic to
`
`the host cell because the marker selection was very rapid. The development of the
`
`neo selection marker was significant because selection occurs more slowly and is
`
`less toxic. Thus, we used a pSV2-neo vector that expressed three genes – the neo
`
`marker, the κ gene, and the µ gene – each under the control of separate promoters.
`
`By using this approach, we were able use a single protoplast fusion per host (a
`
`technique we had already validated in Ochi I), thereby minimizing the number of
`
`transfections and utilized the least toxic selection that was available at the time.
`
`
`
`9
`
`Merck Ex. 1093, Pg. 9
`
`

`

`that the foregoing is true and correct.
`
`Executed this 7th day of April 2017. I declare under penalty of perjury
`
`Atsuo Ochi
`
`Merck Ex. 1093, Pg. 10
`
`

`

`Merck Ex. 1093, Pg. 11
`
`
`
`EXHIBIT A
`
`EXHIBIT A
`
`
`
`
`
`Merck Ex. 1093, Pg. 11
`
`

`

`CURRICULUM VITAE (MAR, 29, 2017)
`
`
`NAME: Atsuo Ochi
`1.
`Contacts: 13-03 Ivy Lane Fair Lawn, New Jersey, 07410 USA
`( Atsuo.Ochi@nyumc.org Tel. 646-499-0555, 551-224-8465)
`
`2.
`
`EDUCATION HISTORY:
`
`
`
`
`3.
`
`
`
`Degree
`
`D.D.S.
`
`University
`
`Tokyo Medical and Dental
`University
`
`Ph.D.
`
`Tokyo University
`
`Year
`
`1978
`
`1982
`
`Field
`
`Dentistry
`
`Immunology
`(Dr. Tomio Tada)
`
`Postdoctoral
`Training
`
`Ontario Cancer Institute and
`
`1982-1986
`
`Medical Biophysics
`
`University of Toronto
`(In the laboratory of Dr. N.
`Hozumi)
`
`
`
`ACADEMIC OR RESEARCH POSITIONS:
`
`Position Held
`
`Date
`
`Department
`
`Institution
`
`Staff Scientist and
`Assistant Professor
`
`June 1986 to May 1994
`
`Staff Scientist and
`Assistant Professor
`
`July 1994 to June 1999
`
`Staff Scientist and
`Associate Professor
`
`July 1999 to June 2003
`
`Associate Professor
`
`July 2003 to June 2005
`
`Associate scientist
`in Research
`
`October 2004 to February
`2010
`
`Medical
`Genetics and
`Immunology
`
`Microbiology
`and
`Immunology
`
`Microbiology
`and
`Immunology
`
`Microbiology
`and
`Immunology
`
`Experimental
`Therapeutics
`
`Mt. Sinai Hospital
`Research Institute
`and The University
`of Toronto
`
`The John P.
`Robarts Research
`Institute and The
`University of
`Western Ontario
`
`The John P.
`Robarts Research
`Institute and The
`University of
`Western Ontario
`
`The University of
`Western Ontario
`
`The University
`Health Network
`Toronto
`
`Merck Ex. 1093, Pg. 12
`
`

`

`Genomic Med.
`Autoimmunity
`
`Mt. Sinai Hospital
`Res.Inst. Toronto
`
`
`
`
`
`Department of
`Surgery
`
`
`
`Department of
`Surgery
`
`New York
`University Medical
`Center
`
`New York
`University Faculty
`of Medicine
`
`
`
`
`
`September 2010 to July 2011
`
`
`
`July 2011 to present
`
`
`
`Associate scientist
`in Research
`
`
`
`Scientist in
`Research
`
`
`
`Assistant Professor
`
`July 2012 to present
`
`
`
`
`
`RESEARCH AWARDS:
`
`Term
`
`1986-90
`
`Agency
`
`National Cancer Institute of Canada (NCI) Research Scholarship
`(RESEARCH SCIENTIST)
`
`RESEARCH GRANT SUPPORT (1991-):
`
`4.
`
`
`
`5.
`
`
`GRANTEE
`
`AGENCY
`
` TITLE
`
`TERM
`
`A. Ochi (PI)
`K. Siminovitch
`(PI)
`
`Arthritis Society Use of bacterial superantigens in the
`treatment and study of autoimmune disease
`
`1991-93
`
`TOTAL
`
`AWARD
`
` $ 240,000
`Ochi’s share:
`$ 120,000
`
`A. Ochi (PI)
`
`MRC
`
`Post-thymic tolerance
`
`1991-93
`
` $ 151,122
`
` $ 113,136
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A. Ochi (PI)
`
`NCI
`
`A. Ochi (PI)
`
`MRC
`
`A. Ochi (PI)
`
`NCI
`
`A. Ochi (PI)
`
`NCI
`
`Molecular approach for tumour infiltrated T
`cell and immunotherapy
`
`1992-93
`
`Molecular determinants of T lymphocyte
`tolerance
`
`1994
`
` $
`
`30,000
`
`The molecular factors of B and T
`lymphocyte costimulatory signal
`
`1994
`
` $
`
`26,436
`
`Characterization of intracellular signals that
`regulate cell death vs. cell survival
`
`1995-98
`
` $ 210,738
`
`A. Ochi (PI)
`
`Arthritis Society Does autoagressive signaling in T cells and
`macrophages cause arthritis?
`
`1996-99
`
` $
`
`178,080
`
`A. Ochi (PI)
`
`NCI
`
`Gatekeepers and messengers of survival
`signalling in T lymphocytes
`
`1998-99
`
` $
`
`34,305
`
`A. Ochi (PI)
`
`A. Ochi
`J. Madrenas
`A. Lazarovits
`
`Leukemia
`Research Fund
`of Canada
`
`Juvenile
`Diabetes
`Foundation/MR
`C
`
`Towards a novel differentiation therapy of
`leukemia by ceramide
`
`1996
`
` $
`
`20,000
`
`Regulation of T cell activation signals in
`Insulitis and Diabetes
`
`1996-
`2000
`
` $ 577,635
`Ochi’s share:
`$ 184,210
`
`Merck Ex. 1093, Pg. 13
`
`

`

`A. Ochi (PI)
`
`Sumitomo
`Pharma-ceuticals
`Co., Ltd.
`
`Autoimmune disease research
`
`A. Ochi [PI]
`
`MRC
`
`The Molecular study of B cell tolerance
`
`A. Ochi [PI]
`
`CIHR
`
`The characterization of the cognate
`interaction between B cells and T cells that
`determine B cell activation.
`
`A. Ochi [PI]
`
`Multi-Organ
`Transplant
`Program
`
`Towards the development of fusion
`proteins useful to establish immunological
`tolerance against the transplant organs.
`
`1994-96
`(overhea
`d
`included)
`1999-02
`
`2002-03
`
` $ 500,000
`
` $ 215,994
`
` $ 9,000
`
`2002-04
`
` $ 70,000
`
`
`
`
`
`
`
`
`
`TEACHING EXPERIENCE TO DATE:
`
`University of Toronto Immunology course 1016: "Recent Advances in
`Immunology".
`1992 Sept.
`
`University of Western Ontario Dental Microbiology course 211. 8 hours
`1995 Sept-Nov.
`
`University of Western Ontario Microbiology and Immunology course
`512b. 9 hours 1998 Mar.-Apr.
`
`University of Western Ontario Microbiology and Immunology course
`512b. 9 hours 2000 Jan.-Feb.
`
`Biochemistry and Microbiology/Immunology course 483 and 484 (1997-
`1998) Tania Simon and Karen Berg
`Biochemistry and Microbiology/Immunology course 483 and 484 (1997-
`1998) Matthew Charles
`Biochemistry and Microbiology/Immunology course 483 and 484 (2000-
`2001) Farzana Haq
`
`University of Western Ontario Microbiology and Immunology course
`512b. 9 hours 2001 Jan.-Feb.
`
`University of Western Ontario Microbiology and Immunology course
`512b. 9 hours 2002 Jan.
`
`University of Western Ontario Microbiology and Immunology course
`585Y. 7 hours 2002 Jan-Apr.
`
`1.
`
`
`2.
`
`
`3.
`
`
`4.
`
`
`5.
`
`
`6.
`
`
`7.
`
`
`8.
`
`
`
`GRADUATE STUDENT SUPERVISION:
`
`Student Name
`
`Degree
`
`Year Obtained
`
`
`
`6.
`
`
`
`7.
`
`
`Merck Ex. 1093, Pg. 14
`
`

`

`Micheline Gravelle.
`
`Rumen Slavkov
`
`Caius Kim
`
`Alberto de Hoyos
`
`Gordon Chan
`
`Anna Stepczynska
`
`Matthew Charles
`
`Sebastian Mikolajczak
`
`M.Sc.
`
`M.Sc.
`
`M.Sc.
`
`
`
`M.Sc.
`
`
`
`M.Sc.
`
`Ph.D.
`
`1986-1988
`
`1988
`
`1989-1992
`
`1991-1993
`
`1995-1996
`
`1996-1997 (Dec)
`
`1999Sep.-2002 Feb.
`
`1999 Sep. –2005 Apr.
`
`
`Currently, Micheline Gravelle is working as a patent attorney in the Canadian law
`firm.
`Caius Kim is working at Sigma-Tau Pharmaceuticals, Inc. as a territory manager.
`Gordon Chan had been completed the Ph.D. program in The Universität
`Würzburg, Germany.
`Sebastian Mikolajczak is now working as Postdoctoral fellow in
`
`GRADUATE STUDENT COMMITTEE:
`
`I served as an advisory committee member for Mark Cameron (Dr. T. Delovitch's
`student), James Lee (Dr. J. Madrenas's student) and Holly Young (Dr. B. Singh’s
`student).
`Student exam members of board:
`Ph. D. Ms. Christine Frhlner-Gardiner April 8, 1999
`M. Sc. Tracey Stephens April 22. 2002
`Ph. D. Marc DeBrice February 2004
`Ph. D. Farbod Shojaei December 15, 2005
`
`POSTDOCTORAL FELLOW SUPERVISION:
`
`Name of Postdoctoral
`Fellow
`
`Term Supervised
`
`Greg Woods
`
`Mar 1986 - Jan 1988
`
`Yojiro Kawabe
`
`Mar 1987-Mar 1989
`
`Fujio Wake
`
`Mai Fu
`
`Kouichi Yuh
`
`Kiyoshi Migita
`
`Hiroaki Nishikata
`
`Tomoki Origuchi
`
`Mar 1988-Mar 1989
`
`Apr 1988-Mar 1989
`
`Mar 1989-Mar 1991
`
`Jul 1990-Mar 1993
`
`Apr 1992-Jul 1994
`
`Sep 1994-May 1996
`
`
`8.
`
`
`
`
`
`9.
`
`
`
`Merck Ex. 1093, Pg. 15
`
`

`

`Scott J. Ragg
`
`Katsuaki Sato
`
`Shuji Kaga
`
`Hiroharu Funaya
`
`Haruo Hanawa
`
`Yong Ma
`
`Tetsuya Yoshida
`
`Jun 1995-May 1997
`
`Feb 1996-Mar 1997
`
`Sep 1994-Jul 1997
`
`Apr 1998-Oct 1998
`
`Nov 1997-Nov 1999
`
`April 1999-April 2003
`
`April 1999-April 2003
`
`
`
`10.
`
`SCIENTIFIC SOCIETY MEMBERSHIPS:
`
`Canadian Association of Immunologists (1994 - 2004)
`American Association of Immunologists (July 1996 - 2004)
`CIHR senior Investigator Awards committee 2002 February 21, 22.
`CIHR senior Investigator Awards committee 2003 February 21, 22.
`
`
`
`
`
`PUBLICATIONS:
`
`
`11.
`
`Total of publication: 54
`Total of abstracts and presentations: 48
`
`a.
`
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`ARTICLES IN PEER-REVIEWED JOURNALS:
`
`Hiramatsu, K., A. Ochi, S. Miyatani, A. Segawa, and T. Tada. 1982. Monoclonal
`antibodies against unique I-gene products expressed only on mature functional T
`cells. Nature 296: 666-668.
`
`Ochi, A., M. Nonaka, K. Hayakawa, K. Okumura and T Tada. 1982. Two loci in
`I-J subregion of the H-2 complex controlling molecules selectively expressed on
`suppressor and helper T cells. J. Immunol. 129: 227-231.
`
`Nakajima, B.P., A. Ochi, E.L. Owen and T. Tada. 1983. Presence of IgT-c and
`I-A subregion-encoded determinants on distinct chains of monoclonal
`antigen-specific augmentingfactor derived from a T cell hybridoma. J. Exp. Med.
`157: 2110-2120.
`
`Ochi, A., R.G. Hawley, M.J. Shulman and N. Hozumi. 1983. Transfer of a cloned
`immunoglobulin light-chain gene to mutant hybridoma cells restores specific
`antibody production. Nature 302: 340-342.
`
`Ochi, A., R.G. Hawley, T. Hawley, M.J. Shulman, A. Traunecker, G. Kohler and
`N. Hozumi. 1983. Functional immunoglobulin M production after transfection of
`cloned immunoglobulin heavy and light chain genes into lymphoid cells. Proc.
`Natl. Acad. Sci. U.S.A. 80: 6351-6355.
`
`Merck Ex. 1093, Pg. 16
`
`

`

`6.
`
`7.
`
`8.
`
`9.
`
`Shulman, M.J., R.G. Hawley, A. Ochi, W.O.T. Baczynsky, C. Collins, N. Pennell,
`M.J. Potash, G. Kohler and N. Hozumi. 1984. Biochemical genetics of the mouse
`immunoglobulin M system. Can. J. Biochem. Cell Biol. 62: 217-224.
`
`Hawley, T., R. Hawley, J. Pauling, A. Ochi and N. Hozumi. 1986.
`Immunoglobulin synthesis in non-B cells Immunol. Letters 12: 257-262.
`
`Ochi, A. and N. Hozumi. 1986. Enhanced transcription in a pre-B cell line
`transformed with cloned antibody genes after antigen specific stimulation. J.
`Immunol. 136: 2705-2708.
`
`Watanabe, M., D.R. Wegmann, A. Ochi and N. Hozumi. 1986. Antigen
`presentation by a B cell line transfected with cloned immunoglobulin heavy and
`light chain genes specific for a defined hapten. Proc. Natl. Acad. Sci. USA 83:
`5247-5251.
`
`10. Watanabe, M., Shinohara, N., A. Ochi, and N. Hozumi. 1986. Functional
`reconstitution of class II major histocompatibility complex molecules, I-Aak and
`I-Abk. Immunol. Lett. 13: 237-244.
`
`11.
`
`Kitagami, K., N. Hozumi and A. Ochi. 1987. Clonal analysis of antigen-specific
`interactions between T cells and genetically engineered B cells. Cellular Immunol.
`108: 438-457.
`
`12. Ochi, A., K.S. Worton, G. Woods, M. Gravelle and K. Kitagami. 1987. A novel
`strategy for immunotherapy using antibody-coupled carriers to focus cytotoxic T
`helper cells. Eur. J. Immunol. 17: 1645-1648.
`
`13. Woods, G., L.A. Lund, M. Naik, V. Ling and A. Ochi. 1988. Resistance of
`multidrug-resistant lines to Natural Killer-like cell mediated cytotoxicity. FASEB
`J. 2: 2791-2796.
`
`14. Woods, G., K. Kitagami and A. Ochi. 1989. Evidence for an involvement of T4
`cytotoxic T cells in tumour immunity. Cellular Immunol. 118: 126-135.
`
`+
`
`15.
`
`16.
`
`17.
`
`18.
`
` T lymphocytes to a B cell
`Gravelle, M. and A. Ochi. 1989. The targeting of CD4
`lymphoma: A comparison of anti-CD3-anti-idiotype antibody conjugates and
`antigen-anti-idiotype conjugates. J. Immunol. 142: 4079-4084.
`
`+
`
` T cells in
` CD4
`Kawabe, Y. and A. Ochi. 1990. Selective anergy of Vß8
`Staphylococcus enterotoxin B-primed mice. J. Exp. Med. 172: 1065-1070.
`
`+
`
`+
`
`Kawabe, Y. and A. Ochi. 1991. Programmed cell death and extrathymic reduction
`+
`of Vß8+, CD4
` T cells in Staphylococcus enterotoxin B-specific tolerance.
`Nature 349: 245-248.
`
`Kim, C., K. A. Siminovitch and A. Ochi. 1991. Reduction of lupus nephritis in
`MLR/lpr mice by a bacterial superantigen treatment. J. Exp. Med. 174: 1431-
`1437.
`
`Merck Ex. 1093, Pg. 17
`
`

`

`19. Migita, K. and A. Ochi. 1993. The fate of anergic T cells in vivo. J. Immunol.
`150: 763-770.
`
`20.
`
`Spaner, D., K. Migita, A. Ochi, J. Shannon, R. G. Miller, P. Pereira, S. Tonegawa,
`R. A. Phillips. 1993. ∂-T cells differentiate into a functional but nonproliferative
`state during a normal immune response. Proc. Natl. Acad. Sci. USA 90: 8415-
`8419.
`
`21. Ochi, A., K. Migita, J. Xu and K. Siminovitch. 1993. In vivo tumor
`immunotherapy by a bacterial superantigen. J. Immunol. 151: 3180-3186.
`
`22.
`
`Yuh, K., K. A. Siminovitch and A. Ochi. 1993. T cell anergy is programmed
`early after exposure to bacterial superantigen in vivo. Int. Immunol. 5: 1375-1382.
`
`23. Migita K. and A. Ochi. 1994. Induction of clonal anergy by oral administration of
`staphylococcal enterotoxin B. Eur. J. Immunol. 24: 2081-2086.
`
`24.
`
`Chan, G. and A. Ochi. 1995. Sphingomyelin-ceramide turnover in CD28
`costimulatory signaling. Eur. J. Immunol. 25: 1999-2004.
`
`25. Migita K., K. Eguchi, Y. Kawabe, T. Tsukada, Y. Ichinose, S. Nagataki and A.
`Ochi. 1995. Defective TCR-mediated signalingin anergic T cells. J. Immunol.
`155: 5083-5087. and Errata 1996. 156: 3090.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`Salojin, K., J. Zang, M. Cameron, B. Gill, G. Arreaza, A. Ochi, and T. L.
`Delovitch. 1997. Impaired plasma membrane of Grb2-mSOS complex and
`differential activation of
`the Fyn-TCRZeta-Cbl pathway mediate T cell
`hyporesponsiveness in autoimmune nonobese diabetic mice. J. Exp. Med. 186:
`887-897.
`
`Kaga, S. S. J. Ragg, K. Roger, and A. Ochi. 1998. Stimulation of CD28 withB7-2
`promotes focal adhesion-like cell contacts where Rho family small G proteins
`accumulate in T cells. J. Immunol. 160: 24-27.
`
`Kaga, S. S. J. Ragg, K. Roger, and A. Ochi. 1998. Activation of p21-CDC42/Rac-
`activated kinases by CD28 signalling: PAK p65/MEKK1 may mediate the
`interplay between CD3 and CD28 signals. J. Immunol. Cutting Edge, 160: 4182-
`4189.
`
`Sato, K. and A. Ochi. 1998. Inhibition of B cell receptor-antigen complex
`internalization by FcRIIB1 signals. Immunol. Lett. 61: 135-143.
`
`Ragg, S. J., Kaga, S. and A. Ochi. 1998. The MAP kinase pathway inhibits
`ceramide-induced terminal differentiation of a human monoblastic leukemia cell
`line, U937. J. Immunol. 161: 1390-1398.
`
`Sato, K. and A. Ochi. 1998. Superclustering of B cell receptor and CD32/FcIIB
`activates Src homology 2-containing protein tyrosine phosphatase-1. J. Immunol.
`161: 2716-2722.
`
`Rahimpour, R., Mitchell, G., Kong, C., Singh, B., Xu, L., A. Ochi, Feldman, R.
`D., Dixson, S. J., Gill, B. M., and Kelvin, D. J. 1999. Bacterial superantigens
`
`Merck Ex. 1093, Pg. 18
`
`

`

`induce down-modulation of Ccchemokine responsiveness via an alternative
`chemokine ligand-independent mechanism. J. Immunol. 162: 2299-2307.
`
`33.
`
`Hanawa, H., Y. Ma, S. A. Mikolajczak, M. L. Charles, T. Yoshida, R. Yoshida, C.
`A. Strathdee, D. W. Litchfield, and A. Ochi. 2002. A novel costimulatory
`signalling in human T lymphocytes by a splice variant of CD28 Blood 99: 2138-
`2145.
`
`
`34. Cook-Mills, J. M., J. D. Johnson, T. L. Deem, A. Ochi, L. Wang, Y. Zheng Y.
`2004. Calcium mobilization and Rac1 activation are required for VCAM-1
`(vascular cell adhesion molecule-1) stimulation of NADPH oxidase activity.
`Biochem J. 378:539-47.
`
`
`35. Ma B.Y., S. A. Mikolajczak, T. Yoshida, R. Yoshida, D. J. Kelvin, and A. Ochi.
`2004. CD28 T cell costimulatory receptor function is negatively regulated by N-
`linked carbohydrates. Biochem Biophys Res Commun. 317:60-7.
`
`
`36. Mikolajczak, S. A., Y. Ma, T. Yoshida, R. Yoshida, D. J. Kelvin, and A. Ochi.
`2004. The Modulation of CD40 Ligand Signaling by Transmembrane CD28 Splice
`Variant in Human T Cells. J Exp Med. 199:1025-31.
`
`
` 37. Ma, Y., S. A. Mikolajczak, T. Yoshida, R. Yoshida, D. J. Kelvin, and A. Ochi.
`2005. The expression and the regulatory role of OX40 and 4-1BB heteromolecular
`complex in activated human T cells. Blood 106: 2002-2010.
`
`
`38. Ochi. A, Danesh, C. Seneviratne, D. Banner, M. E. Devries, T. Rowe, L. Xu, L.
`Ran, M. Czub, S. E. Bosinger, M. J. Cameron, C. M. Cameron, and D. J. Kelvin.
`2008. Cloning, expression and immunoassay detection of ferret IFN-gamma.Dev
`Comp Immunol. 2008;32(8):890-7. Epub 2008 Jan 28.
`
`
`39. Yoshida T, Yoshida R, Ma B. Y., Mikolajczak S, Kelvin D. J., and A. Ochi. A
`novel mitogen fusion protein against CD40+ cells with potent vaccine adjuvant
`properties. Vaccine. 2010 May 7;28(21):3688-95. Epub 2010 Mar 30.
`
`
`40. Ibrahim J, Nguyen AH, Rehman A, Ochi A., Jamal M, Graffeo CS, Henning JR, Zambirinis CP,
`Fallon NC, Barilla R, Badar S, Mitchell A, Rao RS, Acehan D, Frey AB,Miller G. Dendritic
`cell populations with different concentrations of lipid regulate tolerance and
`immunity in mouse and human liver. Gastroenterology. 2012 Oct;143(4):1061-72.
`
`
`
`
`
`41. Ochi A, Nguyen AH, Bedrosian AS, Mushlin HM, Zarbakhsh S, Barilla R,
`Zambirinis CP, Fallon NC, Rehman A, Pylayeva-Gupta Y, Badar S, Hajdu CH,
`Frey AB, Bar-Sagi D, Miller G. MyD88 inhibition amplifies dendritic cell capacity
`to promote pancreatic carcinogenesis via Th2 cells. J Exp Med. 2012 Aug
`27;209(9):1671-87.
`
`42. Ochi A, Graffeo CS, Zambirinis CP, Rehman A, Hackman M, Fallon N, Barilla
`RM, Henning JR, Jamal M, Rao R, Greco S, Deutsch M, Medina-Zea MV, Bin
`
`Merck Ex. 1093, Pg. 19
`
`

`

`Saeed U, Ego-Osuala MO, Hajdu C, Miller G. Toll-like receptor 7 regulates
`pancreatic carcinogenesis in mice and humans. J Clin Invest. 2012 Nov
`1;122(11):4118-29.
`
`
`43. Henning JR, Graffeo CS, Rehman A, Fallon NC, Zambirinis CP, Ochi A, Barilla R,
`Jamal M, Deutsch M, Greco S, Ego-Osuala M, Saeed UB, Rao RS, Badar S,
`Quesada JP, Acehan D, Miller G. Dendritic cells limit fibro-inflammatory injury in
`NASH. Hepatology. 2013 Jan 15.
`
`
`44. Rehman A, Hemmert KC, Ochi A, Jamal M, Henning JR, Barilla R, Quesada JP,
`Zambirinis CP, Tang K, Ego-Osuala M, Rao RS, Greco S, Deutsch M, Narayan S,
`Pachter HL, Graffeo CS, Acehan D, Miller G. Role of Fatty-Acid synthesis in
`dendritic cell generation and function. J Immunol. 2013 May 1;190(9):4640-9.
`
`
`45. Zambirinis CP, Ochi A, Barilla R, Greco S, Deutsch M, Miller G. Induction of
`TRIF- or MYD88-dependent pathways perturbs cell cycle regulation in pancreatic
`cancer. Cell Cycle. 2013 Apr 15;12(8):1153-4
`
`
`46. Rao, R S; Graffeo, C S; Gulati, R; Narayan, S; Mohaimin, T; Greco, S; Tomkoetter,
`L; Van, Heerden E; Barilla, R M; Carazas, O; Blobstein, R; Gelbstein, Y; Ochi, A;
`Zambirinis, C P; Deutsch, M; Miller, G T cells promote liver regeneration via
`Dectin-1 dependent IL-17/IL-22 mediated inflammatory interplay 2013-12-10;
`0270-9139,Hepatology
`
`
`47. Rao R, Graffeo CS, Gulati R, Jamal M, Narayan S, Zambirinis C, Barilla R,
`Deutsch M, Greco S, Ochi A, Tomkötter L, Blobstein R, Avanzi A, Tippens DM,
`Gelbstein Y, Van Heerden E, Miller G. Interleukin 17-producing γδT cells promote
`hepatic regeneration in mice. Gastroenterology. 2014 Aug;147(2):473-84.
`
`
`48. Deutsch M, Graffeo CS, Rokosh R, Pansari M, Ochi A, Levie EM, Van Heerden E,
`Tippens DM, Greco S, Barilla R, Tomkötter L, Zambirinis CP, Avanzi N, Gulati R,
`Pachter HL, Torres-Hernandez A, Eisenthal A, Daley D, Miller G. Divergent
`effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death
`and Disease. 2015; 6:e1759. doi: 10.1038/cddis.2015.126
`
`
`49. Greco SH, Tomkötter L, Vahle A, Rokosh R, Avanzi A, Mahmood SK, Deutsch M,
`Alothman A, Alqunaibit D, Ochi A, Zambirinis CP, Mohaimin T, Rendon M, Levie
`E, Pansari M, Torres-Hernandez A, Daley D, Barilla R, Pachter HL, Tippens D,
`Malik H, Boutajangout A, Wisniewski T, Miller G. TGF-β Blockade Reduces
`Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic
`Cancer Cachexia. Plos One. 2015; doi: 10.1371/journal.pone.0132786
`
`
`50. Seifert L, Deutsch M, Alothman S, Alqunaibit D, Werba G, Pansari M, Pergamo
`M, Ochi A, Torres-Hernandez A, Levie E, Tippens D, Greco SH, Tiwari S, Ly NN,
`Eisenthal A, van Heerden E, Avanzi A, Barilla R, Zambirinis CP, Rendon M, Daley
`D, Pachter HL, Hajdu C, Miller G. Dectin-1 Regulates Hepatic Fibrosis and
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`Merck Ex. 1093, Pg. 20
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`

`Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways. Cell Rep. 2015
`Dec 1;13(9):1909-21. doi: 10.1016/j.celrep.2015.10.058.
`
`
`51. Greco SH, Mahmood SK, Vahle AK, Ochi A, Batel J, Deutsch M, Barilla R, Seifert
`L, Pachter HL, Daley D, Torres-Hernandez A, Hundeyin M, Mani VR, Miller G.
`Mincle suppresses Toll-like receptor 4 activation. J Leukoc Biol. 2016
`Jul;100(1):185-94. doi: 10.1189/jlb.3A0515-185R
`
`
`52. Seifert L, Werba G, Tiwari S, Giao Ly NN, Alothman S, Alqunaibit D, Avanzi A,
`Barilla R, Daley D, Greco SH, Torres-Hernandez A, Pergamo M, Ochi A,
`Zambirinis CP, Pansari M, Rendon M, Tippens D, Hundeyin M, Mani VR, Hajdu
`C, Engle D, Miller G. The necrosome promotes pancreatic oncogenesis via CXCL