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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`________________
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`SAMSUNG BIOEPIS CO., LTD., Petitioner,
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`
`v.
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`GENENTECH, INC., Patent Owner.
`
`________________
`
`United States Patent No. 6,407,213
`Title: Method for Making Humanized Antibodies
`
`
`Case No.: IPR2017-02139
`
`________________
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`DECLARATION OF MARK GERSTEIN, Ph.D
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`BIOEPIS EX. 1191
`Page 1
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`TABLE OF CONTENTS
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`I.
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`INTRODUCTION ....................................................................................... 3
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`A. Background, Education, Experience, and Qualifications ................. 3
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`B.
`
`Compensation .................................................................................... 5
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`C. Materials Relied Upon and Bases for Opinions ................................ 6
`
`II.
`
`SUMMARY OF OPINIONS ....................................................................... 6
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`III. RELEVANT LAW ....................................................................................10
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`A. Claims and Claim Construction ......................................................10
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`B. Anticipation and Obviousness .........................................................11
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`C.
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`Person of Ordinary Skill in the Art .................................................12
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`IV. THE ’213 PATENT ...................................................................................14
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`V. MONOCLONAL ANTIBODY THERAPY AND CANCER ..................14
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`VI. STATE OF THE ART OF MONOCLONAL ANTIBODY THERAPIES
`AND CANCER .........................................................................................17
`
`A.
`
`B.
`
`C.
`
`D.
`
`Early Antibody Therapy ..................................................................17
`
`Efforts to Reduce Immunogenicity – Chimerization and
`Humanization ..................................................................................21
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`Breast Cancer and HER-2 ...............................................................26
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`Identification and Characterization of 4D5, a Potential Therapeutic
`Mouse Monoclonal Antibody to HER-2/neu ..................................33
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`E. Humanization of 4D5 to Enable Therapeutic Use ..........................40
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`2
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`BIOEPIS EX. 1191
`Page 2
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`I, Mark Gerstein, Ph.D. declare as follows:
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`I.
`
`INTRODUCTION
`
`1.
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`I have been retained by White & Case LLP (“Counsel”), counsel for
`
`Samsung Bioepis Co., Ltd. (“Bioepis”), as an expert in the above captioned inter
`
`partes review (“IPR”) concerning United States Patent No. 6,407,213 (the “’213
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`Patent”). This declaration sets forth my opinions concerning the invalidity of the
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`’213 Patent; as well as technical background information; the bases for my
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`opinions; my qualifications; and my compensation for services provided in this
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`matter. My opinions and the facts set forth in this declaration are based upon
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`information I reviewed in connection with this matter and over 25 years of
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`education, knowledge, and experience.
`
`A.
`
`Background, Education, Experience, and Qualifications
`
`2.
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`I am currently a Professor of Comupter Science, a Professor of
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`Molecular Biophysics and Biochemistry, and the AL Williams Professor of
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`Biomedical Informatics at Yale Univerity. I am also the co-director of the Yale
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`Computational Biology and Bioinformatics Program at the Yale University Center
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`for Biomedical Data Science. In these positions, I teach a number of courses
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`regarding computational biology and macromolecules, among other topics. I have
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`over 25 years of experience studying protein structure and function and related
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`3
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`BIOEPIS EX. 1191
`Page 3
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`computational methods. A copy of my curriculum vitae is attached to this report
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`as Exhibit 1.
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`3.
`
`I received an AB from Harvard College in Physics and the History of
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`Science in 1989. I then received a Ph.D. from Cambridge University in 1993. My
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`Ph.D. work was partially supervised by Dr. Cyrus Chothia at the MRC Laboratory
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`in Cambridge, England. Dr. Chothia, along with his collaborator Dr. Athur Lesk,
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`worked extensively on modeling antibody structures. Through this work, Drs.
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`Chothia and Lesk showed that a few key residues often determined antibody
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`confirmation; the implication being that researchers could freely modify other
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`residues without affecting the antibody’s affinity or specificity. This work
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`occurred during my tenure in Dr. Chothia’s laboratory. Following my graduate
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`work, I took a post-doctoral position at Stanford University from 1993 through
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`1996 studying bioinformatics under the supervision of Dr. Michael Levitt. Like
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`my Ph.D. advisor, Dr. Levitt studied antibody models and modeling
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`methodologies, occasionally in collaboration with Protein Design Labs.
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`4.
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`Following my post-doctoral position, I became an assistant professor
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`of molecular biophysics and biochemistry at Yale University. I was then promoted
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`to an associate professor in 2001 and a full professor in 2006. At Yale, I supervise
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`the research of post-doctoral researchers, graduate and undergraduate students,
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`research associates, research scientists, and laboratory staff.
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`4
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`BIOEPIS EX. 1191
`Page 4
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`5.
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`I also run a number of programs related to computational biology at
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`Yale. I serve as the co-DGS and co-director of the Yale Computational Biology &
`
`Bioinformatics (CBB) Program. I have also been a member of the Computational
`
`Biology admissions committee since 2003.
`
`6.
`
`I have published a number of publications in peer-reviewed scientific
`
`journals (over 500 such publications), including, for example, M. Gerstein & R.
`
`Altman, Average Core Structures and Variability Measures for Protein Famailies:
`
`Application to the Immunoglobulins, 251(1) J. Molecular Biology 161-175 (Aug.
`
`1995) and M. Gerstein, A resolution-sensitive procedure for comparing protein
`
`surfaces and its application to the comparison of antigen-combining sites, A48
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`Acta Cryst. 271-276 (1992).
`
`B. Compensation
`
`7.
`
`I am working as an independent consultant in this matter. I have no
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`financial interest in the outcome of this IPR. I have no financial interest in the
`
`Petitioner or the ’213 Patent. I have had no contact with the named inventions of
`
`the ’213 Patent concerning this matter.
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`8.
`
`I am being compensated at $750 per hour. In addition, I receive
`
`reimbursement for expenses. This compensation is entirely unrelated to the
`
`outcome of this matter.
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`
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`5
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`BIOEPIS EX. 1191
`Page 5
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`C. Materials Relied Upon and Bases for Opinions
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`9.
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`A list of the materials that I have relied upon and otherwise
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`considered in formulating my opinions is set forth in this declaration as Exhibit 2.
`
`I have also relied on my general knowledge and experience.
`
`10.
`
`I understand that a third-party – Pfizer Inc. (“Pfizer”) – previously
`
`filed IPR petitions challenging claims of the ’213 patent. I have reviewed and
`
`considered Pfizer’s IPR petitions and the declarations filed in support of Pfizer’s
`
`IPR petitions. Applying my independent judgment and expertise, after having
`
`independently reviewed and analyzed all of the materials in Pfizer expert Mr.
`
`Timothy Buss’s materials considered lists, and having done the additional work of
`
`fact checking and considering whether potential counterarguments may exist, I
`
`have come to the same conclusions as Mr. Buss and I agree with the analysis in his
`
`declaration as set forth below. Readers of this declaration may note that the
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`language and organization is similar to that of Mr. Buss’s declaration because it
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`did not seem necessary to rewrite the material which I independently confirmed as
`
`acceptable and correct. The opinions in this declaration should be considered
`
`mine.
`
`II.
`
`SUMMARY OF OPINIONS
`
`11.
`
`I have been asked to assess the validity of the ’213 Patent from a
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`scientific perspective. Specifically, I have been asked to consider whether the ’213
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`6
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`BIOEPIS EX. 1191
`Page 6
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`Patent is invalid because it is anticipated by and/or obvious over the prior art (i.e.,
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`literature published before June 14, 1991).
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`12. For the reasons set forth below, it is my opinion that one of ordinary
`
`skill in the art would have recognized the power and potential of monoclonal
`
`antibodies (MAbs or MoAbs) as therapies for a number of diseases including
`
`breast cancer while acknowledging the limitation of their use due to immunogenic
`
`effects upon repeated administration of mouse monoclonal antibodies. Moreover,
`
`one of ordinary skill in the art would have recognized that humanization of mouse
`
`monoclonal antibodies as developed by Queen et al., A Humanized antibody that
`
`binds to the interleukin 2 receptor, 86 PROC. NAT’L ACAD. SCI. USA 10029–33
`
`(1989) (“Queen 1989”) (Ex. 1034) and others would overcome this limitation.
`
`With respect to cancer, one skilled in the art would have identified HER-2/neu as a
`
`target for breast cancer therapy based on the prevalence of this gene in a significant
`
`number of human breast cancer and other types of cancers as well as the
`
`overexpression of HER-2/neu to cause cell transformation and tumorigenesis.
`
`13. Accordingly, it is my opinion that because of the well-documented
`
`pre-1991 reports of excellent specificity and potent anti-proliferative and cytotoxic
`
`effects of the mouse monoclonal 4D5 antibody directed to HER-2/neu as presented
`
`in Hudziak et al., p185HER2 Monoclonal Antibody Has Antiproliferative Effects In
`
`
`
`
`7
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`BIOEPIS EX. 1191
`Page 7
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`Vitro and Sensitizes Human Breast Tumor Cells to Tumor Necrosis Factor, 9(3)
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`MOLECULAR CELLULAR BIOLOGY 1165 (1989) (“Hudziak 1989”) (Ex.
`
`1021), a person of ordinary skill in the art would have identified 4D5 as a
`
`promising candidate for humanization, at least as early as March 1989. After
`
`singling out 4D5 from a panel of monoclonal antibodies, Hudziak 1989 (Ex. 1021)
`
`identified the 4D5 antibody as showing good specificity toward the HER-2
`
`receptor extracellular domain and did not cross-react or bind to the EGF receptor
`
`(HER-1). The 4D5 antibody also demonstrated growth inhibitory and anti-
`
`proliferative effects on HER-2 positive SK-BR-3 breast cancer cells. As Hudziak
`
`1989 (Ex. 1021) noted, the 4D5 antibody had the best effect of the tested anti-
`
`HER-2 antibodies in inhibiting the growth of these cells leading the authors to
`
`conclude that “[m]aximum inhibition was obtained with monoclonal antibody 4D5
`
`which inhibited cellular proliferation by 56%.” Id. at 12. The 4D5 antibody was
`
`also shown to downregulate p185HER2 by allowing the protein to be degraded
`
`more quickly in the cell. Finally, the 4D5 antibody sensitized HER-2 positive
`
`breast cancer cells to TNF-alpha mediated cytotoxicity.
`
`14. Furthermore, Shepard et al., Monoclonal Antibody Therapy of Human
`
`Cancer: Taking the HER2 Protooncogene to the Clinic, 11(3) J. CLINICAL
`
`IMMUNOLOGY, 117 (1991) (Ex. 1048) reported that a human tumor xenograft
`
`model was used to “support[] the application of muMAb 4D5 to human cancer
`
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`8
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`BIOEPIS EX. 1191
`Page 8
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`therapy” and “its ability to inhibit the growth of tumor cells overexpressing
`
`p185HER2 in vivo.” Id. at 8. In tumor bearing athymic mice, the authors
`
`administered either the 4D5 antibody, a control antibody 5B6, or PBS and
`
`observed that “[o]n day 20, average tumor weights of animals receiving muMAb
`
`4D5 were significantly less than those receiving the same dose of the control
`
`antibody muMAb 5B6.” Id. at 9. These observations allow Shepard et al. to
`
`conclude that “[t]he muMAb 4D5 also serves as a template for antibody
`
`engineering efforts to construct humanized versions more suitable for chronic
`
`therapy or other molecules which may be directly cytotoxic for tumor cells
`
`overexpressing the HER2 protooncogene.” Id. at 12.
`
`15. Thus in my opinion, one of ordinary skill in the art would have
`
`acknowledged and recognized the above-described promising properties of the
`
`mouse monoclonal antibody 4D5 in vitro and in vivo and have strong motivation to
`
`select this antibody as a prime candidate for further development as a therapy for
`
`breast cancer. It then follows, that one of ordinary skill in the art would logically
`
`proceed to develop the monoclonal 4D5 antibody as a breast cancer therapeutic via
`
`well-established humanization
`
`techniques,
`
`thereby reducing
`
`the antibody’s
`
`immunogenicity and restoring antibody-dependent cell-mediated cytotoxicity
`
`(ADCC) and effector cell binding.
`
`
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`9
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`BIOEPIS EX. 1191
`Page 9
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`III. RELEVANT LAW
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`16. For the purposes of this declaration, I have been informed about
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`certain aspects of the law that are relevant to my opinion. My understanding of the
`
`law is as follows:
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`17.
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`I understand a patent has three primary parts: the specification, the
`
`drawings, and the claims. The specification consists of a written description of the
`
`invention and must provide a sufficient description to enable one skilled in the art
`
`to practice the invention. The drawings illustrate the invention. The claims appear
`
`at the end of the specification as numbered paragraphs. I am told the claims define
`
`the metes and bounds of the property right conveyed by the patent.
`
`A. Claims and Claim Construction
`
`18.
`
`I understand claims can be independent or dependent. Dependent
`
`claims refer back to and incorporate at least one other claim. Dependent claims
`
`include all the limitations of any claims incorporated by reference into the
`
`dependent claim.
`
`19.
`
`I have also been told that claims should be given their broadest
`
`reasonable interpretation in light of the specification from the perspective of a
`
`person of ordinary skill in the art at the time of the alleged invention.1
`
`
`1 In my analysis, I have assumed that the priority date of the ’213 patent (June 14,
`1991) is the date of the alleged invention.
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`10
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`BIOEPIS EX. 1191
`Page 10
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`20.
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`I understand prior art to the ’213 patent includes patents, printed
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`publications and products in the relevant art that predate the priority date of the
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`’213 patent.
`
`B. Anticipation and Obviousness
`
`21.
`
`I am told a claim is invalid if it is anticipated or obvious. I understand
`
`anticipation requires that every element and limitation of the claim was previously
`
`described in a single prior art reference, either expressly or inherently, before the
`
`date of the alleged invention.
`
`22. To determine whether a claim is obvious, I understand the scope and
`
`content of the prior art are to be determined, differences between the prior art and
`
`the claims at issue are to be ascertained, and the level of ordinary skill in the
`
`pertinent art resolved. I also understand that secondary considerations such as
`
`commercial success, long felt but unsolved needs, failure of others, etc., may have
`
`some relevancy to whether or not the claim is obvious or nonobvious. I understand
`
`that obviousness is assessed at the time of the alleged invention.
`
`23.
`
`I am also informed that when there is some recognized reason to solve
`
`a problem, and there are a finite number of identified, predictable and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
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`options within his or her technical grasp. If such an approach leads to expected
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`success, it is likely not the product of innovation but of ordinary skill and common
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`11
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`BIOEPIS EX. 1191
`Page 11
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`sense. In such a circumstance, when a patent simply arranges old elements with
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`each performing its known function and yields no more than what one would
`
`expect from such an arrangement, the combination is obvious.
`
`24.
`
`I understand that Bioepis bears the burden of proving unpatentability
`
`by a preponderance of the evidence. I understand that this preponderance of the
`
`evidence standard means that Bioepis must show that unpatentability is more
`
`probable than not. I have taken these principles into account when forming my
`
`opinions in this case.
`
`C.
`
`Person of Ordinary Skill in the Art
`
`25.
`
`I understand that in defining a person of ordinary skill in the art the
`
`following factors may be considered: (1) the educational level of the inventor; (2)
`
`the type of problems encountered in the art; (3) prior art solutions to those
`
`problems; (4) rapidity with which innovations are made; and (5) sophistication of
`
`the technology and educational level of active workers in the field.
`
`26.
`
`In my opinion a person of ordinary skill in the art related to the ’213
`
`patent, as of June 14, 1991, would be an individual that developed protein
`
`therapeutics. This person would have a Ph.D. or equivalent (for example,
`
`knowledge gained through 4–5 years of work experience) in molecular biology,
`
`immunology, biochemistry or a closely related field, and may work as a member of
`
`a team. A team member or advisor or consultant would have an M.D. with clinical
`
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`12
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`BIOEPIS EX. 1191
`Page 12
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`experience in the disease or disease area (e.g., oncology) for which the antibody
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`development is intended.
`
`27. For example, as a Ph.D. or equivalent the person of ordinary skill in
`
`the art would have the educational background above with experience in common
`
`laboratory techniques in molecular biology. This experience is consistent with the
`
`types of problems encountered in the art of protein engineering, which would have
`
`included performing three-dimensional computer modeling of protein structures,
`
`domain and sequence manipulation and swapping, construction and expression of
`
`recombinant proteins, antibody binding assays (for specificity and affinity),
`
`immunogenicity testing and the like. The experience may come from the person of
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`ordinary skill in the art’s own experience, or may come through research or work
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`collaborations with other
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`individual(s) with experience
`
`in
`
`the medical,
`
`pharmaceutical or biotech industry, e.g., as members of a research team or group.
`
`28. A person of ordinary skill in the art would also be well-versed in the
`
`world-wide literature on antibody therapeutics that was available as of June 14,
`
`1991. As mentioned above, the person of ordinary skill in the art may work as part
`
`of a team or collaboration to develop a humanized monoclonal antibody for
`
`therapeutic use, including consulting with others to select non-human monoclonal
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`antibodies (such as a mouse monoclonal antibody) for humanization, as well as
`
`subsequent testing of the humanized antibody and its intermediates. In the prior art
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`13
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`BIOEPIS EX. 1191
`Page 13
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`(i.e., before, at least, June 14, 1991), computer modeling for humanization was a
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`known methodology. The field was advancing rapidly, and individuals working in
`
`the field were highly sophisticated and using the most advanced scientific
`
`techniques.
`
`IV. THE ’213 PATENT
`
`29.
`
`I have read the ’213 patent entitled “Method for Making Humanized
`
`Antibodies,” as well as its issued claims. I understand Bioepis is challenging
`
`claims 1, 2, 4, 12, 25, 29–31, 33, 42, 60, 62–67, 69 and 71–81 (“Challenged
`
`Claims”). The Challenged Claims include claims that relate to a humanized
`
`antibody which binds to p185HER2, i.e., claims 30, 31, 33, 42 and 60. I have been
`
`asked by Bioepis to comment on antibody therapies, and in particular those that
`
`relate to p185HER2 and breast cancer.
`
`V. MONOCLONAL ANTIBODY THERAPY AND CANCER
`
`30. To summarize, for the reasons set forth below, it is my opinion that
`
`one of ordinary skill in the art would have recognized the power and potential of
`
`monoclonal antibodies (MAbs or MoAbs) as therapies for a number of diseases
`
`including breast cancer while acknowledging the limitation of their use due to
`
`immunogenic effects upon repeated administration of mouse monoclonal
`
`antibodies. Moreover, one of ordinary skill in the art would have recognized that
`
`humanization of mouse monoclonal antibodies as developed by Queen et al., A
`
`
`
`
`14
`
`
`
`
`
`BIOEPIS EX. 1191
`Page 14
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`
`
`Humanized antibody that binds to the interleukin 2 receptor, 86 PROC. NAT’L
`
`ACAD. SCI. USA 10029–33 (1989) (“Queen 1989”) (Ex. 1034) and others would
`
`overcome this limitation. With respect to cancer, one skilled in the art would have
`
`identified HER-2/neu as a target for breast cancer therapy based on the prevalence
`
`of this gene in a significant number of human breast cancer and other types of
`
`cancers as well as the overexpression of HER-2/neu to cause cell transformation
`
`and tumorigenesis.
`
`31. Accordingly, it is my opinion that because of the well-documented
`
`pre-1991 reports of excellent specificity and potent anti-proliferative and cytotoxic
`
`effects of the mouse monoclonal 4D5 antibody directed to HER-2/neu as presented
`
`in Hudziak et al., p185HER2 Monoclonal Antibody Has Antiproliferative Effects In
`
`Vitro and Sensitizes Human Breast Tumor Cells to Tumor Necrosis Factor, 9(3)
`
`MOLECULAR CELLULAR BIOLOGY 1165 (1989) (“Hudziak 1989”) (Ex.
`
`1021), a person of ordinary skill in the art would have identified 4D5 as a
`
`promising candidate for humanization, at least as early as March 1989. After
`
`singling out 4D5 from a panel of monoclonal antibodies, Hudziak 1989 (Ex. 1021)
`
`identified the 4D5 antibody as showing good specificity toward the HER-2
`
`receptor extracellular domain and did not cross-react or bind to the EGF receptor
`
`(HER-1). The 4D5 antibody also demonstrated growth inhibitory and anti-
`
`proliferative effects on HER-2 positive SK-BR-3 breast cancer cells. As Hudziak
`
`
`
`
`15
`
`
`
`
`
`BIOEPIS EX. 1191
`Page 15
`
`
`
`
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`1989 (Ex. 1021) noted, the 4D5 antibody had the best effect of the tested anti-
`
`HER-2 antibodies in inhibiting the growth of these cells leading the authors to
`
`conclude that “[m]aximum inhibition was obtained with monoclonal antibody 4D5
`
`which inhibited cellular proliferation by 56%.” Id. at 12. The 4D5 antibody was
`
`also shown to downregulate p185HER2 by allowing the protein to be degraded more
`
`quickly in the cell. Finally, the 4D5 antibody sensitized HER-2 positive breast
`
`cancer cells to TNF-alpha mediated cytotoxicity.
`
`32. Furthermore, Shepard et al., Monoclonal Antibody Therapy of Human
`
`Cancer: Taking the HER2 Protooncogene to the Clinic, 11(3) J. CLINICAL
`
`IMMUNOLOGY, 117 (1991) (Ex. 1048) reported that a human tumor xenograft
`
`model was used to “support[] the application of muMAb 4D5 to human cancer
`
`therapy” and “its ability to inhibit the growth of tumor cells overexpressing
`
`p185HER2 in vivo.” Id. at 8. In tumor bearing athymic mice, the authors
`
`administered either the 4D5 antibody, a control antibody 5B6, or PBS and
`
`observed that “[o]n day 20, average tumor weights of animals receiving muMAb
`
`4D5 were significantly less than those receiving the same dose of the control
`
`antibody muMAb 5B6.” Id. at 9. These observations allow Shepard et al. to
`
`conclude that “[t]he muMAb 4D5 also serves as a template for antibody
`
`engineering efforts to construct humanized versions more suitable for chronic
`
`
`
`
`16
`
`
`
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`BIOEPIS EX. 1191
`Page 16
`
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`
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`therapy or other molecules which may be directly cytotoxic for tumor cells
`
`overexpressing the HER2 protooncogene.” Id. at 12.
`
`33. Thus in my opinion, one of ordinary skill in the art would have
`
`acknowledged and recognized the above-described promising properties of the
`
`mouse monoclonal antibody 4D5 in vitro and in vivo and have strong motivation to
`
`select this antibody as a prime candidate for further development as a therapy for
`
`breast cancer. It then follows, that one of ordinary skill in the art would logically
`
`proceed to develop the monoclonal 4D5 antibody as a breast cancer therapeutic via
`
`well-established humanization
`
`techniques,
`
`thereby reducing
`
`the antibody’s
`
`immunogenicity and restoring antibody-dependent cell-mediated cytotoxicity
`
`(ADCC) and effector cell binding.
`
`VI. STATE OF THE ART OF MONOCLONAL ANTIBODY THERAPIES
`AND CANCER
`
`A.
`
`Early Antibody Therapy
`
`34. Because of their specificity to an antigen, antibodies were considered
`
`very early on as potential therapeutics for the treatment of diseases and conditions.
`
`In particular, monoclonal antibodies created from mice, developed by Georges
`
`Köhler and César Milstein in 1975, were of great interest to researchers as these
`
`types of antibodies were of a single clonal population of antibodies which all
`
`bound to the same antigen with the same specificity. See, e.g., Köhler et al.,
`
`Continuous cultures of fused cells secreting antibody of predefined specificity,
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`17
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`BIOEPIS EX. 1191
`Page 17
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`256(5517) NATURE 495 (1975) (Ex. 1022). In this seminal paper, Köhler and
`
`Milstein developed the hybridoma cell technique that fused a mouse myeloma cell
`
`with antibody-producing mouse spleen cells from an immunized donor. It then
`
`became “possible to hybridise antibody-producing cells from different origins” and
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`that “[s]uch cells [could] be grown in vitro in massive cultures to provide a specific
`
`antibody.” Id. at 5. The authors, who went on to receive the 1984 Nobel Prize for
`
`medicine for this work, contemplated that “[s]uch cultures could be valuable for
`
`medical and industrial use.” Id. Monoclonal antibody technology thus enabled the
`
`isolation and large scale production of a single specific antibody and opened the
`
`door to using antibodies for therapeutic and diagnostic purposes. See, e.g.,
`
`Prabakaran, The Quest for a Magic Bullet, 349(6246) SCIENCE 389 (2015) (Ex.
`
`1023 at 5) (“Milstein sent samples and protocols of his newly created antibody-
`
`secreting cell lines to other research institutions and even trained scientists to
`
`generate their own hybridomas.…In the years that followed, there was an
`
`explosion in Mab research. Some were generated to identify different types of
`
`white blood cells, and several proved to be important in investigating HIV/AIDS.
`
`The first medical application of this technology used Mabs to purify interferons,
`
`signaling proteins that are released by cells in response to the presence of
`
`pathogens.”); Marks, The story of Cesar Milstein and Monoclonal Antibodies: A
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`Healthcare Revolution
`
`in
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`the Making, http://www.whatisbiotechnology.org/
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`
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`18
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`BIOEPIS EX. 1191
`Page 18
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`exhibitions/milstein (last visited April 13, 2017) (Ex. 1024 at 56–57). (“By the
`
`time the Nobel Prize was awarded to Milstein and his colleagues, monoclonal
`
`antibodies had become a ubiquitous method for researchers in a multitude of
`
`disciplines. The technology not only provided the tool for those involved in basic
`
`science, but also for those looking to develop new diagnostics and therapies.”)
`
`35. Researchers thus immediately recognized the therapeutic potential of
`
`monoclonal antibodies, and began administering murine monoclonal antibodies in
`
`humans in an attempt to treat a variety of diseases, including cancer and
`
`immunological disorders. For example, the first Mab approved for human use,
`
`murine monoclonal anti-CD3 antibody, OKT3
`
`(muromonab-CD3), was
`
`investigated for its immunosuppressive activities in preventing organ graft
`
`rejection. See, e.g., Cosimi et al., Treatment of Acute Renal Allograft Rejection
`
`with OKT3 Monoclonal Antibody, 32 TRANSPLANTATION 535−39 (1981) (Ex.
`
`1025); Ortho Multicenter Transplant Study Group, A Randomized Clinical Trial of
`
`OKT3 Monoclonal Antibody for Acute Rejection of Cadveric Renal Transplants,
`
`313(6) NEW ENG. J. MED. 337 (1985) (Ex. 1026). Administration of OKT3,
`
`which binds to CD3 on human T-cells and suppresses T-cell function, in patients
`
`with kidney transplants was found to be more effective in treating and reversing
`
`kidney transplant rejections than conventional steroids. Id. at 2, Abstract. Despite
`
`OKT3’s impressive and potent immunosuppressive effects, it was also found that
`
`
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`19
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`BIOEPIS EX. 1191
`Page 19
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`OKT3, as a murine monoclonal antibody, elicited a strong human antibody
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`response against OKT3 itself (HAMA Human Anti-Mouse Antibody). Jaffers et
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`al., Monoclonal Antibody Therapy: Anti-idiotypic and Non-anti-idiotypic
`
`Antibodies
`
`to OKT3 Arising Despite
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`Intense
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`Immunosuppression, 41(5)
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`TRANSPLANTATION 572 (1986) (Ex. 1027). When patients with a kidney
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`transplant received repeated administration of OKT3 over the course of 10–20
`
`days, it was found that 75% of the patients had already developed detectable
`
`antibodies against the administered OKT3 murine monoclonal antibody. Id. at 7,
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`Abstract. The authors postulate that “the immune response to this and probably
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`other monoclonal antibodies can block their therapeutic effectiveness and can arise
`
`despite
`
`intense
`
`immunosuppression.”
`
`Id. Thus, prolonged or
`
`repeated
`
`administration of murine monoclonal antibodies was recognized as an obstacle to
`
`their use in therapy.
`
`36. With respect to cancer, Hilary Koprowski’s group from the Wistar
`
`Institute in Philadelphia in 1982, investigated the use a murine monoclonal
`
`antibody 17-1A, which was shown to lyse and specifically inhibit growth of human
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`colon carcinomas xenografted in athymic (nu/nu) mice. See Sears et al., Phase-I
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`Clinical Trial of Monoclonal Antibody in Treatment of Gastrointestinal Tumours,
`
`LANCET 762 (1982) (“Sears”) (Ex. 1028). The authors noted that while there was
`
`promise of therapeutic efficacy, three of four patients developed antibodies against
`
`
`
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`20
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`BIOEPIS EX. 1191
`Page 20
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`the administered mouse immunoglobulin, with one patient exhibiting an adverse
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`clinical reaction to the last injection of the antibody. Id. at 4. The investigators also
`
`postulated that the development of an immune reaction to the administered mouse
`
`immunoglobulins “may limit repeated administration of whole molecules of mouse
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`immunoglobulins.” Id. at 5 (emphasis added); see also Sikora, Monoclonal
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`antibodies in oncology, 35 J. CLINICAL PATHOLOGY 369–75 (1982) (Ex.
`
`1029) (review article disclosing use of monoclonal antibodies in diagnostic and
`
`oncology treatment areas).
`
`B.
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`to Reduce Immunogenicity – Chimerization and
`Efforts
`Humanization
`
`37. An approach to reduce the well-documented problems of immune or
`
`immunogenic responses observed in the therapeutic use of murine monoclonal
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`antibodies was developed in the 1980s as researchers began producing chimeric
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`antibodies that combined the variable (V) region binding domain of a murine
`
`antibody with human antibody constant (C) domains. Morrison et al., Chimeric
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`human antibody molecules: Mouse antigen-binding domains with human constant
`
`region domains, 81 PROC. NAT’L ACAD. SCI. USA 6851 (1984) (Ex. 1031).
`
`Hence, a chimeric antibody would retain the binding specificity of the original
`
`murine monoclonal antibody but have the human constant domain. As a result, the
`
`chimeric antibody would contain less amino acid sequences foreign to the human
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`immune system and therefore be less immunogenic relative to the murine
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`21
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`BIOEPIS EX. 1191
`Page 21
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`monoclonal antibody. Id. at 10. Further, because of the presence of a human
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`constant domain, chimeric antibodies can also have improved function with respect
`
`to a patient’s effector cells over its murine monoclonal counterparts. Liu et al.,
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`Chimeric mouse-human IgG1 antibody that can mediate lysis of cancer cells, 84
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`PROC. NAT’L ACAD. SCI. USA 3439 (1987) (Ex. 1032). In cytotoxicity studies
`
`of carcinoma cell lines with effector cells, Liu et al. reported that the chimeric L6
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`antibody mediated antibody-dependent cellular cytotoxicity (ADCC) at 100 times
`
`lower concentration than the mouse monoclonal L6 antibody. Id. at 9, Abstract, 13,
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`Fig. 6. Further, the chimeric L6 antibody gave higher human complement
`
`dependent cytotoxicity (CDC) when lysing tumor cells in the presence of human
`
`complement. Id. at 12, Fig. 5.
`
`38. The properties of chimeric antibodies, which include reduced
`
`immunogenicity and improved effector function, are therefore advantageous over
`
`their murine monoclonal antibody counterparts. Unfortunately, this chimeric
`
`approach would not be applicable for OKT3 and others like it, because it was
`
`discovered that much of the strong immune response is directed against the
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`variable region of OKT3 rather than the constant domain. Ex. 1027 at 12.
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`(“Overall, 75% of our patients who had any antibody response made a
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