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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
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`Celltrion, Inc. and Pfizer, Inc.
`Petitioners,
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`v.
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`Genentech, Inc.
`Patent Owner.
`
`Case IPR2017-01122
`Patent 7,892,549
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`DECLARATION OF ROBERT EARHART, M.D., Ph.D.
`IN SUPPORT OF CELLTRION’S REPLY TO
`PATENT OWNER’S RESPONSE
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`I.
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`1.
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`I, Robert Earhart, M.D., Ph.D., declare as follows:
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`Introduction
`2.
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`I am the same Robert Earhart who submitted a declaration in support
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`of Celltrion’s Petition for Inter Partes Review of U.S. Patent 7,892,549 (the ’549
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`patent) in March 2017. A detailed description of my background and
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`qualifications may be found in that declaration, which I refer to as my “first
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`declaration.”
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`3.
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`I am being compensated at my standard rate for my time spent
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`preparing this declaration, and my compensation is not contingent on the outcome
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`of any matter or on any of the opinions provided below. I have no financial
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`interest in the outcome of this proceeding.
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`4.
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`I provided my understanding of legal concepts as they relate to this
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`proceeding in my first declaration. My understanding of those concepts has not
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`changed since I submitted my first declaration.
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`5.
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`I understand that the parties have proposed different definitions for a
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`person of ordinary skill in the art. (Petition at 43; POR at 35.) In the institution
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`decision, the Board adopted Patent Owner’s definition, but noted that it does not
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`discern an appreciable difference in the parties’ respective definitions. (Paper 9 at
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`9-10.) It further noted that “both parties contend that a person of ordinary skill in
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`the art would have had experience with breast-cancer research and treatment.” I
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`have such experience, including experience in the evaluation of data which either
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`support or reject the decision to conduct a clinical trial to administer anticancer
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`treatments in adult patients with solid tumors. My own professional experience of
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`40 years in strategic clinical program design, protocol development, clinical study
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`monitoring and conduct under Good Clinical Practice principles, clinical data
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`analysis, manuscript and report generation, analysis of published clinical trial
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`reports, and teaching of principles in the field of oncology drug development have
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`provided me with an intimate understanding of the processes and standards by
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`which such a person of ordinary skill in the art decides that a given course of
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`clinical trial development is obvious. I have reviewed both definitions and to the
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`extent there are difference, those differences do not affect the opinions set forth in
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`either my first declaration or this declaration.
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`II. A Person of Ordinary Skill in the Art Would Have Used Standard
`Principles of Combination Therapy with Antibodies
`6.
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`As discussed in my first declaration, a person of ordinary skill in the
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`art would have used the principles of combination therapy with antibodies like
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`trastuzumab, because these principles provided a framework to facilitate clinical
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`development of combination regimens of anticancer agents. Dr. Susan
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`Tannenbaum, one of Patent Owner’s experts, argued that these principles were
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`limited to traditional chemotherapy agents (Ex. 2062 (Tannenbaum Decl.) at
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`¶ 199), but nothing in the prior art suggests that. The prior art taught that these
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`principles “should continue to be used in the design of new regimens” with agents
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`that showed “demonstrated antitumor activity.” (Ex. 1016 (Abeloff) at 204.)
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`Throughout my career in drug development, these principles have provided useful
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`guidance to the construction of successful combination regimens for cancer
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`treatment, and neglect of these principles has often resulted in failure of well-
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`intentioned clinical trials to produce advances in the field. Given the promise
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`shown by trastuzumab, a person of ordinary skill in the art would have been
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`motivated to use these well recognized principles to develop combination therapies
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`with antibodies and more traditional chemotherapy agents. Indeed, the prior art
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`suggests that “progress will best be made by combining [monoclonal antibodies]
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`with chemotherapy.” (Ex. 1007 (Abrams) at 1164.) I am not aware of any
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`scientific rationale that suggests that these principles would not apply to the
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`combination of chemotherapy agents and antibodies.
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`7.
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`Given that the prior art taught the promise of antibody therapy in
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`treating cancer and that the best progress would likely be made in using antibodies
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`in conjunction with chemotherapy agents, a person of ordinary skill in the art
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`would have been motivated to pursue combination therapies, and would have used
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`the well-established principles of combining chemotherapy agents because those
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`principles provided an adaptable framework with proven success.
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`III. A Person of Ordinary Skill in the Art Would Have Relied on
`Preclinical Data Regarding Safety and Efficacy
`8.
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`Preclinical data provides necessary information regarding the safety
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`and efficacy of anticancer agents and combination therapies. Information
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`regarding safe starting dosing, as well as acute toxicity, from preclinical studies is
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`a necessary step prior to clinical testing in human subjects. This is particularly true
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`with anticancer agents, which are known to have high degrees of toxicity. (Ex.
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`1053 (Teicher) at 233-35.) Indeed, the FDA would likely not approve the use in
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`humans of any drug that had not been shown to be sufficiently effective and safe in
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`preclinical models. (Ex. 1053 (Teicher) at 295.) That being said, when each
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`element of a combination therapy had previously been shown to be safe and
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`effective on its own in clinical studies, it would not be necessary to run preclinical
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`studies on the combination. (See, e.g., Ex. 1004 (De Vita) at 12 of 122
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`(“Development of new treatments is based on the effectiveness of the cancer drugs
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`in rodent models. Combinations of drugs are fashioned based on the effectiveness,
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`the level of cross-resistance, and the limiting toxicity of the available drugs when
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`used alone in similar patient populations.”).)
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`9.
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`Dr. Robert S. Kerbel, one of Patent Owner’s experts, argued that the
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`xenografts discussed in Baselga 1996 were of limited utility because the tumors were
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`injected subcutaneously rather than orthotopically. (Ex. 2061 (Kerbel Decl.) at ¶¶
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`77-81.) A person of ordinary skill in the art would not have considered the
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`location of the tumor injection to be important, because while both methods had
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`advantages and disadvantages, both were reliable and routinely used. In my
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`experience, no person of ordinary skill in the art would question the validity of
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`subcutaneous xenograft studies in comparing proposed combination treatment
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`regimens. I agree with Dr. Kerbel that in the 1990s subcutaneous testing was more
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`common than orthotopic (Ex. 1040 (Kerbel), 26:24-27:4), and it remains more
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`common today. Regardless, since all of the agents tested by Baselga were tested
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`subcutaneously, it is proper and useful to compare the data for the efficacy of those
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`agents with each other as all of the tests were done in the same manner.
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`10. Both Dr. Kerbel and Dr. Tannenbaum criticize Baselga Abstract 53
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`for using the BT-474 cell line, which overexpress HER2 genes at a higher rate than
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`what is found in biopsies from patients with HER2+ breast cancer. (Ex. 2061
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`(Kerbel) at ¶ 62; Ex. 2062 (Tannenbaum) at ¶ 161.) However, a higher rate of
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`HER2 gene expression is advantageous, rather than detrimental, to the research
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`process as high level of HER2 expression correlated with poor treatment outcomes.
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`A person of ordinary skill in the art would consider positive results using the BT-
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`474 cell line as a motivation to pursue the tested agent. Further, because all of
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`agents were compared using the same cell lines, the data are properly comparable.
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`11. The prior art regarding the clinical efficacy of each of trastuzumab
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`and paclitaxel in humans, i.e., “the species of interest,” and the satisfaction of the
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`other principles of combination therapy that I described in my first declaration,
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`would have motivated a person of ordinary skill in the art to pursue the clinical use
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`of the combination of paclitaxel and trastuzumab. Because of the positive clinical
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`data, preclinical results are not necessary before using the combination in humans.
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`But, the presence of this preclinical data certainly bolsters the motivation to treat
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`patients with the trastuzumab/paclitaxel combination.
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`IV. A Person of Ordinary Skill in the Art Would Have Been Motivated
`to Use the Combination of Paclitaxel and Trastuzumab
`12. Dr. Tannenbaum argued that paclitaxel’s approval as a second line
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`therapy would have given clinicians pause in using it, because “the fact that
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`paclitaxel was not approved as a first-line treatment suggests that it is not as
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`efficacious as other treatments and/or there are other reasons (such as toxicity)
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`limiting paclitaxel to second-line treatments.” (Ex. 2062 (Tannenbaum Decl.) at
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`¶ 191).) I disagree. First, doctors used paclitaxel as a first-line therapeutic despite
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`the labelled indication, and the prior art taught that paclitaxel was “highly active as
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`initial therapy for metastatic breast cancer.” (Ex. 1039 (Reichman) at 1943.)
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`Paclitaxel also showed efficacy in patients who had anthracycline resistant
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`metastatic breast cancer. (Ex. 2013 (Dombernowsky) at 14.) Further, the second
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`line approval for paclitaxel is merely a reflection of how the sponsor of that drug,
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`Bristol-Myers Squib, performed its clinical trials and not any belief about its
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`relative efficacy. Paclitaxel had also shown “excellent activity” both in xenografts
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`and in breast cancer patients. (Ex. 1053 (Teicher), 112-14; Ex. 1007 (Abrams),
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`1164; Ex. 1011 (Seidman 1996).)
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`13. Additionally, a person of ordinary skill in the art would not have
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`been discouraged in using paclitaxel due to the hypersensitivity reactions that
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`sometimes occurred. Hypersensitivity reactions, which at the time of the alleged
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`invention were thought most likely to be related to vehicle rather than the taxane,
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`are well recognized to be different from allergic reactions that occur with other
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`agents. (Ex. 1006 (DeVita) at 415.) The prior art taught how to limit these
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`reactions and that a patient who did suffer from them could be successfully
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`retreated even after a major hypersensitivity reaction. (Ex. 1007 (Abrams) at 1156;
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`Ex. 2014 (Fisherman) at 780.) True allergic reactions are mediated by IgE and are
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`likely to be more severe if the sufferer is exposed repeatedly to the offending
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`allergen. Vehicle-mediated histamine release reactions, known as hypersensitivity
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`reactions, can be blunted or eliminated by brief pretreatment with corticosteroids,
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`and do not contraindicate subsequent administration of taxanes. Neutropenia,
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`another potential side effect, was predictable and transient in nature, much less
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`significant with paclitaxel than with docetaxel, and treatable with administration of
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`G-CSF agents such as filgrastim (Neupogen®) or with prophylactic oral
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`antibiotics, and the other side effects were generally not dose-limiting. (Ex. 1004
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`(DeVita) at 50-51.) Given that without treatment, patients with HER2+ metastatic
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`breast cancer have a very short life expectancy, these reactions were well within
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`the bounds of accepted and acceptable risks associated with chemotherapy in
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`general and did not limit the use of paclitaxel.
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`14. Dr. Tannenbaum also argues that a later publication by the authors of
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`Seidman 1996 contradict what Seidman 1996 taught regarding the efficacy of
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`paclitaxel in HER2+ breast cancer patients and that a person of ordinary skill in the
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`art therefore would not have relied on Seidman 1996. (Ex. 2062 (Tannenbaum
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`Decl.) at ¶ 183.) Logically, the later article, published in 2002 (see Ex. 2024 (Van
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`Poznak)), could not have informed the opinion of a person of ordinary skill in the
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`art in 1996.
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`15. A close reading of Van Poznak (Ex. 2024) confirms that the later
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`paper did not negate the finding that HER2+ patients are sensitive to paclitaxel.
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`Instead, the paper suggests that the results may be “partly in contrast” to their
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`earlier results. (Ex. 2024 (Van Poznak) at 2323.) Van Poznak hypothesizes that
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`some of the difference may be attributable to different methods of detecting
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`whether a sample is HER2+ (id. at 2323-24), and restates its earlier finding: “[o]ur
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`prior assessment of tumor HER2 expression through monoclonal antibody (4D5)
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`and the polyclonal antibody (pAB-1) demonstrated that 4D5 positivity was
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`predictive of positive response to taxane monotherapy.” (Id. at 2320.) If Van
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`Poznak and Seidman et al. had been convinced that their earlier-reported data was
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`incorrect, a POSA would have expected to see a clear statement disavowing their
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`earlier conclusion.
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`16. Dr. Tannenbaum criticizes Seidman 1996, stating that it is only an
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`abstract and is therefore not as reliable as “a more fulsome analysis in a peer-
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`reviewed journal.” (Ex. 2062 (Tannenbaum Decl.) at ¶ 154.) I disagree with Dr.
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`Tannenbaum that the abstract format of the reference affects its reliability. Peer
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`review is most important for analysis and discussion. It is not as important for
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`short reports of data. The Seidman 1996 abstract simply reports the facts as its
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`authors observed them: HER2+ patients were sensitive to taxanes. There is no
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`editorial and no analysis that needs peer review. Absent any allegation of
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`misconduct on the part of the authors, a person of ordinary skill in the art would
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`have had no reason to doubt their reported data.
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`17. Dr. Tannenbaum also argues that a person of ordinary skill in the art
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`would have been dissuaded from pursuing a combination therapy involving
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`paclitaxel for patients with HER2+ breast cancer based on Yu (Ex. 2029). (Ex.
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`2062 (Tannenbaum) at ¶ 58.) In Yu, paclitaxel was tested using cell lines growing
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`on culture plates. (Ex. 2029 (Yu) at 1360-62.) Cell-line-based in vitro research
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`such as that reported in Yu is useful for examining specific biochemical questions,
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`but is less predictive of clinical efficacy than are in vivo tumors of mouse origin,
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`which in turn are not as good as human cell lines in xenograft models, which in
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`turn are not as good as clinical trial data in the species of interest (humans). In this
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`study, the cells were modified by the introduction of foreign genetic material
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`through an artificial plasmid construct so that they overexpressed HER2, and were
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`then subjected to further selection to produce a population of cells with consistent
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`expression of the artificial gene that was introduced and to have reproducible
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`growth characteristics. Data from such studies are not regarded as definitive for
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`conclusions about human clinical trials. That is possibly why Genentech
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`apparently disregarded these results at the time, and did not terminate their ongoing
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`clinical trial.
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`V. A Person of Ordinary Skill in the Art Would Have Known that
`Response Rate Was Correlative of Overall Survival
`18. Dr. Tannenbaum argued that the positive results reported in Baselga
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`1996 regarding the clinical efficacy of trastuzumab would not have provided a
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`reasonable expectation of success. (Ex. 2062 (Tannenbaum Decl.) at ¶ 222.) I
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`disagree.
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`19. A person of ordinary skill in the art would have been motivated to
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`combine trastuzumab with paclitaxel, with a reasonable expectation of success that
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`the combination would perform better than no treatment and better than paclitaxel
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`alone, because of (1) the very low occurrence of severe adverse events with
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`treatment with trastuzumab (Ex. 1020 (Baselga 1996) at 737-38, Table 3 (out of
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`768 administrations, there were eleven adverse events)), in combination with (2)
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`the expectation of increased efficacy over either therapy alone, and (3) the lack of
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`overlapping toxicities. (Ex. 1019 (Baselga Abstract 53) (showing positive results
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`for combination of trastuzumab and a taxoid); Ex. 1053 (Teicher) at 291 (“If … the
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`new agent X, because of different dose-limiting toxicity, can be added [to the first
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`agent] without compromising dose, there is a reasonable expectation that A + B +
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`X will be superior to A + B.”).)
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`20. Effective dosage amounts of trastuzumab and paclitaxel in breast
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`cancer patients, together with TTP data, were known in the prior art. (Ex. 1020
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`(Baselga 1996) at 740 (trastuzumab median TTP was 5.1 months); Ex. 1012 (1995
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`PDR) at 683 (paclitaxel median TTP was 3.0 or 4.2 months, depending on dose).)
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`A person of ordinary skill in the art would have had a reasonable expectation that
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`adding trastuzumab would achieve an extension of TTP over paclitaxel alone based
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`on the superior TTP of trastuzumab.
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`21. Based on the positive results reported in the Baselga 1996 Phase II
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`trial, a person of ordinary skill would have had a reasonable expectation that a
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`combination treatment with paclitaxel and trastuzumab would extend the time to
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`disease progression relative to treatment with paclitaxel and relative to no
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`treatment. Baselga 1996 reported a response rate of 11.6%. (Ex. 1020 (Baselga) at
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`741.) Patent Owner argued that this response rate would not have provided a
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`person of ordinary skill in the art an expectation regarding an extension of time to
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`disease progression. (POR at 9). I do not agree with Patent Owner’s assessment of
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`endpoints and how they are used and understood in clinical trials.
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`22. Response rate (RR), time to progression (TTP), and progression-free
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`survival (PFS) are clinical surrogate end-points used in drug development efforts to
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`estimate the likelihood of an improvement in overall survival (OS), which is the
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`best proof of clinically useful activity. The clinical surrogate end-points are
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`generally expected to correlate with OS and with each other. This means that the
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`person of ordinary skill in the art, presented with RR data from a phase II clinical
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`study, would expect that the data would likely correlate with TTP and OS, when
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`the treatment is tested in further trials or used in the clinic. Further, the FDA
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`accepts studies with RR or TTP data in lieu of overall survival data because
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`experience has shown that these three endpoints often have a positive correlation.
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`Indeed, a published review of FDA approvals in oncology indications between
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`1990 and 2002 noted that response rate was accepted as a surrogate for overall
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`survival as the basis for FDA approval in 26 of 57 approvals. Johnson JR, et al,
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`End Points and United States Food and Drug Administration Approval of
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`Oncology Drugs, J CLIN. ONCOL. 2003; 21:1404-1411 (Ex. 1055).
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`23. Therefore, a person of ordinary skill in the art would have understood
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`that the response rate results reported in Baselga were likely to correlate with an
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`extension of time to disease progression and an increase in overall survival.
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`VI. Patent Owner’s Amended Claim Language Does Not Render the
`Claim Patentable Over the Prior Art
`24.
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`In its Motion to Amend, Patent Owner’s proposed claim amendment
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`would specify that the comparator for the claim term “extend time to disease
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`progression without an increase in overall severe adverse events” in the ’441
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`patent’s claim 1 is treatment with paclitaxel alone. Similarly, Patent Owner’s
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`proposed claim amendment would specify that the comparator for the claim term
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`“extend time to disease progression” in the ’549 patent’s claim 11 is treatment with
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`paclitaxel alone. I have compared Patent Owner’s reasoning set forth in the
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`Motion to Amend regarding how the proposed claimed language is patentable over
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`the prior art to the Patent Owner’s arguments in its response regarding the
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`patentability of the original claim language. The explanation for the proposed
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`amendments includes nothing that is not also included in the explanation for the
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`existing claim. Accordingly, my opinion and analysis regarding the obviousness of
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`the proposed amended claims is identical to my opinion and analysis regarding the
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`obviousness of the original claims
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`25.
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`I have been advised that a claim amendment in an inter partes review
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`cannot introduce new matter, and that “new matter” is defined as an addition to the
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`claim that lacks support in the original application that led to the patent.
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`26. With respect to the proposed amendment to the ’441 patent claims, I
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`reviewed the specifications of the original patent applications that led to ’441
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`patent, including the citations provided by Patent Owner on pages 5-6 of the
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`Motion to Amend in IPR2017-01121. The specifications do not support the
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`proposed amended claim term “without an increase in overall severe adverse
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`events” for the trastuzumab/paclitaxel combination compared to paclitaxel alone.
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`With respect to the data provided in the specification regarding treatment of the
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`combination compared to paclitaxel alone, the patent application states:
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`A syndrome of myocardial dysfunction similar to that
`observed with anthracyclines was reported more
`commonly with a combined treatment of AC+H (18%
`Grade 3/4) than with AC alone (3%), T (0%), or T+H
`(2%).
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`(Ex. 1057 (’441 File History) at 47.)
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`27. A person of ordinary skill in the art would understand the reference
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`to “Grade 3/4” to reference severe adverse events, as defined by the Common
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`Toxicity Criteria scale that was in use at the time. Accordingly this passage says
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`that severe adverse events were, in fact, more common in the
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`paclitaxel/trastuzumab arm (T+H, 2%) than in the paclitaxel only arm (T, 0%).
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`28. The tabular results in the original specification also show the
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`percentage of adverse events for paclitaxel alone and for the paclitaxel/trastuzumab
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`combination. (Ex. 1057 (’441 File History) at 47.) Whether or not this table
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`includes all adverse events or only severe adverse events, the total number of
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`adverse events for the monotherapy were more than that for the combination (59%
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`vs. 70%, respectively). (Id.) Accordingly, a person ordinary skill in the art would
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`not have recognized from the specification that the inventor disclosed a
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`combination treatment of paclitaxel/trastuzumab that has fewer overall severe
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`adverse events than paclitaxel alone.
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`29. With respect to the proposed amendment to the ’549 patent claims, I
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`reviewed the specifications of the original patent applications that led to ’549
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`patent, including the citations provided by Patent Owner on pages 5-6 of the
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`Motion to Amend in IPR2017-01122. The specifications do not support the
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`proposed amended claim term “in an amount effective to extend the time to disease
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`progression” for a combination of trastuzumab, paclitaxel, and a third agent,
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`compared to paclitaxel alone. Specifically, the specification does not report any
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`experimental data for a triple combination of agents. Accordingly, a person
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`ordinary skill in the art would not have recognized from the specification that the
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`inventor has possession of a triple combination treatment that extends TTP
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`compared to paclitaxel alone.
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`VII. Materials Considered
`In preparing this Declaration, I reviewed the declarations submitted
`30.
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`by Dr. Tannenbaum (Ex. 2062) and Dr. Kerbel (Ex. 2061), the Patent Owner’s
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`Response, the Motion to Amend, and the documents cited therein, the current label
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`for Herceptin® (Ex. 1038), which I downloaded from https://www.herceptin.com/
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`in March 2018, the documents cited above, and the additional documents described
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`below.
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`31. The Journal of Clinical Oncology (“JCO”) is a peer-reviewed
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`publication that is generally accepted and regarded as authoritative within the
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`oncology field. It is generally relied on by physicians, researchers and other
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`members of the public, including those who are interested in cancer and its
`
`treatments, and has been since 1993. I have relied on JCO throughout my career.
`
`In particular, I have relied on the documents at Exhibits 1055 and 1048, titled End
`
`Points and United States Food and Drug Administration Approval of Oncology
`
`Drugs. Another important publication was Multinational Study of the Efficacy and
`
`Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have
`
`HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After
`
`Chemotherapy for Metastatic Disease, respectively, while preparing this
`
`Declaration. The last was a seminal study from Dr. Slamon, the champion of
`
`trastuzumab clinical development, and his group.
`
`32. The Journal Biotechnology Healthcare was a peer-reviewed
`
`publication that published between 2004 and 2012. The journal was directed to
`
`healthcare payors, and focused on articles regarding the clinical, economic, benefit
`
`design, and health policy implications of biologic medicine. The journal is
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`Celltrion, Inc. 1054
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`archived in the United States National Library of Medicine. I have relied on the
`
`document at Exhibit 1033, titled The Off Label Conundrum, while preparing this
`
`declaration.
`
`33. The Journal of the National Comprehensive Cancer Network
`
`(“JNCCN”) is a peer reviewed publication that is generally accepted and regarded
`
`as authoritative within the oncology field. It is generally relied on by physicians,
`
`researchers and other members of the public, including those who are interested in
`
`cancer and its treatments, and has been since 2003. JNCCN is of particular value
`
`in assessing national cancer demographics and national standards in oncology
`
`practice. I have relied on JNCCN throughout my career. In particular, I have
`
`relied on the document at Exhibit 1034, titled Prevalence and Safety of Off-Label
`
`Use of Chemotherapeutic Agents in Older Breast Cancer Patients: Estimates from
`
`SEER Medicare Data, while preparing this Declaration.
`
`34. The journal Oncology, published by the Cancer Network, is a peer
`
`reviewed publication that is generally accepted and regarded as authoritative
`
`within the oncology field. It is generally relied on by physicians, researchers and
`
`other members of the public, including those who are interested in cancer and its
`
`treatments, and has been since 1987. I have relied on Oncology throughout my
`
`career. In particular, I have relied on the document at Exhibit 1043, titled HER2
`
`Overexpression and Paclitaxel Sensitivity in Breast Cancer: Therapeutic
`
`
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`17
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`Implications, while preparing this Declaration. Dr. Larry Norton’s group is
`
`particularly well-known and respected in the field of breast cancer research.
`
`35. The Journal of Cancer Research is a peer reviewed publication that is
`
`generally accepted and regarded as authoritative within the oncology field. It is
`
`generally relied on by physicians, researchers and other members of the public,
`
`including those who are interested in cancer and its treatments, and has been for
`
`decades. I have relied on the Journal of Cancer Research throughout my career. In
`
`particular, I have relied on the document at Exhibit 1047, titled Recombinant
`
`Humanized Anti-HER2 Antibody (HerceptinTM) Enhances the Antitumor Activity
`
`of Paclitaxel and Doxorubicin against HER2/neu Overexpressing Human Breast
`
`Cancer Xenografts, while preparing this Declaration. This article from Dr.
`
`Norton’s research team at the University of California San Diego, published in
`
`1998, was selected in 2016 as a classic article on the occasion of the 75th
`
`anniversary of the journal Cancer Research.
`
`36. Baselga, J. et al., Antitumor Effects of Doxorubicin in Combination
`
`with Anti-epidermal Growth Factor Receptor Monoclonal Antibodies, 85 J. NAT’L
`
`CANCER INSTITUTE 1327-33 (Aug. 1993) (Ex. 1045), was published in the Journal
`
`of the National Cancer Institute (“JNCI”) in 1993. In 1993, I was personally
`
`familiar with the JNCI. It was directed to cancer researchers. In the late 1990s,
`
`
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`this journal was widely available to and consulted by persons of ordinary skill in
`
`the art around the world, including in the United States.
`
`37.
`
`I agree with Dr. Tannenbaum that Shan, K., et al., Anthracycline-
`
`Induced Cardiotoxicity, 125 ANN. INTERN. MED. 47-58 (1996) (Ex. 1050), was
`
`published in 1996, in the respected, peer-reviewed, medical journal, Annals of
`
`Internal Medicine. (Ex. 1052 (Tannenbaum Depo.) at 244:3-245:7.) Further, the
`
`face of the article states that it was published in the July 1996 issue. In the late
`
`1990s, this journal was widely available to and consulted by persons of ordinary
`
`skill in the art around the world, including in the United States.
`
`38. Gottlieb, S.L., et al., Late, Late Doxorubicin Cardiotoxicity, 78
`
`CHEST 880-82 (Dec. 1980) (Ex. 1036), was published in 1980 in Chest, which is
`
`an official publication of the American College of Chest Physicians. It is a
`
`monthly, peer-reviewed publication directed toward research in multidisciplinary
`
`specialties of chest medicine. In the late 1990s, this journal was widely available
`
`to and consulted by persons of ordinary skill in the art around the world, including
`
`in the United States.
`
`39. Grever, M.R., et al., The National Cancer Institute: Cancer Drug
`
`Discovery and Development Program, 19 SEMINARS IN ONCOL. 622-38 (Dec.
`
`1992) (Ex. 1037), was published in Seminars in Oncology in 1992. In 1992, I was
`
`personally familiar with Seminars in Oncology. It was directed to cancer
`
`
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`Celltrion, Inc. 1054
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`IPR2017-01122
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`researchers. In the late 1990s, this journal was widely available to and consulted
`
`by persons of ordinary skill in the art around the world, including in the United
`
`States.
`
`40. Reichman, B.S., et al., Paclitaxel and Recombinant Human
`
`Granulocyte Colony-Stimulating Factor as Initial Chemotherapy for Metastatic
`
`Breast Cancer, 11 J. CLIN. ONCOL. 1943-51 (Ex. 1039), was published in 1993 in
`
`the JCO. In 1993, I was personally familiar with JCO. It was directed to cancer
`
`researchers. In the late 1990s, this journal was widely available to and consulted
`
`by persons of ordinary skill in the art around the world, including in the United
`
`States.
`
`
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`VIII. Conclusion
`
`41.
`
`For all of the reasons discussed above and stated in my first
`
`declaration, it is my opinion that the claims of the '441 patent and proposed
`
`amended claim are obvious in view of the prior art.
`
`42.
`
`I hereby declare that all statements made herein of my own
`
`knowledge are true and that all statements made on information and belief are
`
`believed to be true; and further that these statements were made with the
`
`knowledge that willful false sta
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