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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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`Celltrion, Inc. and Pfizer, Inc.
`Petitioners,
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`v.
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`Genentech, Inc.
`Patent Owner.
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`Case IPR2017-01122
`Patent 7,892,549
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`DECLARATION OF ROBERT EARHART, M.D., Ph.D.
`IN SUPPORT OF CELLTRION’S SUR-REPLY IN OPPOSITION TO
`PATENT OWNER’S MOTION TO AMEND
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`1 of 9
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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, and a declaration in support of Celltrion’s Reply to Patent
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`Owner’s Response in March 2018. A detailed description of my background and
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`qualifications may be found in the first declaration that I submitted in March 2107,
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`which I refer to as my “first 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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`any of my declarations.
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`II.
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`Standard Statistical Methods Should Be Used in Determining
`Whether There Was an Increase in Severe Adverse Events
`6.
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`A person of ordinary skill in the art would have noted that the
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`specification reports a difference of 2% in the incidence of serious adverse events
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`observed with the combination of trastuzumab and paclitaxel versus paclitaxel
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`alone, and thus there was an increase in adverse events with the combination.
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`7.
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`The ’549 patent does not provide enough information for a person of
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`ordinary skill in the art to determine, however, whether the increase in severe
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`adverse events observed with the combination of trastuzumab and paclitaxel over
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`paclitaxel alone was statistically significant.
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`8.
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`A person of ordinary skill in the art thus would not have been able to
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`determine whether the disclosed treatment with trastuzumab and paclitaxel was
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`“without increase in overall serious adverse events” as required by the claims.
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`III. Dr. Kerbel’s Criticisms of Baselga’s Data and Methods Are
`Misplaced
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`9.
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`Dr. Kerbel, Patent Owner’s expert, argues in his Supplemental
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`Declaration that the data set forth in Baselga Abstract 53 was unreliable as it only
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`measured response rate one point in time. In a prominent group like Baselga’s
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`from Sloan-Kettering, it would have been highly unusual to measure response rate
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`at a single point in time. As is confirmed by the later publication of Baselga 1998,
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`Baselga collected the data daily and plotted it on a curve, using standard methods
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`employed in the analysis of xenograft data. Ex. 1047 at 2828. A person of
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`ordinary skill in the art would have understand that xenograft data would have
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`been collected over a series of time points, which would have been plotted to
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`develop a curve of tumor size. Baselga Abstract 53 simply reports a data point, at
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`35 days, where the curve for the paclitaxel/trastuzumab combination showed
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`greater tumor inhibition than the other curves. Ex. 1019. That does not mean, or
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`even suggest, that that was the only time point at which data was collected or
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`analyzed.
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`10. Dr. Kerbel also argues that xenograft studies could not predict all of
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`the toxicity issues associated with treatment. Ex. 2143 at ¶¶ 16-18. Once again,
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`Dr. Kerbel misunderstand that purpose of xenograft studies. These studies are
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`designed to show acute toxicity and immediate reactions, and not to show every
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`potential long-term complication. See Ex. 1053 at 111, 121. For example, a five -
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`week xenograft study would not be expected to reveal potential long-term
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`cardiotoxicity in humans; the animals are only observed for a small part of their
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`overall lifespan, and in any case their cardiac status is not specifically investigated
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`in such studies. Yet, that does not preclude a person of ordinary skill in the art
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`from having a reasonable expectation that there would be no increase in overall
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`severe adverse events based on the available clinical data for each individual agent.
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`11. Dr. Tannenbaum, another of Patent Owner’s experts, criticized
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`Baselaga 1996 for its “small” sample size. Baselga 1996 was a Phase II clinical
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`trial, and as such, would have been designed to be appropriately powered for its
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`desired endpoint. This means that the study would have been designed to enroll
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`enough patients to establish whether a new therapeutic agent shows statistically
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`significant efficacy in the target patient population. In my experience, 46
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`participants is not unusual for a phase II study. The fact that there were only 46
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`participants does not affect the quality of the data collected, nor would it suggest
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`that a person of ordinary skill in the art would not have relied upon it.
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`12.
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`Furthermore, if the prior art raised as much doubt as Dr. Kerbel and
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`Dr. Tannenbaum suggested that it does, Patent Owner and the inventors would
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`have been ethically bound to disclose that information to the participants in the
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`clinical trials. We have no evidence that they did so.
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`IV. Hsu 1997 Does Not Add Anything to the Obviousness Analysis
`13. Hsu 1997 does not detail the drug doses and schedules used in the
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`xenograft study, when and how the data were collected, or what the xenograft data
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`actually were. (Ex. 2135) More importantly, unlike in Baselga Abstract 53, Hsu
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`1997 died not use xenografts that naturally overexpress HER2. Id. Rather, it used
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`xenografts that were transfected, or artificially engineered, to overexpress HER2.
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`Id. In my opinion, a POSA, would not have regarded Hsu 1997 as negating the
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`teachings of Baselga Abstract 53. Also, it has not been established that Hsu 1997
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`is prior art. In my opinion, it adds little to the obviousness analysis.
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`V. The Prior Art Provides a Reasonable Expectation of Success for the
`Use of the Four Principles of Combination Therapy with Antibodies
`and Chemotherapy Agents
`14.
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`IDEC, a predecessor to the Patent Owner, sponsored research on the
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`combination of IDEC-C2B8, an chimeric anti-CD20 antibody, and CHOP (a
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`combination of traditional chemotherapy agents including cyclophosphamide,
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`hydroxydaunorubicin, vincristine, and prednisone), which was published in an
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`abstract in 1995. (Ex. 1101 (Czuczman 1995).) Czuczman 1995 stated that the
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`“rationale for combination of IDEC-C2B8 with CHOP included: single agent
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`efficacy, non cross-resistant mechanisms of action, synergy with chemotherapeutic
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`agents and non-overlapping toxicities. (Id.). These are the same principles of
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`chemotherapy that I discussed in my first declaration at paragraphs 89-91. The
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`efficacy and toxicity data was later reported to be “encouraging” and the
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`combination of CHOP and the antibody “superior” to CHOP alone. (Ex. 1102
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`(Czuczman 1996).)
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`15. Further, Dr. Tannenbaum’s reliance on Wadler (Ex. 2136) to support
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`the argument that the four principles of combination therapy were inapplicable to
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`non-traditional chemotherapy agents is misplaced. Dr. Tannenbaum argues that
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`Wadler teaches that combining biological agents with chemotherapies is a
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`“challenge” because “assumptions for their use likely differ from those for
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`chemotherapeutic agents.” Dr. Tannenbaum ignores the fact that Wadler
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`addressed theoretical issues concerning interferon, which is a cytokine, not a
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`monoclonal antibody. The biological sources and roles, mechanisms of action,
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`therapeutic indications, toxicities, and pharmacokinetics of interferon and other
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`cytokines are quite different from those of humanized monoclonal antibodies such
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`as trastuzumab. In addition, as of 1996, the mechanism of action of trastuzumab
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`and other monoclonal antibodies was much better understood than the mechanism
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`of action for interferon was as of 1990. Wadler also does not teach that the four
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`factors cannot be applied to interferon. In fact, it explicitly states that “the
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`combination of interferon (IFN) and conventional chemotherapeutic agents offers a
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`promising therapeutic approach for the treatment of cancer” and recommends
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`further study of a combination of interferon alfa with 5-fluorouracil. See Ex. 2136
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`at 3483.
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`VI. Materials Considered
`16.
`In preparing this Declaration, I reviewed the declarations submitted
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`by Dr. Tannenbaum (Ex. 2144) and Dr. Kerbel (Ex. 2143), the Patent Owner’s
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`Reply to Petitioner’s Motion to Amend, and the documents cited therein. I also
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`downloaded and reviewed the December 9, 1996 press released entitled to “IDEC
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`Pharmaceuticals and Genentech Announce Positive Final Results” from
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`Genentech’s website, https://www.gene.com/media/press-releases/4800/1996-12-
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`09/idec-pharmaceuticals-and-genentech-annou.
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`17.
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`The journal Blood is a peer-reviewed publication that is generally
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`accepted and regarded as authoritative within the hematology field. It is generally
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`relied on by physicians, researchers, and other members of the public, including
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`those who are interested in cancer and its treatments, and has been since 1946. I
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`have relied on Blood. In particularly, I have relied on Exhibit 1101.
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`18.
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`The journal Cancer Investigation is a peer-reviewed publication that
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`is generally accepted and regarded as authoritative within the oncology field. It is
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`generally relied on by physicians, researchers, and other members of the public,
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`including those who interested in cancer and its treatments, and has been since
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`1983. I have relied on Cancer Investigation. In particularly, I have relied on
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`Exhibit 1102.
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`***
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`19.
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`I hereby declare that all statements made herein of my own
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`knowledge are true and that all statements made on information and belief are
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`believed to be true; and further that these statements were made with the
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`knowledge that willful false statements and the like so made are punishable by fine
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`or imprisonment, or both, under Section 1001 of Title 18 of the United States
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`Code.
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`Dated: 3 0 ft.pYL 1 c. i o 1 t
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`By:
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`Robert Earhart, M.D., Ph.D.
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