Case No. [PR2017-01122
`Supplemental Declaration of Dr. Susan Tannenbaum
`
`Filed on behalf of Patent Owner Genentech,Inc. by:
`
`David L. Cavanaugh (Reg. No. 36,476)
`Lauren V. Blakely (Reg. No. 70,247)
`Robert J. Gunther, Jr. (Pro Hac Vice)
`Lisa J. Pirozzolo (Pro Hac Vice)
`Kevin S. Prussia (Pro Hac Vice)
`Andrew J. Danford (Pro Hac Vice)
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 2000
`
`Adam R. Brausa (Reg. No. 60,287)
`Daralyn J. Durie (Pro Hac Vice)
`DURIE TANGRI LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`CELLTRION,INC.,
`Petitioner,
`
`Vv.
`
`GENENTECH,INC.,
`Patent Owner.
`
`Case IPR2017-01122
`Patent No. 7,892,549
`
`SUPPLEMENTAL EXPERT DECLARATION OF
`DR. SUSAN TANNENBAUM
`
`Genentech 2144
`Celltrion v. Genentech
`IPR2017-01122
`
`
`Supplemental Declaration of Dr. Susan Tannenbaum
`
`Filed on behalf of Patent Owner Genentech,Inc. by:
`
`David L. Cavanaugh (Reg. No. 36,476)
`Lauren V. Blakely (Reg. No. 70,247)
`Robert J. Gunther, Jr. (Pro Hac Vice)
`Lisa J. Pirozzolo (Pro Hac Vice)
`Kevin S. Prussia (Pro Hac Vice)
`Andrew J. Danford (Pro Hac Vice)
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 2000
`
`Adam R. Brausa (Reg. No. 60,287)
`Daralyn J. Durie (Pro Hac Vice)
`DURIE TANGRI LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`CELLTRION,INC.,
`Petitioner,
`
`Vv.
`
`GENENTECH,INC.,
`Patent Owner.
`
`Case IPR2017-01122
`Patent No. 7,892,549
`
`SUPPLEMENTAL EXPERT DECLARATION OF
`DR. SUSAN TANNENBAUM
`
`Genentech 2144
`Celltrion v. Genentech
`IPR2017-01122
`
`
`
`Case No. IPR2017-01122
`Supplemental Declaration of Dr. Susan Tannenbaum
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION AND BACKGROUND.......ccccccceccescesssssseeeserseceateseetseeaes 1
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`IL.
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`MATERIALS CONSIDERED100... ccccceccccseescscescessescscessesseesaceuvaceastaceaesaeanens 3
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`IL.
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`LEGAL PRINCIPLES 0.000. eccecccecsssesssssesessecsesscscesessceusaseeesessavasnesessesaceceaness 3
`
`IV.
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`OPINIONS200. cececcccccceceeeeseseesesesaesscsecsesassecsesscsscscsassssaevavsasansaseasaavarsatsasars 4
`
`A.
`
`B.
`
`C.
`
`The patent application supports the substitute claims.....0..ccceeecees 4
`
`Theprior art would not have motivated the combination of
`rhuMAb HER2 andpaclitaxel oo... ccccccccccsccssssssessecesssecesveceeseereeterereees 4
`
`l.
`
`A person ofskill in the art would not have seen rhuMAb HER2
`and paclitaxel as drugs which both had demonstrated efficacy
`against HER2+ metastatic breast Cancer......ccececesseseeeeseessereeees 5
`Dr. Earhart’s “principles of combination therapy” would not
`have motivated the claimed combination .....0.0cceeceeeceeeeeees 10
`Preclinical results of rhuMAb HER2andpaclitaxel would not
`have predicted the clinical results of the claimed combination 12
`Genentech’s experience demonstrates skepticism regarding the
`combination of rhuMAb HER2 and paclitaxel... eee 17
`A person of ordinary skill in the art would not have reasonably
`expected the claimed combination to extend TTP compared to
`paclitaxel alone... ee eeeceseseseseeeeseesesesscessceesscessassessessesvaseeveceevecensass 18
`
`2.
`
`3.
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`4.
`
`l.
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`A person of ordinary skill in the art would not have a
`reasonable expectation of success based on the TTP data
`reported in Baselga ’96 and the 1995 Taxol PDR......... cee 19
`Single-agent response rate data reported in Baselga ’96 would
`not predict extension of TTPas recited in the claims............... 23
`Dr. Earhart’s formula does not provide a reasonable expectation
`Of SUCCESS .ooeeceececscecesecseeseesestesesecsecsscecsscsseecsucsceeeanvaseaseasaees 25
`
`
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`Case No. IPR2017-01122
`Supplemental Declaration of Dr. Susan Tannenbaum
`
`I.
`
`INTRODUCTION AND BACKGROUND
`
`1,
`
`I, Dr. Susan Tannenbaum,have been retained by counsel for
`
`Genentech, Inc. (“Patent Owner”) as an expert in this proceeding.
`
`I understand
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`that, in an October 4, 2017 decision, the Patent Trial and Appeal Board (the
`
`“Board”) instituted inter partes review (“IPR”) as to claims 1-11 and 14-18 of U.S.
`
`Patent No. 7,892,549 (the “’549 patent”).
`
`I further understand that the references
`
`relied upon by the Board in instituting IPR include (1) Baselgaet al., Phase I
`
`Study of Weekly Intravenous Recombinant Humanized Anti-p185""*’ Monoclonal
`
`Antibody in Patients with HER2/neu-Overexpressing Metastatic Breast Cancer,
`14(3) J. Clin. Oncol. 737-44 (1996) (“Baselga ’96”) (Ex. 1020); (2) Seidmanetal.,
`
`Over-Expression and Clinical Taxane Sensitivity: A Multivariate Analysis in
`
`Patients with Metastatic Breast Cancer (MBC), 15 Proc. Am. Soc. Clinical
`
`Oncology 104, abs. 80 (March. 1996) (“Seidman 96”) (Ex. 1011); (3) Pegram et
`
`al., phase II Study ofIntravenous Recombinant Humanized Anti-p185 HER-2
`
`Monoclonal Antibody (rhuMAB HER-2) Plus Cisplatin in Patients with HER-
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`2/NEUOverexpressing Metastatic Breast Cancer, 14 Proc. Am. Soc. Clincial
`
`Oncology 106, abs (“Pegram ’95”) (Ex. 1022); and (4) Taxol® (Paclitaxel) for
`
`Injection Concentrate, PHYSICIANS’ DESK REFERENCE, 682-685 (49"ed. 1995)
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`(“1995 Taxol PDR”) (Ex. 1012). (Paper 9, Decision Granting Institution at 27-28.)
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`Case No. IPR2017-01122
`Supplemental Declaration of Dr. Susan Tannenbaum
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`2.
`
`Tam aware that Patent Owner has proposed a contingent amendment
`
`to the claimsofthe ’549 patent, in the event the Boardfindsthe original claims
`
`unpatentable. Specifically, I understand that Patent Owner has contingently
`
`proposed the addition of three substitute claims, numbered 18-20.
`
`I will
`
`henceforth refer to this proposed new claim as the “substitute claims.”
`
`3.
`
`I previously offered written testimony in this proceeding in my Expert
`
`Declaration, dated December 21, 2017 (Ex. 2062, “Tannenbaum Decl.”). In that
`
`|
`
`Declaration, I opined that, amongother things, both the original and substitute
`
`claimsof the patent-at-issue were not unpatentable as obvious.
`
`4.
`
`I am awarethat both Petitioner and its expert, Dr. Robert Earhart,
`
`have recently asserted that the substitute claims of the patent-at-issue are invalid.
`
`I
`
`have reviewedPetitioner’s Opposition to Patent Owner’s Contingent Motion to
`
`Amend (Paper 43) as well as the supplemental declaration filed by Dr. Earhart (Ex.
`
`1054), along with additional materials as described in my Supplemental Materials
`
`Considered list. These materials do not change my opinion expressed in my
`
`December21, 2017 declaration. Accordingly, I submit this declaration to respond
`
`to Petitioner’s and Dr. Earhart’s assertions regarding the alleged invalidity of the
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`substitute claims.
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`Case No. IPR2017-01122
`Supplemental Declaration of Dr. Susan Tannenbaum
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`5.
`
`I incorporate by reference the entirety of my prior Declaration in this
`
`proceeding. While I will periodically refer to my opinions expressed in myprior
`
`Declaration, I will not, for the sake of brevity, repeat the sections ofthat
`
`Declaration regarding my qualifications, the claims of the patents-at-issue, legal
`
`concepts relevant to my opinions, mytutorial on the backgroundscientific issues
`
`relevant to my testimony, my prior testimony in other proceedings, and my
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`compensation. (Ex. 2062, Tannenbaum Decl. §] 5-112.)
`
`Tl. MATERIALS CONSIDERED
`
`6.
`
`A list of materials I have reviewedin the preparation ofthis
`
`supplemental Declaration is attached as Exhibit A.
`
`I also have reviewed and
`
`considered all the materials included in the Materials Consideredlist attached as
`
`Exhibit B to my prior declaration (Ex. 2062.) I have further relied upon my
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`scientific knowledge as of December1997 when the ’549 patentwasfiled.
`
`TI. LEGAL PRINCIPLES
`
`7.
`I have been informed and understand that to amend the claims, Patent
`Owner must show, amongother things, that the substitute claims are supported by
`
`the written description of the original disclosure of the patent as well as any patent
`
`application to which the claim seeks the benefit of priority. To satisfy the written
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`description requirement, I have been informed and understand that the substitute
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`claims must be disclosed in sufficient detail such that a POSA can reasonably
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`3
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`conclude that the inventor has possession of the claimed invention as ofthe filing
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`date sought. In other words, the written description must show,to one of ordinary
`
`skill in the art, that the inventor invented the claimed invention.
`
`IV. OPINIONS
`
`A.
`
`8.
`
`The patent application supports the substitute claims.
`
`As I explained in myprior declaration, the patent application supports
`
`the recitation in the substitute claims that the claimed combination extendstimeto
`
`disease progression, or “TTP,” as comparedto paclitaxel alone.
`
`(Ex. 2026,
`
`Tannenbaum Decl. {{§ 123-128.) For example, the specification containsclinical
`
`data from a PhaseIII trial showing that the combination of rhuMAb HER2 and
`
`paclitaxel had a longer time to disease progression (7.1 months) than paclitaxel
`
`alone (4.2 months) (Ex. 1004-1, °824 Application, at 48-49 (43:10-44:15); Ex.
`
`2009, °346 Application, at 42:28-43:26.)
`
`B.
`
`9.
`
`‘The prior art would not have motivated the combination of
`rhuMAb HER2 and paclitaxel.
`
`In the 1990s there were a wide variety of chemotherapeutic agents
`
`available for treatment, including anthracyclines (Adriamycin and Epirubicin),
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`cytoxan, methotrexate, and Sflurouracil (often as a combination referred to as
`
`“CMF”), Taxol (aka paclitaxel), Taxotere, cisplatinum, Navelbine, Gemzar, and
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`Xeloda. Amongthese options, as I described in my opening declaration, paclitaxel
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`was new, and had only been approved as a second-line therapy for breast cancer in
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`1994. Moreover,it could trigger significant adverse events, including
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`hypersensitivity, peripheral neuropathy, and cardiac disturbances. (Ex. 2062,
`
`Tannenbaum Decl. 49 54-61.) Dr. Earhart admitted that hypersensitivity was
`
`always a risk when administering paclitaxel at the time of the invention. (Ex.
`
`2130, Earhart Second Dep. 99:7-100:3.) By comparison, anthracyclines were one
`
`of the most widely-used chemotherapies at the time, formed the standard first-line
`
`therapy for treatment of metastatic breast cancer, and were knownto be very useful
`
`in the design of drug combinations. (Ex. 2062, Tannenbaum Decl. 4] 43-53.)
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`Thus, in my opinion a person of ordinary skill in the art would have been
`
`motivated to combine rhuMAbwith anthracyclines rather than paclitaxel.
`
`1.
`
`A personof skill in the art would not have seen rhuMAb
`HER2 and paclitaxel as drugs which both had
`demonstrated efficacy against HER2+ metastatic breast
`cancer.
`
`10.
`
`Petitioner claims a POSA would have recognized that rhuMAb HER2
`
`and paclitaxel both were demonstrated to be effective in HER2+ breast cancer, and
`
`that therefore a clinician would have been motivated to use those drugsin
`
`combination. (Opp. at 7-8.) I disagree.
`11.
`First, Baselga ’96 (Ex. 1020) was the only Phase II clinical trial to test
`
`rhuMAb HER2asa single agent in humansprior to the invention. As I explained
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`5
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`Supplemental Declaration of Dr. Susan Tannenbaum
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`in my opening declaration (Ex. 2062, Tannenbaum Decl. {§ 143-152), Baselga ’96
`
`was a small study of only 46 patients with HER2+ metastatic breast cancer. The
`
`study had no control arm, and thus it does not enablea clinician to compare the
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`efficacy of rhuMAb HER2relative to other treatments. Thus, while Baselga ’96
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`providesa signal of potential clinical activity as a single agent, given the small
`
`patient population and lack of a control arm, it does not demonstrate that rhuMAb
`
`HER2 will be beneficial clinically against HER2+ breast cancer.
`
`12.
`
`Second,at the time of the invention paclitaxel had not been proven
`
`effective for treating HER2+ metastatic breast cancer. Rather, at the time of the
`
`invention, there was conflicting data, with somedata indicating that “breast
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`cancers that overexpress p85 [i.e., HER2] will not respond well to Taxol” (Ex.
`
`2029, Yu 1996 at 1362).
`
`13.
`
`Dr. Earhart claims that at the time of the invention, “doctors used
`
`paclitaxel as a first-line therapeutic despite the labelled indication.” (Ex. 1054,
`
`Earhart Reply Decl. § 12.) However, no PhaseITI data was available at the time of
`
`the invention regarding the results of paclitaxel for treating breast canceras a first
`
`line therapy. While some doctors may haveprescribed paclitaxel as a first-line
`
`therapy, a person of ordinary skill in the art would have been lesslikely to
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`prescribe somethingfirst-line when there was noclinical data supporting first-line
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`treatment.
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`14.
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`Dr. Earhart also takes the position that a person of ordinary skill in the
`
`art would have disregarded the Yu study (Ex. 2029), which suggested that
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`indicating that “breast cancers that overexpress p185 [i.e., HER2] will not respond
`
`well to Taxol” (Ex. 2029, Yu 1996 at 1362) and instead would haverelied upon
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`Seidman ’96, which stated that “HER2 over-expression in MBC seemsto confer
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`sensitivity rather than resistance to taxanes.” (Ex. 1011, Seidman 1996 at 5). (Ex.
`
`1085, Earhart Reply Decl. §§ 14-17.) I disagree.
`
`15. AsI described in my prior declaration (Ex. 2062, Tannenbaum Decl.
`
`qq 153-157), a POSA would understood Seidman ’96 (Ex. 1011) to provide only a
`
`preliminary analysis of how HER2+breast cancer patients might respondto
`
`taxanes, including paclitaxel. There are several reasonsfor this. First, the paper
`
`collected data retrospectively on patients who werenotall treated under the same
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`protocol and therefore could not be directly compared. Studies like this are
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`generally designed to generate hypotheses, but do not draw conclusionsas to
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`efficacy. Second, the study was reported as an abstract; a person ofordinary skill
`
`in the art would expect that the authors would likely expand their work and provide
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`a further analysis in a peer-reviewed journal. Third, the authors indicated that they
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`Case No. IPR2017-01122
`Supplemental Declaration of Dr. Susan Tannenbaum
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`needed to “control[] for confounding variables” and that the “mechanismsfor
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`[taxanes’ effect on HER2+ breast cancer] are under investigation,” indicating that
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`the relationship between HER2+ breast cancer and taxanes wasnotfully
`
`understood. (Ex. 1011, Seidman 1996 at 5.)
`
`16.
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`Dr. Earhart claims the fact that Seidman ’96 was an abstract would
`
`not affect how muchpersonsof ordinary skill in the art were willing to rely onit.
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`(Ex. 1054, Earhart Reply Decl. § 16.) I disagree. In particular, Seidman ’96
`
`reports an analysis of tumor samples that involved several “confounding
`
`variables,” and a POSA would want to see a further report on this analysis before
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`fully relying upon it. As Dr. Earhart himself stated in his first deposition in this
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`case, Seidman 796 is “simply reporting an observation ... that perhaps someone
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`else will be able to shed greater light on.” (Ex. 2050, Earhart First Dep. 338:2-7.)
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`17. Most importantly, it is not my position that a person of ordinary skill
`
`in the art would have disregarded Seidman ’96 and only relied upon Yu, as Dr.
`
`Earhart indicates. Rather, a person of ordinary skill in the art at the time of the
`
`invention would have recognizedthatlittle was known about how HER2+ breast
`
`cancer patients would respondto paclitaxel—and what data there was, was
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`conflicting. While some papers suggested HER2+ metastatic breast cancer patients
`
`would respond well to paclitaxel, others suggested patients would respond poorly.
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`Case No. IPR2017-01122
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`Indeed, this debate persisted until well after the date of the invention, when a 2002
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`peer-reviewed publication from the same laboratory as Seidman ’96 reported that
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`HER2-positive overexpression did not showastatistically significant association
`
`with clinical response to taxane therapy. (Ex. 2024, Van Poznak at 2322.)
`
`18.
`
`Dr. Earhart claims that Van Poznak “did not negate the finding” of
`
`Seidman °96, but rather “suggests that the results may be ‘partly in contrast’ to
`
`their earlier results.” (Ex.1054, Earhart Reply Decl. § 15.) Notably, Dr. Earhart
`
`does not deny Van Poznak’s finding that HER2-positive overexpression did not
`
`showastatistically significant association with clinical response to taxane therapy,
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`which I pointed out in my prior declaration as well. (Ex. 2062, Tannenbaum Decl.,
`
`4 157.) And regardless of the magnitude ofthe difference between the Seidman
`
`°96 and Van Poznakresults, the Van Poznak paper showsthat persons of ordinary
`
`skill in the art were continuing to study the relationship between paclitaxel and
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`HER2+ breast cancer well after the date of the invention—andthat some of the
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`data produced even then showed that HER2+ breast cancer may notbe sensitive to
`
`paclitaxel as Seidman °96 claimed.
`
`19.
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`In summary, paclitaxel wasa relatively new chemotherapeutic agent,
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`and it was unclear to clinicians whether it would effectively treat patients with
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`HER2+ metastatic breast cancer—with some data indicating that such patients
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`would fare poorly. As a result, a person of ordinary skill in the art would have
`
`been moreinclined to combine rhuMAbwith a well-understood first-line standard
`
`of care for metastatic breast cancer, like anthracyclines. This is particularly the
`
`case because rhuMAb HER2itself had only been evaluated in HER2+ metastatic
`
`breast cancer patients in one small PhaseII trial, as reported in Baselga ’96 (Ex.
`
`1020), and thusits clinical efficacy was not yet fully understood.
`
`2.
`
`Dr. Earhart’s “principles of combination therapy” would
`not have motivated the claimed combination.
`
`20.
`
`Dr. Earhart claimsthat a person of ordinary skill in the art would have
`
`“used the principles of combination therapy”that he identifies in his expert report
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`“with antibodies like trastuzumab.” (Ex. 1054, Earhart Reply Decl. ¥ 6.) I
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`disagree. As I explained in my opening brief (Ex. 2062, Tannenbaum Decl.
`
`202-210), these “principles”at the time of the invention were applied to
`
`chemotherapy combinations.
`
`(Ex. 1016 at 10 (discussing “[a] series of principles
`
`for the developmentofeffective clinical chemotherapy programs’); id. at 10
`
`Table 12-5 (table titled “Principles of Combination Chemotherapy”).) rhuMAb
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`HER2, on the other hand, was from a new class of treatment—monoclonal
`
`antibodies—which raised many unknownsand for which “much additional study”
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`wasstill needed. (Ex. 2031, Junghans 1996 at 683.)
`
`10
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`21.
`Dr. Earhart claims that “nothing in the prior art suggests” that “these
`principles were limited to traditional chemotherapy agents.” (Ex. 1054, Earhart
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`Reply Decl. { 6.) Dr. Earhart howeverignores that the prior art recognized how
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`different biologic agents, like monoclonal antibodies, were from traditional
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`chemotherapy. Asthe prior art explained, “The incorporation of biological agents
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`... into combination regimens with standard chemotherapeutic agents offers an
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`important challenge to the medical oncologist since the assumptionsfortheir use
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`likely differfrom those for chemotherapeutic agents.” (Ex. 2136, Wadler 1990,
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`3473 (emphasis added); see also id.(listing five factors “impeding the
`
`developmentofrational strategies for incorporation of this compoundsinto clinical
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`regimens”).) Tellingly, Dr. Earhart does not cite any examplesof these principles
`
`being applied to combinations of chemotherapy and biologic agents in his
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`declaration, nor could he recall any publication as of December 1996 applying
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`these principles to combine a chemotherapeutic agent and an antibody. (Ex. 1054,
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`Earhart Reply Decl. {§ 6-7; Ex. 2050, Earhart First Dep. 274:1-10.)
`
`22. Moreover, as I stated in my prior declaration, to the extent Dr.
`
`Earhart’s principles could apply to a combination involving rhuMAb HER2,they
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`would just as easily support a combination with almost any chemotherapy. (Ex.
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`11
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`2062, Tannenbaum Decl. § 204.) Dr. Earhart does not even attempt to rebut this
`
`point.
`
`3.
`
`Preclinical results of rhuMAb HER2and paclitaxel would
`not have predicted the clinical results of the claimed
`combination.
`
`23.
`
`Dr. Earhart claims the preclinical results in xenograft studies reported
`
`in Baselga ?94 (Ex. 1019) would have motivated the combination. (Ex. 1054,
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`Earhart Reply Decl. { 11.) However, as I have stated before, skilled artisans could
`
`not have predicted the results of a combination in humansbased onthe results of a
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`combination in mice.
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`24. Mousestudies serve as a foundation to allow clinicians to test novel
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`therapies on humans, and provide a preliminary indication of whether a drug or
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`drug combination might be safe and effective. However, they are not predictors of
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`ultimate clinical success. As I described in my prior declaration, mouse
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`physiology differs from human physiology: xenograft tumors grow faster in mice
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`than in humans; xenograft tumors do not metastasize in mice as they do in humans;
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`mice recover from treatment faster; and different pharmacokinetic characteristics
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`often lead to an overestimation of the effects of therapy in mouse studies.
`
`(Ex.
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`2062, Tannenbaum Decl. { 75.) Because of these differences and others, while
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`xenograft studies did provide some basic information about the effects of a
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`potential treatment on cancercells, they would frequently identify compounds for
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`further study that ultimately failed to show safety and efficacy in humans. (Ex.
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`2051, Gura 1997 at 1041; Ex. 2023, Marsoni 1984 at 77.)
`
`25.
`
`Dr. Earhart appears to claim that Dr. Kerbel and I “question the
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`validity” of the xenograft studies based on certain aspects of the studies’ design.
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`(Ex. 1054, Earhart Reply Decl. 4 9, see also id. §§ 10-11.) This is not a correct
`
`description of my opinion.
`
`[ do not claim that these studies are not valid or did not
`
`meet scientific standards at the time. Rather, there are steps that the designers of
`
`these studies could have taken to make these studies more predictive, such as using
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`multiple cell lines, using cell lines that had a number of HER2 genes that more
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`closely approximated the numberin humans,and using orthotopic implantation.
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`(Ex. 2062, Tannenbaum Decl. 4 192.) But they did not take these steps.
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`Moreover, based on the limited information available in Baselga 96 and ’94 about
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`the xenograft studies, a person of ordinary skill in the art could not tell many
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`details about the studies, such as how many mice were used, and what the
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`administration schedule was for paclitaxel. This would further limit a person of
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`ordinary skill in the art’s ability to determine how reliable and replicable these
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`results were, which would further limit the xenograft studies’ ability to predict
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`results in humans.
`
`13
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`26.
`
`Further, Petitioner claimsthat, “perhaps most importantly, the prior
`
`art indicated that on the basis of the xenograftresults, clinical trials of the
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`combination were already underway.” (Opp. at 12.) I disagree with Petitioner’s
`
`reading of the prior art. Petitioner cites the statement in Baselga ’94 that “anti
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`HER2 MAbscaneradicate well established tumors and enhancethe activity of
`
`paclitaxel and doxorubicin against human breast cancer xenografts. Clinicaltrials
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`are underway.” (Ex. 1019, Baselga ’94.) However, while Baselga ’94 mentions
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`that “[c]linical trials are underway,”it did not provide any description of those
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`clinical trials. Andin fact, the only clinical trials involving anti HER2 MAbsthat
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`had taken place and/or were “underway”at this time were Phase | andIItrials
`testing rhuMAb HER2 alone orin combination with cisplatin. (Ex. 2111, Shak
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`1999 at 72-73.) At the time of Baselga ’94, no clinical trials of Herceptin in
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`combination with paclitaxel had yet occurred. Petitioner also cites Baselga ’96 to
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`support this point, presumably for Baselga ’96’s statementthat “[i]n preclinical
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`studies ... rhuMAb HER2 markedly potentiated the antitumoreffects of several
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`chemotherapeutic agents, including cisplatin, doxorubicin, and paclitaxel, without
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`increasing their toxicity” and that “clinical trials of such combination therapy are
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`in progress.” (Ex. 1020, Baselga ’96 at 743.) However, a person of ordinary skill
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`in the art would not understand this disclosure to mean that a trial of Herceptin in
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`Case No. IPR2017-01122
`Supplemental Declaration of Dr. Susan Tannenbaum
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`combination with paclitaxel was in progress, particularly given that Baselga ’96
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`suggests that rhuMAb HER2 “markedly potentiated ... several chemotherapeutic
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`agents,” with doxorubicin, cisplatin, and paclitaxel offered only as examples.
`
`27.
`Finally, the xenograft data reported in Baselga 94 would have been
`further undermined by other xenograft results from a study by Dennis Slamon,
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`amongothers, showedthat “xenografts treated with rhuMAb HER-2plustaxol...
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`were not significantly differentfrom drug alonecontrols with the doses and dose
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`schedules tested in this model.” (Ex. 2135, Hsu 1997 Abstract.) These results
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`were published as an abstract and made available at a special conference of the
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`American Association of Cancer Research in March of 1997,titled “Basic and
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`Clinical Aspects of Breast Cancer.” (/d.; Ex. 2130, Earhart Second Dep. 167:14-
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`20) The American Association of Cancer Research, or AACR,is a very well-
`
`reputed organization, and special conferences hosted by the AACRattract several
`
`hundred individuals whose area of specialization matchesthe focus of the
`
`conference. Given that the focus ofthis conference wasbreast cancer, I would
`
`expect that numerous personsof ordinary skill in the art would have been present
`
`and in attendance.
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`28.
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`Dr. Earhart testified that he has been'a memberof the AACRsince the
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`late 1970s or early 1980s, and that he has attended AACR conferencessince he
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`15
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`Supplemental Declaration of Dr. Susan Tannenbaum
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`joined the AACR,including during the 1990s. (Ex. 2130, Earhart Second Dep.
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`163:15-164:14.) He also testified that abstracts like the Hsu 1997 abstract (Ex.
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`2135) would usually have been provided to conference attendees in an abstract
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`book, and made available afterwards to individuals whodid not attend, through
`
`libraries among other means. (Ex. 2130, Earhart Second Dep. 164:15-165:10.) Dr.
`
`Earhart further agreed that “if you are a researcher whosefocusis on breast cancer
`
`research,” the conference at which Hsu 1997 was presented would have been “a
`
`conference of interest to attend.” (Ex. 2130, Earhart Second Dep. 167:1-5.) Thus,
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`the data disclosed in Hsu 1997 would have further caused personsof ordinary skill
`
`in the art to be skeptical of the results reported in Baselga ’94.
`
`29.
`
`These issues I have raised above regarding preclinical models
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`generally, and the xenograft study described in Baselga ’94 in particular, are also
`
`addressed in the Declaration of Dr. Robert Kerbel, submitted concurrently with this
`
`Declaration. (Ex. 2143.) [have read and agree with the statements in Dr. Kerbel’s
`
`declaration regarding the limitations of pre-clinical models and the xenograft
`
`studies at issue in this case, and it is my opinion that these limitations would have
`
`been knownto a clinical oncologist specializing in breast cancer with several years
`
`of experience with breast cancerresearch orclinical trials in the 1996-1997 time
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`frame.
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`Supplemental Declaration of Dr. Susan Tannenbaum
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`4.
`
`Genentech’s experience demonstrates skepticism regarding
`the combination of rhuMAb HER?and paclitaxel.
`
`30.
`
`Finally, the history of the development of rhuMAb HER2 and
`
`paclitaxel at Genentech showssubstantial doubt regarding whether to go forward
`
`with the combination of rhuMAb HER2andpaclitaxel in PhaseIII trials, and
`
`whether that combination would beclinically successful.
`
`31.
`
`Initially, Genentech chose not to use paclitaxel in its Phase ITItrial of
`
`rhuMAb HER2at all. Rather, Genentech tested rhuMAb HER2in combination
`
`with anthracyclines. (Ex. 2111, Shak 1999 at 73.) Only after Genentech had
`
`begun the PhaseIII study, and spentsignificant resources developingit, did they
`
`add the paclitaxel arm out of necessity, to address problems with patient accrual.
`
`(/d.) Internal Genentech documents show that Genentech and others saw this
`
`decision as uncertain and risky.
`
`(See, e.g.,Po
`
`P| Ex. 2004 at 3 (“Inconsistent results have been obtained with two different
`
`preclinical models” for rhuMAb HER2 and taxol); Ex. 2004 at 7 (“Based on pre-
`
`clinical data alone, the expected clinical outcome for the administration of rhuMAb
`
`HER2with taxolis less certain than co-administration with cisplatinum or
`
`doxorubicin. Because our experience with H0648¢ to date indicates that
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`Supplemental Declaration of Dr. Susan Tannenbaum
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`enrollment is a problem, we must weigh the inconsistency ofthe scientific data
`
`versus the need to expediently enroll the trial.”).)
`
`32.
`
`Genentech’s communications with the FDA further demonstrate that
`
`the FDA wasskeptical of adding a paclitaxel arm to the Phase III trial, in part
`
`because of the lack of data supporting the combination of rhuMAb HER2 and
`
`pect,ae
`
`33.
`
`Thus, the history of development at Genentech of the combination of
`
`rhuMAb HER2and paclitaxel showsthat even those at Genentech and the FDA
`
`were skeptical about using this combination, and doubted that it would succeed at
`
`extending time to disease progression over paclitaxel alone.
`
`C.
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`A person of ordinary skill in the art would not have reasonably
`expected the claimed combination to extend TTP compared to
`paclitaxel alone.
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`Supplemental Declaration of Dr. Susan Tannenbaum
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`34. Aslexplained in my prior declaration, a person of ordinary skill in
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`the art would not have reasonably expected an extension of TTP from the claimed
`
`combination compared to paclitaxel alone. (See Ex. 2062, Tannenbaum Decl.
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`211-220.) Dr. Earhart presents several arguments for why a person of ordinary
`
`skill in the art would have expected the claimed combination to extend TTP
`
`compared to paclitaxel alone. As I explain here, I disagree with each of these
`
`arguments.
`
`1.
`
`A person of ordinary skill in the art would not have a
`reasonable expectation of success based on the TTP data
`reported in Baselga ’96 and the 1995 Taxol PDR.
`
`35.
`
`Dr. Earhart claimsthat “[a] person of ordinary skill in the art would
`
`have had a reasonable expectation that adding trastuzumab would achieve an
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`extension of TTP over treatment with paclitaxel alone based on the superior TTP
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`of trastuzumab,” because Baselga ’96 (Ex. 1020) disclosed a median TTP of5.1
`
`months for rhuMAb HER2, and the 1995 Taxol PDR (Ex. 1012) disclosed a
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`median TTP of 3.0 or 4.2 months for paclitaxel, depending on dose size. (Ex.
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`1054, Earhart Reply Decl. { 20.) I disagree.
`
`36.
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`‘First, the combination of rhuMAb HER2 andpaclitaxel had never
`
`before been tested in humans—a point which Dr. Earhart does not dispute. And
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`the outcomes of drug combinations are unpredictable. Sometimes a combination
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`Case No. IPR2017-01122
`Supplemental Declaration of Dr. Susan Tannenbaum
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`of drugs improvesresults in comparison to the drugs when administered alone, but
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`sometimes the combination does no better than the drugs alone, or performs even
`
`worse. This is true even when the drugs in the combination are well understood,as
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`can be seen through the example of tamoxifen. Prior to the date of the claimed
`
`invention, tamoxifen, an antiestrogen drug, had becomethe “usual
`
`recommendation for many postmenopausal women with breast cancer.” (Ex. 2132,
`
`Pritchard 1997 at 2302.) However, when it was evaluated in clinical studies in
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`combination with cyclophosphamide, methotrexate, and fluorouracil (CMF), a
`
`commonand well-understood chemotherapy treatment, it was foundthat the
`
`combination provided “no advantagein overall survival, progression-free survival,
`
`or locoregional or distant progression free survival.” (Ex. 2132, Pritchard 1997 at
`
`2308.)
`
`37.
`
`In this case, the drugs in the combination were not well understood.
`
`One of the agents was rhuMAb HER2, a humanized antibody. Humanized —
`
`antibody therapy was very new, and as of 1997 no antibodies had been approved
`
`for treatment of solid tumors. (Ex. 2031, Junghans 1996 at 684.) Indeed, most of
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`the work on developing antibodies up to that date had failed.
`
`(Ex. 2025,
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`Riethmuller and Johnson 1992 at 647 (1992) (“The hope that monoclonal
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`antibodies ... would revolutionize the diagnosis and treatment of cancer, has failed
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`20
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`Case No. IPR2017-01122
`Supplemental Declaration of Dr. Susan Tannenbaum
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`to materialize.”).) (See Ex. 2062, Tannenbaum Decl. 7§ 97-103.) And rhuMAb
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`HER2itself had not been shownto be safe and effective for treating patients in a
`
`large, Phase III trial. Indeed, as of 1997, there was no known and approved dose
`
`for rhuMAb HER2as a single agent. (See Ex. 2062, Tannenbaum Decl. § 110.)
`
`The example of interferons, another biological agent, had shown how difficult
`
`incorporating biological agents like monoclonal antibodies into cancer therapy
`
`could be. (Ex. 2136, Wadler 1990, 3473 (“The incorporation of biological agents
`
`..
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