Case 1:18-cv-01363-CFC Document 88-1 Filed 03/22/19 Page 1 of 77 PageID #:
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`EXHIBIT 1
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`Adam R. Brausa (Reg No. 60,287)
`Daralyn J. Durie (Pro Hac Vice)
`DURIE TANGRI LLP
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`217 Leidesdorff Street
`San Francisco, CA 94111
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`Case 1:18-cv-01363-CFC Document 88-1 Filed 03/22/19 Page 2 of 77 PageID #:
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`IPR2017-00804
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`Patent Owner’s Response
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`Filed on behalf of Patent Owner Genentech, Inc. by
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`David L. Cavanaugh (Reg. No. 36,476)
`Rebecca A. Whitfield (Reg. No. 73,756)
`Robert J. Gunther, Jr. (Pro Hac Vice)
`Lisa J. Pirozzolo (Pro Hac Vice)
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`Kevin S. Prussia (Pro Hac Vice)
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`Andrew J. Danford (Pro Hac Vice)
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`WILMER CUTLER PICKERING
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` HALE AND DORR LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________________________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________________________________________
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`HOSPIRA, INC., and
`SAMSUNG BIOEPIS CO. LTD.1
`Petitioners,
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`v.
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`GENENTECH, INC.,
`Patent Owner.
`____________________________________________
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`Case IPR2017-00804
`U.S. Patent 6,627,196
`____________________________________________
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`PATENT OWNER’S RESPONSE
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`1 Case IPR2017-01958 has been joined with this proceeding.
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`2.
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`2.
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`I.
`II.
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`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`TECHNOLOGY BACKGROUND ................................................................. 4
`A.
`Trastuzumab Opened the Door to Targeted Treatment of
`Breast Cancer ........................................................................................ 4
`1.
`Trastuzumab offered hope to women with HER2-
`positive breast cancer .................................................................. 4
`The biologic mechanisms of trastuzumab differed
`from traditional anti-cancer treatment ........................................ 5
`B. Armed with a New Therapeutic Approach, Researchers
`Sought to Improve Treatment and to Learn More ................................ 8
`1.
`At the time of the invention, researchers focused
`on improving efficacy ................................................................. 8
`The pharmacokinetic data in the prior art presented
`a complex picture ...................................................................... 11
`a.
`The prior art taught that trastuzumab exhibited dose-
`dependent (i.e., non-linear) pharmacokinetics ............... 11
`The prior art did not contain the data that a skilled artisan
`would need to predict the efficacy and safety of
`alternative dosing regimens for trastuzumab .................. 13
`III. THE ’196 PATENT ....................................................................................... 14
`A.
`The Invention ...................................................................................... 14
`B.
`Challenged Claims .............................................................................. 15
`IV. PETITIONERS’ ASSERTED REFERENCES ............................................. 17
`A.
`Baselga ’96 Does Not Disclose or Suggest the Claimed
`Dosing Regimen .................................................................................. 17
`Pegram ’98 Does Not Disclose or Suggest the Claimed
`Dosing Regimen .................................................................................. 18
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`b.
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`B.
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`- i -
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`C.
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`2.
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`b.
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`c.
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`d.
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`The 1998 Herceptin® Label Does Not Disclose or
`Suggest the Claimed Regimen ............................................................ 20
`V. ARGUMENT ................................................................................................. 22
`A. A Person of Ordinary Skill Would Not Have Been
`Motivated to Administer Trastuzumab on a Three-Week
`Schedule .............................................................................................. 23
`1.
`Petitioners provide no justification for selection of
`the claimed dose amounts ......................................................... 24
`A skilled artisan would not have been motivated to
`extend the dosing interval for the sake of
`convenience ............................................................................... 27
`a.
`The evidence shows that in August 1999, skilled artisans
`were not focused on convenience ................................... 27
`A clinical oncologist would not have been motivated to
`dose trastuzumab on a three-week schedule like a
`chemotherapy agent ........................................................ 30
`Dr. Lipton’s conclusory reference to compliance and
`quality of life is insufficient to establish a motivation to
`combine ........................................................................... 33
`Petitioners’ generalized convenience argument is counter
`to law .............................................................................. 36
`i.
`Motivation must be viewed in the context of the
`prior art at issue and the perspective of a skilled
`artisan ................................................................... 36
`Petitioners’ reliance on Hoffman-La Roche is
`misplaced .............................................................. 38
`The pharmacokinetic data in the prior art would
`not have motivated a skilled artisan to extend the
`dosing interval of trastuzumab .................................................. 40
`Petitioners Have Failed to Show that a Skilled Artisan
`Would Have a Reasonable Expectation of Success ............................ 43
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`ii.
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`3.
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`B.
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`- ii -
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`Dr. Jusko’s analysis contradicts fundamental
`teachings of the prior art ........................................................... 44
`a.
`Petitioners’ application of linear pharmacokinetics to
`support their position is erroneous ................................. 45
`i.
`The prior art does not support application of linear
`pharmacokinetics .................................................. 45
`Linear pharmacokinetic equations likely
`overestimate trough concentrations after three
`weeks .................................................................... 48
`Dr. Jusko’s selection of a 12-day half-life to model the
`claimed dose regimens is not supported by the prior art 51
`There is insufficient data in the prior art to accurately
`predict whether a three-week dosing regimen would be
`clinically effective .......................................................... 55
`A clinical oncologist would not have used three-
`week dosing based on Dr. Jusko’s pharmacokinetic
`analysis ...................................................................................... 56
`Foreign Proceedings Are Not Relevant ............................................... 57
`C.
`These Proceedings are Unconstitutional ............................................. 58
`D.
`VI. CONCLUSION .............................................................................................. 59
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`b.
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`c.
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`2.
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`1.
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`ii.
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`- iii -
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`TABLE OF AUTHORITIES
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` Page(s)
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`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 26
`Apple Inc. v. Samsung Elecs. Co.,
`839 F.3d 1034 (Fed. Cir. 2016) (en banc) .......................................................... 37
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .......................................................................... 25
`Arctic Cat Inc. v. Bombardier Recreational Prod. Inc.,
`No. 2017-1475, --- F.3d ----, 2017 WL 6044237 (Fed. Cir. Dec. 7,
`2017) ................................................................................................................... 43
`Biomarin Pharm. Inc. v. Genzyme Therapeutic Prods., LP,
`IPR2013-00537, Paper 79 (Feb. 23, 2015) (Ex. 1025), aff’d
`Genzyme Therapeutic Prods. LP v. Biomarin Pharm. Inc., 825
`F.3d 1360 (Fed. Cir. 2016) ................................................................................. 27
`Böhler-Edelstahl GmbH & Co. KG. v. Rovalma S.A.,
`IPR2015-00150, Paper 51 (Dec. 6, 2017)........................................................... 30
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 25
`Depomed, Inc. v. Actavis Elizabeth LLC,
`No. CIV.A. 12-1358 JAP, 2014 WL 4215435 (D.N.J. Aug. 25,
`2014) ................................................................................................................... 30
`Endo Pharm. Inc. v. Depomed, Inc.,
`IPR2014-00654, Paper 69 (Sept. 21, 2015) ........................................................ 54
`Hoffman-La Roche Inc. v. Apotex, Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ...................................................................passim
`Innogenetics, N.V. v. Abbott Labs.,
`512 F.3d 1363 (Fed. Cir. 2008) .......................................................................... 37
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`- iv -
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`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 43
`In re Magnum Oil,
`829 F.3d 1367 (Fed. Cir. 2016) .......................................................................... 40
`Markman v. Westview Instruments, Inc.,
`517 U.S. 370 (1996) ............................................................................................ 58
`McCormick Harvesting Mach. Co. v. C. Aultman & Co.,
`169 U.S. 606 (1898) ............................................................................................ 58
`Medtronic, Inc. v. Daig Corp.,
`789 F.2d 903 (Fed. Cir. 1986) ............................................................................ 57
`Metalcraft of Mayville, Inc. v. The Toro Co.,
`848 F.3d 1358 (Fed. Cir. 2017) .......................................................................... 37
`In re Nuvasive,
`842 F.3d 1376 (Fed. Cir. 2016) .......................................................................... 35
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 54
`In re Patel,
`566 F. App’x 1005 (Fed. Cir. 2014) ................................................................... 26
`Rovalma, S.A. v. Bohler-Edelstahl GmbH & Co. KG,
`856 F.3d 1019 (Fed. Cir. 2017) .......................................................................... 29
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) .......................................................................... 36
`Smith & Nephew v. ConvaTec Techs. Inc.,
`IPR2013-00097, Paper 76 (Feb. 24, 2014) ......................................................... 57
`W.L. Gore & Assocs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .......................................................................... 47
`In re Woodruff,
`919 F.2d 1575 (Fed. Cir. 1990) .......................................................................... 25
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`- v -
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`Constitutional Provisions
`U.S. Const. Amendment VII .................................................................................... 58
`Other Authorities
`M.P.E.P. § 2141.02(VI) ........................................................................................... 47
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`- vi -
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`I.
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`INTRODUCTION2
`The’196 patent inventors discovered that trastuzumab, the first antibody ever
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`approved to treat breast cancer, could be administered on a three-week dosing
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`regimen without compromising the safety or efficacy shown with weekly
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`administration. Prior to trastuzumab’s approval in September 1998, chemotherapy
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`was the most common breast-cancer treatment. But for the estimated 25-30% of
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`patients afflicted with virulent HER2-positive breast cancer, the prognosis was
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`poor and life expectancy following a diagnosis was 12-18 months. Oncologists
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`welcomed the introduction of trastuzumab, which finally gave these patients hope.
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`2 The Board previously terminated IPR2017-01958 and joined it to the instant
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`proceeding, IPR2017-00804. (IPR2017-01958, Paper 9.) In its motion for joinder,
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`Petitioner Samsung Bioepis argued, and the Board agreed, that Samsung’s petition
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`was “essentially a copy of” and “substantially identical to” Hospira’s petition; that
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`Samsung’s petition “relies solely on the same prior art analysis and expert
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`testimony submitted by Hospira;” and that Samsung is merely participating in an
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`“understudy capacity.” (IPR2017-01958, Paper 1 at 1-5; IPR2017-01958, Paper 9
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`at 5.) Thus, while this response cites to Hospira’s petition and evidence, Patent
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`Owner’s argument and evidence apply equally to Samsung’s petition.
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`1
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`Efforts to better understand and use this new therapy did not end when
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`trastuzumab was first approved for weekly administration to treat metastatic breast
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`cancer. Use of targeted antibody therapy to destroy or inhibit cancer cell growth
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`was a novel approach that had been largely unsuccessful until the late 1990s. In
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`addition, the biologic mechanism of trastuzumab differed dramatically from
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`chemotherapy. With chemotherapy, clinicians sought to kill as many cancer cells
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`as possible without causing side effects that were even worse than the cancer being
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`treated. In contrast, trastuzumab was known to specifically target breast-cancer
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`cells. Nevertheless, much remained to be studied and learned about this
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`groundbreaking therapy.
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`The prior art relied upon by Petitioners reveals the extent to which skilled
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`artisans were still learning about trastuzumab, and does not support the contention
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`that the claimed dosing regimens would have been obvious. There is no dispute
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`that the prior art only described weekly administration of trastuzumab, and that the
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`authors of the prior art opted for weekly dosing based on the very same
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`pharmacokinetic data upon which Petitioners rest their case. Indeed, Petitioners’
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`own clinical expert—a co-author of one of Petitioners’ three prior art references—
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`has proffered no evidence from the late 1990s that he or any other oncologist ever
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`suggested an extended dosing interval for trastuzumab. Petitioners thus base their
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`obviousness case on conclusory expert testimony referencing a generalized desire
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`2
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`for “convenience,” “quality of life,” and “compliance” that is nowhere evident in
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`the prior art. In short, there is nothing in the prior art mentioning the claimed
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`extended dose interval or the alleged motivation.
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`Petitioners’ proof of “reasonable expectation of success” is no more
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`compelling. In the face of varied and conflicting data, Petitioners’
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`pharmacokinetics expert oversimplified his analysis, and then relied upon data in
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`the prior art that would support his position while ignoring data that would not.
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`For example, Petitioners’ expert conceded that while the prior art taught that
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`trastuzumab had “dose dependent” kinetics (i.e., varying half-life depending upon
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`dose), he assumed a single half-life when performing his analysis. Even worse,
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`when confronted with prior art disclosing half-lives for trastuzumab ranging from
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`1.7 days to 12 days, Petitioners’ expert opted to plug into his equations the longest
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`reported half-life and to ignore prior art data reporting a shorter half-life. In
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`defending these choices, Petitioners’ expert sought to justify his analysis on the
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`grounds that he “used the best information available at the time,” but the prior art
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`did not disclose sufficient detail such that a skilled artisan could accurately model
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`an extended interval dosing regimen for a drug with non-linear kinetics like
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`trastuzumab. (Ex. 2037, Jusko Dep., at 42:10-16, see id. at 42:10-16, 124:20-
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`125:5.)
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`3
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`At bottom, Petitioners’ obviousness case does not properly account for the
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`seriousness of the disease condition at issue or the novelty of targeted cancer
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`therapy at the time. With respect to “motivation,” the prior art makes clear that
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`convenience and compliance were not of concern to women with HER2-positive
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`breast cancer or their physicians; treating the cancer was the driving force behind
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`dosing regimens then being explored. Similarly, with respect to “reasonable
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`expectation of success,” there is no support for the proposition that a skilled artisan
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`would rely on oversimplified analyses to predict pharmacokinetics for a complex
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`and novel cancer therapy where errors could have fatal consequences.
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`II. TECHNOLOGY BACKGROUND
`A. Trastuzumab Opened the Door to Targeted Treatment of Breast
`Cancer
`1. Trastuzumab offered hope to women with HER2-positive
`breast cancer
`The ’196 patent is directed to the treatment of “HER2-positive” cancers, a
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`class of cancers characterized by the overexpression of human epidermal growth
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`factor 2 receptor (“HER2”), also known as human ErbB2. HER2-positive breast
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`cancer is a particularly aggressive form of cancer, in which cancer cells grow and
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`spread rapidly. (Ex. 2040, Gelmon Decl., ¶12.) HER2-positive status was
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`associated with a high rate of tumor recurrence and spreading of the cancer to other
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`areas of the body, as well as a shorter time to relapse. (Ex. 2041, Kopreski ’96 at
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`4
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`433; Ex. 2042, Lehrer ’93 at 1420; Ex. 2043, Slamon ’87 at 179-80.) The life
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`expectancy of HER2-positive patients in 1996 was only 18 months post-diagnosis.
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`(Ex. 2044, Holzman ’96 at 138; see also Ex. 2045, Hoyle ’98 at 887; Ex. 2040,
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`¶12.)
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`In 1998, HER2-positive breast cancer made up 25-30% of the 180,000
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`yearly new breast cancer diagnoses. (See Ex. 1011 at 1, 5; see also Ex. 1013 at 9;
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`Ex. 2040, ¶13). As a result, even before FDA approval of trastuzumab, Genentech
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`was “swamped” by demand for trastuzumab and teamed with patient advocacy
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`groups to design a lottery system to equitably distribute a limited supply to
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`severely affected patients. (Ex. 2045, Hoyle ’98 at 887.)
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`2. The biologic mechanisms of trastuzumab differed from
`traditional anti-cancer treatment
`Until the approval of trastuzumab in September 1998, the treatment most
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`commonly prescribed for breast cancer was chemotherapy. (Ex. 2040, ¶¶6, 29,
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`39.) Chemotherapy agents work by killing tumor cells, but they also kill healthy
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`cells in the process and are thus considered non-targeted cancer treatments. (Id. at
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`¶30.) Rapidly dividing cells—such as hair follicles, cells lining the intestine, and
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`bone marrow cells—tend to be damaged the worst, leading to symptoms such as
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`hair loss, gastrointestinal issues, myelosuppression, and neutropenia. 3 (Id.) In
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`1999, the goal of most chemotherapy dosing was to kill the greatest number of
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`tumor cells without causing life-threatening toxicity. (Id. at ¶31; see also Ex.
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`2038, Lipton Dep., at 37:15-39:21; 45:12-46:2.) Typically, that was done by
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`administering the largest tolerable dose followed by a dosing interval that would
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`allow a patient time to recover before the next dose. (Ex. 2040, ¶30.)
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`The use of antibodies to treat cancer involved a radically different approach.
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`In contrast to the broad-based DNA-damaging activity of chemotherapeutic agents,
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`targeted cancer therapies interact with specific molecular targets involved in the
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`growth, progression, and spread of cancer. (Id. at ¶30; Ex. 2060, Stadler 2000 at 7;
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`see also Ex. 2038 at 37:20-11, 39:12-21, 47:17-19.) At the time of the invention,
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`although numerous antibodies had been tested in patients with different cancers
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`(including breast cancer), consistent therapeutic efficacy had not been shown. (Ex.
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`2002 at 649; id., Table 2 (identifying failed antibody clinical trials for numerous
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`cancers); Ex. 2040 at ¶¶14, 16.) Prior to August 1999, the FDA had approved only
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`3 Myelosuppression results in a reduction of white blood cells, which can decrease
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`a person’s ability to fight infection. (Ex. 2040, ¶30.) Neutropenia occurs when a
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`person has an abnormally low number of a particular type of white blood cell. (Id.)
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`Both conditions can be life-threatening. (Id.)
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`one other antibody for use in treating cancer—Genentech’s rituximab product,
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`which was approved for non-Hodgkin’s lymphoma treatment in 1997. (Ex. 2003,
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`Reichert ’09 at 388; see also Ex. 2038, 33:8-17.) Trastuzumab was the first
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`antibody approved to target solid tumors and the first approved to treat breast
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`cancer. (Id.; see also Ex. 2040, ¶15.)
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`At the time of the invention, most clinical investigators were well-aware of
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`the distinctions between the newer target-based agents and classic chemotherapy
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`agents. (Ex. 2060 at 7-8; Ex. 2038 at 37:13-39:21.) As a consequence, they
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`appreciated that trastuzumab worked differently from traditional chemotherapy.
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`(Ex. 1013 at 13 (“[T]he biologic action of [trastuzumab] … differs markedly from
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`conventional anticancer agents.”); see also Ex. 2038 at 37:15-39:21.) It was
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`known that as a targeted cancer treatment, trastuzumab bound to HER2 receptors
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`on HER2 cancer cells. Once there, it inhibited tumor cell growth and induced cell
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`death by flagging HER2-overexpressing tumor cells for destruction by the body’s
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`immune system. (See, e.g., Ex. 1001, 35:45-58; Ex. 1008 at 1.)
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`Skilled artisans also knew that for trastuzumab to be effective, adequate
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`blood levels had to be maintained over the entire course of treatment. (Ex. 2040,
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`¶¶8, 36; Ex. 2039, ¶¶37-39.) Failure to maintain therapeutic serum concentrations
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`throughout the dosing interval risked jeopardizing clinical efficacy. (Ex. 2040,
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`¶36; Ex. 2039, ¶39.) Preclinical studies of trastuzumab identified 10-20 µg/mL as
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`the target trough concentration for clinical efficacy, and early clinical studies
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`showed that failure to reach this target was associated with a lack of clinical
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`response. (Ex. 2040 at ¶¶36, 65; Ex. 1014 at 9; Ex. 1013 at 10.) Moreover, at the
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`time of the invention, the weekly dosing regimens in the prior art resulted in higher
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`mean trough concentrations for the average patient. For example, the regimen
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`described in Baselga ’96 resulted in a mean trough concentration of 54 µg/mL.
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`(Ex. 1014 at 14, Table 6.) The 1998 Herceptin® Label (Ex. 1008, “The Label”)
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`reported that the approved weekly dosing regimen resulted in mean trough serum
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`concentration levels of approximately 79 µg/mL. (Ex. 1008 at 1.)
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`B. Armed with a New Therapeutic Approach, Researchers Sought to
`Improve Treatment and to Learn More
`1. At the time of the invention, researchers focused on
`improving efficacy
`Trastuzumab’s 1998 approval marked a breakthrough in the breast oncology
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`field, providing patients with hope of treatment for a condition previously viewed
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`as a death sentence. (See Ex. 2038 at 234:10-18; Ex. 2040, ¶24.) In the wake of
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`the approval, skilled artisans seeking to maximize clinical outcomes for patients
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`with HER2-positive breast cancer now focused on how trastuzumab could be used
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`more effectively. (Ex. 2040, ¶¶24-25; Ex. 2028, Baselga 2000 at 27-33; Ex. 2046,
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`Shak ’99 at 76.). As one inventor of the ’196 patent noted, trastuzumab’s success
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`prior to August 1999 offered “proof of principle,” but further research was needed
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`to improve patient outcomes. (Ex. 2046, Shak ’99 at 76). During the five years
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`following trastuzumab’s approval, hundreds of papers and abstracts were published
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`in which researchers explored various ways to maximize the effective use of
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`trastuzumab. (Ex. 2040 at ¶29.)
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`For example, in the late 1990s, skilled artisans were actively investigating
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`how to combine trastuzumab with chemotherapy, including paclitaxel, the
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`chemotherapy agent administered with trastuzumab in the Phase III studies that led
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`to trastuzumab’s approval. (Ex. 2040, ¶¶25, 37-38, 57; Ex. 2028 at 28.) Inspired
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`by the favorable results of the Phase III trials reported in the Label, researchers—
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`including coauthors of the prior art upon which Petitioners rely—studied
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`administering paclitaxel to match weekly trastuzumab administration. (Ex. 2040,
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`¶¶38, 57; Ex. 2023, Seidman ’98 at 3360; Ex. 2030, Perez ’98 at 373; Ex. 2029,
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`Fornier ’99.) In this regimen, paclitaxel was administered more frequently than the
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`then-standard three-week regimen. (Id.)
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`This trend was bolstered by studies reporting that that weekly paclitaxel
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`administration had a remarkably favorable toxicity profile, with the same or better
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`efficacy as compared to the three-week regimen. (See Ex. 2040, ¶38; Ex. 2023,
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`Seidman ’98 at 3353, 3357-58; Ex. 2034, Frasci ’98 at 24.) Indeed, by 1999,
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`studies showed that weekly paclitaxel was more effective than a three-week
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`regimen. (Ex. 2026, Sikov ’98 at 432 (weekly paclitaxel study had the highest
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`response rate in advanced breast cancer for single agent paclitaxel and suggesting
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`further study); Ex. 2023, Seidman ’98 at 3357-58 (weekly paclitaxel may have
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`advantages over three-week dosing).) As described by a preeminent researcher in
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`1998, weekly paclitaxel was generating “much interest” given the high relative
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`dose intensity and density delivered, and very modest side effects. (Ex. 2030,
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`Perez ’98 at 373, 375-76; id. at 385 (“Further investigation into the role of weekly
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`paclitaxel … is ongoing.”); see also Ex. 2034, Frasci ’98 at 15 (“The weekly
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`administration of paclitaxel has raised much interest in the last few years in view
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`of the quite astonishing doses delivered with this schedule.”).) At his deposition,
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`Petitioner’s oncology expert, Dr. Allan Lipton, conceded that this was an
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`“important theory” that many people were exploring prior to the invention. (Ex.
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`2038 at 134:4-135:7; 273:7-13.)
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`In contrast, nothing in the prior art reflects any motivation to extend the
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`dosing interval for trastuzumab to match the three-weekly dosing of paclitaxel,
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`(Ex. 2038 at 173:20-174:10.) On the contrary, prominent researchers were taking
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`the opposite approach. (Ex. 2040, ¶¶32-33, 38, 57; Ex. 2023, Seidman ’98; Ex.
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`2028, Baselga 2000.)
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`2. The pharmacokinetic data in the prior art presented a
`complex picture
`Although researchers had some understanding of how trastuzumab worked
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`(and that it differed from chemotherapy), the experience and data available to
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`skilled artisans regarding trastuzumab pharmacokinetics were limited and varied.
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`The prior art taught that trastuzumab was dose-dependent and that half-life
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`increased with dose amount when the drug was dosed weekly. But at the time of
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`the invention, the degree to which half-life varied, and the reasons for the variance
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`were not known.
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`a.
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`The prior art taught that trastuzumab exhibited dose-
`dependent (i.e., non-linear) pharmacokinetics
`The prior art explicitly taught that trastuzumab exhibited dose-dependent
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`pharmacokinetics over the dosing ranges tested. (Ex. 2039, Grass Decl., ¶¶8, 28-
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`33.) For example, the Label reports that: “Short duration intravenous infusions of
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`10 to 500 mg once weekly demonstrated dose-dependent pharmacokinetics.” (Ex.
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`1008 at 1; Ex. 2037, Jusko Dep., 66:1-9.) Similarly, Baselga ’96 reports: “The
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`resulting recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb
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`HER2) was found to be safe and to have dose-dependent pharmacokinetics in two
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`prior phase I clinical trials.” (Ex. 1013 at 9; Ex. 2037, Jusko Dep., 83:16-84:7.)
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`Moreover, the data presented in the prior art is consistent with this conclusion.
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`(Ex. 2039, ¶28.; see also Ex. 2037, Jusko Dep., 73:11-14.) A skilled artisan would
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`understand the prior art’s teaching that trastuzumab exhibited dose-dependent
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`pharmacokinetics to mean that trastuzumab had non-linear kinetics. (Ex. 2039,
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`¶¶8, 30; see also Ex. 2037, Jusko Dep., 66:7-13.)
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`In the case of drugs with linear kinetics, the half-life of a drug (i.e., the time
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`it takes for a drug’s concentration in the body to decrease by half) remains the
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`same across any dose amount or dose interval. (Ex. 2008, Gabrielsson & Weiner
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`’97 at 145-46; Ex. 2039, ¶19.) A drug with linear kinetics is thus eliminated at a
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`rate proportional to the drug’s plasma concentration. (Id. at ¶¶20-21.) In contrast,
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`for drugs with non-linear kinetics, the drug’s half-life changes as its concentration
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`in the body changes, i.e., the half-life is dependent on the drug’s concentration in
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`body. (Id. at ¶¶22-23, 27.) That means that plasma concentrations do not change
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`proportionally with dose or interval. (Id.; Ex. 2037, Jusko Dep., 65:16-19.) Thus,
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`the pharmacokinetic parameters from one dose amount and interval cannot be
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`reliably used to predict the effects of a different dose amount or interval. (Ex.
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`2039, ¶¶12-13, 24-27, 35.) More data is needed. (Id. at ¶¶56-60, 66)
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`While the prior art taught that trastuzumab had non-linear kinetics, it did not
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`contain sufficient data from which to determine the specific characteristics or cause
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`of the non-linearity. (Ex. 2039, ¶¶48, 56; Ex. 2037, Jusko Dep., 66:1-6, 83:16-
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`84:7.) One such potential source of non-linear kinetics was the presence of shed
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`antigen. (Ex. 2039, ¶¶56, 72.) “Shed antigen” refers to circulating extra-cellular
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`domain ECDHER2 “shed” from the tumor source, and circulating in the blood
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`stream. (Ex. 2039, ¶71; Ex. 2001 at 313.) The prior art taught that 64% of patients
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`with HER2-positive breast cancer had detectable levels of shed antigen and that the
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`presence of shed antigen was correlated with lower trough serum concentrations of
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`trastuzumab, lower half-life values, and the lack of a clinical response. (See e.g.,
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`Ex. 1008