Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 1 of 45 PageID #: 25807
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`GENENTECH, INC. and CITY OF HOPE,
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`v.
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`AMGEN, INC.,
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`Plaintiffs,
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`Defendant.
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`C.A. No. 18-924-CFC
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`EXPERT DECLARATION OF GEORGE M. GRASS, Ph.D.
`IN SUPPORT OF GENENTECH’S EMERGENCY MOTION FOR
`TEMPORARY RESTRAINING ORDER AND PRELIMINARY INJUNCTION
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`- i -
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`PUBLIC VERSION FILED:
`JULY 25, 2019
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 2 of 45 PageID #: 25808
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`Pages
`Introduction ..........................................................................................................................1 
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`TABLE OF CONTENTS
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`Qualifications .......................................................................................................................1 
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`Summary of Opinions ..........................................................................................................3 
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`Person of Ordinary Skill in the Art ......................................................................................6 
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`State of the Art .....................................................................................................................7 
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`I. 
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`II. 
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`III. 
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`IV. 
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`V. 
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` 
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`1. 
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`2. 
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`3. 
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`4. 
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`5. 
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` 
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`1. 
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`2. 
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`3. 
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`Brief Description of the Principal Prior Art Relied Upon By Amgen .............................7 
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`The Watanabe Abstract ................................................................................................8 
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`Baselga ’96...................................................................................................................8 
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`Pegram ’98 ...................................................................................................................9 
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`Herceptin Label ............................................................................................................9 
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`Hellmann Patent .........................................................................................................10 
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`Pharmacokinetic Factors A Skilled Artisan Would Consider In Designing Dosing
`Regimens For Trastuzumab In View of the Prior Art ....................................................10 
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`A Skilled Artisan Would Seek to Maintain Therapeutically Effective Levels of
`Trastuzumab ...............................................................................................................11 
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`A Skilled Artisan Would Account for the Teaching that Trastuzumab Had Non-
`Linear Kinetics ...........................................................................................................12 
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`A Skilled Artisan Would Know that Shed Antigen Could Be A Source of the Non-
`Linearity of Trastuzumab ...........................................................................................17 
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`VI. 
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`The Claimed Inventions .....................................................................................................19 
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`VII.  The Prior Art Did Not Provide Data Sufficient to Predict the Efficacy of a Three-Week
`Dosing Interval for Trastuzumab .......................................................................................21 
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`A Skilled Artisan Would Not Have Relied on the Prior Art’s Half-Life Data to Predict
`the Efficacy of a Three-Week Dosing Interval for Trastuzumab ..................................21 
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`The Prior Art Did Not Provide Enough Data from Which a Skilled Artisan Could
`Accurately Predict the Efficacy of a Three-Week Dosing Interval of Trastuzumab .....24 
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 3 of 45 PageID #: 25809
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`A Skilled Artisan Would Be Concerned that Using Flawed Assumptions to Predict the
`Efficacy of Three-Week Dosing Could Result in Overestimates of Trough Serum
`Concentrations ...............................................................................................................28 
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`VIII.  Rebuttal to Other Arguments Made by Amgen .................................................................30 
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 4 of 45 PageID #: 25810
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`I.
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`Introduction
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`1.
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`I have been retained as an expert in this matter by counsel for Genentech, Inc.,
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`and submit this declaration in support of Genentech’s Emergency Motion for Temporary
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`Restraining Order and Preliminary Injunction.
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`2.
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`I have been asked for my opinion concerning various assertions made by Amgen
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`in support of its contentions regarding the obviousness of claims 11 of U.S. Patent No. 6,627,196
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`(the “’196 patent”); 11of U.S. Patent No. 7,371,379 (the “’379 patent”); and 7 of U.S. Patent No.
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`10,160,811 (the “’811 patent”). I will refer herein to these three patents as the “dosing patents”
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`and to the three claims as the “asserted claims.”
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`3.
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`For the reasons set forth in this declaration, it is my opinion that the prior art upon
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`which Amgen relies does not contain sufficient information with respect to trastuzumab to
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`reasonably predict that the three-week dosing regimen recited in the asserted claims would be
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`effective to treat HER2-positive cancer. On the contrary, a skilled artisan considering the prior
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`art would be concerned that extending the dosing interval from the weekly regimen approved by
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`the Food and Drug Administration to a three-week regimen, even at higher doses, would not
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`maintain adequate serum trough concentrations of trastuzumab.
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`II.
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`Qualifications
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`4.
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`I am President of G2 Research, Inc., a company I founded in August 2001 to
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`provide consulting services to pharmaceutical and biotechnology companies in a variety of areas.
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`Among other things, I have performed pharmacokinetic modeling to evaluate clinical regimens
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`for antibodies and small molecules. I have also developed computer simulation software and
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`models to predict drug pharmacokinetics.
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`5.
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`I obtained a Ph.D. in Pharmaceutics at the University of Wisconsin, Madison in
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`1985. My Ph.D. thesis was entitled “Mechanisms of Corneal Drug Penetration.” As a result of
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 5 of 45 PageID #: 25811
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`this research, I was the co-recipient of the 1989 Ebert Prize, awarded by the American
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`Pharmacists Association Academy of Pharmaceutical Research and Sciences, for a series of
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`manuscripts published in the Journal of Pharmaceutical Sciences entitled “Mechanisms of
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`Corneal Drug Penetration.” I obtained a M.S. degree in Pharmaceutics at the University of
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`Wisconsin, Madison in 1983. I obtained a Pharm. D. degree from the University of Nebraska in
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`1980, and was formerly licensed to practice pharmacy in the state of Nebraska.
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`6.
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`I have spent more than thirty years working in the pharmaceutical industry. From
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`1985 to 1991, I worked as a Research Scientist at Syntex Research in Palo Alto, where I was
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`responsible for formulation development and research in oral drug absorption, including methods
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`to orally deliver peptides. Since 1991, I have been a pharmaceutical industry consultant. In
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`1991, I started my own company, Precision Instrument Design Inc., and, in 1997, another
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`company, NaviCyte, Inc. In 1999, NaviCyte, Inc. was acquired by Trega Biosciences, and I
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`served as Chief Technology Officer at Trega Biosciences, Inc. until 2001. In 2001, I founded G2
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`Research, Inc., and also founded RaptorGraphics, Inc., a computer graphics and simulation
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`business. From 2005 to 2007, I was Vice President of Product Development and Chief
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`Technology Officer for PDxRx, Inc., a specialty-focused pediatrics company. From 2007 to
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`2010, I was Senior Vice President of Research and Development for Sorbent Therapeutics, Inc.,
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`a company developing novel polymer therapeutics for sodium fluid removal. From January 2016
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`until May 2017, I was Senior Vice President of non-clinical development and founder for
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`NeuroVia, Inc., a company developing a novel compound for childhood cerebral
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`adrenoleukodystrophy.
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`7.
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`I am the author or co-author of more than 30 published scientific articles,
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`primarily in the areas of models to predict drug pharmacokinetics, corneal permeability and drug
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 6 of 45 PageID #: 25812
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`transport, and intestinal transport and drug absorption. I have authored book chapters related to
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`drug delivery and have been an invited speaker at multiple scientific meetings, including
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`meetings of the American Association of Pharmaceutical Scientists. I have been a peer reviewer
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`for a number of journals such as Pharmaceutical Research and Journal of Pharmaceutical
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`Sciences. I have presented technical information and development plans to the FDA. I am an
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`inventor or co-inventor on eight U.S. patents and four additional U.S. patent applications and
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`several foreign patents. My curriculum vitae is attached as Appendix A.
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`8.
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`I have been retained and provided declarations in other proceedings related to the
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`asserted patents. I provided declarations in the following proceedings: prosecution of the ’811
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`patent (U.S. Patent Application No. 14/073,659) before the U.S. Patent and Trademark Office;
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`inter partes review proceedings (“IPRs”) related to the ’196 and ’379 patents (IPR2017-00804, -
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`00805, -01139, -01140); and foreign counterpart proceedings in Japan, South Africa, Europe,
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`and Mexico. I provided deposition testimony in IPR2017-00804, -00805, -01139, -01140.
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`III.
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`Summary of Opinions
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`9.
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`The principal prior art references upon which Amgen relies to support its
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`obviousness claims report on studies in which trastuzumab was administered at weekly dosing
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`intervals. The Watanabe Abstract describes a Phase I study in which a first dose of either
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`1 mg/kg, 2 mg/kg, 4 mg/kg, or 8 mg/kg of trastuzumab was administered and then followed in
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`three weeks by nine weekly doses in the same amount as the first. Based on this study,
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`Watanabe concluded that further clinical trials with “2-4 mg/kg weekly intravenous infusions is
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`warranted.” Baselga ’96 and Pegram ’98 likewise describe Phase II studies of trastuzumab in
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`which patients were given a 250 mg loading dose of trastuzumab followed by weekly doses of
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`100 mg. The Herceptin Label describes the first FDA-approved dosing regimen for Herceptin, a
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`4 mg/kg loading dose followed by weekly doses of 2 mg/kg. This is significant not only because
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 7 of 45 PageID #: 25813
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`it suggests that skilled artisans at the time of the invention would have known that weekly dosing
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`worked, but also because the prior art did not include pharmacokinetic data with respect to
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`intervals of longer than one week. The “different prior art” cited by Amgen, U.S. Patent No.
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`8,309,087 (the “Hellmann patent”) also describes the weekly FDA approved dosing regimen for
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`Herceptin, a 4 mg/kg loading dose followed by weekly doses of 2 mg/kg, but does not describe
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`extended dosing intervals or include any pharmacokinetic data for trastuzumab. In my opinion,
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`the Hellmann patent does not provide any relevant information that was not provided in
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`Watanabe, Baselga ’96, Pegram ’98 and the Herceptin Label.
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`10.
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`It is also my opinion that a skilled artisan would conclude that it was not possible
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`to reliably model a new dosing regimen based on the limited pharmacokinetic data in the
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`references upon which Amgen relies. I base this opinion on two key pharmacokinetic properties
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`of trastuzumab that were expressly described in the prior art. First, the prior art reported that
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`trastuzumab had dose-dependent, non-linear kinetics, which means that the half-life of the drug
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`varied with dose amount and dose interval. A skilled artisan at the time of the invention would
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`have known that reliably modeling a dosing regimen for a drug with non-linear kinetics would
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`require more data than one would need to model a dosing regimen for a drug with linear kinetics,
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`i.e., a half-life that remained constant regardless of the dose amount or interval. For example,
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`the prior art upon which Amgen relies reported many different half-lives for trastuzumab,
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`depending on the dose administered. The half-life reported in the Amgen prior art includes 1.7
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`days, 5.8 days, and 12 days in the Herceptin Label, 1.8, 8.3, and 9.1 days in Baselga ’96, and 2.9,
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`4.0, 9.2, and 11.0 days in Pegram ’98.
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`11.
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`The prior art disclosure that trastuzumab had non-linear pharmacokinetics would
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`have injected substantial uncertainty into modeling a dosing regimen for trastuzumab because the
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 8 of 45 PageID #: 25814
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`scope and extent of such non-linear effects could not be predicted from the limited data reported
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`in the prior art. Many aspects of the pharmacokinetics of trastuzumab were not well understood
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`at the time. I disagree with Amgen’s assertion that “long-established modeling tools were
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`available to confidently estimate Herceptin dosing” at higher levels and longer intervals. (See
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`Amgen Br. at 17). I also disagree with Amgen’s assertion that a skilled artisan would make
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`assumptions about trastuzumab based on general knowledge with respect to the
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`pharmacokinetics of other monoclonal antibodies.
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`12.
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`Second, the prior art reported that higher levels of shed antigen (HER2 receptors
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`that have shed from the surface of tumor cells) present in some patients appeared to correlate
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`with reduced serum trough concentration and therefore lower efficacy. The prior art reported
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`that 64% of patients had shed antigen present and that shed antigen had a direct effect on the
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`half-life of trastuzumab. This would have injected yet more uncertainty into modeling a dosing
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`regimen based on limited data from studies done with weekly dose regimens. Given the high
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`prevalence of shed antigen among the patient population and its documented ability to lower
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`trastuzumab’s half-life, a skilled artisan would not have had a reasonable expectation of success
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`with respect to the claimed three-week dosing regimen based on the data available in the prior
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`art. I disagree with Amgen’s assertion (Amgen Br. at 18) that a skilled artisan would not have
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`been concerned with shed antigen levels; on the contrary, the prior art taught that high levels of
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`shed antigen correlated with lower serum trough concentrations.
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`13.
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`Thus, while it is true that skilled artisans had methods and approaches to model
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`dosing regimens at the time of the claimed invention, there was simply not enough data on
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`trastuzumab reported in the prior art to reliably model a three-week dosing regimen. As such, a
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`skilled artisan would not have had a reasonable expectation of success in predicting that the
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 9 of 45 PageID #: 25815
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`claimed three-week dosing regimen would be safe and effective. Specifically, none of this prior
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`art would have suggested to a skilled artisan that three-week dosing as claimed in the asserted
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`claims of the dosing patents would reliably achieve and maintain therapeutically effective trough
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`concentrations.
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`14.
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`Amgen relies on statements by the named inventors about their approach to
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`pharmacokinetic modeling for trastuzumab. (Amgen Br. at 15.) But it is important to note the
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`inventors had access to more pharmacokinetic data than is contained in the prior art. More of the
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`right type of data, such as data from a washout study or robust Phase III data, can allow a skilled
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`artisan to more accurately simulate an alternative dosing regimen. It can also allow a skilled
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`artisan to observe certain characteristics of a drug’s pharmacokinetics, which can in turn inform
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`simulation techniques. In sum, access to informative types of pharmacokinetic data that were not
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`in the prior art would allow a skilled artisan to have confidence in certain simulation approaches
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`that otherwise would have been considered inaccurate.
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`IV.
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`Person of Ordinary Skill in the Art
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`15.
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`I understand that Amgen has defined a person of ordinary skill in the art as having
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`the following areas of substantive expertise:
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`[A POSA] would have knowledge and experience regarding at least oncology
`and/or in drug development. Such an individual would also have had familiarity
`with the treatment of cancer and experience in the design and/or implementation
`of clinical trials, as well as expertise in clinical pharmacology, including
`pharmacokinetics and experience in working in consultation with a
`pharmacokinetic specialist.
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`(Ex. 14, Amgen Second Suppl. ROG Responses, at 105.)
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`16.
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`I believe my background, knowledge, and experience gives me sufficient insight
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`as to the perspective of a skilled artisan. I have a Pharm.D. (clinical pharmacy degree) and a
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 10 of 45 PageID #: 25816
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`Ph.D. in Pharmaceutics and have worked on cross-disciplinary teams on drug development to
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`design and evaluate clinical regimens.
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`17.
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`For the purpose of this declaration, I have applied this definition of a skilled
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`artisan, and my opinions are offered from the perspective of a skilled artisan as that hypothetical
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`person would have understood matters on August 27, 1999.
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`V.
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`State of the Art
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`18.
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`Certain types of breast cancers are caused by overexpression of human epidermal
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`growth factor receptor 2 (HER2) or ErbB2. The humanized monoclonal antibodies claimed in
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`the dosing patents are large, complex molecules that bind to HER2 receptors on the surface of
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`breast cancer tumor cells. Although trastuzumab’s mechanisms of action are still being
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`researched today, it was understood in August 1999 that the binding of trastuzumab to HER2
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`receptors inhibits tumor cell proliferation and induces a process known as antibody-dependent
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`cellular cytotoxicity, during which trastuzumab flags HER2 overexpressing tumor cells for
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`destruction by the body’s immune system.
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`19.
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`At the time of the invention, the use of antibodies to treat cancer was quite new.
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`Prior to August 1999, the FDA had approved only one other monoclonal antibody for use in
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`treating cancer—Genentech’s rituximab product, which was approved for the treatment of non-
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`Hodgkin’s lymphoma in 1997. Trastuzumab was the first antibody approved to target solid
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`tumors and the first approved to treat breast cancer.
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`
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`Brief Description of the Principal Prior Art Relied Upon By Amgen
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`20.
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`I have below summarized certain prior art upon which Amgen has relied in
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`support of its assertion that the dosing patents are obvious, including the references cited in the
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`legal opinion provided to Amgen on May 1, 2019 and the Hellmann patent described in Amgen’s
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`opposition brief. (Amgen Br. at 15-16.) I have not undertaken to address all of the references
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 11 of 45 PageID #: 25817
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`cited by Amgen in its invalidity contentions but reserve the right to do so and to respond to any
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`expert opinions that Amgen may offer to support its opposition to Genentech’s request for a
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`temporary restraining order and preliminary injunction.
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`1.
`
`The Watanabe Abstract
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`21.
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`The Watanabe Abstract consists of two brief paragraphs reporting results of a
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`Phase I dose- escalation study of trastuzumab. (Amgen Ex. 3.) In the study, a total of 18
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`patients received a first trastuzumab dose of 1, 2, 4, or 8 mg/kg (6 patients, 3 patients, 3 patients, and 6
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`patients in each dose group, respectively) and then, after three weeks, received nine weekly doses.
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`(Id.) The Abstract reports that the trough level of each tested dose ranged from 9 µg/mL for the
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`1 mg/kg dose amount to 248 µg/mL for the 8 mg/kg dose amount. (Id.) The Watanabe Abstract
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`demonstrates that the effect of increased dose amount on trough levels is not linear, a
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`characteristic associated with dose-dependent kinetics. But the Abstract does not report any
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`other pharmacokinetic information, such as half-life. Based on the data collected, the authors
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`concluded that 2-4 mg/kg weekly doses of trastuzumab should be investigated in further clinical
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`trials. (Id.)
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`2.
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`Baselga ’96
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`22.
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`Baselga ’96 reports results of a Phase II clinical study designed to “evaluate[] the
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`efficacy and toxicity of weekly intravenous administration of rhuMAb HER2 in patients with
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`HER2- overexpressing metastatic breast cancer.” (Amgen Ex. 4 at AMGKAN01191049.)
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`Patients received a loading dose of 250 mg of trastuzumab followed by weekly doses of 100 mg.
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`(Id.) According to the authors, the weekly regimen was determined to be the “optimal dose and
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`schedule of rhuMAb HER2 … based on two prior phase I clinical trials ….” (Id. at
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`AMGKAN01191050 (emphasis added).) Baselga ’96 notes that trastuzumab has “documented
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`dose dependent pharmacokinetics” (id.) and reports, for the weekly regimen tested, a mean
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 12 of 45 PageID #: 25818
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`serum half-life of 8.3 +/- 5.0 days. (Id. at AMGKAN01191051). Baselga ’96 sought to achieve
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`trough concentrations of at least 10 µg/mL based on preclinical studies. (Id. at
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`AMGKAN01191050.) Baselga ’96 reported that over 90% of patients had trough serum
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`concentrations above the 10 µg/mL target, and that patients with trough concentrations below 10
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`µg/mL did not demonstrate a therapeutic response. (Id. at AMGKAN01191051,
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`AMGKAN01191053-54.)
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`3.
`
`Pegram ’98
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`23.
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`Pegram ’98 describes the results of a Phase II clinical study in which 39 patients
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`with metastatic breast cancer received trastuzumab in combination with the chemotherapeutic
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`agent cisplatin. (Amgen Ex. 5, at AMGKAN01193130.) Patients were treated with a loading
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`dose of 250 mg of trastuzumab followed by weekly doses of 100 mg for nine weeks. Patients
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`also received 75 mg/m2 doses of cisplatin about every four weeks. (Id. at AMGKAN01193130-
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`32.) Pegram ’98 provides only limited pharmacokinetic information on trastuzumab.
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`Specifically, Table 6 of Pegram ’98 reports a half-life of 11.0 ± 4.0 days for patients treated with
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`trastuzumab and cisplatin. (Id. at AMGKAN01193136, Table 6.) Pegram ’98 also includes
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`results from Baselga ’96, reporting that when administered alone, trastuzumab had a mean half-
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`life of 9.2 ± 5.3 days. Pegram ’98 further reports that mean maximum trough serum
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`concentrations reached 54 µg/mL when trastuzumab was administered without chemotherapy,
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`and 85 µg/mL when trastuzumab was administered with cisplatin. (Id.)
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`4.
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`Herceptin Label
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`24.
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`The Herceptin Label describes the initial FDA-approved indications and dosing
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`regimen for trastuzumab. (Ex. 40 at AMGKAN02731815.) Based on Phase III clinical trials,
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`the FDA approved a regimen of a loading dose of 4 mg/kg followed by weekly maintenance
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`doses of 2 mg/kg to treat HER2 positive metastatic breast cancer. (Id.) The Label contains
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 13 of 45 PageID #: 25819
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`limited pharmacokinetic data. For example, the Label states that trastuzumab exhibited dose-
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`dependent kinetics and reports that in dose-rising studies, 10 mg doses administered weekly had
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`an average half-life of 1.7 days and 500 mg doses administered weekly had an average half-life
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`of 12 days. (Ex. 40 at AMGKAN02731815.) No half-life is reported for doses between 10 mg
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`and 500 mg. (Id.) The Label also reports a mean half-life of 5.8 days (range of 1 to 32 days) for
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`regimens using a loading dose of 4 mg/kg followed by a weekly maintenance dose of 2 mg/kg.
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`(Id.)
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`5.
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`Hellmann Patent
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`25.
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`The Hellmann patent is directed to methods of treating cancer by administering
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`anti-ErbB2 antibodies, including trastuzumab, with chemotherapeutic agents other than an
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`anthracycline derivative. (Amgen Ex. 36, at 4:7-22.) The patent describes a clinical study in
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`which trastuzumab was administered weekly with chemotherapy. (Id. at 30:61-31:32.) The
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`Hellmann patent does not contain any discussion of extended dosing intervals for anti-Erb2
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`antibodies such as trastuzumab. It also lacks pharmacokinetic data of any kind. The ranges of
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`possible trastuzumab doses that it volunteers is expansive: “about 1 µ/kg to 15 mg/kg (e.g. 0.1-
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`20 mg/kg) of antibody is an initial candidate dosage for administration to the patient.” (Id. at
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`28:24-28.) The lower end of the range differs from the upper end by many orders of magnitude;
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`it is 15,000 times larger. (See id.) It also states that “a typical daily dosage might range from
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`about 1 µg/kg to 100 mg/kg or more.” Id. at 28:28-30.
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`
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`Pharmacokinetic Factors A Skilled Artisan Would Consider In Designing
`Dosing Regimens For Trastuzumab In View of the Prior Art
`
`26.
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`A skilled person would consider many factors, including pharmacokinetics, when
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`designing an alternative dosing regimen for trastuzumab.
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`Case 1:18-cv-00924-CFC Document 329 Filed 07/25/19 Page 14 of 45 PageID #: 25820
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`1.
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`A Skilled Artisan Would Seek to Maintain Therapeutically Effective
`Levels of Trastuzumab
`
`27.
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`For most drugs that are administered with repeat dosing—including
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`trastuzumab—the goal is to achieve plasma concentration levels within a therapeutic window,
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`i.e., above a certain minimum or “trough” level where efficacy is maintained and below a ceiling
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`or “peak” where unacceptable toxicity may occur. For a drug that has already been shown to be
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`safe and effective at a particular dose amount and dose interval, a pharmacokineticist would
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`generally seek to ensure that any alternative dose amount and interval would yield serum
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`concentration data within the range previously known to be safe and clinically effective.
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`Without an adequate understanding of the pharmacokinetics of a drug, it is impossible to make
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`such a determination.
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`28.
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`Serum drug concentration reaches a “peak” or maximum concentration shortly
`
`after administration. As the drug is eliminated from the body over time, it reaches a “trough” or
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`minimum concentration just prior to the next dose. Dose amount and dose interval affect both
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`peak and trough levels. For example, increasing the dose and extending the dose interval can
`
`result in significantly higher peak levels and significantly lower trough levels as compared to the
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`same overall amount of drug given in lower doses more frequently. In fact, administering lower
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`doses more frequently is a common method to minimize the variation between peak and trough
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`levels.
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`29.
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`At the priority date of the dosing patents in August 1999, a skilled artisan
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`considering an alternative dosing regimen for trastuzumab would know that efficacy was
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`associated with maintaining adequate steady-state trough serum levels, i.e., maintaining a
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`“therapeutic trough concentration.” A skilled artisan would thus want to ensure that any
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`alternative dosing regimen maintained therapeutic trough concentrations throughout the course
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`of treatment. A dosing regimen with a potential to result in concentrations below therapeutic
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`trough levels would not be considered acceptable as it would risk leaving patients without
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`therapeutic benefit.
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`2.
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`A Skilled Artisan Would Account for the Teaching that Trastuzumab
`Had Non-Linear Kinetics
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`30.
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`To develop a dose regimen for any drug, including trastuzumab, a person of
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`ordinary skill in the art would need to understand the pharmacokinetics of the drug at issue.
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`Pharmacokinetics is the study of the absorption, distribution, metabolism, and elimination of
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`drugs in the body over time, i.e., where the drug goes and the rates at which it gets there. The
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`kinetics of a drug affect its concentration at the site of drug action, the potential for toxic
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`response, the onset and duration of effects, the dosing amounts and frequency of dosing, and the
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`rates of metabolism (if any) and elimination.
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`31.
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`Of particular relevance here, the study of pharmacokinetics is useful to
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`understanding of the relationship between the concentration of drug in plasma and therapeutic
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`effects. If the relationship between the blood plasma concentration and clinical safety and
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`efficacy is well-understood, then it becomes possible to draw inferences about safety and
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`efficacy based on anticipated plasma concentrations.
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`32.
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`In the case of drugs with linear pharmacokinetics, plasma concentration levels
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`change proportionally to dose amount and dose interval, such that the period of time for the drug
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`serum concentration to decrease by half—i.e., the drug’s half-life—remains constant over time,
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`regardless of the concentration of the drug in the serum (or plasma). Such drugs are said to have
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`“dose-independent” pharmacokinetics.
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`33.
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`A drug’s half-life can be determined by the rate at which the drug is eliminated
`
`from the plasma. For drugs with linear kinetics, a constant fraction of drug in the body is
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`eliminated per unit of time. The drug concentration halves predictably according to fixed time
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`intervals. Thus, for drugs with linear pharmacokinetics, there is a linear relationship between
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`rate of elimination and concentration. More specifically, for a drug with linear
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`pharmacokinetics, the rate at which the drug is eliminated from the body will always change in
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`proportion to the concentration of drug in the plasma such that the elimination constant will
`
`remain a constant value. Half-life is thus constant and independent of concentration.
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`34.
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`In contrast to drugs with linear, dose-independent pharmacokinetics, dose-
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`dependent drugs exhibit non-linear pharmacokinetics, meaning that plasma concentrations do not
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`change proportionally with dose or interval. (Ex. 231, Rowland & Tozer at 394-95.) Half-life
`
`can change with changes in concentration. (Ex. 232, Gabrielsson at 123.)
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`35.
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`The graph above shows differences in kinetics that can exist between dose-
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`independent and dose-dependent drugs.1 Dose-independent drugs exhibit linear kinetics,
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`meaning that the elimination rate (and thus half-life) remains constant regardless of serum
`
`concentration, as illustrated by the straight dotted lines in the graph above. In contrast, for dose-
`
`dependent drugs, the elimination rate and half-life vary depending upon concentration of drug in
`
`plasma. (Ex. 231, Rowland & Tozer at 394-95.) For example, as drug concentration decreases
`
`over time, half-life can decrease, which means that elimination increases. This is illustrated by
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`the solid lines with slopes that change depending on the dose amount—high, medium, and low,
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`as shown in the graph above—and/or the change in elimination (or half-life) as drug
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`concentration decreases over time. One pharmacokinetics textbook describes that drugs with
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`“dose dependent . . . kinetic behavior[] defy easy quantitative description and prediction.” (Id. at
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`395). As will be discussed more fully below, the prior art taught that trastuzumab had dose-
`
`dependent, non-linear kinetics.
`
`36.
`
`In August 1999, a skilled artisan would know that for a dose-independent drug,
`
`the half-life and elimination rate will remain constant over any dose interval, whether the dose
`
`interval is 7, 14, or 21 days. A skilled artisan would also know that for a dose-dependent drug,
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`the half-life will not remain constant across different doses and dosing intervals, or even within a
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`single dose interval, but can vary as drug concentration changes. (Ex. 232, Gabrielsson at 123.)
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`However, the actual rates of elimination for a dose-dependent drug would be unknown and
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`unpredictable without sufficient data, such as a “washout study” where serum concentration data
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`is collected over a period of several half-lives after a single administration of the drug or by
`
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`1 The diagram is for explanation and is not specific to a parti