Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 1 of 27 PageID #: 10635
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`C.A. No. 18-924-CFC
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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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`Plaintiffs and Counterclaim Defendants,
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`AMGEN INC.,
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`Defendant and Counterclaim Plaintiff.
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`GENENTECH, INC. and CITY OF HOPE, )
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`SAMSUNG BIOEPIS CO., LTD,
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`Defendant and Counterclaim Plaintiff.
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`C.A. No. 18-1363-CFC
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`DECLARATION OF MICHAEL F. PRESS, M.D., PH.D.
`IN SUPPORT OF DEFENDANTS’
`CLAIM CONSTRUCTION BRIEF
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`C.A. No. 18-924-CFC
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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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`)
`Plaintiffs and Counterclaim Defendants,
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`v.
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`AMGEN INC.,
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`Defendant and Counterclaim Plaintiff.
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`GENENTECH, INC. and CITY OF HOPE, )
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`Plaintiffs and Counterclaim Defendants,
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`v.
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`SAMSUNG BIOEPIS CO., LTD,
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`Defendant and Counterclaim Plaintiff.
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`C.A. No. 18-1363-CFC
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`DECLARATION OF MICHAEL F. PRESS, M.D., PH.D.
`IN SUPPORT OF DEFENDANTS’
`CLAIM CONSTRUCTION BRIEF
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 2 of 27 PageID #: 10636
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`Table of Contents
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`Page
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`Background and Qualifications .......................................................................................... 1
`I.
`Nature of Assignment and Materials Considered .............................................................. 3
`II.
`Person of Ordinary Skill in the Art .................................................................................... 4
`III.
`Legal Standards .................................................................................................................. 5
`IV.
`Technical Background ....................................................................................................... 7
`V.
`Claim Term of The ’834 Patent ....................................................................................... 12
`VI.
`VII. Claim Term of The ’066 Patent ....................................................................................... 18
`VIII. Summary of the Opinion .................................................................................................. 22
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`-i-
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 3 of 27 PageID #: 10637
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`I, Dr. Michael F. Press, declare as follows:
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`I.
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`Background and Qualifications
`1.
`I have more than 40 years of experience in studying molecular genetic
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`alterations in breast and gynecologic cancers. I received my Ph.D. in 1975 and M.D.
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`in 1977 from the University of Chicago. I completed a residency at the University
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`of Chicago in 1981. I am board certified in Anatomical Pathology.
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`2.
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`I was a member of the University of Chicago faculty for seven years
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`before joining the faculty of the University of Southern California (“USC”) in 1988.
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`I am currently a Professor in the Department of Pathology of the USC. I am also the
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`director for the Breast Cancer International Research Group, now known as
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`Translational Research in Oncology (“TRIO”), Central Laboratory. I was formerly
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`the Co-Leader of the USC Breast Cancer Program (1993-2003) and the Women’s
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`Cancers Program (2003-2013) at USC Norris Comprehensive Cancer Center. I now
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`hold the Harold E. Lee Chair in Cancer Research in the USC Norris Comprehensive
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`Cancer Center.
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`3.
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`I am very familiar with the various pathological tests for determining
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`HER2 protein expression and HER2 gene amplification. From 1994 through 1997,
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`as the study principal investigator I helped to develop and characterize one of the
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`1
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 4 of 27 PageID #: 10638
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`earliest FDA-approved fluorescence in situ hybridization (“FISH”) tests, the Oncor
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`INFORM HER-2/neu gene detection system.
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`4.
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`I am also familiar with the HER2-status assays used for selecting
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`patients for trastuzumab treatment. From 1999 to 2000, I participated in a
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`retrospective study of evaluating clinical outcomes according to HER2 detection by
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`FISH using archived tissues from three different prospective clinical trials (H0648,
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`H0649 and H0650 trials) of trastuzumab in metastatic breast cancer patients. I also
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`participated in the Breast Cancer International Research Group (BCIRG) 006 Trial
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`(NCT00021255): “Multicenter phase III randomized trial comparing doxorubicin
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`and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and
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`cyclophosphamide followed by docetaxel and trastuzumab (Herceptin) (ACTH)
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`and with docetaxel, carboplatin and trastuzumab (TCH) in the adjuvant treatment of
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`node positive and high risk node negative patients with operable breast cancer
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`containing the HER2 alteration.”
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`5.
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`Since 1998, as the head of the USC Breast Cancer Analysis Laboratory,
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`I have routinely evaluated the HER2-status of breast cancer patient tissue samples
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`to determine the patients’ eligibility for trastuzumab treatment.
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`6.
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` Additional details of my background are set forth in my curriculum
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`vitae, attached as Exhibit A to this Declaration, which provides a more complete
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`
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`2
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 5 of 27 PageID #: 10639
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`description of my educational background and work experience. I am being
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`compensated for the time I have spent on this matter at the rate of $400 per hour.
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`My compensation does not depend in any way upon the outcome of this proceeding.
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`I hold no interest in any party to this action.
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`II. Nature of Assignment and Materials Considered
`7.
`I have been asked by counsel for Amgen to opine regarding the
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`construction of certain claim terms in U.S. Patent No. 7,993,834 (“the ’834 patent”)
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`and U.S. Patent No. 8,076,066 (“the ’066 patent”) (collectively, the “Gene Detection
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`Patents”).1 Specifically, I have been asked to provide my understanding of how a
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`Person of Ordinary Skill in the Art (“POSA”) would have understood the following
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`claim terms and phrases appearing in the claims of the patents listed above:
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` “A method for increasing likelihood of effectiveness of breast cancer
`treatment with humanized anti-ErbB2 antibody huMAb4D5-8”
`JA00000132(’834 patent, claims 2, 5)
`
`
`1 I understand that Genentech is asserting specific dependent claims against Amgen:
`claims 2 and 5 of the ʼ834 patent, and claims 2 and 6 of the ʼ066 Patent. I understand
`that these dependent claims incorporate the terms of the parent independent claims
`that they refer back to, which is where the disputed claim terms are first recited.
`Accordingly, I reference those independent claims in this declaration and generally
`refer to the group of claims as the “asserted claims.” An appendix of the asserted
`claims, and the parent claims they reference, is provided at the end of this
`declaration.
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`3
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 6 of 27 PageID #: 10640
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` “wherein the patient’s cancer cells express HER2 at a 0 or 1+ level by
`immunohistochemistry” JA00000150-51(’066 patent, claims 2, 6).
`In forming my opinions, I have relied on my knowledge, education,
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`8.
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`skills, experience, and training, in addition to the documents and materials cited in
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`this declaration. Counsel for Amgen have provided me with certain legal standards
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`that are germane to my opinions. Those legal standards are set forth in this
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`declaration, and I have applied them in considering the issues and forming the
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`opinions I express in this declaration.
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`9.
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`I have reviewed the Gene Detection Patents and the references and
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`materials cited in the text of my declaration. I have also reviewed the prosecution
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`histories of the Gene Detection Patents. I have also reviewed the portion of
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`Genentech Inc.’s Opening Claim Construction Brief regarding the Gene Detection
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`Patents.
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`III. Person of Ordinary Skill in the Art
`10.
`I understand that claim terms are interpreted from the perspective of a
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`POSA at the time of the invention. I understand that a POSA is a hypothetical person
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`who is presumed to have known the relevant art at the time of the invention. I have
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`been asked to assume that the relevant time of invention is May 19, 2000, which is
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`the filing date of the earliest application listed on the first page of the Gene Detection
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`Patents (provisional application No. 60/205,754). In analyzing the interpretation of
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`4
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 7 of 27 PageID #: 10641
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`the claims and teachings of the written record, and in preparing the opinions set forth
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`in this declaration, I have applied the POSA perspective as of the time of the
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`invention.
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`11.
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` I have been informed that the following factors may be considered in
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`determining the level of ordinary skill: (A) type of problems encountered in the art;
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`(B) prior art solutions to those problems; (C) rapidity with which innovations are
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`made; (D) sophistication of the technology; and (E) educational level of active
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`workers in the field.
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`12.
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`In my opinion, a POSA for the Gene Detection Patents would have had
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`a medical degree and a minimum of 2-3 years of experience in pathology or
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`oncology relating to breast cancer treatment as of May 19, 2000. Such an individual
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`would also have familiarity with the pathological tests used for selecting HER2-
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`positive breast cancer patients.
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`IV. Legal Standards
`13.
`I am not a lawyer and do not purport to offer legal opinions. In forming
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`my opinions, however, I have been asked to apply certain legal standards that were
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`provided to me by counsel for Amgen. These standards are provided below.
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`A. Claim Construction
`14.
`I am informed that claim construction is the process of interpreting
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`certain terms in the patent claims. Patent claims define the scope of the patented
`5
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`invention, and they must be definite in that they must particularly point out and
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`distinctly claim the invention.
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`15.
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`I am informed that words in a claim are generally given their ordinary
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`and customary meaning to a POSA, in view of the context of the claim language in
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`which the term appears, other claims, the specification and figures of the patent, and
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`the prosecution history. I understand that these sources are collectively called the
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`“intrinsic” evidence and that claim terms must be interpreted in light of the
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`“intrinsic” record because a POSA would read the term in the context of that
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`evidence.
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`16.
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`I am also informed that a patentee may define a term in the specification
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`and act as a lexicographer. I am informed by counsel that to act as a lexicographer,
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`the patentee must clearly set forth a definition of the term that is different from its
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`plain and ordinary meaning, doing so in a manner that expresses a clear intent to
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`redefine the term.
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`17.
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`I am informed by counsel that the prosecution history, as part of the
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`“intrinsic” record as noted above, can be informative for understanding the meaning
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`of a claim term. I am informed that if the patentee makes clear and unambiguous
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`disavowals of claim scope during prosecution, that a claim term should be
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`interpreted to exclude the disclaimed or disavowed scope.
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`6
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 9 of 27 PageID #: 10643
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`I am informed by counsel that “extrinsic evidence” refers to evidence
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`18.
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`outside of the intrinsic evidence, such as expert testimony, scientific articles not cited
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`in the patent or prosecution history, and dictionary definitions. I am informed that
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`extrinsic evidence can also be considered and may be useful in understanding the
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`meaning of claim terms to one of ordinary skill in the art at the time of the invention,
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`but that extrinsic evidence is generally considered less significant than intrinsic
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`evidence.
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`B.
`19.
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`Indefiniteness
`I have been informed by counsel and I understand that a patent claim is
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`invalid for indefiniteness if the claim, read in light of the specification delineating
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`the patent, and the prosecution history, fails to inform, with reasonable certainty,
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`those skilled in the art about the scope of the invention.
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`V. Technical Background
`20.
`I provide the following general overview and explanations on the state
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`of the art as of May 2000 to provide context and background for the claim
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`construction analysis. I understand that May 2000 is the relevant date for evaluating
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`the meaning of the terms of the Gene Detection Patents claims. I have not conducted
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`a prior art analysis and am not providing any opinion as to invalidity of the patents
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`over prior art at this time.
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`
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`7
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 10 of 27 PageID #:
`10644
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`21. By May 2000, it was well known in the art that the HER2 gene (also
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`known as the ERBB2 gene) encoded a HER2 protein, which is a receptor found on
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`the surface of cells. A normal cell has 2 copies of the HER2 gene. Cancer cells of
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`HER2 positive patients have more than 4 copies of this gene. This is referred to as
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`amplification of the HER2 gene. It was understood that having extra copies of the
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`HER2 gene results in overexpression of HER2 protein, i.e., a higher than normal
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`level of the HER2 protein expressed on the surface of the cell. See JA00001519;
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`Ex. 6 (Pauletti 1996) at 662; Ex. 7 (Pegram 1998) at 65. An illustration of the extra
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`copies of the HER2 gene and resulting HER2 protein overexpression is provided
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`below.3 Overexpression of HER2 protein is shown in the HER2+ cell as many green-
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`colored HER2 receptors extending through the cell membrane. HER2 gene
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`amplification is shown in the HER2+ cell on the right by the multiple HER2 genes
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`in the cell nucleus.
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`2 All exhibits (“Ex. #”) cited herein are Exhibits to the Declaration of Michelle S.
`Rhyu, as described in the Exhibit List at the end of this declaration, unless
`otherwise noted.
`3 Adapted from http://www.whathealth.com/breastcancer/her2receptor.html.
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 11 of 27 PageID #:
`10645
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`22. Amplification of the HER2 gene and overexpression of the HER2
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`protein occur in approximately 20% of human breast cancers. This genetic alteration
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`was known to be associated with a poor clinical prognosis in women with breast
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`cancers as measured by lower overall survival and disease free survival. Ex. 6
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`(Pauletti 1996) at 63; Ex. 13 (Press 1997) at 2894.
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`23. By May 2000, there was a variety of methods available to determine
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`the HER2 status of breast cancer tissues. In the clinical setting, the routine choices
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`for HER2 analysis were
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`two
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`types of well-known pathology
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`tests: (i)
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`immunohistochemistry
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`(“IHC”)
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`tests, which measured protein
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`levels
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`(overexpression of HER2 protein), and (ii) fluorescence in-situ hybridization
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`(“FISH”) tests, which measured the number DNA copies of the gene (amplification
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`of the HER2 gene). Ex. 8 (Jacobs 1999) at 1974-75. By May 2000, the U.S. Food
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`9
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`and Drug Administration (“FDA”) had approved three kits for testing HER2 status
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`— one IHC and two FISH. Ex. 14 (Nelson 2000) at 292.
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`24. HER2 IHC assays used anti-HER2 antibodies to visualize HER2
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`proteins in tissue sections, allowing evaluation of HER2 protein expression in tissue
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`samples from patients. In general, pathologists evaluated IHC assays using a 0, 1+,
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`2+, and 3+ scoring system, with 0 for no apparent protein detection and 3+ for a
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`strong signal indicating presence of high levels of protein expression. In May 2000,
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`a score of 0 to 1+, was considered HER2-negative. If the score was 2+, it was
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`considered “borderline” or “equivocal.” A score of 3+ was considered HER2-
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`positive. Ex. 1 (Herceptin 1998 Label) at 1.
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`25.
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`In contrast to IHC assays, which detected protein expression, HER2
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`FISH assays were used to visualize the HER2 gene copies within a cell. Typically,
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`FISH assays determine the ratio of the copy numbers of HER2 gene on chromosome
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`17 to the centromere on the same chromosome, chromosome 17. FISH+ tissue
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`samples have a HER2 gene copy number greater than 4.0 per tumor cell or a HER2-
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`to-chromsome 17 centromere ratio greater than or equal to 2.0, and are, therefore,
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`considered to have HER2 gene amplification. FISH- tissue samples have a normal
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`number of HER2 gene copies (a HER2 gene copy number less than 4.0 per tumor
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`10
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 13 of 27 PageID #:
`10647
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`cell or a HER2-to-chromsome 17 centromere ratio less than 2.0). Ex. 13 (Press
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`1997) at 2895.
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`26. Trastuzumab (Herceptin®) is an antibody that binds to the HER2 protein
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`and inhibits the growth of breast cancer cells that overexpress HER2. Ex. 9 (Baselga
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`1999) at 78. In September 1998, the FDA approved trastuzumab for the treatment
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`of patients with metastatic breast cancer whose tumors overexpressed the HER2
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`protein. Ex. 10 (Check 1999) at 1.
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`27. On the same day of trastuzumab approval, the FDA approved the
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`HercepTest (an IHC test) as the companion test for selecting patients who would
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`receive the trastuzumab treatment. Ex. 10 (Check 1999) at 1. Herceptin was
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`indicated as a treatment for patients who had a score of 2+ or 3+ in an IHC assay.
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`Ex. 1 (Herceptin 1998 Label) at 1. Thus, patients with IHC scores of 0 or 1+ did not
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`qualify for trastuzumab treatment.
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`28.
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`IHC results were known to be subjective and highly variable depending
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`on the types of anti-HER2 antibodies used (Ex. 12 (Press 1994) at 2771 (“The ability
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`of these antibodies to detect overexpression was extremely variable ….”)) and due
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`to anomalies caused by the way tissue samples were processed. JA00000122(2:33-
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`37 (“IHC of formaldehyde-fixed, paraffin embedded tissue samples only
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`demonstrated 50%-80% sensitivity ….”)). As early as 1989, IHC tests on formalin-
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`11
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 14 of 27 PageID #:
`10648
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`fixed paraffin embedded tissues were known to yield false negative results, that is,
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`tumors that overexpressed HER2 protein nevertheless received an IHC score of 0 or
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`1+. Id.(2:36-38); Ex. 7 (Pegram 1998) at 73-74; Ex. 11 (Slamon 1989) at 710; Ex.
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`8 (Jacobs 1999) at 1977. These false negatives excluded patients from receiving
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`treatment who might have benefited from it.
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`29. While there generally is a high level of correlation between FISH and
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`IHC test results in the evaluation of HER-2 status, FISH tests were known to be more
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`reliable than IHC and were able to identify patients who had false negative IHC
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`results. Ex. 7 (Pegram 1998) at 73-74; Ex. 8 (Jacobs 1999) at 1977. This is because
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`FISH tests circumvented the shortcomings of the IHC tests by targeting HER2 DNA
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`(detecting gene amplification) instead of HER2 protein. Ex. 7 (Pegram 1998) at 73-
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`74.
`
`VI. Claim Term of The ’834 Patent
`A.
`“A method for increasing likelihood of effectiveness of breast
`cancer
`treatment with humanized anti-ErbB2 antibody
`huMAb4D5-8” (’834 claims 2, 5)
`In my opinion, a POSA would not be able to determine with reasonable
`
`30.
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`certainty the scope of this preamble language. Thus, the claims are indefinite.
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`31. Each claim in the ’834 patent depends on claim 1 and therefore includes
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`the preamble: “a method for increasing the likelihood of effectiveness of breast
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`cancer treatment with humanized anti-erbB2 antibody huMAb4D5-8.” This
`12
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 15 of 27 PageID #:
`10649
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`language, “a method for increasing the likelihood of effectiveness . . .” calls for a
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`comparison between the claimed method and another (undefined) method to
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`determine whether the claimed method increases the likelihood of effectiveness of
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`the treatment. No language in the claims however provides a comparator or baseline
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`as a reference point for determining whether the claimed method in fact increases
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`the likelihood of effectiveness of the treatment.
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`32. The specification mentions “a method for increasing likelihood of
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`effectiveness” twice, but those portions of the specification say nothing about what
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`baseline measure of effectiveness of treatment should be used as a reference point.
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`See, e.g., JA00000122-23(2:65-67; 3:7-9).
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`33.
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`I have reviewed the examples in the specification of the ’834 patent and
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`they too fail to identify what the baseline is for comparing the likelihood of
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`effectiveness. For example, Example 1 discloses the existence of the claimed patient
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`population. These patients have been found to have an IHC score of 0 or +l and
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`show HER2 gene amplification. But the example does not disclose the “likelihood
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`of effectiveness” of trastuzumab in this population or any other population by
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`comparison. In particular, Example 1 compares the results of the CTA test (a type
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`of IHC test used in pivotal trastuzumab clinical trials) to HER2 gene amplification
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`measured by PathVysion FISH assay. JA00000131(19:11-14.) Example 1 teaches
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`13
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 16 of 27 PageID #:
`10650
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`that among the 206 HER2-gene-amplified (FISH+) patients4, 7 patients had an IHC
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`0 score, and 2 patients had an IHC 1+ score. Id.(Table 1). However, none of these
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`9 patients received trastuzumab treatment, thus there is no disclosure in the
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`specification about whether trastuzumab was effective for these patients.
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`JA00000131(19:5-6 (“Subjects were eligible [to receive trastuzumab treatment] if
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`either [IHC] assay was scored at 2+ or 3+”)).
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`34. As such, the specification is deficient in providing guidance on how to
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`interpret the preamble in at least two ways: first, it does not identify what the baseline
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`is for comparing the likelihood of effectiveness; and second, by failing to include
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`any efficacy data, a POSA would not have been able to ascertain the likelihood of
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`effectiveness of treating the FISH+, IHC 0 or 1+ patients recited in the ’834 patent
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`claims with trastuzumab. Consequently, a POSA would not have been able to
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`determine whether there is an “increase[ed] likelihood of effectiveness” in the
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`claimed method of treating patients with FISH+, IHC 0 or 1+ breast cancers
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`compared to any identifiable baseline.
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`35. Example 2 focuses on comparing the response rates in FISH+ patients
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`with response rates in patients with IHC 2+ and 3+ scores, and thus provides no
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`4 The 206 HER2 gene amplified (FISH+) patients included 7 IHC 0 patients, 2 IHC
`1+ patients, 21 IHC 2+ patients, and 176 IHC 1+ patients.
`14
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 17 of 27 PageID #:
`10651
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`guidance regarding the claimed IHC 0 or 1+ patients. Specifically, Example 2
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`teaches that IHC 3+ patients had an equal or better response to trastuzumab than
`
`FISH+ patients in terms of patient response rates (see JA00000132(Table 7)), time
`
`to progression (see id.(Table 8)), and survival (see id.(Table 9)). However, when the
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`IHC 2+ patients were pooled with IHC 3+ patients, “FISH+ selection has about 1/3
`
`(30%) greater response rate than 2+/3+ IHC-selection.” JA00000132(22:15-16).
`
`36. A POSA reading Example 2 would have understood that the greater
`
`response rate observed in FISH+ patients relative to the pooled IHC 2+ and 3+
`
`patients was due to inclusion of false positive IHC patients, often in the IHC 2+
`
`group.5 In other words, a POSA would have known that the IHC2+ patient group
`
`included patients treated with trastuzumab but would not respond to the treatment
`
`since they in fact do not have HER2 gene amplification or HER2 protein
`
`overexpression. Using FISH tests for patient selection thus not including the false
`
`positive IHC patients, the response rate in FISH+ patients was expectedly higher
`
`than the pooled IHC 2+ and 3+ patients.
`
`
`5 Before May 2000, the false positive results associated with IHC tests were well
`known in the art. Ex. 14 (Nelson 2000) at 294; Ex. 10 (Check 1999) at 42.
`
`
`
`
`15
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 18 of 27 PageID #:
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`
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`37. Given that the higher response rate in FISH+ patients relative to the
`
`pooled IHC 2+ and 3+ patients were caused by inclusion of false positive IHC
`
`patients, that higher response rate cannot be translated to the claimed FISH+ and
`
`IHC 0/1+ patients, because IHC 0 or 1+ score was, by definition, a negative result.
`
`That is, the advantage of using FISH tests and excluding false positive IHC patients
`
`is not applicable to the claimed patient population. The specification does not
`
`explain why the clinical data in the FISH+, IHC 2+ or 3+ patients would be
`
`applicable to the claimed patient population.
`
`38. As such, Example 2 does not provide any guidance on how to determine
`
`an “increase[ed] likelihood of effectiveness” in the claimed patient population. A
`
`POSA therefore is left with no point of comparison to determine whether or not there
`
`has been an “increase[ed] likelihood of effectiveness” as required by the preamble.
`
`39.
`
`In addition, the specification fails to provide guidance to a POSA how
`
`to measure “likelihood of effectiveness.” According to the specification, “efficacy
`
`can, for example, be measured by assessing the time for disease progression (TTP),
`
`survival, tumor size, or determining the response rates (RR) ….” JA00000125(8:24-
`
`27). Such definition of “effectiveness” encompasses
`
`too many possible
`
`measurements to delineate clearly the scope of “increasing likelihood of
`
`effectiveness.”
`
`
`
`16
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 19 of 27 PageID #:
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`
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`40. Because nothing in the claim language or the specification sheds light
`
`on what to use as a baseline for measuring “increasing likelihood of effectiveness,”
`
`a POSA would not be able to determine, with reasonable certainty, an objective
`
`boundary for the preamble in claim 1 and thus claims 2 and 5 of the ’834 patent.
`
`These claims are therefore indefinite.
`
`41.
`
`I understand that, according to Genentech, the preamble should be
`
`construed as “[a] method of treatment of patients who have a greater likelihood of
`
`responding to treatment by administering humanized anti-ErbB2 antibody
`
`huMAb4D5-8.” I disagree. In addition to being a complete rewrite of the claim
`
`language, this construction also contains a term of degree — “a greater likelihood of
`
`responding to treatment” but fails to provide a comparator. Is it a comparison
`
`between the patients with HER2 gene amplification and those without? Or is it a
`
`comparison between patients with HER2 gene amplification and those with HER2
`
`protein overexpression? Neither the specification nor the prosecution history resolve
`
`the ambiguity. A POSA thus would not be able to determine, with reasonable
`
`certainty, an objective boundary for the preamble even if Genentech’s proposed
`
`construction is adopted.
`
`
`
`17
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`
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 20 of 27 PageID #:
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`
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`VII. Claim Term of The ’066 Patent
`A.
`“wherein the patient’s cancer cells express HER2 at a 0 or 1+ level
`by immunohistochemistry” (’066 claims 2, 6)
`It is my opinion that this term in claims 2 and 6 requires that an IHC
`
`42.
`
`test must have been performed on the patient’s cancer cells, resulting in a score of 0
`
`or 1+.
`
`43.
`
`It is my understanding that Genentech proposed a construction of
`
`“wherein the patient’s cancer cells express HER2 at a 0 or 1+ level by
`
`immunohistochemistry” as an inherent property of certain patients’ cells, such that
`
`the wherein clause would not require the IHC test to have been performed. In my
`
`opinion, this proposed construction is problematic for at least the following reasons.
`
`44. First, a POSA reading the wherein clause would have understood that
`
`IHC test needs to be performed because he would not be able to determine whether
`
`a patient has “an antigen level corresponding to a 0 or 1+ score for HER2 by
`
`immunohistochemistry” without actually performing the IHC test and obtaining the
`
`0 or 1+ score.
`
`45. Although HER2 protein level can be measured using another assay
`
`called Western blot, this assay requires frozen tissue, not formalin-fixed, paraffin-
`
`embedded clinical samples, and its results are not directly correlated with an IHC
`
`test score on formalin-fixed, paraffin-embedded tissues. This is because Western blot
`
`
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`18
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`
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 21 of 27 PageID #:
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`
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`is vulnerable to significant misinterpretation of data resulting from dilution of HER2
`
`proteins from malignant cells by those from normal cells. This is a particular
`
`problem in human breast cancer where non-malignant cells may constitute 50% or
`
`more of the tissue. Ex. 6 (Pauletti 1996) at 63; see also JA00000140(1:33-44
`
`(“methods that require disaggregation of the tissue, such as ... Western blot analysis,
`
`are rendered less accurate by dilution of the malignant cells by the normal or
`
`otherwise non-malignant cells that are present in the same tissue…. This issue is
`
`particularly problematic in tissue types known to be heterogeneous, such as in
`
`human breast carcinoma, where a significant percentage of the cells present in any
`
`area may be non-malignant.”)). By contrast, by visualizing cellular proteins in situ,
`
`IHC tests avoid the issue associated with Western blot.
`
`46. Second, the specification and Genentech’s statements made during
`
`prosecution contradict its current position that “express HER2 at a 0 or 1 + level by
`
`any immunohistochemistry test” is an inherent property of certain patients’ cells.
`
`The specification discusses the fact that IHC tests can have false negative results.
`
`That is, the patient’s tissue actually overexpresses HER2 protein, but receives an
`
`IHC score of 0 or 1+ due to the limitations of the IHC test. In that scenario, the IHC
`
`0 or 1+ score merely reflects an erroneous test result likely due to improper tissue
`
`handling, rather than a true condition or inherent property of the patient’s tissue.
`
`
`
`19
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`
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 22 of 27 PageID #:
`10656
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`
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`See JA00000140(2:30-35 (“IHC of formaldehyde-fixed, paraffin embedded tissue
`
`samples only demonstrated 50%-80% sensitivity, relative to frozen IHC samples
`
`(Press, Cancer Research 54:2771 (1994)).”)). Because IHC assays can lead to false
`
`negative results, patients who might benefit from the treatment are excluded from
`
`treatment. See JA00000140(2:33-35).
`
`47. During prosecution, Genentech also stated that the 0 or l+ IHC scores
`
`in FISH+ samples represent false negative results in the “invention claimed.” See,
`
`e.g., JA00002149 (“The invention claimed in the present application is based, at least
`
`in part, on the unexpected finding that part (about 4%) of the tumor samples tested
`
`0 or +l by immunohistochemistroy [sic] (IHC) show HER2 gene amplification when
`
`using FISH. This indicates that IHC gives about 4% false negative result.”)
`
`(emphasis added).
`
`48. By contrast, Amgen’s interpretation is supported by the ’066 patent
`
`specification as the specification repeatedly refers to a 0 or 1+ level as a score or
`
`result of an IHC test that was performed. See, e.g., JA00000141(3:22-27); see also
`
`JA00000150(21:65-67 (“FISH [status] also identifies patients who, because of 0 or
`
`1+ status as determined by IHC, would otherwise be excluded from treatment.”)
`
`(emphasis added)); see also JA00000148-50(18:20-24; 19:42-46; 21:65-67).
`
`
`
`20
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`
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`Case 1:18-cv-01363-CFC Document 84 Filed 03/22/19 Page 23 of 27 PageID #:
`10657
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`
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`Nowhere in the specification is a 0 or 1+ immunohistochemistry level identified as
`
`an inherent property of a patient’s cells.
`
`49. By May 2000, in the clinical setting, almost all patient-breast-cancer
`
`tissue samples for HER2 testing were formaldehyde-fixed, paraffin embedded tissue
`
`samples. The ’066 patent specification recognizes that, in such samples, the IHC
`
`tests only “demonstrated 50%-80% sensitivity.” See JA00000140(2:30-35); see also
`
`Ex. 12 (Press 1994) at 2771
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