IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In the Inter Partes Review of:
`
`Trial Number: To Be Assigned
`
`
`
`U.S. Patent No. 7,892,549
`
`Filed: February 3, 2003
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`Issued: February 22, 2011
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`Inventor(s): Virginia E. Paton, Steven Shak,
`Susan D. Hellmann
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`Assignee: Genentech, Inc.
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`
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`Title: Treatment with Anti-ErbB2 Antibodies
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`Panel: To Be Assigned
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`Mail Stop Inter Partes Review
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`
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`DECLARATION OF ALLAN LIPTON, M.D.
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`I.
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`II.
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`TABLE OF CONTENTS
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`PAGE
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`INTRODUCTION ........................................................................................... 1
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`QUALIFICATIONS ........................................................................................ 2
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`III. MATERIALS REVIEWED ............................................................................ 3
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`IV. PERSON OF ORDINARY SKILL IN THE ART .......................................... 4
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`V. APPLIED LEGAL PRINCIPLES ................................................................... 4
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`VI. THE CLAIMS OF THE ʼ549 PATENT & CLAIM
`CONSTRUCTION .......................................................................................... 5
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`VII. TECHNOLOGY BACKGROUND ................................................................. 8
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`A.
`
`B.
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`C.
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`D.
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`E.
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`State of the Art Prior to the ʼ549 Patent ................................................ 8
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`HER2 Positive Breast Cancer ............................................................. 10
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`FDA Research and Regulatory Approval ........................................... 17
`
`The ʼ549 Patent Claims an Effective Combination Without
`Providing Any Efficacy Data .............................................................. 19
`
`The ʼ549 Patent is not Entitled to Earlier Priority Based on the
`Disclosure of the ʼ649 Application or the ʼ346 Application ............... 21
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`VIII. OVERVIEW OF THE PRIOR ART ............................................................. 23
`
`A. Nabholtz Reports the Results of Two Phase II Trials of
`rhuMAb HER2 with Docetaxel and either Cisplatin or
`Carboplatin .......................................................................................... 23
`
`B.
`
`C.
`
`Leyland-Jones Reports the Results of a Phase III Trial
`Comparing Two- and Three-Drug Combinations Involving
`rhuMAb HER2 .................................................................................... 25
`
`Yardley Reports the Results of a Phase II Study of Paclitaxel,
`Carboplatin, and rhuMAb HER2 ........................................................ 26
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`IX. DETAILED INVALIDITY ANALYSIS ...................................................... 27
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`A.
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`Claims 1–8, 10–11, and 14–17 Are Invalid Based on Nabholtz ......... 28
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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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`6.
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`7.
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`8.
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`9.
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`Claim 1 is anticipated by Nabholtz ........................................... 28
`
`Claim 2 is anticipated by Nabholtz ........................................... 31
`
`Claim 3 is anticipated by Nabholtz ........................................... 32
`
`Claim 4 is anticipated by Nabholtz ........................................... 32
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`Claim 5 is anticipated by Nabholtz ........................................... 33
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`Claim 6 is anticipated by Nabholtz ........................................... 35
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`Claim 7 is anticipated by Nabholtz ........................................... 35
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`Claim 8 is anticipated by Nabholtz ........................................... 35
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`Claim 10 is anticipated by Nabholtz ......................................... 36
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`10. Claim 11 is anticipated by Nabholtz ......................................... 36
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`11. Claim 14 is anticipated by Nabholtz ......................................... 37
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`12. Claim 15 is anticipated by Nabholtz ......................................... 37
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`13. Claim 16 is anticipated by Nabholtz ......................................... 37
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`14. Claim 17 is anticipated by Nabholtz ......................................... 39
`
`B.
`
`Claims 1–11 and 14–17 Are Invalid Based on Leyland-Jones ........... 40
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Claim 1 is anticipated by Leyland-Jones .................................. 40
`
`Claim 2 is anticipated by Leyland-Jones .................................. 43
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`Claim 3 is anticipated by Leyland-Jones .................................. 44
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`Claim 4 is anticipated by Leyland-Jones .................................. 44
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`Claim 5 is anticipated by Leyland-Jones .................................. 45
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`Claim 6 is anticipated by Leyland-Jones .................................. 47
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`Claim 7 is anticipated by Leyland-Jones .................................. 47
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`8.
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`9.
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`Claim 8 is anticipated by Leyland-Jones .................................. 47
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`Claim 9 is anticipated by Leyland-Jones .................................. 48
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`10. Claim 10 is anticipated by Leyland-Jones ................................ 48
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`11. Claim 11 is anticipated by Leyland-Jones ................................ 48
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`12. Claim 14 is anticipated by Leyland-Jones ................................ 49
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`13. Claim 15 is anticipated by Leyland-Jones ................................ 49
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`14. Claim 16 is anticipated by Leyland-Jones ................................ 50
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`15. Claim 17 is anticipated by Leyland-Jones ................................ 52
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`C.
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`Claims 1–11 and 14–17 Are Invalid Based on Yardley ...................... 52
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`1.
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`2.
`
`3.
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`4.
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`5.
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`6.
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`7.
`
`8.
`
`9.
`
`Claim 1 is anticipated by Yardley ............................................. 52
`
`Claim 2 is anticipated by Yardley ............................................. 55
`
`Claim 3 is anticipated by Yardley ............................................. 56
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`Claim 4 is anticipated by Yardley ............................................. 56
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`Claim 5 is anticipated by Yardley ............................................. 57
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`Claim 6 is anticipated by Yardley ............................................. 59
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`Claim 7 is anticipated by Yardley ............................................. 59
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`Claim 9 is anticipated by Yardley ............................................. 59
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`Claim 10 is anticipated by Yardley ........................................... 60
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`10. Claim 11 is anticipated by Yardley ........................................... 60
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`11. Claim 14 is anticipated by Yardley ........................................... 60
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`12. Claim 15 is anticipated by Yardley ........................................... 61
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`13. Claim 16 is anticipated by Yardley ........................................... 61
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`14. Claim 17 is anticipated by Yardley ........................................... 63
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`X.
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`CONCLUSION .............................................................................................. 63
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`APPENDIX A: CURRICULUM VITAE ............................................................... 65
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`APPENDIX B: MATERIALS CONSIDERED .....................................................160
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`APPENDIX C: NABHOLTZ CLAIM CHART ....................................................163
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`APPENDIX D: LEYLAND-JONES CLAIM CHART .........................................169
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`APPENDIX E: YARDLEY CLAIM CHART.......................................................175
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`I.
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`I, Allan Lipton, M.D., declare under penalty of perjury as follows:
`
`INTRODUCTION
`1.
`
`I have been retained by Hospira, Inc. as an independent expert
`
`consultant in this proceeding before the United States Patent and Trademark
`
`Office. Although I am being compensated at my usual and customary rate of $600
`
`per hour for the time I spend on this matter, my compensation does not depend on
`
`the outcome of this inter partes review. I have no other interest in this matter.
`
`2.
`
`I understand that this proceeding involves U.S. Patent No. 7,892,549
`
`(the “ʼ549 patent”) (attached as Ex. 1101 to the petition), the application for which
`
`was filed as U.S. Application No. 10/356,824 (“ʼ824 application”). The ʼ824
`
`application claims priority to U.S. Patent Application No. 09/208,649 (the “ʼ649
`
`application”) (Ex. 1121) which itself claims priority to U.S. Provisional Patent
`
`Application No. 60/069,346 (the “ʼ346 application”) (Ex. 1120) filed on December
`
`12, 1997 (which I understand to be the “earliest possible priority date”).
`
`3.
`
`I have been asked to consider whether certain claims of the ’549
`
`patent are invalid as anticipated or would have been obvious to a person of
`
`ordinary skill in the art (“POSITA”) at the time of the alleged invention, which I
`
`have been asked to assume is the earliest possible priority date to which the patent
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`is entitled (i.e., February 3, 2003). My opinions are set forth below.
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`1
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`II. QUALIFICATIONS
`4.
`I am currently a Professor of Medicine and Oncology at Milton S.
`
`Hershey Medical Center of Pennsylvania State University.
`
`5.
`
`I earned a Bachelor of Arts degree from Amherst College in 1959 and
`
`my medical degree (M.D.) from New York University School of Medicine in 1963.
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`After an internship and residency at the Cornell Medical Division, Bellevue
`
`Hospital, I worked as a Research Associate at the National Institute of Healthʼs
`
`(“NIH”) National Institute of Arthritis and Metabolic Diseases and Laboratory of
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`Biochemistry and Cellular Metabolism.
`
`6.
`
`After my time with NIH, I completed a fellowship in medical
`
`oncology at Memorial Sloan-Kettering Cancer Center in New York City. This was
`
`followed by two years of research as an American Cancer Society Dernham Fellow
`
`at the Salk Institute in San Diego, California.
`
`7.
`
`I joined the faculty of the Milton S. Hershey Medical Center of
`
`Pennsylvania State University in 1971. I served as the Chief of the Division of
`
`Medical Oncology from 1973 to 1998. I also served as a Professor of medicine and
`
`oncology from 1978 to the present time.
`
`8.
`
`I personally participated in the early clinical trials of rhuMAb HER2
`
`(also known as trastuzumab or Herceptin®) that led to its approval by the U.S.
`
`Food and Drug Administration (“FDA”). I was also a co-author with Dr. Mark
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`
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`Pegram, among others, of the results of a phase II trial of the combination therapy
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`using rhuMAb HER2 and cisplatin. See Ex. 1118 at 8; Ex. 1113 at 5.
`
`9.
`
`Over the course of my career, I have also been involved in several
`
`other phase I and II clinical trials that examined potential new cancer therapies.
`
`10. My laboratory has also extensively investigated tests to detect the
`
`presence of the HER2/neu receptor, and has correlated the presence of the receptor
`
`with response to different types of anti-cancer therapies. I have presented the
`
`results of my research on HER2/neu testing at both national and international
`
`oncology meetings.
`
`11.
`
`I have authored or co-authored several dozen book chapters, more
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`than 350 peer-reviewed scientific papers, and more than 450 abstracts.
`
`12. As a clinician, I have personally prescribed rhuMAb HER2 in
`
`combination with chemotherapy (e.g., Adriamycin (doxorubicin), Cytoxan, Taxol
`
`(paclitaxel), Taxotere (docetaxol), Carboplatin, and Cisplatin) to treat patients
`
`suffering from breast cancer and gastric cancer.
`
`13. A copy of my current curriculum vitae is attached as Appendix A.
`
`III. MATERIALS REVIEWED
`14.
`In forming my opinions, I reviewed the ʼ549 patent, parts of the
`
`prosecution history of the ʼ549 patent, and the references included in Appendix B.
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`
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`IV. PERSON OF ORDINARY SKILL IN THE ART
`15.
`I understand that a POSITA is presumed to be aware of all pertinent
`
`art, think along the line of conventional wisdom, and possess ordinary creativity in
`
`the pertinent field. I also understand that a POSITA is not a real individual, but
`
`rather a hypothetical individual having these qualities.
`
`16.
`
`In my opinion, a POSITA at the time of the alleged invention is at
`
`least a clinical or medical oncologist specializing in breast cancer with several
`
`years of experience with breast cancer research or clinical trials. I base this opinion
`
`on my own knowledge and experience as described above.
`
`17. Under this definition, I was a POSITA at the time of the alleged
`
`invention. By that time, I was a clinical oncologist and professor specializing in
`
`breast cancer with several years of experience in breast cancer research and clinical
`
`trials. See Appendix A. I also had exposure to others who met the definition of
`
`POSITA at and around the time of the alleged invention during my work as a
`
`professor in the Departments of Medicine and Oncology at the Milton S. Hershey
`
`Medical Center of the Pennsylvania State University.
`
`V. APPLIED LEGAL PRINCIPLES
`18.
`I have been informed of the various legal standards with regard to the
`
`validity or patentability of a United States patent. My understanding of these
`
`
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`standards, which I applied to the facts of this matter and my analysis, are set forth
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`below:
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`19. Prior art to the ʼ549 patent includes patents, printed publications and
`
`products in the relevant art that predate the priority date of the ʼ549 patent.
`
`20. Anticipation analysis proceeds in two steps. First, the claims must be
`
`construed. Second, the construed claims are compared to a prior art reference to
`
`determine whether every limitation is found in the single reference, either
`
`expressly or inherently.
`
`21. A claim is invalid if it is anticipated. A claim is anticipated if every
`
`element of the claim is disclosed expressly or inherently in a single prior art
`
`reference as arranged in the anticipated claim.
`
`22. Anticipation does not require the actual performance of suggestions in
`
`a disclosure. Rather, anticipation requires that those suggestions enable a POSITA
`
`to practice the invention without undue experimentation.
`
`VI. THE CLAIMS OF THE ʼ549 PATENT & CLAIM CONSTRUCTION
`23. The ʼ549 patent has seventeen claims:
`
`1.
`
`A method for the treatment of a human patient with breast cancer that
`
`overexpresses ErbB2
`
`receptor,
`
`comprising
`
`administering
`
`a
`
`combination of an antibody that binds ErbB2, a taxoid, and a further
`
`growth inhibitory agent to the human patient in an amount effective to
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`
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`extend the time to disease progression in the human patient, wherein
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`the antibody binds to epitope 4D5 within the ErbB2 extracellular
`
`domain sequence.
`
`2.
`
`The method of claim 1 wherein the antibody is a humanized 4D5 anti-
`
`ErbB2 antibody.
`
`3.
`
`The method of claim 1 wherein the antibody crossblocks binding of
`
`4D5 to the ErbB2 extracellular domain sequence.
`
`4.
`
`The method of claim 1 wherein the antibody binds to amino acid
`
`residues in the region from about residue 529 to about residue 625 of
`
`the ErbB2 extracellular domain sequence.
`
`5.
`
`A method for the treatment of a human patient with breast cancer
`
`characterized by overexpression of ErbB2 receptor, comprising
`
`administering an effective amount of a combination of an anti-ErbB2
`
`antibody which binds epitope 4D5 within the ErbB2 extracellular
`
`domain sequence, a taxoid, and a further therapeutic agent, to the
`
`human patient.
`
`6.
`
`The method of claim 5 wherein the breast cancer is metastatic breast
`
`carcinoma.
`
`7.
`
`The method of claim 5 wherein the antibody is a humanized 4D5 anti-
`
`ErbB2 antibody.
`
`6
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`8.
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`The method of claim 7 wherein the antibody is administered as a 4
`
`mg/kg dose and then weekly administration of 2 mg/kg.
`
`9.
`
`The method of claim 5 wherein the taxoid is paclitaxel.
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`10. The method of claim 5 wherein efficacy is measured by determining
`
`the time to disease progression or the response rate.
`
`11. The method of claim 5, wherein the further therapeutic agent is
`
`selected from the group consisting of: another ErbB2 antibody, EGFR
`
`antibody, ErbB3 antibody, ErbB4 antibody, vascular endothelial
`
`growth factor (VEGF) antibody, cytokine, and growth inhibitory
`
`agent.
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`12. The method of claim 5 wherein the further therapeutic agent is
`
`another ErbB2 antibody.
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`13. The method of claim 5 wherein the further therapeutic agent is a
`
`vascular endothelial growth factor (VEGF) antibody.
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`14. The method of claim 5 wherein the further therapeutic agent is a
`
`growth inhibitory agent.
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`15. The method of claim 14 wherein the growth inhibitory agent is a DNA
`
`alkylating agent.
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`16. A method for the treatment of a human patient with ErbB2
`
`overexpressing breast cancer, comprising administering a combination
`
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`of an antibody that binds epitope 4D5 within the ErbB2 extracellular
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`domain sequence, a taxoid, and a further growth inhibitory agent, in
`
`the absence of an anthracycline derivative, to the human patient in an
`
`amount effective to extend the time to disease progression in the
`
`human patient.
`
`17. The method of claim 16 wherein the breast cancer is metastatic breast
`
`carcinoma.
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`24.
`
`I have been advised that, in an inter partes review, claim terms are
`
`given their broadest reasonable interpretation in light of the patent specification
`
`from the perspective of a POSITA. I have applied this broadest reasonable
`
`construction in my analysis.
`
`VII. TECHNOLOGY BACKGROUND
`A.
`State of the Art Prior to the ʼ549 Patent
`25. A tumor is an abnormal growth of cells in the body. Tumors can be
`
`either benign or malignant. A benign tumor is a localized abnormal growth of cells
`
`that does not pose a risk of spreading throughout the body. A malignant tumor is a
`
`growth of cells that has invaded surrounding tissue, and thus has the potential to
`
`spread throughout the body—i.e., to metastasize. When cancer metastasizes,
`
`tumors may grow throughout the body, eventually affecting important organs and
`
`threatening or ending the patientʼs life.
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`26. The first chemotherapy treatment for cancer was developed after
`
`World War II. E.g., Ex. 1137 at 7–8. Responses were seen in patients treated with
`
`single-drug therapies using certain chemical compounds, such as nitrogen mustard
`
`and other alkylating agents. E.g., Ex. 1137 at 8–9. However, these responses were
`
`relatively short-lived, and diseases were not cured. E.g., Ex. 1137 at 10. Over the
`
`next two decades, other types of anti-cancer drugs with different mechanisms of
`
`action were developed, e.g., 5-fluoro-uracil, vincristine, and procarbazine. E.g., Ex.
`
`1137 at 11–14.
`
`27. A major advance in the treatment of cancer occurred in the early
`
`1960s when investigators used combinations of anti-cancer drugs to treat children
`
`with leukemia. E.g., Ex. 1137 at 11–14. What followed was an explosion of
`
`research in the area of combination therapies, to treat a whole host of other
`
`malignancies. See, e.g., Ex. 1137 at 12–14. Combination therapies significantly
`
`increased the cure rates in conditions such as Hodgkinʼs disease, testicular cancer,
`
`childhood leukemia and choriocarcinoma. Ex. 1137 at 14.
`
`28. Childhood leukemia provides a good example. Early work in this area
`
`focused on the so called “VAMP” combination therapy. E.g., Ex. 1137 at 13.
`
`VAMP stands for vincristine, amethopterin, 6-mercaptopurine, and prednisone. Ex.
`
`1137 at 13. Each of these drugs acts via a different mechanism, and the hypothesis
`
`was that rapid cell division in tumor cells increased the probability that the tumor
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`could gain adaptive resistance to any one drug. By providing a combination
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`therapy, the total tumor killing effect of the combination was so effective that the
`
`tumor could not undergo sufficient divisions to gain any adaptive resistance.
`
`29. Similarly, early work with breast cancer involved the combination
`
`chemotherapeutic regimen known as “CMF.” E.g., Ex. 1137 at 14. CMF stands for
`
`cyclophosphamide, methotrexate, and 5-fluorouracil. Ex. 1137 at 14. As with the
`
`VAMP regimen, each of these drugs acts on a different mechanism and the results
`
`of this early work led to substantial follow-on work with different drug
`
`combinations that resulted in much of the improvements in breast cancer survival
`
`observed since the 1980s. Ex. 1137 at 14.
`
`30. Thus, beginning in the 1960s, and continuing to today, oncologists
`
`learned that combinations of anti-cancer drugs that work by different mechanisms
`
`of action are superior to single agent therapies. As with other forms of cancer, the
`
`cure rate of breast cancer has been significantly improved by using combination
`
`chemotherapy in the adjuvant setting. E.g., Ex. 1137 at 14–16. Time has proven
`
`that combinations of different types of anti-cancer drugs can prevent a cancer cell
`
`from developing resistance to therapy.
`
`B. HER2 Positive Breast Cancer
`31. Each year in the United States, approximately 225,000 women are
`
`diagnosed with breast cancer. Of these women, approximately 40,000 of them will
`
`
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`die each year due to their disease. Over the last 70 years, researchers have learned
`
`that there are various subtypes of breast cancer. Each of these subtypes of breast
`
`cancer
`
`is
`
`typically
`
`treated using hormone
`
`therapy, combinations of
`
`chemotherapeutic drugs, or combinations of both, in addition to surgery and/or
`
`radiation
`
`therapy. One such subtype
`
`is HER2/neu positive
`
`(or HER2
`
`overexpressing) disease which is treated with combinations using rhuMAb HER2
`
`plus chemotherapeutic agents.
`
`32. One of the most commonly used classes of chemotherapeutic drugs in
`
`the late 1990s was the anthracycline derivatives. While these drugs showed
`
`excellent efficacy, they were also shown to have significant cardiotoxicity. See,
`
`e.g., Ex. 1142 at 4, 12. The toxicity from anthracyclines is cumulative—i.e., the
`
`damaged tissue does not recover, and subsequent use of anthracyclines will cause
`
`further damage. E.g., Ex. 1142 at 5. It is notable that, by the mid-1990s, the
`
`cardiotoxic effects of anthracycline derivatives were extremely well known
`
`throughout the oncology field. E.g., Ex. 1142 at 4. Largely for this reason, also
`
`during the mid to late-1990s researchers in the area of chemotherapeutics were
`
`interested in finding chemotherapeutic regimens that avoided the use of
`
`anthracyclines.
`
`33. HER2/neu is a gene that encodes a cell surface receptor whose
`
`activation initiates a variety of signaling pathways in the cell that primarily
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`promote cell proliferation and oppose apoptosis (programmed cell death). E.g., Ex.
`
`1105 at 9; Ex. 1107 at 6. The HER2 receptor is also known (interchangeably) as
`
`p185HER2 and ErbB2. E.g., Ex. 1105 at 9; Ex. 1107 at 6.
`
`34. HER2 is over-expressed in 25–30% of human breast cancers. E.g., Ex.
`
`1105 at 9; Ex. 1107 at 6. HER2 over-expression is indicative of a worse prognosis.
`
`E.g., Ex. 1105 at 9; Ex. 1107 at 6, Ex. 1101 3:41–45. Further, patients with HER2
`
`positive tumors have a high probability of drug resistance to even the most
`
`effective chemotherapy combinations. Ex. 1101 3:45–50; see also Ex. 1107 at 9–
`
`10; Ex. 1141 at 6. In this context, monoclonal antibodies against HER2 were
`
`developed. Antibodies are proteins that are produced by the immune system that
`
`bind to target molecules (“antigens”) causing a variety of downstream responses.
`
`Monoclonal antibodies are a group of antibodies that all bind to the same epitope
`
`on the target antigen. By contrast, polyclonal antibodies are a group of antibodies
`
`that bind to different epitopes on the same target antigen.
`
`35.
`
`In the context of a HER2/neu positive breast cancer patient, the terms
`
`“malignant progressing tumor,” “cancer,” “breast cancer,” and “breast carcinoma”
`
`are often used by persons of skill in the art interchangeably. The term “metastatic
`
`breast carcinoma” refers to a breast cancer that has spread to other parts of the
`
`body from the breast. A “carcinoma” specifically refers to a cancer derived from
`
`epithelial cells.
`
`
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`36. Antibodies against HER2 are known interchangeably as anti-HER2
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`antibodies or anti-ErbB2 antibodies. One such antibody is the monoclonal antibody
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`rhuMAb HER2. RhuMAb HER2 primarily works by binding to the extracellular
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`portion of the HER2 receptor at a point that prevents the receptor from binding to
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`adjacent
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`receptors of
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`the same
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`family
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`(“dimerization”). By preventing
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`dimerization, the antibody “deactivates” the receptor preventing it from enhancing
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`cell survival thereby sensitizing the cell to other therapies.
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`37. RhuMAb HER2 began in the 1980s as a murine (mouse) monoclonal
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`antibody called 4D5. See, e.g., Ex. 1108 at 20:15–20; Ex. 1105 at 9; Ex. 1107 at 7;
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`Ex. 1101 at 1:23–32 (citing Ex. 1133; Ex. 1134). Once experiments demonstrated
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`that the 4D5 antibody could control tumor growth in vitro and in vivo in xenograft
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`tumor models,1 the antibody was “humanized” for use in patients. Ex. 1105 at 9;
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`Ex. 1107 at 7. Humanized antibodies are antibodies from a non-human species
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`whose protein sequences have been modified to maximize their similarity to
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`naturally produced antibodies in humans to minimize the probability that the
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`immune system will target the antibodies as foreign proteins. Ex. 1116 at 10.
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`RhuMAb HER2 contains “the antigen binding loops from [the 4D5 antibody] and
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`human variable region framework residues plus IgG1 constant domains” (i.e.,
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`1 A xenograft tumor model is an animal model in which tumor cells from one
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`species, e.g., humans, are grown in the body of another species, e.g., mice.
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`13
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`includes Fc region) to produce an intact antibody. E.g., Ex. 1116 at 10, 13; see also
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`Ex. 1145 at 5–6. Because rhuMAb HER2 has the antigen binding loops of the
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`mouse 4D5 antibody, it binds to the same site on the ErbB2 receptor as the 4D5
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`antibody.
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`38. During early clinical studies involving the single therapy of rhuMAb
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`HER2 in women with metastatic breast cancer, Dr. Jose Baselga and colleagues
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`demonstrated that the antibody was effective even in patients with metastatic
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`disease that was non-responsive to traditional therapies. Ex. 1105 at 13. In that
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`study, patients were administered a loading dose of 250 mg followed by weekly
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`doses of 100 mg. Ex. 1105 at 10. The constant dosing that is disclosed in Baselga
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`ʼ96 is simple because it is easy for technicians and other personnel to determine the
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`appropriate dose to administer to the patient. However, as a clinician, a POSITA at
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`the time of the invention of the ʼ549 patent would have some concerns about the
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`possibility that a constant dose administration irrespective of patient size could
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`result in lower than effective concentrations of antibody in the patient between
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`weekly doses, especially for larger patients. Indeed, later prior art references
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`(including Leyland-Jones and Nabholz) teach a weight-based rhuMAb HER2
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`regimen of 4 mg/kg on day 1 followed by 2 mg/kg weekly.
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`39. This pathway to human research—beginning in vitro with tumor cell
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`lines, moving in vivo to preclinical mouse models, and finally using the most
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`promising drug candidates in vivo in humans—is the same methodology that has
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`been applied in the cancer field since the 1970s, and continues today. See, e.g., Ex.
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`1137 at 9.
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`40. When it was invented, rhuMAb HER2 was a new kind of anti-cancer
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`therapy with a new mechanism of action. As noted above, over the past 60 years,
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`oncologists had learned to combine anti-cancer therapies that have different
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`mechanisms of action. The obvious next step with this anti-cancer therapy was to
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`combine rhuMAb HER2 with more established anti-cancer therapies to look for
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`expected additive or synergistic responses. See Ex. 1107 at 9 (collecting
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`references); Ex. 1143 at 6 (“there is ample experimental evidence that the
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`sensitivity of tumor cells to cisplatin and other chemotherapeutic agents may be
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`enhanced by antibodies and inhibitors that act on receptors in the EGF and HER-
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`2/neu receptor family to block cell proliferation”).
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`41.
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`Indeed, beginning in the early 1990s, a number of investigators
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`published abstracts, gave presentations, and published articles on combinations of
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`rhuMAb HER2 with various chemotherapeutic agents like paclitaxel, docetaxel,
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`cisplatin, doxorubicin, methotrexate, and velban. E.g., Ex. 1115 at 8; Ex. 1140 at 5;
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`Ex. 1123 at 3; Ex. 1106 at 4; Ex. 1113 at 5; Ex. 1105 at 15; Ex. 1107 at 8–10; Ex.
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`1141 at 6; Ex. 1143 at 6. In other words, by the time antibody treatments, like
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`rhuMAb HER2, were invented, POSITAs had over 30 years of experience teaching
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`that combination drug therapies were dramatically more effective than single agent
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`treatments making such combinations with rhuMAb HER2 the obvious next step.
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`42. Given that there were significant early efforts in the 1990s to find
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`promising drug combinations with rhuMAb HER2, there were a finite number of
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`such candidate combinations to try for efficacy in clinical trials—including
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`rhuMAb HER2 and paclitaxel—and it was hardly surprising that several of these
`
`combinations turned out to produce the expected synergistic effects that preclinical
`
`testing demonstrated. See Ex. 1106 at 4; Ex. 1113 at 5; Ex. 1105 at 15; Ex. 1107 at
`
`8–10; Ex. 1141 at 6. The natural next step to advancing promising therapies, such
`
`as the combination of rhuMAb HER2 and paclitaxel, is to look to other traditional
`
`chemotherapeutic agents operating by yet another mechanism to provide further
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`treatment benefits. See, e.g., Gelmon et al., Phase I/II Trial of Biweekly Paclitaxel
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`and Cisplatin in the Treatment of Metastatic Breast Cancer, 14(4) J. CLIN. ONCOL.
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`1185–91 (1996) (“Gelmon ʼ96”) (Ex. 1125) at 9.
`
`43. This is precisely what several different groups located around the
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`world began doing at roughly the same time. Ex. 1114 at 29; Ex. 1150 at 31; Ex.
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`1151 at 5; Ex. 1152 at 5; Ex. 1153 at 31. Combinations involving platinum-based
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`drugs, such as cis- or carbo-platin, were sought because there was a low probability
`
`that patients would have already received one of these drugs during earlier primary
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`or adjuvant therapy. E.g., Ex. 1125 at 9–10. As a counterpart to the platinum drugs,
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`taxoids provided a natural combination. E.g., Ex. 1125 at 9–10. The taxoids—
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`paclitaxel and docetaxel—operate on a different mechanism as compared to the
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`platinum drugs. E.g., Ex. 1125 at 9–10. The two classes of drugs also largely do
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`not have overlapping toxicities and the combination avoids the known cardiac
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`toxicity associated with anthracycline drugs. E.g., Ex. 1125 at 9–10; Ex. 1114 at
`
`29; Ex. 1151 at 5; Ex. 1152 at 5. Thus, a whole series of phase II and phase III
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`clinical trials were conducted using combinations of rhuMAb HER2, a taxoid, and
`
`a platinum drug in early 2000. E.g., Ex. 1114 at 29; Ex. 1150 at 31; Ex. 1151 at 5;
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`Ex. 1152 at 5; Ex. 1153 at 31. Unsurprisingly, every one of these studies reported
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`high response rates and reported toxicity profiles that were well tolerated by
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`patients. E.g., Ex. 1114 at 29; Ex. 1150 at 31; Ex. 1151 at 5; Ex. 1152 at 5; Ex.
`
`1153 at 31.
`
`C.
`FDA Research and Regulatory Approval
`44. As discussed above in ¶¶ 4–13, over the course of my 50 years in
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`medicine, I gained significant personal experience in clinical research, including
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`research projects that go through all phases of the FDA approval process.
`
`45. The FDA approval process typically begins before a particular drug,
`
`therapy, or other treatment is ever tested on humans. This so called “preclinical
`
`phase” often involves laboratory work. Laboratory research in the medical sciences
`
`can be simplified into two main categories: in vitro and in vivo experimentation. In
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`
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`vivo experimentation takes place inside of a living organism whereas in vitro
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`typically takes place in a petri dish or test tube. See, e.g., Ex. 1115 at 8; Ex. 1123 at
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`3; Ex. 1140 at 5.
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`46.
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`In the case of drug development, at the time of the earliest possible
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`priority date to which the ʼ549 patent is entitled, mice were—and remain—one of
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`the primary animals