UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`APOTEX INC.,
`Petitioner,
`v.
`IPSEN BIOPHARM LTD.,
`Patent Owner.
`____________________
`Case No. IPR2025-01531
`Patent No. 11,344,552
`____________________
`EXPERT DECLARATION OF
`ROBERT DREICER, M.D., M.S., MACP, FASCO
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`TABLE OF CONTENTS
`I. QUALIFICATIONS ...................................................................................... 2
`II. SUMMARY OF OPINIONS......................................................................... 7
`III. MATERIALS RELIED UPON .................................................................... 9
`IV. THE UNDERSTANDING APPLIED TO MY ANALYSIS ....................12
`V. LEVEL OF ORDINARY SKILL IN THE ART ......................................18
`VI. CLAIM CONSTRUCTION ........................................................................19
`VII. BACKGROUND AND STATE OF THE ART ........................................26
`A. Adenocarcinoma of the Pancreas ........................................................26
`B. Combination Chemotherapy Was Commonly Used to Treat
`Pancreatic Cancers ..............................................................................26
`C. FOLFIRINOX Was a Known and Well-Used Treatment But It
`Had Significant Drawbacks .................................................................27
`D. A POSA Understood How To Create Different Combination
`Regimens .............................................................................................28
`E. A POSA Would Have Understood That Liposomal Irinotecan
`May Be Superior To Irinotecan ...........................................................34
`VIII. OVERVIEW OF KEY PRIOR ART AND STATE OF THE ART
`REFERENCES ............................................................................................38
`A. Conroy (Ex. 1003) ...............................................................................39
`B. Conroy Protocol (Ex. 1004) ................................................................42
`C. Mahaseth (Ex. 1005) ...........................................................................43
`D. Bayever (Ex. 1006)..............................................................................45
`E. Saif (Ex. 1007) ....................................................................................57
`F. Ko (Ex. 1008) ......................................................................................59
`G. Conroy 2013 (Ex. 1041) ......................................................................61
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`H. Masi (Ex. 1012) ...................................................................................62
`I. Ginocchi (Ex. 1016) ............................................................................65
`J. Carnevale (Ex. 1013) ...........................................................................65
`K. Dean (Ex. 1014) ..................................................................................66
`L. Additional Prior Art and References ...................................................67
`M. Rebuttal of Patentee Arguments Regarding Unexpected Results
`During Patent Prosecution ...................................................................67
`IX. OVERVIEW OF THE ’552 PATENT .......................................................71
`A. The Specification and Claims of the ’552 Patent ................................71
`B. The Prosecution History of the ’552 Patent ........................................78
`C. The Priority Date of the ’552 Patent ...................................................89
`X. UNPATENTABILITY OF THE ’552 PATENT .......................................95
`A. GROUND 1: CLAIMS 1, 3-6, AND 8-14 WOULD HAVE
`BEEN OBVIOUS OVER CONROY, CONROY PROTOCOL,
`AND MAHASETH IN COMBINATION WITH THE SKILL
`AND KNOWLEDGE OF A POSA, INCLUDING BAYEVER,
`SAIF, KO, AND CANTORE; ANY ALLEGED
`UNEXPECTED RESULTS ARE CONTRADICTED BY
`NICHETTI AND NEVALA-PLAGEMANN .....................................95
`B. GROUND 2: CLAIMS 7 AND 15 WOULD HAVE BEEN
`OBVIOUS IN VIEW OF THE PRIOR ART DISCLOSED IN
`GROUND 1 IN FURTHER VIEW OF MASI AND
`GINOCCHI .......................................................................................121
`C. GROUND 3: CLAIMS 1 AND 3-15 WOULD HAVE BEEN
`OBVIOUS BASED ON THE PRIOR ART DISCUSSED IN
`GROUNDS 1 AND 2 AND IN FURTHER VIEW OF
`CARNEVALE, AND/OR DEAN .....................................................123
`XI. CONCLUSION ..........................................................................................127
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`1
`1. I, Robert Dreicer, M.D., M.S., MACP, FASCO, of Earlysville,
`Virginia, declare as follows:
`2. I have been retained by counsel for Petitioner Apotex Inc. (“Apotex”).
`I understand that Apotex is submitting a petition for inter partes review (“IPR”) of
`U.S. Patent No. 11,344,552 (“the ’552 patent,” attached as Ex.1001), which is
`assigned to Ipsen Biopharm Ltd. (“Patent Owner”). It is my understanding that
`Apotex is requesting that the United States Patent and Trademark Office
`(“USPTO”) cancel all claims of the ’552 patent as unpatentable. I also understand
`that CSPC Pharmaceutical Group Limited, CSPC Ouyi Pharmaceutical Co., Ltd.,
`and Conjupro Biotherapeutics, Inc. (collectively “CSPC”) have filed an IPR with
`respect to the ’552 patent in IPR2025-00505 (the “CSPC IPR”), which the Board
`has instituted. In support of the CSPC IPR, Mark J. Ratain, M.D. submitted a
`declaration (Ex.1002). I have reviewed and considered Dr. Ratain’s declaration. I
`agree with Dr. Ratain’s opinions set forth in his declaration, so I have adopted
`them. Accordingly, I submit this expert declaration in support of Apotex’s IPR
`petition for the ’552 patent. I make the following statements based on personal
`knowledge and, if called to testify to them, could and would do so.
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`I. QUALIFICATIONS
`3. I graduated from Colorado State University in 1977 with a B.S.
`degree. I obtained my M.S. from the University of Texas Graduate School of
`Biomedical Sciences in 1979. I obtained my M.D. from the University of Texas
`Medical School at Houston in 1983. I completed my internship and residency in
`internal medicine at Indiana University School of Medicine from 1983-1986. I
`completed a fellowship in Medical Oncology at the University of Wisconsin
`Comprehensive Cancer Center from 1986-1988.
`4. I am board-certified in Internal Medicine and Medical Oncology. I
`received my Internal Medicine certification on September 10, 1987 and my
`Medical Oncology certification on November 7, 1989, with voluntary
`recertification on May 2, 2013 and am participating in ABIM’s maintenance of
`certification program (LKA).
`5. I joined the faculty of the University of Iowa College of Medicine in
`1989 as an Associate in the Departments of Internal Medicine and Urology. I was
`promoted to Assistant Professor in 1990 and to Associate Professor in 1995. From
`1999-2001, I served as Associate Division Director of the Division of
`Hematology/Oncology.
`6. From 2001-2014, I served at the Cleveland Clinic in various
`leadership positions, including Professor of Medicine at the Cleveland Clinic
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`Lerner College of Medicine (2004-14), Chair of the Department of Solid Tumor
`Oncology (2006-14), Director of GU Medical Oncology (2000-2014), and Deputy
`Associate Director for Clinical Research at the Case Comprehensive Cancer Center
`(2012-2014).
`7. Since 2015, I have served at the University of Virginia School of
`Medicine as Professor of Medicine and Professor of Urology. I currently serve as
`Head of the Section of Medical Oncology, Deputy Director of the University of
`Virginia Comprehensive Cancer Center, Associate Director for Clinical Research,
`and Co-Director of the Paul Mellon Urologic Cancer Institute.
`8. I have directed and participated in numerous clinical trials for patients
`with various malignancies, with particular focus on genitourinary cancers
`including urothelial (bladder), kidney, and prostate cancers, as well as experience
`with pancreatic cancer and other solid tumors. I have been directly involved in the
`design, conduct, and analysis of phase 1, 2, and 3 trials of more than 100 drugs,
`including small molecule, peptide, and protein drugs. Some of these studies
`included patients with pancreatic cancer.
`9. I have extensive experience in the development of therapeutics for
`cancer treatment, including combination chemotherapy regimens. This experience
`includes membership in the Eastern Cooperative Oncology Group (ECOG)
`Genitourinary Core Committee (1991-2015) and chair of the bladder cancer
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`subcommittee (1996-2014). I have also served on numerous data safety monitoring
`boards (Phase I/II and III trials) and scientific protocol review committees.
`10. I have also consulted for the pharmaceutical industry for over 30
`years, primarily regarding the development and commercialization of oncology
`drugs. I have interacted extensively with the pharmaceutical industry as an
`investigator.
`11. I have been extensively involved with professional oncology
`organizations. I have served on the Editorial Board of the Journal of Clinical
`Oncology (2005-2010), served as a reviewer for numerous journals including the
`Journal of Clinical Oncology, Cancer, Lancet Oncology, Clinical Cancer Research,
`European Urology, and Urology, among others. I served 6 years as a member of
`the American Board of Internal Medicine (ABIM) Oncology Exam Committee and
`another 6 years as a member of the ABIM Medical Oncology Longitudinal
`Assessment Approval Committee. I have served as a Deputy Editor for NEJM
`Journal Watch Hematology/Oncology since 2006.
`12. I have served as a research reviewer for multiple committees and
`working groups at the NIH, including serving as Chair of the Department of
`Defense Prostate Cancer Research Program Integration Panel (2004-2005) and as a
`member from 2000-2009.
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`13. I have received numerous honors and awards throughout my career in
`recognition of my work in oncology and clinical research. I am a Master of the
`American College of Physicians (MACP) and a Fellow of the American Society of
`Clinical Oncology (FASCO).
`14. I have been frequently asked to speak at national and international
`meetings on cancer treatment and drug development. I have given over 250
`presentations on various oncology topics, including many on the management of
`advanced cancers and combination therapies.
`15. I have served as an editor and reviewer for numerous journals and
`have participated in the development of clinical practice guidelines for cancer
`treatment.
`16. I have authored numerous articles in peer-reviewed journals
`concerning clinical studies and/or pharmacology of cancer drugs. Many of these
`publications relate to combination chemotherapy regimens and the treatment of
`advanced cancers.
`17. I have experience with pancreatic cancer treatment, including
`familiarity with the FOLFIRINOX regimen and its modifications. Through my
`clinical practice and research, I have treated patients with metastatic pancreatic
`cancer and am familiar with the standard treatment approaches and their evolution
`over time.
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`18. I have knowledge and experience with liposomal drug formulations,
`and understand the rationale for developing liposomal formulations of
`chemotherapy drugs to modify their pharmacokinetic properties and toxicity
`profiles.
`19. I am familiar with the development of combination chemotherapy
`regimens and the principles involved in dose optimization to balance efficacy and
`toxicity. This includes experience with dose modifications based on patient
`tolerability and toxicity management strategies.
`20. Additional information regarding my education, experience,
`publications, awards and honors, patents, publications, and presentations is detailed
`in my curriculum vitae (Appendix A).
`21. A list of the materials relied upon, in addition to my experience,
`education, and training, to provide the opinions contained in this declaration is
`listed below in Section III.
`22. I am being compensated for my time in connection with this IPR at
`my standard consulting rate, which is normally $650 per hour, $5,000 per day for
`depositions, hearings, etc., that require me to be away from my practice, and $325
`per hour for travel time. My compensation is not dependent in any way upon the
`outcome of this matter.
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`23. Among other things, I have reviewed the ’552 patent and relevant
`parts of its prosecution history with the United States Patent and Trademark Office.
`Specifically, I have reviewed the ’552 patent and its prosecution history in relation
`to the asserted prior art and arguments at issue in the present IPR.
`24. Based on my experience described above and contained in my CV
`provided in Appendix A, I have an established understanding of the relevant field
`in the relevant timeframe and the knowledge that would have been known by a
`person of ordinary skill in the art (POSA), as defined above and during the relevant
`time frame (on or before August 21, 2015 – the claimed priority date of the
`’552 Patent).
`II. SUMMARY OF OPINIONS
`25. I have been asked to consider whether claims 1 and 3-15 (“Challenged
`Claims”) of the ’552 Patent are obvious in view of the prior art. The Challenged
`Claims are directed to methods of treating metastatic pancreatic cancer in a human
`who has not previously been treated with an anticancer agent with a combination
`of four chemotherapy drugs: (1) 60 mg/m2 of liposomal irinotecan, (2) 60 mg/m2
`oxaliplatin, (3) 400 mg/m2 of leucovorin, and (4) 2400 mg/m2 of 5-fluorouracil.
`26. In my opinion, claims 1, 3-6, and 8-14 would have been obvious over
`Conroy, et al., N. Engl. J. Med., 364(19):1817-25 (2011) (“Conroy” (Ex. 1003))
`and Mahaseth, et al., Pancreas, 42(8):1311-15 (2013) (“Mahaseth” (Ex. 1005)) in
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`combination with International Publication No. WO2013/188586A1 (“Bayever”
`(Ex. 1006)) and the knowledge and skill of a POSA, exemplified by multiple
`publications regarding liposomal irinotecan, including Saif, Journal of the
`Pancreas, 15(3):278-79 (2014) (“Saif” (Ex. 1007)), Ko, et al., British J. of Cancer,
`109(4):920-25 (2013) (“Ko” (Ex. 1008)), and Cantore, et al., Oncology, 67(2):93-
`97 (2004) (“Cantore” (Ex. 1009)) and other references discussed herein. My
`opinions are further supported by post-filing references Nichetti, et al., JAMA
`Network Open, 7(1):1-13 (2024) (“Nichetti” (Ex. 1010)) and Nevala-Plagemann
`and Garrido-Laguna, Nature Reviews Clinical Oncology, 21(8):567-68 (2024)
`(“Nevala-Plagemann” (Ex. 1011)).
`27. In my opinion, claims 7 and 15 would also have been obvious in view
`of the prior art disclosed in ground 1 in view of Masi, et al., Annals of Oncology,
`15:1766-72 (2004) (“Masi” (Ex. 1012)) and Ginocchi, et al., Annals of Oncology,
`23(9 Suppl.):ix238 (2012) (“Ginocchi” (Ex. 1016)).
`28. In my opinion, claims 1 and 3-15 would have been obvious based on
`the prior art discussed in grounds 1 and 2 and further in view of Carnevale and Ko,
`Future Oncology, 12(4):453-464 (2016) (“Carnevale” (Ex. 1013)), and/or Dean, et
`al., J Clin Oncol, 34(4 Suppl.):tps482 (2016) (“Dean” (Ex. 1014)).
`29. Finally, I am not aware of any secondary considerations that support
`non-obviousness of the claims. I reserve the right to address any secondary
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`considerations put forth by Patent Owner (including but not limited to unexpected
`results) in any later response to this declaration or the petition it accompanies.
`III. MATERIALS RELIED UPON
`30. I have reviewed the Petition and supporting evidence. I have also
`reviewed all Challenged Claims of the ’552 patent (claims 1 and 3-15), as well as
`the specification of the ’552 patent and relevant parts of its file history, with
`particular attention to rejections by the Patent Examiner and the responses on
`behalf of the alleged inventors. I have examined the prior art references asserted
`against the ’552 patent in the Petition. My opinions are based on my own
`knowledge, experience, and education and with further reference to the exhibits
`cited herein. I will use the exhibit numbers listed on the “Table of Exhibits” on
`pages iii-v of the Petition (Paper 1), which I have included for ease of reference
`below:
`LIST OF EXHIBITS
`Exhibit Description
`Ex. 1001 U.S. Patent No. 11,344,552 to Bayever et al. (“the ’552 patent”)
`Ex. 1003 Conroy, et al., N. Engl. J. Med., 364(19):1817-25 (2011) (“Conroy”)
`Ex. 1004 Certified English Translation of the Protocol of Conroy, et al,
`https://www.nejm.org,1 (2011) (“Conroy Protocol”)
`Ex. 1005 Mahaseth, et al., Pancreas, 42(8):1311-15 (2013) (“Mahaseth”)
`Ex. 1006 International Publication No. WO2013/188586 A1 to Bayever
`(“Bayever”)
`1 https://www.nejm.org/doi/full/10.1056/NEJMoa1011923#APPNEJMOA1011923PRO
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`Exhibit Description
`Ex. 1007 Saif, Journal of the Pancreas, 15(3):278-79 (2014) (“Saif”)
`Ex. 1008 Ko, et al., British J. of Cancer, 109(4):920-25 (2013) (“Ko”)
`Ex. 1009 Cantore, et al., Oncology, 67(2):93-97 (2004) (“Cantore”)
`Ex. 1010 Nichetti, et al., JAMA Network Open, 7(1):1-13 (2024) (“Nichetti”)
`Ex. 1011 Nevala-Plagemann and Garrido-Laguna, Nature Reviews Clinical
`Oncology, 21(8):567-68 (2024) (“Nevala-Plagemann”)
`Ex. 1012 Masi, et al., Annals of Oncology, 15:1766-72 (2004) (“Masi”)
`Ex. 1013 Carnevale and Ko, Future Oncology, 12(4):453-464 (2016)
`(“Carnevale”)
`Ex. 1014 Dean, et al., J Clin Oncol, 34(4 Suppl.):tps482 (2016) (“Dean”)
`Ex. 1015 U.S. Provisional Application No. 62/208,209 to Bayever et al. (“the
`’209 Provisional”)
`Ex. 1016 Ginocchi, et al., Annals of Oncology, 23(9 Suppl.):ix238 (2012)
`(“Ginocchi”)
`Ex. 1017 Conroy Supplementary Appendix, N. Engl. J. Med., 364(19): 1817-25
`Supplementary Appendix (2011) (“Conroy Appendix”)
`Ex. 1018 Wainberg, et al., Ann Oncol., 3l (Suppl. 3):S241 (2020) (“Wainberg
`abstract”), corresponding poster (“Wainberg poster”), corresponding
`presentation (“Wainberg presentation”)
`Ex. 1019 Wainberg, et al., European Journal of Cancer, 151:14-24 (2021)
`(“Wainberg 2021”)
`Ex. 1020 U.S. Non-Provisional Patent Application No. 15/241,106 to Bayever et
`al. (“the ’106 Application”)
`Ex. 1021 Hatachi, et al., Cancer Diagn & Progn, 2(1):101-06 (2022)
`Ex. 1022 Zaniboni, et al., Cancer Chemother Pharmacol., 69(6):1641-45 (2012)
`Ex. 1023 Tsai, et al., J Gastrointest Oncol., 2(3):185-94 (2011)
`Ex. 1024 U.S. Patent No. 8,147,867 to Hong, et al (“the ’867 patent”)
`Ex. 1025 Press Release by Merrimack Pharmaceuticals, Inc. on August 1, 2011
`Ex. 1026 International Publication No. WO 2016/094402 A1 to Bayever
`(“Bayever II”).
`Ex. 1027 Alcindor, et al., Curr Oncol, 18(1):18-25 (2011)
`Ex. 1028 U.S. Provisional Application No. 62/216,736 to Bayever et al. (“the
`’736 Provisional”)
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`Exhibit Description
`Ex. 1029 U.S. Provisional Application No. 62/273,244 to Bayever et al. (“the
`’244 Provisional”)
`Ex. 1030 U.S. Provisional Application No. 62/281,473 to Bayever et al. (“the
`’473 Provisional”)
`Ex. 1031 U.S. Provisional Application No. 62/302,341 to Bayever et al. (“the
`’341 Provisional”)
`Ex. 1032 U.S. Provisional Application No. 62/323,245 to Bayever et al. (“the
`’245 Provisional”)
`Ex. 1033 Leucovorin Calcium Injection Label (2011)
`Ex. 1034 Gemcitabine Injection Label (2012)
`Ex. 1035 Abraxane Paclitaxel Label (2013)
`Ex. 1036 XELODA Capecitabine Label (2000)
`Ex. 1037 Camptosar FDA Label (2006)
`Ex. 1038 Eloxatin Oxaliplatin Injection Label (2012)
`Ex. 1039 Tarceva Erlotinib Tablets Label (2013)
`Ex. 1040 Fluorouracil Injection Label (2012)
`Ex. 1041 Conroy, et al., Curr Oncol Rep., 15(2):182-9 (2013)
`Ex. 1042 Ko, J Clin Oncol, 29(28):3727–29 (2011)
`Ex. 1043 Blazer, et al., ASCO Meeting Abstr. 32(Suppl. 3):275 (2014)
`Ex. 1044 Alessandretti, et al., ASCO Meeting Abstr. 31 (Suppl. 15): e15176
`(2013)
`Ex. 1045 Paller, et al., Clin Cancer Res., 20(16); 4210–17 (2014)
`Ex. 1046 Hamberg, et al., Eur J Cancer, 46(16):2870-78 (2010)
`Ex. 1047 Hess, et al., Annals of Oncology, 21(12):2390-95 (2010)
`Ex. 1048 Goel, et al., Anti-Cancer Drugs, 18(3):263-71 (2007)
`Ex. 1049 Rachamalla, et al., Anticancer Drugs, 15(3):211-7 (2004)
`Ex. 1050 Wildiers, Eur J Cancer, 43(15):2235-41 (2007)
`Ex. 1051 Gajra, et al., J Geriatr Oncol, 6(2):133-40 (2015)
`Ex. 1052 Shayne, et al., Cancer, 110(7):1611-20 (2007)
`Ex. 1053 Sharma, et al., J Clinical Oncology, 32(3 Suppl.): 562 (2014)
`Ex. 1054 Chang, et al., Cancer Chemother Pharmacol., 75(3):579-86 (2015)
`Ex. 1055 Roy, et al., Annals of Oncology, 24(6):1567-73 (2013)
`Ex. 1056 Slingerland, et al., Drug Discov Today, 17(3-4):160-66 (2012)
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`Exhibit Description
`Ex. 1057 Chen, et al., J Clin Oncol, 26(15 Suppl.):2565 (2008)
`Ex. 1058 Kim, et al., Cancer Res., 72(14 Suppl.): A41 (2012)
`Ex. 1059 Hann, et al., Cancer Res., 67(9 Suppl.): 5648 (2007)
`Ex. 1060 U.S. Non-Provisional Patent Application No. 62/343,313 to Bayever et
`al (“the ’313 Provisional”)
`Exs. 1084
`– 1123
`File History of U.S. Patent No. 11,344,552 Parts 1 to 40
`IV. THE UNDERSTANDING APPLIED TO MY ANALYSIS
`31. In preparing and forming my opinions set forth in this declaration, I
`have been informed by counsel of the relevant legal principles. I applied my
`understanding of those principles in forming my opinions. My understanding of
`those principles is summarized below. In performing my analysis and reaching my
`opinions and conclusions, I have been informed of and have been advised to apply
`various legal principles relating to unpatentability, which I set forth herein. In
`setting forth these legal standards, it is not my intention to testify about the law. I
`only provide my understanding of the law, as explained to me by counsel, as a
`context for the opinions and conclusions I am providing.
`32. I understand that my opinions regarding unpatentability are presented
`from the viewpoint of a person of ordinary skill in the art (“POSA” or “skilled
`artisan”) in the field of technology of the patent as of the patent’s priority date. In
`this declaration, my opinions are premised on the perspective of a POSA at the
`time of the earliest claimed priority date for the ’552 patent, which I have been
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`informed for this proceeding is August 21, 2015. (Ex. 1001 at 2.) To the extent
`Patent Owner asserts that the claims of the ’552 patent are entitled to an earlier
`priority or invention date, I reserve the right to supplement this declaration.
`33. I understand that in an IPR proceeding, claims should be construed as
`having their ordinary and customary meaning as understood by a POSA at the time
`of the invention. I understand that claims should be read in the context of the claim
`language of which they are a part. I further understand that the specification and
`file history can also inform the scope of the claims. If, after a review of this
`evidence, the construction is not apparent, I understand that extrinsic evidence,
`such as dictionary definitions, treatises, and trade journals, may be consulted to
`discern the meaning of a term. For terms where no construction is necessary, I
`have simply read the terms according to their ordinary and customary meaning. My
`understandings herein are made in light of how a POSA in or around 2015 would
`view the ordinary and customary meaning of the claim terms. I reserve the right to
`supplement my Declaration should any claim terms be given different
`constructions.
`34. I understand that a limitation can be expressly disclosed by the
`reference or be inherent. I further understand that for a feature to be inherently
`disclosed, a POSA would understand the inherent feature would necessarily and
`inevitably be present when the teaching of the reference is practiced. That is, I
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`understand that if a feature is not necessarily and inevitably present, it is not
`inherently disclosed.
`35. I understand that a patent claim may be unpatentable for obviousness
`if the difference between the claimed subject matter and the prior art is such that
`the subject matter as a whole would have been obvious at the time the invention
`was made to a person having ordinary skill in the art. I understand that a finding of
`obviousness requires a determination of: (1) the scope and content of the prior art;
`(2) the difference(s) between the claimed invention and the prior art; and (3) the
`level of skill of the POSA. I understand this analysis looks at whether the
`differences are such that the claimed invention as a whole would have been
`obvious to one of ordinary skill in the art at the time the invention was made. I also
`understand that a patent claim may be unpatentable for obviousness if the prior art
`discloses a range of doses and there is no evidence that a narrower claimed range
`(or specific dose) is critical for the operability of the claimed invention.
`36. It is my understanding from counsel that when there is some
`recognized reason to solve a problem, and there are a finite number of identified,
`predictable, and known solutions, a POSA has good reason to pursue the known
`options within his or her technical grasp. If such an approach leads to the expected
`success, it is likely not the product of innovation but of ordinary skill and common
`sense. It is my understanding that any need or problem known in the field of
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`endeavor at the time of invention or addressed by the patent can provide a reason
`for combining prior art elements to arrive at the claimed subject matter. I
`understand that only a reasonable expectation of success is necessary to show
`obviousness.
`37. My understanding is that the obviousness inquiry is not limited to just
`the prior art references being applied, but includes the knowledge and
`understanding of one of ordinary skill in the art. However, I understand that merely
`demonstrating that each element, independently, was known in the prior art is, by
`itself, insufficient to establish a claim was obvious. My understanding is that the
`test for obviousness is not whether the features of one reference can be
`incorporated into the structure of another reference, but rather what the combined
`teachings would have suggested to those of ordinary skill in the art. I further
`understand that a party seeking to invalidate a patent must show that a POSA
`would have been motivated to combine the teachings of the prior art references to
`achieve the claimed invention.
`38. I understand that a combination of old, familiar, or known elements
`according to known methods is likely to be obvious when it does no more than
`yield predictable results. Predictable variations of a work from one field are likely
`to be obvious, even if the variation is in another field. For example, where a
`technique has been used to improve a device, use of the same technique to improve
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`similar devices is a predictable variation and likely obvious. Likewise, if the use of
`prior art for improvements is simply done according to the prior art’s established
`functions, a POSA has simply implemented a predictable variation. If there existed
`at the time of invention a known problem for which there was an obvious solution,
`a patent claim encompassing that solution is not patentable.
`39. I further understand that any obviousness analysis must consider
`objective evidence of non-obviousness, where such evidence is present. I
`understand that objective evidence of non-obviousness includes (1) copying, (2)
`long felt but unsolved need, (3) failure of others, (4) commercial success of the
`invention, (5) unexpected results created by the claimed invention, (6) unexpected
`properties of the claimed invention, (7) licenses showing industry respect for the
`invention, (8) skepticism of skilled artisans before the invention, (9) recognition of
`invention’s advancement, and (10) contemporaneous invention by others or
`absence thereof. In general, there must be a connection between any of the factors
`and the claimed invention.
`40. I understand that a claim in a granted patent must be sufficiently
`supported by the original disclosure of the granted patent, read in the context of
`what one of ordinary skill in the art would have known at the time of the claimed
`invention. I understand that the basic inquiry for written description is whether the
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`specification provides sufficient information for a skilled artisan to recognize that
`the named inventors possessed the full scope of the claimed invention.
`41. I also understand that claims must be enabled by the original
`disclosure of the patent. For the claims to be enabled, the information contained in
`the disclosure must be sufficient to inform those skilled in the relevant art how to
`make and use the claimed invention without undue experimentation. I understand
`that the enablement requirement is separate and distinct from the written
`description requirement.
`42. I understand that to establish priority to a previously filed patent
`application, the earlier application must describe the later-claimed invention in
`sufficient detail that a POSA can clearly conclude that the inventor invented and
`had possession of each element of the claimed invention as of the earlier filing date
`being sought. I understand that this requires that the earlier disclosure must
`describe and enable every limitation of the later-claimed invention.
`43. Although the following analysis cites to particular pages, lines,
`paragraphs, or figures of many of the references discussed, these citations are
`intended to assist in understanding the various bases of my conclusions, and prior
`art teachings used to reach them. These citations are not intended to be an
`exhaustive recitation of every page, line number, or paragraph in which these
`teachings may be found. Similar teachings or disclosures may be found at other
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`pages, lines, or paragraphs, as well as in other references, and it is to be understood
`that my opinions and statements are made in view of all of the references and
`teachings I have reviewed.
`V. LEVEL OF ORDINARY SKILL IN THE ART
`44. In my opinion, the following definition of a POSA applies to the
`claims of the ’552 patent.
`45. Based on the ’552 patent, a POSA would have been a physician (e.g.,
`M.D. degree) who would have completed training in medical oncology, a
`pharmacist (e.g., Pharm.D. degree) with oncology experience, and/or a
`pharmaceutical scientist (e.g., Ph.D. degree with at least 2 years of postdoctoral
`experience). The POSA would also have experience in gastrointestinal oncology,
`as well as an understanding of pharmacogenomics. This POSA would have been
`part of a team of professionals with these credentials and post-doctoral experience.
`46. A POSA would have understood the prior art references referred to
`herein and would have the capability to draw inferences. It is understood that, to
`the extent necessary, a POSA may collaborate with one or more other POSAs for
`one or more aspects with which the other POSA may have expertise, experience,
`and/or knowledge. Additionally, a POSA could have had a lower level of formal
`education than what I describe here if the person has a higher degree of experience.
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`47. As shown by the qualifications provided in Appendix A and as
`explained in this declaration, I met the qualifications of a POSA for purposes of the
`’552 patent.
`VI. CLAIM CONSTRUCTION
`48. I understand that claims of a patent subject to IPR should be construed
`in accordance with the plain and ordinary meaning of such claim as understood by
`a POSA in view of the specification of the patent and the prosecution history
`pertaining to the patent.
`49. In my opinion, in view of the specification and prosecution history of
`the ’552 patent, the plain and ordinary meaning of “[a] method of treating
`metastatic adenocarcinoma of the pancreas in a human patient who has not
`previously received an antineoplastic agent to treat the metastatic adenocarcinoma
`of the pancreas,” would be understood by a POSA to broadly encompass
`administration of the recited four-drug regimen for the purpose of alleviating or
`reducing the symptoms, tumor size, and/or complications associated with
`metastatic adenocarcinoma of the pancreas or otherwise managing the disease
`without requiring any specified treatment effect. Specifically, the claims do not
`require that the treatment regimen be superior to any other standard treatment;
`simply that the POSA would expect that the treatment regim