IPR2016-01284
`Declaration of Dr. Paul Bunn
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`APOTEX INC., APOTEX CORP., APOTEX PHARMACEUTICALS
`HOLDINGS INC., AND APOTEX HOLDINGS, INC.,
`Petitioners,
`v.
`OSI PHARMACEUTICALS, INC.,
`Patent Owner.
`____________________________________________
`Case IPR2016-01284
`U.S. Patent No. 6,900,221
`____________________________________________
`
`DECLARATION OF DR. PAUL BUNN
`
`OSI 2021
`APOTEX V. OSI
`IPR2016-01284
`
`
`Declaration of Dr. Paul Bunn
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`APOTEX INC., APOTEX CORP., APOTEX PHARMACEUTICALS
`HOLDINGS INC., AND APOTEX HOLDINGS, INC.,
`Petitioners,
`v.
`OSI PHARMACEUTICALS, INC.,
`Patent Owner.
`____________________________________________
`Case IPR2016-01284
`U.S. Patent No. 6,900,221
`____________________________________________
`
`DECLARATION OF DR. PAUL BUNN
`
`OSI 2021
`APOTEX V. OSI
`IPR2016-01284
`
`
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
`
`TABLE OF CONTENTS
`
`Page
`I.
`BACKGROUND .............................................................................................1
`OVERVIEW....................................................................................................4
`II.
`LEGAL PRINCIPLES.....................................................................................9
`III.
`INTRODUCTION AND SUMMARY OF OPINIONS................................11
`IV.
`DRUG DEVELOPMENT AND CLINICAL TRIALS.................................12
`V.
`THE ’221 PATENT.......................................................................................18
`VI.
`VII. SUMMARY OF REFERENCES ..................................................................20
`A. U.S. Patent No. 5,747,498 (“Schnur”) ................................................20
`B.
`OSI 10-K .............................................................................................22
`C.
`Jackson B. Gibbs, Anticancer drug targets: growth factors and
`growth factor signaling, 105 J. Clinical Investigation 9 (2000)
`(“Gibbs”) .............................................................................................24
`VIII. THE COMBINATION OF SCHNUR AND OSI 10-K OR GIBBS DOES
`NOT RENDER THE CHALLENGED CLAIMS OBVIOUS ......................31
`A.
`A Skilled Artisan Would Not Have Been Motivated to Combine
`Schnur with Either OSI 10-K or Gibbs...............................................31
`1.
`A Medical Oncologist Would Not Rely on a Securities
`Disclosure Filing to Develop a Method of Treating Cancer ....31
`The Correlation Between the Chemical Structure and Chemical
`Name Known Today as Erlotinib and CP-358,774 Would Not
`Have Been Part of the Common General Knowledge of a
`POSA.........................................................................................32
`Because There is No Efficacy Data in OSI 10-K or Gibbs, A
`Skilled Artisan Would Not Have Been Motivated to Combine
`
`2.
`
`3.
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`2.
`
`B.
`
`Either Reference with Schnur to Achieve the Claimed
`Invention ...................................................................................33
`A Skilled Artisan Would Not Have Had a Reasonable Expectation of
`Success in Treating NSCLC With a Therapeutically Effective Amount
`of Erlotinib Based on the Combination of Schnur with Either OSI 10-
`K or Gibbs ...........................................................................................34
`1.
`A Skilled Artisan Would Not Have Had a Reasonable
`Expectation of Success by Combining Schnur with OSI 10-K 35
`A Skilled Artisan Would Not Have Had a Reasonable
`Expectation of Success by Combining Schnur and Gibbs........39
`IX. OBJECTIVE INDICIA OF NON-OBVIOUSNESS.....................................45
`A.
`Long-Felt Unresolved Need and the Failure of Others.......................45
`1.
`Erlotinib Addressed a Long-Felt Unresolved Need for a
`Targeted, Well Tolerated and More Effective NSCLC
`Therapy .....................................................................................45
`Other Attempts to Develop Targeted, NSCLC Drug Products
`Failed Clinical Trials.................................................................47
`Tarceva Provided a Targeted, Well Tolerated and More
`Effective NSCLC Treatment.....................................................51
`Unexpected Results.............................................................................54
`B.
`X. AVAILABILITY FOR CROSS EXAMINATION.......................................55
`XI. RIGHT TO SUPPLEMENT..........................................................................55
`XII. JURAT...........................................................................................................55
`
`2.
`
`3.
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`I, Dr. Paul Bunn, declare as follows:
`1.
`My name is Paul Bunn.
`
`I.
`
`BACKGROUND
`2.
`I am currently a Distinguished Professor at the University of Colorado
`
`School of Medicine, Division of Medical Oncology, where I hold the James
`
`Dudley Chair in Cancer Research. I joined the University of Colorado as a
`
`Professor and Head of the Division of Medical Oncology in 1984, which position I
`
`held until 1994. From 1986 to 2009, I served as the Director of the University of
`
`Colorado Comprehensive Cancer Center.
`
`3.
`
`I received a B.A. in Biology from Amherst College in 1967, and an
`
`M.D. from Cornell University in 1971. After obtaining my M.D., I completed first
`
`my internship and then my residency at the University of California, San
`
`Francisco.
`
`4.
`
`In 1973, I became a Clinical Associate in the Medicine Branch of the
`
`National Cancer Institute at the NIH in Bethesda. From 1976 to 1981, I was a
`
`Senior Investigator for the National Cancer Institute’s VA Medical Oncology
`
`Branch at the Washington VA Hospital. From 1981 to 1984, I served as the Head
`
`of the Cell Kinetic Section at the National Cancer Institute’s Navy Medical
`
`Oncology Branch in Bethesda.
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`Declaration of Dr. Paul Bunn
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`5.
`
`In 1981, I became an Associate Professor of Medicine at the
`
`University of Health Sciences in Bethesda, a position I held until I joined the
`
`University of Colorado in 1984.
`
`6.
`
`I am licensed to practice medicine in Colorado, and hold board
`
`certifications in internal medicine and medical oncology.
`
`7.
`
`I am a member of numerous societies in the field of oncology and
`
`lung cancer, including the American Society of Clinical Oncology (“ASCO”), the
`
`International Association for the Study of Lung Cancer (“IASLC”), The American
`
`Association of Cancer Institutes (“AACI”), and the American Association for
`
`Cancer Research. I have served as President of ASCO, IASLC, and AACI. I also
`
`served as the Executive Director of the IASLC from 2003-2013.
`
`8.
`
`From 1992 to 1996, I was a member of the U.S. Food and Drug
`
`Administration’s (“FDA”) Oncology Drug Advisory Committee, which consists of
`
`recognized authorities in the fields of general oncology, pediatric oncology,
`
`hematologic oncology, immunologic oncology, biostatistics, and other related
`
`professions and which reviews and evaluates data concerning the safety and
`
`effectiveness of marketed and investigational new drugs for use in the treatment of
`
`cancer and makes recommendations to the FDA. I served as Chairman of the
`
`Committee from 1995 to 1996.
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`9.
`
`Throughout my career, my research has focused on therapies for lung
`
`cancer and I have treated thousands of lung cancer patients. I have published more
`
`than 320 articles in peer-reviewed journals, 122 reviews, and 90 book chapters on
`
`lung cancer. I have been a principal investigator on numerous national and local
`
`therapeutic trials of investigational lung cancer treatments. I am the principal
`
`investigator of the Lung Cancer Mutation Consortium (“LCMC”) that consists of
`
`16 academic medical centers with a primary goal of conducting panels of lung
`
`cancer molecular and immunologic tests on patients with lung cancers to place
`
`those with certain biomarker characteristics on therapeutic trials of novel targeted
`
`therapies. I am the principal investigator for the SPORE grant in lung cancer that
`
`is designed to conduct translational research, the goal of which is to expand
`
`understanding of the biology of lung cancer, to find new methods of diagnosis,
`
`prevention and treatment, and to serve as a regional, national and international
`
`resource for the study of lung cancer.
`
`10.
`
`I have served on the editorial boards of various publications in the
`
`field, including the Journal of Clinical Oncology, Lung Cancer, and Oncology
`
`Times.
`
`11.
`
`I have received numerous awards for my research in the field of lung
`
`cancer and for my work treating individuals with lung cancer. For example,
`
`in 2016, I was awarded the Karnofsky Award, which is the highest honor bestowed
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`by the American Society of Clinical Oncology. I was also awarded the James
`
`Addison Sewall Award by the University of Colorado in 2001, the American
`
`Italian Cancer Research Foundation Award in 2002, the IASLC Merit Award in
`
`2003, and the SPORE Leadership Award in 2004.
`
`12. Over the course of my career, I have trained and supervised
`
`approximately 50 Ph.D. students, post-doctoral scientists and medical oncology
`
`fellows.
`
`13.
`
`I am named as an inventor on at least seven issued U.S. patents and
`
`three European patents relating to the treatment of cancer.
`
`14.
`
`I have testified in one other case in the last four years: Dana-Farber
`
`Cancer Institute, Inc. v. Gatekeeper Pharmaceuticals, Inc., Case No.
`
`1:10-cv-11613 (D. Mass).
`
`15. My complete curriculum vitae is attached hereto as Appendix 1.
`
`II. OVERVIEW
`16.
`I have reviewed:
`
`(1) U.S. Patent No. 6,900,221 (the “(cid:1932)221 patent”), Exhibit 1001;
`
`(2) U.S. Application No. 09/711,272 filed on November 9, 2000;
`
`(3)
`
`the three provisional applications filed in 1999 and 2000 to
`
`which the ’221 patent claims priority; and
`
`(4)
`
`the related prosecution history.
`
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`Declaration of Dr. Paul Bunn
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`17.
`
`I also have reviewed the following documents:
`
`(1)
`
`Paper 3 – Petition for Inter Partes Review of U.S. Patent No.
`
`(2)
`
`(3)
`
`(4)
`
`(5)
`
`(6)
`
`(7)
`
`(8)
`
`6,900,221 (the “Petition”)
`
`Paper 7 – Patent Owner’s Preliminary Response
`
`Paper 8 – Decision on Institution
`
`Exhibit 1002 – Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`Exhibit 1009 – U.S. Patent No. 5,747,498 (“Schnur”)
`
`Exhibit 1010 – Jackson B. Gibbs, Anticancer drug targets:
`
`growth factors and growth factor signaling, 105 J. Clinical
`
`Investigation 9 (2000)
`
`Exhibit 1011 – OSI 10-K
`
`Exhibit 1016 – James D. Moyer et al., Induction of Apoptosis
`
`and Cell Cycle Arrest by CP-358,774, an Inhibitor of
`
`Epidermal Growth Factor Receptor Tyrosine Kinase, 57
`
`Cancer Research 4838 (1997) (“Moyer”)
`
`(9)
`
`Exhibit 1028 – OSI Pharmaceuticals, Inc. v. Mylan
`
`Pharmaceuticals Inc., Case No. 09-cv-185-SLR (D. Del. May
`
`1, 2012)
`
`(10) Exhibit 2004 – Center for Drug Evaluation and Research
`
`Approval Package for: Application Number 21-743 for
`
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`Declaration of Dr. Paul Bunn
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`Tarceva™ (erlotinib hydrochloride), Statistical Review(s),
`
`available at
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-
`
`743_Tarceva_StatR.PDF (“Tarceva Approval Package”)
`
`(11) Exhibit 2006 – J.R. Woodburn et al., ZD1839, an epidermal
`
`growth factor tyrosine kinase inhibitor selected for clinical
`
`development, 38 AACR Program / Proceedings 633 (1997)
`
`(“Woodburn”)
`
`(12) Exhibit 2007 – Cover Page and Table of Contents for Volume
`
`105 of the Journal of Clinical Investigation,
`
`http://www.jci.org/105/1 (last visited 10/5/2016)
`
`(13) Exhibit 2017 – Order on Joint Motion to Limit Petition Under
`
`37 C.F.R. § 42.71 – IPR 2016-01284
`
`(14) Exhibit 2018 – International Nonproprietary Names for
`
`Pharmaceutical Substances (INN), 15 WHO Drug Information
`
`(Nov. 2, 2001)
`
`(15) Exhibit 2019 – Giuseppe Giaccone, Targeting HER1/EGFR in
`
`cancer therapy: experience with erlotinib, 4 Future Oncology
`
`449 (2005) (“Giaccone 2005”)
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`Declaration of Dr. Paul Bunn
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`(16) Exhibit 2020 – The transcript of the deposition of Dr. Giuseppe
`
`Giaccone in this case
`
`(17) Exhibit 2024 – Abstracts from 1999 ASCO Proceedings
`
`L.L. Siu et al., Dose and Schedule-Duration Escalation of the
`Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase
`(TK) Inhibitor CP-358, 774: A Phase I and Pharmacokinetic
`(PK) Study, 18 ASCO Program / Proceedings 388a (1999)
`D.D. Karp et al., Phase I Dose Escalation Study of Epidermal
`Growth Factor Receptor (EGFR) Tyrosine Kinase (TK)
`Inhibitor CP-358,774 in Patients with Advanced Solid Tumors,
`18 ASCO Program / Proceedings 388a (1999)
`(18) Exhibit 2025 – Abstracts from the 1999 AACR-NCI-EORTC
`
`International Conference
`
`(19) Exhibit 2026 – 2004 Tarceva® Package Insert, available at
`
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/02
`
`1743lbl.pdf
`
`(20) Exhibit 2027 – 2005 Tarceva® Package Insert, available at
`
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/02
`
`1743s003lbl.pdf
`
`(21) Exhibit 2028 – 2010 Tarceva® Package Insert, available at
`
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/02
`
`1743s14s16lbl.pdf
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`Declaration of Dr. Paul Bunn
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`(22) Exhibit 2029 – 2013 Tarceva® Package Insert, available at
`
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?eve
`
`nt=overview.process&ApplNo=021743
`
`(23) Exhibit 2030– 2016 Tarceva® Package Insert, available at
`
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/02
`
`1743s025lbl.pdf
`
`(24) Exhibit 2031 – 2005 Iressa® Package Insert, available at
`
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/02
`
`1399s008lbl.pdf
`
`(25) 2015 Iressa® Package Insert, available at
`
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/20
`
`6995s000lbl.pdf
`
`(26) Exhibit 2032 – Letter from Dr. Richard Padzur, Director of the
`
`FDA’s Division of Oncology Drug Products to Patricia
`
`Palumbo, AstraZeneca Pharmaceuticals LP’s Regulatory
`
`Affairs Director (June 17, 2005)
`
`(27) Exhibit 2036 – Roy S. Herbst & Paul A. Bunn, Jr., Targeting
`
`the Epidermal Growth Factor Receptor in Non-Small Cell Lung
`
`Cancer, 9 Clinical Cancer Research 5813 (2003)
`
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`(28) Exhibit 2039 – Paul A. Bunn, Jr. & Nick Thatcher, Conclusion,
`
`13 Oncologist 37 (2008)
`
`18.
`
`I am being compensated at my typical university consulting rate for
`
`my work on this matter. The University of Colorado School of Medicine receives
`
`$500/hour for the time I spend on this matter and I am compensated by the
`
`University. My compensation is not dependent on and in no way affects the
`
`substance of my statements in this Declaration.
`
`19.
`
`I have no financial interest in Patent Owner. I similarly have no
`
`(cid:73)(cid:76)(cid:81)(cid:68)(cid:81)(cid:70)(cid:76)(cid:68)(cid:79)(cid:3)(cid:76)(cid:81)(cid:87)(cid:72)(cid:85)(cid:72)(cid:86)(cid:87)(cid:3)(cid:76)(cid:81)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:1932)221 patent.
`
`III. LEGAL PRINCIPLES
`20.
`I have been informed that a patent claim is obvious if the subject
`
`matter as a whole would have been obvious to one of ordinary skill in the art at the
`
`time the invention was made. The obviousness analysis involves several factual
`
`inquiries: (1) the scope and content of the prior art; (2) the differences between the
`
`prior art and the claimed invention; (3) the level of ordinary skill in the art at the
`
`time of the invention; and (4) the existence of objective indicia of non-obviousness
`
`(“objective indicia”), such as a long-felt but unresolved need, the failure of others,
`
`unexpected results and commercial success. I understand that for objective indicia
`
`to be given weight, there must be a nexus between the evidence and the merits of
`
`the claimed invention.
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`21.
`
`I have been informed that, for a claim to have been obvious, there
`
`must have been some reason or motivation for a skilled artisan to modify or
`
`combine the teachings of the prior art references to achieve the claimed invention,
`
`and the skilled artisan must have had a reasonable expectation of success in doing
`
`so. I have also been informed that it is improper to rely on hindsight reasoning in
`
`the obviousness analysis.
`
`22.
`
`The analysis I provide in this declaration is from the perspective of a
`
`person of ordinary skill in the art of the ’221 patent at the time of the invention. I
`
`have been asked to assume a priority date for the claimed invention of March 30,
`
`2000. In my view, one of ordinary skill in the art as of that time would be a
`
`medical oncologist who would hold an M.D. degree and would have completed
`
`several years of practice in the field of oncology. I qualify (and have qualified
`
`since before 2000) as a person having at least ordinary skill in the art under this
`
`definition.
`
`23.
`
`I understand that Dr. Giaccone has offered an alternative definition of
`
`the level of skill in the art, which incorporates additional requirements (specialized
`
`training in thoracic oncology and experience using medications and therapies
`
`effective for treating lung cancers). Declaration of Giuseppe Giaccone at ¶ 19
`
`(“Giaccone Decl.”) (Ex. 1002). I qualify (and have qualified since before 2000) as
`
`a person having at least ordinary skill in the art under the definition offered by Dr.
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`Giaccone. Both as of March 2000 and today, I hold specialized training in thoracic
`
`oncology, have several years of clinical experience, and have a substantive
`
`understanding and experience using the medications and therapies effective for
`
`treating various lung cancers. I was then, and remain, aware of current advances in
`
`the use of various medications and therapies to treat cancer, including lung cancer.
`
`The opinions I offer in this declaration regarding the validity of the ’221 patent are
`
`the same regardless of which definition of the level of skill in the art is adopted.
`
`IV.
`
`INTRODUCTION AND SUMMARY OF OPINIONS
`24.
`I understand that in its Petition Apotex contends that claims 44, 45, 46
`
`and 53 of the ’221 patent are rendered obvious by Schnur in combination with OSI
`
`10-K or Gibbs, and that the Board instituted this IPR proceeding on the basis of
`
`those alternative obviousness combinations. I have read the Petition and disagree
`
`that the combination of Schnur and OSI 10-K or Gibbs renders claims 44, 45, 46
`
`and 53 of the ’221 patent obvious.
`
`25. A skilled artisan would not have been motivated to combine OSI 10-K
`
`or Gibbs with Schnur at least because (1) a skilled artisan would not have been
`
`motivated to combine the Schnur reference with a securities disclosure statement,
`
`(2) OSI 10-K and Gibbs do not refer to compound structures or chemical names
`
`identified in Schnur and only refer to CP-358,774, and (3) none of these references
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`contains specific disclosure of or efficacy data relating to use of erlotinib against
`
`NSCLC.
`
`26. A skilled artisan also would not have had a reasonable expectation of
`
`success in achieving the claimed invention by combining OSI 10-K or Gibbs with
`
`Schnur, because none of the references describes treatment of NSCLC with
`
`erlotinib or any efficacy data relating to such treatment. Without any efficacy data,
`
`one could not predict whether, or in what amount, erlotinib would provide a
`
`therapeutically effective treatment for NSCLC as claimed.
`
`27. Objective indicia, including addressing the long-felt unresolved need
`
`for new NSCLC treatments and the unexpected results associated with developing
`
`erlotinib as a NSCLC drug product, provide additional evidence of the
`
`non-obviousness of the challenged claims of the ’221 patent.
`
`V.
`
`DRUG DEVELOPMENT AND CLINICAL TRIALS
`28.
`Lung cancer is divided into 4 histologic subtypes according to the
`
`World Health Organization (“WHO”) classification: adenocarcinoma, squamous
`
`carcinoma, large-cell carcinoma, and small-cell carcinoma. As of 2000,
`
`adenocarcinoma, squamous carcinoma, and large-cell carcinoma had similar
`
`treatment and staging paradigms, and were frequently grouped together as non-
`
`small cell lung cancer (“NSCLC”). In 2000 (and over the last few decades),
`
`non-small cell lung cancer has been the leading cause of cancer death in humans in
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`the United States and in the world, causing more than 1 million deaths worldwide
`
`annually.
`
`29. Unfortunately, most NSCLC patients have advanced, unresectable
`
`disease at diagnosis, which has a very poor prognosis. In the 1990s, the standard
`
`of care for NSCLC was chemotherapy. Roy S. Herbst & Paul A. Bunn, Jr.,
`
`Targeting the Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer,
`
`9 Clinical Cancer Research 5813, 5813 (2003) (Ex. 2036). Response rates to
`
`chemotherapy in NSCLC are modest, and limited by the toxicity associated with
`
`those treatments.
`
`30. Chemotherapy agents nonspecifically kill normal proliferating cells in
`
`addition to cancer cells, and therefore are frequently associated with dose-limiting
`
`toxicities. For example, chemotherapy can cause nausea, vomiting, hair loss,
`
`severe fatigue, neuropathy (i.e., the malfunction of the nerves) and severe fluid
`
`retention or effusion. Id. at 5814. All of the chemotherapy agents produce
`
`hematological toxicities, which include lowering of white blood cell count, making
`
`patients vulnerable to infection, lowering of platelet count, making patients
`
`vulnerable to bleeding, and lowering of red blood cells, causing anemia and
`
`fatigue. Id. Any of these hematological toxicities can be life threatening and
`
`occasionally fatal. Id. Furthermore, increasing rounds of chemotherapy generate
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`an increased risk that tumors will develop multidrug resistance, limiting future
`
`therapeutic options. Id.
`
`31.
`
`The limitations associated with chemotherapy agents led to efforts to
`
`develop alternative treatments. In the 1980s, medical oncologists began
`
`considering whether autocrine/paracrine growth factor stimulation was causally
`
`related to cancer cell growth. Several growth factor receptor pathways were
`
`identified for a range of cancers, including lung cancer. According to the
`
`developing theory, cancer cells were thought to overexpress growth factor
`
`receptors that are used by normal cells to divide and replenish themselves. The
`
`overexpression of these receptors on cancer cells was believed to lead to
`
`uncontrolled cancer growth in response to growth factors secreted by the cancer
`
`cells themselves (autocrine growth) or by neighboring normal cells (paracrine
`
`growth).
`
`32.
`
`In the 1990s, several types of growth factor receptors were described,
`
`including the epidermal growth factor receptor (“EGFR”). EGFR expression is
`
`one step in a complex signaling pathway leading to cell proliferation. For
`
`example, the EGFR phosphorylation process triggers other downstream signaling
`
`proteins leading to cell reproduction. EGFR was frequently overexpressed on
`
`epithelial cancers (carcinomas) including lung cancers.
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`33. Medical oncologists became interested in developing therapies
`
`designed to inhibit the EGFR pathway. Whereas chemotherapeutic drugs affect all
`
`dividing cells, agents were designed to selectively inhibit specific growth factor
`
`receptor pathways, such as the EGFR pathway. These molecules were designed to
`
`be target specific agents, and it was postulated that they might maximize
`
`therapeutic benefit while minimizing toxicity to normal cells. Monoclonal
`
`antibodies were designed to bind to the external domain of the EGFR and small
`
`molecule tyrosine kinase inhibitor (“TKI”) drugs were designed to bind to the
`
`intracellular ATP binding site of EGFR.
`
`34. Medical oncologists hoped that the inhibition of the EGFR pathway
`
`would provide a targeted treatment for cancers that overexpressed the EGFR.
`
`However, the great majority of the initial trials for the targeted agents of the EGFR
`
`pathway were disappointing, as the response rates for cancer patients were
`
`significantly lower than expected. Assays measuring the in vitro inhibition of
`
`EGFR by TKIs were a poor proxy for the in vivo activity of TKIs for the treatment
`
`of cancer. As of the late 1990s, it remained an unproven hypothesis that the
`
`overexpression of EGFR was causally connected to cancer progression, and it was
`
`unknown whether any TKI would be a successful treatment for NSCLC.
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`35. Despite their potential promise, the overwhelming majority of
`
`investigational therapies, including monoclonal antibodies to EGFR and TKIs like
`
`EGFR inhibitors, failed in clinical trials.
`
`36. As of the late 1990s, clinical trials of investigational cancer treatments
`
`generally involved three Phases: Phase I, Phase II and Phase III. Phase I trials
`
`were designed as safety trials (1) to measure whether the proposed dose of a drug
`
`was safe and (2) to evaluate the pharmacokinetic properties of the drug product in
`
`patients. Phase II trials were designed to evaluate whether a particular drug
`
`product was an effective treatment for a particular cancer type at a safe dosage
`
`level. Phase III trials were designed to compare the efficacy of the proposed drug
`
`product with approved cancer therapies.
`
`37. During early clinical development of antigrowth factor receptor TKIs,
`
`it was learned that the inhibition of an overexpressed receptor was generally
`
`insufficient to inhibit cancer growth in people. The vast majority of TKIs that
`
`entered Phase II and Phase III trials around the time of the invention for the
`
`treatment of NSCLC failed because the TKIs had insufficient efficacy (the TKIs
`
`did not generate sufficient clinical response or prolonged survival), among other
`
`reasons, even if they had shown promising in vitro inhibition or other promising
`
`activity in preclinical models.
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`38. As described in Section IX.A.2 infra, CI1066, CI1033, AZ6274, PKI-
`
`166, PD153035, BIBX1382, EKB-569, CXL-647, dacomitinib and rociletinib were
`
`EGFR inhibitors that entered human clinical trials, including for the treatment of
`
`NSCLC. All of these TKIs failed in clinical trials despite promising in vitro
`
`activity.
`
`39.
`
`The reasons for the failures of these and countless other TKIs were
`
`multi-factorial. Some of the TKIs had poor pharmacokinetic profiles characterized
`
`by poor absorption and/or short half-lives due to rapid metabolism. Other TKIs
`
`were limited by drug-drug interactions and the metabolism of the TKIs could be
`
`altered by other drugs and diseases. Many of the TKIs failed due to toxicities
`
`produced by the binding of the TKI to the target receptors of healthy cells or the
`
`binding of the TKI to other receptors expressed on normal cells. Other TKIs were
`
`limited by toxicities from metabolites of the TKI. Finally, other TKIs failed due to
`
`drug class toxicities causing QTc prolongation and sudden death. Many of the
`
`TKIs had dose-limiting toxicities such that they were not even studied in patients
`
`with growth factor mutations. Many TKIs were limited by a combination of these
`
`shortcomings.
`
`40. Around the year 2000, drugs targeting many other receptors also
`
`failed in clinical trials underscoring the high failure rates and the inability to
`
`predict outcomes in lung cancer.
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`41. Despite the poor performance of TKIs as a class, erlotinib was
`
`discovered as an effective targeted therapy for the treatment of NSCLC. Tarceva®
`
`is the commercial embodiment of Patent Owner’s claimed method of treating
`
`NSCLC with a therapeutically effective amount of erlotinib. The successful use of
`
`Tarceva (erlotinib) for the treatment of NSCLC was not known or expected, and
`
`could not have been predicted by one of ordinary skill in the art, as of March 30,
`
`2000. Tarceva addressed a long-felt unresolved need for new treatment options for
`
`NSCLC, and changed the paradigm for how NSCLC is treated. To this day, I
`
`continue to prescribe Tarceva to patients with NSCLC.
`
`VI. THE ’221 PATENT
`42.
`I have reviewed U.S. Patent No. 6,900,221 and the outstanding
`
`claims 44, 45, 46 and 53, which the Petitioner has challenged in this proceeding.
`
`I understand that claim 44 is an independent claim, from which claims 45, 46 and
`
`53 depend. Claim 53 focuses specifically on treatment of NSCLC. Claim 44
`
`reads:
`
`44. A method for the treatment of NSCLC (non small
`cell lung cancer), pediatric malignancies, cervical and
`other tumors caused or promoted by human papilloma
`virus (HFV), Barrett’s esophagus (pre-malignant
`syndrome), or neoplastic cutaneous diseases in a
`mammal comprising administering to said mammal a
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`therapeutically effective amount of a pharmaceutical
`composition comprised of at least one of N-(3-
`ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine, or pharmaceutically acceptable salts
`thereof in anhydrous or hydrate forms, and a carrier.
`
`’221 Patent col. 35:26-36.
`43. My understanding of the plain meaning of “therapeutically effective”
`
`and “treatment” as those terms are used in claim 44 within the context of the ’221
`
`patent, is that those limitations require an amount of erlotinib necessary to have a
`
`therapeutic effect with respect to one or more of the cancers recited in claim 44
`
`(and for claim 53, NSCLC in particular). See ’221 patent col. 14:9-15 (“The term
`
`‘treating’ as used herein, unless otherwise indicated, means reversing, alleviating,
`
`inhibiting the progress of, or preventing the disorder or condition to which such
`
`term applies, or one or more symptoms of such disorder or condition. The term
`
`‘treatment’, as used herein, refers to the act of treating, as ‘treating’ is defined
`
`immediately above.”). In the context of the ’221 patent, a therapeutically effective
`
`treatment comprises reversing, alleviating, inhibiting the progress of or preventing
`
`the growth of the enumerated cancers. A reasonable expectation of success in
`
`practicing the claimed methods requires a reasonable expectation of successfully
`
`treating NSCLC with a therapeutically effective amount of erlotinib. The mere use
`
`or administration of erlotinib in NSCLC (e.g., in a Phase I safety trial that does not
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`report efficacy data) would not give a person having ordinary skill in the art a
`
`reasonable expectation of success in achieving therapeutically effective treatment
`
`according to the claimed methods.
`
`VII. SUMMARY OF REFERENCES
`A.
`U.S. Patent No. 5,747,498 (“Schnur”)
`44. U.S. Patent No. 5,747,498 (“Schnur”) is titled “Alkynyl and Azido-
`
`substituted 4-Anilinoquinazolines” and is assigned to OSI and Pfizer. I understand
`
`that Schnur was filed May 28, 1996 and issued May 5, 1998; it claims priority (as a
`
`continuation-in-part) to a PCT application filed June 6, 1995.
`
`45.
`
`Schnur relates to compounds of the formula I
`
`and to pharmaceutically acceptable salts thereof, which are useful for treating
`
`hyperproliferative diseases such as cancer. Schnur exemplifies 105 compounds
`
`falling within this large structural genus, including N-(3-ethynylphenyl)-6,7-bis(2-
`
`methoxyethoxy)quinazolin-4-amine, which is depicted below.
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`IPR2016-01284
`Declaration of Dr. Paul Bunn
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`46.
`
`Schnur generally provides that the compounds of the invention may
`
`be used on a “variety of human tumors (renal, liver, kidney, bladder, breast,
`
`gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic
`
`carcinomas, sarcomas, glioblastomas, various head and neck tumors),” as well as
`
`against “a range of leukemias and lymphoid malignancies” and “inflammatory,
`
`angiogenic and immunologic disorders.” Schnur cols. 13:1-14:30. Schnur lists
`
`“lung” cancer among the list of numerous potential cancers for which the broad
`
`genus and 105 exemplified compounds (including erlotinib) may be useful.
`
`Schnur does not describe the specific use of erlotinib for the treatment of NSCLC,
`
`which is a specific subset of “lung” cancer.
`
`47.
`
`Schnur generally describes the “approximate” determination of “the
`
`in vitro inhibition of EGFR kinase activity.” See Schnur col. 15:4-10 (“Although
`
`the inhibitory properties of the compounds of Formula I vary with structural
`
`change as expected, the activity generally exhibited by these agents, determined in
`
`the manner described above, is in the range of IC50 = 0.0001-(cid:22)(cid:19)(cid:3)(cid:541)(cid:48)(cid:17)”). Schnur
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`IPR2016-01284
`Declaration of Dr. P
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