`
`In the United States Patent and Trademark Office
`
`
`Before the Patent Trial and Appeal Board
`
`
`
`ACTAVIS LABORATORIES FL, INC., AMNEAL PHARMACEUTICALS LLC,
`AMNEAL PHARMACEUTICALS OF NEW YORK, LLC, DR. REDDY’S
`LABORATORIES, INC., DR. REDDY’S LABORATORIES, LTD., SUN
`PHARMACEUTICALS INDUSTRIES, LTD., SUN PHARMACEUTICALS
`INDUSTRIES, INC., TEVA PHARMACEUTICALS USA, INC., WEST-WARD
`PHARMACEUTICAL CORP., and HIKMA PHARMACEUTICALS, LLC
`
`Petitioners
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`
`Patent Owner
`
`
`
`U.S. Patent No. 8,822,438 to Auerbach et al.
`Issue Date: September 2, 2014
`Title: Methods and Compositions for Treating Cancer
`
`
`Inter Partes Review No. IPR2017-00853
`
`
`
`
`
`DECLARATION OF MARC B. GARNICK, M.D.
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1002, p. 1 of 92
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`
`
`I, Marc B. Garnick, M.D., do hereby declare:
`
`I.
`
`INTRODUCTION
`1.
`
`I am making this declaration at the request of Actavis Laboratories FL,
`
`Inc., Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals Of New York, LLC,
`
`Dr. Reddy’s Laboratories, Inc., Dr. Reddy’s Laboratories, Ltd., Sun Pharmaceuticals
`
`Industries, Ltd., Sun Pharmaceuticals Industries, Inc., Teva Pharmaceuticals USA,
`
`Inc., West-Ward Pharmaceutical Corp., and Hikma Pharmaceuticals, LLC in the
`
`matter of the Inter Partes Review (IPR) of U.S. Patent No. 8,822,438 (the “’438
`
`Patent”), as set forth in the above caption.
`
`A. Education and Professional Background
`2.
`I am a medical oncologist specializing in the care of patients with
`
`prostate cancer in the Division of Hematology and Oncology, Department of
`
`Medicine at the Beth Israel Deaconess Medical Center, Harvard Medical School, in
`
`Boston MA. My clinical and research interests have focused on urologic cancers,
`
`with a special interest in prostate cancer. I am actively involved in clinical research
`
`and in the past have devoted my professional activities to the development of drugs
`
`that are currently being used in the management of prostate cancer. I serve as the
`
`medical director for Cancer Services Brockton Hospital/Signature Health Care,
`
`Cambridge Health Alliance, which includes Cambridge Hospital and Whidden
`
`Memorial Hospital and the medical liaison for all of the cancer services that the
`
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`BIDMC provide. I am the director of Cancer Programs for Network Development
`
`at the Beth Israel Deaconess Medical Center. I am Gorman Brothers Clinical
`
`Professor of Medicine at Harvard Medical School, an endowed professorial chair in
`
`medicine.
`
`3.
`
`I received a Bachelor of Arts degree in Biology from Bowdoin College,
`
`Brunswick, Maine. I obtained my medical degree from the University of
`
`Pennsylvania School of Medicine (now the Perelman School of Medicine at the
`
`University of Pennsylvania) in 1972. I completed my internship and residency in
`
`internal medicine at the Hospital of the University of Pennsylvania in 1974. I then
`
`completed two fellowships: one at the National Institutes of Health in the National
`
`Institute of Arthritis, Metabolism and Digestive Diseases in 1976 and then a
`
`fellowship in Medical Oncology at the Dana Farber Cancer Institute, Boston MA in
`
`1978. My curriculum vitae is attached as Exhibit A.
`
`4.
`
`From 1978 until 1996, I practiced medicine at the Dana Farber Cancer
`
`Institute and Brigham and Women’s Hospital in Boston, MA. Since 1996, I have
`
`practiced at the Beth Israel Deaconess Medical Center. Between the years of 1987
`
`and 2006, I also held positions at the Genetics Institute and Praecis Pharmaceuticals
`
`where my responsibilities dealt with the development of new drug therapies for
`
`cancer, including prostate cancer and other medical illnesses. I served as the
`
`academic principal investigator for the development and approval of leuprolide
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`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
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`acetate (Lupron®), one of the world’s most widely-prescribed medicines for prostate
`
`cancer, and most recently served as the industry leader for abarelix, a pharmaceutical
`
`that is used for a subset of patients with prostate cancer, which was previously
`
`marketed in the United States and Europe.
`
`5.
`
`I have been directly involved in the development of multiple drugs that
`
`have gained approval by both United States regulatory agencies and European
`
`regulatory agencies. I have participated as either an academic or industry leader and
`
`principal investigator/contributor for multiple drugs that have gained either FDA or
`
`European regulatory approvals.
`
`6.
`
`I have had issued to me over 20 patents, mainly dealing with drug
`
`development and treatments for prostate cancer.
`
`7.
`
`I enclose a representative sample of the types of activities I have been
`
`involved in relating to the diagnosis, treating, and evaluation of therapies for prostate
`
`cancer, with an emphasis on Lupron® and other hormonal therapies:
`
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`B. Representative sample of accomplishments related to prostate
`disorders, prostate cancer, and Lupron®-treated related
`disorders1
`1.
`
`Prostate cancer and Lupron®-related accomplishments
`a.
`
`Lupron®-related and LHRH analogue-related
`
`(cid:120)
`
`Academic Principal Investigator and one of three academic presenters to the
`
`FDA advisory committee related to the initial FDA approval of Lupron® for
`
`prostate cancer;
`
`(cid:120)
`
`Lead investigator on multiple Phase II studies and the pivotal Phase III study
`
`of Lupron® for prostate cancer, published in the New England Journal of
`
`Medicine;
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`Investigator on multiple follow-on studies following the approval of
`
`Lupron®, in order to assess its post-marketing safety and efficacy;
`
`Lead developer of abarelix, the first approved LHRH/GnRH antagonist for
`
`prostate cancer in the U.S., Germany, and other EU Countries;
`
`Co-organizer (with the late William Fair, M.D.) of the annual International
`
`Conferences on Neoadjuvant Hormonal Therapy for Prostate Cancer; and
`
`
`1Lupron® is one of the world’s most prescribed therapies for prostate cancer; I
`
`served as the principal investigator that led to its approval by FDA and other
`
`worldwide regulatory bodies in the mid-1980s.
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`(cid:120)
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`Inventor listed on multiple patents related to the use of LHRH analogues for
`
`the management of prostate cancer and other Lupron®-related disorders
`
`outside of prostate cancer (adjunct to mammography for dense breast
`
`imaging, differential suppression of FSH (follicle-stimulating hormone)
`
`between Lupron® and LHRH antagonists).
`
`b.
`
`Prostate cancer-related
`
`(cid:120)
`
`Founder of Hershey Foundation for Basic and Clinical Research in Prostate
`
`Cancer, housed at the Beth Israel Deaconess Medical Center, that
`
`established basic and clinical research programs, young investigator awards,
`
`educational colloquia and de novo establishment of a prostate cancer tissue
`
`bank, available for use by all Massachusetts researchers;
`
`Reviewer for SPORE (Specialized Program of Research Excellence) grant
`
`applications in the formative years of the SPORE program;
`
`Panel Reviewer on NIH Consensus Development Conference for
`
`management of clinically localized prostate cancer; and
`
`Special Government Employee (SGE) for United States Food and Drug
`
`Administration (FDA) and have served on approximately 15 advisory
`
`committees as an invited and voting member in multiple divisions of FDA.
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
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`2.
`
`Publishing and educational accomplishments
`
`(cid:120)
`
`Author, The Patient’s Guide to Prostate Cancer, published by
`
`Viking/Penguin Imprints (a lay book on prostate cancer, based upon several
`
`articles initially published in Scientific American);
`
`(cid:120)
`
`Editor in chief and founder of Perspectives on Prostate Diseases, a quarterly
`
`journal published by Harvard Medical School’s Harvard Health
`
`Publications, and founder of a companion website (available to anyone with
`
`an internet connection) at www.harvardprostateknowledge.org. This has
`
`now been supplanted by The Harvard Medical School Annual Report on
`
`Prostate Diseases;
`
`(cid:120)
`
`Founder and director (until 1992), HMS Continuing Medical Educational
`
`program entitled Urologic Cancer, the premier course in Urologic Cancer for
`
`physicians;
`
`(cid:120)
`
`Author, American College of Physicians policy statement on Screening for
`
`Prostate Cancer, published through its PIER (Physician Information
`
`Educational Resource), a point of care resource for physicians worldwide;
`
`(cid:120)
`
`Author (along with three others) of a widely distributed prostate cancer and
`
`PSA decision tool for internists and primary care physicians, for Harvard
`
`Institutions Risk Management Foundation;
`
`(cid:120)
`
`Lecturer at multiple national and international colloquia on prostate-related
`
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`disorders and prostate cancer and LHRH analogues, including Lupron® and
`
`other hormonal therapies for prostate cancer;
`
`Founder of Prostate Cancer Educational Breakfast Series, a series of
`
`colloquia for general education related to prostate cancer;
`
`Participant in several regional programs to increase awareness of prostate
`
`cancer issues for the African-American Communities;
`
`Lead author on two review articles on prostate cancer screening, published
`
`in Annals of Internal Medicine; and
`
`First author on three separate Scientific American articles on issues relating
`
`to prostate cancer, including an evaluation of the effectiveness of various
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`therapies.
`
`8.
`
`In 2010, I was appointed as a Special Government Employee (SGE) to
`
`the United States Food and Drug Administration (FDA) Oncology Drug Advisory
`
`Committee (ODAC) to review matters related to cancer in general and prostate
`
`cancer specifically. I was a member of the FDA ODAC review panel that deliberated
`
`on the use of the five-alpha-reductase inhibitors, finasteride and dutasteride, as a
`
`means of preventing the development of prostate cancer, and recently served on the
`
`FDA ODAC advisory panel that deliberated the issues in drug development
`
`associated with non-metastatic castrate resistant prostate cancer. In 2014, I was a
`
`voting member of the FDA advisory committee in the deliberations of testosterone
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
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`
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`replacement therapy conducted by FDA in a joint meeting of Drug Safety and
`
`Division of Urologic Drug products.
`
`9.
`
`I have participated as both an academic and industry investigator in the
`
`development of agents for the treatment of prostate cancer, and lecture nationally
`
`and internationally on issues related to prostate cancer diagnosis, management,
`
`treatment and assessment of outcomes.
`
`10.
`
`I am Board Certified in both Internal Medicine and Medical Oncology.
`
`My clinical practice at the Beth Israel Deaconess Medical Center focuses on the
`
`management and counseling of patients who have been diagnosed with all stages of
`
`prostate cancer, including those eligible for treatments such as abiraterone and
`
`prednisone, as well as individuals who are questioning their risk of having prostate
`
`cancer. The discussion about the use of alternate or complementary forms of
`
`interventions is discussed frequently. In my position as Editor in Chief of the HMS
`
`Annual Report on Prostate Diseases, we cover, assess and write about information
`
`related to complementary and alternative methods of prostate cancer interventions.
`
`11.
`
`I am an affiliate member of the American Urological Association;
`
`Fellow of the American College of Physicians; member of the American Society of
`
`Clinical Oncology and have held leadership positions in that organization; as well
`
`as other organizations. I have been asked to provide plenary lectures at the National
`
`Meetings of the American Urological Association and the American College of
`
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`
`
`Physicians on topics that include an understanding of prostate cancer. I have also
`
`completed 15- and 9-year terms, respectively, as Trustee of Bowdoin College
`
`(2011); and Trustee of Penn Medicine and the Perelman School of Medicine of the
`
`University of Pennsylvania, where I have served as interim chairperson of its
`
`subcommittee on Research, Education and Patient Care.
`
`12.
`
`I am, and have been, a reviewer for a number of medical journals,
`
`including New England Journal of Medicine; Annals of Internal Medicine; Journal
`
`of Clinical Oncology; Urology; British Journal of Urology International; and others.
`
`Over the past 30 years, I have peer reviewed numerous papers submitted for
`
`publication to scientific and medical journals which will often include studies that
`
`employ randomized, double-blind, placebo controlled studies. As part of this review
`
`process, I will evaluate the adequacy of the design, the conduct of the study and
`
`clinical research; and make an assessment as to the integrity of the data presented,
`
`and accuracy and rigor of the statistical methodologies employed. I also serve as the
`
`only physician-medical advisor to the World Book Encyclopedia. I have written and
`
`reviewed numerous US FDA regulatory submissions dealing with the evaluation of
`
`novel and investigational agents and have authored multiple Integrated Summary
`
`Basis of Risk Benefit documents, Integrated Summary of Safety and Efficacy, and
`
`Clinical Investigational Brochures, and contributed in meaningful ways to
`
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`regulatory submissions from IND filings to NDA filings and post marketing
`
`approvals.
`
`13.
`
`As detailed in my CV, I have engaged in scholarly research and writing
`
`from several perspectives: that of an academic principal investigator on many drugs
`
`that were approved or that had their label extended; as a leader in industry teams that
`
`develop pharmaceuticals, leading to approval by both U.S. and foreign regulatory
`
`bodies; and as a governmental employee who has advised members of FDA on the
`
`adequacy, conduct and interpretation of studies related to prostate cancer, including
`
`endpoints of studies, modulation of safety issues related to treatments, and surrogate
`
`markers of prostate cancer outcomes.
`
`14.
`
`I have authored several hundred articles, book chapters, books, reviews,
`
`and monographs pertaining to prostate cancer.
`
`15.
`
`Based upon my education, training and experience, as summarized
`
`above, I believe I am qualified to provide opinion testimony as an expert in 1)
`
`medical oncology; 2) urologic cancer; 3) prostate cancer, including diagnosis,
`
`treatment, prevention, assessment of metrics to evaluate the disease, regulatory
`
`conduct of studies of prostate cancer, and evaluation of methods that claim efficacy
`
`and safety in prostate cancer; 4) all hormonal therapies for prostate cancer; and 5)
`
`assessment of adequate study design and conduct of studies that evaluate safety and
`
`efficacy carried out by academic, industry and government bodies.
`
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`16.
`
`In the past four years, I have testified as an expert in either deposition
`
`or trial in approximately 10 separate medical malpractice proceedings. I am being
`
`compensated at an hourly rate of $850/hour and am available to appear live for
`
`testimony in support of my opinions. My compensation in no way depends on the
`
`outcome of this proceeding. The opinions to which I will testify are based on the
`
`education, experience, training and skill that I have accumulated in the course of my
`
`career as a practicing medical oncologist and researcher, as well as materials I have
`
`reviewed in connection with this case.
`
`II. MATERIALS CONSIDERED
`17.
`The list of materials I considered in forming the opinions set forth in
`
`this declaration includes the following:
`
`Exhibit #
`
`Description
`
`1001
`
`1003
`
`1004
`
`1005
`
`1006
`
`1009
`
`U.S. Patent No. 8,822,438 to Auerbach and Belldegrun, “Methods
`and Compositions for Treating Cancer” (“the ’438 patent”)
`O’Donnell, A. et al., “Hormonal impact of the 17α-
`hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in
`patients with prostate cancer,” Br. J. Cancer 90:2317-2325 (2004)
`(“O’Donnell”)
`Gerber, G.S. et al., “Prostate specific antigen for assessing response
`to ketoconazole and prednisone in patients with hormone refractory
`metastatic cancer,” J. Urology 144(5):1177-9 (1990) (“Gerber”)
`U.S. Patent No. 5,604,213, Barrie S.E. et al., “17-Substituted
`Steroids Useful In Cancer Treatment” (“the ’213 patent”)
`Tannock, I. et al., “Chemotherapy with mitoxantrone plus
`prednisone or prednisone alone for symptomatic hormone- resistant
`prostate cancer,” J. Clin. Oncology 14(6):1756-1764 (1996)
`Ryan, C.J. et al., “Abiraterone in metastatic prostate cancer without
`previous chemotherapy,” New Engl. J. Med. 368:138-148 (2012).
`
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`
`
`Exhibit #
`
`Description
`
`1010
`
`1012
`
`1018
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`January 11, 2013 Response (excerpt from prosecution history of
`’438 patent)
`June 4, 2013 Response (excerpt from prosecution history of ’438
`patent)
`Zytiga® Prescribing Information (2011)
`Zytiga® Prescribing Information and Co-administration Brochure
`(2015)
`Harris, K.A. et al., “Low dose ketoconazole with replacement doses
`of hydrocortisone in patients with progressive androgen
`independent prostate cancer,” J. Urol. 168(2):542-5 (2002)
`Oh, W., “Secondary hormonal therapies in the treatment of prostate
`cancer,” Urology, 60(Supp. 3A):87-93 (2002)
`Tannock, I. et al., “Docetaxel plus prednisone or mitoxantrone plus
`prednisone for advanced prostate cancer,” N. Eng. J. Med.
`351:1502-12 (2004)
`Attard, G. et al., “Selective blockade of androgenic steroid
`synthesis by novel lyase inhibitors as a therapeutic strategy for
`treating metastatic prostate cancer,” Br. J. Urol. 96(9):1241-1246
`(2005)
`Hellerstedt et al., “The Current State of Hormonal Therapy for
`Prostate Cancer,” CA Cancer J. Clin. 52:154-179 (2002)
`Kasper, D.L. et al. (Eds.), Harrison’s Principles of Internal
`Medicine 549 (16th ed. 2005)
`Auchus, R.J. “The genetics, pathophysiology, and management of
`human deficiencies of P450c17,” Endocrinol. Metab. Clin. North
`Am. 30(1):101-119 (2001)
`Costa-Santos, M. et al., “Two prevalent CYP17 mutations and
`genotype-phenotype correlations in 24 Brazilian patients with 17-
`hydroxylase deficiency,” J. Clin. Endocrin. & Metabol. 89(1):49-60
`(2004)
`Jubelirer, S.J. et al., “High dose ketoconazole for the treatment of
`hormone refractory metastatic prostate carcinoma,” J. Urol.
`142(1):89-901 (1989)
`U.S. Patent 5,688,977, Sisti, N.J. et al., “Method for Docetaxel
`Synthesis”
`
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`
`
`Exhibit #
`
`Description
`
`1030
`
`1031
`
`U.S. Food and Drug Administration (“FDA”) FDA News Release
`dated May 19, 2004, “FDA Approves New Indication for Taxotere-
`Prostate Cancer”
`Tannock, I. et al., “Treatment of metastatic prostatic cancer with
`low-dose prednisone: evaluation of pain and quality of life as
`pragmatic indices of response,” J. Clin. Oncology, 7:590-7 (1989)
`Scher, H.I. et al., “Increased survival with enzalutamide in prostate
`cancer after chemotherapy,” New Eng. J. Med. 367:1187-97 (2012)
`de Bono, J.S. et al., “Abiraterone and increased survival in
`metastatic prostate cancer,” New Engl. J. Med. 364:1995-2005
`(2011)
`Orange Book listing for Zytiga®
`Barrie et al., “Pharmacology of novel steroidal inhibitors of
`Cytochrome P45017α (17α-hydroxylase/C17,20 lyase),” J. Steroid
`Biochem. Molec. Biol. 50:267-73 (1994)
`Fakih, M. et al., “Glucocorticoids and treatment of prostate cancer:
`A preclinical and clinical review,” Urology 60:553-561 (2002)
`Lam, J.S. et al., “Secondary hormonal therapy for advanced prostate
`cancer,” J. Urology 175:28-34 at 30-31(2006).
`III. LEGAL STANDARDS
`18.
`In my opinion, given the disclosure of the ’438 Patent, I consider a
`
`1033
`
`1034
`
`1035
`1078
`
`1079
`
`1080
`
`person of ordinary skill in the art at the time of filing of this patent to be someone
`
`who is a physician specializing in urology, endocrinology or oncology, or holds a
`
`Ph.D. in pharmacology, biochemistry or a related discipline.2 Additional experience
`
`could substitute for the advanced degree.
`
`19.
`
`I understand that, to the extent necessary, a person of ordinary skill in
`
`the art may collaborate with one or more other persons of skill in the art for one or
`
`
`2 A related discipline may include, for example, pharmaceutical sciences.
`
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`
`
`more aspects in which the other person may have expertise, experience and/or
`
`knowledge that was obtained through his or her education, industrial or academic
`
`experiences.
`
`20.
`
`I understand that a person of ordinary skill in the art may consult with
`
`an endocrinologist, oncologist or medical biochemist and thus may rely on the
`
`opinions of such specialists in evaluating the claims.
`
`21.
`
`I have been told that the obviousness inquiry is a question of law based
`
`on four factual predicates: (1) “the scope and content of the prior art,” (2) the
`
`“differences between the prior art and the claims at issue,” (3) “the level of ordinary
`
`skill in the pertinent art,” and (4) “secondary considerations” such as commercial
`
`success, long-felt but unsolved needs, failure of others, and unexpected results. I
`
`have been told that the combination of familiar pharmaceutical elements according
`
`to known methods is likely to be obvious when it does no more than yield predictable
`
`results. I have also been told that the motivation to combine may be found in many
`
`different places and forms. Thus, for example, a challenger is not limited to the same
`
`motivation that the patentee had.
`
`22.
`
`I have been
`
`informed
`
`that secondary considerations of non-
`
`obviousness include commercial success, satisfaction of a long-felt unmet need,
`
`unexpected results, prior failure of others, industry praise, licensing, and copying. I
`
`understand that evidence of such secondary considerations is only relevant to the
`
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`
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`obviousness analysis if the patentee can show a direct link, or nexus, between the
`
`secondary consideration and the claims of the patent, and that the evidence must be
`
`commensurate in scope with the asserted claims. I also understand that for results
`
`to be considered unexpected for these purposes, there must be a substantial
`
`difference from the prior art. In other words, a difference of kind, and not merely of
`
`degree.
`
`IV. BACKGROUND AND THE ’438 PATENT
`A. Background
`23.
`The prostate gland is part of the human male reproductive system and
`
`is involved in the synthesis and storage of seminal fluid. Prostate cancer is an
`
`androgen-dependent disease, meaning that the growth of prostate cancer is
`
`dependent upon male androgens such as testosterone and dihydrotestosterone (DHT)
`
`and derivatives, and is the most common non-cutaneous cancer among men and the
`
`second-most most common form of death from cancer among men in the United
`
`States. Ex. 1001 (’483 patent) col. 1, ll. 20-52; Ex. 1022 (Tannock) at 1503.
`
`24.
`
`The activation of androgen receptors (“AR”) on prostate cells regulates
`
`the transcriptional activation of a wide variety of genes involved in controlling the
`
`growth of the normal prostate gland and in promoting the progression and
`
`proliferation of prostate cancer. Ex. 1023 (Attard) at 1241; Ex. 1003 (O’Donnell) at
`
`2317. The two most important androgens responsible for activating the AR are
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1002, p. 16 of 92
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`
`
`testosterone and its derivative DHT. Testosterone is synthesized primarily in the
`
`testes and secondarily in the adrenal gland. Ex. 1003 (O’Donnell) at 2317. In non-
`
`castrate men, the testicles are responsible for producing the vast majority of
`
`circulating testosterone. Ex. 1003 (O’Donnell) at 2317. The production of
`
`testosterone is regulated by endocrine feedback loops involving the hypothalamus
`
`and pituitary glands that respond to varying levels of hormones involved in the
`
`testosterone synthetic pathway, including hormonal precursors to testosterone, and
`
`testosterone itself.
`
`25.
`
`The treatment options for treating prostate cancer depend to a great
`
`extent on whether the prostate cancer is confined or localized to the prostate, whether
`
`it is regionally advanced, which would include extension beyond the prostate capsule
`
`or into the seminal vesicles, or whether it has spread (i.e., metastasized) to other
`
`organs distant from the prostate, such as lymph nodes or bone. The goal of treating
`
`primary prostate cancer (i.e., prostate cancer localized to the prostate) is to remove
`
`the prostate gland, seminal vesicles and regional draining lymph nodes by surgical
`
`techniques or with the use of radiation therapy. For patients with advanced or
`
`metastatic prostate cancer, the mainstay of treatment is designed to interfere with the
`
`proliferation of prostate cancer cells by interrupting production of testosterone and
`
`DHT in the testes, or interfere with their function. Ex. 1003 (O’Donnell) at 2317;
`
`Ex. 1024 (Hellerstedt) at 154, Fig. 2.
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1002, p. 17 of 92
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`
`
`26.
`
`As of 2006, the most common course of treatment for localized prostate
`
`cancer would have been surgical removal of the prostate (prostatectomy) or radiation
`
`therapy of the prostate. Ex. 1001 (’438 patent) col. 1, ll. 26-28; Ex. 1023 (Attard) at
`
`1241. There are circumstances in which patients with localized prostate cancer, who
`
`are primarily treated with radiation, are also treated with pharmaceutical hormone
`
`agents that lower testosterone and DHT levels.
`
`27.
`
`A significant number of patients either progress after localized therapy
`
`or present with metastatic/non-localized prostate cancer. Ex. 1023 (Attard) at 1241.
`
`Metastatic prostate cancer is cancer that has spread beyond the primary tumor in the
`
`prostate to other parts of the body. “Prostate cancer metastasizes most often to pelvic
`
`lymph nodes and to bone,” and the most significant symptom, if symptoms are
`
`present, may include pain, depending upon the anatomic location of the metastatic
`
`deposits. Ex. 1025 (Harrison’s) at 549; Ex. 1006 (Tannock) at 1756. Non-localized
`
`disease and/or metastatic disease is usually treated with reduction of testosterone
`
`production by either hormonal manipulation or orchiectomy (surgical removal of the
`
`testicles).
`
`28.
`
`The treatment of metastatic prostate cancer requires systemic therapy.
`
`It was known that as much as ten percent of baseline circulating testosterone remains
`
`in prostate cancer patients who have undergone localized androgen ablation through
`
`surgical or medical castration. Ex. 1003 (O’Donnell) at 2317. The adrenal glands
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1002, p. 18 of 92
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`
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`were known to be responsible for the production of a substantial amount of this
`
`extratesticular source of testosterone, which was known to be an important
`
`alternative source of AR stimulation. Ex. 1003 (O’Donnell) at 2317. The first-line
`
`treatment for metastatic prostate cancer patients since at least the 1980s has involved
`
`systemic suppression of testicular testosterone production, either medically with
`
`estrogen agents or more routinely with so called LHRH analogues (both LHRH
`
`agonists such as Lupron and LHRH/GnRH antagonists such as degarelix). In
`
`addition, abrogation of the remaining adrenal sources of androgens can be blocked
`
`by the co-administration of agents that are antagonists of the androgen receptor, so
`
`called antiandrogens. These therapies are known as hormonal or endocrine
`
`therapies. Ex. 1024 (Hellerstedt) at 154.
`
`29.
`
`As the diagram below shows, approximately 90% of the testosterone is
`
`produced in the testes and 10% in the adrenals. Ex. 1024 (Hellerstedt) at 159, Fig.
`
`2. The diagram also shows that LHRH is produced in the hypothalamus, a small
`
`gland in the brain. “LHRH is normally released [by] the hypothalamus in pulses.”
`
`Ex. 1024 (Hellerstedt) at 157. This leads to the pulsatile release of LH from the
`
`anterior pituitary. Ex. 1024 (Hellerstedt) at 157. LH then acts on receptors on the
`
`Leydig cells of the testes, leading to production of testosterone. Ex. 1024
`
`(Hellerstedt) at 157. LHRH agonists such as Lupron® bind to LHRH receptors in
`
`the hypothalamus and stimulate the increased production and release of LH by the
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1002, p. 19 of 92
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`
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`pituitary. Ex. 1024 (Hellerstedt) at 157. Initially, this surge in LH triggers a surge
`
`of testosterone production. See, e.g., Ex. 1024 (Hellerstedt) at 157, 159, Fig. 2.
`
`
`
`30.
`
`The testosterone surge is followed by a decrease in testosterone
`
`
`
`production as the hypothalamic-pituitary-gonadal axis results in lowered or absent
`
`levels of luteinizing hormone (LH), as a result of internalization or down
`
`regulation/desensitization of LHRH receptors in the pituitary. In particular, the
`
`LHRH surge triggers downregulation of LHRH receptors in the pituitary, inhibiting
`
`further production and release of LH, and causing a corresponding decrease in the
`
`production of testosterone. Ex. 1024 (Hellerstedt) at 157. In addition to the use of
`
`LHRH agonists to interrupt production of testosterone produced by the testicles, the
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1002, p. 20 of 92
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`
`
`first-line treatment of metastatic prostate cancer usually also includes systemic anti-
`
`androgen therapy using drugs such as bicalutamide. Ex. 1024 (Hellerstedt) at 158.
`
`Anti-androgens work by interfering with or antagonizing the binding of testosterone
`
`and DHT to the androgen receptors on prostate cancer cells. Ex. 1024 (Hellerstedt)
`
`at 158. The objective of anti-androgens is to prevent testosterone from binding to
`
`AR on prostate cancer cells.
`
`31.
`
`In almost all cases, patients with metastatic prostate cancer over time,
`
`measured in months or years, develop what is referred to as metastatic castration-
`
`resistant (or hormone-refractory) prostate cancer (“mCRPC”), i.e., prostate cancer
`
`that has usually initially responded to lowered testosterone levels and now no longer
`
`responds to a reduction in testosterone levels and resumes growth. Ex. 1023 (Attard)
`
`at 1241; Ex. 1024 (Hellerstedt) at 154. It was known that in these patients, the
`
`sensitivity of the AR is greatly increased, so that activation of the AR is enhanced at
`
`lower levels of testosterone. Ex. 1003 (O’Donnell) at 2317; Ex. 1023 (Attard) at
`
`1241.
`
`32.
`
`It was also known that the prognosis for patients with mCRPC as of
`
`2006 was poor and almost invariably resulted in incurable progression of the disease.
`
`Ex. 1021 (Oh) at Abstract; Ex. 1022 (Tannock 2004) at 1503; Ex. 1023 (Attard) at
`
`1241. The treatment of mCRPC usually also comprised the use of one or more
`
`ACTAVIS, AMNEAL, DR. REDDY’S LABORATORIES, SUN, TEVA, WEST-WARD
`IPR2017-00853 - Ex. 1002, p. 21 of 92
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`
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`“second-line” hormone therapies. Ex. 1021 (Oh) Abstract; Ex. 1023 (Attard) at
`
`1241-1242.
`
`33.
`
`Ketoconazole, a non-specific
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