In the United States Patent and Trademark Office
`
`
`Before the Patent Trial and Appeal Board
`
`
`
`MYLAN PHARMACEUTICALS INCORPORATED,
`
`Petitioner
`
`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. IPR2016-01332
`
`
`
`
`
`DECLARATION OF MARC B. GARNICK, M.D.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 1
`
`
`
`
`Before the Patent Trial and Appeal Board
`
`
`
`MYLAN PHARMACEUTICALS INCORPORATED,
`
`Petitioner
`
`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. IPR2016-01332
`
`
`
`
`
`DECLARATION OF MARC B. GARNICK, M.D.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 1
`
`
`
`I, Marc B. Garnick, M.D., do hereby declare:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am making this declaration at the request of Mylan Pharmaceuticals
`
`Inc., 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
`I am a medical oncologist specializing in the care of patients with
`2.
`
`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 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.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 2
`
`
`
`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 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.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 3
`
`
`
`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:
`
`B. Representative sample of accomplishments related to prostate
`disorders, prostate cancer, and Lupron®-treated related
`disorders1
`Prostate cancer and Lupron®-related accomplishments
`1.
`a.
`
`Lupron®-related and LHRH analogue-related
`
`•
`
`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;
`
`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.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 4
`
`
`
`•
`
`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;
`
`•
`
`•
`
`•
`
`•
`
`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
`
`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
`
`•
`
`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;
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 5
`
`
`
`•
`
`•
`
`•
`
`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.
`
`2.
`
`Publishing and educational accomplishments
`
`•
`
`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);
`
`•
`
`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;
`
`•
`
`Founder and director (until 1992), HMS Continuing Medical Educational
`
`program entitled Urologic Cancer, the premier course in Urologic Cancer for
`
`physicians;
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 6
`
`
`
`•
`
`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;
`
`•
`
`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;
`
`•
`
`Lecturer at multiple national and international colloquia on prostate-related
`
`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
`
`therapies.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 7
`
`
`
`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 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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 8
`
`
`
`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 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
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 9
`
`
`
`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 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.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 10
`
`
`
`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.
`
`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 $750/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.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 11
`
`
`
`II. MATERIALS CONSIDERED
`The list of materials I considered in forming the opinions set forth in
`17.
`
`this declaration includes the following:
`
`Exhibit
`
`Description
`
`MYL 1001 U.S. Patent No. 8,822,438 to Auerbach and Belldegrun, “Methods
`and Compositions for Treating Cancer” (“the ’438 patent”)
`MYL 1003 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”)
`MYL 1004 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”)
`MYL 1005 U.S. Patent No. 5,604,213, Barrie S.E. et al., “17-Substituted
`Steroids Useful In Cancer Treatment” (“the ’213 patent”)
`MYL 1006 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)
`MYL 1009 Ryan, C.J. et al., “Abiraterone in metastatic prostate cancer without
`previous chemotherapy,” New Engl. J. Med. 368:138-148 (2012).
`January 11, 2013 Response (excerpt from prosecution history of
`’438 patent)
`June 4, 2013 Response (excerpt from prosecution history of ’438
`patent)
`MYL 1018 Zytiga® Prescribing Information (2011)
`MYL 1019 Zytiga® Prescribing Information and Co-administration Brochure
`(2015)
`MYL 1020 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)
`MYL 1021 Oh, W., “Secondary hormonal therapies in the treatment of prostate
`cancer,” Urology, 60(Supp. 3A):87-93 (2002)
`MYL 1022 Tannock, I. et al., “Docetaxel plus prednisone or mitoxantrone plus
`prednisone for advanced prostate cancer,” N. Eng. J. Med.
`351:1502-12 (2004)
`
`MYL 1010
`
`MYL 1012
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 12
`
`
`
`Exhibit
`
`Description
`
`MYL 1028
`
`MYL 1023 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)
`MYL 1024 Hellerstedt et al., “The Current State of Hormonal Therapy for
`Prostate Cancer,” CA Cancer J. Clin. 52:154-179 (2002)
`MYL 1025 Kasper, D.L. et al. (Eds.), Harrison’s Principles of Internal
`Medicine 549 (16th ed. 2005)
`MYL 1026 Auchus, R.J. “The genetics, pathophysiology, and management of
`human deficiencies of P450c17,” Endocrinol. Metab. Clin. North
`Am. 30(1):101-119 (2001)
`MYL 1027 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)
`MYL 1029 U.S. Patent 5,688,977, Sisti, N.J. et al., “Method for Docetaxel
`Synthesis”
`MYL 1030 U.S. Food and Drug Administration (“FDA”) FDA News Release
`dated May 19, 2004, “FDA Approves New Indication for Taxotere-
`Prostate Cancer”
`MYL 1031 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)
`MYL 1033 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)
`MYL 1035 Orange Book listing for Zytiga®
`MYL 1078 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)
`
`MYL 1034
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 13
`
`
`
`Exhibit
`
`Description
`
`MYL 1079 Fakih, M. et al., “Glucocorticoids and treatment of prostate cancer:
`A preclinical and clinical review,” Urology 60:553-561 (2002)
`MYL 1080 Lam, J.S. et al., “Secondary hormonal therapy for advanced prostate
`cancer,” J. Urology 175:28-34 at 30-31(2006).
`
`III. LEGAL STANDARDS
`In my opinion, given the disclosure of the ’438 Patent, I consider a
`18.
`
`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
`
`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
`
`
`2 A related discipline may include, for example, pharmaceutical sciences.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 14
`
`
`
`“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
`
`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.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 15
`
`
`
`IV. BACKGROUND AND THE ’438 PATENT
`A. Background
`The prostate gland is part of the human male reproductive system and
`23.
`
`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. MYL Ex. 1001 (’483 patent) col. 1, ll. 20-52; MYL 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. MYL Ex. 1023 (Attard) at 1241;
`
`MYL Ex. 1003 (O’Donnell) at 2317. The two most important androgens
`
`responsible for activating the AR are testosterone and its derivative DHT.
`
`Testosterone is synthesized primarily in the testes and secondarily in the adrenal
`
`gland. MYL Ex. 1003 (O’Donnell) at 2317. In non-castrate men, the testicles are
`
`responsible for producing the vast majority of circulating testosterone. MYL Ex.
`
`1003 (O’Donnell) at 2317. The production of testosterone is regulated by
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 16
`
`
`
`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. MYL Ex. 1003 (O’Donnell) at 2317; MYL Ex. 1024 (Hellerstedt)
`
`at 154, Fig. 2.
`
`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. MYL Ex. 1001 (’438 patent) col. 1, ll. 26-28;
`
`MYL Ex. 1023 (Attard) at 1241. There are circumstances in which patients with
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 17
`
`
`
`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. MYL 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. MYL Ex. 1025 (Harrison’s) at
`
`549; MYL 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. MYL Ex. 1003 (O’Donnell) at
`
`2317. The adrenal glands 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. MYL Ex. 1003
`
`(O’Donnell) at 2317. The first-line treatment for metastatic prostate cancer
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 18
`
`
`
`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. MYL 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. MYL 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.” MYL Ex. 1024 (Hellerstedt) at 157. This leads to the pulsatile release of
`
`LH from the anterior pituitary. MYL Ex. 1024 (Hellerstedt) at 157. LH then acts
`
`on receptors on the Leydig cells of the testes, leading to production of testosterone.
`
`MYL 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 pituitary. MYL Ex. 1024 (Hellerstedt) at 157. Initially, this
`
`surge in LH triggers a surge of testosterone production. See, e.g., MYL Ex. 1024
`
`(Hellerstedt) at 157, 159, Fig. 2.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 19
`
`
`
`
`
`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. MYL Ex. 1024 (Hellerstedt) at 157. In
`
`addition to the use of LHRH agonists to interrupt production of testosterone
`
`produced by the testicles, the first-line treatment of metastatic prostate cancer
`
`usually also includes systemic anti-androgen therapy using drugs such as
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 20
`
`
`
`bicalutamide. MYL 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. MYL 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. MYL
`
`Ex. 1023 (Attard) at 1241; MYL 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. MYL Ex. 1003 (O’Donnell) at
`
`2317; MYL 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. MYL Ex. 1021 (Oh) at Abstract; MYL Ex. 1022 (Tannock 2004) at 1503;
`
`MYL Ex. 1023 (Attard) at 1241. The treatment of mCRPC usually also comprised
`
`the use of one or more “second-line” hormone therapies. MYL Ex. 1021 (Oh)
`
`Abstract; MYL Ex. 1023 (Attard) at 1241-1242.
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 21
`
`
`
`33.
`
`Ketoconazole, a non-specific antifungal inhibitor of 17α-hydroxylase,
`
`an enzyme critical to steroid synthesis, was commonly used off-label (in much
`
`larger doses than used for its antifungal activity) in combination with prednisone or
`
`hydrocortisone to treat mCRPC. MYL Ex. 1004 (Gerber) at 1177; MYL Ex. 1021
`
`(Oh) at Abstract; MYL Ex. 1020 (Harris) at Abstract; MYL Ex. 1025 (Harrison’s)
`
`at 548. It was well known that the co-administration of either prednisone or
`
`hydrocortisone was required with these large doses of ketoconazole to modulate or
`
`mitigate
`
`the adverse effects of mineralocorticoid excesses
`
`induced by
`
`ketoconazole. Although there were some data and publications suggesting that
`
`prednisone may have independent anti-cancer activity, see, e.g., MYL Ex. 1020
`
`(Harris) at 544; MYL Ex. 1021 (Oh) at 89, MYL Ex. 1079 (Fakih) at 553, 559,
`
`MYL Ex. 1080 (Lam) at 30-31, it was very well known that high doses of
`
`prednisone (supraphysiologic levels of substantially greater than 5-10 mg per day)
`
`had short-term palliative effects in patients with terminal prostate cancer.
`
`B.
`34.
`
`The ’438 patent
`
`The ’438 Patent is directed to a method for treating a prostate cancer
`
`in a human, the method including administration of a therapeutically effective
`
`amount of abiraterone acetate and a therapeutically effective amount of prednisone.
`
`The ’438 Patent includes one independent claim and 19 dependent claims. Claim
`
`1, the only independent claim, recites as follows:
`
`MYLAN PHARMS. INC. EXHIBIT 1002 PAGE 22
`
`
`
`1. A method for the treatment of a prostate cancer in a human comprising
`administering to said human a
`therapeutically effective amount of
`abiraterone acetate or a pharmaceutically acceptable salt thereof and a
`therapeutically effective amount of prednisone.
`MYL Ex. 1001 (’438 patent) at claim 1.3
`The dependent claims of the ’438 Patent further specify the amount of
`35.
`
`
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