UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
`
`V.
`
`JANSSEN ONCOLOGY, INC,
`Patent Owner
`
`Patent No. 8,822,438
`
`Case No. Unassigned
`
`Declaration of Devalingam Mahalingam, M.D., Ph.D.
`
`ARGENTUM EX1073
`
`Page 1
`
`ARGENTUM EX1073
`
`Page 1
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
`
`V.
`
`JANSSEN ONCOLOGY, INC,
`Patent Owner
`
`Patent No. 8,822,438
`
`Case No. Unassigned
`
`Declaration of Devalingam Mahalingam, M.D., Ph.D.
`
`ARGENTUM EX1073
`
`Page 1
`
`ARGENTUM EX1073
`
`Page 1
`
`
`
`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`TABLE OF CONTENTS
`
`I.
`
`IL
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`Qualifications ................................................................................................ .. 2
`
`ScopeofVVofl§ ............................................................................................... "3
`
`Legal Standards ............................................................................................. .. 7
`
`Background and the ’438 Patent ................................................................... .. 9
`
`Claim Construction ..................................................................................... .. 22
`
`Claim 1 is Unpatentable as Obvious over O'Donnell in View of Gerber or the
`'213 patent in view of Gerber ...................................................................... .. 23
`
`VII. Claims 2-20 are unpatentable as obvious over O'Donnell and/or the '213
`patent in View of Gerber .............................................................................. .. 27
`
`VIII. Secondary Considerations Do Not Indicate that the Claims of the ‘438 Patent
`Are Non-Obvious ........................................................................................ .. 36
`
`IX.
`
`The Prior Art Taught That Prednisone was “Effective for Treating Prostate
`Cancer” as Construed by the Board ............................................................ .. 47
`
`X.
`
`Conclusion ................................................................................................... .. 50
`
`-1-
`
`Page 2
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`Page 2
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`
`
`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`I, Devalingarn Mahalingam, M.D., Ph.D., do declare and state as follows.
`
`QUALIFICATIONS
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`My name is Devalingam Mahalingarn.
`
`I am currently an Associate
`
`Professor in the Division of Hematology/Oncology, Department of Medicine in the
`
`University of Texas Health Science Center, San Antonio, Texas.
`
`In 2011, I was
`
`appointed co—Leader of the Genitourinary and Gastrointestinal Malignancies
`
`Program of the Cancer Therapy and Research Center, San Antonio, Texas, which
`
`is a position that I continue to hold to this day. I have been a staff physician at the
`
`University Health Care system since 2009 and also a staff physician at St. Lul<e’s
`
`Baptist Health System since 2014. I have published at least 50 peer-reviewed
`
`journal articles and at least three book chapters in the field of gastrointestinal and
`
`genitourinary cancers.
`
`3.
`
`In 2009, I earned a Ph.D. in Cancer Research from the Department of
`
`Medicine of the National University of Ireland and completed my Higher Specialty
`
`in Medical Oncology at the Royal College of Physicians Ireland. I also completed
`
`an Oncology Fellowship at the Institute of Drug Development University of Texas
`
`Health Science Center in 2009.
`
`Page 3
`
`Page 3
`
`
`
`Declaration in Support of Petition
`for Inter Partes Review
`
`
`
`Patent No. 8,822,438
`
`4.
`
`A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is submitted separately. Ex. 1074. In view of my professional experience
`
`and expertise outlined above and provided in my curriculum vitae, I am considered
`
`an expert in the field of gastrointestinal and genitourinary cancers, including
`
`prostate cancer.
`
`II.
`
`
`
`SCOPE OF WORK
`
`5.
`
`I have been retained as an expert witness on behalf of Argentum
`
`Pharmaceuticals LLC ("Petitioner") for a inter partes review ("IPR") of U.S.
`
`Patent No. 8,822,438 (hereinafter, "the '438 patent," Ex. 1001). I am being
`
`compensated for my time in connection with this IPR at a rate of $500 per hour.
`
`My compensation is not contingent on the conclusions I reach herein or on the
`
`specifics of my testimony. I have no financial stake in the outcome of this
`
`proceeding.
`
`6.
`
`I understand that the '438 patent is currently subject to a previous
`
`IPR, Amerigen Pharmaceuticals, Ltd. v. Janssen Oncology, Inc., IPR2016- 00286
`
`(the "Amerigen IPR"). I understand that Petitioner Argentum seeks to become a
`
`party to the Amerigen IPR. I have reviewed the materials submitted in the
`
`Amerigen IPR, including the Declaration of Dr. Scott R. Serels (Ex. 1002). In
`
`fonnulating my opinion, I considered the following documents:
`
`
`
`-3-
`
`Page 4
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`
`
`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`Exhibit
`
`1001
`
`U.S. Patent No. 8,822,438, Auerbach and Belldegrum, “Methods and
`Compositions for Treating Cancer” (“the ‘438 patent”)
`
`1002 Declaration of Dr. Scott Serels, MD (“Serels Decl.”)
`
`
`
`O’Donne1l, A. et al., “Hormonal impact of the 1701-hydroxylase/C17-
`20-lyase inhibitor abiraterone acetate (CB7630) in patients with
`prostate cancer,” British Journal of Cancer, (90):2317-2325 (2004)
`(“O’Donne11”)
`
`
`
`Gerber, G.S. er al., “Prostate specific antigen for assessing response
`to ketoconazole and prednisone in patients with hormone refractory
`metastatic cancer,” The Journal of Urology, 144(5): 1 177-9 (1990)
`(“Gerber”)
`
`U.S. Patent No. 5,604,213, Barrie S.E. er,‘ al., “17—Substituted
`Steroids Useful In Cancer Treatment” ("the ‘213 patent")
`
`Tannock er al., “Chemotherapy with mitoxantrone plus prednisone or
`prednisone alone for symptomatic hormone—resistant prostate cancer:
`a Canadian randomized trial with palliative end points,” The Journal
`of Clinical Oncology, 14:1756—1764 (1996) (“Tannock”)
`
`February 3, 2012 Office Action (excerpt from prosecution history of
`,
`438 patent)
`
`July 3, 2012 Response (excerpt from prosecution history of ‘438
`patent)
`
`Ryan at al., “Abiraterone in metastatic prostate cancer Without
`previous chemotherapy,” The New England Journal ofMedicine,
`368:138—148 (2012).
`
`January 11, 2013 Response (excerpt from prosecution history of
`,
`43 8 patent)
`
`March 4, 2013 Office Action (excerpt from prosecution history of
`,
`438 patent)
`
`
`
`Page 5
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`
`
`Page 5
`
`
`
`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`
`
`
`
`1012
`
`June 4, 2013 Response (excerpt from prosecution history of ‘438
`patent)
`
`1013
`
`July 3, 2013 Notice of Allowance (excerpt from prosecution history
`.
`of 438 patent)
`
`1014
`
`October 25, 2013 Notice of Allowance (excerpt from prosecution
`.
`,
`history of 438 patent)
`
`1015
`
`1016
`
`February 11, 2014 Notice of Allowance (excerpt from prosecution
`.
`,
`history of 438 patent)
`
`June 2, 2014 Notice of Allowance (excerpt from prosecution history
`,
`of 438 patent)
`
`1017 Declaration of Dr. DeForest McDuff, PhD (“McDuff Declaration”)
`
`
`
`
`
`1018
`
`2011 Zytiga® Approval Prescribing Information
`
`2015 Zytiga® Prescribing Information, Co-administration Brochure
`
`Harris at al., “Low dose Ketoconazole with replacement doses of
`hydrocortisone in patients with progressive androgen independent
`prostate cancer,” The Journal of Urology, volume l68:542—545
`(August 2002)
`
`
`
` William Oh, “Secondary hormonal therapies in the treatment of
`
`
`prostate cancer,” Urology, volume 60:87-93 (Supplement 3A)
`(September 2002)
`
`
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`
`
`Tannock, I. et al., “Docetaxel plus Prednisone or Mitoxantrone plus
`Prednisone for Advanced Prostate Cancer,” N. Eng. J. Meal,
`351:1502—12 (2004)
`
`
`
`by novel lyase inhibitors as a therapeutic strategy for treating
`metastatic prostate cancer,” Br. J. Urol. 96(9): 1241-1246 (2005)
`
`
` Attard, G. er al., “Selective blockade of androgenic steroid synthesis
`
`
`
`Hellerstedt er al., “The Current State of Hormonal Therapy for
`1024
`Prostate Cancer,” CA CancerJ. Clin., 52:154-179 (2002).
`
`
` 1025 Kasper, D.L. er al. (Eds.), Harrisorfls Principles ofInternal
`
`
`
`Page 6
`
`Page 6
`
`
`
`Declaration in Support of Petition
`0
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`2 Medicine, 16‘ Edition (2005), p. 549.
`
`1026
`
`Auchus, RI. “The genetics, pathophysiology, and management of
`human deficiencies of P450017,” Endocrinol. Merab. Clin. North Am.
`(30)1:101—1 19 (2001)
`
`Costa—Santos, M. et 4511., “Two PreVa1entCYPl7 Mutations and
`1027 Genotype-Phenotype Correlations in 24 Brazilian Patients with 17-
`Hydroxylase Deficiency,” J. Clin. Endocrin. &Metal:vol. (89)l:49-
`60(2004)
`
`1028
`
`Jubelirer, S.J., er al., “High dose ketoconazole for the treatment of
`hormone refractory metastatic prostate carcinoma,” J. Urol., 142(1):89-
`901 (1989)
`
`1029
`
`U.S. Patent 5,688,977, Sisti, N.J. et al., “Method for Docetaxel
`.
`,,
`Synthesis
`
`U.S. Food and Drug Administration ("FDA") FDA News Release dated
`1030 May 19, 2004, “FDA Approves New Indication for Taxotere— Prostate
`Cancer”
`
`103l
`
`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,” Journal ofClz'n. Oncology, 7:590-7 (1989)
`
`1032
`
`TaXotere® Prescribing Information (2004)
`
`1033
`
`Scher, H.I. er al., “Increased survival with Enzalutamide in Prostate
`Cancer after Chemotherapy,” New Eng. J. Med., 36721187-97 (2012)
`
`1034
`
`de Bono, J.S. er al., “Abiraterone and Increased Survival in Metastatic
`Prostate Cancer,” New Engl. J. Meal, 364:1995-2005 (2011)
`
`1035 Orange Book listing for Zytiga®
`
`7.
`
`I agree in all material respects with the analysis and opinions set forth
`
`by Amerigen’s expert, Dr. Serels, in the declaration that was submitted in the
`
`Amerigen IPR (Ex. 1002). Without reservation, I agree fully with the ultimate
`
`-5-
`
`Page 7
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`Page 7
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`
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`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`conclusions reached by Dr. Serels that, as of 2006, a person of ordinary skill would
`
`have regarded claims 1-20 of the "438 patent as obvious over O’Donnell (Ex.
`
`1003) in View of Gerber (Ex. 1004) or over the ’2l3 patent (Barrie, Ex. 1005) in
`
`View of Gerber (Ex. 1004). Because my independent analysis of the claims and
`
`prior art led to the same conclusions of obviousness as Dr. Serels, coupled with the
`
`fact that the Petitioner Argentum is seeking to become a party to the Amerigen
`
`IPR, I hereby incorporate Dr. Serels’s opinions and characterizations as my own,
`
`except as specifically noted herein.
`
`III.
`
`LEGAL STANDARDS
`
`8.
`
`In my opinion, given the disclosure of the ’438 Patent, I consider a
`
`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 or oncology, or holds a Ph.D.
`
`in
`
`pharmacology, biochemistry or a related discipline} Additional experience could
`
`substitute for the advanced degree.
`
`9.
`
`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 with which the other person may have expertise, experience and/or
`
`1 A related discipline may include, for example, pharmaceutical sciences.
`
`-7-
`
`Page 8
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`Page 8
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`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
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`knowledge that was obtained through his or her education, industrial or academic
`
`experiences.
`
`10.
`
`I understand that a person of ordinary skill in the art may consult with
`
`an enzymologist and/or molecular biologist and thus may rely on the opinions of
`
`such specialists in evaluating the claims.
`
`11.
`
`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 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.
`
`12.
`
`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
`
`-3-
`
`Page 9
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`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
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`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
`
`13.
`
`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, and is the most common 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, 11. 20-34; Ex. 1022, (Tannock) p. 1501).
`
`14.
`
`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) page 1241; Ex.
`
`1003, (O’Donnell) p. 2317). The two most important androgens responsible for
`
`activating the AR are testosterone and its derivative dihydrotestosterone or DHT.
`
`Testosterone is synthesized primarily in the testes and the adrenals. (Ex. 1003,
`
`(O’Donnell) p. 2317). In non—castrate men, the testes are responsible for producing
`
`the vast majority of circulating testosterone. (Ex. 1003, (O’Donnell) p. 2317). The
`
`-9-
`
`Page 10
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`Declaration in Support of Petition
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`
`Patent No. 8,822,438
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`production of testosterone is regulated by endocrine feedback loops that respond to
`
`varying levels of hormones involved in the testosterone synthetic pathway,
`
`including hormonal precursors to testosterone and testosterone itself.
`
`15.
`
`The treatment options for treating prostate cancer depend to a great
`
`extent on whether the prostate cancer is confined or localized to the prostate or
`
`whether it has spread to other organs (i.e., metastasized) from the prostate. The
`
`goal of treating primary prostate cancer (i.e., prostate cancer localized to the
`
`prostate)
`
`is
`
`to interfere with the proliferation of prostate cancer cells by
`
`interrupting production of testosterone and DHT in the testes, or interfere with
`
`thehlbncfion.(Ex.l003,UDflDonnefl)p.23l7;Ex.l024,UfleHennedt)p.l54)
`
`16. 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, C438 patent) col. 1, 11. 25-34; Ex.
`
`1023, (Attard) p. 1241).
`
`17.
`
`In addition, a significant number of patients either progress after
`
`localized therapy or present with metastatic/non-localized prostate cancer.
`
`(Ex.
`
`1023, (Attard) p. 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 the bone, and the most
`
`significant symptom is pain. (EX. 1025, (Harrison's) p. 549; Ex. l006, (Tarmock) p.
`
`_10_
`
`Page 11
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`Page 11
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`Declaration in Support of Petition
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`Patent No. 8,822,438
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`1756). Non-localized disease and/or metastatic disease is usually treated with
`
`reduction of testosterone production by either hormonal manipulation or
`
`orchiectomy.
`
`18.
`
`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), p. 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.
`
`(Ex. 1003, (O’Donnel1) p.
`
`2317). The first-line treatment for metastatic prostate cancer patients since at least
`
`the 1980's has involved systemic suppression of extratesticular testosterone
`
`production by the peripheral organs,
`
`including the adrenal glands, and is
`
`commonly referred to as hormone therapy.
`
`(Ex. 1024,
`
`(Hellerstedt) p. 154).
`
`Hormone therapy involves
`
`systemic administration of luteinizing hormone-
`
`releasing hormone agonists ("LHRH agonists"), such as leuprorelin (marketed
`
`under the brand name Lupron®). (See, e.g., Ex. 1024, (Hellerstedt) p. 154). LHRH
`
`agonists like Lupron® work by triggering a negative feedback mechanism in the
`
`adrenal system that eventually results in a decrease in production of testosterone
`
`and DHT by the adrenal glands.
`
`-11-
`
`Page12
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`Page 12
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`Declaration in Support of Petition
`for Inter Partes Review
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`Patent No. 8,822,438
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`19.
`
`As the diagram below shows, approximately 90% of the testosterone
`
`is produced in the testes and 10% in the adrenals. (Ex. 1024, (Hellerstedt), p. 159).
`
`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), p. 157). This leads to the pulsative release of LH from the
`
`anterior pituitary. LH then acts on receptors on the Leydig cells of the testes,
`
`leading to production of testosterone. LHRH agonists such as Lupro11® bind to
`
`LHRH receptors in the hypothalamus and stimulate the increased production and
`
`release of LH by the pituitary. Initially,
`
`this surge in LH triggers a flare in
`
`testosterone production.
`
`(See, e.g., EX. 1024, (Hellerstedt) p. 157, Fig. 2 at p. 159).
`
`-12-
`
`Page13
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`Page 13
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`Declaration in Support of Petition
`for Inter Partes Review
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`20.
`
`The testosterone flare is followed by a decrease in testosterone
`
`production as the adrenal endocrine system responds to the overproduction of
`
`LHRH by feedback inhibition of the hypothalamic—pituitary-adrenal axis.
`
`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, (He11erstedt),
`
`p. 157). In addition to the use of LHRH agonists to interrupt production of
`
`testosterone in the adrenal glands, the first—line treatment of metastatic prostate
`
`-13-
`
`Page 14
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`Page 14
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`Declaration in Support of Petition
`for Inter Partes Review
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`Patent No. 8,822,438
`
`cancer usually also includes systemic anti-androgen therapy using drugs such as
`
`bicalutamide.
`
`(Ex. 1024,
`
`(Hellerstedt), p. 158). Anti- androgens work by
`
`interfering with or antagonizing the binding of testosterone and DHT to the
`
`androgen receptors ("AR") on prostate cancer cells. (Ex. 1024, (Hellerstedt), p.
`
`158). The objective of anti-androgens is to prevent testosterone from binding to
`
`AR on prostate cancer cells.
`
`21.
`
`In almost all cases, patients with metastatic prostate cancer develop
`
`what is referred to as refractory or castratiomresistant prostate cancer ("CRPC"),
`
`i.e., prostate cancer that does not respond to a reduction in testosterone levels by
`
`surgical or chemical means and resumes growth. (Ex. 1024, (Hellerstedt), p. 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) p. 2317; Ex. 1023, (Attard) p. 1241).
`
`22.
`
`It was also known that the prognosis for these patients as of 2006 was
`
`poor and almost invariably resulted in incurable progression of the disease. (Ex.
`
`1021, (Oh) Abstract; Ex. 1022, (Tannock 2004) p. 1503; EX. 1023, (Attard) p.
`
`1241). The treatment of metastatic refractory prostate cancer usually also
`
`comprised the use of secondary hormone therapy, usually in combination with
`
`anti-androgen therapy. (Ex. 1021, (Oh) Abstract; Ex. 1023, (Attard) pp. 1241-
`
`1242)
`
`-14-
`
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`Declaration in Support of Petition
`for Inter Partes Review
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`Patent No. 8,822,438
`
`23. Ketoconazole, a non-specific inhibitor of 17-or hydroxylase, an
`
`enzyme critical
`
`to steroid synthesis, also was commonly used off—label
`
`in
`
`combination with prednisone to treat metastatic refractory prostate cancer. (Ex.
`
`1021, (Oh) Abstract; EX. 1020, (Harris) Abstract; Ex. 1025, (Harrison’s) p. 548).
`
`24.
`
`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:
`
`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. (EX. 1001, (‘438 patent) claim 1).
`
`25.
`
`The dependent claims of the '438 Patent further specify the amount of
`
`abiraterone acetate and/or prednisone administered to a human patient, the type of
`
`prostate cancer including refractory prostate cancer to be treated in such patient,
`
`and particular anti—cancer agents administered previously to such patient.
`
`26. Abiraterone acetate is a 17d-hydroxylase/C17,20-lyase inhibitor. (Ex.
`
`1003, (O’Donnell) pp. 2318, 2322). l7ot—hydroXylase/Cl7,20—lyase inhibitors (also
`
`referred to as "CYPI7 inhibitors") were known in the art to be useful in the
`
`treatment of androgen-dependent
`
`cancers,
`
`including prostate
`
`cancer, by
`
`-15-
`
`Page 16
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`Page 16
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`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`contributing to suppression of peripheral androgen production.
`
`(Ex.
`
`1003,
`
`(O’Donne1l) p. 2318). As I explained before, the two sites thought to produce most
`
`of the androgenic steroids in human males are the testes and the adrenal cortex.
`
`(Ex. 1023, (Attard) p. 1242-1243). It was known in the art that plasma testosterone
`
`is not completely suppressed by castration,
`
`in part because of peripheral
`
`conversion
`
`of
`
`adrenal
`
`androgenic
`
`steroids
`
`to
`
`testosterone
`
`by
`
`170--
`
`hydroxylase/Cl7,20—1yase. (Ex. 1003, (O’Donnell) p. 2317; Ex. 1023, (Attard) pp.
`
`1242-1243). It was also known that AR on the prostate cancer cells of patients with
`
`refractory metastatic prostate cancer was "hypersensitive" to androgenic steroid
`
`stimulation. (Ex. 1003, (O’Donnell) p. 2317; Ex. 1023, (Attard) p. 1241).
`
`27.
`
`CYP17 inhibitors were known to inhibit 17o.-hydroxylase/Cl7,20-
`
`lyase (“CYP17”), an enzyme that is critical to androgen synthesis in both the testes
`
`and the adrenal cortex. (Ex. 1003, (O’Donne1l) p. 2318; Ex. 1023, (Attard) p.
`
`1242). The following diagram explains how CYP17 inhibitors work to inhibit
`
`production of testosterone?
`
`2 The diagram shows CYP17 at the reaction in which it adds a hydroxyl (OH)
`group to pregnenolone and removes the side chain from 17-hydroxypregnenolone.
`Similarly, CYP17 is used in the reaction to add a hydroxyl (—OH) group to
`progesterone and remove the side chain from 17-hydroxy progesterone, although
`not explicitly labeled as such in the diagram. The use of CYP17 in these two
`reactions was well known as seen in, for example, Ex. 1003, (O’Donne1l) p. 2318
`which has a diagram that shows CYP17 in these reactions.
`
`-16-
`
`Page 17
`
`Page 17
`
`
`
`Declaration in Support of Petition
`for Inter Partes Review
`
`‘~x.._ _,x““~»,
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`
`Page18
`
`Page 18
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`
`
`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`28.
`
`The CYP17 enzyme has two activities in the steroidogenic pathway:
`
`(1) acting as a 1701-hydroxylase, and (2) acting as a 17,20 lyase. (Ex. 1003,
`
`(O’Donnell) p. 2318, Fig. 1). As a 17oc—hydroxy1ase, CYPl7 adds a hydroxyl group
`
`(-OH) to pregnenolone and progesterone at carbon 17 of the steroid D ring,
`
`converting both compounds to their 17-hydroxy forms. (Ex. 1003, (O’Donnell) p.
`
`2318, Fig. 1). As a 17,20 lyase,
`
`it acts to split
`
`the side chain off of 17-
`
`hydroxyprogesterone and l7—hydroxypregnenolone.
`
`(Ex. 1003,
`
`(O’Donne1l) p.
`
`2318, Fig. 1). Importantly, the 17d-hydroxylase activity of CYPl7 is essential to
`
`the synthesis of both (1) sex hormones,
`
`i.e., androgens (z'.e.,
`
`testosterone) and
`
`estrogens, and (2) cortisol. Cortisol is an essential steroid that is critical to basic
`
`metabolic functions including the formation of glucose, cardiovascular function,
`
`and the activation of the anti—stress and inflammatory pathways. One of skill in the
`
`art would have expected that
`
`the administration of a CYPI7 inhibitor would
`
`interfere with the production of both testosterone (in men) and cortisol. (Ex. 1027,
`
`(Costa—Santos) Abstract, p. 49; Ex. 1026, (Auchus) Abstract).
`
`29. While the CYP17 enzyme is essential for androgen biosynthesis,
`
`it
`
`also plays an important role in the production of cortisol, a glucocorticoid. The
`
`diagram below shows the control of cortisol production in the adrenal cortex. As
`
`more cortisol is produced, there is a negative feedback on the hypothalamus and
`
`anterior pituitary that reduces the production of ACTH, which consequently
`
`-13-
`
`Page19
`
`Page 19
`
`
`
`Declaration in Support of Petition
`for I11ter Partes Review
`
`Patent No. 8,822,438
`
`reduces the production of cortisol. It is this negative feedback mechanism that
`
`gives the pulsative production of cortisol described above.
`
`Cortisol: Negative Feedback Loop
`<,._..._..__.__.____i._____.E
`5
`
`‘ Releasing hormone
`
`cortisol
`
`
`
`Negative feedback by
`
`(The Human Body In Health and Illness, 4th Edition, Barbara Herlihy, Chapter 14,
`
`endocrine system.)
`
`30. When a CYP17 inhibitor is administered, cortisol production is
`
`compromised (e.g.,
`
`reduced), which interferes with the negative feedback
`
`mechanism that maintains cortisol levels Within the normal physiological range.
`
`Specifically,
`
`the pituitary gland produces more adrenocorticotropic hormone
`
`(ACTH) to stimulate greater production of glucocorticoids, which are formed from
`
`-19-
`
`Page 20
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`Page 20
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`
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`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`ACTH, in part, by a reaction involving CYP17. However, in the presence of a
`
`CYP17 inhibitor, the conversion in the CYP17 pathway from ACTH to cortisol
`
`cannot occur. In other words, an increase in ACTH will not provide the necessary
`
`quantities of cortisol because the CYP17 pathway from ACTH to cortisol
`
`is
`
`blocked by the CYP17 inhibitor. However, a different, minor pathway results in
`
`some of the ACTH being converted to cortisol, although the majority of the ACTH
`
`will be converted into mineralocorticoids.
`
`31.
`
`It was known that CYP17 inhibition of cortisol increased ACTH drive
`
`(i.e., increased ACTH production), which resulted in a corresponding increase in
`
`mineralocorticoids. (Ex. 1027, (Costa—Santos) Abstract, p. 49; EX. 1026, (Auchus)
`
`Abstract; Ex. 1025, (Harrison’s) p. 2145). An increase in rnineralocorticoids
`
`beyond normal levels, known as “rnineralocorticoid excess,” was known to have
`
`adverse effects,
`
`including hypertension, hypokalernia (decrease in circulating
`
`potassium levels), and fluid retention. (Ex. 1027, (Costa-Santos) Abstract, p. 49;
`
`Ex. 1025, (Harrison’s) pp. 2143, 2145, 2146).
`
`32.
`
`It also was known in the art to administer a glucocorticoid, such
`
`hydrocortisone or prednisone,
`
`to suppress ACTH drive by way of a negative
`
`feedback loop akin to that
`
`triggered by cortisol.
`
`(Ex. 1027,
`
`(Costa-Santos)
`
`Abstract, p. 49; AMG Ex. 1025,
`
`(Harrison’s) pp. 2143, 2145, 2146). By
`
`suppressing ACTH drive, fewer rnineralocorticoids are produced and the adverse
`
`-20-
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`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
`
`side effects of hypertension, hypokalemia, and fluid retention are reduced even in
`
`the presence of the CYPl7 inhibition.
`
`33. Ketoconazole was known to be a non-specific inhibitor of CYPl7,
`
`was known to have a direct anti—tumor effect
`
`in vitro and was known to be
`
`effective as a second-line treatment for metastatic hormone refractory prostate
`
`cancer. (Ex. 1003, (O’Donne11) p. 2318; EX. 1021, (Oh) Abstract, p. 49; Ex. 1020,
`
`(Harris) pp. 542-543).
`
`34. However, the administration of ketoconazole to treat prostate cancer
`
`was known to reduce cortisol levels and potentially result in rnineralocorticoid
`
`excess, giving rise to side effects commonly associated with mineralocorticoid
`
`excess,
`
`including hypertension, hypokalernia, and fluid retention.
`
`(Ex. 1028,
`
`(lubelirer) Abstract; Ex. 1003, (O’Donnell) p. 2323; Ex. 1021, (Oh) Abstract, p.
`
`49; Ex; 1020, (Harris) pp. 542-544). These side effects reduced the safety and
`
`tolerability of administering ketoconazole. (Ex. 1028, (lubelirer) Abstract; Ex.
`
`1003, (O’Donnell) p. 2323; Ex. 1021, (Oh) Abstract, p. 49; Ex. 1020, (Harris) pp.
`
`542-544). To address these side effects, it was standard practice in the art to co-
`
`administer
`
`a glucocorticoid such as hydrocortisone
`
`or prednisone with
`
`ketoconazole to improve the safety and tolerability of administration of
`
`ketoconazole to treat prostate cancer in a human patient. (Ex. 1003, (O'Donnell) p.
`
`2323; Ex. 1020, (Harris) Abstract, 542; Ex. 1021, (Oh) Abstract).
`
`-21-
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`Page 22
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`Declaration in Support of Petition
`for Inter Partes Review
`
`Patent No. 8,822,438
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`35.
`
`The combination of ketoconazole with prednisone, although not
`
`approved by the FDA in combination for treating prostate cancer, was reported in
`
`the literature to be safe and effective in treating patients with hormone refractory
`
`metastatic prostate cancer. (Ex. 1004, (Gerber) Abstract).
`
`36. Abiraterone acetate was known to be a more efficacious anti~cancer
`
`agent in the treatment of prostate cancer, including metastatic hormone refr
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