Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
` Paper 84
`Entered: January 17, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC., 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,
`Petitioner,
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-013321
`Patent 8,822,438 B2
`____________
`
`
`Before LORA M. GREEN, RAMA G. ELLURU, and
`KRISTINA M. KALAN, Administrative Patent Judges.
`
`KALAN, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`1 Case IPR2017-00853 has been joined with this proceeding.
`
`
`Tel: 571-272-7822
`
`
`
`
` Paper 84
`Entered: January 17, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC., 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,
`Petitioner,
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-013321
`Patent 8,822,438 B2
`____________
`
`
`Before LORA M. GREEN, RAMA G. ELLURU, and
`KRISTINA M. KALAN, Administrative Patent Judges.
`
`KALAN, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`1 Case IPR2017-00853 has been joined with this proceeding.
`
`
`
`IPR2016-01332
`Patent 8,822,438 B2
`
`
`I. INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Mylan”) filed a Petition (Paper 1, “Pet.”)
`to institute an inter partes review of claims 1–20 of U.S. Patent
`No. 8,822,438 B2 (Ex. 1001, “the ’438 patent”) pursuant to 35 U.S.C.
`§§ 311–319. Janssen Oncology, Inc. (“Patent Owner”) filed a Preliminary
`Response (Paper 14, “Prelim. Resp.”). We instituted an inter partes review
`of claims 1–20 on certain grounds of unpatentability alleged in the Petition
`(Paper 21, “Dec.”).
`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 (collectively,
`the “Actavis Petitioners”) filed a Petition for inter partes review of claims 1–
`20 of the ’438 patent. Case IPR2017-00853, Paper 8. Together with its
`Petition, the Actavis Petitioners filed a Motion for Joinder to join the case
`with the previously instituted proceeding in IPR2016-01332. Id., Paper 9.
`We instituted trial in IPR2017-00853 and joined the Actavis Petitioners as a
`Petitioner in IPR2016-01332. Id., Paper 19.
`After institution of trial, Patent Owner filed a Patent Owner Response
`(Paper 35, “PO Resp.”). Mylan and the Actavis Petitioners (collectively,
`“Petitioner”) filed a Reply (Paper 55, “Reply”). Pursuant to a Board Order
`(Paper 64), Patent Owner filed an Identification of New Arguments and
`Evidence in Petitioner’s Reply (Paper 65), to which Petitioner filed a Reply
`
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`(Paper 74). An oral hearing was held on May 24, 2017. A transcript of the
`hearing has been entered into the record. Paper 82 (“Tr.”).
`The Board has jurisdiction under 35 U.S.C. § 6. In this Final Written
`Decision, issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73, we
`determine that Petitioner has shown by a preponderance of the evidence that
`all claims of the ’438 patent for which trial was instituted, namely, claims 1–
`20, are unpatentable.
`
`II. BACKGROUND
`
`A. Related Matters
`The parties indicate that the ’438 patent is being asserted in a number
`of district court proceedings, some of which have been terminated. Pet. 1–2;
`Paper 7, 3. Patent Owner represents that the following proceedings have not
`been terminated: BTG Int’l Ltd. v. Actavis Labs. FL, Inc., C.A. No. 2:15-cv-
`05909-KM-JBC (D.N.J.); and Janssen Biotech, Inc. v. Mylan Pharms. Inc.,
`C.A. No. 1:15-cv-00130-IMK (N.D. W. Va.), BTG Int’l Ltd. v. Amerigen
`Pharms., Inc., C.A. No. 2:16-cv-02449-KM-JBC (D.N.J.); and BTG Int’l Ltd.
`v. Glenmark Pharms. Inc., USA, C.A. No. 2:16-cv-5909 (D.N.J). Paper 27,
`3.
`
`Patent Owner also states that the ’438 patent was the subject of ex
`parte reexamination request No. 90/020,096, but “will not be granted a filing
`date for failure to comply with the requirements of 37 C.F.R. § 1.501(a).”
`Paper 7, 2.
`B. The ’438 Patent
`The ’438 patent, titled “Methods and Compositions for Treating
`Cancer,” describes methods that comprise “administering a 17α-
`hydroxylase/C17, 20-lyase inhibitor, such as abiraterone acetate (i.e., 3β-
`
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`acetoxy-17-(3-pyridyl)androsta-5,16-diene), in combination with at least one
`additional therapeutic agent such as an anti-cancer agent or a steroid.”
`Ex. 1001, at [54], [57]. As described in the ’438 patent, it is believed that
`testosterone and dihydrotestosterone promote the growth of prostate cancer.
`Id. at 1:49–51. Hormone therapy can be used to suppress the production or
`block the effects of hormones such as testosterone. Id. at 1:43–51.
`The enzyme 17α-hydroxylase/C17, 20-lyase (“CYP17”) is involved in
`testosterone synthesis. Id. at 3:66–4:1. CYP17 inhibitors have been shown
`to be useful in the treatment of cancer, specifically, androgen-dependent
`disorders like prostate cancer. Id. at 5:23–27. Abiraterone acetate, a prodrug
`of abiraterone, is a CYP17 inhibitor. Id. at 2:10–12.
`The ’438 patent describes administration of a therapeutically effective
`amount of a CYP17 inhibitor, such as abiraterone acetate, with a
`therapeutically effective amount of at least one additional therapeutic agent
`including, but not limited to, an anti-cancer agent, such as mitoxantrone,
`paclitaxel, docetaxel, leuprolide, goserelin, triptorelin, seocalcitol,
`bicalutamide, or flutamide, or a steroid, such as hydrocortisone, prednisone,
`or dexamethasone. Id. at 2:9–3:20.
`C. Challenged Claims
`Claim 1 of the ’438 patent is reproduced below:
`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, 16:16–20. Dependent claims 2–20 of the ’438 patent describe
`additional limitations of the method, including the amount of abiraterone
`
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`acetate and the amount of prednisone used and the type of prostate cancer
`being treated. Id. at 16:21–17:14.
`D. Prior Art References Relied Upon by Petitioner
`Petitioner relies on the following prior art:
`1. O’Donnell, A. et al., Hormonal impact of the 17α-hydroxylase/
`C17, 20-lyase inhibitor abiraterone acetate (CB7630) in patients with
`prostate cancer, 90 British Journal of Cancer 2317–25 (2004)
`(“O’Donnell”) (Ex. 1003);
`2. Gerber, G.S. & Chodak, G.W., Prostate specific antigen for
`assessing response to ketoconazole and prednisone in patients with
`hormone refractory metastatic prostate cancer, 144 J. Urol. 1177–
`79 (1990) (“Gerber”) (Ex. 1004); and
`3. U.S. Patent No. 5,604,213 to Barrie, issued February 18, 1997
`(“Barrie”) (Ex. 1005).
`
`
`E. Instituted Grounds of Unpatentability
`We instituted inter partes review of claims 1–20 of the ’438 patent on
`the following grounds:
`References
`O’Donnell and Gerber
`
`Basis
`§ 103
`
`Claims Challenged
`1–20
`
`Barrie and Gerber
`
`§ 103
`
`1–4 and 6–11
`
`In support of its challenges, Petitioner relies on the declarations of
`Marc B. Garnick, M.D. (Ex. 1002; Ex. 1104, 1153), Ivan T. Hoffman (Ex.
`1017; Ex. 1134, 1146, 1151, 1154), Ian McKeague, Ph.D. (Ex. 1091), John
`Bantle, M.D. (Ex. 1097) and Bryan D. Beel (Ex. 1152). Patent Owner relies
`on the declarations of Ian Judson, M.D. (Ex. 2028), Matthew Rettig, M.D.
`(Ex. 2038), Richard Auchus, M.D., Ph.D. (Ex. 2040), Christopher A.
`Vellturo, Ph.D. (Ex. 2044), and Johann S. De Bono (Ex. 2118).
`
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`
`III. ANALYSIS
`
`A. Claim Interpretation
`The Board interprets claim terms in an unexpired patent according to
`the broadest reasonable construction in light of the specification of the patent
`in which they appear. See Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131,
`2144–46 (2016) (upholding the use of the broadest reasonable interpretation
`standard); 37 C.F.R. § 42.100(b). Under that standard, and absent any special
`definitions, we give claim terms their ordinary and customary meaning as
`would be understood by one of ordinary skill in the art at the time of the
`invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007). Any special definitions for claim terms must be set forth with
`reasonable clarity, deliberateness, and precision. See In re Paulsen, 30 F.3d
`1475, 1480 (Fed. Cir. 1994). Only those terms which are in controversy need
`to be construed, and only to the extent necessary to resolve the controversy.
`See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd., 868 F.3d
`1013, 1017 (Fed. Cir. 2017) (“we need only construe terms ‘that are in
`controversy, and only to the extent necessary to resolve the controversy’”)
`(quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed.
`Cir. 1999)).
`With respect to claim interpretation, “[u]sually [the specification] is
`dispositive; it is the single best guide to the meaning of a disputed term.” In
`re Abbott Diabetes Care Inc., 696 F.3d 1142, 1149 (Fed. Cir. 2012) (citations
`omitted). “To act as its own lexicographer, a patentee must ‘clearly set forth
`a definition of the disputed claim term’ other than its plain and ordinary
`meaning.” Thorner v. Sony Computer Entm’t Am. LLC, 669 F.3d 1362, 1365
`
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`(Fed. Cir. 2012) (quoting CCS Fitness, Inc. v. Brunswick Corp., 288 F.3d
`1359, 1366 (Fed. Cir. 2002)).
`Petitioner proposes that we construe the claim terms “treat,” “treating,”
`“treatment,” “anti-cancer agent,” and “refractory cancer.” Pet. 17–19. We
`adopted constructions for these claim terms in the Decision on Institution in
`IPR2016-00286.2 Pet. 18 (citing IPR2016-00286, Paper 14). In our Decision
`on Institution in IPR2016-00286, we construed those terms, as well as the
`term “therapeutically effective amount of prednisone” as follows:
`
`Claim term(s)
`“treat,” “treating,” and
`“treatment”
`
`“anti-cancer agent”
`
`“refractory cancer”
`
`“therapeutically effective
`amount of prednisone”
`
`
`Construction
`include the eradication, removal,
`modification, management or control
`of a tumor or primary, regional, or
`metastatic cancer cells or tissue and the
`minimization or delay of the spread of
`cancer
`Ex. 1001, 3:46–50
`any therapeutic agent that directly or
`indirectly kills cancer cells or directly
`or indirectly prohibits, stops or reduces
`the proliferation of cancer cells
`Ex. 1001, 4:8–16
`cancer that is not responding to an anti-
`cancer treatment or cancer that is not
`responding sufficiently to an anti-
`cancer treatment
`Ex. 1001, 4:23–27.
`an amount of prednisone effective for
`treating prostate cancer
`
`
`2 IPR2016-00286 is an earlier-filed case involving the ’438 patent, the same
`grounds, and the same Patent Owner. Petitioner filed a motion for joinder of
`this case with IPR2016-00286 (Paper 3), which we denied (Paper 21).
`
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`
`Patent Owner, in its Response, states: “The Panel’s construction of
`‘treat,’ ‘treating’ and ‘treatment’ is consistent with the disclosure of the ’438
`patent and should be maintained.” PO Resp. 6. Patent Owner also states that
`it “understands the Panel’s construction to mean that administration of
`prednisone with abiraterone acetate, must at least cause an anti-cancer effect,
`regardless of whether it has any other non-anti-cancer effects.” Id. at 5.
`Petitioner replies that “the Board clearly held that ‘treatment’ does not
`require an antitumor or anticancer effect.” Reply 18 (citing IPR2016-00286,
`Decision on Institution (Paper 14) at 5; IPR2016-00286, Decision Denying
`Request for Rehearing (Paper 23) at 3 (rejecting Janssen’s request for
`rehearing and noting that the Board’s construction of “treating” does not
`require “having an anti-cancer effect on”).)
`Patent Owner also submitted a claim construction of the terms
`“treatment” and “treating” by the district court in a companion litigation.
`Ex. 2004. The district court, after a lengthy analysis, construed the disputed
`terms as follows: “Treatment/treating means the eradication, removal,
`modification, management or control of a tumor or primary, regional, or
`metastatic cancer cells or tissue and the minimization or delay of the spread
`of cancer.” Id. at 30. The district court read out of the definition the term
`“includes.” Id. Although we are not bound by the district court’s reasoning
`and claim constructions in related proceedings, we do not disregard the
`determinations of a court interpreting the same claim term in a related patent
`in a concurrent proceeding. Power Integrations, Inc. v. Lee, 797 F.3d 1318,
`1326–27 (Fed. Cir. 2015) (“The fact that the board is not generally bound by
`a previous judicial interpretation of a disputed claim term does not mean,
`however, that it has no obligation to acknowledge that interpretation or to
`
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`assess whether it is consistent with the broadest reasonable construction of
`the term.”). Thus, although we acknowledge and have considered the district
`court’s interpretation, we retain our broadest reasonable construction of the
`terms “treat,” “treatment,” and “treating.”
`We see no reason to modify our claim construction positions in light of
`the record developed at trial, and we maintain our claim constructions from
`the Decision on Institution for the purposes of this Decision. No other claim
`terms have been presented to us for construction following institution of trial,
`and we determine that no other claim terms require express construction.
`B. Principles of Law
`A claim is unpatentable under 35 U.S.C. § 1033 if the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations including: (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and (4) objective evidence of
`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). A
`decision on the ground of obviousness must include “articulated reasoning
`with some rational underpinning to support the legal conclusion of
`
`
`3 The Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`(2011) (“AIA”), amended 35 U.S.C. § 103. Because the ’438 patent has an
`effective filing date before the effective date of the applicable AIA
`amendments, throughout this Decision we refer to the pre-AIA versions of
`35 U.S.C. § 103.
`
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`obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). The
`obviousness analysis “should be made explicit” and it “can be important to
`identify a reason that would have prompted a person of ordinary skill in the
`relevant field to combine the elements in the way the claimed new invention
`does.” KSR, 550 U.S. at 418. We analyze the asserted grounds of
`unpatentability in accordance with the above-stated principles.
`C. Level of Skill in the Art
`We adopt Petitioner’s contention that a person of ordinary skill in the
`
`art
`
`would be a physician specializing in urology, endocrinology, or
`oncology, or a person holding a Ph.D. in pharmacology,
`biochemistry or a related discipline, such as pharmaceutical
`science. Additional experience could substitute for the advanced
`degree. To the extent necessary, one of 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 knowledge that was obtained
`through his or her education, industrial or academic experiences.
`For example, one of skill may consult with an endocrinologist,
`oncologist, or medical biochemist and thus may rely on the
`opinions of such specialists in evaluating the claims.
`
`Pet. 7 (citations omitted). Patent Owner does not appear to dispute
`Petitioner’s definition in its Patent Owner Response. See generally PO Resp.
`The level of ordinary skill in the art in this case is further demonstrated by
`the prior art asserted in the Petition. See Okajima v. Bourdeau, 261
`F.3d 1350, 1355 (Fed. Cir. 2001).
`
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`D. Overview of the Prior Art
`1. O’Donnell
`O’Donnell, which is titled “Hormonal impact of the 17α-
`hydroxylase/C17,20-lyase inhibitor abiraterone acetate (CB7630) in patients
`with prostate cancer,” discloses that treatment of prostate cancer with
`abiraterone acetate, at a dose of 500–800 mg, can successfully suppress
`testosterone levels. Ex. 1003, Abstract. O’Donnell also discloses that
`ketoconazole, another CYP17 inhibitor, has been evaluated as a possible
`agent with which to achieve decreased production of adrenal steroids, but that
`abiraterone acetate was developed as a more selective inhibitor. Id. at 2318.
`O’Donnell further discloses that adrenocortical suppression may require
`administration of replacement glucocorticoid. Id. at Abstract, 2323.
`O’Donnell states that “[s]ome impact on adrenal reserve was predictable
`from the steroid synthesis pathway.” Id. at 2323. Regarding administration
`of ketoconazole, O’Donnell states that “it is common practice to administer
`supplementary hydrocortisone” and that this may prove necessary with
`abiraterone acetate. Id. On the basis of the clinical evidence, O’Donnell
`reports that the need for concomitant therapy of abiraterone acetate with a
`glucocorticoid needs to be further investigated. Id.
`2. Gerber
`Gerber, which is titled “Prostate Specific Antigen for Assessing
`Response to Ketoconazole and Prednisone in Patients with Hormone
`Refractory Metastatic Prostate Cancer,” discloses use of ketoconazole, a
`known CYP17 enzyme inhibitor and inhibitor of gonadal and adrenocortical
`steroid synthesis, with prednisone to treat patients with progressive prostate
`cancer. Ex. 1004, 1177. Gerber provides that patients exhibiting
`
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`progressively increasing prostate specific antigen (“PSA”) levels, when
`treated with ketoconazole and prednisone, experienced a decrease in PSA
`levels. Id. at 1178–79. Based on its study, Gerber concludes that “there
`appears to be a small subgroup of patients with progressive prostate cancer
`despite hormonal therapy who will derive significant benefit from the
`combination of ketoconazole and glucocorticoid replacement therapy.” Id.
`at 1179.
`3. Barrie
`Barrie, which is titled “17-Substituted Steroids Useful in Cancer
`Treatment,” is directed to a class of 17-substituted steroids and their use in
`the treatment of androgen-dependent and estrogen-dependent disorders.
`Ex. 1005, 1:11–14. Specifically, Barrie discloses abiraterone, acid addition
`salts and 3-esters of abiraterone, and abiraterone acetate. Id. at 5:21–26,
`7:23–26, 11:39–55. Barrie discloses that abiraterone acetate may be
`administered in a method of treating disorders, including prostate cancer, as a
`pharmaceutical composition comprising a therapeutically effective amount of
`abiraterone acetate. Id. at 10:27–57. Barrie compares the inhibition levels of
`hormone production by abiraterone acetate with ketoconazole, concluding
`that the decrease in testosterone levels resulting from administration of
`abiraterone acetate was much more marked than for ketoconazole. Id.
`at 26:32–38.
`E. Obviousness Analysis
`1. Petitioner’s Arguments
`Petitioner argues, generally, that it was “known that in using a CYP17
`inhibitor to reduce testosterone synthesis, the CYP17 inhibitor also
`undesirably suppressed the production of cortisol, a glucocorticoid, which is
`
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`necessary for other biochemical cycles in the body.” Pet. 5. In particular,
`reduced production of cortisol “caused adverse effects, including
`hypertension, hypokalemia (decrease in circulating potassium levels), and
`fluid retention.” Id. (citing Ex. 1002 ¶¶ 42, 44, 58). Administration of a
`CYP17 inhibitor to suppress androgen synthesis results in the “undesired side
`effect” that “cortisol production is compromised (e.g., reduced), which
`interferes with the negative feedback mechanism that usually maintains
`cortisol levels within the normal physiological range.” Id. at 26. Petitioner
`also argues that it was “known that CYP17 inhibition of cortisol increased
`ACTH drive (i.e., increased ACTH production), which resulted in a
`corresponding increase in mineralocorticoids,” leading to mineralocorticoid
`excess. Id. at 27 (citing Ex. 1002 ¶ 41). It was general knowledge in the art,
`Petitioner argues, “to administer a glucocorticoid, such as prednisone or
`hydrocortisone, to a patient with ACTH drive, such as a patient administered
`a CYP17 inhibitor, to reduce ACTH drive, and consequently, reduce
`mineralocorticoid excess.” Id. (citing Ex. 1002 ¶ 42).
`a. Ground Based on O’Donnell and Gerber
`Petitioner challenges claims 1–20 as obvious under 35 U.S.C. § 103
`over O’Donnell and Gerber. Pet. 38–50.
`Regarding claim 1, Petitioner argues that O’Donnell teaches “that
`abiraterone acetate is a selective CYP17 inhibitor that is more effective than
`ketoconazole, a CYP17 inhibitor known in the art, in suppressing testosterone
`levels in a mammal in vivo.” Pet. 38 (citing Ex. 1003, 2138, 2322, 2323,
`2325). Petitioner further argues that, although O’Donnell does not disclose
`administration of abiraterone acetate with prednisone, “O’Donnell taught that
`concomitant hormone replacement therapy with a glucocorticoid may be
`
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`needed when using abiraterone acetate to treat a prostate cancer in a human
`patient.” Id. at 39 (citing Ex. 1003, 2323). Gerber, Petitioner argues, teaches
`that “the combination of ketoconazole and prednisone (a glucocorticoid) is
`safe and effective in treating human patients with hormone-refractory
`advanced prostate cancer.” Id. at 39–40 (citing Ex. 1005 [sic], 1177–79).
`Regarding motivation to combine, Petitioner reasons that one of skill
`in the art “would have been motivated to add prednisone to a method of using
`abiraterone acetate (a CYP17 inhibitor)” to treat prostate cancer in a human
`patient “by Gerber’s teaching that administering 5 mg prednisone twice daily
`with ketoconazole, also a CYP17 inhibitor, is a safe and effective treatment
`in human patients with hormone-refractory prostate cancer.” Id. at 40.
`Petitioner also argues that one of ordinary skill in the art would have been
`“motivated by suggestions in the prior art that prednisone could have some
`amount of anti-cancer activity.” Id. (citing Ex. 1002 ¶¶ 33, 89–90). Overall,
`Petitioner argues, one of ordinary skill in the art would have combined
`abiraterone acetate and prednisone “with a reasonable expectation of
`success” because the “prior art taught that abiraterone acetate was a more
`effective CYP17 inhibitor than ketoconazole and that the combination of
`ketoconazole and prednisone was safe and effective to treat patients with
`hormone refractory metastatic prostate cancer, which would have motivated
`the combination.” Id. at 6 (citing Ex. 1002 ¶¶ 55–59).
`Claims 2–20 each depend directly or indirectly from claim 1.
`Petitioner contends these claims are also unpatentable under 35 U.S.C. § 103
`based on O’Donnell and Gerber. Pet. 42–50.
`
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`b. Ground Based on Barrie and Gerber
`Petitioner challenges claims 1–4 and 6–11 as obvious under 35 U.S.C.
`§ 103 over Barrie and Gerber. Pet. 38–47.
`Regarding claim 1, Petitioner argues that Barrie teaches “that
`abiraterone acetate is a selective CYP17 inhibitor that is more effective than
`ketoconazole, a CYP17 inhibitor known in the art, in suppressing testosterone
`levels in a mammal in vivo.” Pet. 38 (citing Ex. 1005, 25:13–26:63). Gerber,
`Petitioner argues, teaches that “the combination of ketoconazole and
`prednisone (a glucocorticoid) is safe and effective in treating human patients
`with hormone-refractory advanced prostate cancer.” Id. at 39–40 (citing
`Ex. 1005 [sic], 1177–79).
`Regarding motivation to combine, Petitioner reasons that one of skill
`in the art “would have been motivated to add prednisone to a method of using
`abiraterone acetate (a CYP17 inhibitor)” to treat prostate cancer in a human
`patient “by Gerber’s teaching that administering 5 mg prednisone twice daily
`with ketoconazole, also a CYP17 inhibitor, is a safe and effective treatment
`in human patients with hormone-refractory prostate cancer.” Id. at 40.
`Petitioner also argues that one of ordinary skill in the art would have been
`“motivated by suggestions in the prior art that prednisone could have some
`amount of anti-cancer activity.” Id. (citing Ex. 1002 ¶¶ 33, 89–90). Overall,
`Petitioner argues, one of ordinary skill in the art would have combined
`abiraterone acetate and prednisone “with a reasonable expectation of
`success” because the “prior art taught that abiraterone acetate was a more
`effective CYP17 inhibitor than ketoconazole and that the combination of
`ketoconazole and prednisone was safe and effective to treat patients with
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`hormone refractory metastatic prostate cancer, which would have motivated
`the combination.” Id. at 6 (citing Ex. 1002 ¶¶ 55–59).
`Claims 2–4 and 6–11 each depend directly or indirectly from claim 1.
`Petitioner contends these claims are also unpatentable under 35 U.S.C. § 103
`based on Barrie and Gerber. Pet. 42–47.s
`2. Patent Owner’s Non-Obviousness Arguments
`Patent Owner presents a series of arguments directed to the art relied
`upon in both of Petitioner’s grounds, arguments directed to the reasons to
`combine the prior art, and arguments related to objective indicia of non-
`obviousness. PO Resp. 10–64. We address each in turn.
`a. Patent Owner’s First Argument
`Patent Owner argues, first, that Petitioner’s “obviousness theory is
`anchored on its assertion that, because abiraterone acetate and ketoconazole
`are both ‘CYP17 inhibitors,’ they will cause the same side effects.” PO
`Resp. 13. Rather, Patent Owner argues, abiraterone acetate and ketoconazole
`cause very different effects on steroid biosynthesis. Id. (citing Ex. 2126,
`29:5–17; 8:5–21). Patent Owner emphasizes that ketoconazole “is
`considered a non-selective steroid synthesis inhibitor” whereas abiraterone
`acetate “is a selective CYP17 inhibitor” that targets only CYP17. Id. at 13–
`15, Figs. 1, 2 (citing Ex. 2038 ¶¶ 19–20, 25–39, 97, 103). Patent Owner
`faults Petitioner’s expert for omitting “any mention of these fundamental
`differences in the effects of ketoconazole and abiraterone acetate on the
`various steroid synthesis pathways, particularly those that might implicate a
`need for glucocorticoid replacement therapy.” Id. at 17.
`Patent Owner argues, next, that Petitioner incorrectly contends that
`ketoconazole and abiraterone acetate cause the same side effects. Id. Rather,
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`Patent Owner argues, there is no prior art evidence that ketoconazole causes
`mineralocorticoid excess. Id. at 18. According to Patent Owner,
`“mineralocorticoid production was reduced in patients administered
`ketoconazole.” Id. (citing Ex. 2040 ¶ 38; Ex. 2067, 585). Patent Owner
`further argues that there was no evidence in 2006 that abiraterone acetate
`would cause mineralocorticoid excess. Id. at 19 (citing Ex. 2038 ¶¶ 154–60,
`162; Ex. 2040 ¶¶ 49–66). Neither Barrie nor O’Donnell, Patent Owner notes,
`measures mineralocorticoid excess. Id. at 19–20.
`Petitioner replies that ketoconazole and aminoglutethimide, known
`treatments for prostate cancer, inhibited production of testosterone and
`numerous other steroids such as cortisol, resulting in conditions such as
`mineralocorticoid excess and adrenal insufficiency and symptoms such as
`hypertension, hypokalemia, fluid retention, fatigue, nausea and vomiting,
`weight loss, and hypotension. Reply 4–5 (citing Ex. 1097 ¶¶ 32–33, 37–39,
`41; Ex. 1104 ¶¶ 16–23). Abiraterone acetate, as a “next generation steroid
`synthesis inhibitor,” is in the same class of treatment agents as ketoconazole
`and aminoglutethimide, argues Petitioner, and therefore, “a skilled artisan
`would have been concerned that abiraterone acetate would induce similar
`side effects as other steroid synthesis inhibitors.” Id. at 5–6 (citing Ex. 1104
`¶¶ 14–31, Ex. 1097 ¶¶ 44–49). Thus, “in light of steroid synthesis inhibitors’
`known effects on the adrenal pathways, a skilled artisan would have been
`motivated to administer glucocorticoids with abiraterone acetate to counteract
`expected endocrine disruptions.” Id. at 7 (citing Ex. 1097 ¶¶ 21–66, Ex. 1104
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`¶¶ 20–22, 40–79). Petitioner also argues that O’Donnell’s test results were
`consistent with mineralocorticoid excess. Id. at 15.
`Based on the information presented during trial, we understand that
`ketoconazole and abiraterone acetate do not have identical mechanisms. See,
`e.g., Ex. 2038 ¶¶ 25–39, Figs. 4, 5). As noted by both Petitioner and Patent
`Owner, however, abiraterone acetate and ketoconazole are both steroid
`synthesis inhibitors, particularly, CYP17 inhibitors. Pet. 26; PO Resp. 13–
`15; Reply 2, 5, 9. Both parties appear to agree that, based on their respective
`mechanisms of action, administration of ketoconazole would inhibit
`production of cortisol, and administration of abiraterone acetate inhibits one
`of the pathways of cortisol production. Pet. 5, 26; Tr. 12:18–19; PO
`Resp. 14, Figs. 1, 2; Ex. 1003, 2318; Ex. 1023, 3, Fig. 1. Patent Owner takes
`the position that abiraterone acetate “allows some cortisol to be made.”
`Tr. 31:27–29. Although Patent Owner urges us to focus on the differences in
`the mechanisms of ketoconazole and abiraterone acetate, we look not only at
`the differences, but also at the similarities. The evidence demonstrates that
`one of ordinary skill would have been aware of the differences and the
`similarities in the mechanisms and, nevertheless, would have compared and
`analogized between the two. See, e.g., Ex. 1003, 2318, Figure 1; Reply 6
`(citing Ex. 1104 ¶¶ 14–31; Ex. 1097 ¶¶ 44–49). Both O’Donnell and Barrie
`refer to ketoconazole in their discussions of abiraterone acetate, indicating
`that teachings regarding ketoconazole administration were a starting point for
`exploration of abiraterone acetate administration. Ex. 1003, 2318; Ex. 1005,
`Table 1. O’Donnell, after evaluating ketoconazole as an agent, turns to an
`evaluation of abiraterone acetate as a more selective CYP17 inhibitor, i.e., as
`an improvement on ketoconazole. Ex. 1003, 2318. After presenting the
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`results from its studies, O’Donnell discusses that, in the clinical use of
`ketoconazole, “it is common practice to administer supplementary
`hydrocortisone” and that, therefore, “further studies with abiraterone acetate
`will be required to ascertain if concomitant therapy with glucocorticoid is
`required on a continuous basis, at times of physiological stress, if patients
`become symptomatic or indeed at all.” Id. at 2323. This statement represents
`the proposition that one of ordinary skill in the art would use the example of
`ketoconazole’s clinical use to take the next investigative steps with
`abiraterone acetate. We have not been presented with evidence that
`dissuades us from taking this statement at face value.
`Thus, we are persuaded that one of ordinary skill in the art would
`understand that both ketoconazole and abiraterone are CYP17 inhibitors,
`albeit with different mechanisms. With this knowledge, and given the
`teachings of the prior art on administration of ketoconazole and
`administration of abiraterone acetate, we find that one of ordinary skill in the
`art would look to the administration of ketoconazole for guidance on how to
`ad
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