Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
` Paper 86
`Entered: January 17, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`AMERIGEN PHARMACEUTICALS LIMITED and
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-002861
`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 IPR2016-01317 has been joined with this proceeding.
`
`
`Tel: 571-272-7822
`
`
`
`
` Paper 86
`Entered: January 17, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`AMERIGEN PHARMACEUTICALS LIMITED and
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`JANSSEN ONCOLOGY, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-002861
`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 IPR2016-01317 has been joined with this proceeding.
`
`
`
`IPR2016-00286
`Patent 8,822,438 B2
`
`
`
`I. INTRODUCTION
`Amerigen Pharmaceuticals Limited (“Amerigen”) 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 12, “Prelim. Resp.”). We instituted an inter partes review
`of claims 1–20 on certain grounds of unpatentability alleged in the Petition
`(Paper 14, “Dec.”).
`Argentum Pharmaceuticals LLC (“Argentum”) filed a Petition for inter
`partes review of claims 1–20 of the ’438 patent. Case IPR2016-01317,
`Paper 2. Together with its Petition, Argentum filed a Motion for Joinder to
`join the case with the previously instituted proceeding in IPR2016-00286.
`Id., Paper 3. We instituted trial in IPR2016-01317 and joined Argentum as a
`Petitioner in IPR2016-00286. Id., Paper 9.
`After institution of trial, Patent Owner filed a Patent Owner Response
`(Paper 33, “PO Resp.”). Amerigen and Argentum (collectively, “Petitioner”)
`filed a Reply (Paper 60, “Reply”). Pursuant to a Board Order (Paper 68),
`Patent Owner filed an Identification of New Arguments and Evidence in
`Petitioner’s Reply (Paper 74), to which Petitioner filed a Reply (Paper 78).
`An oral hearing was held on February 16, 2017. A transcript of the hearing
`has been entered into the record. Paper 85 (“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.
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`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 6, 2–3. 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.), 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-03743-KM-JBC (D.N.J).
`Paper 57, 2–3.
`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 18, 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-
`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.
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`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
`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);
`
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`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
`Scott R. Serels, M.D. (Ex. 1002; Ex. 1095), DeForest McDuff, Ph.D.
`(Ex. 1017; Ex. 1096), Mark J. Ratain, M.D. (Ex. 1091), and Richard Dorin,
`M.D. (Ex. 1093). Patent Owner relies on the declarations of Matthew Rettig,
`M.D. (Ex. 2038), Richard Auchus, M.D., Ph.D. (Ex. 2040), Gerald Walter
`Chodak, M.D. (Ex. 2042), and Christopher A. Vellturo, Ph.D. (Ex. 2044).
`
`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
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`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
`(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. Those
`claim terms are discussed and defined explicitly in the specification of the
`’438 patent, as noted by Petitioner. Id. at 18; Ex. 1001, 3:31–5:5. In our
`Decision on Institution, we construed those terms, as well as the term
`“therapeutically effective amount of prednisone” as follows:
`
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`Claim term(s)
`“treat,” “treating,” and
`“treatment”
`
`“anti-cancer agent”
`
`“refractory cancer”
`
`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
`
`“therapeutically effective
`amount of prednisone”
`
`Patent Owner, in its Response, states that our Decision on Institution
`properly construed “a therapeutically effective amount of prednisone” and
`the terms “treat,” “treating,” and “treatment.” PO Resp. 8.
`Patent Owner also submitted a claim construction of the terms
`“treatment” and “treating” by the district court in a companion litigation.
`Ex. 2122. 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
`
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`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
`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. § 1032 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
`
`
`2 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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`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
`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 or oncology, or
`holding a Ph.D. in pharmacology, biochemistry or a related
`discipline. 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 enzymologist
`and/or molecular biologist 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
`
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`the prior art asserted in the Petition. See Okajima v. Bourdeau, 261
`F.3d 1350, 1355 (Fed. Cir. 2001).
`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
`
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`steroid synthesis, with prednisone to treat patients with progressive prostate
`cancer. Ex. 1004, 1177. Gerber provides that patients exhibiting
`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.
`
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`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.” Pet. 6
`(citing Ex. 1002 ¶¶ 32, 34, 48). Cortisol is “necessary for other biochemical
`cycles in the body and its reduced production caused adverse effects,
`including hypertension, hypokalemia (decrease in circulating potassium
`levels), and fluid retention.” Id. 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. (citing
`Ex. 1002 ¶ 31). 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 ¶ 32).
`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. 36–48.
`Regarding claim 1, Petitioner argues that O’Donnell teaches “that
`abiraterone acetate is a selective CYP17 inhibitor that is more effective in
`
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`suppressing testosterone levels in a mammal in vivo than ketoconazole, a
`CYP17 inhibitor known in the art.” Pet. 37 (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
`teaches that concomitant hormone replacement therapy with a glucocorticoid
`may be needed for continuous use of abiraterone acetate in treating a prostate
`cancer in a human patient.” Id. at 38 (citing Ex. 1003, Abstract, 2323).
`Gerber, Petitioner argues, teaches that “the combination of ketoconazole and
`prednisone is safe and effective in treating human patients with hormone-
`refractory advanced prostate cancer.” Id. at 38–39 (citing Ex. 1004,
`Abstract, 1177–79).
`Regarding motivation to combine, Petitioner reasons that the
`“motivation to add prednisone to a method of treating prostate cancer in a
`human patient that includes abiraterone acetate is clearly seen in Gerber,”
`which “teaches that the administration of ketoconazole, a CYP17 inhibitor, in
`combination with 5 mg prednisone twice daily, is safe and effective in
`treating human patients with hormone-refractory prostate cancer.” Id. at 38.
`One of ordinary skill in the art, Petitioner argues, would have combined
`abiraterone acetate and prednisone “with a reasonable expectation of success
`because the prior art taught abiraterone acetate as a more effective CYP17
`inhibitor than ketoconazole and the combination of ketoconazole and
`prednisone as safe and effective to treat patients with hormone refractory
`metastatic prostate cancer.” Id. at 7 (citing Ex. 1002 ¶¶ 45–49).
`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. Id. at 40–48.
`
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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. 36–45.
`Regarding claim 1, Petitioner argues that Barrie teaches “that
`abiraterone acetate is a selective CYP17 inhibitor that is more effective in
`suppressing testosterone levels in a mammal in vivo than ketoconazole, a
`CYP17 inhibitor known in the art.” Pet. 37, 39 (citing Ex. 1005, 25:13–
`26:63). Gerber, Petitioner argues, teaches that “the combination of
`ketoconazole and prednisone is safe and effective in treating human patients
`with hormone-refractory advanced prostate cancer.” Id. at 39 (citing
`Ex. 1004, Abstract, 1177–79).
`Petitioner reasons that the “motivation to add prednisone to the method
`of treating prostate cancer of [Barrie] is clearly seen in Gerber,” which
`“teaches that the administration of ketoconazole, a CYP17 inhibitor, in
`combination with 5 mg prednisone twice daily, is safe and effective in
`treating human patients with hormone-refractory prostate cancer.” Id. (citing
`Ex. 1004, Abstract, 1177–79). Thus, 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 abiraterone acetate as a
`more effective CYP17 inhibitor than ketoconazole and the combination of
`ketoconazole and prednisone as safe and effective to treat patients with
`hormone refractory metastatic prostate cancer.” Id. at 7 (citing Ex. 1002
`¶¶ 45–49).
`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. Id. at 40–45.
`
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`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. 12–65. We address each in turn.
`a. Patent Owner’s First Argument
`Patent Owner argues, first, that the “central premise of Petitioner’s
`flawed arguments is that abiraterone acetate and ketoconazole act in the same
`manner and would have been assumed to have the same hormonal side
`effects.” PO Resp. 13. Rather, Patent Owner argues, “ketoconazole and
`abiraterone acetate have very different mechanisms of action and do not act
`in the same way,” and these differences “mean that a POSA would not have
`translated the clinical experience with ketoconazole to abiraterone acetate.”
`Id. (citing Ex. 2038 ¶¶ 103, 122–23; Ex. 2090, 2413–14, Ex. 2018, 90;
`Ex. 1020, 544). Because “abiraterone acetate was understood not to suppress
`production of all adrenal steroids” and because “abiraterone acetate was not a
`‘potent inhibitor’ of glucocorticoids,” one of ordinary skill in the art “would
`not have found it appropriate to simply apply the clinical experience with
`ketoconazole, including its side effects, and methods of managing those side
`effects, to abiraterone acetate.” Id. at 15–17 (citing Ex. 2038 ¶¶ 103–04).
`Patent Owner argues next that O’Donnell confirms that abiraterone
`acetate allows cortisol to be made in normal levels in patients, unlike
`ketoconazole. Id. at 17. In view of the data in O’Donnell, Patent Owner
`argues, a person of ordinary skill in the art would have understood “that there
`was no need for glucocorticoid replacement therapy” and that the decision to
`give glucocorticoid replacement would not have been made lightly. Id.
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`at 18–19 (citing Ex. 1003, 2322–23; Ex. 2038 ¶¶ 107–15; Ex. 2040 ¶¶ 13–15,
`30–35, 59–62). Regarding the Synacthen test administered in O’Donnell,
`Patent Owner argues that these results “lack any significance” because, inter
`alia, the Synacthen test “only measures a patient’s cortisol levels in response
`to stress.” Id. at 20–21 (citing Ex. 2040 ¶¶ 27–29, 31–34).
`Patent Owner argues, finally, that Barrie confirms that abiraterone
`acetate acts differently from ketoconazole. Id. at 22. Barrie reports that
`administration of ketoconazole to mice caused an increase in adrenal weight,
`whereas administration of abiraterone acetate resulted in no significant effect
`in adrenal weight, indicating that “abiraterone acetate acts differently from
`ketoconazole and its mechanism of action was much more selective.” Id.
`at 22–23 (citing Ex. 2040 ¶ 45; Ex. 1005, 25:46–48).
`Petitioner agrees that the prior art “including Barrie and O’Donnell,
`disclose that (1) the CYP 17 enzyme has two separate activities in the adrenal
`androgen synthesis pathway, a 17α-hydroxylase and a C 17,20 lyase activity,
`and (2) [abiraterone acetate] is a more selective and potent inhibitor of both
`CYP 17 activities than ketoconazole.” Reply 2–3. Petitioner, nevertheless,
`replies that one of ordinary skill in the art “would have expected that cortisol
`deficiency from administration of [abiraterone acetate] to treat prostate
`cancer would diminish adrenal reserve and potentially cause adrenal
`insufficiency (AI), particularly during times of physiological stress.” Id.
`at 3–4 (citing Ex. 1003, 2323; Ex. 1093 ¶¶ 20–24).
`Petitioner further replies that O’Donnell “expressly states that the
`administration of AA to treat a patient with prostate cancer may require co-
`administration of a glucocorticoid as replacement therapy based on abnormal
`cortisol responses in all patients in Study C.” Id. at 5 (citing Ex. 1003, 2321,
`
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`2323). Petitioner challenges Patent Owner’s “attempts to argue that
`[O’Donnell’s] clear statements do not actually mean what they say” and
`Patent Owner’s arguments that a person of ordinary skill in the art would
`have “disregarded [O’Donnell’s] unequivocal teachings, performed their own
`analysis of the underlying data, and reached a contrary conclusion.” Id.
`Based on the information presented during trial, we understand that
`ketoconazole and abiraterone acetate do not have identical mechanisms. See,
`e.g., Ex. 1003, 2318, Figure 1. As noted by both Petitioner and Patent
`Owner, however, abiraterone acetate and ketoconazole are both CYP17
`inhibitors. PO Resp. 5; Reply 2. 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. 29; Tr. 28:19–24;
`Ex. 1003, 2318. Patent Owner agrees that abiraterone acetate “inhibits
`cortisol to an extent.” Tr. 29:10–14. Although Patent Owner urges us to
`focus on the differences in the mechanisms of operation of ketoconazole and
`abiraterone acetate (PO Resp. 13–17), 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., Tr. 14:20–15:5; Ex. 1003, 2318, Figure 1; Ex. 1188, 168:22–169:23.
`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. For example, O’Donnell,
`
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`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 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. Patent Owner’s expert
`testified that ketoconazole, as “an inhibitor of steroid biosynthesis that had
`been used at that point,” was a basis for comparison: “When you write
`scientific papers, you always like to make comparisons with what is known
`and explain why your results are different or the same or what the caveats
`are. And I think that’s setting up . . . to understand what comes next, why
`they did this experiment.” Ex. 1188, 169:15–23. 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 administer abiraterone acetate.
`
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`Regarding the interpretation of O’Donnell’s Synacthen test, we do not
`agree with Patent Owner that the results “lack any significance.” See PO
`Resp. 20. We are persuaded that one of ordinary skill in the art would
`understand the results of this test to be an indicator that something was amiss
`with the O’Donnell Study C patients’ cortisol levels following administration
`of abiraterone acetate. Results of the Synacthen test led O’Donnell to
`conclude that further studies were needed to determine whether
`glucocorticoid replacement would be necessary. Ex. 1003, 2323. We
`understand Patent Owner’s position that the “Synacthen test results in
`O’Donnell do not give a complete picture of a patient’s glucocorticoid
`production.” PO Resp. 21. We, however, do not perceive that a complete
`picture of a patient’s glucocorticoid production is required for one of
`ordinary skill in the art to be motivated to explore whether glucocorticoid
`replacement therapy was necessary. Petitioner’s experts opine that
`O’Donnell’s results for the Study C patients were “unquestionably abnormal”
`and implied that abiraterone acetate could result in chronic cortisol deficiency
`“for
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