Filed on behalf of: Corcept Therapeutics, Inc.
`
`Entered: November 21, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`NEPTUNE GENERICS, LLC,
`Petitioner,
`
`v.
`
`
`CORCEPT THERAPEUTICS, INC.,
`Patent Owner.
`_______________________
`Case IPR2018-01494
`U.S. Patent No. 8,921,348
`_______________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
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`

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`IPR2018-01494 (USP 8,921,348)
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`Patent Owner’s Preliminary Response
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`TABLE OF CONTENTS
`
`III.
`
`I.
`II.
`
` Page(s)
`INTRODUCTION .......................................................................................... 1
`BACKGROUND TO THE ’348 CLAIMED INVENTION .......................... 2
`A.
`The Belanoff ’348 Claimed Invention is the Subject of this IPR
`Proceeding ............................................................................................ 2
`Belanoff ’348 Patent Claims ................................................................ 6
`B.
`Summary of the Prosecution History ................................................... 7
`C.
`SCOPE AND CONTENT OF ALLEGED PRIOR ART ............................. 12
`A.
`Belanoff ’953 ...................................................................................... 13
`B.
`Belanoff ’848 ...................................................................................... 14
`C.
`Belanoff 2002 ..................................................................................... 15
`D.
`Chu & Belanoff .................................................................................. 16
`E.
`Sitruk-Ware ........................................................................................ 16
`F. Murphy ............................................................................................... 17
`IV. PERSON OF ORDINARY SKILL IN THE ART (“POSA”) ...................... 18
`V.
`CLAIM CONSTRUCTION ......................................................................... 18
`VI. THE BOARD SHOULD DENY INSTITUTION OF GROUNDS 1-6 ....... 18
`VII. ALL SIX OBVIOUSNESS GROUNDS SHOULD BE DENIED
`UNDER 35 U.S.C. §§ 325(D) AND 314(A) BECAUSE THE SAME
`OR SUBSTANTIALLY THE SAME PRIOR ART AND
`ARGUMENTS WERE PREVIOUSLY CONSIDERED AND
`OVERCOME DURING PROSECUTION ................................................... 19
`A. Grounds 1-6 Should Be Denied Because the Petitioner’s Prior
`Art and Arguments Have Already Been Considered and
`Rejected by the Patent Office ............................................................. 21
`1.
`Petitioner Relies on the Same or Substantially the Same
`Prior Art Previously Presented to the Office ........................... 21
`(a) Belanoff ’953 Was Considered and Overcome
`During Prosecution ........................................................ 22
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`IPR2018-01494 (USP 8,921,348)
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`Patent Owner’s Preliminary Response
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`2.
`
`B.
`
`B.
`
`(b)
`
`Petitioner’s Other Relied Upon References Are
`Cumulative of Belanoff ’953 ......................................... 26
`Petitioner Relies on the Same or Substantially the Same
`Arguments Already Considered and Rejected During
`Prosecution ............................................................................... 28
`VIII. GROUNDS 1-6 SHOULD BE DENIED BECAUSE PETITIONER
`RELIES ON UNSUPPORTED, CONCLUSORY ASSERTIONS
`AND IMPERMISSIBLE HINDSIGHT ....................................................... 30
`A.
`There is No Dispute that None of the Relied Upon References
`Disclose the Efficacious 1300 ng/mL Mifepristone Serum Level ..... 33
`Petitioner’s Assertion that the Claimed Method Employing the
`Efficacious 1300 ng/mL Level Would Have Been Obvious is
`Based on Unsupported, Conclusory Assertions and
`Impermissible Hindsight .................................................................... 34
`IX. GROUNDS 1-6 SHOULD BE DENIED BECAUSE PETITIONER
`FAILS TO ARTICULATE WITH THE REQUISITE SPECIFICITY
`HOW THE COMBINATIONS WOULD PREDICTABLY LEAD TO
`THE CLAIMED INVENTION OR HOW A POSA WOULD HAVE
`HAD A REASONABLE EXPECTATION OF SUCCESS ......................... 40
`A.
`Petitioner Fails to Explain How a POSA Would Predictably
`Arrive at the Efficacious 1300 ng/mL Level, and Design a
`Treatment Protocol Based Thereon, With a Reasonable
`Expectation of Success, Particularly in View of the
`Unpredictability in the Art ................................................................. 41
`Contemporaneous Literature from Petitioner’s Own Expert
`Confirms That a POSA Would Have Had No Reasonable
`Expectation of Success in Arriving at the 1300 ng/mL Level
`and Deriving an Effective Treatment Protocol .................................. 44
`X. GROUNDS 2-6 SHOULD BE DENIED BECAUSE PETITIONER
`FAILS TO ARTICULATE ANY MOTIVATION TO COMBINE
`THE CITED REFERENCES ........................................................................ 49
`XI. CONCLUSION ............................................................................................. 51
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`IPR2018-01494 (USP 8,921,348)
`
`Patent Owner’s Preliminary Response
`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`CASES
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) .......................................................................... 49
`AnyLogic North America, LLC v. TheBrain Techs., LP,
`IPR2018-00546, Paper 10 (P.T.A.B. May 24, 2018) ................................... 30, 31
`Apple Inc. v. Voip-pal.com, LLC.,
`IPR2016-01201, Paper 54 (P.T.A.B. Nov. 20, 2017) ......................................... 31
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01587, Paper 8 (P.T.A.B. Dec. 15, 2017) ......................... 19, 22, 30, 31
`Biodelivery Scis. Int’l, Inc. v. Monosol,
`IPR2015-00167, Paper 6 (P.T.A.B. May 20, 2018) ............................... 40, 41, 48
`Cultec, Inc. v. StormTech LLC,
`IPR2017-00777, Paper 7 (P.T.A.B. Aug. 22, 2017) ....................................passim
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 43
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 41
`Graham v John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 38
`Harmonic Inc. v. Avid Tech., Inc.,
`815 F.3d 1356 (Fed. Cir. 2016) .......................................................................... 31
`Hengdian Grp. DMEGC Magnetics Co., Ltd., v. Hitachi Metals, Ltd.,
`IPR2017-01313, Paper 7 (P.T.A.B. Nov. 6, 2017) ............................................. 27
`Illumina, Inc. v. Cornell Research Found., Inc.,
`IPR2016-00549, Paper 15 (P.T.A.B. Aug. 8, 2016) ........................................... 38
`
`iii
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`IPR2018-01494 (USP 8,921,348)
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`Patent Owner’s Preliminary Response
`
`Initiative for Medicines, Access & Knowledge (I-Mak), Inc. v. Gilead
`Pharmasset LLC,
`IPR2018-00119, Paper 7 (P.T.A.B. May 4, 2018) ............................................. 32
`
`Initiative for Meds., Access & Knowledge (I-Mak), Inc. v. Gilead
`Pharmasset LLC,
`IPR2018-00103, Paper 7 (P.T.A.B. June 13, 2018) ..................................... 32, 40
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 41
`K/S Himpp v. Hear-Wear Techs., LLC,
`751 F.3d 1362 (Fed. Cir. 2014) .......................................................................... 32
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ............................................................................ 49
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .......................................................................... 28, 38, 41, 49
`Larson Mfg. Co. of S.D. v. Aluminart Prods. Ltd.,
`559 F.3d 1317 (Fed. Cir. 2009) .......................................................................... 13
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 43
`Neil Ziegman, N.P.Z., Inc. v. Stephens,
`IPR2015-01860, Paper 11 (P.T.A.B. Feb. 24, 2016) .............................. 20, 21, 22
`Neil Ziegman, N.P.Z., Inc. v. Stephens,
`IPR2015-01860, Paper 13 (P.T.A.B. Sept. 6, 2017) ........................................... 20
`R.J. Reynolds Vapor Co. v. Fontem Holdings 1 B.V.,
`IPR2017-01642, Paper 10 (P.T.A.B. Jan. 16, 2018) .......................................... 27
`Shenzhen Liown Elecs. Co., Ltd. v. Disney Enters., Inc.,
`IPR2016-01785, Paper 14 (P.T.A.B. Apr. 3, 2017) ........................................... 13
`Siemens Healthcare Diagnostics Inc. v. Radiometer Med. APS,
`IPR2018-00311, Paper 6 (P.T.A.B. June 25, 2018) ........................................... 27
`Symantec Corp. v. Finjan, Inc.,
`IPR2015-01897, Paper 7 (P.T.A.B. Feb. 26, 2016) ............................................ 12
`
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`IPR2018-01494 (USP 8,921,348)
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`Patent Owner’s Preliminary Response
`
`Unified Patents Inc. v. Berman,
`IPR2016–01571, Paper 10 (P.T.A.B. Dec. 14, 2016) ................................... 20, 30
`Unified Patents, Inc. v. Custom Media Techs. LLC,
`No. IPR2015-00516, Paper 9 (P.T.A.B. June 25, 2015) .................................... 33
`Volkswagen Grp. of Am., Inc. v. Velocity Patent LLC,
`IPR2015-00276, Paper 8 (P.T.A.B. June 1, 2015) ....................................... 49, 51
`STATUTES
`35 U.S.C. § 103 .................................................................................................... 9, 23
`35 U.S.C. § 311(b) ....................................................................................... 32, 36, 40
`35 U.S.C. § 312(a)(3) ........................................................................................... 1, 19
`35 U.S.C. § 313 .......................................................................................................... 1
`35 U.S.C. § 314(a) ............................................................................................... 1, 19
`35 U.S.C. § 325(d) ............................................................................................passim
`REGULATIONS
`37 C.F.R. § 42.65(a) ................................................................................................. 31
`37 C.F.R. § 42.107 ..................................................................................................... 1
`OTHER AUTHORITIES
`U.S. PATENT AND TRADEMARK OFFICE,
`TRIAL PRACTICE GUIDE UPDATE (Aug. 2018) ........................................ 32, 36, 40
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`IPR2018-01494 (USP 8,921,348)
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`Patent Owner’s Preliminary Response
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`EXHIBIT LIST
`Description
`Ex.
`2001 Corcept Therapeutics, KORLYM® (mifepristone),
`http://www.corcept.com/korlym.html (last visited Nov. 19, 2018)
`2002 Burford Capital, Learn About Burford’s Litigation & Arbitration Finance
`Solutions, The Leading Global Finance Firm Focused on Law,
`http://www.burfordcapital.com/about/ (last visited on Nov. 19, 2018)
`2003 U.S. Patent No. 8,598,149 (“the ’149 Patent”)
`
`2004 MedlinePlus Medical Encyclopedia, Therapeutic Drug Levels,
`http://www.nlm.nih.gov/medlineplus/ency/article/003430.htm (last visited on
`Nov. 19, 2018) (“Medical Encyclopedia”)
`2005 N.N. Sarkar, Mifepristone: Bioavailability, Pharmacokinetics and Use-
`Effectiveness, 101 EUROPEAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
`AND REPRODUCTIVE BIOLOGY, 113-120 (2002) (“Sarkar”)
`2006 Oskari Heikinheimo, et al., Quantitation of RU 486 in Human Plasma by
`HPLC and RIA After Column Chromatography, 34 CONTRACEPTION No. 6,
`613-624 (Dec. 1986) (“Heikinheimo 1986”)
`2007 Oskari Heikinheimo, et al., Antiprogesterone RU 486—a Drug for Non-
`Surgical Abortion, 22 ANNALS OF MEDICINE, 75-84 (1990) (“Heikinheimo
`1990”)
`2008 Declaration Of Michelle L. Ernst In Support Of Patent Owner’s Motion For
`Pro Hac Vice Admission Under 37 C.F.R. § 42.10(C)
`
`
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`IPR2018-01494 (USP 8,921,348)
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`I.
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`Patent Owner’s Preliminary Response
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`INTRODUCTION
`Pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, Corcept Therapeutics,
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`Inc. (“Patent Owner” or “Corcept”) submits this preliminary response to the Petition
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`for Inter Partes Review (“Petition”) of U.S. 8,921,348 (the “’348 Patent”), filed by
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`Neptune Generics, LLC (“Petitioner” or “Neptune”).
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`The PTAB should deny institution since Petitioner failed to meet its burden to
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`show “there is a reasonable likelihood that the petitioner would prevail with respect
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`to at least 1 of the claims” (35 U.S.C. § 314(a)) due to a number of glaring
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`deficiencies in the Petition and its supporting declaration. For example, every
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`ground relies on the same or substantially similar references and arguments that
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`were already considered and overcome during prosecution. Every ground relies on
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`unsupported and conclusory assertions and impermissible hindsight. Every ground
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`fails to provide the requisite specificity for demonstrating predictability or a
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`reasonable expectation of success from the proposed combinations. And finally,
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`every obviousness ground fails to articulate any motivation to combine. In short,
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`Petitioner has failed to meet its burden in every ground since it failed to identify
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`“with particularity . . . the evidence that supports the grounds for the challenge to
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`each claim[.]” 35 U.S.C. § 312(a)(3).
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`Due to these deficiencies and others discussed herein, Petitioner cannot meet
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`its burden of showing unpatentability and thus, institution should be denied on all
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`IPR2018-01494 (USP 8,921,348)
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`grounds.
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`Patent Owner’s Preliminary Response
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`II. BACKGROUND TO THE ’348 CLAIMED INVENTION
`A.
`The Belanoff ’348 Claimed Invention is the Subject of this IPR
`Proceeding
`Patent Owner’s ’348 Patent resulted from the company’s investment and
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`commitment to the research and development of pharmaceuticals that regulate the
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`effects of cortisol for the treatment of severe and life-threatening conditions,
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`including Cushing’s syndrome. (See Ex. 2001.) In contrast, Petitioner is not
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`involved in any pharmaceutical research and development, nor the regulatory,
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`manufacturing and marketing investments required for offering pharmaceuticals and
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`healthcare solutions to physicians and patients. Rather, Petitioner is backed by
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`Burford Capital Ltd., a U.K.-based company, whose business is providing financing
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`for litigation. (See Ex. 2002.) Patent Owner’s ’348 Patent, inter alia, is listed in the
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`FDA publication, “Approved Drug Product with Therapeutic Equivalence
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`Evaluations” (the “Orange Book”) for Patent Owner’s KORLYM® product for the
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`treatment of hyperglycemia secondary to hypercortisolism in certain adult patients
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`with endogenous Cushing’s syndrome.
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`The Inventor, Dr. Belanoff, was the first to discover how to optimize levels of
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`mifepristone for the efficacious treatment of disorders associated with excess
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`glucocorticoid activity. The ’348 Patent provides a method for optimizing levels of
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`mifepristone in a patient suffering from a disorder amenable to treatment by
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`Patent Owner’s Preliminary Response
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`mifepristone, by administering seven or more daily doses of mifepristone over a
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`period of seven or more days; testing the serum levels of the patient to determine
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`whether the blood levels of mifepristone are greater than 1300 ng/mL; and adjusting
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`the daily dose of the patient to achieve mifepristone levels greater than 1300 ng/mL.
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`(See Ex. 1001 (’348 Patent) at Abstract.)
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`While the mifepristone molecule was first identified in the 1980s, prior to the
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`invention described in the ’348 Patent, no one had discovered the necessary serum
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`level for treating glucocorticoid disorders. Indeed, early research focused on
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`mifepristone’s antiprogesterone applications, with the introduction of Mifeprex in
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`the United States in 2000. While Mifeprex is indicated for the medical termination
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`of early pregnancy, additional research, largely conducted by the Inventor, later
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`discovered that mifepristone also had antiglucocorticoid properties. However,
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`efforts to identify the efficacious serum level for these disorders were complicated
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`by several impediments in the art.
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`Specifically, mifepristone (when administered in dosages above 200 mg)
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`exhibits non-linear pharmacokinetics. In other words, increasing the dose did not
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`result in a corresponding increase in blood serum level, as would normally be
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`expected for a drug displaying linear pharmacokinetics. This also meant that
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`administering the same dosage of mifepristone to two different patients did not result
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`in the same amount of mifepristone in their blood. Indeed, the Inventor of the ’348
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`Patent Owner’s Preliminary Response
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`
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`Patent “discovered that administration of the same dose of mifepristone can produce
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`widely varying blood serum levels in different patients” and that “[f]or the same
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`dose of mifepristone, the blood serum levels can differ by as much as 800% from
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`one patient to another.” (Ex. 1001 at 1:28-34 (emphasis added); see also id. at 2:52-
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`55, 6:8-11.)
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`This unpredictable drug activity complicated the efficacious treatment of
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`patients suffering from glucocorticoid disorders. Doctors had no assurance that
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`administration of the same mifepristone dose would result in the same effects across
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`patients, and before the invention of the ’348 Patent, no one had discovered that a
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`serum level of greater than 1300 ng/mL following seven or more daily doses was a
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`key to bringing about and maintaining the desired therapeutic effect. As explained
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`by the ’348 Inventor, “[t]he varied blood serum levels can result in some patients not
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`receiving an efficacious dose of mifepristone.” (Ex. 1001 at 30-32; see also id. at
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`2:55-57, 6:8-11.)
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`In addition to mifepristone’s non-linear pharmacokinetics, mifepristone
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`exhibits rapid metabolism resulting in high serum levels of mifepristone’s
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`metabolites. The ’348 Patent explains that mifepristone has at least three
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`metabolites: RU42633, RU42698, and RU42848. (Id. at 12:23-25.) Indeed, at least
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`one of the metabolites has a higher serum level than mifepristone itself shortly after
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`administration. Further, certain of the detection methodologies available in the art
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`Patent Owner’s Preliminary Response
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`
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`at the time (e.g., radioimmunoassay (“RIA”)) were unable to differentiate
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`mifepristone from its metabolites in the blood. This resulted in inaccurate reporting
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`of mifepristone levels in the prior art because the amount reported also included the
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`blood levels of mifepristone’s metabolites. Only certain methodologies, such as
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`reverse-phase high pressure liquid chromatography (“HPLC”), could accurately
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`segregate and measure the plasma levels of mifepristone and its derivatives. (See
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`Ex. 1001 at 12:23-25). Thus, mifepristone’s metabolism and the insensitivity of
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`certain measurement methodologies further complicated the ability for a person of
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`ordinary skill in the art (“POSA”) to determine the serum level needed for
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`efficacious treatment.
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`At the time of the ’348 invention, there was a vast amount of unpredictability
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`in the field. While the antiglucocorticoid properties of mifepristone had been
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`recognized, there had been no substantial advancements in moving the molecule
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`outside the laboratory phase towards a clinically effective glucocorticoid
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`application. And while the art recognized that mifepristone could be useful in
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`treating glucocorticoid disorders, no one had identified the serum level that was
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`required for efficacious treatment. The ’348 Inventor was the first to overcome the
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`impediments presented by mifepristone’s non-linear pharmacokinetics, rapid
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`metabolism, and the insensitive serum detection methodologies in determining a
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`regimen for reliably achieving therapeutic efficacy. The ’348 invention thereby
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`Patent Owner’s Preliminary Response
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`provides a method whereby each patient can be effectively treated with mifepristone
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`for various glucocorticoid disorders, even though variations between patients could
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`vary up to 800%.
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`B.
`Belanoff ’348 Patent Claims
`The Belanoff ’348 Patent contains 7 claims. Independent claim 1 is directed
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`to a method for optimizing mifepristone levels with various discrete, yet interrelated
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`steps, including: (1) treating the patient with seven or more daily doses of
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`mifepristone over a period of seven or more days; (2) testing the serum levels for
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`mifepristone levels greater than 1300 ng/mL; and (3) adjusting the daily dose to
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`achieve mifepristone levels greater than 1300 ng/mL. The precise claim language is
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`as follows.
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`1. A method for optimizing levels of mifepristone in a patient suffering
`from a disorder amenable to treatment by mifepristone, the method
`comprising:
`treating the patient with seven or more daily doses of mifepristone
`over a period of seven or more days;
`testing the serum levels of the patient to determine whether the blood
`levels of mifepristone are greater than 1300 ng/mL; and
`adjusting the daily dose of the patient to achieve mifepristone blood
`levels greater than 1300 ng/mL.
`
`(Ex. 1001 at Claim 1). Claims 2 and 3 are directed to various disorders amenable to
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`treatment by mifepristone; Claim 4 covers oral administration of the seven or more
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`Patent Owner’s Preliminary Response
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`
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`daily doses; Claim 5 is directed to treating with 28 or more daily doses over a period
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`of 28 or more days; Claim 6 describes a plasma sampling collection device for
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`testing; and Claim 7 specifies that the adjusting step involves increasing the daily
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`dose to achieve mifepristone blood levels greater than 1300 ng/mL.
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`C.
`Summary of the Prosecution History
`U.S. Patent No. 8,921,348 (“the ’348 Patent”) is a continuation of U.S. Patent
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`No. 8,598,149 (“the ’149 Patent”), and thus, both patents contain the same
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`specification and claim priority to the same provisional application. In addition, the
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`’348 and ’149 Patents contain similar claims. (Cf. Ex. 1001 at claim 1 (emphasis
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`added) (“A method for optimizing levels of mifepristone in a patient suffering from
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`a disorder amenable to treatment by mifepristone”) with Ex. 2003 (’149 Patent) at
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`claim 1 (emphasis added) (“A method for optimizing levels of mifepristone in a
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`patient suffering from a mental disorder amenable to treatment by mifepristone”).
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`The applications which issued as the ’348 and ’149 Patents were prosecuted by the
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`same attorney and examined by the same Examiner (San-Ming Hui) during
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`approximately the same time period.
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`As explained in Section VII, Petitioner relies on one reference—Belanoff ’953
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`(Ex. 1010)—and other substantially similar references—already assessed and
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`overcome during prosecution. Belanoff ’953 was cited during the prosecution of the
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`IPR2018-01494 (USP 8,921,348)
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`’348 and ’149 Patents, and formed the basis of two rejections which were overcome
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`Patent Owner’s Preliminary Response
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`
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`by Patent Owner. Yet, here, Petitioner recycles the same arguments (that were
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`already considered and overcome during prosecution), namely that the claimed
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`invention would have been obvious even though none of the prior art references
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`identified or led a POSA to the claimed regimen and blood levels greater than 1300
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`ng/ml.
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`The application that resulted in the ’348 Patent was filed on October 29, 2013,
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`approximately three months after the Examiner, Mr. Hui, issued a Notice of
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`Allowance for the parent ’149 Patent. Through an Information Disclosure Statement
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`in the ’348 prosecution, Patent Owner disclosed Belanoff ’953 (one of Petitioner’s
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`main references), “Medical Encyclopedia” (Ex. 2004), and “Sarkar” (Ex. 2005).
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`(Ex. 1002 (’348 Patent File History) at 37-43.) Patent Owner “requested that the
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`cited references be expressly considered during the prosecution of this application,”
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`and explained that “Reference [sic] A1-A3 [Belanoff ’953, Medical Encyclopedia,
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`and Sarkar] were cited in an Office Action dated August 3, 2011 in related U.S.
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`Application No. 12/199,114” [the ’149 Patent]. (Id. at 42-43.) Because Mr. Hui (the
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`same examiner) presided over the referenced Office Action, Patent Owner stated that
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`“[a] copy of the Office Action is available on PAIR and is believed to be readily
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`accessible to the Examiner.” (Id. at 43.)
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`During the prosecution of the ’149 Patent, on August 3, 2011, in an Office
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`IPR2018-01494 (USP 8,921,348)
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`Action the examiner, Mr. Hui, rejected the pending claims under 35 U.S.C. § 103 in
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`Patent Owner’s Preliminary Response
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`
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`view of Belanoff ’953, Medical Encyclopedia, and Sarkar. (Ex. 1003 (’149 Patent
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`File History) at 160-165.) The Examiner stated that Belanoff ’953 teaches
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`mifepristone is useful in treating Acute Stress Disorder (“ASD,” a mental disorder)
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`at various dosages, Sarkar teaches serum concentrations of various dosages of
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`mifepristone administered, and Medical Encyclopedia teaches that therapeutic drug
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`levels are usually determined based on drug levels in the blood. (Id.) Thus, the
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`Examiner asserted that it would have been obvious to optimize the serum levels of
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`mifepristone in patients suffering from ASD because adjusting serum levels to
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`obtain a therapeutic effect was well-known, as were the serum concentration and
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`dosage of mifepristone useful for treating ASD. (Id.) Mr. Hui further alleged that
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`adjusting the serum level would have been seen as equivalent to adjusting the dosage
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`and thus there would have been a reasonable expectation of success. (Id.)
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`In response, Patent Owner explained that Belanoff ’953 in combination with
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`Medical Encyclopedia and Sarkar only teach that mifepristone can treat ASD and
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`disclose various dosages that afford certain serum levels. (Ex. 1003 at 141-148.)
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`However, Belanoff ’953, and the cited combination, do not describe the surprising
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`discovery of greater than 1300 ng/mL as a dividing line for effectiveness. (Id.)
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`Patent Owner explained that this discovery was surprising because mifepristone
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`exhibits non-linear pharmacokinetics at doses greater than 200 mg. (Id.) Therefore,
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`it was unpredictable which serum levels would provide effective treatment, and thus
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`Patent Owner’s Preliminary Response
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`surprising that 1300 ng/mL was the dividing line between effective and ineffective
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`mifepristone levels. (Id.)
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`On April 4, 2012, Mr. Hui issued a Second Office Action based on the same
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`three prior art references, including Belanoff ’953. (Ex. 1003 at 132-137.) The
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`Examiner argued that it was well-known that mifepristone dose and serum level are
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`positively correlated such that a POSA would understand that increasing the dosage
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`would increase the serum level. (Id.) Notably, as explained further herein, this
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`statement fails to appreciate the complication inherent in the non-linear
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`pharmacokinetics of mifepristone. On this faulty premise, Mr. Hui concluded that a
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`POSA would have been motivated to employ various dosages to achieve the 1300
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`ng/mL serum level. (Id.)
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`In Response, the Patent Owner emphasized that there is no description or
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`motivation in Belanoff ’953 or the combination of references regarding the criticality
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`of the greater than 1300 ng/mL serum level for effective treatment. (Id. at 60-69.)
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`Patent Owner also noted that many of the historical measurements for mifepristone
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`serum levels (like the RIA used in Sarkar) failed to accurately measure mifepristone
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`serum levels due to the inability of distinguishing mifepristone from its metabolites,
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`compounded by the rapid metabolism of mifepristone which results in metabolite
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`concentrations higher than mifepristone itself. (Id.) Thus, data like Sarkar
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`overestimated the serum levels in providing numbers for mifepristone and its
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`Patent Owner’s Preliminary Response
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`metabolites collectively, rather than separately quantifying mifepristone alone, a
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`separation which could be accomplished by the HPLC methods described in the
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`present application. (Id.) Because none of the art reported or motivated the
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`achievement of greater than 1300 ng/mL with a reasonable expectation of success,
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`Belanoff ’953, Medical Encyclopedia and Sarkar did not render the invention
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`obvious. (Id.)
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`On August 2, 2013, Mr. Hui accepted Patent Owner’s arguments (overcoming
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`Belanoff ’953 et al.) and issued a Notice of Allowance for the ’149 Patent finding
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`that “[t]he method of using the mifepristone level for adjusting the treatment of
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`mental disorder is not taught or fairly suggested by the prior art.” (Ex. 1003 at 28-
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`35.) Thus, the Examiner agreed that prior art (like Belanoff ’953) disclosing various
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`effective dosages of mifepristone did not render obvious the surprising greater than
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`1300 ng/ml discovery because “the correlation of the level of mifepristone to the
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`therapeutic effectiveness of mifepristone is not known.” (See id.)
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`In issuing a Notice of Allowance for the ’348 Patent approximately one year
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`later (on August 29, 2014), Mr. Hui noted that the Patent Owner’s 5/8/2014 IDS
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`(disclosing Belanoff ’953, and referencing Mr. Hui’s earlier Office Action based on,
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`inter alia, Belanoff ’953) was considered in determining patentability. (Ex. 1002 at
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`7-19.) Specifically, Mr. Hui’s ’348 Notice of Allowance includes Patent Owner’s
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`Belanoff ’953 IDS with a footnote: “ALL REFERENCES CONSIDERED EXCEPT
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`Patent Owner’s Preliminary Response
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`WHERE LINED THROUGH. /S.H./” (emphasis in original). (Id. at 18.) There is
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`no line through Belanoff ’953 (or Medical Encyclopedia or Sarkar) and “S.H.” are
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`the Examiner, San-Ming Hui’s initials. (Id.) In his “Reasons for Allowance,” Mr.
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`Hui explained that “[t]he herein claimed method is not taught or fairly suggested by
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`the prior art.” (Id. at 12.)
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`III. SCOPE AND CONTENT OF ALLEGED PRIOR ART
`Petitioner relies on various combinations of six references, four of which
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`identify the ’348 Inventor, Dr. Belanoff (see infra Sections III.A-III.D, Exs. 1010,
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`1024, 1007, 1023) as an inventor or author. As discussed above in Section II.C, one
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`of Petitioner’s primary references, Belanoff ’953 was previously considered and
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`overcome during prosecution. The remainder of Petitioner’s prior art references
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`present cumulative disclosures, with no identification of or motivation for the
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`claimed regimen and serum level of greater than 1300 ng/mL.
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`In presenting the Belanoff references, Petitioner makes reference to an alleged
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`“lack of candor” (see Petition at 7, 12) presumably to posture an inequitable conduct
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`argument. These assertions—in addition to being unfounded—are entirely
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`inappropriate in the context of inter partes review. See, e.g., Symantec Corp. v.
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`Finjan, Inc., IPR2015-01897, Paper 7 at 15 (P.T.A.B. Feb. 26, 2016) (recognizing
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`that “Petitioner is essentially alleging inequitable conduct” which is improper for
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`inter partes review, and thereby disregarding the argument noting that “we do not
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`Patent Owner’s Preliminary Response
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`make any determination with respect to Petitioner’s allegations regarding the
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`veracity of Patent Owner’s statements to the Office in prior proceedings.”); see also
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`Shenzhen Liown Elecs. Co., Ltd. v. Disney Enters., Inc., IPR2016-01785, Paper 14
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`at 12, n. 4 (P.T.A.B. Apr. 3, 2017) (explaining that “[a]lthough we acknowledge the
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`parties’ allegations of copying and inequitable conduct [], the legally cognizable
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`issues before us are whether [the alleged references] are prior art and whether they
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`disclose or teach the specific limitations of the [challenged] patent as Petitioner
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`contends.”). Beyond this, Petitioner has absolutely no support for its asserted “lack
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`of candor” where the other Belanoff references it cites are merely cumulative of the
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`prior art submitted to the Patent Office during prosecution. See Larson Mfg. Co. of
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`S.D. v. Aluminart Prods. Ltd., 559 F.3d 1317, 1327 (Fed. Cir. 2009) (citat