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`Filed on behalf of: Corcept Therapeutics, Inc.
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`Entered: September 18, 2019
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
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`NEPTUNE GENERICS, LLC,
`Petitioner,
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`v.
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`CORCEPT THERAPEUTICS, INC.,
`Patent Owner.
`_______________________
`Case IPR2018-01494
`Patent 8,921,348 B2
`_______________________
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`PATENT OWNER’S SURREPLY
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`TABLE OF CONTENTS
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`I.
`II.
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`Page
`INTRODUCTION ........................................................................................... 1
`CLAIM CONSTRUCTION ............................................................................ 2
`A.
`The PTAB Should Adopt Patent Owner’s Undisputed
`Construction .......................................................................................... 2
`1. Method for Optimizing Levels of Mifepristone ......................... 2
`2.
`Disorder Amenable to Treatment with Mifepristone .................. 3
`Petitioner’s Attempt to Interject Belated Claim Constructions
`Not Raised in its Petition Should Be Rejected ...................................... 3
`1.
`To Achieve Blood Levels Greater Than 1300 ng/mL ................ 3
`2.
`Disorder ....................................................................................... 5
`III. GROUND ONE ............................................................................................... 6
`A.
`The Board Properly Rejected Petitioner’s Arguments Based on
`Belanoff ’848 ......................................................................................... 6
`1.
`Petitioner’s Reiterated Argument Does Not Render the
`’348 Patent Obvious Because There is No Direct
`Translation Between Dose and Serum Level .............................. 6
`Petitioner’s New Argument that the ’348 Claims are
`Obvious Based on “Routine Optimization” In View of
`Belanoff ’848 Is Unsupported and Contradicted by
`Petitioner’s Own Expert .............................................................. 9
`IV. GROUND TWO ............................................................................................ 13
`A.
`Petitioner Fails to Overcome the Fact that None of the Prior Art
`Discloses or Motivates the Key 1300 ng/mL Level Nor
`Optimization Based On That Level ..................................................... 13
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`B.
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`2.
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`Patent Owner’s Evidence is Not “Extraneous” But Instead
`Demonstrates the Vast Unpredictability in the Art Which
`Undermines Any Reasonable Expectation of Success ........................ 16
`Petitioner Ignores the Complexity Involved in Determining a
`Drug’s PK-PD Relationship ................................................................ 19
`Petitioner’s Remaining Arguments Are Irrelevant to the
`Obviousness Inquiry ............................................................................ 21
`V. GROUNDS 3-6 .............................................................................................. 22
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`C.
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`D.
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`TABLE OF AUTHORITIES
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`CASES
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`Patent Owner’s Surreply
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` Page(s)
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`Avant Tech., Inc. v. Anza Tech., Inc.,
`No. IPR2018-00828, 2018 WL 5099380 (P.T.A.B. Oct. 16, 2018) ................. 1, 9
`Christianson v. Colt Indus. Operating Corp.,
`822 F.2d 1544 (Fed. Cir. 1987), vacated on other grounds, 486
`U.S. 800 (1988) ................................................................................................... 21
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`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig., 676 F.3d 1063 (Fed. Cir. 2012) .................................................... 20
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 21
`Elbit Sys. of Am., LLC v. Thales Visionix, Inc.,
`881 F.3d 1354 (Fed. Cir. 2018) ............................................................................ 9
`Gen. Elec. Co. v. United Techs. Corp.,
`No. IPR2017-00428, 2018 WL 3105491 (P.T.A.B. June 22, 2018) .................. 21
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ................................................................ 9, 13, 16
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ............................................................................ 7
`Polaris Indus., Inc. v. Arctic Cat, Inc.,
`882 F.3d 1056 (Fed. Cir. 2018) .......................................................................... 21
`In re Lee,
`277 F.3d 1338 (Fed. Cir. 2002) ............................................................................ 7
`Vasudevan Software, Inc. v. MicroStrategy, Inc.,
`782 F.3d 671 (Fed. Cir. 2015) ............................................................................ 22
`W.L. Gore v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) ............................................................................ 7
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`Ex Parte Wang,
`No. 2017-011244, 2019 WL 3202860 (P.T.A.B. July 9, 2019) ........................... 9
`STATUTES
`35 U.S.C.§ 312(a)(3) ...................................................................................... 9, 13, 16
`REGULATIONS
`37 C.F.R. § 42.23(b) ............................................................................................ 9, 13
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`EXHIBIT INDEX
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`Ex.
`Description
`2001 Corcept Therapeutics, KORLYM® (mifepristone),
`http://www.corcept.com/korlym.html (last visited Nov. 19, 2018)
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`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)
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`2003 U.S. Patent No. 8,598,149 (“the ’149 Patent”)
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`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”)
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`2005 N.N. Sarkar, Mifepristone: Bioavailability, Pharmacokinetics and Use-
`Effectiveness, 101 EUROPEAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
`AND REPRODUCTIVE BIOLOGY, 113-120 (2002) (“Sarkar”)
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`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”)
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`2007 Oskari Heikinheimo, et al., Antiprogesterone RU 486—a Drug for Non-
`Surgical Abortion, 22 ANNALS OF MEDICINE, 75-84 (1990) (“Heikinheimo
`1990”)
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`2008
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`[Corrected] 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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`2009 Transcript of deposition of Mikko Oskari Heikinheimo, Ph.D., taken May 2,
`2019 in Neptune Generics, LLC v. Corcept Therapeutics, Inc., IPR No. 2018-
`01494 (“Heikinheimo Deposition”)
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`2010 Unit conversion table, marked as Exhibit 1 to the Heikinheimo Deposition
`(“Heikinheimo Deposition Exhibit 1”)
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`Ex.
`Description
`2011 Ann Robbins & Irving M. Spitz, Mifepristone: Clinical Pharmacology, 39
`CLIN. OBSTET. GYNECOL. 436 (1996) marked as Exhibit 2 to the Heikinheimo
`Deposition (“Robbins-Spitz”)
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`2012
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`Irving M. Spitz & C.W. Bardin, Clinical Pharmacology of RU 486—An
`Antiprogrestin and Antiglucocorticoid, 48 CONTRACEPTION 403 (1993)
`marked as Exhibit 3 to the Heikinheimo Deposition (“Spitz-Bardin”)
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`2013 Donna Shoupe et al., Effects of the Antiprogesterone RU 486 in Normal
`Women, 157 AM. J. OBSTET. GYNECOL. 1415 (1987) marked as Exhibit 4 to
`the Heikinheimo Deposition (“Shoupe”)
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`2014 Declaration of Hartmut Derendorf, Ph.D. in Support of Patent Owner’s
`Response (“Derendorf”)
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`2015 Curriculum Vitae of Hartmut Derendorf, Ph.D.
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`2016 Declaration of Dr. Ned H. Kalin, M.D. in Support of Patent Owner’s
`Response (“Kalin”)
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`2017 Curriculum Vitae of Ned H. Kalin, M.D.
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`I.
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`INTRODUCTION
`Petitioner’s Reply is notable for its nearly complete avoidance of any mention
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`of its own expert’s testimony. Having brought its Petition supported only by a 13-
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`page expert declaration, Petitioner now retreats from even that. On cross-
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`examination, it became clear that Dr. Heikinheimo’s views did not support
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`unpatentability and that his own experience, documented in his publications,
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`confirms Patent Owner’s case. Petitioner attempts to remedy this fatal deficiency
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`by filling its Reply with attorney argument without any grounding in expert or
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`evidentiary support. This attempt should be rejected. Avant Tech., Inc. v. Anza
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`Tech., Inc., No. IPR2018-00828, 2018 WL 5099380, at *8 (P.T.A.B. Oct. 16, 2018)
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`(“As the Federal Circuit has consistently explained, ‘[a]ttorney argument is not
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`evidence.’”).
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`Petitioner cannot escape the fact that none of its prior art combinations teach,
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`motivate, or provide a reasonable expectation of success in determining that 1300
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`ng/mL was the key serum level threshold to exceed for efficacy. Mifepristone’s
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`complex non-linear PK profile, the vast interpatient variability in serum levels, and
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`the inaccuracies across the various prior art publications all demonstrate the
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`significant unpredictability that prevailed at the time of the invention. Indeed,
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`Petitioner’s own expert—after experimenting with mifepristone for over 30 years—
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`concluded that (1) there was no correlation between dose and clinical outcome, (2)
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`it remained “an enigma” why anti-glucocorticoid (“AGC”) effects are never seen at
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`mifepristone doses below 400 mg given that plasma concentrations are the same for
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`100-800 mg doses, and (3) because serum concentrations are the same across this
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`broad dosage range, measuring drug serum levels “may not be informative.” Ex.
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`2009, 103:20-104:20, 111:9-122:8, 106:22-107:10.
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`Petitioner is now left with only its hindsight argument, cobbling together
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`references directed to neuropsychiatric tests for AGC efficacy assessment with one
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`anti-progestin (“AP”) reference for pregnancy termination (through only a single
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`dose of mifepristone) which entirely fails to render obvious the surprising discovery
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`embodied in the ’348 Patent.
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`II. CLAIM CONSTRUCTION
`A. The PTAB Should Adopt Patent Owner’s Undisputed
`Construction
`1. Method for Optimizing Levels of Mifepristone
`The Board should adopt Patent Owner’s construction and construe “method
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`for optimizing levels of mifepristone” in the preamble as limiting and as “the process
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`of testing mifepristone blood levels and adjusting the dosage of mifepristone
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`administered to the patient in need in order to achieve mifepristone blood levels
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`above 1300 ng/mL”—a construction directly from the ’348 Patent specification—
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`which Petitioner does not dispute. See Reply at 1-2; POR at 17-18; see Ex. 1001,
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`5:53-56; Ex. 2014, ¶¶20, 22.
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`2.
`Disorder Amenable to Treatment with Mifepristone
`The Board should adopt Patent Owner’s construction and construe “disorder
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`amenable to treatment by mifepristone” in the preamble as limiting and as “a
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`condition that is known to be treated by glucocorticoid antagonists such as
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`mifepristone”—another construction directly from the ’348 Patent specification—
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`which Petitioner does not dispute. See Reply at 1-2; POR at 17-18; Ex. 1001, 3:7-
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`9; Ex. 2014, ¶¶20-21.
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`B.
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`Petitioner’s Attempt to Interject Belated Claim Constructions Not
`Raised in its Petition Should Be Rejected
`It is also undisputed that Petitioner did not argue that the claim terms “to
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`achieve blood levels greater than 1300 ng/mL” or “disorder” should be construed in
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`its original Petition. See Petition at 12-15. Rather, Petitioner stated that these terms
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`should “be given their broadest reasonable interpretation as well as their normal and
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`customary meaning.” Id. at 12. Regretting its decision, Petitioner now argues that
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`it is Patent Owner who is “implicitly” arguing for particular constructions.
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`Petitioner’s gamesmanship trying to propose new and belatedly raised claim
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`constructions should be rejected.
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`1.
`To Achieve Blood Levels Greater Than 1300 ng/mL
`Petitioner argues that Patent Owner implicitly construes the term “to achieve
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`blood levels greater than 1300 ng/mL” as the blood level at all times or trough level
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`at steady state. See Reply at 2-4. First, Petitioner did not argue for any construction
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`of this term in its Petition. Second, Patent Owner is not “implicitly” urging any
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`construction. Rather, Patent Owner and its experts properly applied the ordinary and
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`customary meaning of this term in their obviousness analysis.
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`The ’348 Patent claims require treating a patient with seven or more daily
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`doses of mifepristone over a period of seven or more days. Ex. 1001, 16:29-30. As
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`explained by Dr. Derendorf, a POSA reviewing the claims in the context of the
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`specification would have understood that the mifepristone blood level to be
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`measured after at least seven or more daily doses would be the trough level or Cmin
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`at steady state. See Ex. 1037, 25:24-28:13; see also id. at 26:20-23 (“[Y]ou want to
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`be above the 1300 nanograms per milliliter at all times of your therapy, so that would
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`be the steady state concentration.”); Ex. 2014, ¶22 (citing Ex. 1001, 2:57-61, 6:11-
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`14) (The purpose of the ’348 Patent optimization method is to ensure that “the blood
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`serum levels remain in an efficacious range” so that “the patient receives the
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`necessary treatment.”).
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`Petitioner and its expert agree stating that the claims “are directed to methods
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`of maintaining certain levels of the drug mifepristone in blood” and explaining Cmin
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`is the standard measurement a POSA would seek to measure. See Petition at 4
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`(emphasis added); Ex. 2009, 105:12-16 (“Q. And why were you interested in looking
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`at that point, the Cmin? A. I guess that’s a typical way when doing pharmacokinetic
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`studies, what the level is before ingestion of the next tablet in such a setting.”).
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`The ’348 Patent specification also confirms that the serum levels that “remain
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`in an efficacious range” (steady state) is the proper measurement. See Ex. 1001,
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`2:57-61 (“The present invention provides a method for optimizing the blood serum
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`levels of mifepristone so that the blood serum levels remain in an efficacious range
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`and the patient receives the necessary treatment.”) (emphasis added); see also id. at
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`1:34-36, 6:11-14. In addition, during the prosecution of the parent ’149 Patent,
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`Patent Owner explained that “the present invention surprisingly discovered that
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`maintaining mifepristone serum levels above 1300 ng/mL provide an effective
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`treatment.” See Ex. 1003, 146 (emphasis added).
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`Even Petitioner’s evidence in Reply supports this view, indicating that
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`“[p]lasma trough mifepristone samples were collected on day 7, before
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`administration of the last dose of study drug.” See Ex. 1040, 2 (emphasis added).
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`Against this weight of evidence, Petitioner’s attempt to read the claims as requiring
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`dosing for seven days and then determining a Cmax rather than steady-state level
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`makes no sense. Indeed, the claim language expressly calls for blood “levels”
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`(plural) which are greater than 1300 ng/mL, not a single Cmax.
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`2.
`Disorder
`In similar vein, Petitioner tries to belatedly construe “disorder” as chronic
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`disorders or mental disorders. Reply at 2-6. This is purely a strawman, as there
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`never was any dispute here. The ’348 Patent specification defines a “disorder,” as
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`specified in the ’348 Patent claims, as “a condition that is known to be treated by
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`glucocorticoid antagonists such as mifepristone.” See Ex. 1001, 3:8-9; supra,
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`Section II.A.2. Mental disorders are an example of the larger universe of disorders
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`treated by AGC antagonists. See Ex. 1001, 3:8-11; Ex. 2014, ¶21; Ex. 1037, 21:22-
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`23:1. What is clear is that the claims require seven or more daily doses for treating
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`disorders by AGC antagonists, and thus are not directed to AP uses of mifepristone,
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`such as contraception, involving only a single dose of the drug. Ex. 2016, ¶¶52-54.
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`III. GROUND ONE
`A. The Board Properly Rejected Petitioner’s Arguments Based on
`Belanoff ’848
`The Board properly rejected Petitioner’s arguments in Ground 1 that Belanoff
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`’848 renders the ’348 Patent obvious based on theories of inherency and/or routine
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`optimization. As discussed in detail below (but absent from Petitioner’s Reply), the
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`testimony of Petitioner’s own expert fully supports non-obviousness over Belanoff
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`’848.
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`1.
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`Petitioner’s Reiterated Argument Does Not Render the ’348
`Patent Obvious Because There is No Direct Translation
`Between Dose and Serum Level
`The crux of Petitioner’s argument through Ground 1 relies on principles of
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`inherency which the Board properly identified and rejected. ID at 22-24. Petitioner
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`admits that Belanoff ’848 does not disclose any mifepristone serum levels, and
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`certainly not the critical 1300 ng/mL level (Petition at 25, 29), but alleges that the
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`dosage levels disclosed “inherently translate” and “necessarily and inevitably result”
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`in the claimed serum levels. Petition at 29-30. The Board correctly found that “the
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`current record does not tend to show that, in every case, administration of
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`mifepristone at the levels disclosed in Belanoff ’848 would necessarily result in the
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`serum levels that satisfy the claim.” ID at 23-24; POR at 31-38; Ex. 2014, ¶¶137-
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`155.
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`Through its Reply, Petitioner attempts to recast its argument in positing an
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`inherency argument based on the ’348 Patent disclosure. Petitioner states that “the
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`’348 patent admits that the dosing range in Belanoff ’848 translates directly into the
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`range of blood levels” disclosed. Reply at 7 (emphasis added). However, using the
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`words “translates directly” to divine undisclosed serum levels from the ’848 dosages
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`is just a disguised inherency argument; Petitioner’s hand-waiving does not transform
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`its argument into something different. And this new tactic is entirely improper—the
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`disclosure of the patent-at-issue (’348 Patent) cannot be used to support an
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`obviousness argument—and it only proves that Petitioner’s arguments are premised
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`on hindsight. See Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1356 (Fed. Cir.
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`2013) (Petitioner “only traverses the obstacles to this inventive enterprise with a
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`resort to hindsight.”); In re Lee, 277 F.3d 1338, 1344 (Fed. Cir. 2002) (alterations in
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`original) (quoting W.L. Gore Assocs. v. Garlock, Inc., 721 F.2d 1540, 1553 (Fed.
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`Cir. 1983) (“It is improper, in determining whether a person of ordinary skill would
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`have been led to this combination of references, simply to ‘[use] that which the
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`inventor taught against its teacher.’”).
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`Besides, the Board previously found Petitioner’s citation to the ’348 Patent
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`actually undermines its inherency argument. ID at 24 (referencing the ’348 Patent’s
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`teachings regarding the 800% variability between patients, and that only 269 of 443
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`patients administered 300-600 mg achieved serum levels exceeding 1357 ng/mL).
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`The ’348 Patent demonstrates the opposite—i.e., that there is no direct translation
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`between dosage and serum level. For example, as Dr. Derendorf explained, Figure
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`5 of the ’348 Patent depicts an experiment wherein each patient received the same
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`dose (1200 mg) and 20% of patients did not achieve serum levels above 1357 ng/mL.
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`Ex. 1037, 62:6-23; see also Ex. 1001, Fig. 5, 2:34-40. Figure 2 of the ’348 Patent
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`similarly shows that upon administration of the same dose, 35% of patients did not
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`achieve serum levels above 1357 ng/mL. Ex. 2014, ¶141, 66-68; Ex. 1001, Fig. 2;
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`see also Ex. 1016, 5, 7-8, Table 2.
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`Even more telling, Petitioner and its expert previously admitted that there is
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`no “direct translation” between dose and serum level. See Petition at 48
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`(“[A]dministration of the same dose of mifepristone can produce widely varying
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`blood serum levels in different patients.”); Ex. 1004, ¶25 (“It is in no way surprising
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`that administration of the same dose of mifepristone can produce widely varying
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`blood serum levels in different patients.”).
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`Petitioner’s New Argument that the ’348 Claims are Obvious
`Based on “Routine Optimization” In View of Belanoff ’848 Is
`Unsupported and Contradicted by Petitioner’s Own Expert
`Petitioner now attempts to recast its Belanoff ’848 inherency argument as one
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`2.
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`based on optimization relying on conclusory attorney argument without any
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`supporting evidence or expert testimony. See Reply at 6, 8-10; Ex Parte Wang, No.
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`2017-011244, 2019 WL 3202860, at *4 (P.T.A.B. July 9, 2019) (“[A]ttorney
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`argument cannot take the place of factually supported objective evidence.”); Avant,
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`2018 WL 5099380, at *8 (“As the Federal Circuit has consistently explained,
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`‘[a]ttorney argument is not evidence.’”); Elbit Sys. of Am., LLC v. Thales Visionix,
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`Inc., 881 F.3d 1354, 1359 (Fed. Cir. 2018) (“‘Attorney argument is not evidence’
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`and cannot rebut other admitted evidence.”).
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`As an initial matter, Petitioner’s new argument that Belanoff ’848’s disclosure
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`of cortisol blood levels renders obvious the measurement of mifepristone blood
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`levels has been waived. See 37 C.F.R. § 42.23(b) (“A reply may only respond to
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`arguments raised in the corresponding opposition, patent owner preliminary
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`response, or patent owner response.”); Intelligent Bio-Sys., Inc. v. Illumina
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`Cambridge Ltd., 821 F.3d 1359, 1369 (Fed. Cir. 2016) (quoting 35 U.S.C.
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`§ 312(a)(3)) (“It is of the utmost importance that petitioners in the IPR proceedings
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`adhere to the requirement that the initial petition identify ‘with particularity’ the
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`‘evidence that supports the grounds for the challenge to each claim.’”). Indeed, there
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`is no mention whatsoever of “cortisol” in Ground 1 of the Petition; nor is there any
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`mention of “cortisol” in the declaration from Petitioner’s expert.
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`In any event, the evidence supports the opposite conclusion. During his
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`deposition, Dr. Heikinheimo confirmed that Example 2 of Belanoff ’848 only
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`describes the measurement of cortisol in the blood, not mifepristone, and that cortisol
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`measurement has no relationship to the measurement of mifepristone levels. See Ex.
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`2009, 67:21-24 (“Q.… [E]xample 2 just talks about measuring cortisol levels, right?
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`A. Yes.”); id. at 79:14-18 (“Q. And to be clear again, example 2 simply refers to
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`measuring cortisol levels, not anything to do with measuring blood levels of RU486,
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`mifepristone, right? A. That’s correct.”).
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`Dr. Heikinheimo also testified that Belanoff ’848 contains no mifepristone
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`blood level measurements whatsoever. Id. at 68:21-24 (“Q. And there’s no actual
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`data or results from – from any blood tests that are included in the ’848 application,
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`right? A. You are correct.”). Instead, Dr. Heikinheimo confirmed that the clinical
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`protocol section of Belanoff ’848 instructs a POSA to use formal psychiatric
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`assessment and a battery of neuropsychological tests to determine the effectiveness
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`of mifepristone treatment. Id. at 67:6-20; see also id. at 79:7-13, 79:19-80:12); Ex.
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`1024, [0098]-[0099]. As Patent Owner’s expert Dr. Kalin explained, the
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`methodology described in Belanoff ’848 is consistent with modern psychiatric
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`treatment monitoring. Ex. 2016, ¶¶17-18, 21-22; Ex. 1036, 63:4-65:24; see also Ex.
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`2014, ¶¶145-149.
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`Against this evidence and its expert’s admissions, Petitioner lacks any support
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`for its new argument. It provides no evidence or expert testimony to establish that
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`“it would have been common sense for a POSA to look at the blood levels of the
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`glucocorticoid receptor antagonist (i.e., mifepristone) which is competing with
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`cortisol in the first place.” Reply at 8-9. No expert has testified that such an
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`approach would be successful in view of the scant numbers of patients treated in the
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`prior art. Moreover, there is no evidence in the record that cortisol levels have any
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`correlation with the efficacy of glucocorticoid inhibitors such that a POSA would
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`have been motivated from a teaching of cortisol measurements to then also measure
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`levels of the AGC inhibitor, mifepristone. Instead, the testimony from its own expert
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`contradicts Petitioner’s argument.
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`Petitioner’s argument that Belanoff ’848’s passing mention of blood and urine
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`mifepristone levels motivates a POSA to measure blood levels in connection with
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`determining efficacy is also unavailing. Dr. Heikinheimo testified directly contrary
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`to Petitioner’s argument, explaining that the disclosure Petitioner relies on is “very
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`general,” “very vague” and untied
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`to
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`the clinical protocol specifying
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`neuropsychiatric tests. See Ex. 2009, 131:5-11 (emphasis added) (“To me that’s a
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`very general sentence…. So to me it’s a very vague laboratory test may be used,
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`11
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`may be useful. It doesn’t really say anything very specific.”). Further, although
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`
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`both blood cortisol and blood mifepristone level measurements are arguably
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`mentioned in passing in the “General Laboratory Procedure” section of Belanoff
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`’848 (Ex. 1024, [0034]-[0044]), only cortisol measurements are mentioned in the
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`examples following the clinical trial protocol—not mifepristone measurements.
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`Compare id. at [0034]-[0044] with id. at [0092]-[0102].
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`Lastly, Dr. Heikinheimo and Patent Owner’s experts demonstrate that the
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`mere fact that a POSA knew how to measure drug levels in the blood (“as early as
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`1987,” see Reply at 9) does not supply a motivation or reasonable expectation of
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`success to measure mifepristone blood levels for treating chronic disorders (e.g.
`
`psychiatric disorders). First, modern psychiatric treatment had not identified any
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`correlation between drug level and effect, and instead taught that neuropsychiatric
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`tests should be used. See Ex. 2016, ¶¶17-19, 35-51. Second, mifepristone’s
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`complicated non-linear PK showed no change in serum level based on different
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`doses, and different effects based on the same serum level. See Ex. 1012, 6 (In view
`
`of the fact that plasma concentrations do not increase with increasing dose from 100
`
`mg to 800 mg, “it still remains an enigma why systemic antiglucocorticoidal effects
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`are virtually never seen at RU 486 doses below 400 mg.”); Ex. 2009, 111:9-112:8.
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`Third as shown in his publications, Dr. Heikinheimo himself tried and failed to
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`12
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`correlate mifepristone blood levels with AGC effects. See, e.g., Ex. 1012.
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`
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`Accordingly, Ground One fails.
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`IV. GROUND TWO
`A.
`Petitioner Fails to Overcome the Fact that None of the Prior Art
`Discloses or Motivates the Key 1300 ng/mL Level Nor Optimization
`Based On That Level
`Petitioner’s Reply not only fails to explain away its expert’s detrimental
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`admissions, but also still does not dispute that Sitruk-Ware and its asserted
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`combination fail to disclose the critical 1300 ng/mL serum level. Petitioner shifts
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`its course, relying on Figure 2 of Sitruk-Ware instead of Figure 3, which was
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`debunked as meaningless.1 While Petitioner now alleges that “[t]here is absolutely
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`no way to derive the ‘2.0 mg/L at 1.35 h (tmax)’ value from Figure 3” (Reply at 12)
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`this is the opposite of what it stated in its Petition and expert declaration (both
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`containing no reference to Figure 2) and the opposite of Dr. Heikinheimo’s
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`deposition testimony. See Ex. 1004, ¶17; Petition at 17, 36; Ex. 2009, 85:12-17.
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`During his deposition, Dr. Heikinheimo testified repeatedly that the data
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`reported in Figure 3 of Sitruk-Ware was generated via radioimmunoassay and
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`1 Petitioner did not rely on Figure 2 in its Petition, and has thus waived this argument.
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`See 37 C.F.R. § 42.23(b); 35 U.S.C. § 312(a)(3); Intelligent Bio-Sys., 821 F.3d at
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`1369.
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`13
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`therefore does not accurately report levels of mifepristone in the blood. See, e.g.,
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`
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`Ex. 2009, 33-34, 57-59, 80-98. Further, the HPLC methodology that did accurately
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`report mifepristone levels showed levels below the critical 1300 ng/mL level. See
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`Ex. 2013, Fig. 6, 3-5 (reporting a serum concentration of less than 1000 ng/mL).
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`Petitioner’s post-hoc attorney argument trying to salvage its obviousness theory
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`including through intimating some alleged trickery in Patent Owner’s deposition
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`questioning is unavailing.
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`While Petitioner now relies on Figure 2, sans expert support, this disclosure
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`still fails to disclose or motivate a POSA to arrive at the critical 1300 ng/mL level.
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`Ex. 2014, ¶¶166-197. First, the claims clearly require serum level measurement after
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`“seven or more daily doses of mifepristone.” Ex. 1001, 16:25-35; Ex. 2009, 46:25-
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`47:3 (“So the protocol here describes a protocol of administering seven days of
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`mifepristone and then testing – then testing the level.”). In contrast, Sitruk-Ware
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`reports alleged mifepristone levels after a single dose. See Ex. 1008, 6 (emphasis
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`added) (“[f]ollowing single dose administration of mifepristone…”); see also Ex.
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`2009, 86:3-7. Second, it is undisputed that Sitruk-Ware discloses a certain type of
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`serum level—the mean, maximum plasma concentration or Cmax. See Ex. 1008, 6
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`(emphasis added) (describing “mean maximum plasma concentrations”); Ex. 2009,
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`84:10-16 (agreeing
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`that Sitruk-Ware references “mean maximum plasma
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`concentration”). Yet, Petitioner’s expert testified that a POSA would understand
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`that the trough or Cmin level is what a skilled artisan would be seeking to measure in
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`this context of the ’348 Patent. See Ex. 2009, 105:12-16. Third, the serum
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`concentration required to terminate pregnancy is entirely different from what is
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`required to treat disorders that respond to AGC treatment. Treatment is disorder
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`dependent. Petitioner’s expert agrees. See Ex. 2009, 31:18-24 (“Q. And the activity
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`of mifepristone in terminating pregnancy is based on its antiprogestin activity? A.
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`Yes. Q. And that activity is separate from its activity as a glucocorticoid antagonist,
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`correct? A. Yes.”); see also id. at 101:20-103:23; Ex. 1012, 5 (“Chronic treatment
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`with 25-200 mg/day of RU 486, doses sufficient to produce uterine bleeding in 80%
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`or more cases, did not result in any apparent antiglucocorticoidal effects.”); Ex.
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`1014, 1 (“Different target organs appear to have different sensitivities to
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`mifepristone.”). As such, a POSA would not consider Sitruk-Ware in approaching
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`the treatment of the ’348 disorders because Sitruk-Ware administers a single dose—
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`a regimen entirely inappropriate and ineffectual for the ’348 disorders and not
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`consistent with the patent claims.
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`Through its Reply, Petitioner attempts to interject a new reference and
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`argument absent from Ground 2 in its Petition. Petitioner argues that Exhibit 1013
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`discloses a Cmin/steady state concentration over 1300 ng/mL (3.6-3.8 µmol),
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`implicitly recognizing that Cmin is the proper concentration for measurement. But
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`this argument and reference were not included in the grounds of the Petition and are
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`thus waived. Intelligent Bio-Sys., 821 F.3d at 1369 (citing 35 U.S.C. § 312(a)(3).
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`Regardless, Figure 2 in Exhibit 1013 still is not within the s
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