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
`_______________________________
`
`
`PETITIONER’S REPLY
`
` 
`
` 
`
`

`

`I. 
`II. 
`
`B. 
`
`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1 
`CLAIM CONSTRUCTION ............................................................................ 1 
`A. 
`Explicit Claim Constructions: “Method of Optimizing Levels of
`Mifepristone” and “Amenable to Treatment with Mifepristone” ......... 1  
`Implicit Claim Constructions: “To Achieve Blood Levels Greater than
`1300 ng/mL” and “Disorder” ................................................................ 2 
`III.  GROUND ONE ............................................................................................... 6 
`A. 
`The Board Improperly Focused Its Determination on Inherency ......... 6 
`B. 
`Patent Owner’s Arguments Fail To Rebut Obviousness. ..................... 8 
`IV.  GROUND TWO ............................................................................................ 10 
`A. 
`The Board Correctly Found That Belanoff 2002, Chu and Belanoff
`and Sitruk-Ware Together Render the Claims Obvious ..................... 10 
`1. 
`“A method for optimizing levels of mifepristone in a patient
`suffering from a disorder amenable to treatment by
`mifepristone” ............................................................................. 10 
`“treating the patient with seven or more daily doses of
`mifepristone” ............................................................................. 11 
`“testing the serum levels of the patient to determine whether the
`blood levels of mifepristone are greater than 1300 ng/mL” ..... 11 
`“adjusting the daily dose of the patient…greater than 1300
`ng/mL” ...................................................................................... 13 
`Patent Owner’s Extraneous Evidence Fails To Rebut The Conclusion
`of Obviousness Claim. ........................................................................ 14 
`1. 
`The pharmacokinetics (PK), pharmacodynamics (PD), and the
`PK/PD relationship for mifepristone was well-known at the
`time of invention. ...................................................................... 15 
`
`2. 
`
`3. 
`
`4. 
`
`B. 
`
` 
`
`i 
`
`

`

`2. 
`
`3. 
`
`C.
`
`D. 
`
`That mifepristone pharmacokinetics are non-linear, and vary
`from patient to patient, was both well-known and irrelevant. .. 16 
`Distinguishing mifepristone blood level measurements from its
`metabolites was well-known in 2007. ....................................... 17
`There is a Motivation to Combine Belanoff 2002, Chu and Belanoff,
`and Sitruk-Ware. ................................................................................. 17
`The Belanoff ‘348 “Invention” Was Not a “Breakthrough” Discovered
`After “Decades of Failure,” and No “More Efficient” Than the Prior
`Art. ....................................................................................................... 17 
`In re Cyclobenzaprine is Inapposite Because it Involved a New
`Formulation. ........................................................................................ 21 
`V.  GROUNDS 3-6 .............................................................................................. 22 
`VI.  CONCLUSION .............................................................................................. 23 
`
`E. 
`
` 
`
`
`
` 
`
`ii 
`
`

`

`TABLE OF AUTHORITIES
`CASES 
`A.C. Techs. S.A. v. Amazon.com, Inc.,
` 912 F.3d 1358, 1366 (Fed. Cir. 2019) ................................................................ 4
`Andersen Corp. v. Fiber Composites, LLC,
`474 F.3d 1361 (Fed. Cir. 2007) ........................................................................... 5
`Biomarin Pharmaceutical Inc. v. Genzyme Therapeutic Products Limited
`Partnership,
`Case No. IPR2013-00534, 2015 WL 1009195 (Patent Tr. & App. Bd.
`Feb. 23, 2015) ...................................................................................................... 9
`Glaxo Grp. Ltd. v. Apotex, Inc.,
`376 F.3d 1339 (Fed. Cir. 2004) ........................................................................... 6
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ............................................................................. 9
`In re Boesch,
`617 F.2d 272 (C.C.P.A. 1980) ............................................................................. 9
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
`Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .................................................................. 15, 21
`In re Ethicon, Inc.,
` 844 F.3d 1344 (Fed. Cir. 2017) ......................................................................7, 9
`In re Nuvasive, Inc.,
`842 F.3d 1376 (Fed. Cir. 2016) ........................................................................... 3
`In re Prindle,
`297 F.2d 251 (C.C.P.A. 1962) ............................................................................. 9
`Luma Corp. v. Stryker Corp.,
` 273 F. App’x 948 (Fed. Cir. 2008) ..................................................................... 4
`Pfizer, Inc. v. Teva Pharms. USA, Inc.,
`429 F.3d 1364 (Fed. Cir. 2005) ........................................................................... 6
`Realtime Data, LLC v. Iancu,
`912 F.3d 1368 (Fed. Cir. 2019) ........................................................................... 2
`
` 
`
`iii 
`
`

`

`RPX Corp. v. Iridescent Networks, Inc.,
`Case No. IPR2017-01661, Paper 29 (Patent Tr. & App. Bd.Dec. 10,
`2018) .................................................................................................................... 3
`Santarus, Inc. v. Par Pharmaceutical, Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) ........................................................................... 8
`STATUTES 
`21 C.F.R. § 314.53(c)(2)(ii)(P) .................................................................................. 6
`21 C.F.R. § 314.53(c)(2)(ii)(R) .................................................................................. 6
`
`
`
` 
`
`
`
`iv 
`
`

`

`EXHIBIT LIST
`
`Exhibit
`1001
`1002
`1003
`1004
`1005
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
` 
`
`
`U.S. Patent 8,921,348 to Belanoff
`U.S. Application 14/065792 File History
`U.S. Application 12/199114 File History
`Declaration of Mikko A. Oskari Heikinheimo, M.D., Ph.D.
`Curriculum Vitae of Dr. Heikinheimo
`Possible Use of Glucocorticoid Receptor Antagonists in the Treatment of Major
`Depression: Preliminary Results Using RU 486 – Murphy et al. (1993) J.
`Psychiatr. Neurosci., Vol. 18, No. 5, 209-213.
`An Open Label Trial of C-1073 (Mifepristone) for Psychotic Major Depression
`by Belanoff et al., Biol. Psychiatry (2002) 52:386-392.
`Pharmacological properties of mifepristone: toxicology and safety in animal and
`human studies by Sitruk-Ware et al., (2003) Contraception 68, 409–420
`Rapid Reversal of Acute Psychosis in the Cushing Syndrome with the Cortisol-
`Receptor Antagonist Mifepristone (RU 486) by van der Lely et al., Annals of
`Internal Medicine. (1991) 114:143-144.
`U.S. Patent 6,964,953 B2 to Belanoff entitled “Methods for treating stress
`disorder using glucocorticoid receptor specific antagonists” issued November
`15, 2005
`Clinical Pharmacokinetics of Mifepristone, Heikinheimo, Clin. Pharmacokinet.
`1997 July, 33 (I): 7-17 (Ex. 1011)
`“Plasma concentrations and receptor binding of RU 486 and its metabolites in
`humans,” Heikinheimo, et al. J. Steroid Biochem. Vol. 26: 279-284, 1987
`Pharmacokinetics of the Antiprogesterone RU 486 in Women During Multiple
`Dose Administration, Heikinheimo, et al. J. Steroid Biochem. Vol. 32, No. 1A,
`pp. 21-25, 1989.
`Pharmacokinetics of Mifepristone After Low Oral Doses,
`Kekkonen, et al. Contraception 1996; 54:229-234.
`A Study of the Effect of Mifepristone (Antiprogesterone) Followed by
`Prostaglandin on Uterine Activity and Fetal Heart Rate in Patients Having a
`Termination of Pregnancy,
`Pulkkinen, et al. Arch Gynecol Obstet (1989) 244:75-
`Pharmacokinetic study of RU 486 and its metabolites after oral administration of
`single doses to pregnant and non-pregnant women, Shi, et al. Contraception
`August 1993:48, 133-149
`
`v 
`
`

`

`1018
`1019
`
`1020
`
`1023
`
`1024
`
`1025
`
`1026
`1027
`1028
`1029
`
`
`Exhibit
`1017 Mifepristone (RU-486) treatment for depression and psychosis: a review of the
`therapeutic implications, Gallagher et al, Neuropsychiatric Disease and
`Treatment 2006:2(1) 33–42
`“Express Scripts – Specialty Drug Update”
`Differential kinetics of serum and cervical insulin-like growth factor-binding
`protein-1 during mifepristone± misoprostol-induced medical termination of early
`pregnancy, Honkanen et al., Molecular Human Reproduction Vol. 10, No. 1 pp.
`65-70, 2004.
`Pharmacokinetic Properties of the Antiglucocorticoid and Antiprogesterone
`Steroid RU 486 in Man,” Kawai et al, Pharmacol. and Experimental Therapeutics
`241:401-406 (1987).
`1021 US 6,150,349 to Schatzberg and Belanoff
`1022
`National Center for Biotechnology Information. PubChem Compound Summary
`for CID 55245; available at
`http://pubchem.ncbi.nlm.nih.gov/compound/55245#section=Top
`Successful Long-Term Treatment of Refractory Cushing’s Disease with High-
`Dose Mifepristone (RU 486), Chu, Belanoff et al. The Journal of Clinical
`Endocrinology & Metabolism 86(8):3568–3573 (2001)
`US 2004/0029848 to Belanoff “Methods for Treating Delirium Glucocorticoid
`Receptor-Specific Antagonists” published February 12, 2004
`“Rapid Reversal of Psychotic Depression Using Mifepristone,” Belanoff et al.,
`(2001) Journal of Clinical Psychopharmacology Vol. 21, No. 5, 516-521
`US 6,362,173 to Schatzberg and Belanoff
`US 8,450,379 to Belanoff (published 2004-07-08 as US 2004/013270)
`US 7,361,646 to Belanoff (published 2004-08-26 as US 2004/0167110)
`DeBattista C, Belanoff J., “The use of mifepristone in the treatment of
`neuropsychiatric disorders.” TRENDS in Endocrinol. and Metab. Apr;17(3):117-
`21. Epub 2006 Mar 10.
`DeBattista, Belanoff et al., “Mifepristone versus Placebo in the Treatment of
`Psychosis in Patients with Psychotic Major Depression” Biol. Psychiatry. Dec
`15;60(12):1343-9. Epub 2006 Aug 4.
`Annual Report of Corcept Therapeutics Incorporated for the fiscal year ending
`December 31, 2016, Form 10-K available at
`https://www.sec.gov/Archives/edgar/data/1088856/000156459017003493/cort-10k_20161231.htm
`
`1030
`
`1031
`
` 
`
`vi 
`
`

`

`Exhibit
`1032
`
`1034
`
`1035
`1036
`
`1037
`
`1038
`
`
`Korlym FDA-approved labeling of Feb. 17, 2012 available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202107s000lbl.pdf
`1033 Mifeprex FDA-approved labeling of Sept. 28, 2000 available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20687lbl.pdf
`“Successful Treatment of Cushing’s Syndrome with the Glucocorticoid
`Antagonist RU 486”, Nieman et al. Journal of Clinical Endocrinology and
`Metabolism 61:536-540 (1985).
`Declaration of Leonard A. Gail
`Transcript of Deposition of Dr. Ned H. Kalin, taken July 30, 2019 in Neptune
`Generics LLC v. Corcept Therapeutics, Inc., IPR No. 2018-01494
`Transcript of Deposition of Dr. Hartmut Derendorf, taken August 2, 2019 in
`Neptune Generics LLC v. Corcept Therapeutics, Inc., IPR No. 2018-01494
`Food & Drug Administration Patent & Exclusivity Data for Korlym, available at
`https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=00
`1&Appl No=202107&Appl type=N
`1039 March 20, 2007 News Release: Corcept Therapeutics announces Phase 3 Study
`Evaluating CORLUX, marked as Exhibit 6 to the Deposition of Dr. Ned H. Kalin
`Block et al., “Combined Analysis of Mifepristone for Psychotic Depression:
`Plasma Levels Associated with Clinical Response”, Biological Psychiatry, 84:46-
`54 (July 1, 2018), marked as Exhibit 1 to the Deposition of Dr. Ned H. Kalin
`
`1040
`
`
`
` 
`
`vii 
`
`

`

`I.
`
`INTRODUCTION
`Patent Owner’s Response (Paper No. 24) sets forth several arguments why
`
`Petitioner’s Ground Two should not render the claims in the ‘348 patent obvious.
`
`Patent Owner variously submits that a person of ordinary skill in the art
`
`(hereinafter “POSA”) would read the claim terms in contravention of their
`
`language, ignore unambiguous statements in the asserted references, and/or fail to
`
`consider certain references at all. These arguments individually and collectively
`
`are meritless, and the Board should uphold Petitioner’s challenge.
`
`In addition, in its Decision to Institute (hereinafter “ID,” Paper No. 11), the
`
`Board misapprehended Petitioner’s Ground One argument. Petitioner does not rely
`
`on inherency. Rather, Petitioner argues (both then and now) simply that
`
`optimizing a known method of treating a disease by administration of a known
`
`product is obvious based on settled case law. In this case, optimizing the method
`
`merely involved finding a “threshold level” of efficacy. Therefore, the Board
`
`should uphold Petitioner’s challenge based on Ground 1 as well.
`
`II. CLAIM CONSTRUCTION
`A. Explicit Claim Constructions: “Method of Optimizing Levels of
`Mifepristone” and “Amenable to Treatment with Mifepristone”
`Patent Owner offers explicit claim constructions for two terms: “method of
`
`optimizing levels of mifepristone” and “amenable to treatment with mifepristone.”
`
`It does not challenge any of Petitioner’s constructions.
`1 
`
` 
`
`

`

`Patent Owner does not explain why its construction of “method of
`
`optimizing levels of mifepristone” results in a different analysis than Petitioner’s
`
`constructions of “mifepristone” or “optimizing” that were adopted in the Board’s
`
`ID (Paper No. 11). As such, Petitioner need not address it. Realtime Data, LLC v.
`
`Iancu, 912 F.3d 1368, 1375 (Fed. Cir. 2019). And while Petitioner agrees with
`
`Patent Owner’s construction of “amenable to treatment with mifepristone,” it
`
`emphatically disagrees that this definition makes references that do not discuss
`
`mifepristone’s glucocorticoid activity irrelevant or not combinable with references
`
`that do. See Section IV.C., infra.
`
`B.
`
`Implicit Claim Constructions: “To Achieve Blood Levels Greater
`than 1300 ng/mL” and “Disorder”
`Although Patent Owner does not acknowledge that these are claim
`
`construction arguments, it implicitly construes two additional terms. First, Patent
`
`Owner implicitly argues that the term “to achieve mifepristone blood levels greater
`
`than 1300 ng/mL” means to achieve these blood levels at all times, or in other
`
`words, “to achieve mifepristone blood levels above 1300 ng/mL at trough level at
`
`steady state,” as Dr. Derendorf confirmed at his deposition. Paper No. 24 at 2, 4,
`
`8, 39, 48-49 and 55; Exh. 1037 at 28:5-13. Second, Patent Owner implicitly argues
`
` 
`
`2 
`
`

`

`that the term “disorder” is limited to either chronic disorders, mental disorders or
`
`chronic mental disorders. See, e.g., Paper No. 24 at 11, 16, 54.1
`
`Patent Owner did not incorporate these arguments into its claim
`
`construction, and accordingly the Board should consider them waived. In re
`
`Nuvasive, Inc., 842 F.3d 1376, 1380-81 (Fed. Cir. 2016); RPX Corp. v. Iridescent
`
`Networks, Inc., Case No. IPR2017-01661, Paper 29 at 7 fn.8 (Patent Tr. & App.
`
`Bd. Dec. 10, 2018). However, even if the Board does not consider them waived,
`
`these arguments are completely unsupported.
`
`With respect to the “to achieve mifepristone blood levels greater than 1300
`
`ng/mL” term, nowhere in the ‘348 patent – not in the claims, not in the
`
`specification, and not in the file history of either the ‘348 patent or the parent ‘149
`
`patent – is the term “steady state” ever used. Further, there is no part of the claim
`
`or the specification that indicates when, after seven daily doses, serum levels are to
`
`be measured. The only thing the specification states is that the serum levels should
`
`be tested. Exh. 1001, 2:62-3:3. Dr. Kalin agrees. Exh. 1036 at 93:2-7. Under the
`
`broadest reasonable interpretation standard, such a test could occur at any time –
`
`immediately after the seventh dosing, hours after the seventh dosing, or even days
`
` 
`1 Patent Owner is cagey about its position, describing the ‘348 patent as directed to
`both “chronic disorders such as certain mental disorders” (Paper No. 24 at 16, 18,
`54), and mental disorders alone in other places (Id. at 11, 54).
`3 
`
` 
`
`

`

`(or weeks) after the seventh dosing (with no understanding as to whether daily
`
`dosing continues after day seven). And depending on when mifepristone blood
`
`levels are measured, there is no dispute that a wide range of blood levels will result
`
`– the antithesis of “steady state.” Thus, if the Board does not rule Patent Owner’s
`
`argument waived, it should give the term “to achieve mifepristone blood levels
`
`greater than 1300 ng/mL” its plain and ordinary meaning and reject Patent
`
`Owner’s attempts to insert “steady state” or “trough” limitations into the claim.
`
`The argument that the ‘348 patent is limited to either chronic disorders or
`
`mental disorders (Paper No. 24 at 53-55) is not just easily dismissed, but borderline
`
`frivolous.
`
`With respect to chronic disorders, as with “steady state,” the Board will
`
`search in vain for any use of the word “chronic” in the specification, claims, or
`
`arguments in the file history of the ‘348 patent or its parent ‘149 patent. Had
`
`Patent Owner wanted to limit its claims to chronic disorders, it could have done so.
`
`It cannot read a non-existent limitation into the claims now to save them. A.C.
`
`Techs. S.A. v. Amazon.com, Inc., 912 F.3d 1358, 1366 (Fed. Cir. 2019); Luma
`
`Corp. v. Stryker Corp., 273 F. App’x 948, 953-54 (Fed. Cir. 2008).
`
`With respect to mental disorders, Patent Owner repeatedly relies on the
`
`Examiner’s Notice of Patentability for the ‘149 patent in support of the ‘349 patent
`
` 
`
`4 
`
`

`

`as well. See, e.g., Paper 24 at 19, 61. However, the Examiner’s reason for
`
`patentability of the ‘149 claims, as quoted in the Response, were explicitly based
`
`on claims that included the “mental disorder” limitation – a term which was
`
`amended to simply “disorder” in the ‘348 patent.2 Exh. 1002, p. 92. Allowing the
`
`Patent Owner to now limit the ‘348 patent claims by implicitly reintroducing the
`
`term “mental” would violate the broadest reasonable interpretation standard, the
`
`doctrine of claim differentiation, and impermissibly read limitations into the claim
`
`from the specification. Andersen Corp. v. Fiber Composites, LLC, 474 F.3d 1361,
`
`1368-70 (Fed. Cir. 2007).
`
`Finally, limiting the claims to mental disorders would be contrary to Patent
`
`Owner’s representations to the FDA regarding the scope of the claims. Patent
`
`Owner asserted that its product, Korlym, is covered by the ‘348 patent. Exh. 1038
`
`(available at https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?
`
`Product_No=001&Appl_No=202107&Appl_type=N). However, Korlym is
`
`approved solely for treatment for Cushing’s syndrome, which is an endocrine
`
`disorder, not a mental disorder. Exh. 1032. Indeed, Dr. Kalin testified that
`
`Korlym is not approved to treat any mental disorder. Exh. 1036 at 95:23-96:12.
`
`Since patents are listed in the Orange Book under penalty of perjury, 21 C.F.R. §§
`
` 
`2 The ‘348 patent does not contain a similar Notice of Patentability with respect to
`its claims.
`
` 
`
`5 
`
`

`

`314.53(c)(2)(ii)(P), (c)(2)(ii)(R), the Board is entitled to consider Corcept’s listing
`
`an admission that the ‘348 patent does not merely cover mental disorders. Pfizer,
`
`Inc. v. Teva Pharms. USA, Inc., 429 F.3d 1364, 1374 (Fed. Cir. 2005); Glaxo Grp.
`
`Ltd. v. Apotex, Inc., 376 F.3d 1339 (Fed. Cir. 2004) (rejecting construction that
`
`would have excluded preferred embodiments).
`
`III. GROUND ONE
`A. The Board Improperly Focused Its Determination on Inherency
`In the ID the Board states that “the current record does not tend to show that,
`
`in every case, administration of mifepristone at the levels disclosed in Belanoff
`
`‘848 would necessarily result in the serum levels that satisfy the claim” and that
`
`“to the extent Petitioner relies on inherency to establish the claimed serum level,
`
`we are unpersuaded based on the present record”. Paper No. 11 at 23-24 (emphasis
`
`added). The Board misapprehends Petitioner’s argument. While Petitioner used
`
`the word “inherent,” Petitioner is not arguing inherency. Rather, Petitioner
`
`submits that the ‘348 patent claims nothing more than the administration of
`
`mifepristone as disclosed in Belanoff ‘848, monitoring mifepristone blood levels as
`
`disclosed in that reference, and optimizing the treatment by looking at the resulting
`
`data to see which patients got better. This would have been the obvious thing to do
`
`based both on the knowledge of a POSA at the time and settled case law.
`
` 
`
`6 
`
`

`

`Belanoff ‘848 discloses treatment of disorders using the same dosing range,
`
`and for the same number of days, as the ‘348 patent – 600-1200 mg/day. Compare
`
`Exh. 1024, ¶ [0096] with Exh. 1001 at 14:8-10, 15:12-14). Belanoff ‘848 also
`
`explicitly teaches a POSA that mifepristone blood levels may need to be
`
`monitored. Exh. 1024, ¶ [0041]. The ‘348 patent shows that in a range of patients,
`
`these treatment levels result in a blood level above 1300 ng/mL. Exh. 1001 at
`
`2:34-47. Thus, the ‘348 patent admits that the dosing range in Belanoff ‘848
`
`translates directly into the range of blood levels (including those above and below
`
`1300 ng/mL) which are shown in Figures 5 and 6 of the specification, and on
`
`which the claims of the ‘348 patent claim support. (Id.) Based on the disclosure of
`
`Belanoff ‘848, one of ordinary skill in the art would have known to test patients
`
`being treated for disorders for blood levels of the “glucocorticoid receptor (GR)
`
`antagonist, mifepristone” (Id., ¶ [0096]), which would have would have resulted in
`
`the discovery of the claimed range.
`
`It is settled case law that the specific level need not be in the prior art to
`
`demonstrate obviousness. In re Ethicon, Inc., 844 F.3d 1344, 1351 (Fed. Cir.
`
`2017) (“normal desire of artisans to improve upon what is already generally
`
`known” can provide motivation to optimize variables). And “[a]n obvious
`
`formulation cannot become nonobvious simply by administering it to a patient and
`
`claiming the resulting serum concentrations.” Santarus, Inc. v. Par
`
` 
`
`7 
`
`

`

`Pharmaceutical, Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012). That is exactly what
`
`Patent Owner has done here – taken the mifepristone tablets of Belanoff ‘848,
`
`administered them to a patient, examined the mifepristone blood levels which the
`
`reference tells POSA to monitor, and claimed the correlation between the resulting
`
`blood concentrations and who got better (i.e., patients with mifepristone levels
`
`greater than 1300 ng/mL).
`
`B.
`Patent Owner’s Arguments Fail To Rebut Obviousness
`Patent Owner argues that a POSA reading Belanoff ‘848 would not have
`
`been motivated to monitor mifepristone levels in evaluating efficiency, would have
`
`had no reasonable expectation of success, and would have been surprised that the
`
`1300 ng/mL level could be used to adjust dosing.
`
`Both the first and second arguments are belied by the teachings of Belanoff
`
`‘848, which draw a direct path for a POSA to monitor mifepristone blood levels
`
`and establish that a POSA would have a reasonable expectation of success in
`
`measuring those blood levels. Belanoff ‘848 discloses that glucocorticoid activity
`
`is related to delirium (i.e., mental illness); that inhibiting binding of cortisol using
`
`the glucocorticoid receptor antagonist mifepristone caused patients to improve; and
`
`that measurement of blood cortisol levels could help the POSA determine if the
`
`patient was improving. Exh. 1024, ¶¶ [0022], [0101]. With these three items, it
`
`would have been common sense for a POSA to look at the blood levels of the
`
` 
`
`8 
`
`

`

`glucocorticoid receptor antagonist (i.e., mifepristone) which is competing with
`
`cortisol in the first place. Indeed, Belanoff ‘848 discusses measurement of blood
`
`mifepristone levels immediately after discussing blood cortisol levels. Id., ¶¶
`
`[0036]- [0041].
`
`Performing blood level tests for mifepristone was known as early as 1987.
`
`Id., ¶ [0044]. A POSA with this information would have been motivated to
`
`examine the blood levels of the patient, which would result in discovery of the
`
`claimed 1300 ng/mL level. In re Ethicon, Inc., 844 F.3d 1344, 1351 (Fed. Cir.
`
`2017) (“normal desire of artisans to improve upon what is already generally
`
`known” can provide motivation to optimize variables). See also Biomarin
`
`Pharmaceutical Inc. v. Genzyme Therapeutic Products Limited Partnership, Case
`
`No. IPR2013-00534, 2015 WL 1009195 (Patent Tr. & App. Bd. Feb 23, 2015) at
`
`*7-8, citing In re Boesch, 617 F.2d 272, 276 (C.C.P.A. 1980) (the “discovery of an
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`optimum value of a result effective variable in a known process is ordinarily within
`
`the skill of the art”).
`
`Patent Owner’s argument based on POSA surprise fails as well. “Mere
`
`recognition of latent properties in the prior art does not render nonobvious an
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`otherwise known invention.” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed.
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`Cir. 1991) (citing In re Prindle, 297 F.2d 251 (C.C.P.A. 1962). Again, Belanoff
`
`‘848 disclosed mifepristone dosing in the same range as the ‘348 patent. Those
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`9 
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`exact dosing levels, when given in the ‘348 patent, resulted in the mifepristone
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`blood levels on which the claims of the ‘348 patent are based. That no one had
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`previously done a statistical analysis on mifepristone blood levels does not mean
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`that the properties of mifepristone in the blood are any less “latent.”
`
`The Board should find that Petitioner has carried its burden on Ground One
`
`and find the claims of the ‘848 patent unpatentable over Belanoff ‘848.
`
`IV. GROUND TWO
`A. The Board Correctly Found That Belanoff 2002, Chu and
`Belanoff and Sitruk-Ware Together Render the Claims Obvious
`“A method for optimizing levels of mifepristone in a patient
`suffering from a disorder amenable to treatment by
`mifepristone”
`The ID accepted Petitioner’s view that “other than identifying the [correct] patient
`
`1.
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`population… the preamble does not add any material limitations to the claim”.
`
`Paper No. 11 at 12. Patent Owner agrees, stating that the preamble’s “method for
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`optimizing levels of mifepristone” should be construed as “the process of testing
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`mifepristone blood levels and adjusting the dosage of mifepristone administered to
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`the patient in need in order to achieve mifepristone blood levels above 1300
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`ng/mL”, which recites nothing more than the limitations of the last two steps.
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`Paper No. 24 at 17-18.
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`10 
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`2.
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`“treating the patient with seven or more daily doses of
`mifepristone”
`The Board also accepted Petitioner’s view that Belanoff 2002 discloses the
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`first step of administering seven or more daily doses of mifepristone. Paper No. 11
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`at 13. Patent Owner does not disagree. Paper No. 24 at 23.
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`3.
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`“testing the serum levels of the patient to determine whether the
`blood levels of mifepristone are greater than 1300 ng/mL”
`It is indisputable that Sitruk-Ware discloses the second step of testing the
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`patient’s mifepristone blood serum levels. Exh. 1008 at 413 and Fig. 2. Rather
`
`than arguing it does not, Patent Owner challenges the accuracy of the
`
`measurement, the motivation for that measurement, as well as the use of such
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`measurements.
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`First, Patent Owner argues that the mifepristone serum level of 2.0 mg/L in
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`Sitruk-Ware derives from Figure 3, refers to the level of mifepristone plus its
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`metabolites, and is therefore invalid. Paper No. 24 at 28-29. However, that
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`number, as Dr. Derendorf acknowledges, is unequivocally derived from Figure 2
`
`in Sitruk-Ware, not Figure 3. See Exh. 1037 at 74:10-75:9. The graph in the upper
`
`left corner of Figure 2 (for the 600 mg dose) clearly shows a mifepristone level of
`
`about 4.8 mol/L (corresponding roughly to 2000 ng/mL, according to Patent
`
`Owner’s own conversion table (Exh. 2010)) at slightly over one hour. That
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`corresponds with the Petitioner’s cite (Paper No. 1 at 16), and clearly measures
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`11 
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`mifepristone alone, as its metabolites are shown in separate tables in the same
`
`figure. Exh. 1008, Fig. 2; Exh. 1037 at 74:23-75:9. The vertical axis on Figure 3,
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`whether showing mifepristone alone or with its metabolites, shows a maximum
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`value (for the 600 mg dose) of roughly 3.8 µmol/L, i.e., 1632 ng/mL using Patent
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`Owner’s molecular weight of 429.5 for mifepristone (Exh. 2010), at four hours.
`
`There is absolutely no way to derive the “2.0 mg/L at 1.35 h (tmax)” value from
`
`Figure 3, which renders Patent Owner’s entire argument on Figure 3 both
`
`meaningless and irrelevant.3
`
`Second, Patent Owner argues that the claim language requires steady-state
`
`measurement of mifepristone levels, and therefore prior art such as Sitruk-Ware,
`
`which reports Cmax data, is irrelevant. Paper No. 24 at 39-40. As explained above
`
`(see Section II.B., supra), this argument is based on an interpretation of the claim
`
`language completely unsupported by the specification or the file history. However,
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`even if the claims are limited to steady-state measurement, the art teaches steady-
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`state levels above 1300 ng/mL as well. See, e.g., Exh 1013, Figure 2 (showing
`
` 
`3 During the deposition of Petitioner’s Expert, Patent Owner’s attorney led Dr.
`Heikinheimo down a rabbit hole and through the looking glass, tracing Figure 3
`from the Sitruk-Ware review article back, one by one, through four earlier
`publications to argue the blood levels measured in Figure 3 included metabolites.
`But the cited 2.0 measure did not come from Figure 3, and Heikinheimo’s
`declaration never so stated. That the attorney was able to convince Dr.
`Heikinheimo otherwise during a wild goose chase is ultimately irrelevant; Figure 2
`of Sitruk-Ware speaks for itself.
`
` 
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`12 
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`Cmin’s of 3.6 and 3.8 mol/L for patients receiving 50 or 100 mg of mifepristone
`
`twice daily for four days, which corresponds roughly to 1540 and 1630 ng/mL,
`
`again using Patent Owner’s own conversion table (Exh. 2010)).
`
`Finally, Petitioner’s expert argues that testing blood levels must be done at
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`the trough level (i.e., Cmin). Exh. 1037 at 82:19-83:13. As with steady state, there
`
`is no support for testing mifepristone blood levels at any specific time, other than
`
`after “seven days.” Only a small subset of the possible measurement times would
`
`occur during the “trough” phase, and therefore only a small subset would actually
`
`measure Cmin. Accordingly, the claims and the specification give no direction to
`
`only look at Cmin levels.
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`4.
`
`“adjusting the daily dose of the patient…greater than 1300
`ng/mL”
`The Board found that Chu and Belanoff teaches the “adjusting” limitation of
`
`step 3 – although based on treatment response rather than serum levels. Paper No.
`
`11 at 17-18. However, the Board agreed with Petitioner that the “greater than 1300
`
`ng/mL” limitation in step 3 is found in the combination of Belanoff 2002 (which
`
`teaches that 600 and 1200 mg doses of mifepristone are efficacious) and Sitruk-
`
`Ware (which teaches that a single 600 mg dose of mifepristone results in a serum
`
`level above 1300 ng/mL). The Board concluded that it would have been obvious to
`
`adjust the dosage if serum levels fell below efficacious levels. Id. As with the
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` 
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`13 
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`

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`second step, Patent Owner disputes whether the “key 1300 ng/mL serum level” is
`
`in the prior art. Paper 21 at 18. But the Board’s ID chastised Patent Owner for the
`
`same argument, with only the word “efficacious” instead of “key” present. Paper
`
`11 at 15 (“Patent Owner argues that ‘none of the references teach or disclose the
`
`efficacious 1300 ng/mL serum level…Patent Owner cannot demonstrate the non-
`
`obviousness of the claimed method by attacking the prior art references
`
`individually”), 17 (applying same analysis to third step of claim). Nothing
`
`presented by Patent Owner compels a contrary conclusion.
`
`B.
`
`Patent Owner’s Extraneous Evidence Fails To Rebut The
`Conclusion of Obviousness
`Faced with these undeniable facts, Patent Owner makes every attempt to
`
`distract the Board with the following irrelevant issues and