`
`Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
`Paper 35
`Entered: February 10, 2020
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`NEPTUNE GENERICS, LLC,
`Petitioner,
`v.
`CORCEPT THERAPEUTICS, INC.,
`Patent Owner.
`____________
`
`IPR2018-01494
`Patent 8,921,348 B2
`____________
`
`
`Before TINA E. HULSE, ROBERT A. POLLOCK, and DAVID COTTA,
`Administrative Patent Judges.
`
`COTTA, Administrative Patent Judge.
`
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`
`35 U.S.C. § 318(a)
`
`
`
`
`
`
`
`

`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
` INTRODUCTION
`Neptune Generics, LLC (“Petitioner”) filed a Petition requesting an
`inter partes review of claims 1–7 of U.S. Patent No. 8,921,348 B2
`(Ex. 1001, “the ’348 patent”).1 Paper 1 (“Pet.”). Corcept Therapeutics, Inc.
`(“Patent Owner”) filed a Preliminary Response to the Petition. Paper 9
`(Prelim. Resp.).2
`Following our Institution Decision, Patent Owner filed a Response to
`the Petition (Paper 24, “PO Resp.”), Petitioner filed a Reply to Patent
`Owner’s Response (Paper 29, “Reply”), and Patent Owner filed a Sur-Reply
`(Paper 30, “Sur-Reply”). On November 19, 2019, the parties presented
`arguments at an oral hearing. The transcript of the hearing has been entered
`into the record. Paper 34 (“Tr.”).
`We have jurisdiction under 35 U.S.C. § 6. We issue this Final Written
`Decision pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. Based on
`the record before us, we conclude that Petitioner has not demonstrated by a
`preponderance of the evidence that claims 1–7 of the ’348 patent are
`unpatentable.
`
`
`
`
`
`1 Petitioner identifies Neptune Generics, LLC; Niagara Funding Co, LLC;
`GKC Partners II, LP; GKC General Partner II, LP; Burford Capital Ireland
`DAC; GKC PII Holdings, LLC; Burford Capital Investment Management
`LLC; Burford Capital Holdings (UK) Limited; and Burford Capital Limited
`as the real parties in interest (collectively, “RPI”). Paper 6, 2–3. Petitioner
`further represents that GKC Partners II, LP is now known as BCIM Partners
`II, LP, GKC General Partner II, LP is now known as BCIM General Partner
`II, LP, and GKC PII Holdings, LLC is now known as BCIM PII Holdings,
`LLC. Paper 28, 3.
`2 Patent Owner identifies Corcept Therapeutics, Inc. as the real party in
`interest. Paper 4, 1.
`
`2
`
`

`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`Related Proceedings
`A.
`Petitioner represents that it is unaware of any other matters related to
`the ’348 patent. Pet. 1. Patent Owner identifies Corcept Therapeutics, Inc.
`v. Teva Pharmaceuticals USA, Inc., No. 18-cv-03632-SDW (D.N.J. Mar. 15,
`2018), and Corcept Therapeutics, Inc. v. Sun Pharma Global FZE et al., No.
`19-cv-15678-SDW-CLW (D.N.J. July 22, 2019) as relating to the ’348
`patent. Paper 4, 1; Paper 27, 1.
`The ’348 Patent (Ex. 1001)
`B.
`The ’348 patent issued December 30, 2014, identifying Joseph K.
`Belanoff as the inventor. Ex. 1001. The patent discloses “a method for
`optimizing levels of mifepristone in a patient suffering from a mental
`disorder amenable to treatment by mifepristone.” Id. at Abstract.
`
`The ’348 patent teaches that “[i]t has been surprisingly discovered that
`administration of the same dose of mifepristone can produce widely varying
`blood serum levels in different patients,” which can result in “some patients
`not receiving an efficacious dose of mifepristone.” Id. at 1:28–32. “[T]he
`blood serum levels can differ by as much as 800% from one patient to
`another. Thus, a method for ensuring that blood serum levels of
`mifepristone remain in an efficacious and safe range is needed.” Id. at 1:33–
`36.
`According to the ’348 patent, the disclosed invention provides a
`
`method for optimizing mifepristone levels by treating the patient with seven
`or more doses for a period of seven or more days and then “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.” Id. at 1:40–49.
`
`3
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`Challenged Claims
`C.
`Petitioner challenges claims 1–7 of the ’348 patent. Claim 1 is
`representative and is reproduced below:
`
`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, 16:26–35.
`
`D. The Prosecution History
`We provide a discussion of the prosecution history of the ’348 patent
`for context given that one of the prior art references asserted in this
`proceeding (Belanoff ‘9533) was cited by the Examiner during prosecution.
`The application that issued as the ’348 patent (Application
`No. 14/065,792), was filed on October 29, 2013 with 8 original claims.
`Ex. 1002, 142. During prosecution, the Examiner entered an obviousness-
`type double patenting rejection over claims 1–7 of US Patent 8,598,149
`(“the ’149 patent”). Id. at 45–48. Patent Owner overcame this rejection by
`filing a terminal disclaimer. Id. at 20–32. No other rejections were entered.
`The application that issued as the ’348 patent was a continuation of
`Application No. 12/199,144 (“the ’144 application”), which issued as the
`’149 patent. The claims at issue in the ’144 application are very similar to
`
`
`3 Belanoff, US Patent No. 6,964,953, issued Nov. 15, 2005 (Ex. 1010,
`“Belanoff ’953”).
`
`4
`
`

`

`IPR2018-01494
`Patent 8,921,348 B2
`
`those in the issued ’348 patent.4 Accordingly, the ’144 application is
`informative as to the reasons why the Examiner allowed the ’348 patent.
`In an Office Action mailed August 3, 2011, the Examiner rejected the
`pending claims of the ’144 application as obvious under 35 U.S.C. § 103(a)
`over the combination of the Medical Encyclopedia of Medline,5 Sarkar,6 and
`Belanoff ’953. The Examiner found that the Medical Encyclopedia of
`Medline taught that “[t]herapeutic drug levels are usually performed to look
`for the presence and the amount of specific drug in the blood” and that
`“[w]ith most medications, a certain level of drug is needed in the blood
`stream to obtain the desired therapeutic effect.” Ex. 1003, 163. The
`Examiner found that Belanoff ’953 disclosed that mifepristone was useful
`for treating acute stress disorder and taught dosages of 1 to 10 mg/kg, which
`
`
`4 Claim 1 of the ’144 application, as originally filed, reads as follows:
`1.
`A method for optimizing levels of mifepristone in a patient
`suffering from a mental 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. 1003, 233 (emphasis added to reflect differences as compared to claim 1
`of the ’348 patent).
`5 U.S. National Library of Medicine, Medical Encyclopedia: Therapeutic
`Drug Levels, http://www.nlm.nih.gov/medlineplus/ency/article/003430.htm,
`(“Medical Encyclopedia of Medline”).
`6 Sarkar, Mifepristone: Bioavailability, Pharmacokinetics, and Use-
`Effectiveness, 101(2) European Journal of Obstetrics and Gynecology and
`Reproductive Biology, 113-120 (2002) (“Sarkar”).
`5
`
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`translates to 75–750 mg for an average adult weighing 75 kg. Id. The
`Examiner found that Sarkar taught that serum concentrations for a 100–200
`mg dose of mifepristone ranged from 1933.2–2276.88 ng/ml. Id.
`Based on the combination of the Medical Encyclopedia, Sarkar, and
`Belanoff ’953, the Examiner concluded that “[i]t would have been obvious
`to one of ordinary skill in the art at the time the invention was made to
`optimize the serum level of mefipristone [sic] in patients suffering from
`Acute Stress Disorder.” Id. The Examiner explained:
`One of ordinary skill in the art would have been motivated to
`optimize the serum level of mefipristone [sic] in patients
`suffering from Acute Stress Disorder. Adjusting the therapeutic
`serum levels to obtain a therapeutic effect is well-known in the
`art. Since both the serum concentration and the dosage of
`mifepristone useful in treating the Acute Stress Disorder are
`both well-known. Adjusting the serum level of mifepristone
`would be seen as equivalent to adjusting the dosage of
`mifepristone to effectively treat Acute Stress Disorder [and]
`would be reasonably expected to be successful.
`Id. at 163–164.
`
`In response to the August 3, 2011 Office Action, Patent Owner argued
`that the claimed method was non-obvious because mifepristone exhibits
`nonlinear serum pharmacokinetics in humans and thus it was “unpredictable
`what mifepristone serum concentration would provide an effective treatment
`for mental disorders.” Id. at 146; see also generally id. at 145–148. In an
`April 4, 2012, Office Action, the Examiner rejected these arguments
`explaining that it was “well-known that mifepristone [dose] and the serum
`level are positively correlated, i.e., increasing the dose will increase the
`serum level.” Id. at 135–136.
`
`In response to the April 4, 2012, Office Action, Patent Owner argued
`that the data the Examiner relied upon to correlate mifepristone dosage with
`
`6
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`serum levels was unreliable because it “was obtained using a
`radioimmunoassay, which is unable to distinguish between mifepristone and
`mifepristone’s metabolites.” Id. at 64. According to Patent Owner, this
`contrasts with what was disclosed in the ’144 application, which was to
`measure mifepristone serum levels using “High Pressure Liquid
`Chromatography (HPLC) methods capable of separating mifepristone from
`its metabolites and accurately measuring mifepristone serum levels.” Id. at
`65 (emphasis omitted). Patent Owner thus argued that
`[i]n view of the inability of [radioimmunoassay] and [radio
`receptor assay] detection methods to distinguish mifepristone
`from its metabolites . . . there is no reasonable expectation of
`success for identifying 1300 ng/ml as the serum level of
`mifepristone only necessary to treat a patient suffering from a
`mental disorder amenable to treatment by mifepristone.
`Id. at 68.
`
`In a May 24, 2013 Office Action, the Examiner indicated that Patent
`Owner’s arguments were persuasive. The Examiner stated:
`The method of using the mifepristone level for adjusting the
`treatment of mental disorder is not taught or fairly suggested by
`the prior art. Although the effective dosages of mifepristone for
`treating mental disorders are known, the correlation of the level
`of mifepristone to the therapeutic effectiveness of mifepristone
`is not known.
`Id. at 52; see also id. at 34 (Notice of Allowability).
`D. The Asserted Ground of Unpatentability
`Petitioner challenges the patentability of claims 1‒7 of the ’348 patent
`on the following grounds:
`
`7
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`35 U.S.C. § Reference(s)/Basis
`
`Claim(s)
`Challenged
`1, 2, 4, 6, 7
`1, 2, 4, 6, 7
`
`3
`
`5
`
`3
`5
`
`§ 103(a)7
`§ 103(a)
`
`§ 103(a)
`
`§ 103(a)
`
`§ 103(a)
`§ 103(a)
`
`Belanoff ’8488
`Belanoff 2002, Sitruk-Ware,9 Chu and
`Belanoff10
`Belanoff 2002, Sitruk-Ware, Chu and
`Belanoff, Belanoff ’953
`Belanoff 2002, Sitruk-Ware, Chu and
`Belanoff, Murphy11
`Belanoff ’848, Belanoff ’953
`Belanoff ’848, Murphy
`
`Petitioner submits the Declaration of Dr. Mikko A. Oskari
`Heikinheimo (Ex. 1004) in support of the Petition. Patent Owner submits
`the Declarations of Dr. Hartmut Derendorf (Ex. 2014) and Dr. Ned. H. Kalin
`(Ex. 2016) in support of its Response to the Petition.
`
`
`7 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
`Stat. 284, 287 (2011), amended 35 U.S.C. § 103. Because the application
`from which the ’348 patent issued has an effective filing date before March
`16, 2013, the effective date of the relevant amendment, the pre-AIA version
`of § 103 applies.
`8 Belanoff, US Patent Publication No. 2004/0029848 A1, published
`Feb. 12, 2004 (Ex. 1024, “Belanoff ’848”).
`9 Sitruk-Ware et al., Pharmacological Properties of Mifepristone:
`Toxicology and Safety in Animal and Human Studies, 68 Contraception 409–
`420 (2003) (Ex. 1008, “Sitruk-Ware”).
`10 Chu et al., Successful Long-Term Treatment of Refractory Cushing’s
`Disease with High-Dose Mifepristone (RU 486), 86(8) Journal of Clinical
`Endocrinology & Metabolism 3568–3573 (2001) (Ex. 1023, “Chu and
`Belanoff”).
`11 Murphy et al., Possible Use of Glucocorticoid Receptor Agonists in the
`Treatment of Major Depression: Preliminary Results Using RU 486, 18(5)
`J. Psychiatr. Neurosci. 209–213 (1993) (Ex. 1006, “Murphy”).
`8
`
`

`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
` ANALYSIS
`Person of Ordinary Skill in the Art
`A.
`Factual indicators of the level of ordinary skill in the art include “the
`various prior art approaches employed, the types of problems encountered in
`the art, the rapidity with which innovations are made, the sophistication of
`the technology involved, and the educational background of those actively
`working in the field.” Jacobson Bros., Inc. v. U.S., 512 F.2d 1065, 1071 (Ct.
`Cl. 1975); see also Orthopedic Equip. Co., v. U.S., 702 F.2d 1005, 1011
`(Fed. Cir. 1983) (quoting with approval Jacobson Bros.).
`Petitioner contends that the person of ordinary skill in the art
`(“POSA”) would have:
`either a Pharm. D. or a Ph.D. in organic chemistry, pharmacy,
`pharmacology, or a related discipline; or a Bachelor’s or
`Master’s degree in organic chemistry or a related field with at
`least four years of experience relating to the study of
`pharmacokinetics or dosing of drugs, their detection and
`quantification, or their metabolism.
`Pet. 12. Patent Owner does not challenge Petitioner’s definition.
`Accordingly, we accept Petitioner’s definition, which is consistent with the
`level of skill reflected in the asserted prior art references. See Okajima v.
`Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (the prior art itself can
`reflect the appropriate level of ordinary skill in the art).
`B.
`Claim Construction
`We interpret claims of an unexpired patent using the “broadest
`reasonable construction in light of the specification of the patent in which
`[they] appear[].” 37 C.F.R. § 42.100(b) (2018); see also Cuozzo Speed
`
`9
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`

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`Patent 8,921,348 B2
`
`Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016).12 Under the broadest
`reasonable construction standard, claim terms are generally given their
`ordinary and customary meaning as would be understood by one of ordinary
`skill in the art at the time of the invention. In re Translogic Tech., Inc., 504
`F.3d 1249, 1257 (Fed. Cir. 2007). “Absent claim language carrying a
`narrow meaning, the PTO should only limit the claim based on the
`specification . . . when [it] expressly disclaim[s] the broader definition.” In
`re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004).
`Although the parties propose constructions for several claim terms
`(Pet. 12–15; PO Resp. 17–18), we determine that no explicit construction of
`any claim term is necessary to resolve this case. See Nidec Motor Corp. v.
`Zhongshan Broad Ocean Motor Co. Ltd., 868 F.3d 1013, 1017 (Fed. Cir.
`2017) (“[W]e need only construe terms ‘that are in controversy, and only to
`the extent necessary to resolve the controversy’” (quoting Vivid Techs., Inc.
`v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999))); Wellman,
`Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim
`terms need only be construed ‘to the extent necessary to resolve the
`controversy’”).
`
`
`12 The broadest reasonable interpretation (“BRI”) construction standard
`applies to inter partes reviews filed before November 13, 2018. 77 Fed.
`Reg. 48,727 (Aug. 14, 2012) (codified at 37 C.F.R. § 42.100(b)), as
`amended at 81 Fed. Reg. 18766 (Apr. 1, 2016); see also 83 Fed. Reg. 51,340
`(Oct. 11, 2018) (changing the standard for interpreting claims in inter partes
`reviews filed on or after November 13, 2018). Because the Petition was
`filed prior to this date, on August 2, 2018, the BRI construction standard
`applies.
`
`10
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`C.
`
`Principles of Law
`
`To prevail in this inter partes review of the challenged claims,
`Petitioner must prove unpatentability by a preponderance of the evidence.
`35 U.S.C. § 316(e) (2012); 37 C.F.R. § 42.1(d).
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are such that
`the subject matter, as a whole, would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations, including (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of skill in the art; and (4) objective evidence of nonobviousness.
`Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`We analyze the instituted grounds of unpatentability in accordance
`with the above-stated principles.
`D. Ground 1: Obviousness of Claims 1, 2, 4, 6, and 7 over Belanoff ’848
`Petitioner asserts that claims 1, 2, 4, 6, and 7 would have been
`obvious over Belanoff ’848. See Pet. 25–32. We have considered the
`question of patentability in view of all the evidence and arguments presented
`in this proceeding. Based on the record developed during this proceeding,
`we determine that Petitioner has not shown by a preponderance of the
`evidence that claims 1, 2, 4, 6, and 7 would have been obvious over Belanoff
`’848.
`
`11
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`
`i. Disclosures of the Asserted Prior Art
`
`Belanoff ’848
`
`Belanoff ’848 discloses administering mifepristone in dosages of 600–
`
`1200 mg daily for one week to treat delirium. Ex. 1024, ¶¶ 94–96. Dosages
`may be “adjusted if necessary.” Id. ¶ 96. “The dosage regimen . . . takes
`into consideration pharmacokinetics parameters well known in the art, i.e.,
`the GR [glucocorticoid receptor] antagonists’ rate of absorption,
`bioavailability, metabolism, clearance, and the like.” Id. ¶ 88. According to
`Belanoff ’848, it was known in the art to “determine the dosage regimen for
`each individual patient, GR antagonist and disease or condition treated.” Id.
`Belanoff ’848 discloses that “it may be necessary to measure blood and
`urine levels of GR antagonist” and that “[m]eans for such monitoring are
`well described in the scientific and patent literature.” Id. ¶ 41. But Belanoff
`’848 also teaches that “[t]o delineate and assess the effectiveness of
`mifepristone in ameliorating the symptoms of delirium, formal psychiatric
`assessment and a battery of neuro-psychological tests and assessments are
`administered to all patients.” Id. ¶ 99. Belanoff ’848 teaches that “[t]hese
`tests and diagnostic assessments take place at baseline (patient’s entry into
`treatment) and periodically throughout treatment.” Id.
`
`ii.
`
`Analysis
`
`Claim 1, the only independent claim in the ’348 patent, requires
`“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 levels greater than 1300 ng/mL.” Ex.
`1001, 16:31–35. With respect to the “greater than 1300 ng/mL” threshold
`
`12
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`

`IPR2018-01494
`Patent 8,921,348 B2
`
`recited in claim 1, the position set forth in the Petition, in its entirety, reads
`as follows:
`
`The only missing claim element from Belanoff ‘848 is the
`desired serum level (1300 ng/mL) of mifepristone. However, it
`is well-settled that optimization of a range or other variable
`within a claim that flows from the “normal desire of scientists
`or artisans to improve upon what is already generally known” is
`prima facie obvious. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d
`1348, 1368-69 (Fed. Cir. 2007) (citing, inter alia, In re
`Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003); In re Aller, 42
`C.C.P.A. 824, 220 F.2d 454, 456 (1955); In re Boesch, 617
`F.2d 272, 276 (C.C.P.A. 1980); In re Geisler, 116 F.3d 1465,
`1470 (Fed. Cir. 1997); In re Kulling, 897 F.2d 1147, 1149 (Fed.
`Cir. 1990)).
`
`Belanoff ‘848 certainly gives a range of mifepristone oral
`dosage levels. (See Ex. 1024 at [0096] (600-1200 mg/day))
`These dosage levels inherently translate directly into
`mifepristone serum levels. See, e.g., Santarus, Inc. v. Par
`Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012) (“The initial
`blood serum concentration resulting from administering a PPI
`dosage is an inherent property of the formulation.”). In fact, the
`mifepristone dosage level ranges taught by Belanoff ‘848 are
`exactly the same as the mifepristone dosage level ranges that
`are taught by the ‘348 Patent. The clinical studies described in
`the ‘348 Patent show mifepristone dosage levels of 300, 600,
`and 1200 mg/day. (Ex. 1001 at. 13:50 through 15:54)[.] Those
`dosages resulted in serum levels over 1357 ng/mL in 269 of 443
`patients, and serum levels over 1661 ng/mL in 166 of 443
`patients (id. at Figs. 1-3). [E]ven higher patient percentages
`above those serum levels at the 1200 mg/day mifepristone
`dosage level (id. at Figs. 4-6).
`
`Accordingly, administration of mifepristone at the dosage
`levels taught by Belanoff ‘848 would necessarily and inevitably
`result in a range of blood serum concentrations that achieve
`mifepristone blood levels greater than 1300 ng/mL as claimed.
`(Ex. 1004 at ¶20)[.] It would have been readily obvious to one
`
`13
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`
`
`of ordinary skill in the art with a very high expectation of
`success that the daily dosing of the patient could be adjusted to
`optimize mifepristone blood level, whatever level that might be.
`(Id.)[.]
`
`Id. at 29–30.
`“In an inter partes review . . . , the petitioner shall have the burden of
`proving a proposition of unpatentability by a preponderance of the
`evidence.” 35 U.S.C. § 316(e); In re Magnum Oil Tools Int’l, Ltd., 829 F.3d
`1364, 1375 (Fed. Cir. 2016). Petitioner has not met this burden here because
`the Petition does not clearly articulate why an optimization rationale would
`have led the skilled artisan to “adjust[] the daily dose of the patient to
`achieve mifepristone blood levels greater than 1300 ng/mL.”
`We analyze the positions set forth in the Petition with respect to this
`limitation in the order set forth in the Petition. Petitioner begins by asserting
`that “optimization of a range or other variable within a claim that flows from
`the ‘normal desire of scientists or artisans to improve upon what is already
`generally known’ is prima facie obvious.” Pet. 29 (citing case law). This
`argument is not persuasive because Petitioner does not establish that
`Belanoff ’848 discloses a range of blood serum levels.
`Recognizing this deficiency, Petitioner next asserts that Belanoff ‘848
`provides a range of oral dosages and that these dosages “inherently translate
`directly into mifepristone serum levels.” Id. We acknowledge that Belanoff
`’848 discloses a range of oral doses. The record, however, does not support
`that administration of mifepristone at the levels disclosed in Belanoff ’848
`would inherently translate into a range of blood serum concentrations that
`achieve mifepristone blood levels greater than 1300 ng/mL as claimed. To
`the contrary, the record supports that blood serum levels were known not to
`
`14
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`
`correlate with dosage. Ex. 1004, Heikinheimo Decl. ¶ 25 (“It is in no way
`surprising that administration of the same dose of mifepristone can produce
`widely varying blood serum levels in different patients.”); Pet. 48
`(“administration of the same dose of mifepristone can produce widely
`varying blood serum levels in different patients.”); Ex. 1001, 1:33–34 (“For
`the same dose of mifepristone, the blood serum levels can differ by as much
`as 800% from one patient to another.”). Accordingly, administration of the
`dosages taught in Belanoff may, or may not, result in blood serum levels
`greater than 1300 ng/ml as claimed. To establish that a prior art reference
`inherently teaches a claim limitation, however, Petitioner must show that
`“the limitation at issue necessarily must be present, or [is] the natural result
`of the combination of elements explicitly disclosed by the prior art.” PAR
`Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186, 1196 (Fed. Cir. 2014).
`Petitioner has failed to make that showing.
`Finally, Petitioner asserts that it would have been obvious that “the
`daily dosing of the patient could be adjusted to optimize mifepristone blood
`level, whatever level that might be.” Pet. 30. This argument is not
`persuasive for several reasons. First, Petitioner must do more than show that
`the ordinary artisan could have done what was claimed. Belden Inc. v.
`Berk–Tek LLC, 805 F.3d 1064, 1073 (Fed. Cir. 2015) (“[O]bviousness
`concerns whether a skilled artisan not only could have made but would have
`been motivated to make the combinations or modifications of prior art to
`arrive at the claimed invention.”).
`Second, the testimony of Petitioner’s own expert calls into question
`whether a POSA could indeed have optimized serum levels by adjusting
`dosing (and whether a POSA would have seen value in doing so). Ex. 2009,
`
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`48:15–49:19 (Dr. Heikenhimo testimony that, absent a clinical trial, a POSA
`would have no reason to expect that they could adjust the dose of
`mifepristone to increase serum level); id. at 135:15–21 (Dr. Heikenhimo
`deposition testimony on redirect examination that he has not “seen any
`scientific evidence” that adjusting the daily dose of mifepristone to levels
`greater than 1,300 nanograms per milliliter “would be of clinical value or
`that it could be done”); Ex. 1013, 24–25 (article coauthored by Dr.
`Heikenhimo stating that “due to saturation of the serum binding capacity for
`[mifepristone], the quantitation of [mifepristone] in serum following intake
`of doses exceeding 50 mg may not be very informative.”); see also Ex. 1012
`(article coauthored by Dr. Heikenhimo reporting that prior studies have
`shown that doses above 400 mg are needed to promote antiglucocorticoid
`effects and stating “[i]n view of the fact that plasma concentrations of
`[mifepristone] are not elevated by increasing the oral dose of [mifepristone]
`from 100 to 800 mg, . . . it still remains an enigma why systemic
`antiglucocorticoidal effects are virtually never seen at [mifepristone] doses
`below 400 mg”).
`Third, even Belanoff ’848 relied upon psychological testing rather
`than blood serum levels to assess the effectiveness of mifepristone and
`adjust the dose. Ex. 1024, ¶¶ 95–99; Ex. 2014, ¶¶ 145–149; Ex. 2016 ¶¶ 36–
`38. Specifically, Belanoff ’848 teaches that mifepristone is administered in
`dosages of 600–1200 mg daily for one week and then the patients are
`evaluated through “a battery of neuro-psychological tests and assessments.”
`Ex. 1024 ¶ 99. Belanoff ’848 further teaches that “[d]osages will be
`adjusted if necessary and further evaluations will be performed periodically
`throughout treatment” as a result of the assessments. Id. ¶ 96.
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`Finally, Petitioner provides no explanation of how or why the ability
`to optimize blood serum levels would have led the ordinary artisan to adjust
`the daily dose of mifepristone administered to achieve the claimed serum
`levels. See Pet. 29–30. Rather, Petitioner and Dr. Heikinheimo conclusorily
`state that “[i]t would have been readily obvious to one of ordinary skill in
`the art with a very high expectation of success that the daily dosing of the
`patient could be adjusted to optimize mifepristone blood level, whatever
`level that might be.” Id. at 30; Ex. 1004 ¶ 20.
`We recognize that Belanoff ’848 teaches that it “may be necessary” to
`measure serum levels and discloses that the dosing regimen takes
`pharmacokinetic parameters into consideration. Ex. 1024 ¶¶ 41, 88. But,
`Petitioner’s own expert, Dr. Heikinheimo concedes that the disclosure in
`Belanof ’848 of measuring plasma concentrations (Ex. 1024 ¶ 41) teaches
`only that “a very vague laboratory test may be used, may by useful.”
`Ex. 2009, 131:9–10. Dr. Heikinheimo further testified that the sentence in
`Belanoff ’848 disclosing measurement of plasma concentrations was a “very
`general sentence” and that “[i]t dosen’t really say anything very specific.”
`Id. at 131:5, 10–11. Even assuming that Belanoff ’848 supports a
`motivation to measure blood serum levels, it is not clear how this motivation
`would lead the POSA to adjust the dose to achieve the specific claimed
`blood serum levels. Petitioner must do more than establish a motivation to
`measure blood serum levels in order to render obvious the limitation
`requiring “adjusting the daily dose of the patient to achieve mifepristone
`blood levels greater than 1300 ng/mL.” Petitioner must explain why the
`motivation to test blood serum levels would cause the ordinary artisan to
`adjust mifepristone dosing to achieve a particular serum level.
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`Considering all of the arguments and evidence provided in the Petition
`with respect to this limitation together, Petitioner does little more than assert
`– without explanation – that the ordinary artisan would have arrived at this
`limitation through routine optimization. Our decision thus turns on whether
`Petitioner can carry its burden to establish that it would have been obvious to
`adjust the dose of mifepristone to attain the claimed serum levels simply by
`invoking the desire of the ordinary artisan to optimize. Our reviewing court
`has instructed that more is required. In re Stepan Co., 868 F.3d 1342, 1346
`(Fed. Cir. 2017) (explaining that there must be “some rational underpinning
`explaining why a person of ordinary skill in the art would have arrived at the
`claimed invention through routine optimization”); see also KSR, 550 U.S. at
`418 (explaining that “rejections on obviousness grounds cannot be sustained
`by mere conclusory statements; instead, there must be some articulated
`reasoning with some rational underpinning to support the legal conclusion of
`obviousness”). Here, we find that Petitioner’s invocation of a desire to
`optimize is not sufficient to render the “adjusting the dose” limitation
`obvious, particularly given that: 1) Petitioner has not established that
`Belanoff ’848 discloses a range of blood serum concentrations, 2) blood
`serum levels were known not to correlate with dosage, 3) Petitioner’s own
`expert questioned the ability of the POSA to adjust serum levels and the
`value in making such adjustments, and 4) Belanoff ’848 relied upon
`psychological testing rather than blood serum levels to adjust dose.
`In sum, for the reasons given above, Petitioner has not established, by
`a preponderance of the evidence, that Belanoff ’848 would have rendered
`the challenged claims obvious.
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`E. Ground 2: Obviousness of Claims 1, 2, 4, 6, and 7 over Belanoff 2002,
`Chu and Belanoff, and Sitruk-Ware
`
`
`
`Petitioner asserts that claims 1, 2, 4, 6, and 7 are rendered obvious by
`the combination of Belanoff 2002, Chu and Belanoff, and Sitruk-Ware.
`Pet. 32–42. We have considered the question of patentability in view of all
`the evidence and arguments presented in this proceeding. Based on the
`record developed during this pro