Case: 21-1360 Document: 34 Page: 1 Filed: 12/07/2021
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`
`
`United States Court of Appeals
`for the Federal Circuit
`______________________
`
`TEVA PHARMACEUTICALS USA, INC.,
`Appellant
`
`v.
`
`CORCEPT THERAPEUTICS, INC.,
`Appellee
`______________________
`
`2021-1360
`______________________
`
`Appeal from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in No. PGR2019-
`00048.
`
`______________________
`
`Decided: December 7, 2021
`______________________
`
`JOHN CHRISTOPHER ROZENDAAL, Sterne Kessler Gold-
`stein & Fox, PLLC, Washington, DC, argued for appellant.
`Also represented by UMA EVERETT, WILLIAM MILLIKEN,
`OLGA A. PARTINGTON, DEBORAH STERLING.
`
` ERIC C. STOPS, Quinn Emanuel Urquhart & Sullivan,
`LLP, New York, NY, argued for appellee. Also represented
`by WILLIAM ADAMS, FRANK CHARLES CALVOSA, FRANCIS
`DOMINIC CERRITO, DANIEL C. WIESNER.
` ______________________
`
`
`

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`Case: 21-1360 Document: 34 Page: 2 Filed: 12/07/2021
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`TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC.
`
`Before MOORE, Chief Judge, NEWMAN and REYNA, Circuit
`Judges.
`
`MOORE, Chief Judge.
`In a final-written decision, the Patent Trial and Appeal
`Board held that Teva Pharmaceuticals USA had failed to
`show claims 1–13 of U.S. Patent No. 10,195,214 would have
`been obvious. Teva Pharms. USA, Inc. v. Corcept Thera-
`peutics, Inc., PGR2019-00048, 2020 WL 6809812 (P.T.A.B.
`Nov. 18, 2020) (Final Decision). Teva appeals, arguing the
`Board misapplied our obviousness law.1 For the following
`reasons, we affirm.
`
`I
`A
`In the 1980s, mifepristone was developed as an anti-
`progestin. See J.A. 1009. But researchers soon realized
`mifepristone functions as a glucocorticoid reception antag-
`onist, meaning it likely inhibits the effect of cortisol on tis-
`sues by competing with cortisol for receptor binding sites.
`See J.A. 870, 1037. As a result, they suggested using mif-
`epristone to treat Cushing’s syndrome, a disease caused by
`excessive levels of cortisol. J.A. 1034–38.
`More than 20 years later, Corcept Therapeutics, Inc.,
`initiated the first major clinical trial of mifepristone in pa-
`tients with Cushing’s syndrome. J.A. 1252. Over a 24-
`week period, 50 participants were given one daily dose of
`mifepristone, starting at a dosage of 300 mg per day and
`possibly increasing to a maximum dosage of 1200 mg per
`day. J.A. 1259. That administration “produced significant
`clinical and metabolic improvement in patients with
`[Cushing’s syndrome] with an acceptable risk-benefit
`
`1 Teva also argues that, under the correct standards,
`the challenged claims would have been obvious. Because
`we discern no legal error, we need not reach that argument.
`
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`Case: 21-1360 Document: 34 Page: 3 Filed: 12/07/2021
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`TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC. 3
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`profile during 6 months of treatment.” J.A. 1259; accord
`J.A. 1259–61.
`Based on its successful study, Corcept filed a New Drug
`Application (NDA) for Korlym, a 300 mg mifepristone tab-
`let. It sought approval for the administration of Korlym to
`control “hyperglycemia secondary to hypercortisolism” in
`certain patients with Cushing’s syndrome. J.A. 982. The
`U.S. Food and Drug Administration approved Corcept’s ap-
`plication, but imposed a few postmarketing requirements
`under 21 U.S.C. § 355(o)(3). One requirement was to con-
`duct “[a] drug-drug interaction clinical trial to determine a
`quantitative estimate of the change in exposure of mife-
`pristone following co-administration of ketoconazole (a
`strong CYP3A4 inhibitor).” J.A. 984.
`To summarize the drug-drug interaction study require-
`ment, the FDA provided Corcept with an Office of Clinical
`Pharmacology memorandum. See J.A. 865–900 (hereinaf-
`ter, Lee). That memorandum explained that “[t]he degree
`of change in exposure of mifepristone when co-adminis-
`tered with strong CYP3A inhibitors is unknown . . . .”
`J.A. 865. Thus, Lee noted that co-administration “may pre-
`sent a safety risk” and that, without a drug-drug interac-
`tion study, a “lack of accurate knowledge” may “deprive the
`patients on strong inhibitors [of] the use of [m]ifepristone.”
`Id. Lee also noted that, “[b]ased on the results of this
`study, the effect of moderate CYP3A inhibitors on mifepris-
`tone pharmacokinetics may need to be addressed.”
`J.A. 866.
`In approving Corcept’s NDA, the FDA also approved
`the prescribing information for Korlym contained in its la-
`bel. J.A. 839–49. The FDA-approved Korlym label “recom-
`mended [a] starting dose [of] 300 mg once daily” and
`allowed for increasing the dosage “in 300 mg increments to
`a maximum of 1200 mg once daily” based on clinical assess-
`ments. J.A. 839. In addition to those conditions, the Kor-
`lym label warned against using mifepristone “with strong
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`TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC.
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`CYP3A inhibitors” and limited the “mifepristone dose to
`300 mg per day when used with strong CYP3A inhibitors.”
`J.A. 839.
`
`B
`Corcept conducted the drug-drug interaction study de-
`scribed in Lee, collecting data on co-administration of mif-
`epristone with a strong CYP3A inhibitor. Based on that
`data, Corcept sought and received the ’214 patent. The ’214
`patent relates to methods of treating Cushing’s syndrome
`by co-administering mifepristone and a strong CYP3A in-
`hibitor. Claim 1 is representative for purposes of this ap-
`peal:
`A method of treating Cushing’s syndrome in a pa-
`tient who is taking an original once-daily dose of
`1200 mg or 900 mg per day of mifepristone, com-
`prising the steps of:
`reducing the original once-daily dose to an
`adjusted once-daily dose of 600 mg mife-
`pristone,
`administering the adjusted once-daily dose
`of 600 mg mifepristone and a strong
`CYP3A inhibitor to the patient,
`wherein said strong CYP3A inhibitor is se-
`lected from the group consisting of ketocon-
`azole, itraconazole, nefazodone, ritonavir,
`nelfmavir, indinavir, boceprevir, clarithro-
`mycin, conivaptan, lopinavir, posaconazole,
`saquinavir, telaprevir, cobicistat, trolean-
`domycin,
`tipranivir, paritaprevir, and
`voriconazole.
`After Corcept asserted the ’214 patent against Teva in
`district court, Teva sought post-grant review of claims 1–
`13. Teva argued those claims would have been obvious in
`light of Korlym’s label and Lee, optionally in combination
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`TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC. 5
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`with FDA guidance on drug-drug interaction studies. In
`support of its petition, Teva provided a declaration from
`Dr. David J. Greenblatt. Most relevant here, Dr. Green-
`blatt opined that, based on the Korlym label and Lee, “it
`was reasonably likely that 600 mg [per day of mifepristone]
`would be well tolerated and therapeutically effective when
`co-administered with a strong CYP3A inhibitor.” J.A. 681.
`The Board instituted review on all asserted grounds.
`In its final-written decision, the Board held Teva had
`failed to prove claims 1–13 would have been obvious to a
`skilled artisan. It first construed the claims to require safe
`administration of mifepristone. Final Decision at *7–9.
`Then, the Board found Teva failed to show that a skilled
`artisan would have had a reasonable expectation of success
`for safe co-administration of more than 300 mg of mifepris-
`tone with a strong CYP3A inhibitor. Id. at *10–22. In do-
`ing so, it discredited the above-quoted statement from
`Dr. Greenblatt, finding it inconsistent with his later testi-
`mony and other evidence in the record. Teva appeals. We
`have jurisdiction under 28 U.S.C. § 1295(a)(4).
`II
`Teva faults the Board for, in its view, committing two
`legal errors. First, it claims the Board required precise pre-
`dictability, rather than a reasonable expectation of success,
`in achieving the claimed invention. That is, Teva argues
`the Board improperly required it “to show an expectation
`that the specific dose recited in the claims would have been
`safe.” Appellant’s Br. at 41. Second, Teva claims the Board
`ought to have applied our prior-art-range precedents. In
`Teva’s view, the Board committed legal error when it found
`Teva had failed to prove the general working conditions
`disclosed in the prior art encompassed the claimed inven-
`tion. We do not agree.
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`TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC.
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`A
`We start by addressing Teva’s reasonable-expectation-
`of-success argument. “The presence or absence of a reason-
`able expectation of success is . . . a question of fact,” which
`we review for substantial evidence. Intelligent Bio-Sys.,
`Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1366 (Fed.
`Cir. 2016). Whether the Board applied the correct stand-
`ard in assessing reasonable expectation of success, how-
`ever, is a question of law that we review de novo. See Endo
`Pharms. Inc. v. Actavis LLC, 922 F.3d 1365, 1377–78 (Fed.
`Cir. 2019).
`The Board did not err by requiring Teva to show a rea-
`sonable expectation of success for a specific mifepristone
`dosage. The reasonable-expectation-of-success analysis
`must be tied to the scope of the claimed invention. See Al-
`lergan, Inc. v. Apotex Inc., 754 F.3d 952, 966 (Fed. Cir.
`2014) (“[F]ailure to consider the appropriate scope of the
`. . . claimed invention in evaluating the reasonable expec-
`tation of success . . . constitutes a legal error . . . .”); see also
`Intelligent Bio-Sys., Inc., 821 F.3d at 1367. Here, claim 1
`of the ’214 patent requires safe administration of a specific
`amount of mifepristone, 600 mg per day. See Final Deci-
`sion at *7–9 (construing claims to require safe administra-
`tion, rather than just administration). Thus, the Board
`was required to frame its reasonable-expectation-of-suc-
`cess analysis around that specific dosage of mifepristone.
`To be clear, this does not mean Teva was required to prove
`a skilled artisan would have precisely predicted safe co-ad-
`ministration of 600 mg of mifepristone. Absolute predicta-
`bility is not required. See, e.g., Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348, 1364 (Fed. Cir. 2007). But Teva was re-
`quired to prove a reasonable expectation of success in
`achieving the specific invention claimed, a 600 mg dosage.
`Applying that standard, the Board found Teva had
`failed to prove a reasonable expectation of success. It found
`that Teva had “not established . . . that [a skilled artisan]
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`TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC. 7
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`would reasonably have expected co-administration of more
`than 300 mg of mifepristone with a strong CYP3A inhibitor
`to be safe for the treatment of Cushing’s syndrome or re-
`lated symptoms in patients.” Final Decision at *22; see also
`id. at *10–22. It went even further, finding “the evidence
`support[ed] that [a skilled artisan] would have had no ex-
`pectation as to whether co-administering dosages of mife-
`pristone above the 300 mg/day threshold set forth in the
`Korlym label would be successful.” Id. at *20 (emphasis
`added). Because there was no expectation of success for
`any dosage over 300 mg per day, there was no expectation
`of success for the specific 600 mg per day dosage. See id. at
`*14 (finding no expectation of success for 600 mg per day
`dosage). Under our precedent, those findings were dispos-
`itive. Honeywell Int’l Inc. v. Mexichem Amanco Holding
`S.A. DE C.V., 865 F.3d 1348, 1356 (Fed. Cir. 2017) (holding
`the reasonable-expectation-of-success requirement is not
`satisfied when the skilled artisan would have had no ex-
`pectation of success). Nothing about this analysis required
`precise predictability, only a reasonable expectation of suc-
`cess tied to the claimed invention.
`The Board’s treatment of Dr. Greenblatt’s testimony is
`similar. Before institution, Dr. Greenblatt opined that “it
`was reasonably likely that 600 mg [per day of mifepristone]
`would be well tolerated and therapeutically effective when
`co-administered with a strong CYP3A inhibitor.” J.A. 681
`(emphasis added). But the Board discredited that opinion
`based on Dr. Greenblatt’s later, inconsistent testimony
`that “unequivocally” stated a skilled artisan “would have
`no expectation as to whether the co-administration of 600
`mg of mifepristone with ketoconazole would be safe.” Final
`Decision at *11 (emphasis added) (discussing testimony at
`J.A. 5493–94). The Board found the later testimony, unlike
`Dr. Greenblatt’s pre-institution testimony, was consistent
`with his other deposition testimony, id. at *12 (discussing
`J.A. 5511); his post-deposition declaration, id. (discussing
`J.A. 3096–97); and other evidence in the record, id. at *14
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`TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC.
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`(citing J.A. 1164–66 (Dr. Greenblatt article), 3111 (Dr.
`Dobbs declaration), 3433 (Dr. Guengerich testimony)). The
`Board then considered and rejected Teva’s attempt to
`square Dr. Greenblatt’s declaration with his deposition tes-
`timony. Id. at *13–14. Put simply, the Board found
`Dr. Greenblatt’s testimony supported a finding of no expec-
`tation of success in achieving the claimed invention, not
`that Dr. Greenblatt had failed to show the specific claimed
`dosage was absolutely predictable in advance.2
`In sum, we see no reversible error in the Board’s rea-
`sonable-expectation-of-success analysis. The Board ap-
`plied the correct standard, requiring only a reasonable
`expectation of success and tying its analysis to the scope of
`the claimed invention.
`
`B
`We next address the applicability of our prior-art-range
`cases—i.e., the cases in which a claimed range of values
`overlap the ranges disclosed in the prior art. The Board
`declined to apply those cases because it found Teva had
`failed to prove the general working conditions disclosed in
`the prior art encompass the claimed invention. The scope
`and content of the prior art is a question of fact, reviewed
`for substantial evidence. SIPCO, LLC v. Emerson Elec.
`Co., 980 F.3d 865, 870 (Fed. Cir. 2020).
`“For decades, this court and its predecessor have rec-
`ognized that where the general conditions of a claim are
`disclosed in the prior art, it is not inventive to discover the
`optimum or workable ranges by routine experimentation.”
`E.I. DuPont de Nemours & Co. v. Synvina C.V., 904 F.3d
`996, 1006 (Fed. Cir. 2018) (quotation marks omitted). “A
`more specific application of this general principle is that a
`
`2 To the extent Teva challenges the Board’s credibil-
`ity findings, see Appellant’s Br. at 39–40, they are sup-
`ported by substantial evidence.
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`TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC. 9
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`prima facie case of obviousness typically exists when the
`ranges of a claimed composition overlap the ranges dis-
`closed in the prior art.” Id. (quotation marks and altera-
`tions omitted). But overlap is not strictly necessary for a
`conclusion of obviousness: “obviousness exists when the
`claimed range and the prior art range do not overlap but
`are close enough such that one skilled in the art would have
`expected them to have the same properties.” In re Peterson,
`315 F.3d 1325, 1329 (Fed. Cir. 2003); accord In re Brandt,
`886 F.3d 1171, 1177 (Fed. Cir. 2018); Valeant Pharms. Int’l,
`Inc. v. Mylan Pharms. Inc., 955 F.3d 25, 32 (Fed. Cir. 2020).
`Substantial evidence supports the Board’s finding that
`the general working conditions disclosed in the prior art
`did not encompass the claimed invention, i.e., there was no
`overlap in ranges. In the Board’s view, “the evidence of
`record support[ed] that the general working conditions lim-
`ited co-administration of mifepristone with a strong
`CYP3A inhibitor to just 300 mg/day.” Final Decision at
`*21. Rephrased, the prior art capped the range of co-ad-
`ministration dosages at 300 mg per day. For support, the
`Board cited the Korlym label, id., which cautioned that
`“[m]ifepristone should be used in combination with strong
`CYP3A inhibitors only when necessary, and in such cases
`the dose should be limited to 300 mg per day.” J.A. 844.
`And it also noted how industry publications echoed this
`limitation. Final Decision at *21 (citing J.A. 1279–80
`(“[T]he dose of mifepristone should not exceed 300 mg/day
`if used in combination with ketoconazole.”), 4164 (For co-
`administration with ketoconazole, “the maximum daily
`dose of mifepristone should be 300 mg.”)). The Board’s
`finding that the prior art ranges do not overlap with the
`claimed range is supported by substantial evidence.
`And the Board’s reasonable-expectation-of-success
`finding, which we have already upheld, forecloses Teva’s
`reliance on monotherapy doses above 300 mg per day. Teva
`claims those monotherapy dosages create an overlap with
`the claimed range. But monotherapy dosages alone cannot
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`TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC. 10
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`create an overlap with the claimed range, which is limited
`to co-administering mifepristone with a strong CYP3A in-
`hibitor. Thus, the only remaining question is whether a
`skilled artisan would have expected monotherapy and co-
`administration dosages to behave similarly. As the Board
`found, a skilled artisan would have had no such expecta-
`tion. And we have already upheld that finding as sup-
`ported by substantial evidence.
`III
`Teva claims this is an “uncommonly clear-cut obvious-
`ness case.” Appellant’s Br. at 37. It describes the prior art
`as “disclos[ing] the problem, . . . the solution, . . . and the
`way to find the solution.” Id. In doing so, it ignores the
`reasonable-expectation-of-success requirement. At best,
`the prior art directed a skilled artisan to try combining the
`Korlym Label, Lee, and the FDA guidance. But without
`showing a reasonable expectation of success, Teva did not
`prove obviousness. Since the Board applied the appropri-
`ate legal standards in finding no expectation of success and
`its fact findings are supported by substantial evidence, we
`affirm.
`
`AFFIRMED
`
`