Teva Pharmaceuticals USA v. Corcept Therapeutics, Inc.

Case: 21-1360 Document: 34 Page: 1 Filed: 12/07/2021
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.
______________________
Case: 21-1360 Document: 34 Page: 2 Filed: 12/07/2021
2 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.
Case: 21-1360 Document: 34 Page: 3 Filed: 12/07/2021
TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC. 3
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
Case: 21-1360 Document: 34 Page: 4 Filed: 12/07/2021
4 TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC.
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
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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6 TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC.
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
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
Case: 21-1360 Document: 34 Page: 8 Filed: 12/07/2021
8 TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC.
(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.
Case: 21-1360 Document: 34 Page: 9 Filed: 12/07/2021
TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC. 9
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
Case: 21-1360 Document: 34 Page: 10 Filed: 12/07/2021
10 TEVA PHARMACEUTICALS USA v. CORCEPT THERAPEUTICS, INC.
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