Korlym: Failure to Show a Reasonable Expectation of Success Dooms Obviousness Allegations

In Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.,1 the Federal Circuit affirmed the obviousness analysis performed by the Patent Trial and Appeal Board (“PTAB”), which found that Corcept’s patent for methods of treating Cushing’s disease by co-administering two different types of drugs with a specific range of dosing amounts was not obvious—even where the prior art directed one to combine the two—because there was no reasonable expectation of success for the specific dose claimed in the patent.

Background

The patent relates to methods for treating Cushing’s syndrome by co-administering mifepristone and a strong CYP3A inhibitor. Cushing’s syndrome is a metabolic disorder caused by excess cortisol.,2 Mifepristone was recognized in the prior art as a potential treatment for Cushing’s syndrome in the 1980’s.,3 Decades later, Corcept sponsored the first major clinical trial of mifepristone in patients with Cushing’s syndrome, in which participants were dosed with 300 to 1200 mg per day of mifepristone. Thereafter, Corcept filed a New Drug Application (“NDA”) with the U.S. Food and Drug Administration (“FDA”) to seek marketing approval for Korlym®, a 300 mg mifepristone tablet to control “hypercalcemia secondary to hypercortisolism” in patients with Cushing’s syndrome.,4

The FDA approved the NDA, including the prescribing information contained in the label.5 The label “recommended [a] starting dose [of] 300 mg once daily” and allowed for a dosage increase “in 300 mg increments to a maximum of 1200 mg once daily.”6 The label specifically warned against using mifepristone “with strong CYP3A inhibitors” and limited the dose to “300 mg per day when used with strong CYP3A inhibitors.”7

However, when it approved the NDA, the FDA issued several post market requirements, one of which was that Corcept must conduct a drug-drug interaction study with mifepristone and a strong CYP3A inhibitor.8 A memo from the Office of Clinical Pharmacology was provided to Corcept by the FDA (“the Lee memo”), which explained that “[t]he degree of change in exposure of mifepristone when co-administered with strong CYP3A inhibitors is unknown” and “may present a safety risk.”9 The concern was that without the required study the patients with Cushing’s syndrome that take strong inhibitors may be unable to use mifepristone.10

Corcept conducted the study requested in the Lee memo.11 Based on the resulting data, Corcept sought a patent claiming a method of treating Cushing’s syndrome by co-administering mifepristone and a strong CYP3A4 inhibitor, which is the patent at issue here.12 Claim 1, which is representative of the claims, reads:

A method of treating Cushing’s syndrome in a patient who is taking an original once-daily dose of 1200 mg or 900 mg per day of mifepristone, comprising the steps of:

reducing the original once-daily dose to an adjusted once-daily dose of 600 mg mifepristone,

administering the adjusted once-daily dose of 600 mg mifepristone and a strong CYP3A inhibitor to the patient,

wherein said strong CYP3A inhibitor is selected from the group consisting of ketoconazole, itraconazole, nefazodone, ritonavir, nelfmavir, indinavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat, troleandomycin, tipranivir, paritaprevir, and voriconazole.13

Procedural Posture

In 2018 Corcept brought suit against Teva in the District of New Jersey alleging that Teva’s proposed generic infringed the patent, among others.14 Teva then sought post-grant review of the patent’s claims at the PTAB, arguing that the claims would have been obvious over the Korlym® label and the Lee memo, optionally in combination with FDA guidance on drug-drug interaction studies.15

The PTAB instituted review, “construed the claims to require safe administration of mifepristone,” and found that Teva failed to meet its burden of showing that a “skilled artisan would have had a reasonable expectation of success for safe co-administration of more than 300 mg of mifepristone with a strong CYP3A inhibitor.”16 Thus, the PTAB concluded that Teva failed to prove obviousness.17

Teva’s Arguments on Appeal

Teva argued to the Federal Circuit that the PTAB committed two legal errors in finding that Teva did not prove obviousness: (1) it “required precise predictability, rather than a reasonable expectation of success in achieving the claimed invention,” and (2) it found that Teva “failed to prove the general working conditions disclosed in the prior art encompassed the claimed invention” instead of applying the Federal Circuit’s “prior-art-range precedents.”18

The Federal Circuit Panel, consisting of Chief Judge Moore and Judges Newman and Reyna, rejected both of Teva’s arguments.19

The Panel determined that the PTAB “did not err by requiring Teva to show a reasonable expectation of success for a specific mifepristone dosage.”

In discussing the proper standard for evaluating a reasonable expectation of success, the Panel cited prior Federal Circuit decisions explaining that the analysis “must be tied to the scope of the claimed invention.”20 It noted that because the claims of the patent require administration of a specific dosage of mifepristone, the PTAB was required to frame its analysis around that specific dosage.21 The Panel emphasized that Teva was not “required to prove a skilled artisan would have precisely predicted safe co-administration of 600 mg of mifepristone” because “[a]bsolute predictability is not required.”22 Teva was, however, required “to prove a reasonable expectation of success in achieving the specific invention claimed, a 600 mg dosage.”23

The Panel explained that the PTAB found that Teva failed to prove a reasonable expectation of success.24 Based on the prior art, a skilled artisan would not have reasonably “expected co-administration of more than 300 mg of mifepristone with strong CYP3A inhibitor to be a safe treatment of Cushing’s syndrome or related symptoms in patients.”25 Moreover, the PTAB found that a skilled artisan “would have had no expectation as to whether co-administering dosages of mifepristone above the 300 mg/day threshold” would be successful.26 Thus, because there was no expectation of success for any dosage over 300 mg, the PTAB concluded that there could not have been an expectation of success for the specific dosage of 600 mg per day.27 The Panel found that this analysis by the PTAB was correct under Federal Circuit precedent, and that “[n]othing about this analysis required precise predictability, only a reasonable expectation of success tied to the claimed invention.”28

The Panel decided that the PTAB did not err in finding that “the prior art ranges do not overlap with the claimed range”

The Panel next considered the applicability of the Federal Circuit’s precedent concerning claimed ranges that overlap with those disclosed in the prior art.29 The PTAB refused to apply that line of cases, finding that “Teva had failed to prove the general working conditions disclosed in the prior art encompass the claimed invention.”30

The Panel noted a Federal Circuit decision 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.”31 In other words, “a prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”32 “But overlap is not strictly necessary for a conclusion of obviousness” and can exist even where the ranges are “close enough” that a skilled artisan would expect them to exhibit similar properties.33

Here, the Panel explained that “[s]ubstantial evidence supports the [PTAB’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.”34 The Korlym® label warned against taking mifepristone with a strong CYP3A inhibitor altogether, and stated that anyone nonetheless combining the two should take a maximum of 300 mg/day of mifepristone.35 This 300 mg/day cap was also repeated in other industry publications.36 The PTAB found that “the prior art capped the range of co-administration dosages at 300 mg per day.”37 The Panel agreed with this finding, concluding that the claimed range was not disclosed in the prior art.38

Teva attempted to argue that the claimed range overlaps with monotherapy dosages—which were dosages of mifepristone alone—in the prior art.39 However, because “monotherapy dosages alone cannot create an overlap with the claimed range, which is limited to co-administering mifepristone with a strong CYP3A inhibitor,” the PTAB had to determine “whether a skilled artisan would have expected “monotherapy and co-administration dosages to behave similarly.”40 As the Panel had already concluded in its reasonable expectation of success analysis, a “skilled artisan would have no such expectation.”41

Conclusion

Although Teva argued that this was an “uncommonly clear-cut obviousness case” where the prior art discloses “the problem, . . . the solution, . . . and the way to find the solution,” the Panel disagreed, explaining that: “At best, the prior art directed a skilled artisan to try combing the Korlym Label, Lee, and the FDA guidance. But without showing a reasonable expectation of success, Teva did not prove obviousness.”42 Thus, the Panel’s decision helps to clarify that evaluating obviousness based on ranges disclosed in the prior art is a fact-specific analysis, in which bright lines should not be drawn.

1 Teva Pharm. USA, Inc. v. Corcept Therapeutics, Inc., No. 21-1360, slip op. (Fed. Cir. Dec. 7, 2021).
2 Id. at 2.
3 Id.
4 Id. at 2-3.
5 Id. at 3.
6 Id.
7 Id. at 3-4.
8 Id. at 3.
9 Id.
10 Id.
11 Id. at 4.
12 Id.
13 Id. at 3.
14 Corcept Therapeutics, Inc. v. Teva Pharmaceuticals USA, Inc., No. 18-3632 (D.N.J.).
15 Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc., PGR2019-00048, 2020 WL 6809812 (P.T.A.B. Nov. 18, 2020) (Final Decision).
16 Id. (emphasis added).
17 Id.
18 Teva Pharm. USA, Inc. v. Corcept Therapeutics, Inc., No. 21-1360, slip op. at 5 (Fed. Cir. Dec. 7, 2021)
19 See generally id.
20 Id. at 6 (citing Allergan, Inc. v. Apotex Inc., 753 F.3d 952, 966 (Fed. Cir. 2014); Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1366 (Fed. Cir. 2016)).
21 Id.
22 Id.
23 Id.
24 Id.
25 Id. at 6-7 (citing Final Decision at *22).
26 Id. at 7.
27 Id.
28 Id.
29 Id. at 8.
30 Id.
31 Id. (citing E.I. DuPont de Nemours & Co. v. Synvina C. V., 904 F.3d 996, 1006 (Fed. Cir. 2018)).
32 Id. at 8-9.
33 Id. at 9.
34 Id.
35 Id.
36 Id.
37 Id.
38 Id.
39 Id.
40 Id. at 9-10.
41 Id. at 10.
42 Id.

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