by Dennis Crouch
Teva Pharmaceuticals, LLC v. Corcept Therapeutics, Inc., Dockt No. 21-1360 (Fed. Cir. 2021)
This is an interesting pro-pharma obviousness decision coming out of the PTAB regarding obviousness of particular drug dosages. Here, the particular drug was known to work well, but there were concerns about drug safety. And, there were a couple of particular tests that clearly would have been obvious to try. In fact, the patentee was legally required by the FDA to conduct the tests in order to ensure drug safety. Still, the outcome of the tests were not predictable. Nobody knew whether the particular dosage being was going to turn out to be “safe.” (Here “safe” is interpreted as having “an acceptable risk-benefit profile.”) The patentee ran the tests, found the dosage to be safe, and then patented a method of administering that safe-dosage to patients. Teva challenged the patent, but the PTAB and the Federal Circuit both sided with the patentee. They held that the unpredictable outcome of the test meant that the outcome was not obvious since there was no “reasonable expectation of success.”
I expect that the Supreme Court would reject the hard line drawn in this case in the same way that it rejected the TSM requirement in KSR v. Teleflex. I.e., obviousness is a flexible, open analysis asking “is there an invention here?” Former Kennedy clerk J.C. Rozendaal handled the appeal for Teva, and so I won’t be surprised to see a petition for writ of certiorari in 2022.
The rest of the story: Corcept’s patent covers a method of treatment of some Cushing’s syndrome symptoms with the drugs mifepristone and ketoconazole (a “strong CYP3A4 inhibitor”). U.S. Patent No. 10,195,214. The basic problem is that these two drugs can interact in problematic ways, and the patent calls for a reduced dose of mifepristone when being taken alongside ketoconazole. When taken alone, mifepristone is prescribed in dosages of up to 1,200 mg per day; but when taken with ketoconazole, the patent calls for reduction of down to 600 mg per day.
The prior art all comes from earlier interaction between Corcept and the FDA. Initially, Corcept filed a New Drug Application (NDA) seeking to market mifepristone in dosages of 300, 600, 900, and 1,200 mg per day. The FDA gave its approval, but suspected interaction with ketoconazole. That suspicion led to the two key prior art references:
- The Korlym Label: The FDA-approved label for Corcept’s original drug product Korlym allowed for dosage of mifepristone at 300, 600, 900, or 1,200 mg increments and also offered a warning against co-administration with a strong CYP3A. In particular it limited the “mifepristone dose to 300 mg per day when used with strong CYP3A inhibitors.” Thus, an easy reading of the label seems to be a strong suggestion that dosages of 600, 900, or 1,200 might be problematic. This label also appears to totally anticipate a dose of 300 mg when taken along with a strong CYP3A inhibitor.
- The FDA Suggestion (“Lee”): The FDA also suggested the possibility of interaction between CYP3A and mifepristone and required Corcepts to study that interaction.
When I think about these two references, I see a strong suggestion of an interaction between the drugs, and also a strong motivation to look into that interaction. In fact, the first two research questions implicitly demanded by the prior art is (1) whether a 300 mg dose interacts with CYP3A and (2) whether a 600 mg dose interacts with CYP3A. Yet, while the two references expressly call for research, the references do not suggest the outcome of the 600 mg test. If anything, the original label suggested that 600 mg dose would be a problematic — since the FDA limited dosage to only 300 mg if also taking the other drug.
The PTAB followed these lines of analysis and eventually concluded that the references failed to prove obviousness. In particular, the Board hung its hat on “reasonable expectation of success” — finding that the references did not suggest that 600 mg would be a safe dosage.
On appeal, the Federal Circuit has affirmed — holding that invalidating the claim would require proof of “a reasonable expectation of success in achieving the specific invention claimed, a 600 mg dosage.”
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.
Slip Op. Affirmed.
Note – Mifepristone is new name for the drug RU-486.