In a decision from the District of Delaware last month, two bodies of patent law converged to potentially open a new frontier in oncology patents. In Sanofi-Aventis U.S. LLC v. Sandoz, Inc., 2023 U.S. Dist. LEXIS 109470 (“Sanofi v. Sandoz”), the Court affirmed the validity of a patent directed to a method of increasing survival, even though the only manipulative difference between the claimed method and the prior art was routine, because the preamble was limiting, and a person of ordinary skill in the art (“POSA”) would not have expected successfully to increase survival practicing the method.
The patent at issue, U.S. Patent No. 10,716,777 (“the ‘777 patent”), covers a method of increasing survival in metastatic castration resistant prostate cancer (“mCRPC”) patients whose cancer has progressed during or after docetaxel treatment, an approved use for Sanofi’s cabazitaxel (JEVTANA®) injection. Claim 1 recites in relevant part:
1. A method of increasing survival comprising administering to a patient in need thereof a dose of 20 to 25 mg/m2 of cabazitaxel, or a hydrate or solvate thereof, in combination with an H2 antagonist, wherein the H2 antagonist is administered to the patient prior to administering the dose of cabazitaxel, wherein said patient has castration resistant metastatic prostate cancer that has progressed during or after treatment with docetaxel.
The H2 antagonist refers to an antiemetic such as ondansetron, which the Court determined would have been combined with cabazitaxel as a matter of routine experimentation.
The case dates back to 2019, when the Federal Circuit held in another case involving JETVANA, in an appeal from an inter-partes review (“IPR”), that a nearly identical preamble in a related patent was limiting. In that case, the PTAB had invalidated a patent claiming a method of increasing survival after finding that the preamble was not limiting. Sanofi Mature IP v. Mylan Labs., Ltd., 2019 U.S. App. LEXIS 3529 (“Sanofi v. Mylan”). The PTAB had reached its decision based primarily on Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc., 246 F.3d 1368 (Fed. Cir. 2001), in which the Federal Circuit found that a preamble reciting a “method for reducing hematologic toxicity” was not limiting.
This was a mistake, the Federal Circuit held, because “In Bristol-Myers Squibb, we concluded that the claim language ‘strongly suggest[ed] the independence of the preamble from the body of the claim.’ But here, the claim language suggests the opposite. Indeed, there is a direct link between the claim as a whole and the preamble, which provides an antecedent basis for ‘in need thereof.’” Based on this distinction, the Federal Circuit concluded that the preamble was limiting and required that the method be practiced for the purpose of increasing survival.
Fast forward to 2023, when the District Court was asked to determine whether the prior art rendered obvious the method of increasing survival in the ‘777 patent. As the Federal Circuit had done in 2019, the District Court construed the preamble in claim 1 as limiting and requiring that the method be practiced for the purpose of increasing survival. Sandoz challenged the validity of the claim based on obviousness, and the main issue before the Court was whether the prior art lent a reasonable expectation of success to the method.
Several pieces of prior art were at issue but three stand out.
The first piece of prior art (the “Mita study”) reported an early study in which cabazitaxel had been tested against a variety of solid tumors in 25 patients. Eight of the patients had prostate cancer. Two of those patients saw a reduction in tumor size. One of those two patients had previously been treated with docetaxel.
The second piece of prior art (the “Pivot study”) reported a larger study of cabazitaxel in seventy-one metastatic breast cancer patients, forty-six of whom had been previously treated with docetaxel. Ten of the patients responded to cabazitaxel, two by complete response.
The third piece of prior art was public knowledge of the phase III study (the “TROPIC” study) that was evaluating whether cabazitaxel would increase overall survival in men with mCRPC and disease progression despite docetaxel.
Despite this evidence, including one prostate cancer patient previously on docetaxel who experienced reduced tumor size while on cabazitaxel, and the reported progression of the drug to a phase III clinical study, the Court determined that a POSA would not have reasonably expected successfully to increase survival. As stated by the Court: “Oncology is unpredictable.” “A POSA would know that many clinical trials fail, even at Stage III, including many studies in men with mCRPC.” Regarding the cabazitaxel prior art:
A POSA would be at most cautiously optimistic about the prospects of cabazitaxel’ s success based on [the prior art.] The existence of the TROPIC trial would have bolstered a POSA’s cautious optimism, but would not have provided enough concrete information to take a POSA beyond cautious optimism.
Sandoz focused on the one success reported by Mita in a mCRPC patient previously treated with docetaxel and argued that a POSA would expect success in at least one patient based on this report, but the Court disagreed. According to the Court:
I do not think Defendant has proven by clear and convincing evidence that a POSA could reasonably expect success even for at least some patients. Dr. Ratain [Sandoz’s expert] testified that a POSA would be sure that the impact on the 50-year-old patient in Mita ‘was not a one-off’ because of the magnitude of anticancer activity. Dr. Nelson [Sanofi’s expert], however, testified that ‘it would be very difficult based on an anecdotal patient here to make conclusions about what would happen to the next patient.’ On balance, I found Dr. Nelson’s testimony that a POSA would be hopeful but unsure to be more credible and persuasive than Dr. Ratain’s testimony that a POSA would expect success.
The case highlights the difficulties interpreting clinical trials particularly in oncology, and the need for multi-patient clinical trials. A single “success” reported in the prior art should not lead a POSA to believe that a drug will work, when that success might just as well have occurred spontaneously in the absence of treatment. At least in the field of oncology, until enough patients have been successfully treated, and enough evidence gathered, a POSA will not reasonably expect that a drug will increase survival.
