Clinical trials are a critical part of the development and approval process for drugs, biologics, and medical devices. The lengthy and public nature of clinical trials, however, can create challenges for protecting relevant IP. A clinical trial is a study or investigation in humans to "evaluate the effect(s) of intervention(s) on biomedical or health-related outcomes." 42 C.F.R. 11. Interventions can take many forms that benefit from patent protection including drugs/small molecules/compounds; biologics; devices; procedures (e.g., surgical techniques); treatment strategies; prevention strategies; and diagnostic strategies. Id.
Currently, Federal law requires clinical trials be registered with ClinicalTrials.gov if:
(1) they involve drugs, devices, or biologics that are regulated by the Food and Drug Administration (FDA), OR
(2) they are federally funded and meet the definition of a clinical trial, OR
(3) there is a plan to publish the results in a medical journal AND the study meets the International Committee of Medical Journal Editors (ICMJE) definition of a clinical trial. See Id. However, clinical trials are a very lengthy process. While Phase 1 clinical trials typically last only several months, Phase 2 clinical trials can frequently last up to two years and Phase three trials last 1 to 4 years. See https://www.fda.gov/patients/drug-development-process/step-3-clinical-research.
Because of the mandatory registration and publication of a clinical trial protocol, applicants dealing with regulated inventions are given a tough choice to either (A) file a patent application prior to the publication of the clinical trial protocol or report and forego all the additional information to be discovered in the trial, or (B) risk the published clinical trial report and protocol (which do not contain the results) being used as prior art against a later-filed patent application. The recent Federal Circuit decision, Salix Pharms., Ltd. v. Norwich Pharms. Inc., encapsulates this conundrum. Salix Pharms., Ltd. v. Norwich Pharms. Inc., 2024 WL 1561195 (Fed. Cir. Apr. 11, 2024) (available here).
In this case, Salix appeals a final judgment from the U.S. District Court for the District of Delaware holding claim 2 of U.S. Patent 8,309,569, claim 3 of U.S. Patent 10,765,667, claim 4 of U.S. Patent 7,612,199, and claim 36 of U.S. Patent 7,902,206 invalid as obvious. Norwich cross-appeals the district court's finding that Norwich infringed claim 8 of U.S. Patent 8,624,573, claim 6 of U.S. Patent 9,421,195, and claims 11 and 12 of U.S. Patent 10,335,397 after it failed to prove those claims invalid. The Federal Circuit affirmed the district court's finding of invalidity.
Rifaximin is the active ingredient in Salix's commercial product Xifaxan®. Rifaximin itself is not new. It was first synthesized in the early 1980s and was approved in Italy as an antibiotic in 1985. In 2004, the FDA approved Xifaxan 200 mg tablets for the treatment of travelers' diarrhea. Subsequently, the uses of Xiafaxan expanded. The FDA approved 550 mg tablets for hepatic encephalopathy ("HE") in 2010 and for irritable bowel syndrome with diarrhea ("IBS-D") in 2015. Norwich sought to market a generic version of rifaximin and, in 2019, filed an abbreviated new drug application ("ANDA") for 550 mg tablets with the same indications as Xifaxan certifying that Salix's rifaximin patents were invalid. Salix timely sued, asserting that Norwich's ANDA infringed dozens of valid, Orange Book-listed patents. This discussion will focus on the IBS-D patents.
The district court found the IBS-D patents invalid as obvious based on a clinical trial protocol that had been published on the ClinicalTrials.gov website in 2005 ("the Protocol") and a 2006 journal article ("Pimentel"). The relevant portions of the '569 patent recite "administering 1650 mg/day of rifaximin for 14 days" and "wherein the 1650 mg is administered at 550 mg three times per day." The district court characterized the Protocol as describing "a Phase II study evaluating twice-daily doses of 550 mg (1,100 mg/day) and 1,100 mg (2,200 mg/day) for 14 and 28 days for the treatment of IBSD," and Pimentel as teaching "administering 400 mg, TID (1,200 mg/day), for the treatment of IBS." The district court noted that Pimentel further states that "optimal dosage of rifaximin may, in fact, be higher than that used in our study."
Salix argued that "a skilled artisan would not have had a reasonable expectation of success in using the claimed 1,650 mg/day dosage to treat IBS-D." Overall, this is a very reasonable argument. The FDA shows that while approximately 70% of drugs pass Phase 1 trials, only about 33% of drugs pass Phase 2 and of those, about 25-30% pass Phase 3. See https://www.fda.gov/patients/drug-development-process/step-3-clinical-research. The Congressional Research Office describes drug development as "a costly and uncertain process," where only "about 12 percent of drugs entering clinical trials are ultimately approved for introduction by the FDA." See https://www.cbo.gov/publication/57126. Given these numbers, it is much more likely that a clinical trial fails than succeeds. The norm, it seems, is an expectation of failure.
The Federal Circuit disagreed, noting it has "rejected the idea that efficacy data [are] always required for a reasonable expectation of success." OSI Pharms., LLC v. Apotex Inc., 939 F.3d 1375, 1385 (Fed. Cir. 2019) (internal quotation marks omitted). The Federal Circuit's opinion further notes that various other references also teach that higher doses of rifaximin, up to 1800 mg/day, are more effective than lower doses in treating small intestinal bacterial overgrowth, a recognized cause of IBS (noting that the court does not recognize a medical difference between IBS and IBS-D). However, the court's conclusion appears to hinge on the suggestion in Pimentel that the "optimal dosage of rifaximin may, in fact, be higher than that used in our study." Ultimately, the Federal Circuit held the district court did not err when it held that "that a skilled artisan would have been motivated to combine the . . . Protocol and Pimentel [] with a reasonable expectation of success." (internal quotation marks omitted).
However, there is a glimmer of hope for inventors or patent applicants under an obligation to register their clinical trials. The Federal Circuit made clear that they "are hesitant to conclude as a general matter that the disclosure of a Phase II clinical trial plan, standing alone, provides an expectation of success sufficient to render obvious a dosage that was not included within the planned clinical trial." (emphasis added). The court noted specifically that here, "the Protocol was not asserted alone; it was asserted in combination with Pimentel."
If possible, players in the pharmaceutical/biologics/devices space should be wary of planting the seeds of an obviousness rejection in their publications whether scientific or non-scientific in nature. Often, however, it is impossible to control every bit of information published about a new drug candidate, let alone one with a long history of investigation or use. There are often incentives, particularly regarding attracting investors and raising capital, to tout successes and build expectations. There may also be third-parties who publicize or opine on inventor- or applicant-derived information. Further, data that is useful for unexpected results arguments in patent prosecution is frequently barred from being included in application filings because it is acquired so late after the publication of the clinical trial protocol.
This case illustrates the critical need for a long-term strategy that integrates both intellectual property protection and regulatory compliance. In the U.S., applicants should take advantage of provisional applications, which should include all the information that will eventually be published in a clinical trial report to at least secure an early priority date that precedes the publication of a clinical trial report. The situation is complicated if the IP protection strategy involves jurisdictions with absolute novelty requirements, where the publication of a clinical trial report could spell the end of the game. Even with a provisional filing, however, support should be included for future developments, such as different dosages or dosing regimens.
Further, great care must be taken to provide the necessary regulatory filings (e.g., filings for clinicaltrials.gov) in a way that satisfies the requirements for the filing but does not give away every patent-relevant detail.
While these are particularly important in situations involving new uses for known compounds, new drugs, biologics, and devices are not immune. It is crucial to develop a comprehensive international IP strategy at early stages to prevent necessary disclosures such as regulatory filings, shareholder updates, or investor pitches from nixing robust IP protections.
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