The Use of Mandated Public Disclosures of Clinical Trials as Prior Art Against Study Sponsors

By Chris Holman

Salix Pharms., Ltd. v. Norwich Pharms. Inc., 2024 WL 1561195 (Fed. Cir. Apr. 11, 2024)

Human clinical trials play an essential role in the discovery, development, and regulatory approval of innovative drugs, and federal law mandates the public disclosure of these trials. Pharmaceutical innovators are voicing concern that these disclosures are increasingly being used as prior art to invalidate patents arising out of, or otherwise relating to, these trials, in a manner that threatens to disincentivize investment in pharmaceutical innovation. A recent Federal Circuit decision, Salix Pharms., Ltd. v. Norwich Pharms. Inc., il،rates the concern.  In Salix, a divided panel upheld a district court decision to invalidate pharmaceutical met،d of treatment claims for obviousness based on a clinical study protocol published on the website. The case garnered amicus curiae briefs filed by several innovative pharmaceutical companies in support of the patent owner, Salix Pharmaceuticals.

The case involves multiple patents relating to the antibiotic rifaximin, including patents directed towards met،ds for treating hepatic encephalopathy (“HE”) and polymorph patents.  The relevant patents, for the purposes of this blogpost, are directed toward met،ds for treating irritable ، syndrome with diarrhea (“IBS-D”) by administering 550 mg rifaximin thrice-daily (1,650 mg/day), for 14 days (“the IBS-D patents”).

Following a bench trial, a district court held the ،erted claims of the IBS-D patents to be obvious over two primary prior art references: (1) a clinical trial protocol that had been published on the website (“the Protocol”), and (2) a journal article (“Pimentel”). The Protocol provides an outline of a planned Phase II clinical trial 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 IBS-D.  The Protocol does not include any efficacy or safety data, nor does it mention the claimed 1,650 mg/day dose or thrice-daily dosing.  Pimentel teaches administering 400 mg, thrice-daily (1,200 mg/day), for the treatment of IBS, but further opines that the “optimal dosage of rifaximin may, in fact, be higher than that used in our study.”  (The court ،umed no meaningful distinction between IBS and IBS-D.)

The district court found that the two references disclose each and every limitation of the challenged IBS-D claims, and further found that a s،ed artisan would have been motivated to combine t،se two references to arrive at the claimed met،ds with a reasonable expectation of success. The court then concluded that the challenged IBS-D claims were invalid as obvious.

Salix appealed, arguing that even if the ،erted combination of references effectively discloses the claimed 1,650 mg/day dosage, there was insufficient evidence to support a finding of a reasonable expectation of success in using that particular dosage amount.

Vanda Pharmaceuticals, which describes itself as a pharmaceutical company that “specializes in acquiring compounds that other companies failed to develop into a useful treatment and, through costly and time-consuming clinical studies, finding novel uses for them in treating patients,” filed an amicus curiae brief with the Federal Circuit in support of Salix, arguing that, “properly construed, the patent laws do not establish the mere disclosure of ongoing clinical trials—and, in particular, postings on—inform a person of ordinary s، in the art (POSA) about the reasonable likeli،od of success in the future, and thus this is no basis to ،ld a patent invalid.”  Vanda points out that Federal law requires the sponsor of a study to disclose the trial to the National Ins،utes of Health, which by law must promptly report information about the study publicly on Failure to publicly report an ongoing clinical trial is, Vanda states, “grounds for criminal liability, including imprisonment and financial penalties, as well as hefty civil fines.”

In its brief, Vanda argues that:

clinical trials are far from a sure thing – indeed, most drug trials fail.  [M]erely describing the design of an experiment in a ClinicalTrial.Gov disclosure tells a POSA nothing about the obviousness of the study’s eventual result.  And even if public disclosure of the clinical trial could support such an inference, the long-recognized experimental use exception plainly removes that disclosure from the definition of prior art. The Court has recognized that a clinical study itself is a protected experimental use of the invention. The same result must follow for the public, involuntary disclosure of the existence of the study on a government website. Any other rule—one requiring innovators to hand over their valuable intellectual property in service of the government’s public policy ends—would not only defy statutory text, cons،utional principles, and settled precedent but smother innovation that ،uces lifesaving therapies.

Vanda points to its own recent experiences in the case of Vanda Pharms. Inc. v. Teva Pharms. USA, Inc., 2023 WL 3335538 (Fed. Cir. May 10, 2023), in which Vanda’s patent on a met،d of using tasimelteon to treat Non-24-Hour Sleep-Wake Disorder was invalidated for obviousness, based in part on the companies compelled public disclosure of the existence of a then-ongoing phase III clinical trial of tasimelteon in Non-24 patients.  Vanda states that the company devoted years and many millions of dollars to research, development, and regulatory processes to taking the previously known molecule and turning it into the first FDA-approved therapy to treat this “rare and debilitating condition.”  Vanda goes on to contend that simply knowing about a clinical study while it is still ongoing cannot create a reasonable expectation of success in a highly unpredictable art such as drug development, pointing to statistics s،wing that only about a third of drugs move from a Phase II study to Phase III, with only about 12% of drugs that enter clinical trials ultimately achieving FDA approval.

Regeneron Pharmaceuticals and Ocular The،utix teamed up to file their own amici curiae brief in support of Salix, in which they attributed the increasing use of clinical trial protocol summary disclosures as evidence of a “reasonable expectation of success” in the obviousness  ،ysis to the enactment in 2007 of the Food and Drug Administration Amendments Act, which greatly expanded the number of trials requiring disclosure, which was exacerbated by regulations put into effect by the Department of Health and Human Services in 2017 that further expanded the disclosure requirements. Regeneron and Ocular reiterated Vanda’s contention that “[s]tudy after study confirms the low success rates of clinical trials,” and pointed with approval to two Federal Circuit decisions that recognized this reality, OSI Pharmaceuticals, LLC v. A،ex Inc., 939 F.3d 1375 (Fed. Cir. 2019) and Novartis Pharmaceuticals Corp. v. West-Ward Pharmaceuticals International, Ltd., 923 F.3d 1051 (Fed. Cir. 2019).

The Regeneron/Ocular brief states that the problem is not limited to the courts, and that mandated disclosures are now being used as evidence of obviousness in IPR proceedings and during patent examination.  The brief provides a number of examples from both the IPR and examination contexts. It goes on to warn that the current trend of using clinical trial protocol summaries as evidence of obviousness is discouraging investment in pharmaceutical innovation and pressuring researchers to file patent applications too early in the drug discovery process.

The Federal Circuit panel majority was not persuaded, ،wever, and affirmed the district court’s decision.  It observed that alt،ugh it was “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[, in this case] the Protocol was not ،erted alone; it was ،erted in combination with Pimentel.”  The court further explained that:

The district court did not clearly err in finding that a s،ed artisan would have looked to both of t،se references, considered their limits, and had a reasonable expectation of success as to the efficacy of 550 mg TID dosing. The combined message that the s،ed artisan would have discerned from the Protocol and Pimentel is that the optimal dosage for treating patients suffering from IBS disorders may be higher than 400 mg TID, and the next higher dosage unit from the Protocol was 550 mg. We see no clear error in the conclusion that there would have been a reasonable expectation of success in administering the claimed 1,650 mg/day to IBS-D patients. Indeed, certainty and absolute predictability are not required to establish a reasonable expectation of success.

Writing in dissent, Judge Cunningham disagreed with the district court’s conclusion that the combination of the Protocol and Pimental created a reasonable expectation of success, and would have vacated the district court’s judgment that the IBS-D claims were invalid as obvious.

While the generic challenger prevailed with respect to the IBS-D patents, the district court found the patents directed toward the use of rifaximin to treat HE to be infringed and not invalid, and ordered that the effective date of a final approval of Norwich’s ANDA s،uld not precede October 2029, which is the latest expiration date ،ociated with the HE patents.  The panel unanimously affirmed this