Can Clinical Trials Negate Patentability for Pharma Inventions?

The answer to this inquiry is “yes” — but maybe “no.” Will confidentiality agreements shield any prior art concerns? Once again, maybe “yes” — but maybe “no.” Indeed, do clinical trials constitute an experimental use that does not become invalidating prior art? Another important question is whether the invention disclosed by the trials is ready for patenting. If not, the trials should not affect the validity of resulting patents.

This brief introduction indicates that conclusions on the prior art effects of clinical trials are fact-intensive. A review of the reported decisions, however, provides some guidance.

Background

Clinical trials are required before the Food and Drug Administration (FDA) approves a new drug or biologic. These trials are divided into different classes or phases. In Phase I, the trials assess safety, appropriate dosage ranges, and possible side effects in a limited number of patients. In Phase II, the trials assess efficacy in a larger pool of patients that have the target disease. In Phase III, the trials involve hundreds or thousands of patients and assess the safety and efficacy of the treatment against the standard treatment to secure FDA approval.

Clinical trials can constitute a public use by, inter alia, disclosing data that are invalidating prior art under Sections 102 and/or 103. As research progresses from Phase I to Phase III, the likelihood of an invalidating prior use increases. This creates a Catch-22 for inventors who need to conduct clinical trials to collect the data necessary to support a patent application under Sections 101 and 112 while at the same time avoiding the creation of prior art that would invalidate their patents under Sections 102 and 103. Strict control over the trials and related publication of the results is necessary to avoid the potentially disastrous consequences where the trials themselves or their results constitute an invalidating public use.ⁱ

Confidentiality agreements

Agreements requiring confidentiality of those participating in a clinical trial, while not determinative, weigh against a finding of prior public use. For example, in Dey, L.P. v. Sunovion Pharmaceuticals, Inc., the Federal Circuit stated: “[w]e have never required a formal confidentiality agreement to show non-public use; in the absence of such an agreement, we simply ask whether there were 'circumstances creating a similar expectation of secrecy[.]’”ⁱⁱ

In Dey, the Federal Circuit vacated and remanded a summary judgment decision holding that the clinical trials in question constituted an invalidating public use. The patients enrolled in the Phase III study were not under any confidentiality restrictions and were encouraged to discuss treatment with doctors. But, critically, (i) the patients did not know the specific drug formulation and (ii) although the clinical trial investigators knew the formulation, they were under strict confidentiality restrictions.ⁱⁱⁱ

That same year, in Pronova Biopharma Norge AS v. Teva Pharms.^iv, the Federal Circuit held that sending samples of a patented drug to employees at a research institute for a clinical trial was a public use. Like Dey, there were no confidentiality restrictions; moreover, the samples included certificates of analysis detailing the claimed formulation. As the court noted:

Where, as here, however, a compound is provided without restriction to one highly skilled in the art, that compound’s formulation is disclosed in detail, and the formulation is subject to confirmatory testing, no other activity is needed to render that use an invalidating one.^v

In Bayer Schering Pharma AG v. Barr Laboratories, Inc.^vi, no formal confidentiality provisions existed during the Phase III clinical trials. The District Court did not find a public use, stating that the “lack of confidentiality provisions for human patients is not outcome determinative on the public nature of any use.”^vii Here, the patients were informed of the test compound, but not the alleged invention. They were required to keep a diary showing compliance with the clinical protocol, and all unused samples were returned.

Similarly, in Eli Lilly and Co. v. Zenith Goldline Pharmaceuticals, Inc.^viii, the court held that lack of a confidentiality agreement was not controlling. The trials were designed to test the safety and efficacy of the drug, and the results were maintained in confidence throughout the study. Moreover, the patients were not informed of the precise formulation. Indeed, the test subjects were confined to a specific facility with full-time security. Significantly, the tests were not designed to treat the target disease, but merely to test the “safety and efficacy of the drug.”^ix As such, the tests were an experimental use that negated any prior art ramifications.

The court noted certain factors to be considered in deciding whether there was a public use:

1. The length of the test period,
2. Any confidentiality agreement,
3. Any records of testing,
4. Any monitoring and control of the test results,
5. The number of tests, and
6. The length of the test period in relation to tests of similar inventions.^x

Experimental use

In addition to Eli Lilly, discussed above, the Federal Circuit addressed the experimental use exception to a prior public use in Sanofi v. Glenmark Pharms, Inc., USA.^xi Although the participants were not bound by a confidentiality agreement, the investigators were. The District Court held that a patent on a method of using dronedarone in treating patients was not ready for patenting before the critical date and thus not a public use:

I conclude that Defendants’ public use argument must fail because the ATHENA clinical trial was plainly an experimental use. . . . [T]he ATHENA trial itself demonstrated that Sanofi was still in the process of determining whether dronedarone could safely and effectively treat high-risk AF patients. . . . The investigators involved in the ATHENA trial were subject to confidentiality obligations in order to gain access to the protocol. Accordingly, the individuals to whom a method of treatment would be most significant, physicians, were held to strict confidentiality obligations.^xii

Once again, although not determinative, it is noteworthy to recognize the key role that a confidentiality provision played in the public use analysis. The Federal Circuit affirmed the District Court decision and analyzed the reasonable-expectation-of-success-prong of obviousness under Section 103. The court’s language provides guidance to investigators in preparing clinical trial submissions, as well as related publications:

The initially proposed enrollee-information “it is expected” language cannot show that the district court's finding regarding reasonable expectation is clearly erroneous when, as far as the record shows, that language was not actually given to enrollees and, indeed, was deleted by Institutional Review Boards (which, we must presume, were concerned about overstatements to lay patients in securing informed consent).^xiii

In In Re Omeprazole Patent Litigation^xiv, the Federal Circuit affirmed the lower court’s decision that the patentee’s Phase III clinical trial was not a public use because the invention had not been reduced to practice and therefore was not ready for patenting. Although the inventors thought the drug might work, they had to test it to determine whether it was effective. As the court stated:

The district court found that the Phase III formulation still required extensive clinical testing and real-time stability testing to determine whether it could treat gastric acid diseases safely and effectively…The existence of the formulation, however, does not establish that the Astra scientists had determined that the invention would work for its intended purpose.^xv

Obviousness and a reasonable expectation of success

Although several decisions address a reasonable expectation of success as part of obviousness, little guidance can be gleaned from these decisions. One could surmise that the more technical the data reported in the clinical studies, the more likely the study meets the obviousness standard. As one example, in OSI Pharms., LLC v. Apotex, Inc.^xvi, the Federal Circuit reversed the Patent Trial and Appeal Board’s holding of obviousness, stating that none of the references, including a Phase II study, contained data or other promising information regarding the drug’s efficacy in treating the target disease:

[T]he asserted references do not disclose any data or other information about erlotinib's efficacy in treating NSCLC. The record does not contain any clinical (human) data or preclinical (animal) data. It does not even include in vitro (test tube) data regarding erlotinib's effect on NSCLC. At the same time, it is undisputed that NSCLC treatment was highly unpredictable with an over 99.5% rate of failure for drugs entering Phase II clinical studies. On this record, we are not persuaded that a reasonable factfinder could conclude that a person of ordinary skill would have reasonably expected success based on the combination of [the prior art].”^xvii

Two recent decisions highlight the difficulty in assessing whether a clinical trial proposal provides a reasonable expectation of success. In Janssen Pharms., Inc v. Teva Pharms., USA, Inc.^xviii, the New Jersey District Court held that the prior art, including a Phase III clinical trial, did not render the claimed invention obvious. Noting that clinical trials often fail, the court once again stressed the lack of data as a key factor:

A POSA would know that Janssen likely would not have pursued the ’548 Protocol and invested significant funds in a Phase III clinical trial without a belief that its hypothesis was correct. But without the data and results from the clinical trial, which were only known to Janssen, a POSA would have only understood that Janssen believed the dosing regimens were likely safe and effective.^xix

Interestingly, the court also found that the dosing regimen in the clinical trial was different from the claimed regimen. Thus, any expectation of success would not affect the validity of the claims.^xx

In Salix Pharms., Ltd. v. Norwich Pharms, Inc.^xxi, the Federal Circuit found that the references, including a Phase II study, provided a reasonable expectation of success for administering the claimed dosage regimen for the treatment of IBS-D. The court had an interesting observation about Phase II studies and efficacy data:

Although we have rejected the idea that “efficacy data [are] always required for a reasonable expectation of success,” we 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. But the Protocol was not asserted alone; it was asserted in combination with [another reference].^xxii

Takeaways

Clinical trials, primarily Phase II and Phase III, must be designed and conducted in a manner to avoid creating an invalidating public use. Whether a specific clinical trial constitutes an invalidating public use or qualifies for an experimental use exception is a fact-intensive inquiry, but some general guidelines do apply. Although the existence of a confidentiality agreement is not determinative of a non-public use, such agreements should always be put in place to cover the physicians/investigators conducting the trials and any others involved in the study (e.g., assistants). These agreements should also restrict access to any results. Moreover, when possible, the precise formulation of the drug should not be disclosed to the participating physicians, and certainly not to patients. While patients need not enter into confidentiality agreements, their use of the drug should be carefully monitored (e.g., usage logs), and unused samples should be returned. Strict protocols should be put into writing and followed.

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ⁱ El. Lilly and Co. v. Zenith Goldline Pharm, Inc., 47 F.3d 1363, 1380 (Fed. Cir. 2006).

ⁱⁱ 715 F.3d 1351,1357 (Fed. Cir. 2013).

ⁱⁱⁱ Id.

^iv 549 F. App’x 934 (Fed Cir. 2013).

^v Id. at 943.

^vii Id. at *40.

^viii 471 F.3d 1369 (Fed. Cir. 2006).

^ix Id. at 1380-81.

^x Id.

^xi 204 F. Supp. 3d 665 (D. Del. 2016), aff’d sub nom., Sanofi v. Watson Lab’ys Inc., 875 F.3d 636 (Fed. Cir. 2017).

^xii 204 F. Supp. 3d at 698-99.

^xiii 875 F.3d at 649.

^xiv 536 F.3d 1361 (Fed. Cir. 2008).

^xv Id. at 1374-75.

^xvi 939 F.3d 1375 (Fed. Cir. 2019).

^xvii Id. at 1382-83.

^xviii 2024 WL 5135666 (D.N.J Dec. 17, 2024).

^xix Id. at * 8.

^xx Id. at *16.

^xxi 98 F.4th 1056 (Fed. Cir. 2024).

^xxii Id. at 1062.