How Clinical Trials Affect Patentability in US and Europe

Innovators in the pharmaceutical field must conduct clinical trials to market their products. These trials often provide the basis for applications that protect innovative therapeutic applications of the candidate products, such as preferred formulations, combinations, dosages, new medical uses, etc. However, disclosures relating to clinical trials may adversely affect the patentability of these inventions.

Three recent decisions in the U.S. and at the European Patent Office, or EPO, have considered the extent to which written disclosures relating to such trials and the conduct of the trials themselves may affect patentability, bringing into focus the importance of managing clinical trial disclosures and implementing appropriate patent filing strategies.

These are the U.S. Court of Appeals for the Federal Circuit decision on April 11 in Salix Pharmaceuticals Ltd. v. Norwich Pharmaceuticals Inc., the EPO Technical Board of Appeal, or TBA, decision on Feb. 9 in T 1437/21, and the EPO opposition decision on March 19 for European patent EP 2345410.

Clinical trials involve the public use of medicine and are often accompanied by written disclosures, such as trial protocols and press releases. In this article, we compare the impact of these disclosures on patentability in both the U.S. and Europe, and provide guidance on good practice when dealing with disclosures relating to clinical trials in these commercially important jurisdictions where clinical trials are typically required before a medicine can be brought to market.

Public Use

Public use of an invention before filing for a patent application can defeat patentability in both Europe and the U.S. However, some inventions may only be identified through administration of a drug candidate to participants during clinical trials.

Therefore, it is important for innovators to understand the circumstances under which clinical trials will qualify as prior public uses.

Europe

At the EPO, a question that must be considered when assessing public use in relation to clinical trials is whether the trial participants are free to dispose of the medication. To assess this, the EPO will consider the trial circumstances.

For instance, in the TBA decision T 7/07 in 2011, there was no requirement for the return of unused medication. The TBA therefore concluded that the trial organizers had lost control of the medication because participants were free to dispose of the medication as they wanted. The TBA held that this effectively made the medication available to the public, and the claims to the medication were therefore found to lack novelty due to public prior use.

Subsequent EPO case law clarified that not all trial protocols lead to public prior use. The European Medicines Agency's guidelines on good clinical practice have an explicit requirement for adherence to the trial protocol. Therefore, the EPO has acknowledged that — for trials conducted in line with the good clinical practice guidelines — participants are expected to comply with the protocol.

The TBA decision T 670/20 in 2022, considered a case where this applied, and the protocol specified that investigators had an obligation to ensure drug accountability and the return of unused medicine. Under these circumstances, clinical trial participants were considered to have entered into a "special relationship" with trial organizers, where they were not able to freely dispose of medicine. Therefore, the TBA held that the medicine was not available to the public, so there was no public prior use.

This principle was tested against actual loss of medication during a clinical trial in the EPO opposition decision on March 19 for European patent EP 2345410. One of the opponents pointed to evidence that numerous patients were "lost during follow-up" by dropping out of the study, and argued that this constituted a loss of control of the drug.

However, the opposition division held that strict adherence to the trial protocol should be the primary consideration. Despite the evidence presented by the opponent that patients with drugs had been lost during follow-up, the opposition division maintained the requirement in the clinical trial protocol for the return of unused medication superseded the loss of patients to follow up.

Therefore, it seems that the expectation of adherence to the trial protocol overrides a demonstrable loss of control of medication. This would seem to provide reassurance to those conducting clinical trials under appropriate protocols. However, the decision has been appealed, so it remains to be seen whether the TBA will reach the same conclusion.

It is important to note that this "special relationship" only applies between the trial investigators and participants. In the TBA decision T 239/16 in 2017, prospective trial participants were actively encouraged to discuss the trial with both their doctor and their family.

The TBA found that neither the participants' family members nor their doctors had entered into a special relationship with the trial organizer. Therefore, they were considered members of the public, and any information shared by participants was publicly disclosed and not deemed subject to any confidentiality obligations.

The U.S. 

In the U.S., whether a clinical trial constitutes public use of a claimed invention may depend on the existence of confidentiality agreements and the level of detail about the trial that is disclosed to the subjects and collaborators.

In Dey Pharma LP v. Sunovion Pharmaceuticals Inc.,[1] in May 2013, the Federal Circuit addressed whether a clinical trial conducted before the effective filing date of the claimed invention qualified as a prior public use. Here, the investigators, but not the subjects, had signed confidentiality agreements.

Although the clinical trial tested the claimed formulation of the drug at issue, the court held that the clinical trial did not constitute a public use because it was conducted with a reasonable expectation of confidentiality.

The court focused on the fact that although the subjects were not bound by a confidentiality agreement, they did not know the specific formulations of the drug. Only the investigators knew the formulation, and they had signed confidentiality agreements. Therefore, the clinical trial did not qualify as a public use.

Contrasting Dey with Pronova BioPharma Norge AS v. Teva Pharmaceuticals USA Inc.,[2] decided in September 2013, confirms that confidentiality agreements are important in determining whether a clinical trial constitutes public use. In Pronova, the Federal Circuit held that shipping samples with a certificate of analysis to a collaborator for use in a clinical trial constituted public use because the analysis detailed the claimed formulation.

The court focused on the lack of a confidentiality agreement and the fact that the collaborator, unlike the subjects in Dey, was highly skilled in the art. Therefore, there was no expectation of secrecy and thus, public use occurred.

In addition to confidentiality agreements, the Federal Circuit considers the level of control clinical trial investigators exercise over drug product.

In Bayer Schering Pharmaceuticals AG v. Barr Laboratories Inc.,[3] decided in 2008, the Federal Circuit held that there was no public prior use in a clinical trial where patients failed to return unused drug product. The court held that because the trial required patients to maintain a diary that recorded compliance with drug protocol, there was adequate control and no public prior use.

Comparison

Therefore, for both the U.S. and Europe, innovators should assess the protocols for clinical trials to ensure express terms prohibit participants from freely disposing of medication. In addition, where possible, innovators should use confidentiality agreements to prevent the public disclosure of information that may be the subject of patents to new therapeutic applications.

Printed Publications

Clinical trial documents can also qualify as prior art in both Europe and the U.S.

Europe

When considering whether a prior art document relating to a clinical trial renders the claimed invention obvious, the EPO considers whether the document provides a reasonable expectation of success.

In the TBA decision T 1806/18 in October 2021, a pediatric investigation plan for a clinical trial was publicly available before the effective date of the patent directed to a cancer therapy — nilotinib — formulated in apple sauce. The plan disclosed treatment with either a capsule or dispersion with yogurt or apple sauce.

In view of the technical information presented, the TBA concluded that the pediatric investigation plan did not provide a reasonable expectation for either the relative direction or magnitude of the food effect of apple sauce on the bioavailability of nilotinib. The TBA therefore held that the invention was not obvious.

However, the absence of a specific pointer toward the claim does not necessarily result in a finding of inventiveness. In the TBA decision T 239/16 in 2017, the patent was directed to a specific dosage regime for zoledronic acid in the treatment of osteoporosis. The TBA found that the clinical trial study documents set up an expectation that the claimed dosage regime would be successful, which rendered the claim obvious.

The EPO also considers the field when assessing whether there is a reasonable expectation of success. In decision T 2963/19 in March 2022, the TBA considered whether a Phase III clinical study protocol for the treatment of gemcitabine-resistant pancreatic cancer resulted in an expectation of success for the treatment in question.

The TBA acknowledged that in a field like this — where development of treatments is challenging, and the success of clinical trials is low — a protocol alone does not provide a real expectation of success. However, the TBA also considered the positive outcome of completed Phase I and II studies and decided that these in combination with the teaching of the Phase III protocol resulted in a reasonable expectation of success.

The EPO does distinguish between a reasonable expectation of success and a hope of success. In TBA decision T 108/21 in February 2022, a press release announcing a Phase III clinical trial with 1.25 mg and 0.5 mg doses was considered as prior art for a claim directed to treatment with a 0.5 mg dose.

However, the TBA considered this announcement to be a "hope of success" or a mere expression of a wish. This was contrasted to the reasonable expectation of success being a presupposed scientific appraisal of available facts.

An alternative frame for whether there is a reasonable expectation of success proposed by the TBA is whether the skilled person would predict rationally, on the basis of existing knowledge, a successful conclusion within reasonable time limits. Therefore, the EPO clearly distinguishes between more detailed disclosures, such as clinical trial protocols, and more limited disclosures, such as press releases.

In decision T 1437/21 on Feb. 9, the TBA reaffirmed that the concept of reasonable expectation of success is decisive when assessing nonobviousness. The specific subpopulation claimed were diabetic patients with moderate renal impairment, whereas the relevant prior art was a press release relating to a broader clinical trial, not focused on the subpopulation of patients.

Here, the TBA found that the mere inclusion of diabetic patients in the clinical trial did not provide a reasonable expectation of success that they would be successfully treated, so the claims were found to be inventive.

The U.S. 

The Federal Circuit has held that a subject's response to a candidate drug is an inherent result of performing a clinical trial. Therefore, a published clinical trial protocol may anticipate or render obvious claims reciting aspects disclosed in the protocol, even where efficacy is a claim feature.[4]

In Salix v. Norwich,[5] the Federal Circuit upheld the use of a clinical trial protocol published on ClinicalTrials.gov as prior art to invalidate the challenged claims as obvious. Although the protocol contained no efficacy or safety data, the Federal Circuit upheld the district court's obviousness judgment because the protocol was used in combination with a journal publication that included efficacy statements on the optimal dosage of the drug at issue.

However, the Federal Circuit has held that for efficacy to be an inherent aspect of a clinical trial publication there must be a requisite expectation of success.

In 2017, the Federal Circuit explained in Sanofi-Aventis U.S., LLC v. Watson Laboratories Inc.[6] that post-hoc statements made about the future implications of a clinical trial may not have the requisite expectation of success to support an obviousness challenge.

At issue in the Sanofi case were two publications where the inventors expressed opinions based on post-hoc analysis of two clinical trials designed to test the effect of a drug on heart arrhythmia.

The inventor's statements in the publications and the claim language were directed at using the drug to reduce hospitalization or death, not toward the reduction of heart arrhythmias. The publications stated that the inventors were planning a new study to assess the effect on hospitalization rates. Both sides had experts supporting opposite arguments as to whether the publications provided an expectation of success in using the drug to reduce hospitalization rates.

The Federal Circuit upheld the U.S. District Court for the District of Delaware's decision in Sanofi v. Glenmark Pharmaceuticals Inc. in 2016, which heavily relied on Sanofi's expert opinion that Watson Laboratories Inc. had failed to show an expectation of success. This case not only demonstrates the importance of reliable expert testimony, but also that success is not inherent in all clinical trial publications.

Comparison

In both jurisdictions, innovators should file as early as possible to minimize the impact of clinical trial disclosures on patentability. Consider filing the application before publication of the clinical trial protocol and submitting subsequent clinical trial data later during prosecution to minimize the prior art impact of the trial.

However, where this is not possible, a detailed consideration of how much information needs to be disclosed, and whether the disclosure risks being viewed as providing an expectation of success should be considered. In addition, any prior art teachings pointing away from the invention can be valuable in obtaining protection where a clinical trial disclosure is already prior art.

Therefore, in addition to running clinical trials in accordance with good clinical practice guidelines, it is advisable to minimize and control the content of written disclosures, to mitigate any risk of these disclosures being found to provide an expectation of success in subsequently filed applications.

Endnotes

[1] Dey, L.P. v. Sunovion Pharms. , 715 F.3d 1351 (Fed. Cir. 2013).

[2] Pronova Biopharma Norge AS v. Teva Pharms ., 549 F. App'x 934 (Fed. Cir. 2013).

[3] Bayer Schering Pharma AG v. Barr Labs., Inc.. , No. 05-CV-2308(PGS), 2008 WL 628592, at *42 (D.N.J. Mar. 3, 2008).

[4] In re Montgomery , 677 F.3d 1375, 1382 (Fed. Cir. 2012).

[5] Salix Pharms. v. Norwich Pharms. , Nos. 22-2153, 23-1952 (Fed. Cir. 2024).

[6] Sanofi v. Watson , 875 F.3d 636 (Fed. Cir. 2017).