25 May 2022
The European Patent Office (EPO) has a growing body of case law relating to the significance of clinical trial protocols when assessing novelty and inventive step. The latest in this line of decisions is T 2963/19. Here, an EPO Technical Board of Appeal considered whether a prior art document disclosing a clinical trial protocol without results provided a reasonable expectation that the treatment under investigation would be safe and effective.
The patent in question claimed a combination therapy for treating pancreatic cancer. The claimed dosage regimen involves administering defined amounts of liposomal irinotecan, 5-fluorouracil and leucovorin.
The patent was opposed on the ground of lack of inventive step (among others). The Opposition Division held that the claimed subject matter was obvious in light of a published clinical trial protocol describing a randomised, open label Phase III study of liposomal irinotecan in combination with 5-fluoruracil and leucovorin for treating patients with metastatic pancreatic cancer. The combined dosage regimen disclosed in the published clinical trial protocol differed from the claimed dosage regimen insofar as the order of administration was not specified and the dose of leucovorin was different. In addition, the published clinical trial did not disclose any results. During appeal proceedings, the question of obviousness essentially turned on whether the skilled person would have had a reasonable expectation that the published clinical trial protocol would have been safe and efficacious given the lack of results.
According to the established case law of the Boards of Appeal, a course of action (for example, conducting a clinical trial according to a given protocol) can be considered obvious if the results are clearly predictable or when there is a reasonable expectation of success (T 149/93).
The idea of what constitutes a ‘reasonable expectation of success’ takes on a specific meaning when talking about clinical trial disclosures, such as published protocols. This is because a published clinical trial protocol will generally lead to an ‘expectation of success’. Clinical studies are, of course, built on extensive in vitro and in vivo pre-clinical studies. Additionally, clinical trials must go through an approval process which typically involves peer review and ethical approval. During the approval process, consideration would be given to the likely benefits of the treatment and any potential risks. Therefore, a published clinical trial protocol would generally lead to an ‘expectation of success’ (see, e.g., T 239/16). Indeed, as reported recently in T 96/20, the Board considered that the disclosure of a Phase II clinical trial protocol provides, in and of itself, the skilled person with a reasonable expectation that the treatment would be a success, unless there was evidence to the contrary in the state of the art. These decisions appear to set a high bar for establishing inventive step over the prior disclosure of a clinical trial protocol. When a claim is alleged to lack inventive step based on the prior disclosure of a clinical trial protocol, inventiveness can be established by demonstrating that a known prejudice, e.g., a widely held but incorrect opinion of a technical fact, needs to be overcome (see, for example, T1212/01).
Perhaps unsurprisingly, the stage of the clinical trial is of significance. For example, in T 715/03 the disclosure that a compound is undergoing a Phase II clinical trial was only considered to be indicative of a therapeutic effect if results were also provided. Here, the Board held that a Phase II trial requires the demonstration of an acceptable safety profile in a Phase I trial, but not therapeutic efficacy. In contrast, since Phase II trials are intended to investigate efficacy as well as safety, a document disclosing a Phase III clinical trial may well be considered an implicit disclosure of therapeutic efficacy.
In the present case, the Board of Appeal held that the mere fact that a prior art document had reported the testing of the dosage regimen in a Phase III clinical trial does not automatically provide the skilled person with a reasonable expectation that the treatment under investigation would be safe and efficacious. Instead, with reference to T239/16 and T2506/12, the Board held that an expectation of success was highly dependent on the facts of the case in question. In this particular case, the Board concluded that there would be no automatic expectation of success based on the known challenges associated with developing a therapy for pancreatic cancer.
Instead, the disclosure of the clinical trial protocol had to be assessed in the context of any other disclosure relating to the safety and efficacy of similar dosage regimens. In the case in question, the clinical trial protocol had been preceded by positive reports of similar treatment regimens comprising the administration of liposomal irinotecan (MM-398), 5-fluorouracil and leucovorin in a Phase I setting. In light of these disclosures, the Board held that a positive outcome of the disclosed clinical trial could reasonably be expected.
Furthermore, the Board noted that the patentees themselves had relied upon prior disclosure of successful treatment using the triple combination of non-liposomal irinotecan, 5-fluorouracil and leucovorin in their arguments for sufficiency and plausibility. Given that the patent had proposed the claimed dosage regimen to be safe and efficacious on the basis of these prior disclosure, the Board stated that the same considerations had to apply when determining whether a positive outcome could reasonably be expected from the published clinical trial document. As such, the subject matter of the patent was considered to be obvious.
In summary, T 2963/19 highlights the potential risk posed by clinical trial protocols to the obviousness of a medical use claim. It is clear from the growing body of case law surrounding this topic that the potential risk of a clinical trial protocol will be highly fact specific. In particular, whether a clinical trial protocol provides an expectation of success will likely depend on whether there are significant safety concerns or other prejudices relating to the protocol, or for a claim to a combination therapy, whether are there known, effective treatments involving one or more of the recited drugs.
Sign up to our mailing list to receive Mathys Matters, our monthly newsletter covering the latest IP news, industry insights, events and case law.
If you are interested in receiving quarterly newsletters relevant to our core sector groups - IT & engineering ('Inside Wires') and life sciences & chemistry ('Under the Microscope') - please select your preference(s) below:
Please select your practice area(s) of interest: