Welcome to the second article in our series on the topic of EPO patentability in the context of clinical trials. In our first article, we reviewed how the EPO assesses clinical trials as prior art in relation to novelty. In this article, we will discuss the EPO’s approach to inventive step, and how this relates to applications based on a clinical trial.
Inventive step at the EPO when a clinical trial protocol is public
In our previous article, we demonstrated the publication of a clinical trial protocol does not destroy the novelty of a medical use claim at the EPO, since the EPO considers the attainment of the therapeutic effect to be a functional feature of such a claim, and a therapeutic effect is not disclosed if no results of the clinical trial are published at the time of filing. However, inventive step is more difficult. The publication of a clinical trial protocol disclosing the same compound, for the same disease, possibly even at the same dose, as claimed in a patent application may render the claim obvious, even in the absence of any results of the trial.
The EPO uses the problem-solution approach for assessing inventive step. This approach comprises 5 steps:
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Identifying the closest prior art
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Determining the difference between the closest prior art and the claimed invention
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Determining the technical effect of that difference
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Formulating the objective technical problem that is solved by the invention, based on the technical effect
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Deciding whether the claimed solution to the problem, starting from the closest prior art, is obvious in view of the state of the art as a whole and the skilled person’s common general knowledge
The final step, to decide if the claimed solution is obvious, is especially important to consider when the closest prior art is a clinical trial protocol. The EPO’s default position is that the existence of a clinical trial protocol establishes a reasonable expectation of success, even without results to demonstrate the efficacy of the invention. The EPO considers that “ethical and economical considerations require that the ‘benefit’ will arise with reasonable certainty and will not only ‘be hoped for’”, and that in view of a clinical trial protocol as prior art, the skilled person would have a reasonable expectation of success “unless [they were] dissuaded from this by the prior art” (see the EPO’s Technical Board of Appeal decision in T239/16).
Arguing against the EPO’s default position
It may be possible to convince the EPO that the prior publication of a relevant clinical trial protocol is not necessarily fatal for inventive step, if you can demonstrate … the skilled person did not have a reasonable expectation of success of solving the objective technical problem.
There are several examples of cases where the applicant was able to convince the EPO that the EPO’s default position that a clinical trial protocol renders a claim obvious should not be followed, and that instead the invention involved an inventive step, despite the disclosure of a relevant clinical trial protocol as the closest prior art.
At the time of writing, the most recent example of this is T1437/21. The patent (EP2981271) was directed to the use of empagliflozin (branded as Jardiance) to treat type II diabetes in patients with moderate renal impairment. The patent was initially revoked by an EPO Opposition Division (OD) due to lack of novelty over a press release describing a phase III clinical trial. The press release disclosed the trial was successful in determining the efficacy of empagliflozin in the treatment of type II diabetes in patients with mild, moderate, and severe renal impairment, as well as a specific statement of efficacy for the “mild” patient group. As such, a lack of novelty objection was maintained by the OD. On appeal, the patentee successfully argued the press release only provided general disclosure of treatment of patients with "mild to severe" renal impairment (and the specific attainment of a therapeutic effect for the “mild” group). By contrast, the patent claimed treatment of a specific subgroup of patients with "moderate" renal impairment, and therefore this patient subgroup was novel over the press release. The Board agreed.
As for inventive step, the patentee pointed out the mechanism of action of empagliflozin depended on renal function, and argued the skilled person would not have expected it to work in patients with decreased renal function. To further aid their inventive step argument, the patentee also submitted post-filed data showing empagliflozin is not effective in patients in the "severe" subgroup. Together, this convinced the Board of Appeal that the skilled person would understand that a clinical trial may be conducted with patient subgroups for which there is no reasonable expectation of success and that the skilled person would derive no expectation from the press release alone that the "moderate" subgroup would show positive results.
In another example, in the case underlying T108/21, the claim was to the treatment of multiple sclerosis using a 0.5mg daily dose. The closest prior art was a press release with results of a phase II clinical trial, disclosing a daily dose of 5mg or 1.25mg. However, the press release also announced an upcoming phase III trial, which included the claimed 0.5mg daily dose. After an initial refusal by the EPO’s Examining Division, the Board of Appeal decided that the claim was inventive on the basis that the prior art apparently taught away from the claimed dose of 0.5mg because skilled person would not have considered such a to be sufficient to meet a certain threshold of lymphocyte reduction thought to be required for therapeutic treatment. A patent was subsequently granted to the 0.5mg daily dose. It is worth noting that this patent is currently under EPO opposition by 23 separate opponents, with oral proceedings scheduled for February 2025.
Another decision where the applicants were able to convince the EPO that the existence of a clinical trial did not render the invention obvious, was T1806/18. In this case, the claim was to nilotinib (a tyrosine kinase inhibitor) for use in treating chronic myeloid leukaemia, wherein the nilotinib was orally administered in apple sauce. The prior art included an EMA decision on an agreement of a paediatric investigation plan (PIP) describing 2 studies:
Study 1: Administration in apple sauce to healthy volunteers
Study 2: Administration of ‘a formulation’ to CML patients
The claim was considered inventive, because the formulation to be used in Study 2 was dependent on the results obtained in Study 1. The Board of Appeal decided that the results of Study 1 were unpredictable in light of evidence that demonstrated the formulation of drugs within different foods, including apple sauce, can alter bioavailability in unpredictable ways, and the claimed invention would therefore not have been obvious to the skilled person.
As such, it may be possible to convince the EPO that the prior publication of a relevant clinical trial protocol is not necessarily fatal for inventive step, if you can demonstrate the particular facts of the case mean that the EPO’s “default position” should not be followed and that, in fact, the skilled person did not have a reasonable expectation of success of solving the objective technical problem.
Watch out for bonus effect!
Although an unexpected effect may be an indicator of inventive step, it does not always confer inventiveness. If it would have been obvious for the skilled person to arrive at something falling within the scope of the claims, for example if the skilled person could have predicted from the prior art the advantageous effect would result from a certain combination (T231/97), the claim may lack an inventive step. An unexpected effect might also not be inventive if there was a lack of alternatives in the means for achieving expected improvements (a one-way street situation as discussed in T192/82), or if the effect is a result of an obvious measure, even if the scale of the effect is surprising to the skilled person (T551/89). In such situations, the effect may simply be a ‘bonus effect,’ which would be considered obvious by the EPO.
Reliance on a “bonus effect” may be one strategy to employ if you are attacking patents in EPO oppositions in which the closest prior art is a relevant clinical trial protocol, as it could be argued the direction to the skilled person to carry out the clinical trial protocol as published is an inherently obvious thing to do. Thus, one could assert that even the attainment of an unexpected advantage should not rescue such a claim from a finding of obviousness.
The motivation of the skilled person in light of an earlier clinical trial
A further tactic to employ may be consideration of the motivation of the skilled person, when considering if a disclosure of related (but different) clinical trial renders it obvious to arrive at the claimed invention. For example, if the invention relates to the use of a compound as a monotherapy for a given disease, and it has only ever been used in a combination therapy for that disease, it may be possible to have an inventive step acknowledged on the basis that the skilled person lacks the motivation to use the compound in a monotherapy, for example due to the intractable nature of the disease. Of course, there may be a plethora of other ways in which the motivation of the skilled person could be brought in to help bolster the position on inventive step, and this should be considered on a case-by-case basis.
A balancing act
Ensuring claims are inventive presents a difficult balancing act for applicants. Filing before the clinical trial protocol publishes may help ensure that the claims are inventive, as the skilled person might not have a reasonable expectation of success in the absence of details of the clinical trial being publicly available. However, applications based on clinical trials require the data produced by the trials to be provided to the patent office to demonstrate the technical effect of the invention (e.g. a therapeutic effect in general, or a therapeutic effect at a specific dose or in a specific clinical scenario, such as for a given patient population) is actually achieved. One way to overcome this hurdle would be to file the application early, before the clinical trial has published, and include the data later during prosecution. However, even assuming the clinical trial data do eventually become available, this approach presents it’sits own issues with regards to sufficiency, and the allowability of post filed data at the EPO.
Subject to the way in which clinical trial protocol publications are treated in other jurisdictions (notably the US), consider if it is appropriate to wait until you will have the clinical trial data available to include in your application as filed, even if the clinical trial protocol has already published. In the event that you are faced with a relevant clinical trial protocol as prior art, make sure you consider all possible angles to convince the EPO that, despite the existence of the protocol, the skilled person still did not have reasonable expectation of success of solving the objective technical problem. The use of expert declarations at the EPO is common and they may be persuasive if the EPO is “on the fence” about whether to recognise an inventive step. Do also take steps to limit the disclosure of as many details of the protocol (such as dosages) as possible, insofar as this is practical in the jurisdiction in which the trials are taking place. Such considerations may even play into decisions on where to conduct clinical trials, depending on how the relevant national or regional authority deals with the publication of the details of recruiting and ongoing clinical trials.
Please stay tuned for our next article where we discuss the new legal test for the admissibility of post filed data in view of the widely discussed G2/21 Enlarged Board of Appeal decision.
If you enjoy our series and have any related questions, please contact Tom Leonard, Juliette Howarth, or your usual Kilburn & Strode advisor.