Navigating clinical trial disclosures: No reasonable expectation of success in a patient sub-population in view of prior art reporting phase III clinical trial (T 1437/21)

Recent EPO Board of Appeal decision T 1437/21 adds to a growing number of decisions concerning the patentability of second or further medical use inventions where the prior art relates to a clinical trial. At a time when the European Medicines Agency (EMA) is requiring increased transparency for EU clinical trials, this case law is of increasing importance to those operating in the pharmaceutical space.

In brief, this decision further supports the position that the disclosure of a clinical trial protocol does not always mean there is a reasonable expectation of success of achieving treatment. The Board considered that the outcome depends on the specific facts, in particular the nature of the investigational product and of the condition to be treated and the presence or absence of information suggestive of failure of the trial.

Background

The patent in dispute (European Patent 2981271, in the name of Boehringer Ingelheim International GmbH) claims the use of empagliflozin for the treatment of diabetes, including prediabetes and type 1 or type 2 diabetes mellitus, in a sub-population of patients having moderate renal impairment.

Empagliflozin is a SGLT-2 inhibitor, sold under the brand name Jardiance® by Boehringer Ingelheim and Eli Lilly for the treatment of type 2 diabetes mellitus.

At first instance, the opposition division (OD) found that the claims were anticipated by a press release from the patentee (in fact, two identical press releases were issued, one by Boehringer Ingelheim and one by Eli Lilly), which announced the results of a Phase III clinical trial assessing the use of empagliflozin for the treatment of type 2 diabetes mellitus in patients with “mild, moderate or severe renal impairment”.

The Decision

Novelty of a second medical use in a subpopulation of patients

Overturning the decision of the OD, the Appeal Board found the claims as granted to be novel.

The Board agreed with the patentee’s line of reasoning that “in accordance with the precise wording of the press releases […] the announced efficacy of treatment with […] empagliflozin […] may well be understood as relating to the patient population having mild, moderate or severe renal impairment as a whole” (section 3.3 of the Reasons; emphasis added). Therefore, from the information in the press releases the skilled person could not directly and unambiguously derive that the treatment with empagliflozin is effective for “each separate subgroup of patients defined by the mentioned levels of renal impairment”, and therefore for patients with moderate renal impairment specifically.

This line of reasoning was further supported by the omission of the specific number of patients involved in the trial corresponding to each subgroup. Whilst the press releases indicated the total number of patients, no “specific information regarding the number of participating patients with moderate renal impairment” was provided. The Board concluded that “[w]ithout this information the positive comments on the results from the trial expressed in the press releases […] do not provide any basis for the skilled reader to conclude that as a matter of fact the [treatment] must also have been effective in the patients with moderate renal impairment” (section 3.3 of the Reasons; emphasis added).

Thus, the Appeal Board disagreed with the OD in finding that the press releases did not provide a direct and unambiguous disclosure of the use of empagliflozin for diabetes treatment in the claimed subpopulation of patients.

Inventive step in the absence of a reasonable expectation of success

Moving to inventive step, the Appeal Board considered whether the claims were obvious in light of the closest prior art which was taken to be the patentee’s press release mentioned above. The Board formulated the objective technical problem as “the provision of effective treatment for diabetic patients with moderate renal impairment” (section 4.2 of the Reasons). In assessing the solution to the problem, the Board considered the “crucial issue” to be whether the press releases disclosing the encouraging safety and efficacy results of the Phase III trial would have given the skilled person “a reasonable expectation of success” (section 4.3.1 of the Reasons).

Referring to decision T 2963/19, the Board held that:

“The approval of a clinical study depends on the assessment of the foreseeable risks to the participants in relation to the anticipated benefit in terms of the relevance of the findings. The approval of a clinical trial does therefore not, by way of a heuristic, imply an expected positive outcome of the treatment.” (section 4.3.1 of the Reasons; emphasis added).

Notably, review articles cited in the proceedings disclosed that the efficacy of empagliflozin by the mechanism (SGLT-2 inhibition) mentioned in the press release prior art documents was dependent on the glomerular filtration rate (GFR) of the kidneys, which is reduced in patients with renal impairments. Post-published evidence showed that “efficacy of treatment was as a matter of fact not expected in patients with severe renal impairment” (section 4.3.2 of the Reasons).

The Board considered that “the mere inclusion of diabetic patients with renal impairment beyond the stage of mild renal impairment in the Phase III clinical trial described in [the press releases] could not by itself have provided the skilled person with a reasonable expectation of success of the treatment in these patients with moderate or severe renal impairment” (section 4.3.2 of the Reasons; emphasis added). The Board qualified the press release documents as “purely speculative” since they “do not provide any specific information on the number of patients in [the study] having moderate renal impairment” (section 4.3.3 of the Reasons; emphasis added).

Thus, in view of the mechanism of action of empagliflozin, which requires proper functioning of the kidneys, and in the absence of any evidence of a reasonable expectation of success of the effective treatment of diabetes with empagliflozin in patients with moderate renal impairments, the Board found the use of empagliflozin for the treatment of diabetes in patients with moderate renal impairment to be inventive.

Concluding remarks

In recent years there have been several EPO Board of Appeal decisions discussing the relevance of clinical trial protocol prior art. Appeal Board decision T 239/16 held that a phase II clinical trial protocol provided an expectation of success that the therapy in the clinical trial would work, unless a person skilled in the art was dissuaded from this by the prior art. Consistent with T 239/16, the Board found in T 1123/16 that in a case where there are no distinguishing features of the therapeutic application claimed other than efficacy, a clinical trial itself provides the expectation of success unless the state of the art provides reasons for not pursuing the solution envisaged in the trial, i.e., provides an ‘expectation of failure’. T 239/16 and T 1123/16 (in each of which the patent was found to lack an inventive step) were considered in the present decision, and the Board considered that the outcome of a case depends on the specific facts, “in particular the nature of the investigational product and of the condition to be treated and the [presence or] absence of information suggestive of failure of the trial”.

As a result, T 1437/21 now sits among a growing number of decisions where the Appeal Board have found that “the approval of a clinical trial does … not … imply an expected positive outcome of the treatment”. For example, in previous decision T 1806/18 (discussed in our article here), the Appeal Board had found that a published paediatric study disclosing a protocol for the use of a drug with apple sauce did not provide a reasonable expectation of success in view of evidence of the unpredictability of the food effect on bioavailability and bioequivalence the drug.

As the bulk of the case law in this area demonstrates, each case requires consideration in its own context. Notably, the onus of proving the lack of “reasonable expectation of success” in light of the clinical trial prior art disclosure lies heavily on the patentee.