What is the significance of a clinical trial protocol as prior art at the EPO? (T 1806/18)

The EPO Appeal Board has further refined their view on when prior art disclosures of clinical trial protocols are an issue for patentability of medical use claims.

Decision T1806/18

In decision T1806/18, published at the end of 2022, the Appeal Board provided their view on the significance of a prior art disclosure of a planned clinical study in a paediatric investigation plan (PIP).

The claim in question related to nilotinib, sold under the brand name Tasigna® by Novartis, for use in the treatment of chronic myeloid leukemia (CML), where nilotinib is orally administered dispersed in apple sauce.

The prior art was an European Medicines Agency (EMA) decision on an agreement of a PIP, which described three clinical studies to be carried out, as follows:

Study 1: Administration of nilotinib capsule, nilotinib/apple sauce formulation, or nilotinib/yogurt formulation to healthy adult volunteers.

Studies 2 and 3: Administration of a nilotinib formulation in paediatric CML patients.

Study 1, which described the nilotinib/apple sauce formulation, was planned for healthy adult volunteers, not CML patients. Studies 2 and 3, which were planned for CML patients, were follow-up studies to Study 1 and therefore the nilotinib formulation to be used in Studies 2 and 3 hinged on the outcome of Study 1. Thus, the formulation for Studies 2 and 3 was not yet known.

In deciding whether the claimed subject matter was obvious or not in view of the PIP protocol, the Board held that a prior art disclosure of a planned clinical study “does not automatically mean that its outcome was predictable and that a reasonable expectation of success had to be acknowledged. Whether this is indeed so, depends on the facts and circumstances of the case”. This is in accordance with previously established case law, which is discussed in more detail below.

The Board was convinced, on the facts of the case, that the skilled person would not have been able to predict the outcome of Study 1.

In the present case, the Board considered that the evidence established the following:

1. Food can alter bioavailability of a drug by various means.
2. The relative direction and magnitude of food effects on bioavailability and bioequivalence of a modified release drug product (such as nilotinib) are difficult to predict.
3. Unexpected food effects had been demonstrated for apple sauce in the context of didanosine, another modified release drug product.
4. Certain safety issues have been identified for Tasigna® capsules in a concentration-dependent manner when inappropriately taken with food.

The Board also did not accept that a food effect study for nilotinib with foods that were not apple sauce could be extrapolated to the claimed formulation.

In view of this, the Board held that the skilled person, starting from Study 1 of the PIP of the prior art document, would not have made any prognosis or had any expectation for the relative direction and magnitude of the food effect of apple sauce on the bioavailability of nilotinib after oral administration of the nilotinib/apple sauce formulation to adult healthy volunteers in Study 1 of the PIP.

Thus, the Board concluded that the claimed subject matter was inventive because the skilled person, being aware of the unpredictability of the food effect of apple sauce on nilotinib, would not have had a reasonable expectation that the nilotinib/apple sauce formulation would exhibit oral nilotinib bioavailability in healthy human adults comparable to that of the known nilotinib capsule formulation. Furthermore, a skilled person would not adopt a “try and see” approach in view of the known safety concerns.

The Board rejected the argument that the agreement by the Paediatric Committee (PDCO) to the proposed PIP meant that the EMA has a reasonable expectation that the nilotinib/apple sauce formulation would be safe and effective. This was because the Board was convinced by the evidence presented that the purpose of the PDCO investigation under the PIP is the design of the proposed studies and not the safety and efficacy of the formulation.

Established case law

This decision is consistent with existing EPO case law. It can be difficult for a patentee to convince the European Patent Office that a claim defining the same composition and indication as a clinical trial protocol is inventive. However, the Appeal Board has reiterated in a number of cases that the outcome depends on the specific facts. Disclosure of a protocol does not always mean that there is an expectation of success of achieving treatment of the claimed indication. Appeal Board decision T0239/16 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. T0239/16 (in which the patent was found to lack an inventive step) was considered in the present decision, and the Board distinguished the fact situation underlying the cases on at least the following:

• The closest prior art in T0239/16 was a phase II clinical study on dosage regimens treating the claimed patient group.
• Phase II clinical studies were known to be based on earlier preclinical studies.
• The skilled person's expectation arising from the suggestion of the closest prior art was not diminished by the relevant state of the art knowledge.

More recently and consistent with T0239/16, the Board found in T1123/16 published in June 2022, 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’. Again, the patent was found to lack inventive step.

Accordingly, a patentee faces a challenge in overcoming a prior art disclosure of a clinical trial protocol but, dependent on the circumstances, the Appeal Board is consistently finding it does not necessarily lead to a lack of inventive step.