05 June 2023
A recent case at the European Patent Office (EPO) Boards of Appeal, T 1806/18, held a known drug dispersed in apple sauce and orally administered to treat its authorised condition could be inventive – despite such a formulation having been disclosed as being administered to healthy individuals in clinical trial documents.
The Appellant-Proprietor appealed the decision of the Opposition Division (OD) to revoke the patent. Claim 1 of the main request read (in simplified form):
“A pyrimidylaminobenzamide of formula (I) … [the compound known as nilotinib] or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic myeloid leukemia (CML), wherein the compound … is orally administered dispersed in apple sauce.”
A key cited prior art document was a document from the European Medicines Agency (EMA) relating to a paediatric investigation plan (PIP) for nilotinib (document D1). D1 included three clinical study protocols: a first study in which the bioavailabilities of nilotinib capsules and dispersions in apple sauce or yoghurt were to be assessed in healthy adult volunteers, and second and third studies in which paediatric CML patients were to be administered nilotinib formulations (with no explicit mention of a dispersion in apple sauce). Whilst nilotinib was known to be effective at treating CML in adults, outcomes for none of the three trials were known by the priority date of the patent. Even though the studies were to include very young children who would not be able to swallow the capsule formulation, the Board held that “this fact does not allow concluding with certainty that this patient subset will receive the nilotinib/apple sauce formulation” (section 6.10 of the reasons), agreeing with the OD’s finding of novelty.
Of interest, the Board agreed with the Respondents-Opponents’ argument that the first study described in D1 was a suitable starting point for the assessment of inventive step, i.e., that this could be considered as a closest prior art disclosure despite the lack of results.
However, the Board disagreed with the Respondents’ argument that safety issues should not be considered when formulating the objective technical problem (OTP) to be solved because the reported safety issues were related to the specific use of apple sauce and not the distinguishing feature, i.e., the therapy. Instead, the Board approved of the Appellant’s reference to decision T 2506/12, which held that for a treatment to be effective, it must meet the criterion of efficacy and acceptable safety.
The Board then disagreed with the Respondents that the formulation was obvious based on D1 in light of the common general knowledge (CGK). The Board pointed to D6, that provided evidence that formulation with different foods altering the bioavailability of drugs in unpredictable ways was CGK. The Board also pointed to D58, which compared formulations of a different drug product in or with different foods, including in apple sauce, and showed there was differing drug bioavailability depending on the specific food type. D58 reports that the authors were surprised when small amounts of apple sauce caused significant delays in gastric emptying. The Board took this as further evidence of unpredictability and concluded the skilled person would not have been able to predict whether apple sauce would have any effect, and if so, how much, on the oral bioavailability of nilotinib. The Board also held that the skilled person would have been aware of other documents (e.g., D21) teaching that nilotinib can have potentially life-threatening adverse events when taken with food.
In reaching this conclusion, the Board made an interesting comment about the attitude of the skilled person when starting from D1. In particular, the Board agreed with the Respondents that “the skilled person would not have adopted a try-and-see attitude in solving the posed technical problem”, but went on to state that “this does not make the unpredictability of the food effect irrational. The fact that a clinical study is announced in a prior art disclosure does not automatically mean that its outcome was predictable and that a reasonable expectation of success had to be acknowledged.” (section 7.21 of the reasons).
The Board also dismissed the Respondents’ argument that the fact that the PIP applicant in D1 was the originator of the nilotinib capsule formulation would indicate that the applicant had a reasonable expectation of success with the claimed formulation (and that this could be inferred by the skilled person). Whilst the Board did not doubt the credibility of the content of D1, it stressed that “the respondents did not explain why the clinicians of the PIP applicant – despite being aware of the known unpredictability of the food effect of apple sauce on nilotinib – would still have had a reasonable expectation that the nilotinib/apple sauce formulation would exhibit an oral nilotinib bioavailability in healthy human adults comparable to that of the [commercial] capsule formulation” (section 7.52 of the reasons). The Board drew a distinction on the facts over decision T 239/16, which had been cited by the Respondents, on the basis that (i) the closest prior art in that case was a phase 2 clinical study; and (ii) there was no knowledge in the state of the art to diminish an expectation of success in the proposed treatment. By contrast, in the case at issue the closest prior art was a pharmacokinetic study in healthy volunteers, the result of which was unpredictable.
As there was no reasonable expectation of success based on D1 (or other documents) that the apple sauce formulation would have a comparable bioavailability to the capsule formulation, and hence be effective in treating CML, claim 1 was held inventive, overturning the OD’s decision.
This case further builds on established case law that the disclosure of planned clinical trials or clinical trials without published results do not mean the outcome of such trials is predictable, or that a reasonable expectation for success has to be acknowledged (see, for example, T 239/16). In this respect, it provides some comfort for patentees and innovators, although the Board does stress repeatedly that the correct approach will depend strongly on the facts of the case.
This particular case goes to show that even when a regulatory authority has approved a planned clinical trial in the intended patient group, a claim to the proposed treatment can still involve an inventive step. The case further illustrates how unpredictable effects of drug formulations can form the basis of a valid medical indication claim at the EPO.
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