The recent decision by the European Patent Office (EPO)'s Technical Board of Appeal 3.3.04 in T 96/20 appears, at first glance, to have raised the bar for acknowledging the inventive step of medical use claims in a situation where the prior art discloses that the claimed therapeutic is undergoing clinical trials. However, a broader view suggests that a more nuanced approach is required.
There have been numerous decisions by the EPO's Boards of Appeal which have demonstrated how clinical trial disclosures can become an obstacle to the patentability of medical use claims.
The Boards have repeatedly recognised the novelty of medical use claims over prior art disclosures indicating that clinical trials were underway, but whose results were not yet reported (e.g.T 158/96, T 715/03 and T 385/07). However, the disclosure that a therapeutic is undergoing clinical trials can nevertheless become a bar to securing an inventive step, even where the results of the trial have not been made available to the public (as discussed in e.g. T 2506/12 and T 239/16).
The decision in T 96/20, at first glance, appears to furtherraise the bar on inventive step. Here, the Board deems that the disclosure of a Phase II clinical trial protocol for eculizumab (Alexion's anti-complement component C5 antibody; marketed as Soliris®) for the treatment of the neuromuscular disorder myasthenia gravis (MG), in and of itself, provides the skilled person with a reasonable expectation that the treatment would be successful.
The Board considers that this expectation would stand "unless there was evidence to the contrary in the state of the art". The Board is not swayed by the appellant's argument that MG was known to be difficult to treat in humans. In view of the complexity of the complement cascade and its implication in a variety of diseases, the Board also rejects the notion that reports in the art of failures to treat other complement-associated disorders using different types of inhibitors would diminish the skilled person's expectation of success. Of interest, on this point, the Board states that:
"In view of this complexity, the board is satisfied that the failure of other complement inhibitors to treat diseases unrelated to MG did not necessarily call into question the skilled person's expectation that MG could be treated successfully with Eculizumab. In fact, in the board's view, only evidence relating to the same compound and disease would be suitable for this purpose".
(Reasons 13; emphasis added)
Consequently, the appellant's medical use claims directed to the use of eculizumab in the treatment of MG are deemed to lack an inventive step by the Board.
The notion that a Phase II clinical trial protocol may provide a reasonable expectation of success is not new. In T 239/16 the Board asserted that a reasonable expectation of success arises because clinical trials are known to be based on earlier preclinical studies (thereby suggesting the success of the therapeutic concerned) and because their approval entails ethical considerations which require that a benefit will arise with "reasonable certainty" (see 6.5 and 6.6 of the Reasons). In that case, however, the class of active agents to which the claimed therapeutic belonged was known to be generally effective in treating the condition in question and the Board decided that there was nothing in the state of the art to lead the skilled person to believe that the claimed once-yearly administration regimen (corresponding to one of the arms in the clinical trial) would not be effective.
The facts underlying T 96/20 are different to T 239/16, in that the claimed medical use is not a specific administration regimen and no effective treatment with the same class of active agents (anti-C5 antibodies) was known in the art. The Board nevertheless comes to the same conclusion, namely that the Phase II trial protocol provides a reasonable expectation that the therapy will be effective. Thus, in T 96/20 the Board seems to be further raising the bar because it appears to endorse a very rigid approach to the assessment of inventive step, in which the disclosure of a clinical trial protocol is automatically deemed to provide an expectation of success which is only diminished if there is evidence to the contrary in the prior art pertaining to the same therapeutic and the same disease.
Reaching such a conclusion would, however, mean disregarding much of the existing EPO case law indicating that a more nuanced approach is required and setting out multiple factors which must be taken into consideration and carefully balanced when establishing whether a prior art disclosure provides the skilled person with a reasonable expectation of success. A useful insight into the thought processes which may underpin the Board's assessment of the skilled person's expectations in T 96/20 is provided by decision T 33/19 which was issued by the same Board (3.3.04) in the same composition on the same date as T 96/20. That decision also pertains to medical uses of eculizumab, albeit for the treatment of a different condition (aHUS).
In T 33/19 the prior art did not include a clinical trial disclosure. Instead, the art suggested investigating anti-C5 antibodies as a therapeutic option for treatment of aHUS. The Board considered that this teaching in the art was merely speculative because it was not based on in vitro or in vivo experiments (anti-C5 antibodies had not been tested in an animal model for aHUS) and the art also expressed uncertainty as to the outcome of such a treatment. Thus, the Board concluded that a reasonable expectation that aHUS could be successfully treated with eculizumab did not exist.
The factors considered by Board 3.3.04 in T 33/19 align with those in earlier decisions pertaining to clinical trial disclosures, for example asking whether the therapeutic belongs to a class of compounds that was known to be effective in the treatment of the disease (which it was in T 239/16, but not in T 715/03). In T 96/20 the Board does not provide any written reasoning in response to the Appellant's argument that, by contrast to T 239/16, eculizumab was the first complement inhibitor approved for the treatment of MG. That does not mean, however, that this factor was ignored by the Board in reaching its decision.
Another factor which is not discussed in the reasoning of T 96/20, but which is important to consider, is that the skilled person has at hand their own knowledge of the clinical trial application process and the varying criteria that must be met in order to receive approval for the different phases of a clinical trial. Whilst it might generally be the case that the approval of a Phase II trial indicates some expectation of success, it cannot be assumed that the level of expectation will be high in all cases. Approval of a Phase II trial does not automatically indicate that Phase I has concluded, neither does it imply any positive therapeutic outcome from Phase I. In reality, Phase I and II may overlap (as seen with the recent trials for the Covid-19 vaccines, for example).
The skilled person also has knowledge that certain clinical trials with specific risk factors may require additional experimental evidence and evaluations prior to approval, e.g. if the drug acts via a species specific mechanism such that animal models are unlikely to be predictive of activity in humans or where target expression differs considerably between healthy subjects and those with the disease1. On the other hand, the skilled person also knows that there are situations in which the level of supporting evidence required for Phase I approval is low, e.g. trials involving a known therapeutic for a new indication. The skilled person is also aware of situations in which approval of a drug for use in humans is based on minimal pre-clinical data. For example, it is known that the scientific evidence required for orphan drug designation can be minimal and, in some circumstances, may only be based on in vitro data2. In such cases, the expectation of achieving a safe and effective treatment is arguably closer to a 'mere hope to succeed' than to any 'reasonable expectation of success'.
Taking all of the above into consideration, it becomes clear that the question as to whether or not the disclosure of a clinical trial protocol provides a reasonable expectation of success is undoubtedly highly subjective and based on a balance of several factors. To assert that there is automatically an expectation of success in every situation which is only diminished by evidence pertaining to the same therapeutic and the same disease seems to set the bar too high. Moreover, it would neglect all of the above considerations and circumstances which are critical to evaluating the skilled person's ability to make a rational and informed prediction as to whether the envisaged treatment would be successful. The fact that the same Board was clearly aware of these factors in their decision T 33/19 indicates that the reasoning in T 96/20 is not intended to depart from the earlier case law of the Boards of Appeal in this area.
For this reason, we consider that T 96/20 should not be seen as a radical departure from earlier EPO jurisprudence, nor should it be seen as a reason to disregard the above considerations. It should, however, act to highlight the complexities of EPO practice in this area and as further encouragement (if any were needed) to applicants and patentees to provide as much evidence as possible about the low expectation of success of the skilled person based on the state of the art, especially where that includes Phase II clinical trial protocols.
Summary of factors which may influence the skilled person's expectation of success
Factors which can contribute to the skilled person's expectation of success
The claimed therapeutic belongs to a class of compounds known to
be effective in the treatment of the disease (T 239/16 Reasons
The art contains no indication that the claimed therapeutic would behave differently to other compounds from the same class which are known to be effective in the treatment of the disease (T239/16 Reasons 6.5)
A suitable animal model for the disease exists and the claimed therapeutic has been tested in that animal model (T239/16 Reasons 6.6)
Factors which can diminish the skilled person's expectation of success
- The claimed therapeutic has a chemical structure and/or belongs to a class of compounds that is dissimilar to those known to treat the disease (T 715/03 Reasons 2.4.3, T 239/16 Reasons 6.6)
- There is no suitable animal model for the disease (T715/03 Reasons 2.2)
- The disease is a complex disorder for which an animal model does not exist and there is an express indication in the art that conclusions as to tolerability and/or efficacy must await the results of the clinical studies (T 715/03 Reasons 2.2)
- Lack of data based on in vitro or in vivo experiments (T 33/19 Reasons 20)
- Evidence relating to a lack of efficacy of the same compound in treating the same disease (T96/20 Reasons 13)
Secondary factors which may or may not influence the skilled person's expectation of success
- No therapy for the disease has been approved for a long period of time (T 96/20, Reasons 10)
- The drug acts via a complex cascade system and the art contains reports of failed attempts to treat diseases associated with that system, but these failures pertain to different compounds and different diseases (T 96/20 Reasons 12-13)
- Clinical trial success is not certain, or the success rate is low for the disease/class of diseases (T 239/16 Reasons 6.6, T 2506/12 Reasons 3.12.2)
- The therapeutic has not yet been tested in humans (T 239/16 Reasons 6.6)
- The medical use claim and clinical trial disclosure relates to a new combination of drugs, but the prior art teaches that each component of that combination is efficacious in treatment of the disease when used alone (T 2506/12 Reasons 3.9-3.10)
1. See, for example, the guidance that is provided under the heading "Applications that need expert advice" found here: Clinical trials for medicines: apply for authorisation in the UK – GOV.UK (www.gov.uk)
2. See e.g. page 5 of the European Medicines Agency's Committee for Orphan Medicinal Products (COMP) recommendation paper on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation (EMA/COMP/15893/2009 Final)
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