Defining a patient population based on clinical trial results (T 2481/22)

Clinical trial data is highly relevant to defining a patient population more likely to respond to a particular treatment. However, in recent Board of Appeal decision T 2481/22, the Patentee’s definition of the patient subgroup in the claims did not establish an inventive step. A later published clinical study provided further insights into additional patient selection criteria impacting the therapeutic response and which were not included in the patent claim.

Background

The patent in dispute (EP3148521) claims a pharmaceutical product comprising fluticasone furoate for use in the treatment of COPD (chronic obstructive pulmonary disease) in a patient sub-group characterised by a blood eosinophil count of ≥150 cells/μL, wherein the product reduces the rate of decline in lung function.

Fluticasone furoate is a corticosteroid that is administered by inhalation ("inhaled corticosteroid" or "ICS"). “ICS medication is typically recommended to reduce symptoms, improve lung function and reduce the risk of exacerbations in COPD” (section 2.2 of the Reasons). At first instance, the opposition division (OD) rejected the opposition in finding the claimed sub-group of COPD patients inventive over the prior art.

The Appeal Board Decision: a lack of inventive step

Overturning the decision of the OD, the Appeal Board found the claims as granted to lack an inventive step.

Closest prior art and distinguishing features

The closest prior art (D37) was a journal article reporting the post-hoc analysis of a randomised, double-blind, placebo-controlled clinical trial investigating, inter alia, the effect of fluticasone propionate in COPD patients (the “TORCH study”) (section 2.8 of the Reasons).

The Appeal Board considered that the subject-matter of claim 1 could be distinguished from the disclosure of the TORCH study by two-parameters: “(i) by the use of fluticasone furoate rather than fluticasone propionate, (ii) by the specified patient group to be treated” (section 2.12 of the Reasons). As the commonly known furoate ester of fluticasone would have been an obvious alternative to the propionate ester used in D37, the key distinction to be considered for inventive step was the specified patient group, i.e. patients having a blood eosinophil count of ≥150 cells/μL.

Technical effect associated with the patient group recited in the claims

According to the general description of the Patent, it was found that COPD patients who have a blood eosinophil count of ≥150 cells/μL derive greater clinical benefit from treatment with an inhaled corticosteroid than those with lower eosinophil level (section 2.5 of the Reasons). In support of the alleged technical effect, the Patentee pointed to Example 1 of the Patent and corresponding evidence in a post-published document (D4). “Example 1 reports on the post hoc analysis of data obtained in the ’ISOLDE’ study, a three-year study of the effects of fluticasone propionate [… in] COPD patients” showing that the claimed sub-group of patients responded better to fluticasone, in terms of a reduced rate of decline in lung function, than the COPD population as a whole (section 2.16.1 of the Reasons).

The Appellant did not contest the results of the post hoc analysis of the ISOLDE study. However, the Appellant, relying on a post-published document (D36) argued that “the alleged improvement could [not] be attained for the entire patient group as defined in claim 1” (section 2.18 of the Reasons, emphasis added).

D36 is a “post-published observational study investigating the rate of decline in lung function of COPD patients”. In said study, “patients were stratified according to two criteria: firstly, based on whether they had been prescribed an ICS at baseline and secondly, based on blood eosinophil count, with a cut-off concentration of 150 cells/μl” (sections 2.19.1 and 2.19.2 of the Reasons). Concerning the first criteria, patients were categorized as “prevalent” if they had “at least one ICS containing medication in the year prior to the patient's index date”, and as “incident” if they had “no prevalent ICS use in the year prior to their index date” (section 2.19.2 of the Reasons). “It was not in dispute that the results reported in D36 for the incident cohort were consistent with those reported in Example 1 of the patent in suit and in D4” (section 2.19.4 of the Reasons). However, in the prevalent cohort, “no statistically significant difference was seen between patient groups when stratified by blood eosinophil level” (section 2.19.3 of the Reasons, emphasis added).

The Appeal Board considered the patients’ eligibility criteria for participation in the ISOLDE study described in D4 and Example 1 of the Patent. Namely, the Appeal Board considered the requirement of an eight-week wash-out period which provided “a setting corresponding to incident fluticasone use”. The Board noted that “D4 and Example 1 do not reflect the alternative therapeutic setting involving prevalent ICS use” (sections 2.19.4 and 2.19.5 of the Reasons, emphasis added).

In this regard the Patentee attempted to argue that looking at the incident data was, in fact, the correct approach to assessing the true effect of ICS on lung function without background interference of a pre-existing ICS treatment. This is because COPD is typically treated initially with bronchodilators, and ICS only added later if this turned out to be necessary. The Patentee argued that claim 1 was, in fact, focusing on the typical situation where a patient was to be initiated into ICS treatment. However, the Board considered that “it is not readily apparent that claim 1 can only refer to ‘incident’ patients who are being newly introduced to ICS treatment. Firstly, […]  the wording of claim 1 provides no such limitation […]. Secondly, there is also no technical reason why fluticasone should not be introduced following upon another ICS medication” (section 2.20.3 of the Reasons, emphasis added).

The Patentee further attempted to argue that “the results of D36 were not obtained exclusively with fluticasone. Rather, they were pooled results based on several ICS medicaments” (section 2.20.1 of the Reasons). The Board did not agree, noting that “[i]f the results of their analysis had differed significantly depending on the type of ICS medication used, the authors would have mentioned this in D26 as a relevant finding”, and concluding that “[o]n the balance of probabilities, […] the conclusions reported in respect of the class apply equally to fluticasone” (section 2.20.2 of the Reasons).

Accordingly, the Appeal Board held that the definition of the patient sub-group in claim 1 “having a blood eosinophil count of ≥150 cells/μL” failed to “distinguish between incident and prevalent ICS use” and that “the alleged technical effect […] would not be obtained for a part of the patient group defined in claim 1, namely those with prevalent ICS use. As a consequence, the alleged technical effect cannot be acknowledged in association with the patient group as defined in claim 1” (section 2.19.7 of the Reasons, emphasis added).

Obviousness

The Board considered that “the objective technical problem starting from the technical teaching of D37 is the provision of an alternative pharmaceutical product comprising fluticasone, for use in the treatment of COPD in a specific patient group, wherein the pharmaceutical product reduces the rate of decline in lung function” (section 2.23 of the Reasons).

The Appellant contended that the selection of this patient group had to be regarded as arbitrary and therefore obvious (section 2.28 of the Reasons). The Board noted that “[f]or performing an arbitrary selection of a patient group, the person skilled in the art would not have required a particular incentive but merely the absence of disincentives” (section 2.29 of the Reasons, emphasis added).

The Board considered that blood eosinophil levels were a known parameter routinely measured in the field for characterising patients with COPD. The Board held that “[s]tarting from D37, and seeking to define a specific patient group in accordance with the objective technical problem, the person skilled in the art would have considered the known group of subjects with a high blood eosinophil level since no disincentive or technical prejudice against this patient group was known in the relevant therapeutic context” (section 2.33 of the Reasons, emphasis added). Consequently, the subject-matter of claim 1 was considered obvious.

Commentary

Data emerging from clinical studies are a great source of information which can often be the subject of a patent claim. The identification of a patient subgroup which is more likely to respond to a particular treatment is a good example of situations where clinical data might be relied on to demonstrate the technical effect. As discussed in this Board of Appeal decision, to demonstrate an inventive step linked to a patient population, a patentee will need to show that the patient subgroup reacts differently (e.g. with added therapeutic benefits) compared to patients falling outside the subgroup. 

However, defining a patient population in a claim can be challenging. This is because, as seen in the present case, the technical effect associated with a patient subgroup may be challenged. In the present decision, the patient subgroup defined in the claims could not be associated with the alleged technical effect in view of post-published clinical data providing further insight on additional criteria for selecting the patient population for which a greater therapeutic benefit is observed. As a result, the claimed patient population was arbitrary, and the objective technical problem was the provision of an alternative application of the drug in the treatment of the disease. In the absence of disincentives in the art, the claimed patient subgroup was found obvious.

This case demonstrates that, when defining a patient subgroup, thoughts must be given to the possible relevance of all patient selection criteria used during a clinical study. Whilst a claim should not be too narrowly restricted, fall backs in dependent claims and in the detailed description should be included to cover any features which may become relevant. As shown here, the relevance of certain patient selection criteria may only become apparent after the filing date, which adds to the challenge faced by pharmaceutical and biotech companies to protect inventions relying on clinical trial outcomes.