Positive and negative pointers in clinical trial prior art: diverging inventive step outcomes at the EPO and UPC

T 136/24 and UPC_CFI_146/2024, 496/2024, 147/2024, 374/2024, 148/2024, 503/2024

Recent EPO Board of Appeal and first instance UPC decisions confirmed that the announcement of a clinical study in the prior art is to be assessed based on the pointers in the art, including both positive and negative pointers. Therefore, whether the disclosure of a clinical study provides a reasonable expectation of success of the trial always depends on the particular circumstances of the case.

However, proceedings before the EPO’s Board of Appeal in T 136/24 and the Munich Local Division (LD) of the UPC^[1] arrived at different decisions in relation to EP 2 493 466. Whilst the Board of Appeal considered the claims to be inventive over the announcement of a phase III clinical trial, the Munich LD disagreed and revoked the patent for lack of inventive step, thus following the decision by the Tribunal Judiciaire de Paris revoking the French designation of the patent in September 2024 (case number 21/06416).^[2]

The EPO’s and the UPC’s views differed regarding what would need to be reasonably achieved, i.e. what “success” would need to be reasonably expected, to result in a finding of lack of inventive step. The EPO and the UPC also differed in their assessment of the positive and negative pointers.

Background

EP 2 493 466 relates to cabazitaxel (sold under the brand name JEVTANA^® - authorised by the European Medicines Agency in 2011), in combination with prednisone or prednisolone for use in treating prostate cancer, in particular castration resistant metastatic prostate cancer (mCRPC) in patients who have been previously treated with a docetaxel-based regimen and have prostate cancer that progressed during or after said treatment.

The patent disclosed the results of a phase III study (TROPIC), the purpose of which was to compare cabazitaxel (in combination with prednisone) with mitoxantrone (in combination with prednisone) in mCRPC patients. These results indicate that the median overall survival of patients receiving cabazitaxel was improved by 2.4 months compared to patients receiving mitoxantrone, including for the subpopulation of patients claimed.

The prior art included:

• The results of a phase I study on cabazitaxel in a variety of different solid tumours. The study included eight patients with prostate cancer, two of whom showed improvements in response to treatment. One of these two patients had previously been treated with docetaxel.
• The results of a phase II study on breast cancer showing an encouraging response to cabazitaxel in patients previously treated with docetaxel and having developed resistance to docetaxel.
• The announcement of the phase III TROPIC clinical trial (for which the results were disclosed in the patent), without any experimental data.

Decisions

At the EPO, the patent was opposed by 12 opponents. At first instance, the Opposition Division rejected the oppositions finding that there was no reasonable expectation of success under Article 56 EPC. At appeal, the Board agreed with the Opposition Division and dismissed the opponents’ appeals, finding that the claimed invention was inventive over the phase III TROPIC trial disclosure.^[3]

However, at the UPC the Munich LD found the patent invalid for lack of inventive step over the phase III TROPIC trial disclosure, in view inter alia of the prior phase I and II clinical data on cabazitaxel. An appeal against this first instance decision may be lodged at the UPC Court of Appeal.

Both the Appeal Board and the Munich LD considered the disclosure of the TROPIC trial as the closest prior art. The TROPIC trial announcement disclosed all the technical features of claim 1, with the exception of attaining the claimed therapeutic effect.

The objective technical problem

The Appeal Board formulated the objective technical problem as how “to put into practice the effective treatment of prostate cancer with cabazitaxel in co-administration with prednisone” in the claimed patient population (section 7.8 of the Reasons).

The Munich LD formulated the objective technical problem more broadly as the provision of “a therapeutic option” for treating the claimed patient population. The Munich LD defined the “therapeutic option” as including both “increased overall survival and palliative treatment only”. The Munich LD opined that the Board of Appeal’s formulation of the objective technical problem contained “part of the solution and thus does not avoid hindsight” (pages 29-30 of the UPC Decision).

Both the Board of Appeal and the Munich LD considered that positive and negative pointers (or indicators) must be evaluated and weighed against each other to arrive at an overall assessment of whether there was reasonable expectation of success to arrive at the claimed invention (section 7.14 of the Reasons and page 33 of the UPC Decision).

No reasonable expectation of success at the EPO

In considering whether there was reasonable expectation of success, the Board held that it is “of the view that the skilled person's expectation of success has to be considered in particular in relation to the TROPIC study's primary endpoint, which was overall survival. Success in the context of a clinical study means meeting the primary endpoint. […] Thus, to lead to a finding of lack of inventive step, an expectation of success for improved overall survival must have been present” (section 7.13 of the Reasons, emphasis added).

The Board held that the case law developed by the boards “mainly focuses on balancing positive and negative pointers. […] Thus the probative value of a clinical study announcement always depends on the particular circumstances of the case”. The Board noted that “ongoing clinical studies [do not] automatically establish a legal presumption of success” (sections 7.14 and 7.14.1 of the Reasons, emphasis added).

Overall, the Board considered the positive pointers brough forward by the opponents not convincing and that they do not provide a reasonable expectation of success of the study (section 7.16 of the Reasons). In particular, the Board noted that:

“Under usual circumstances, the fact that a phase III clinical trial is carried out might indeed provide a pointer indicating a successful development path of a new drug/new drug application (see D18).

D18 is written on the basis of a standard clinical study development programme, which includes a phase I study, followed by a phase II study to assess dosage and efficacy, followed by a ‘confirmatory’ phase III study in a large population to confirm the efficacy demonstrated in the phase II study.

However, in the case in hand, the usual path of drug development is only poorly reflected.” (section 7.15.3 of the Reasons).

For example, the Board noted that “the data from the preclinical phase were sparse and incomplete”. Additionally, the phase I clinical data were “not of the type to allow any insights on a possible increase in overall survival”. The phase I study “did not focus on prostate cancer and was not powered to show therapeutic efficacy, cabazitaxel was administered to patients having a variety of different solid tumours [with only one] patient in the phase I study meeting the definition of the patient group in claim 1”. The Board found that the health changes in this single patient could not “be attributed with certainty to therapeutic efficacy of cabazitaxel”.  There was also “no relevant data from a phase II clinical study are available” (sections 7.15.2, 7.15.3, 7.25 and 7.32 of the Reasons).

The Board stated that “the majority of phase III clinical studies fail”, and in this case “the extremely poor prospects for patients with mCRPC, especially docetaxel-refractory mCRPC, was a major factor in the TROPIC study being permitted to proceed” (section 7.15.4 of the Reasons).

In the absence of a reasonable expectation of success, the Board found that the claimed subject-matter involves an inventive step.

Reasonable expectation of success at the UPC

The Munich LD held that the assessment of inventive step should not be based on whether the TROPIC trial will meet its primary endpoint, i.e. increased overall survival in patients in the cabazitaxel group compared to the control group. The Munich LD held that “[t]his is because the technical problem that the patent in suit intends to solve is to provide a therapeutic option for [the claimed patient population]. This includes both increased overall survival and palliative treatment” (page 33 of the UPC Decision).

The Munich LD considered that in the absence of a phase III trial, the results of the phase I study in a single patient may not have been viewed “as sufficient to reasonably expect that cabazitaxel would provide an improved treatment to patients having progressed during or after the treatment with docetaxel”. However, in the present case “the phase III trial TROPIC was almost complete, without interruption or discontinuation. This implied for the skilled person that this was effective in the treatment of patients with mCRPC previously treated with docetaxel” (page 37 of the UPC Decision).

The Munich LD further held that “it is not unusual in the field of oncology that a clinical phase III trial is based on a phase I trial including patients having different types of cancer besides the cancer type selected for the phase III trial and a phase II trial concerning a different type cancer as such of the phase III trial” (page 38 of the UPC Decision). The Munich LD also noted that anecdotally, a post-published document revealed that the breast cancer Phase II trial had been relied on to support the application to have the Phase III prostate cancer trial approved (page 39 of the UPC Decision).

The Munich LD agreed with the Appeal Board that “the fact that a study is nearing completion per se, is in the absence of knowledge of the parameters selected for monitoring, neither a positive nor a negative pointer when assessing expectation of success”. However, the Munich LD noted that:

“what can however be derived from the fact that the Tropic trial had been approved and had been in progress for three years at the priority date without having been stopped, is that at least the sponsor of this trial had not considered it disappointing at the start and at no time until the priority date.

This supports the expectation of success, because the Phase III study ‘TROPIC’ was based on successful previous preclinical and clinical data and was expected to end very soon in May 2010 after 4 years. Six months before the ending of the trial the skilled person knowing that in a clinical trial interim results must be evaluated in view of benefits and risks according to the clinical trial plan periodically, and noticing that no negative events had occurred or were published, had a reasonable expectation for success for the use of the combination of cabazitaxel and prednisone in the treatment of the patient group in question” (page 42 of the UPC Decision).

Additionally, the experts agreed that whilst “the failure rate of phase III trial in general is between 40 to 50 percent”, “the percentage goes down with the progress of the trial” (page 31 of the UPC Decision).

Overall, the Munich LD held that “the crucial point in the present case […] is the course of the trial without incident and the near ending of the trial, which leads to an expectation of success” (page 43 of the UPC Decision, emphasis added).

The Munich LD found that the claims do not involve an inventive step.

Commentary

The differing outcomes in the proceedings before the EPO and the UPC appear to heavily lie in the differing assessments of the positive and negative pointers - in particular, in the relevance attributed to the phase I and phase II data, as well as what constitutes “success”. Whilst the Board of Appeal found these data not sufficient to establish a reasonable expectation of success of the phase III trial, the Munich LD disagreed. Of note, although both decisions are based on the same/similar disclosures, the UPC decision additionally relied on the testimony of experts, who were asked for their views on “whether the skilled person would have had reason to expect the TROPIC study to be successful” (pages 7 and 42 of the UPC Decision). It remains to be seen whether the UPC Court of Appeal will agree with the Munich LD if the Patentee appeals the decision.

In view of the differing outcomes in these proceedings, it remains challenging to predict how a clinical trial disclosure may impact a patent and thus challenging to establish a filing strategy, and may lead to greater use of expert evidence in EPO proceedings in the future. As noted by the Patentee themselves, “drug patents are often revoked on the grounds that they are filed too early, before possession of the invention (in the case of finasteride, raloxifene), and that this would have been the case here before the results of the Tropic trial were obtained” (page 22 of the UPC Decision).

^[1] UPC_CFI_146/2024 - UPC_CFI_496/2024, UPC_CFI_147/2024 - UPC_CFI_374/2024, UPC_CFI_148/2024 - UPC_CFI_503/2024.

^[2] As previously reported by Juve here.

^[3] In relation to Novelty, the Appeal Board found the claims to be novel over the prior art since none of the prior art documents disclosed the claimed treatment, i.e. treatment of mCPRPC patients with cabazitaxel with prednisone or prednisoloner. Additionally, the claims were found to be novel over a public prior use. The announcement of the TROPIC study set up established a public prior use, in part because it was an open-label study and thus the patients would have been aware of whether they were being treated with the study drug and informed on the progression of their disease. However, the Board held that “this is not sufficient to objectively establish efficacy of the treatment” (section 6.22.10 of the Reasons).