T 0883/23: Dosage claims and their entitlement to priority when only the clinical trial protocol was disclosed in the priority application

In a recently issued decision by the EPO’s Board of Appeal (BoA), the BoA held that claims directed to a combination of active pharmaceutical ingredients (APIs) at particular doses were not entitled to the priority date because the priority application only contained the clinical trial protocol rather than the clinical trial data.

The BoA held there was no pointer in the priority application to the specific dose combination claimed, as the dose combination disclosed in the protocol was only to be used in the event that higher doses were not tolerated. Nevertheless, the patent was maintained, providing further guidance on the patentability of dosage regimes in Europe.

The Decision

The patent in question, EP 3337478 (Ipsen Biopharm Ltd), has claims directed to liposomal irinotecan for use in a method of treating metastatic adenocarcinoma of the pancreas in a patient who has not previously received chemotherapy. Claim 1 of the granted patent requires administering an antineoplastic therapy consisting of 60 mg/m² liposomal irinotecan in combination with specific doses of oxaliplatin, leucovorin and 5-fluorouracil.

The patent was opposed by two Opponents on the grounds that the claims lack an inventive step. The Opposition Decision found that the claims were entitled to the earliest priority claimed and that the claims of the main request were inventive. Both Opponents filed appeals against this decision.

Priority

The claimed dosage regimen was derived from a combination of claims present in the earliest priority document and crucially a selection of the specific doses of liposomal irinotecan and oxaliplatin.

In the earliest priority application, a clinical trial protocol was disclosed which included details regarding initial doses, dose escalation and de-escalation of the combined administration of liposomal irinotecan, oxaliplatin, leucovorin and 5-fluoroouracil. The protocol described how the clinical trial will use 80 mg/m² liposomal irinotecan in both the initial and the dose escalation part of the trial. Crucially, the protocol further detailed that in the event the combination of APIs were not tolerated in the initial or escalation parts of the trial, then the dose of liposomal irinotecan was to be reduced to 60 mg/m².

The generated clinical trial data, which was added subsequently to the application,   demonstrated that the initial and escalation doses of 80 mg/m² liposomal irinotecan were not tolerated, while the claimed dose of 60 mg/m² liposomal irinotecan was.

The BoA held that the clinical trial protocol did not provide a pointer to the claimed subject matter. As decided in a previous decision, T 1261/21, the Board held that “[a] pointer is an (implicit or explicit) indication or hint towards the combination of features in question. The pointer needs to be suited to demonstrate that the claimed combination of features is envisaged in the application as filed” and “there is not normally only one pointer towards the most preferred example or embodiment, e.g. exemplified by a specific example or embodiment of the invention”.[1] In the present case, while the claimed doses were included in the clinical trial protocol, they were only to be used in the event the higher doses of liposomal irinotecan in combination with the other APIs were not tolerated. In other words, the claimed doses were a conditional proposal. The BoA held that this not constitute a pointer to the claimed combination of doses.

As determined in G 2/98, for claimed subject matter to be entitled to the priority date, the condition for compliance with the requirement of “the same invention” is that “the claimed subject-matter is directly and unambiguously derivable from the earlier application”.  The board in T 0883/23 observed that since attaining a therapeutic effect is a functional feature of a medical use claim, and since tolerability is a prerequisite for efficacy, the tolerability of the claimed dose combination (as opposed to the intolerability of alternative combinations with higher doses) is a functional feature of claim 1. However, this functional feature is not directly and unambiguously derivable from the priority document.  As such, the “same invention” requirement was not met.  Accordingly, the BoA found that the claim to priority was invalid.

This decision confirms the need for sufficient disclosure of the functional features of the claimed invention in the priority document. In other words, there needs to be some evidence of the therapeutic effect at the priority date; a clinical trial protocol in the priority application alone may not be sufficient.

Inventive Step

In their assessment of inventive step, the BoA found the closest prior art to describe a dosing regimen for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas. The BoA considered the differences between the claimed invention vs. the closest prior art to be the dose and form of irinotecan (60 mg/m² liposomal irinotecan vs. 180 mg/m² non-liposomal irinotecan) and the dose of oxaliplatin (60 mg/m² vs. 85 mg/m²).

The BoA considered that while the closest prior art did discuss the possibility of reducing the dose of irinotecan, in order to reduce toxicity while maintaining efficacy, this was in respect of non-liposomal irinotecan. Other pieces of prior art were considered in respect of liposomal irinotecan including disclosures of its use alone or in combination in different cancers and patient populations. However, in view of the cited prior art the BoA held that the skilled person had no reasonable expectation that the claimed dosing regimen using liposomal irinotecan would be effective and tolerable.

Finally, the BoA considered whether arriving at the claimed dose combination should be viewed as mere dose optimisation. In previous decisions (T 1760/08, T 1409/06 and T 237/15) the BoAs have held that the optimisation of a dose of a single agent did not constitute an inventive step. In contrast, in the present case, the claimed dosage regimen involves the combination of four APIs. The BoA held that while it was known from the prior art that there are associated problematic side effects with non-liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin, there was no information regarding the combined toxicity of the APIs when liposomal irinotecan is used.

Accordingly, the BoA found the claimed dosage regime to be inventive.

Key Points

This decision highlights:

1) The importance of including evidence of a therapeutic effect in priority application or at least a pointer to the claimed subject matter; and

2) Dosage regimes of known APIs can be inventive in Europe in certain situations, especially if in relation to a combination of APIs.

[1] see 4.2.12 of decision T 1261/21

This article was written by Senior Patent Attorney Joanna Pownall.