Thursday, 20 September 2012

T 1408/10 – In Vitro Veritas

This is an appeal against the refusal of the application under consideration by the Examining Division (ED).

Claim 1 of the main request before the Board read:
1. Defibrotide for use in the treatment of angiogenesis-dependent tumour, characterised in that it is administered to a human on a daily basis. (my emphasis)
The ED had come to the conclusion that the feature “administered to a human on a daily basis” had no basis in the original application as the administration of defibrotide on a daily basis only referred to in vitro tests or animal models which could not be transferred to the treatment of humans.

The Board agreed with the ED:

[1.1] The appellant indicated page 5, lines 5-8 and 22, as the basis for the characterising feature of present claim 1. As was correctly pointed out in the decision under appeal, the passage on page 5, lines 5-8 relates to an in vitro test, i.e. the Matrigel® tube formation assay involving the administration of defibrotide to endothelial cells of the rat aorta.

The passage on page 5, line 22, which stresses the superiority of daily application, concerns an in vitro assay performed on the basis of microvascular endothelial cells vascularising through a layer of dermal fibroblasts.

In vitro assays constitute valuable tools in pharmacy for testing the usefulness of potential active agents for therapy but it goes without saying that the specific environment of an in vitro test cannot be compared to the situation in which said agents are administered to a mammal such as a human. In connection with the dosage regimen (daily administration), it is noted that in vitro assays do not encompass parameters such as resorption, pH changes within the gastrointestinal tract (if orally administered), distribution of the active agent within the human or animal body or its release profile from the galenic vehicle, which play a very important role for determining which quantities of the active agent have to be administered at which intervals for obtaining the desired pharmacological effect. In this context, it is noted that in general, a specific dosage regimen cannot be transferred even from one mode of administration to another: thus, an intravenous administration of an active agent once per day does not imply that the desired pharmacological effect is also obtained by daily administration of a tablet or a suppository. As a consequence, the fact that the daily administration of difenobrate was suitable in an in vitro assay does not allow the conclusion that the same dosage regimen would also work for the therapy of humans.

The appellant, making reference to the paragraph bridging pages 5 and 6, argued that the original application also referred to in vivo models. The board, however, notes that this paragraph is completely silent as regards the dosage regimen.

It follows therefrom that the dosage regimen applied for the in vitro assays on page 5 of the original application cannot be transferred to the treatment of mammals or humans. As a consequence, the requirements of A 123(2) are not met.

Should you wish to download the whole decision, just click here.

The file wrapper can be found here.