Friday, 18 February 2011

T 1364/08 – Old And Young Together

This decision deals with an appeal subsequent to a refusal of an application by the Examining Division (ED).

Claim 1 on file before the Board read:
An adenovirus in which the VAI gene is lacking or mutated and which is capable of replicating in cells having an activated Ras-pathway but not in normal cells for treating a Ras-mediated cell proliferative disorder in a mammal, whereby the adenovirus is to be administered to proliferating cells in a mammal having a Ras-activated pathway under conditions which result in substantial lysis of the proliferating cells or for treating a neoplasm suspected of having an activated Ras-pathway in a mammal, wherein after the surgical removal of substantially all of the neoplasm the adenovirus is to be administered to the surgical site in an amount sufficient to result in substantial oncolysis of any remaining neoplasm.
The Board considers whether the invention is sufficiently disclosed:

[1] [As stated in the application,] “Genetic alteration of the proto-oncogen Ras is believed to contribute to approximately 30% of all human tumours. The role that Ras plays in the pathogenesis of human tumours is specific to the type of tumour” […].

[2] Protein kinase R (PKR), is an interferon-induced, double-stranded (ds) RNA-activated protein kinase which protects cells against viral infections.

In situations of viral infection, the dsRNA created by viral replication binds to the N-terminal domain of PKR and thus activates it. Once active, PKR is able to phosphorylate the translation initiation factor eIF2a. This inhibits further cellular mRNA translation, thereby also preventing viral protein synthesis such that viral replication and thus also cell lysis is prevented.

[3] Claim 1 refers to an adenovirus in which the VAI gene is lacking or mutated and which is capable of replicating in cells having an activated Ras-pathway but not in normal cells for treating a Ras-mediated cell proliferative disorder in a mammal.

[4] It has been established by case law that for a claim referring to a therapeutic application of a substance or composition, it is a requirement according to A 83 that it is demonstrated that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease to be treated. This mechanism can be either known from the prior art, or be shown in the application per se, for example by the provision of experimental tests. Once this evidence is available, post-published evidence may be taken into account to back up these findings (see decision T 609/02 [9]).

[5] The application does not provide any experimental data proving that an adenovirus of claim 1 is able to replicate in cells having an activated Ras-pathway but not in normal cells. No data is present demonstrating that such a virus can be useful for the treatment of Ras-mediated cell proliferative disorders.

[6] However, […] the application as published contains a detailed summary of the “state of the art”.

Reference is made to document D16 of the list of documents given on pages 1 and 2 of the application, which is also document D16 in the present case. Page 5, lines 7 to 8 of the present application read:
“It has been demonstrated that in Ras transformed cells, dsRNA-mediated activation of PKR was blocked at the level of autophosphorylation.”
Document D16 itself moreover discloses that reoviruses, being dsRNA viruses, in their wild-type form lack an effective PKR counteracting mechanism. They cannot therefore replicate in normal cells but only in cells having an activated Ras pathway because downstream effectors of Ras inactivate PKR. This makes them a useful tool for the treatment of Ras-mediated cell proliferative disorders.

This is also disclosed in document D8, a published International patent application whose inventors and applicants are the authors of document D16.

On page 6, lines 12 to 13 it is stated that reoviruses use the host cell’s Ras pathway machinery to down-regulate PKR and thus reproduce. Claim 1 of document D8 reads:
“Use of reovirus for the manufacture of a medicament for treating Ras-mediated neoplasm in a mammal.”
[7] It was known that, contrary to reoviruses, various other viruses have evolved PKR inhibitory functions as a mechanism of defence against the host’s antiviral response in order to counteract viral replication restrictions. This is acknowledged [in] the application as published where the different “strategies” of four viruses to inhibit PKR activation in response to their presence are described.

[8] [Moreover] it is said that adenovirus produces large amounts of VAI RNA which inactivates PKR by acting as a competitive inhibitor of the full length viral dsRNA. PKR bound to VAI RNA is not activated. Reference is made to document D8 of the application’s own reference list, which is document D21 in the present case. In the section “Materials and Methods” under “Cells and virus” […] the authors of document D21 mention that the used adenovirus mutant has been described previously and was provided to them by the authors of a prior art document which is document D20 in the present case.

A further document on file, published by the authors of document D20, is document D7, which reports that a significant number of adenoviruses, in which the VAI gene has been mutated, lost their ability to counteract the cellular antiviral response mediated by the interferon-induced, dsRNA-activated protein kinase PKR (abstract), which made them unable to replicate in normal cells.

[9] Besides the description of the viral anti-PKR strategies of Vaccinia virus and of Parapoxvirus, the present application […] describes also that the Herpes simplex virus (HSV) infected cell protein 34.5 (ICP34.5) encoded by the γ34.5 gene of HSV prevents the antiviral effects exerted by PKR.

[… T]he application refers to document D32 of its own reference list (which is document (14) in the present case), by saying that it
“generically describes methods for selectively killing neoplastic cells which utilize altered viruses that are capable of replication in neoplastic cells while sparing surrounding normal tissue”.
Document D14 refers to the use of a HSV mutant that is incapable of expressing a functional γ34.5 gene product (see claim 1).

[10] The Board is of the opinion that the disclosure in the prior art is such that it is plausible that the adenovirus of claim 1 is useful for the therapeutic application referred to in the claim.

Under these circumstances the disclosure in post-published document T1 can be taken into account to back up these findings. In fact, document T1 contains experimental data demonstrating that an adenovirus in which the VAI gene is lacking or mutated can be used for oncolytic virotherapy of Ras-mediated cell proliferative disorders such as pancreatic tumours […].

Therefore the application is considered to disclose the invention in a manner sufficiently clear and complete to be carried out by a person skilled in the art as required by A 83.

NB: This decision was first reported on a nice weblog dedicated to French patent case law. The author notes that the case law relied upon, T 609/02, dealt with Swiss-type claims. The reasons for this decision contain the following paragraph:
“[9] Where a therapeutic application is claimed in the form allowed by the Enlarged Board of Appeal in its decision G 5/83 i.e. in the form of the use of a substance or composition for the manufacture of a medicament for a defined therapeutic application, attaining the claimed therapeutic effect is a functional technical feature of the claim (see G 2/88 and G 6/88 [headnote III; 9], for non-medical applications, see also T 158/96 [3.1]). As a consequence, under A 83, unless this is already known to the skilled person at the priority date, the application must disclose the suitability of the product to be manufactured for the claimed therapeutic application.”
Although the present decision presents its conclusion as a mere application of the established case law, it extends the reasoning to claims covering second or higher therapeutic applications that are not drafted in Swiss-claim form. The underlying assumption is that even in non-Swiss claims the claimed therapeutic effect is to be understood as a functional technical feature of the claim. Sounds reasonable to me.

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

To have a look at the file wrapper, click here.

A post on a similar decision can be found here.