Wednesday, 13 May 2015

T 995/10 - Purity isn't everything


A clear cut case, wherein the Board of Appeal overrules an earlier decision by the Opposition Division. The decision deals with an aspect in claim 1 that relates to the purity of a virus preparation that is used in cancer therapy. It was indicated in the application as filed and also not disputed by the parties, that a virus preparation should be 'clonal' or as clean as possible, which means that it should have low numbers of defective particles to reduce negative side effects (such as immune responses by the patient). The invention as claimed was directed to the word 'clonal' in the main claim, but unfortunately did not show (in the application as filed) that there was a difference in activity between a clonal preparation and a non-clonal preparation. Post-filed data did not help the proprietor to re-formulate the problem to be solved in the inventive step assessment. Yet another example that it is still wise to have the real data in there, when filing the application, and not simply rely on what might appear logical as the solution to the posed problem, or new formulated problem to be solved.

Summary of Facts and Submissions
I. The appeal of the opponent (hereafter "appellant") lies against the decision of the opposition division rejecting the opposition filed against
European patent No. 1 032 269.
II. The patent at issue has the title "Treatment of neoplasms with interferon-sensitive, clonal viruses".
Claim 1 as granted reads as follows:
"1. Use of an interferon-sensitive, replication-competent clonal RNA virus for the manufacture of a medicament for treating a neoplasm in a mammal." [...]
IV. The opposition division decided that the subject-matter of the claims as granted was novel and involved an inventive step.
V. The following documents are referred to in this decision:
D1 WO 94/25627
[...]
D14 Technical information, submitted by the respondent with letter dated 14 July 2005
[...]
VIII. The parties were summoned to oral proceedings to be held on 11 December 2014. The board expressed its preliminary view in a communication pursuant to Article 15(1) RPBA.
IX. By letter dated 22 October 2014 the respondent announced that it would not attend the oral proceedings.
[...]
XI. The appellant's arguments as submitted in writing and orally may be summarised as follows:
Main (sole) request
Inventive step (Article 56 EPC)
Document D1 represented the closest prior art. The subject-matter of claim 1 differed from the disclosure of document D1 only in the clonal character of the virus population. The technical effect of this difference was, according to paragraph [0079] of the opposed patent: "to ensure or increase the genetic homogeneity of a particular virus strain and to remove defective interfering particles". The objective technical problem was thus the provision of an improved virus-based therapy for the treatment of neoplasms in a mammal, where the improvement consisted in increased purity.
Defective virus particles could cause an unwanted stimulation of the patient's immune system. This was in particular disadvantegous in the treatment of cancer patients due to their usually weak constitution. A high genetic homogeneity of the administered virus particles was moreover desirable for safety reasons, as viruses with deviating sequences could show increased virulence and cause non-reproducible therapeutic effects. These aspects played a crucial role in market authorisation for viral preparations for therapeutic purposes. Hence, it was the constant aim of the person skilled in the field to improve virus-based therapies by reducing the number of defective particles in the virus preparation and by ensuring that the functional virus particles were genetically homogenous. The skilled person would thus be motivated to improve the purity and genetic homogeneity of the virus population disclosed in document D1 and to provide a clonal virus population. Therefore, the skilled person would combine the teaching of document D1 with the virus purification methods disclosed in either document D4 or D11 and arrive at the claimed subject-matter in an obvious manner.
A comparison between a parent virus and a clonal population derived therefrom had not been carried out in the patent in suit. The technical effect - high therapeutic index of the clonal population - allegedly shown in document D14 could not be relied on for the formulation of the technical problem because this effect was neither disclosed in nor derivable from the patent in suit.
Document D12 would not have deterred the skilled person from using a clonal virus population in the treatment of neoplasms in mammals.
XII. The respondent's arguments as submitted in writing may be summarised as follows:
Main (sole) request
Inventive step (Article 56 EPC)
Document D1 represented the closest prior art. In the light of document D1, the objective technical problem was to provide an improved virus-based therapy for treating neoplasms. This problem was solved by the use of an interferon-sensitive clonal virus as defined in the claims of the main request.
Since the examples of the patent demonstrated a credible anti-cancer activity for clonal viruses, the supplementary post-filed evidence provided by document D14 could be taken into consideration. This document, which compared clonal virus strain PV701 and the non-clonal parent strain MK701, showed that clonal viruses resulted in lower mortality of non-cancer cell types and a higher therapeutic index. The principal concept underlying the claimed invention was that clonal viruses demonstrated lower cytotoxicity to normal cells than non-clonal viruses.
Starting from document D1, the skilled person would have found no suggestion to use a clonal virus for the treatment of neoplasms. Even if in view of document D1 a skilled person could have produced a clonal virus, the question was whether he would have done so in the expectation of some improvement. Also, there was a general acceptance in the art that viral therapies should use non-clonal viruses, see for example document D12, page 1, last paragraph, which confirmed that NDV vaccines should use uncloned NDV. Hence, the skilled person seeking to prepare an improved anti-cancer therapy would have been led towards the use of a non-clonal virus.
XIII. The appellant requested that the decision under appeal be set aside and the patent be revoked.
The respondent had requested in writing by letter dated 10 December 2010 that the appeal be rejected in its entirety, i.e. that the patent be maintained as granted.
Reasons for the Decision
[...]
Main (sole) request
Introduction
3. The patent in suit concerns the treatment of mammalian neoplasms with viruses that are able to cause the death of neoplastic cells which have a deficiency in the interferon-mediated anti-viral response while normal cells which possess an intact interferon-mediated anti-viral response limit the replication of the virus and are not killed. The viruses are RNA viruses, in particular paramyxoviruses such as Newcastle Disease Virus (NDV).
Inventive step (Article 56 EPC)
[...] 5. It is common ground between the parties that document D1 represents the closest prior art with respect to the claimed subject-matter. Document D1 (see paragraph bridging pages 3 and 4; page 10, lines 11 to 15; examples) discloses a method of treating cancer in mammals by administering to the mammal an effective amount of a paramyxovirus. In a preferred embodiment the virus is NDV. The document discloses that NDV has direct cytolytic activity on the cancer cells and is capable of specifically differentiating cancer cells from normal, healthy cells. It is reported that one dose of NDV, given intralesionally to athymic mice, causes complete and permanent eradication of a wide variety of human tumours. Document D1 thus relates to the same purpose as the patent in suit - the treatment of cancer using interferon-sensitive, replication-competent RNA viruses capable of selectively killing neoplastic cells - and discloses one of the preferred viruses of the patent in suit, namely NDV.
The technical problem to be solved
6. There was no dispute among the parties that the subject-matter of claim 1 differed from the disclosure of document D1 only in the feature relating to the clonal character of the virus population. [...]
9. The board notes that the patent in suit does not compare the efficacy of the parent non-clonal virus and a clonal population derived therefrom. Pursuant to paragraph [0074] of the patent in suit the viruses of the invention possess the following three characteristics: "(i) they infect neoplastic cells resulting in their death; (ii) they are replication-competent in the neoplastic cells; and (iii) they are limited in killing of normal cells by the antiviral effects of interferon". This passage refers to the specific cytotoxicity of the viruses of the invention towards neoplastic cells, but not to a possible advantage of cloned versus uncloned virus populations. Indeed, the mention of "limited killing of normal cells" in this paragraph applies to any interferon-sensitive virus regardless of its clonality because, unlike neoplastic cells which are deficient in an interferon-mediated anti-viral response, normal healthy cells possess an intact interferon-mediated anti-viral response which protects them from virus-induced cytolysis, see paragraph [0050] of the patent in suit.
10. Accordingly, document D14 can not be relied on for the formulation of the technical problem because the technical effect shown in document D14 is neither disclosed in nor derivable from the patent in suit (see Case Law of the Boards of Appeal of the EPO, 7th edition 2013, section I.D.4.4.1).
11. It follows from points 7 to 10 above that starting from document D1 the problem to be solved is the provision of an improved virus-based therapy for the treatment of neoplasms in a mammal. The board is satisfied that the solution provided by the subject-matter of claim 1 solves this problem.
Obviousness
12. It remains to be answered whether or not the skilled person, when faced with the technical problem defined in point 11 above, would have modified the teaching in the closest prior art document D1 so as to arrive at the claimed invention in an obvious manner.
13. The prior art describes the provision of clonal sub-populations of NDV strains by plaque purification, see document D4, page 435, third full paragraph, and document D11, page 116, lines 1 to 3.
14. Moreover, as submitted by the appellant, the skilled person would have known that the regulatory approval of any virus-based therapeutic composition would require detailed information indicating that the composition was safe and that the therapeutic effect was reproducible. For this it was necessary to provide a virus population which was devoid of defective particles which could cause an unwanted stimulation of the patient's immune system. A high genetic homogeneity of the administered virus particles was also desirable for safety reasons, as viruses with deviating sequences could show increased virulence and cause non-reproducible therapeutic effects. The respondent has not disputed this line of argument. [...]
16. The board is not convinced that document D12 would have deterred the skilled person from using a clonal virus population in the treatment of neoplasms in mammals. The paragraph relied on by the respondent states that "[w]e must be aware that the populations of Newcastle disease virus that spread in the field, or the populations that make up a vaccine stock [note by the board: the NDV vaccine for use in chickens] are not clonal". In the board's view this corresponds to what was known in the art at the priority date, namely that "both wild-type isolates and laboratory cultured strains of Newcastle disease virus contain several subpopulations", see document D11, page 113, first paragraph. A requirement that NDV should be uncloned when used in mammals, not in chickens, and for the treatment of neoplasms, and not as a vaccine, is not apparent from document D12.
17. Starting from the teaching of document D1 and faced with the problem of providing an improved virus-based therapy for the treatment of neoplasms in a mammal, the skilled person aware of the non-clonal character of NDV strains and of the regulatory requirements for obtaining marketing authorisation for viral preparations for therapeutic purposes would have readily considered providing a clonal virus population by plaque-purifying the NDV strain of document D1 pursuant to the teaching of document D4 or D11. He would thus have arrived at the subject-matter of claim 1 in an obvious manner. [...]
Order
For these reasons it is decided that:
1. The decision under appeal is set aside.
2. The patent is revoked.
This decision has European Case Law Identifier: ECLI:EP:BA:2014:T099510.20141211. The whole decision can be found here. The file wrapper can be found here. Picture by GH.

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