Saturday, 16 June 2012

T 1205/07 – Confirmation

This appeal was filed by the patent proprietor after the Opposition Division (OD) had maintained the patent in amended form.

The Board found the main request before it not to comply with A 123(2) and then examined auxiliary request 1, which had also been auxiliary request 1 before the OD. Claim 1 of this request read:
1. A combination consisting of:
a recombinant nucleic acid molecule based on or derived from an adenovirus, said nucleic acid molecule having a functional encapsidating signal and at least one functional Inverted Terminal Repeat or a functional fragment or derivative thereof, and
a packaging cell, said recombinant nucleic acid and said packaging cell together comprising all elements which are necessary to generate a recombinant adenoviral particle comprising said recombinant nucleic acid molecule,
wherein said recombinant nucleic acid molecule has no overlapping sequences which allow for homologous recombination leading to replication competent virus in said packaging cell, and wherein the genome of said packaging cell comprises an adenoviral sequence consisting of Ad5 nucleotides 459-3510.
The OD had found this claim to lack sufficiency of disclosure. The Board disagreed:

[20] In the decision under appeal the OD held that the invention claimed in claims 1 and 22 of the first auxiliary request did not fulfil the requirements of A 83, because neither the application nor the common general knowledge (CGK) in the relevant technical field provided the guidance required for carrying out the claimed invention over the whole scope of the claims, in particular as regarded the preparation of packaging cells starting from primary cells other than HEL, HEK or HER cells. As evidence in support of these findings, the OD pointed to the patent itself and to documents D8 and D43 which were cited as expert opinion.

[21] The OD correctly found that neither claim 1 nor claim 22 imposes any limitation to the type of cell suitable for use as packaging cell, except for the presence in its genome of an adenoviral sequence consisting of Ad5 nucleotides 459 to 3510. Thus, claim 22 encompasses any possible type of cell of any possible origin, be it a primary human cell or a cell from an established cell line. Similarly, claim 1 encompasses any combination of a recombinant nucleic acid molecule as defined in the claim with any type of packaging cell harbouring in its genome the Ad5 sequences specified in the claim.

[22] The OD also held that the examples of the patent described successful generation of packaging cell lines only by transfection of human embryonic retina (HER) cells with E1A and E1B sequences of Ad5, while the transformation of the established human bronchial carcinoma cell line A549 was not successful because a significant expression of E1A could not be achieved. The OD thus concluded that the patent provided only one example of how to obtain packaging cells as defined in claim 22.

[23] These findings, although based on the disclosure content of the patent – instead of the application as filed which is the relevant disclosure for the assessment whether or not the requirements of A 83 are fulfilled – are, in principle, correct, since in the present case the disclosure content of the application as filed and the patent as granted are, at least in the relevant passages, identical.

[24] The OD went on to observe that the patent did not provide the skilled person with a general teaching how to obtain a human cell line expressing adenoviral E1A and E1B proteins, and that, therefore, the question to be addressed was whether or not the skilled person would have been able to carry out the invention over the whole scope of claims 1 and 22 based on the CGK at the relevant date.

[25] In this respect the board does not agree with the OD. A general teaching how to obtain a human cell line expressing adenoviral E1A and E1B proteins is found in the passage from page 17, line 25 to page 19, line 19 of the application as filed. A plasmid including adenoviral sequences encoding E1A and E1B proteins (plasmid pIG.E1A.E1B) is described on page 25, lines 19 to 33 and Figure 4, and a standard protocol for transfection of cells with suitable plasmids on page 28, lines 10 to 16. Thus, the application as filed discloses indeed technical details and measures which enable a person skilled in the art to prepare, possibly with some amount of trial and error, a packaging cell as defined in claims 1 and 22.

[26] Apart from the failure to transform the established cell line A549 reported in the application as filed, there are no other verifiable facts on file that support the allegation that, at the filing date of the patent in suit, there were insurmountable difficulties in transforming primary human cells by transfecting them with adenoviral E1A and E1B sequences. There is, however, documentary evidence, in particular documents D43 and D32 showing that primary human cells can be transformed applying the teachings of the application.

[27] While the documents in question were published after the filing date, the board believes that the evidence they provide is not aimed at “curing” any alleged insufficiency of disclosure, but rather at confirming that the teachings of the application are, in fact, applicable to cell lines other than HEL, HEK or HER cells. Thus, contrary to the OD’s view, the board holds that, under the circumstances of the present case, post-published evidence may be considered (see decision T 1262/04).

[28] Documents D43 and D32 describe the efficient transformation of primary human amniocytes by transfection with adenoviral E1 sequences. It is stated in document D43 that the E1-transformed cell lines produced the E1A proteins and the 21-kDa E1B proteins in comparable amounts, whereas in preliminary experiments expression of the 55-kDa E1B protein was found to be more variable (see page 2111, left column, paragraphs under the heading “Synthesis of Ad5 E1 proteins in E1-transformed amniocyte cell lines”, and Figure 4). Whether or not the primary human amniocytes used in the experiments described in document D32 are mentioned in the specification of the patent in suit is, contrary to the OD’s view, immaterial. The decisive fact is that primary human amniocytes, i.e. primary human cells other than HEK, HEL or HER cells, can transformed by transfection with adenoviral E1 sequences, as shown in documents D32 and D43.

[29] As regards post-published document D33, an international application filed in 1998 claiming the priority of a previous application filed in 1997, the OD remarked that only the expression of E1B p55 but not of any other E1B proteins was reported. This is correct. However, in Example 3 of this document it is stated that E1-deleted Ad5-CA-GFP adenovirus was propagated through 20 passages on A549E1-68 cells, a cell line obtained by transfection of A549 human lung carcinoma cells with E1A and E1B sequences of Ad5. This implies that all E1 functions missing in the Ad5-CA-GFP adenoviral vector, including those of other E1B proteins were necessarily supplied by the packaging cell. The same applies in respect of the Hela-E1 packaging cell line described in document D35, which the OD regarded as disclosing solely the expression of E1A.

[30] The board observes that the A549 cell line used in the experiments described in document D33 appears to be the same cell line which, in the examples of the application, failed to produce detectable levels of E1A and E1B. Since document D33 does not appear to describe any particular technical measures which may have been necessary to obtain a different result - nor did the [opponents] indicate any such measures -, it seems that the failure reported in the application, on which the OD based its doubts concerning the sufficiency of the disclosure, may have been either fortuitous or due to factors unrelated to the ability of the A549 cell line to be transformed upon transfection with adenoviral E1 sequences.

[31] In view of the above the board is persuaded that, in spite of the alleged difficulties in transforming primary human cells, the evidence on file shows that with the guidance given in the application as filed supplemented with the CGK at the filing date, and with a reasonable amount of experimentation, a person skilled in the art could obtain packaging cells for replication-defective adenoviruses starting from either primary cells or established cell lines.

[32] It is therefore concluded that, as regards the packaging cell according to claim 22 and the combination of claim 1, the requirements of A 83 are met.

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