T 0882/01 (Protein Expression System/CELLTECH) 01-07-2004

Main request

Novelty (Claim 1)

1. Novelty of the subject-matter of claim 1 is denied by the respondents over either of documents (22) and (32).

2. Claim 1 is directed to a method for producing one or more heterologous protein(s) in a bacterial host cell comprising culturing in a defined medium in the absence of antibiotic selection a bacterial host cell transformed with one or more expression vector(s) comprising one or more heterologous DNA sequence(s) under the control of at least one regulatable promoter, an origin of replication maintaining medium vector copy number and a transcriptional terminator.

3. There is no definition in the patent of a medium vector copy number, the only information relating to this being given on page 5, lines 7 and 8 in the form of a statement of a preferred range of values (6 to 50), a preferred sub-range (10 to 20) and a discrete most preferred value (15). Nor does the experimental part of the description give any method of measuring the copy number of the illustrated expression vectors used to produce antibodies or fragments thereof.

4. In the absence of precise information in the patent on the meaning of "medium vector copy number" or even of how or under what growth conditions to measure this, the claims can only be interpreted broadly to cover anything which reasonably might be considered as having medium copy number, when answering the question whether a method as defined in claim 1 is described in document (22) or document (32).

Vis-à-vis document (22)

5. Document (22) deals with the problem posed by the undesirable incorporation of norleucine into proteins produced in E. coli.

6. In passing (see page 533, right-hand column), production of methionyl bovine somatotropin (MBS) using a phototrophic strain of E. coli, W3110G, harbouring the plasmid pBGH1, is described. Fermentations were conducted in a defined medium, the composition of which is detailed in the last paragraph of page 532 without any antibiotic being mentioned. Plasmid pBGH1 is succinctly described, the indication being given that it encodes resistance to ampicillin and tetracycline (see page 532, left-hand column, Chapter entitled "Bacteria, Phage and Plasmids") and that it carries the bovine somatotropin structural gene under control of the E. coli tryptophan promoter (see page 533, right-hand column, first sentence of the Chapter entitled "Production of Bovine Somatropine"). By definition, being a plasmid, pBGH-1 has an origin of replication. According to document (23), cited in document (22) (see reference to Calcott et al. at the end of the afore- mentioned sentence) which describes in detail the plasmid, it further contains a transcriptional terminator (see page 259, right-hand column, lines 9 to 12).

7. Thus, the skilled person reading document (22) would conclude that it incidentally describes a method for producing a heterologous protein (MBS) in a bacterial host cell (E.coli strain W 3110G) transformed with an expression vector (plasmid pBGH1) having a sequence encoding said protein placed under the control of a regulatable promoter (the E. coli tryptophan promoter), an origin of replication and a transcriptional terminator, said bacterial host cell being cultured in a defined medium.

8. Although the precise copy number per cell of plasmid pBGH1 was not mentioned in document (22), the skilled person, aware of the fact that the copy number of an expression vector is largely controlled by the origin of replication, would have taken the copy number of 30 to 35 reported in document (23) as a reliable indication and, on this basis, would have reasonably considered that plasmid pBGH1 was present in the bacterial host cell of document (22) at a medium copy number.

9. Assessment vis-à-vis document (22) further only requires consideration of whether the skilled reader would take it as implicit that the fermentation medium referred to therein actually contained an antibiotic.

10. Because plasmid pBGH1 encodes two antibiotic resistance genes (see point 6, supra), if there would have been a need for antibiotic selection, the skilled reader would have expected that precise guidance be given in the document indicating which antibiotic(s) (one of them only or both) and what amount thereof should be used. The absence of any data in this respect must lead the skilled reader to the conclusion that the fermentation medium of document (22) did not contain any antibiotic. This conclusion is further supported by the fact that the skilled reader would have recognized from the data given in the Chapter entitled "Fermentation Methods" on pages 532 and 533 that the growth phase during fermentation comprises only a few generations in which no significant loss of plasmid would have been expected, a finding which is not contested by the appellant. This fact means that there was no need for antibiotic selection, ie no need to introduce an antibiotic in the fermentation medium.

11. In view of the above remarks, the board concludes that claim 1 lacks novelty over document (22).

Vis-à-vis document (32)

12. Document (32) reports on an investigation of the instability of plasmids directing the expression of Met- prochymosin in Escherichia coli with, as in the patent, the underlying purpose of avoiding the need for antibiotic selection (see last sentence of the abstract on page 3355).

13. One of the plasmids tested was pCT66 which contained the gene coding for Met-prochymosyn, the trp regulatable promoter, the T7 transcriptional terminator (see Figure 1 page 3357 and 3359) and by definition an origin of replication. E. coli HB 101 cells were transformed with said plasmid, the plasmid being present in the bacterial host at intermediate copy numbers of approximately 40 to 60 per chromosome, and cultured in a defined medium in the absence of antibiotics (see Chapter "Methods" on pages 3356 and 3357). Samples were removed from the fermenters and analysed by Western blotting. Said analysis showed that Met-prochymosin was expressed (see Figure 4, tracks 4 to 6, on page 3359).

14. Thus, document (32) describes a method for producing, in a bacterial host cell (E.coli HB 101 strain) which is cultured in a defined medium that does not contain any antibiotic, a heterologous protein (Met-prochymosin), said cell being transformed with an expression vector (plasmid pCT66) having a sequence encoding said protein placed under the control of a regulatable promoter (the E. coli tryptophan promoter), an origin of replication and a transcriptional terminator (T7 terminator) and being present in the host cell at a copy number which may be reasonably considered as a medium copy number. This is a method which is encompassed within the scope of claim 1.

15. The argument is made by the appellant that, as only minute amounts of Met-prochymosin were produced, the afore-mentioned method of document (32) had no utility for an industrial production and, therefore, was not a method as defined in claim 1. As claim 1 does not contain any indication as to the amount of heterologous protein to be produced, the argument is not acceptable.

16. In view of the above remarks, the board concludes that claim 1 covers subject-matter (see point 2, supra) which lacks novelty over document (32).

Conclusion

17. As claim 1 is not novel, the main request is not allowable under Article 54 EPC.

Admissibility of the first auxiliary request into the proceedings

18. It has not been disputed by the respondents that claim 1 of the first auxiliary request meets the requirements of Articles 123(2), 123(3) and 54 EPC, it being fairly based on the original application, of more restricted scope that claim 1 as granted, and novel over documents (22) and (32), the only documents relied on as destroying the novelty of claim 1 of the main request. Claim 1 of the first auxiliary request being a combination of claims 1 and 9 as granted, an Article 84 EPC objection would not be open against it, and no such objection has been made.

19. The only basis on which the respondents thus object to admission of this auxiliary request into the proceedings is that the appellant having been invited to file one or more auxiliary requests by the opposition division at the oral proceedings before it, but choosing not to do so, the board would condone an abuse of procedure by allowing the appellant to file an auxiliary request on appeal, as remittal of this to the first instance pursuant to the appellant's request would greatly delay any final decision being reached.

20. The board agrees that exercising its discretion to admit an auxiliary request on appeal is not in conformity with the main purpose of appeal proceedings stated in Enlarged Board of Appeal decision G 9/91 (OJ EPO 1993, 408, point 18) "to give the losing party the possibility of challenging the decision of the opposition division on its merits." This the board has already done by considering and refusing the main request on appeal. By allowing into the proceedings an auxiliary request the board is faced with the choice of either considering this request as only instance or remitting it to the opposition division for further prosecution with an inevitable delay, probably of some years, before any final decision is reached.

21. The board does indeed consider the appellant's failure to file auxiliary requests when invited to do so at the oral proceedings before the opposition division, and then introducing these on appeal as amounting to a procedural abuse. The board does not accept the appellant's argument that it could not be expected to file auxiliary requests at the oral proceedings before the opposition division. The objection that claim 1 as granted lacked novelty over document (22), on which ground the appellant has lost before the opposition division and this board, had been raised in writing at the opposition stage. That the opposition division in its preliminary, non-binding opinion had indicated that it did not agree with the objection, and then at the oral proceedings indicated that it had changed its mind is irrelevant, and something a patentee must be prepared for: the important point is that the objection based on this document had been raised by an opponent and the appellant should have been prepared to counter it by arguments or avoid it by an auxiliary request if its arguments did not succeed.

22. The appellant's argument that it is entitled to have its requests considered by two instances is not in accordance with the European Patent Convention. Article 111(1) EPC makes clear that the boards have a discretion whether to consider an issue themselves, or whether to remit it for further prosecution to the first instance. If every issue had to be considered by two instances, this would be a very strong argument for not allowing into the proceedings on appeal, requests not already in substance considered by the opposition division.

23. The strongest argument in favour of the board allowing the first auxiliary request into the proceedings is the past practice of the boards of appeal, under which such a request which avoided the grounds of appeal was invariably allowed into the proceedings. Decision T 796/02 (supra) concerned a different situation, namely the opposition division refusing to allow into the proceedings a broader claim than the one on which a first board of appeal had remitted a case. Whether the past practice should guide the boards of appeal also in future under the Rules of Procedure of the Boards of Appeal in force since 1 May 2003 is questionable. The purpose of the changes in these rules is to streamline and speed up the procedure: the purpose is not to deprive the parties of any rights. This double purpose can however only be achieved if the parties present their case in full already during the first instance proceedings, and the opposition division is put in a position to decide all issues, including those of sufficiency of disclosure and inventive step. But the present appeal was filed before these new rules came into force.

24. Given the practice of the boards of appeal, and the fact that in this case the respondents' arguments for not allowing the first auxiliary request into the proceedings at all were only put forward at the oral proceedings, whereas in writing respondent I had asked only that the board consider all issues itself without remittal, whereas respondent II had asked for the case to be remitted to the first instance, the board decides to exercise its discretion in favour of admission of the first auxiliary request into the proceedings.

25. On the question of whether the board should exercise its discretion to itself consider all issues, or to remit the case to the first instance, there have been occasions such as occurred in decisions T 91/98 (supra) or T 455/96 (supra) where the board has itself considered a new case as only instance, though these are exceptional and in circumstances where the patents had less time to run than here, and the patentee and at least the majority of the parties were in favour of this course. In the present case the board considers as decisive for exercising its discretion in favour of remittal, the fact that the issues of both inventive step and sufficiency of disclosure have yet to be decided, and that by not remitting, the board and the respondents would be deprived of having a first instance decision serving to focus the arguments on appeal. Article 104 EPC provides a remedy if it should turn out that there has been an unnecessary number of oral proceedings due to the conduct of one of the parties.

26. Whether any other auxiliary requests are allowed into the proceedings is not a matter which this board proposes to decide.