W 0003/99 (Chemically defined media/GIST-BROCADES) 24-08-1999
Download and more information:
Fermentative production of valuable compounds on an industrial scale using chemically defined media
I. International patent application PCT/EP 98/01122 was filed on 20 February 1998 with thirty-five claims.
Claims 1, 9 to 12, 15 to 16, 19 to 20, 27 to 30, 32 to 35. read as follows:
"1. A process for the production of a valuable compound, comprising the steps of:
fermentation of a microbial strain on an industrial scale in a fermentation medium which is a chemically defined medium essentially composed of chemically defined constituents, and
recovery of the valuable compound from the fermentation broth.
9. The process of any one of the claims 1 to 8, wherein the valuable compound is a pharmaceutical protein or peptide, a primary or a secondary metabolite, or an industrial enzyme.
10. The process of claim 9, wherein the valuable compound is a secondary metabolite.
11. The process of claim 10, wherein the secondary metabolite is a ß-lactam compound.
12. The process of claim 9, wherein the valuable compound is an enzyme.
15. The process of any one of the claims 1 to 9, wherein the microbial strain is a filamentous microbial strain.
16. The process of claim 15, wherein the filamentous strain is a fungus.
19. The process of claim 16, wherein the fungus is a Penicillium strain.
20. The process of claim 19, wherein the fungus is Penicillium chrysogenum and the valuable compound is a ß-lactam compound.
27. The process of claim 15, wherein the filamentous strain is a bacterium.
28. The process of claim 27, wherein the bacterium is an Actinomycete.
29. The process of claim 28, wherein the Actinomycete is a Streptomyces strain and the valuable compound is glucose isomerase.
30. The process of claim 28, wherein the Actinomycete is Streptomyces clavuligerus and the valuable product is clavulanic acid.
32. A method for preparing and/or improving a microbial strain producing a valuable compound of interest which is capable of being fermented on an industrial scale in a chemically defined medium, comprising the steps of:
- subjecting a suitable parent strain to a mutagenic treatment selected from the group of physical means and chemical mutagens, and/or to DNA transformation,
- screening the resulting mutants and/or transformants for their growth performance on a chemically defined medium and their production level of said valuable compound of interest,
- selecting mutants and/or transformants which have a good growth performance on a chemically defined medium and/or an improved production level of said valuable compound of interest as compared to said parent strain.
33. The method of claim 32, wherein the parent strain is selected from the group consisting of strains which have a good growth performance on a chemically defined medium, but which need to be improved on production level.
34. The method of claim 32, wherein the parent strain is selected from the group consisting of strains which have a high production level of a desired compound but a relatively bad growth performance on a chemically defined medium.
35. Use of a chemically defined fermentation medium for the production of a valuable compound by fermentation of a microbial strain on an industrial scale".
II. On 21 August 1998 the European Patent Office (EPO), acting as an International Search Authority (ISA), invited the Applicant to pay within a time limit of 30 days eight additional search fees pursuant to Article 17(3)(a), Rule 40.1 and 40.3 PCT and issued a partial search report on claims 1 to 9, 15, 27 to 28, 35. (all partially) and claims 12 and 29 (completely) relating to the invention first mentioned. The invitation stated the following nine groups of inventions:
1. Claims 1 to 9, 15, 27 to 28, 35 (all partially) and claims 12 and 29 (completely), relating to a process for the production of a pharmaceutical protein or a peptide, including an industrial enzyme, by fermentation in a chemically defined fermentation medium on an industrial scale: production of glucose isomerase by Streptomyces.
2. Claims 1 to 9, 15 to 16, 35 (all partially) and claims 10 to 11, 19 to 20 (completely) relating to a process for the production of a secondary metabolite by fermentation in a chemically defined fermentation medium on an industrial scale: production of a ß-lactam compound by Penicillium chysogenum.
3. Claims 1 to 9, 35 (all partially) and claims 13 to 14. (completely) relating to a process for the production of a valuable compound by fermentation in a chemically defined fermentation medium on an industrial scale: production of astaxanthin by the yeast Phaffia.
4. Claims 1 to 9, 15 to 16, 35 (all partially) and claims 17 to 18 (completely) relating to a process for the production of a valuable compound by fermentation in a chemically defined fermentation medium on an industrial scale: production of lovastatin by Aspergillus terreus.
5. Claims 1 to 9, 15 to 16, 21, 35 (all partially) and claims 22 to 24 (completely) relating to a process for the production of a valuable compound by fermentation in a chemically defined fermentation medium on an industrial scale: production of arachidonic acid by Mortierella alpina.
6. Claims 1 to 9, 15 to 16, 21, 35 (all partially) and claims 25 to 26 (completely) relating to a process for the production of a valuable compound by fermentation in a chemically defined fermentation medium on an industrial scale: production of ß-carotene by Blakeslea trispora.
7. Claims 1 to 9, 15, 27 to 28, 35 (all partially) and claim 30 (completely) relating to a process for the production of a valuable compound by fermentation in a chemically defined fermentation medium on an industrial scale: production of clavulanic acid by Streptomyces clavuligerus.
8. Claims 1 to 9, 15, 27 to 28, 35 (all partially) and claim 31 (completely) relating to a process for the production of a valuable compound by fermentation in a chemically defined fermentation medium on an industrial scale: production of erythromycin by Saccharopolyspora.
9. Claims 32 to 34 (completely) and claim 35 (partially) relating to a method for preparing and/or improving by a mutagenic treatment and/or DNA transformation a microbial strain producing a valuable compound.
III. The invitation stated that there was no single inventive concept underlying the plurality of claimed inventions. Reference was made in particular to the following prior art documents:
(1) US-A-5 494 808;
(2) US-A-4 374 929;
(3) Weiying Mao et al., J. Industrial Microbiology, Vol. 11, 1992, pages 1 to 6.
It was found that, since the use of chemically defined media in microbial fermentation processes was known in the art, there was no special technical feature which could link the inventions of groups 1 to 8 with the invention of group 9, as they related to two separate technical problems for which two separate solutions were offered, as well as the inventions of groups 1 to 8. with each other, as they all related to the production of different compounds by different microbial strains.
IV. On 16 September 1998, the Applicant paid additional fees for the inventions of groups 2, 7 and 9. The additional fees were paid under protest pursuant to Rule 40.2(c) PCT. The Applicant submitted that the fermentative production of a valuable compound using a chemically defined medium on an industrial scale (ie a scale 10m3; cf page 4, lines 32 to 36 of the application) was not known in the art, where such media were used only on a substantially smaller scale. This provided the single inventive link between the different groups of invention. Moreover, as in improvement programs for industrial strains it was important to measure performance of any improved strain on a chemically defined medium, also group 9 fulfilled the same inventive concept.
V. On 1 December 1998 the ISA issued the International search report for three additional groups and communicated to the Applicant the result of its review under Rule 40.2(e) PCT. The finding of lack of unity was confirmed because it was held that, since scaling-up from a laboratory scale or from a pilot scale to an industrial scale was common practice in fermentation industry, the use of chemically defined media on an industrial scale was not a special technical feature which could link together the different groups of inventions. Moreover, group 9 related to a different technical problem. Therefore, the Applicant was invited to pay within one month the protest fee.
VI. The protest fee was paid by the Applicant on 22. December 1998.
1. The protest is admissible.
2. According to Rule 13.1 PCT, the international patent application shall relate to one invention only or to a group of inventions so linked as to form a single inventive concept. If the ISA considers that the claims lack this unity, it is empowered, under Article 17(3)(a) PCT, to invite the Applicant to pay additional fees.
3. Lack of unity may be directly evident a priori, ie before the examination of the merits of the claims in comparison with the state of the art revealed by the search (cf, for example, decision W 13/87 of 9 August 1988). Alternatively, having regard to decision G 1/89 of the Enlarged Board of Appeal (OJ EPO 1991, 155), the ISA is also empowered to raise an objection a posteriori, ie after having taken the prior art revealed by the search into closer consideration. This practice is laid down in the PCT Search Guidelines, Chapter VII,9 (PCT Gazette 30/1992, 14025) which are the basis for a uniform practice of all International Searching Authorities. The Enlarged Board of Appeal indicated that such consideration represents only a provisional opinion on novelty and inventive step which is in no way binding upon the authorities subsequently responsible for the substantive examination of the application (point 8.1. of the Reasons for the decision). In point 8.2 of the Reasons, the Enlarged Board mentioned that such invitation to pay additional fees should always be made "with a view to giving the Applicant fair treatment" and should only be made in clear cases.
4. According to Rule 13.3 PCT, the determination whether a group of inventions is so linked as to form a single general inventive concept shall be made without regard to whether the inventions are claimed in separate claims or as alternatives within a single claim.
5. The question here is whether or not the subject-matter of the claims of the groups 1, 2, 7 and 9 (see section II above) can be considered to be part of the same general inventive concept.
6. In the Applicant's view, the unitary link is provided by the fact that the present application proposes for the first time the use of a chemically defined fermentation medium for the production of a valuable compound by fermentation of a microbial strain on an industrial scale (cf claim 35).
7. The board does not share the Applicant's view for the following reasons:
(a) Firstly, the expression "on an industrial scale" per se is open to interpretation and thus questionable. The Applicant refers to page 4, lines 32 to 36 of the application where it is stated that it encompasses a fermentation process on a volume scale which is 10m3. This statement does however not necessarily exclude lower volumes, especially in view of the fact that, as stated on page 3, lines 8 to 11 of the application, a relatively small fermentative scale typically does not exceed a volume of about 20-40L. Thus, it is left open to interpretation whether the whole area of fermentation carried out in fermentors of eg more than 40L and less than 10. m3 (eg pre-seed or seed-fermentors, pilot scale fermentors) falls also under the general definition of an "industrial scale";
(b) It is well known from the art that chemically defined media are often used up to the seed stage of fermentation to ensure rapid and reproducible growth. The use on a larger scale of media based on raw materials is normally based on considerations of costs and availability (cf as a general textbook eg the Kirk-Othmer "Encyclopaedia of Chemical Technology", Fourth Edition, 1993 Vol. 10, page 369, lines 4 to 8);
(c) Examples of the use of chemically defined media in relatively large scale fermentations for the manufacture of a valuable compound are known in the art. Document (1) referred to by the ISA describes the use of a wholly synthetic medium in a 250L production fermenter for the production of a protein complex by Neisseria meningitidis. The following further document:
(4) Ghulam N. Qazi et al. J. Ferm. Bioeng., 1990, Vol. 69, No. 1, pages 72 to 74
describes citric acid fermentations with Aspergillus niger in tanks of 500 and 2.6 m3 carried out inter alia using a synthetic medium.
8. Thus, the general proposal of using a chemically defined medium in fermentation processes on an industrial scale (cf claim 35) was already part of the prior art knowledge and thus cannot in itself constitute a unitary link between the subject-matter of the claims of groups 1, 2, 7 and 9.
9. In the light of the said knowledge, the technical problems underlying the four groups of inventions are all different as they are in relation either to the finding of the proper fermentation conditions (eg the design of the chemically defined media) for the production of compounds of different nature by different kinds of microorganisms (group 1: production of glucose isomerase by Streptomyces; group 2: production of a ß-lactam compound by Penicillium chysogenum; group 7: production of clavulanic acid by Streptomyces clavuligerus) or to the finding of a method for preparing and/or improving a microbial strain producing a valuable compound (group 9).
10. The solutions to such different technical problems, ie the designed nutrient media among themselves (groups 1, 2. and 7) and the mutagenic/DNA transformation method (group 9), are not necessarily interrelated from a technical point of view so as to form a single general inventive concept.
11. For the foregoing reasons, in the Board's judgement, there is no "special technical feature" in the sense of Rule 13.2 PCT to link the four groups of inventions. Thus, the international application does not comply with the requirement of Rule 13.1 PCT and the invitation to pay the additional fees was justified.
ORDER
For these reasons it is decided that:
The protest according to Rule 40.2(c) PCT is dismissed.