T 0877/90 (T-cell growth factor/HOOPER) 28-07-1992

1. The appeal is admissible.

2. Novelty (Article 54 EPC)

2.1. Main request

2.1.1. Claim 1 of the main request is a product claim wherein a T-cell growth factor is defined as being derived from the peripheral mononuclear blood cells of a donor and being serum-free and mitogen-free and the donor being human, bovine or porcine.

2.1.2. The documents in discussion as representing the closest prior art are the Erlangen and Geisenheim meetings (citations (12) and (13)) and document (17) which is an abstract of the lecture presented by the inventors of the patent in suit at the Geisenheim meeting.

2.1.3. As to the question whether or not the Erlangen and Geisenheim meetings constitute prior art within the meaning of Article 54(2) EPC, the Board confirms the position taken by the Opposition Division in its impugned decision. For the same reasons as those adequately developed under point 2.2 in the impugned decision (see paragraph III(a) above), the Board considers both meetings as constituting prior art.

2.1.4. It is an undisputed fact that the date of both meetings fall before the priority date of the patent in suit.

2.1.5. Further, the Board is unable to follow the submissions of the Respondents to the effect that the meetings were not "public" within the meaning of Article 54(2) EPC.

An oral disclosure is regarded as made available to the public if, at the relevant date, it was possible for members of the public to gain knowledge of the content of the disclosure and there was no bar of confidentiality restricting the use or dissemination of such knowledge. It is plausible that the meetings at Erlangen and Geisenheim were not open to everybody, because only certain persons were invited to participate. Those, however, were not subject to a secrecy agreement. So the oral disclosure of the meetings was freely available to the public. Everything that was said at the Erlangen and Geisenheim meetings was therefore made available to the public.

2.1.6. There is no need to refer this question to the Enlarged Board of Appeal under Article 112 EPC. In this connection, however, the Board would like to remark that the conjunction made by the Respondents between the words "made available to the public" in Article 54(2) EPC and "to be carried out by a person skilled in the art" in Article 83 EPC cannot be understood as meaning that the word "public" in Article 54(2) EPC refers not to the person skilled in the art but to the man in the street. It is the converse which makes sense, i.e. that an oral disclosure before a skilled person makes it "public" in the sense that the skilled person is able to understand the oral disclosure and is potentially able to distribute it further to other skilled members of the public.

Had the oral disclosure taken place before a circle of persons, all of whom were unable to understand its technical teaching, it could be argued that the disclosure had not been made available to the public because the teaching would not have been understood by the audience. Therefore, in this respect the word "public" in Article 54(2) EPC has the same meaning as the words "skilled person" in Article 83 EPC, but whereas in the case of Article 54(2) EPC the making available to the public of a disclosure is seen from the stand-point of passive reception, Article 83 EPC requires sufficient disclosure for a skilled person to be able to actively reproduce the invention.

In any event, the term "made available to the public" in Article 54(2) EPC cannot be interpreted in such a way that the addressees of an oral disclosure were only to be considered as being "public" if they were to be considered as unskilled persons. This, however, would be the consequence of the Respondent's arguments.

2.1.7. Finally, after consideration of the minutes of the thorough hearing of witnesses before the Opposition Division and all further evidence on file, the Board shares the Opposition Division's opinion in its impugned decision under point 2.22 that there remain doubts about the true content of what was said at the meetings about the method to stimulate and produce IL-2. In the Board's opinion, it is not likely that now, 12 and 13 years after the two meetings took place, the facts could be elucidated more clearly than they were before the Opposition Division. All the written facts on file about the meetings, i.e. handwritten notes taken during the meetings by the witnesses, have been correctly assessed by the Opposition Division. In view of this situation the Opposition Division correctly decided that any oral disclosure at the Erlangen or Geisenheim meetings could not be considered as state of the art within the meaning of Article 54(2) EPC.

2.1.8. Disregarding the oral disclosures at the meetings as relevant state of the art, the disclosure of document (17) remains to be considered. The Appellants contended that this document had been distributed at the Geisenheim meeting and represented an abstract of what had already been presented orally at a lecture at the Geisenheim meeting by one of the inventors. The Respondents did not seriously contest that this paper had been distributed to the participants at the Geisenheim meeting. Document (17), therefore, is a written disclosure of the role of serum proteins in PHA-induced products of IL-2 by human peripheral blood lymphocytes before the priority date of the patent in suit.

2.1.9. Independently of the different interpretation put on the true teaching of document (17) by the parties, there is agreement among them, and this was also the position of the Opposition Division, that document (17) represents the closest prior art. The Board shares this view.

As already stated correctly in the decision of the Opposition Division, the technical teaching of document (17) is ambiguous. The purpose of the experiments carried out and described in document (17) was, as the title of this paper already indicates, to investigate the role of serum proteins in PHA-induced production of IL-2. There is to this extent a clear and unambiguous disclosure in this document as two methods are compared. The one comprises a stimulation of the peripheral blood cells by PHA in the absence of serum, a situation in which no production of IL-2 could be detected (page 5, paragraph 3, lines 5 to 7). Literally, it is said that "if the cells first were incubated with serum then washed and incubated with PHA in absence of a serum, hardly any IL-2-activity could be seen either. Contrastingly, a very good IL-2-activity was seen in the conditioned supernatants if the cells first were incubated with PHA-containing culture medium in the absence of serum, then washed and incubated in culture medium supplemented with serum only, before the cells were washed and allowed to condition the supernatants" (page 5, third paragraph, lines 7 to 10, page 6, first paragraph, lines 1 to 6).

2.1.10. From these results, the authors of document (17) drew the conclusion that for the lectin-mediated induction of IL-2- production a double signal was needed, namely that first PHA reacted with the membrane of the IL-2-producer cell and uncovered or activated a receptor, which secondly interacted with serum protein. The production of IL-2 did not begin until after this double signal. It was then the purpose of the presentation given in document (17) to characterise the endogenous co-mitogenic factor. The more ambiguous information given in document (17) has to be interpreted in the light of the above-cited disclosure read with knowledge of the purpose of the experiments carried out and described therein. In doing so, the sentence which has led to controversy between the parties and reads "during PHA stimulation the culture medium is substituted with 15% human AB serum, whereas production of IL-2 and bio-assays are performed in absence hereof", can only have the meaning that PHA as a mitogen and human AB serum are applied in sequence and not at the same time so that the words "substituted with" have to be interpreted as meaning "replaced by".

2.1.11. Document (17) further mentions assay systems for IL-2 activity, namely growth support of human T-cell lines and proliferation and blast transformation of PBL in absence of serum. From the above literal citation (see point 2.1.9) it becomes apparent that by the experiments carried out an IL-2 activity could be established by one of the assay systems. There is no mention in document (17) about purity or concentration of IL-2.

2.1.12. Independent product Claim 1 has as its essential characteristic that the T-cell growth factor is serum-free and mitogen-free. The analysis of the teaching of document (17) above shows that by the experiments carried out in document (17) an IL-2 activity could be demonstrated. There is no clear and unambiguous disclosure that any product was obtained containing IL-2 but no PHA, i.e. mitogen and no serum at all. The purpose of any washing step described in document (17) was to make sure when applying in sequence either PHA or serum that any effect observed could be distinguished as being the result of the action of PHA or of serum. The disclosure of document (17) cannot be understood therefore, as to provide a real mitogen- and serum-free T-cell growth factor, as claimed in Claim 1. A product of this kind is, therefore, novel.

2.1.13. Besides independent Claim 1 there is an independent Claim 3 the novelty of which has to be examined. It refers to a process for producing a serum-free and mitogen-free T-cell growth factor (see above paragraph I).

2.1.14. Following the analysis of the technical teaching of document (17), as given above, it may be concluded that there are two process steps in Claim 3, which are not clearly and unambiguously disclosed in document (17) namely step (2) to stimulate the cells by incubating the cells in a liquid tissue culture medium supplemented with serum and mitogen and process step (4) to condition the cells obtained in a preceding step by incubating the cells in the presence of a serum-free and mitogen-free liquid tissue culture medium. Process Claim 3 has, therefore, also to be considered novel.

2.1.15. The Appellants mentioned document (6) in an aside, where on page 365 under the headline "Materials and Metals, No. 2 Conditioning of Media", it is mentioned that PBL were incubated in a medium, containing 15% pooled inactivated human AB serum and 4 µg/ml of PHA, which was considered to be the same process step as that defined under step (2) in Claim 3. For the sake of completeness the Board notes that the mentioned paragraph further contains the process steps that after thorough washing the cells were incubated in a culture medium supplemented only with AB serum. This process step differs, thus, from process step (4), where it is an essential feature that further conditioning of the cells is to be carried out in the presence of a serum-free culture medium. Therefore, process Claim 3 is novel also with regard to document (6).

2.1.16. The claims of the main request thus fulfil the requirements of Article 54 EPC.

3. Inventive step (Article 56 EPC)

3.1. Main Request

3.1.1. Product Claim 1 of the main request being novel, it is necessary to examine whether it involves the required inventive step.

3.1.2. In the light of the technical teaching of document (17) (see points 2.1.9 to 2.1.11 above), the technical problem can be seen in the improvement of the purity and concentration of a T-cell growth-factor product.

The problem is solved by providing a product as claimed in Claim 1 and a process as claimed in Claim 3. The specification states in column 2, lines 52 to 55, that through serum-free production the growth factor could be highly concentrated and the activity thereof could be increased between 300 and 500 times. Examples 1 to 3, in particular, provide sufficient evidence that the problem was actually solved.

3.1.3. The question to be answered is whether a mitogen-and serum-free T-cell growth-factor constitutes an inventive contribution to the art.

In the specification of the patent in suit there is a discussion of certain prior art documents which disclose a T-cell growth-factor product which is contaminated either by PHA or by serum. Serum is necessary for cell growth and as a result, serum was always used in cell culture. It is, apparently, highly desirable to provide a T-cell growth factor product which does not contain any toxic substances. It is known that PHA has toxic effects and further on that the presence of serum may mask the true effect of IL-2 because of numerous proteins being present in serum and repeated injections of such a serum- containing preparation regularly cause allergic and anaphylactic reactions in patients. On the other hand, any process to remove undesired contaminating substances resulted in a decrease of the activity of a T-cell growth factor. This discussion of the prior art shows that the Respondents, at the time of the priority of the patent in suit, were well aware of the disadvantages of the presence of mitogen and serum in a T-cell growth factor product. This is further supported by other prior art documents filed before the Opposition Division by the Appellants, for example by document (6) (page 365) mentioned above. Thus, as far as product Claim 1 is concerned, the Board considers the mitogen- and serum-free T-cell growth factor product as such to be an obvious desideratum.

3.1.4. In the view of the Board, starting from document (17), the next obvious step in the light of the problem to be solved would have been to develop the process described unambiguously in document (17) in such a way that the desired end product, as obtained by the scientific experiments described in document (17), would have been freed from any contaminating and toxic substances.

3.1.5. The Board accepts that there are cases in which an acknowledged inventive step of a process may also influence the inventive contribution for a product claim. In the present case, however, document (17) provides the information that, in the supernatant of a culture medium containing PBL, incubated with PHA, then washed and incubated in a culture medium supplemented with serum only, a very good IL-2-activity could be observed. Being equipped with the information that neither mitogen nor serum are desired in a pharmaceutically acceptable end product it would have been the next obvious and evident step for the skilled person within the meaning of an obvious desideratum to further develop the substance whose activity was determined in documents (17) to make the product completely mitogen- and serum-free.

3.1.6. Since an inventive step for the product as claimed in Claim 1 cannot be accepted, the main request, containing a non-allowable claim, thus is not allowable.

3.2. Auxiliary request 1

3.2.1. Claim 1 of this request relates to a method for producing a serum-free and mitogen-free T-cell growth factor comprising several steps (see above paragraph I). The closest prior art document with respect to this process claim is also document (17) as correctly analysed by the Opposition Division. The differences between the method clearly and unambiguously disclosed in document (17) and the method as claimed are stated above under point 2.1.14. The question remains whether these variations of the method to obtain IL-2 disclosed in document (17) contribute to the art in an inventive way or whether these measures would have been an obvious technical development which would not be patentable.

3.2.2. The purpose of the experiments described in document (17) was to investigate the role of serum proteins in PHA- induced production of IL-2 by human peripheral blood lymphocytes. From those investigations, as summarised above under point 2.1.9, it follows that it was not within the frame of the teaching of document (17) to supplement mitogen and serum simultaneously for stimulating the PBL to produce IL-2 because in this case an unambiguous scientific answer to the question of the role of serum and mitogen cannot be given. If, therefore, an IL-2 production showing good activity is one of the desired aims, the skilled person would turn to that sequence of addition of mitogen or serum which was shown to be good. Any hint to supplement mitogen and serum simultaneously cannot be derived from document (17).

3.2.3. Moreover, neither step (3) of the claimed process to separate and wash the stimulated cells to remove substantially all of the serum and mitogen nor step (4) to condition the cells obtained by further incubating the cells in the presence of serum-free and mitogen-free culture medium was obvious in the light of the teaching of document (17), because nowhere is there any hint that any one could achieve, faced with the problem to be solved, a reasonable yield of the desired T-cell growth factor when incubating the cells in a serum-and mitogen-free culture medium. Thus, taking the technical teaching of document (17) alone, the skilled person could not arrive at the claimed process without an inventive contribution.

3.2.4. It remains to investigate whether there are possibly other documents which could have led the skilled person on the basis of the teaching of document (17) and in the light of the problem to be solved, to arrive at the claimed process. Besides less relevant prior art it is the disclosure of already mentioned document (6) which could possibly be relevant. It deals with a method of establishing human T-cell lines in tissue culture media containing T-cell growth factor but not PHA. It is thus the technical teaching of document (6) to investigate whether it is PHA or the T-cell growth factor which is causing the T-cells to grow for a certain period of time. The result of the experiments carried out according to this document was that not PHA but T-cell growth factor was considered to be the T-cell mitogen. Even if, as already stated above (see point 2.1.15), a medium is described which contains serum and PHA, the process disclosed is such that PBL were firstly incubated with the mentioned media, thereafter thoroughly washed and then incubated for 48 hours in the medium supplemented only with serum. After centrifugation the supernatant were then decanted off and stored. In particular, on page 370 under the heading "Discussion", it is disclosed that PHA is needed for the production of T-cell growth factor in PBL- cultures but is only needed during an initial stimulation period. After several washing steps, a virtually PHA-free T-cell growth factor conditioned culture medium was obtained without need for further manipulation. It is concluded that PHA is able to induce a short-lasting production of the growth factor upon which the respondent cells mount their mitogenic response. After the decline of the growth factor production and exhaustion of the supply, the respondent cells die (page 370, fourth paragraph). Accordingly, this teaching does not give any indication to the skilled person that an incubation of the PBL in the simultaneous presence of mitogen and serum, followed by a washing step to remove any mitogen and serum and a further incubation step in a medium not containing mitogen and serum, could result in an effective, long lasting production of IL-2, ending up with a mitogen- and serum- free product.

3.2.5. The fact that the process as claimed appears to be simple does not necessarily mean that it is obvious. In the Board's opinion, the prior art disclosures as analysed above would lead a person of ordinary skill to a process according to which PHA and serum, each playing apparently sensitive roles in the process of inducing IL-2, could not be applied at the same time and furthermore should not be removed from the growth media completely without the process being terminated or at least disturbed. In the light of this, the simplicity of the claimed method comprises an elegant feature which is considered by the Board to go beyond ordinary skill.

3.2.6. Claim 1 of the first auxiliary request, therefore, is inventive and this request consequently is allowable; a discussion of the remaining auxiliary requests is not necessary.