T 0552/00 (3D-MPL/SMITHKLINE) 30-10-2003

Reasons for the Decision

Admissibility of the appeals

1. The appeal of appellant II is admissible, since it complies with Articles 106 and 108 EPC and with Rules 1(1) and 64. EPC.

2. The objection put forward by appellant II, concerning the admissibility of the appeal filed by appellant I, is based on the assumption that the new main and auxiliary requests are virtually identical to the claims as granted. Since the latter was withdrawn prior to the oral proceedings before the opposition division, appellant I could not be considered as being adversely affected, pursuant to Article 107 EPC, by the decision under appeal.

3. In the Board's view, appellant II's assumption is not convincing.

4. Indeed, as far as the main request is concerned, whereas claims 1 to 26 are identical with claims 1 to 26 as granted, claim 27 corresponds to claim 29 as granted, at the end of which "and a carrier" has been added and claim 28 to claim 28 as granted with addition of "until the particle size does not exceed 120nm adsorbing the 3-O-deacylated monophosphoryl lipid A solution to aluminium hydroxide, and adding antigen". There is no claim corresponding to granted claims 27, 30 and 31 in the main request. Therefore, the claims of the new main request are not identical with those granted by the first instance.

5. The claims of the main request are hence not only formally different from the claims as granted, but also in their "substance", since, in particular, the broad granted claim 27 has been deleted. Therefore, their submission in the appeal proceedings does not amount to a simple re-introduction of the claims as granted.

6. The deletion of the term "in general" from the claims of the main request is an attempt to overcome an objection under Articles 84 and 123(3) EPC having led the opposition division to reject the claims of the main and auxiliary requests I and II (pages 4 to 6 of the decision of the opposition division). The claims of the main request are hence bona fide attempts to overcome objections of the opposition division.

7. On the other hand, the subject-matter of the main request (ie 3D-MPL particles with a size below 120nm, in the range 60- 120nm or below 100nm, their use for the preparation of a vaccine, methods related thereto and use thereof) is similar to that of the requests considered by the opposition division. Therefore, even though the opposition division has not based their decision on the claims of the main request presently on file, they have nevertheless given a decision on their subject- matter, so that appellant I can be considered as being adversely affected by the decision under appeal.

8. The Board thus concludes that the appeal of appellant I complies with Articles 106 to 108 EPC and Rules 1(1) and 64 EPC.

Article 114(2) EPC

9. The admissibility of the main and auxiliary requests already on file before the oral proceedings was questioned by appellant II. These requests were in fact filed (although as auxiliary requests II and III, respectively) with the letter dated 4 August 2000 and, therefore, were known to appellant II since three years. Accordingly, no inconvenience can be derived to appellant II from the mere fact that two weeks prior to the oral proceedings these requests were declared as main and auxiliary requests, respectively.

10. During the oral proceedings, appellant I filed two new sets of claims, as main and auxiliary requests. In the Board's view, these late-filed requests are admissible, since they only contain few amendments to the wording of the main and auxiliary requests already on file, amendments which can be considered as a direct consequence of the discussion during oral proceedings.

Main request

Articles 84, 123(2)(3) EPC

11. No objection has been raised by appellant II in view of these Articles. The Board also considers that the claims of the main request are clear, have a basis in the application as filed and do not extend the scope of protection.

Article 83 EPC

12. Appellant II objected that the patent in suit does not enable the skilled person, using his/her common general knowledge, to prepare 3D-MPL particles as defined in claims 1 to 3. To confirm their objection, appellant II submitted experimental data (documents (25) and (29)) showing that, using the method and apparatus of the patent in suit, preparations in which all the 3D-MPL particles had a size less than 120nm could not be achieved. The same result was even obtained with better detectors than that of the patent in suit. Further, appellant II objected to the assumption that the claims should be interpreted in a way larger than that suggested by their formulation.

13. The patent in suit and documents (25), (29) and (33) show that 3D-MPL particles with a size below 100nm, below 120nm or in the range 60-120nm, as requested by claims 1 to 3 of the main request, can be obtained, when the conditions of Example 1 are followed and that increasing the time of sonication, as suggested in the patent in suit, also increases the amount of particles exhibiting the required size. However, documents (25), (29) and (33) show that not all the particles exhibit the required size.

14. As stated in decision T 190/99 (cf supra section IX), claims should be considered in a way which rules out interpretations which are illogical or which does not make technical sense and in a manner to arrive at an interpretation which is technically sensible and takes into account the whole disclosure of the patent.

Following this principle, the Board is convinced that the essential element of the disclosure of the patent in suit lies in the teaching that lowering the size of the 3D-MPL particles increases their adjuvancy, which is not precluded by the presence of some few percent of particles with a size greater than the upper limit of 120nm or lower than the lowest one of 60nm mentioned in claims 1 to 3. Furthermore, the Board is also convinced that the skilled person at the priority date of the patent in suit would have encountered no difficulty in separating the particles with the sizes required by the claims from that having a size greater than 120nm or less than 60nm using his/her common general knowledge, because document (14), a textbook reflecting the common general knowledge of the skilled person and published about 10 years before the priority date of the patent in suit, shows that ultrafiltration is the method of choice for such a purpose.

15. Therefore, the patent in suit fulfils the requirements of Article 83 EPC, even if a strict interpretation is given to the upper (120nm) and lower (60nm) limits mentioned in claims 1 to 3, since it discloses the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art using his/her common general knowledge.

Articles 87 to 89

16. Before considering the novelty objection raised by appellant II against the claims in view of document (2), the question of whether the patent in suit enjoys the priority right of its first priority GB 9306029 (23 March 1993) has to be dealt with. Indeed, document (2) has a priority (27 March 1992), which lies before that of the patent in suit, and has been filed (24 March 1993) and published (4 October 1993) after said priority date, but before the filing date of the patent in suit (14 March 1994). As a consequence, if the patent in suit does enjoy the priority right of GB 9306029, then document (2) is a prior art document in the sense of Article 54(3) EPC which can only be considered for novelty objection. On the contrary, if the patent in suit does not enjoy said priority right, then document (2) is a prior art document in the sense of Article 54(2) EPC and can be considered for both novelty (Article 54 EPC) and inventive step (Article 56 EPC) objections. Of course, following the objection raised by appellant I (cf supra section VIII), it should also be determined whether document (2), in the context of the patent in suit, enjoys its priority right, because if it does not, whereas the patent in suit does, then document (2) cannot at all be taken into consideration.

17. The question of the priority right is dealt with in Articles 87 to 89 EPC which state that a European patent application is only entitled to priority in respect of the same invention as was disclosed in a previous application. Opinion G 2/98 (cf supra section VIII) indicates that the concept of the "same invention" should be given a narrow interpretation.

18. The subject-matter claimed in claims 1 to 3 (ie the vaccine composition using 3D-MPL particles with a size less than 120nm, in the range 60-120nm or less than 100nm, respectively) is disclosed in Example 1 of the patent in suit. Example 1 of the first priority document is the same as Example 1 of the patent in suit and, as the latter (cf points 12 to 15), enables the skilled person to produce 3D-MPL particles with a size as required in claims 1 to 3. Therefore, the patent in suit is entitled to the priority date of the first application as far as the subject-matter disclosed in Example 1 is concerned. The relevant date for the assessment of the prior art in the sense of Article 54(2) EPC is thus 23. March 1993 for any subject-matter corresponding to that disclosed in Example 1. The consequence of this is that document (2) is a prior art document under Article 54(3) EPC which can only be taken into consideration for novelty objection, provided it enjoys its priority right.

Article 54 EPC

19. Document (2) discloses in Example 5 (Part A, Experiment III and Part B, Experiment II) MPL particles with a size less than 100nm. However, documents (3) and (4), the priority documents of document (2) do not contain said Example 5. and do not appear to disclose elsewhere in their specifications its subject-matter in a way sufficiently clear and complete for it to be carried out by the skilled person. Therefore, in the context of the patent in suit, the Board concludes that document (2) does not enjoy its priority right for this feature and considers that the relevant date for document (2), as far as this feature is concerned, is the filing date, ie 24 March 1993, which is posterior to the first priority date of the patent in suit, so that document (2) cannot be taken into consideration in view of particles with a size less than 100nm.

20. Document (2) also discloses in Example 1 the use of 3D-MPL particles with a size ranging from 80 to 500nm for a purpose identical to that of the patent in suit and is entitled to its first priority date for this feature, which is disclosed in Example I of documents (3) and (4). The lower part of the disclosed range overlaps with the sizes given in the claims of the main request. The established case law (Case Law of the Boards of Appeal of the European Patent Office, 4th edition, 2001, pages 82 and 83) suggests that for determining whether a technical teaching has been made available to the public the question should be asked whether the person skilled in the art would seriously contemplate applying the technical teaching of the prior art document in the range of overlap. In the present case, the range defined in document (2) is large, since it extends from 80nm to 500nm and the region of overlap (80nm to 120nm) represents less than 10% of the whole range and is placed at the lowest end of it. The information which can be retrieved from document (2) for preparing the 3D-MPL particles (page 7, lines 6 to 9) is scarce and undifferentiated insofar as it does not provide the skilled person with any guidance for preparing particles with a specific size within this broad range. Document (2) only teaches to continue the sonication until the desired size is obtained (page 7, lines 6 to 9), but does not indicate any particularly preferred sub-range within this "80 to 500nm" range. In the absence of any precise guidance from document (2), the skilled person would follow the protocol suggested by Ribi Immunochem Research (the supplier of MPL and 3D-MPL), which according to document (27) gave particles in the range 115 to 951nm with a mean size of about 375nm. Furthermore, the skilled person knows that the size distribution of the particles follows a Gauss-curve and would hence assume that the lower and upper limits of the range defined in document (2) only represent both ends of said Gauss-curve. Therefore, the Board is convinced that document (2) does not seriously contemplate applying the technical teaching described therein in the range of overlap, which cannot be considered as having been made available to the public in the sense of Article 54 EPC.

21. Document (12) discloses the use of liposomes containing MPL to trigger an immune response to a hexapeptide antigen. The particles obtained have a diameter of 90nm (page 187, left column, last paragraph). However, the Board is convinced that document (12) uses MPL and not 3D-MPL. The reasons therefor are that, when MPL is defined in document (12) as an adjuvant (page 189, left column, 3rd paragraph), "reference 29" is mentioned, which corresponds to document (1) on file. Document (1), however, deals with the preparation of MPL (not 3D-MPL) from LPS (lipopolysaccharide). Further, document (30) states that Ribi Immunochem Research (the supplier of both MPL and 3D- MPL) replaced MPL by 3D-MPL, without changing the trade name and the accession number, in May 1990. Moreover, document (12) was, according to page 192 (left column, line just before the heading "References"), received for publication on 20 August 1990. The Board has serious doubts whether the study described therein and the writing of the publication could have been made within a period of three months or even less, since document (26) shows that 3D-MPL was not available before June 1990. Finally, the subject-matter of document (12) is, in the Board's view, different from that of the patent in suit, since MPL is not said to be used as particles, but appears to be dissolved within the liposomes (page 186, right column first paragraph, lines 10 to 12) in which it is introduced as a solution in chloroform. On the contrary, in the patent in suit, when liposomes are used (claim 5), 3D-MPL is in the form of a particle.

22. Therefore, the Board is convinced that no prior art document on file describes 3D-MPL particles with a size as requested in claims 1 to 3, so that these claims, independent claims 26 and 28 also mentioning said size features and dependent claims 4 to 25, 27 and 29 meet the requirements of Article 54 EPC.

Article 56 EPC

23. The Board, in agreement with the appellants, considers that each of documents (5), (6) or (7) can be considered as the closest prior art, since these documents teach essentially the same, ie the use of 3D-MPL as an adjuvant to produce vaccine compositions. Document (5) states on page 29 (lines 20 to 35) that "submicron particles" have been used and document (7) defines on page 9 (lines 19 and 20) said submicron particles as having a size between 100 and 400nm. Document (6) is silent about the size of the said 3D-MPL particles.

24. The technical problem to be solved in view of each of these documents can be defined as improving the adjuvant properties of 3D-MPL.

25. The solution given in claims 1 to 3, respectively, is the reduction of the size of the 3D-MPL particles below 120nm, to a range from 60 to 120nm or below 100nm.

26. The first question in view of the assessment of inventive step is whether the skilled person would have been led to this solution in an obvious manner by the cited prior art. The second question is whether, as argued by appellant II, this problem has been solved, ie whether the patent in suit shows that the 3D-MPL particles with reduced size display improved adjuvant properties.

27. None of documents (5), (6) and (7) suggests that a reduction of the 3D-MPL particle size would be of any advantage. They only use particles with a size distribution following a Gauss-curve, the extremities of which are represented by 100nm and 400nm and hence centred on a mean size of about 250nm.

28. Document (12) does not use 3D-MPL as particles and the size mentioned refers to that of the carrier particles (liposomes)(cf supra point 21).

29. Document (24) concerns an adjuvant (GMDP) which is structurally unrelated to MPL and there is no evidence that its mode of action could be similar to that of 3D-MPL. Therefore, its teaching cannot be extrapolated to 3D-MPL particles.

30. Document (16) even teaches away from the use of small size MPL particles, since it states on page 274 (last paragraph) that MPL is rapidly cleared. This being confirmed by document (10) on page 2866 (bridging sentence between the left and right columns) and document (11) on page 1081 (left column first sentence). A rapid clearance is inappropriate for an adjuvant in presenting the antigen to the immune system of the host.

31. Document (17) only stresses the adjuvant properties of MPL (not 3D-PL) without making any comment on the particle size.

32. The Board does not share the conclusion of document (31) considering that the skilled person would expect a reduction of the size of the 3D-MPL particles to result in improved adjuvant properties, since it was not established at the priority date of the patent in suit whether or not the mechanism of action of 3D-MPL involves a ligand/receptor interaction.

33. Therefore, the Board is convinced that the first question mentioned above (cf supra point 26) has to be negatively answered, since no cited prior art document considered alone or in combination with other documents or the common general knowledge leads in an obvious manner to the solution disclosed in the claims of the main request.

34. As far as the second question is concerned, Experiment 2 of the patent in suit, which is concerned with the primary HSV2 (herpes simplex virus 2) disease, shows in Table 3 that, having regard to all the parameters used, the use of small size 3D-MPL particles results in a better adjuvancy than the control. Experiment 1 confirms this teaching and extends it to a comparison with the large size particles, showing that all the parameters used for the comparison (ie the antibody titres, the median lesion severity, the PI index and the lesion score incidence) give better values with small size particles.

35. A similar conclusion can be drawn from Table 4 dealing with the recurrent HSV2 disease.

36. Table 9 (large particles) is to be compared with Table 12 (small size particles): at low 3D-MPL particle concentrations, higher total IgG titres are obtained with small particles and at every 3D-MPL particle concentration higher IgG2a titres are obtained with small particles.

37. The comparison between Table 13 (large 3D-MPL particles) and Table 14 (small 3D-MPL particles) shows that small 3D-MPL particles favour the IL-2 synthesis more than the larger ones do, whereas the influence of the small particles on the synthesis of IFN- Gamma is lowered. This shows a shift in the quality of the immunological response which is unexpected in view of the prior art documents on file.

38. Therefore, the Board, in contradiction to document (34), does consider that the patent in suit shows that the reduction of the particle size to the values given in the claims results in an improvement of the properties of said particles, so that the second question (cf supra point 26) must be answered positively.

39. Thus, the Board is convinced that the claims of the main request cannot be derived in an obvious manner from the closest prior art (documents (5), (6) or (7)) considered alone or in combination with other cited prior art documents and that the solution disclosed in these claims does solve the technical problem underlying the patent in suit. Therefore, the claims of the main request fulfil the requirements of Article 56 EPC.