T 0523/11 (Muscle-derived progenitor cells for treatment/UNIVERSITY OF PITTSBURGH) 16-04-2015

1. Both appeals are admissible.

2. Main request - Article 123(2) EPC

2.1 According to Article 123(2) EPC, a European patent application or a European patent may not be amended in such a way that it contains subject-matter which extends beyond the content of the application as filed.

In accordance with the established case law of the boards, the relevant question to be decided in assessing whether an amendment adds subject-matter extending beyond the content of the application as filed is whether the proposed amendments are directly and unambiguously derivable from the application as filed, meaning that they must not result in the introduction of technical information which a skilled person would not have objectively derived from the application as filed. In the present case, wherein a product is defined by a combination of features, it is necessary not only for each of the features, as well as their combination as claimed, to be disclosed in the application as filed, but also that there is a direct and unambiguous disclosure of a product which is defined by the particular combination of features.

2.2 In the claims of the main request, the muscle-derived progenitor cells (MDC cells) are defined as being "desmin-expressing, muscle-derived progenitor cells (MDC) having long-term survivability in situ".

2.2.1 Nowhere in the original application as filed is an explicit disclosure of such a definition to be found. Instead, the cells are generally disclosed as being "muscle-derived progenitor cells that show long-term survival following introduction into soft tissues and bone" (page 1, lines 11 to 13) or more specifically disclosed as comprising "early progenitor muscle cells, i.e., muscle-derived stem cells, that express progenitor cell markers, such as desmin, M-cadherin, MyoD, myogenin, CD34, and Bcl-2" (page 6, lines 11 to 15), and which, "[i]n addition, (...) express the Flk-1, Sca-1, MNF, and c-met cell markers, but do not express the CD45 or c-kit cell markers" (page 6, lines 15 to 17). The same definition is repeated on the same page in lines 22 to 26. Reference to the "long-term survival rates following transplantation into body tissues, preferably soft tissues" is made again on page 16, lines 18 to 19, but without any indication of the markers which should be expressed, let alone desmin. Page 18 then discloses the PP6 population as being a preferred embodiment; this population is disclosed as being muscle-derived progenitor cells which "express the desmin, CD34, and Bcl-2 cell markers" (page 18, lines 15 to 16), and then as having "long-term survivability following transplantation" (page 18, lines 18 and 19). A further definition of the PP6 cells on page 18 states that this population "comprises a significant percentage of cells that express progenitor cell markers such as desmin, CD34, and Bcl-2" and "[i]n addition, PP6 cells express the Flk-1 and Sca-1 cell markers, but do not express the CD45 or c-kit markers" (page 18, lines 20 to 25). This latter definition of the PP6 cells is again put forward on page 19 (lines 14 to 18) in relation to "the muscle-derived progenitor cells of this invention" in general.

2.2.2 As regards the experimental part of the description, in Example 1, a method is disclosed for "MDC enrichment, isolation and analysis", wherein cells designated as PP6 cells are obtained by serial plating of cell cultures derived from muscle explants. Table 2 on page 34 shows the results of the immunohistochemical analysis performed on the PP6 cells: desmin, CD34, Bcl-2, Flk-1 and Sca-1 are each detected in more than 95% of the cells, M-cadherin in 5 to 50% of the cells, and MyoD and myogenin in 40 to 80% of the cells. Example 9 then discloses a PP6-derived clone, mc13, which was obtained by stable transfection of the PP6 cells with a plasmid containing the LacZ, mini-dystrophin, and neomycin resistance genes. While observing that the mc13 cells did not express CD34 or CD45 (page 50, lines 2 to 7), the inventors state that the PP6 cells can be used to "obtain clonal isolates that express cell markers characteristic of the muscle-derived progenitor cells" and further clarify that "[f]or example, the clonal isolates express progenitor cell markers, including desmin, CD34, and Bcl-2" and "[p]referably, the clonal isolates also express the Sca-1 and Flk-1 cell markers, but do not express the CD45 or c-Kit cell markers" (page 50, lines 10 to 17). Again, Table 4 shows the results of the immunohistochemical analysis peformed on the PP6 and the mc13 cells: desmin, CD34, Bcl-2, Flk-1 and Sca-1 are each expressed in more than 98% of the PP6 cells, M-cadherin and MyoD in 5 to 30%, and myogenin in 40 to 80%; the results for the mc13 cells are similar, with the exception of CD34, which is not expressed, and Bcl-2, which is expressed only on 40 to 80% of the cells; no data is given for MyoD expression on mc13 cells.

2.2.3 Finally, as regards the claims as originally filed, all independent claims - except claim 74 - characterise the MDC cells to be used as having long-term survivability in situ, and as expressing cell markers comprising at least desmin, CD34, Bcl-2, Sca-1 and Flk-1, and as not expressing CD45 and c-Kit cell markers. Originally filed claim 74, on the other hand, refers only to "muscle-derived progenitor cells", without further characterisation.

2.3 Taking into account the above disclosure in the application as filed, the cells of the invention are disclosed to the person skilled in the art either generally as just being muscle-derived progenitor cells (as in original claim 74) or as muscle-derived progenitor cells with long-term survivability after transplantation (pages 1 and 16 supra) or specifically by reference to their cell marker expression, wherein the cell markers include not only desmin but also a number of other markers. Even if the passages on page 6 were to be interpreted as meaning that only one of desmin, M-cadherin, MyoD, myogenin, CD34, and Bcl-2 has to be present, the definition would still require that Flk-1, Sca-1, MNF, and c-met cell markers are also expressed, and that the CD45 or c-kit cell markers are not expressed.

2.4 The board thus concludes that the main request contravenes the requirements of Article 123(2) EPC.

3. First auxiliary request - Article 123(2) EPC

3.1 In this claim set, the muscle-derived progenitor cells are defined by their long-term survivability together with expression of at least desmin, M-cadherin, MyoD, myogenin, CD34 and Bcl-2.

3.2 The relevant passages on page 6 describing the MDC cells of the invention clearly require that Flk-1, Sca-1, MNF, and c-met cell markers are also expressed, and that the CD45 or c-kit cell markers are not expressed: "[i]n addition, these early progenitor muscle cells express Flk-1, Sca-1, MNF and c-met cell markers, but do not express the CD45 or c-kit cell markers" (page 6, lines 15 to 17); "[t]his MDC population also expresses Flk-1, Sca-1, MNF and c-met cell markers, but does not express the CD45 or c-kit cell markers" (page 6, lines 24 to 26). Contrary to the appellant-proprietor's arguments, these passages cannot be interpreted as referring to optional markers.

3.3 Since there is no other disclosure in the application as filed which could constitute a basis for this amendment, as evident from the discussion above (sections 2.2.1 to 2.2.3), the claims of the first auxiliary request add subject-matter, contrary to the requirements of Article 123(2) EPC.

4. Second auxiliary request - Admissibility

4.1 Article 12(4) RPBA leaves it to the board's discretion to hold inadmissible requests which could have been presented in the first instance proceedings. When exercising its discretion, the board takes into account the circumstances of the particular case and the arguments put forward by the parties.

4.2 The second auxiliary request, submitted with the statement of grounds of appeal, corresponds to the "amended" second auxiliary request which was filed during oral proceedings before the opposition division and then withdrawn to be replaced by the "twice amended" second auxiliary request. Notwithstanding the fact that the opposition division made reference to this request in both the decision and the minutes of the oral proceedings, there is nevertheless no reasoned decision by the opposition division on this set of claims.

4.3 If the second auxiliary request was to be admitted, the board would have to decide on an issue for which no decision was given by the opposition division. Even though it might not have been the appellant-proprietor's intention to avoid a decision by the opposition division, the inevitable result of the withdrawal of the request was that it was not the subject of the reasoned decision of the opposition division. The purpose of the appeal proceedings is to review what has been decided at first instance and not to review what has not been decided. No further reason was given why the board should deal with the second auxiliary request on appeal. The board therefore uses its discretionary power according to Article 12(4) RPBA not to admit the main request into the appeal proceedings.

5. Third auxiliary request

5.1 Admissibility

5.1.1 Article 13(1) RPBA leaves it to the board's discretion to admit any amendment to a party's case after it has filed its grounds of appeal. This discretion shall be exercised in view of inter alia the complexity of the new subject-matter submitted, the current state of the proceedings and the need for procedural economy.

5.1.2 The third auxiliary request was only submitted at the oral proceedings, in reaction to the board's preliminary opinion on the main request as regards Article 123(2) EPC. It was based on the second auxiliary request, with deletion of the feature "gastroesophageal muscle tissue" in claim 1 and deletion of claims 3 and 4. It is thus almost identical to the claim request which was considered allowable by the opposition division, only differing therefrom by deletion of the feature "gastroesophageal muscle tissue".

5.1.3 In the notice of opposition, the opponent had objected to the feature "gastroesophageal muscle tissue" under Article 123(2) EPC. The opposition division, however, came to the conclusion that said feature did not add subject-matter, and the opponent did not pursue this objection during appeal. It was only with the communication accompanying the summons to oral proceedings that the parties were informed that this could be an issue to discuss. Thus, while this amendment could have been introduced earlier, the appellant-proprietor had in fact no reason to do so until receiving the summons to oral proceedings. Certainly it could then have replied to the summons and submitted the amendment in writing rather than wait until the oral proceedings. However, in view of the fact that the amendment just consists of the removal of one alternative from a claim which has already been thoroughly analysed by the opposition division and by the appellant-opponent, its admission does not lead to increased complexity nor does it run counter to the need for procedural economy.

5.1.4 The third auxiliary request is thus admitted to the proceedings (Article 13 RPBA).

5.2 Article 123(2) EPC

5.2.1 With the statement of grounds of appeal, the appellant-opponent raised an objection under Article 123(2) EPC to the claims as maintained - which merely differ from the claims of the present fourth auxiliary request by the presence of the feature "gastroesophageal muscle tissue" in claim 1 (supra). Contrary to the appellant-proprietor's observations that this objection had not been raised at first instance, the board notes that it is in fact apparent from the minutes of the oral proceedings before the opposition division (page 2, section entitled "AR2-Article 123(2)EPC") that the opponent had indeed raised an objection under Article 123(2) EPC to the then second auxiliary request in relation to the same amendment. Thus, the appellant-proprietor's request not to admit this objection, on the basis that it constitutes a new objection, is unfounded.

5.2.2 Moreover, the board remarks that, according to G 9/91, in the case of amendments to the claims or other parts of a patent in the course of opposition or appeal proceedings, such amendments are to be fully examined as to their compatibility with the requirements of the EPC (G 9/91, point 19 of the Reasons ). Thus, independently of any objection by the opponent, the board has to assess Article 123(2) EPC.

5.2.3 In the third auxiliary request, the MDC cells are characterised by process features taken from Example 1 of the application as filed. The opposition division found that said amendment fulfilled the requirements of Article 123(2) EPC, being correctly based on Example 1. In the decision of the opposition division, reference was also made to page 16, line 20 and to page 19, lines 9 and 10, to justify that it was not required to include in the claims the exact source of muscle cells given in Example 1.

5.2.4 The board, however, notes that there is no indication in the application as filed that the method of Example 1, which is disclosed in relation to specific skeletal muscle cell sources, will always produce cells with the characteristics of the cells of the invention (as defined in the description; see above) when using different cells from skeletal muscle tissue from any possible mammal source, as encompassed in the claim. On the contrary, the application provides evidence that when using e.g. transfected cells - which are not excluded from the claim - clonal isolates can be obtained which do not express the cell markers that should be expressed by the cells of the invention (mc13 cells in Example 9). Moreover, cells from different sources may express other cell markers, as admitted by the appellant-proprietor. Hence, the cells defined by the process as now in the claims may indeed include the cells of the invention (e.g. the PP6 cells), but they certainly also include other cells which are not part of the cells of the invention.

5.2.5 The disclosure of Example 1 thus cannot be generalised to any cell source, and in particular cannot be combined with each of the therapeutic indications claimed. Indeed, the specific method of producing the cells is only disclosed in the Examples and not in the general part of the description; such cells are then used for specific applications disclosed in the Examples. For the more generally defined uses in the claims, the application only provides a basis for MDC cells which are defined by reference to their marker expression profile, including the specific cell population PP6 (page 17, line 13 to page 18, line 26).

5.2.6 Accordingly, the board comes to the conclusion that the claims of the third auxiliary request do not fulfil the requirements of Article 123(2) EPC.

6. Fourth auxiliary request - Admissibility

6.1 Like the third request, this request was only submitted during oral proceedings before the board and thus its admissibility is also governed by Article 13 RPBA. In this context, the need for procedural economy requires that amended claims submitted at such a late stage as oral proceedings be only admitted if it can be quickly ascertained that they might overcome the outstanding issues without raising new ones.

6.2 In this request, the MDC cells have been defined by reference to their expression of markers desmin, CD34, Bcl-2, Sca-1 and Flk-1, and the absence of expression of markers CD45 and c-Kit, the amendment being based on the definition of the originally filed claims (e.g. claim 1).

6.3 The board notes that objections under Article 123(2) EPC concerning the definition of the MDC cells have been on file since the very beginning of the opposition and have been maintained throughout the proceedings including the appeal. While the opposition division found that the definition contained in the claims of the then "twice amended" second auxiliary request was allowable, the fact that the appellant-opponent raised again an objection under Article 123(2) EPC against the maintained claims should have prompted the appellant-proprietor to react and produce amended claims, preferably with its reply to the opponent's appeal. At the very latest, such amendments should have been submitted in writing in reaction to the summons to oral proceedings, where the board expressed its preliminary opinion that the claims as maintained did not fulfil Article 123(2) EPC.

6.4 The board further notes that, contrary to appellant-proprietor's statement, the present amendment does indeed increase the complexity of the case, creating a new examination burden on both the appellant-opponent and the board. In view of the fact that not all other features now in the claims, such as some therapeutic indications (e.g. "augmenting or bulking sphincter muscle tissue" - claim 2; "augmenting or bulking tissue comprising one or more of a cutaneous depression, ...," - claim 3) as well as "clonal population", were part of the originally filed claims, it would still have to be examined whether all new combinations now in the claims are also disclosed as such in the application as filed. Moreover, in view of the new definition of the cells, it is conceivable that new issues under Articles 54 and / or 56 EPC could arise, which might even require to return to written proceedings.

6.5 The board thus makes use of its discretionary power under Article 13 RPBA and decides not to admit the fourth auxiliary request into the proceedings.