T 0658/04 (Simvastatin/RANBAXY LABORATORIES) 01-02-2007

Reasons for the Decision

1. The appeal is admissible.

Main request

2. Article 100(b) EPC

2.1 The patent in suit describes a multiple step process to prepare simvastatin of formula IIa (see point II above).

2.1.1 The first step consists in the amidification, with an n-alkylamine or a cycloalkylamine of formula R3-NH2, in particular n-butylamine or cyclopropylamine, of a compound of formula (i)

FORMULA/TABLE/GRAPHIC

which is lovastatin of formula (Ia) when R1 is a radical of formula

FORMULA/TABLE/GRAPHIC

and which is the mevinolinic acid salt of formula (Ic) when R1 is the radical of formula

FORMULA/TABLE/GRAPHIC

wherein R2 is Na, K, NH4 (see reaction scheme, page 4 and [0015], page 5). The intermediate of formula (III) (see point II above) is obtained.

2.1.2 The second step consists essentially in the C-methylation of the intermediate of formula (III) in tetrahydrofuran (THF) by the addition of a solution in THF of n-BuLi and pyrrolidine, which form in situ lithium pyrrolidide, then addition of methyl halide, preferably methyl iodide to yield the intermediate of formula IV according to the following reaction scheme

FORMULA/TABLE/GRAPHIC

(see scheme, page 4 and [0016], page 5)

2.1.3 The third step consists in the lactonisation of the intermediate (IV) to obtain simvastatin (see scheme, page 4 and paragraphs [0017] and [0018], page 5).

2.1.4 Example I discloses the preparation of simvastatin from mevinolic acid ammonium salt using cyclopropylamine. Example II discloses the preparation of simvastatin from lovastatin using cyclopropylamine and examples III and IV disclose the preparation of simvastatin from lovastatin and mevinolinic acid ammonium salt using n-butylamine (see paragraphs [0021] to [0030], pages 4 and 5).

2.2 In the present case, the objection under Article 100(b) raises three different issues which are to be dealt with separately.

2.3 The first issue is whether the patent in suit as a whole discloses sufficiently and completely the technical conditions by which the person skilled in the art, to whom the relevant common general knowledge is imputed, can reliably and effectively perform the claimed process "wherein step (ii) and step (iii) are performed without protecting and deprotecting the two hydroxy groups of the open pyranone ring of said compounds of structural formulae III and IV" as required by Claim 1 (see point II above).

2.4 The Appellant argued that the process described in the patent specification, in particular the examples, did not involve the steps of protection and deprotection of hydroxy groups and, therefore, enabled the person skilled in the art to achieve the claimed process. The Respondent argued, by contrast, that the process described in the patent specification involved the steps of protection and deprotection of hydroxy groups, which rendered the claimed process non enabling for the skilled person since he could not find in this patent the relevant information to achieve the claimed process.

2.5 According to the Jurisprudence of the Boards of Appeal, each of the parties to the proceedings carries the burden of proof for the facts it alleges (see e.g. decision T 270/90, OJ EPO 1993, 725, point 2.1). In order to establish insufficiency, the burden of proof is upon the Opponent (now Respondent) to establish that a skilled reader would not be able to carry out the invention (see e.g. T 182/89, OJ EPO 1991, point 2, third paragraph).

2.6 Since the patent specification does not explicitly say whether or not a step of protection and a step of deprotection of the hydroxy groups occur, and since none of the parties have submitted experimental results to support their views, the Board can only rely on the common general knowledge of the person skilled in the art to decide whether or not the process as disclosed in the patent in suit as a whole implies a step of protection and deprotection of the hydroxy groups.

2.7 According to the jurisprudence of the Boards of Appeal, textbooks and general technical literature form part of the common general knowledge. Patent specifications and scientific publications cannot form part of common general knowledge except for some particular cases not relevant in the present situation (see Case Law of the Boards of Appeal 4th Ed. 2001, II.A.2.(a), page 145).

2.7.1 Therefore, the Board holds that documents (1), (2), (3) and (13) which are extracts of textbooks can be considered as forming part of the common general knowledge. The content of document (4), although being a scientific publication, can nevertheless be regarded as forming part of the common general knowledge given that document (3) refers explicitly to document (4) on page 325 (see reference No. 364) which is evidence not merely that the information contained in document (4) belongs to the state of the art but that it represents common general knowledge.

2.7.2 By contrast, documents (5), (6), (7), (9), and (14) which are scientific publications and documents (8) and (10) which are patent applications do not form part of the common general knowledge and, therefore, are not relevant to the assessment of the sufficiency of disclosure of the patent in suit.

2.7.3 The declaration of U.K Pandit submitted by the Appellant as expert opinion, i.e. document (12), contains general considerations that the Board cannot consider as representing common general knowledge in the absence of supporting evidence. Furthermore, the fact that this expert concludes that the detailed role of lithium pyrrolidide in the transformation of [I] to [III] (see scheme on page 4 of the declaration) is mechanistically complex and undefined (see last page, last sentence of the declaration) tends to reduce the relevance of the whole declaration for defining the common general knowledge of the skilled person at the filing date.

In the Board's judgment, an expert's declaration which is not supported by verifiable facts but which merely constructs some hypotheses, cannot reflect the common general knowledge to be considered for assessing the sufficiency of disclosure in the sense of Articles 100(b) and 83 EPC. For this reason, document (12) does not form part of the common general knowledge.

2.8 In view of documents (1) and (13), the skilled person is aware that:

"When a chemical reaction is to be carried out selectively at one reactive site in a multifunctional compound, other reactive sites must be temporarily blocked. Many protective groups have been, and are being, developed for this purpose. A protective group must fulfil a number of requirements. It must react selectively in good yield to give a protected substrate that is stable to the projected reactions. The protective group must be selectively removed in good yield by readily available, preferably non-toxic reagents that do not attack the regenerated functional group." (see page 1 of document (1), first seven lines).

Amongst the numerous groups identified in the list of the protecting groups for the hydroxy group, lithium salts are not mentioned (see pages 17 to 23 of document (13)). Document (13) is later than the priority date, it dates from 1999. Therefore, if lithium salts were not known as protective groups in 1999, they were also not known in 1991 since the Preface of the third edition, page v, states that said edition adds 348 new protective groups to the second edition (1991).

It can only be concluded that in the common general knowledge of the person skilled in the art in organic synthesis, the notion of protecting and deprotecting had a clear meaning and that lithium pyrrolidide is not a protecting group in the sense of documents (1) and (13).

2.9 The Respondent argued, in particular, that the reaction disclosed in documents (1) and (13) was only a particular way for achieving protection and deprotection. Protection and deprotection was to be viewed as a strategy which could be implemented by other ways such as manipulating solvent, temperature, polarity and so on as, for instance, taught by documents (3) and (4).

2.9.1 Document (3) examines the way a nucleophile attacks an atom. It is, in particular, pointed out that the solvent influences the position of the attack. In that context, this document cites the attack by sodium beta-naphtoxide on benzyl bromide by reference to document (4). In view of document (4), depending on the solvent used, O-alkylation or C-alkylation occurs (see page 1148, right-hand column). However, neither in document (3) nor in document (4) is such an orientation in the reaction described as a reaction of protection and deprotection. Therefore, the Respondent's submission that protection and deprotection had to be seen as a strategy going beyond the definition given in documents (1) and (13) is not substantiated.

2.9.2 Furthermore, accepting the Respondent's submission would be at variance with the teaching of documents (1) and (13) which require a subsequent removal step that is not present in the reactions described in documents (3) and (4). That would render the notion of protection and deprotection indefinite and meaningless. Document (2) merely relating to a list of pKa values for many types of acids, in particular RCH2OH, is irrelevant for rebutting that finding.

2.10 The Appellant also pointed out that the description of the patent in suit confirmed that the protection and deprotection of hydroxy groups occurred when lithium pyrrolidide was used in a process involving the C-methylation step of 2-(s)-methylbutyryloxy side chain of mevilonin to yield simvastatin. Reference was made in that respect to document US-A-4 582 915, namely the American counter-part of the European application No. 137 445, i.e document (10), (see "background of the invention", paragraph [0008], page 3) in conjunction with the subsequent phrase "Heretofore, the methods described in the prior art required the protection and deprotection of the hydroxy groups as essential steps for the preparation of simvastatin" (see "Summary of the invention", paragraph [0011], (b), page 5).

However, neither the above referred to passage of the patent in suit concerning US patent 4 582 915, nor the content of document (10) mention such protection and deprotection steps. Furthermore, the phrase "Heretofore…." is drawn from another context and does not refer explicitly to this document but only refers to "the prior art".

The Board cannot, therefore, consider the combination of those separate statements as an evidence that protection and deprotection of hydroxy groups occur in the process disclosed in US patent 4 582 915.

2.11 In conclusion

(a) The sole meaning that the skilled person can give to the reaction of protection or deprotection of hydroxy groups is that set out in documents (1) and (13), namely the reaction of a particular reagent, not including lithium pyrrolidide, and subsequently removal of that protecting group (see point 2.8 above). No other interpretation is realistic. It derives therefrom that the second and third steps of the process disclosed in the patent in suit (see points 2.1.2 and 2.1.3) along with the examples (see point 2.1.4) which are carried out in the presence of lithium pyrrolidide do not involve the steps of protection and deprotection of the hydroxy groups.

(b) The subject-matter of Claim 1 defines a process for producing simvastatin "wherein step (ii) and step (iii) are performed without protecting and deprotecting the two hydroxy groups of the open pyranone ring of said compounds of structural formulae III and IV " (see point II above).

(c) The patent in suit thus provides the person skilled in the art with the relevant information to achieve a process for preparing simvastatin as defined in Claim 1 in a way whereby step (ii) and step (iii) are performed without protecting and deprotecting the two hydroxy groups of the open pyranone ring of said compounds of structural formulae III and IV.

(d) The Respondent's first line of argument is, therefore, not properly substantiated and is to be rejected.

2.12 As a second line of attack under Article 100(b) EPC, the Respondent argued that it was not credible in view of the teaching of document (10), on pages 4 and 5, that the procedure of Example 1 of the patent in suit would also succeed if the corresponding sodium or potassium salt were to be used in place of the ammonium salt. Furthermore the patent in suit failed to teach the skilled person how to achieve the claimed process with a starting material other than lovastatin.

2.12.1 Although the Board found that document (10) did not form part of the common general knowledge (it is a patent, see point 2.7.2 above), a party may present any facts or evidence he finds appropriate to bring the proof of what he alleges. Document (10) is, in that context, taken as a piece of evidence.

2.12.2 The first question is, therefore, whether document (10) renders credible the Respondent's assertion that the procedure of Example 1 of the patent in suit would not succeed if the corresponding sodium or potassium salt were to be used in place of the ammonium salt.

2.12.3 This document relates, in particular, to a process of C-methylation of lovastatin to form simvastatin. This process involves, as a first step, the conversion of the lactone to its alkali metal salt, followed by C-methylation in the presence of, e.g. lithium pyrrolidide. This process however does not reflect the experimental conditions of Example 1 of the patent in suit which requires the amidification of the salt prior to the C-methylation. Such a document cannot, therefore, be considered as an evidence liable to reverse the burden of proof which still remains upon the Respondent and which he has not discharged (see point 2.5 above).

2.12.4 Furthermore, the more general argument concerning the alleged lack of sufficiency of disclosure regarding the processes involving starting material other than lovastatin is at variance with the fact that Example I discloses the preparation of simvastatin from mevinolic acid ammonium salt (see point 2.1.4 above). This line of attack remains unsubstantiated in the absence of evidence to the contrary.

2.13 As a third argument with respect to the objection under Article 100(b) EPC, the Respondent submitted that the patent in suit failed to teach the person skilled in the art processes for preparing simvastatin for conditions other than those recited in Claims 8, 10 and 11 (see point II above). However in the absence of evidence in support of his contention, this argument is unsubstantiated and is also to be rejected.

2.14 Since none of the three attacks raised by the Respondent against the sufficiency of disclosure of the patent in suit can succeed, the objection under Article 100(b) EPC is to be rejected.

3. Remittal to the first instance

3.1 The Board has come to the conclusion that the patent in suit did not give rise to objection under Article 100(b) EPC, overcoming, therefore, the sole reason for revoking the European patent as granted. Having so decided, the Board has not taken a decision on the complete case.

3.2 Indeed, with its opposition the Respondent also sought revocation of the patent in suit on the ground that its subject-matter did not involve an inventive step (see point III above). The decision of the Opposition Division is silent regarding this issue.

3.3 Given that the purpose of the appeal proceedings inter partes is primarily to give the losing party the possibility of challenging the decision of the Opposition Division (see G 9/91, OJ EPO 1993, 408, point 18), the Board finds appropriate to exercise its discretion under Article 111(1) EPC to remit the case to the first instance in order not to deprive the parties of the possibility of being heard by two instances with regard to the other issue raised in the opposition proceedings.