T 1324/21 (Rifaximin/SANDOZ) 12-01-2024

1. Admittance of evidence

1.1 Document D44

Document D44 is a declaration by Mr Viscomi, who was from 2002 to 2020 Director of Research and Development of Alfa Wassermann SPA, later Alfasigma SPA, concerning the amount of filler and the nature of the filler present in Xifaxan 550 mg tablets as available on the market before the priority date of the patent (see D44, page 1, lines 1-6). The declaration reports on the production of Xifaxan 550 mg tablets of batch 15384 with the expiration date of 2018 by Alfasigma in December 2015 (see D44, page 1, Table 1). The declaration cites the used amounts of ingredients from the record of the software managing the manufacturing process of the tablets to calculate an amount of 29.9 wt% for the MCC in the Xifaxan 550 mg tablets (see D44, Table 2 and page 4, lines 4-9 and Table 3). The declaration further refers to a Certificate of Analysis indicating that the used MCC had a water content of 3.2% (see D44, pages 2-3, bridging paragraph).

The opposition division decided not to admit the late filed document D44 for lack of prima facie relevance, because the content of document D44 concerned in-house information which had not been publicly available and did not demonstrate that the relevant amount of filler in the Xifaxan tablets could be analytically determined.

The Board notes, however, that it was not in dispute that the Xifaxan tablets of batch 13012 had been publicly available. In view of the public availability of these tablets the finding in the decision under appeal on the prima facie lack of relevance of the in-house information in document D44 regarding the amount of filler used for preparing the tablet would in the Board's view only seem reasonable, if it were justified to assume that the actual analysis of the amount of filler in the tablets would present the skilled person with undue burden. However, the Board finds no basis for this assumption.

The patent proprietor argued during the appeal proceedings that document D44 refers to the record of production of Xifaxan tablets of batch 15384 and therefore lacked relevance regarding the prior use of the tablets of batch 13012. However, the declaration in document D44 specifically addresses the amount of the filler and nature of the filler present in Xifaxan 550 mg tablets as available on the market before the priority date of the patent. In this context the Board finds no ground for doubt that the record for the production of batch 15384 cited in document D44 was representative for the Xifaxan 550 mg tablets available on the market, including the tablets of batch 13012.

Accordingly, the Board has admitted document D44 into the appeal proceedings under Article 12(6) RPBA.

1.2 Documents A54-A57

Documents A54-A57 were filed by appellant-opponent 1 with the statement of grounds of appeal. They constitute an amendment to appellant-opponent 1's under Article 12(4) RPBA which may be admitted at the discretion of the Board.

Document A54 represents hand-book information that MCC is used as a filler in capsules and tablets in a concentration of 20-90% (see page 132, Table 1).

Documents A55-A57 represent evidence that the Xifaxan tablets of batch 13012 could be analysed to comprise a MCC content of 28.2-29.0% on the basis of dry MCC or 29.4-30.1% on the basis of MCC with max. 7% water (see A55, page 9, "Results/Summary table") using methods which were available at the relevant time (see A56 and A57).

The Board considers the filing of documents A54-A57 justified as reaction to the finding in the decision under appeal that a mere expectation of an amount of filler (MCC) of more than 10% in Xifaxan tablets did not qualify as a direct and unambiguous disclosure of the amount of filler in these tablets and the opposition division's rejection of the admittance of document D44.

The Board considers document A54 prima facie relevant to the appeal proceedings, because document A54 presents evidence of the common knowledge regarding the amount of MCC used as binder or filler in tablets, whereas in the appeal proceedings the amount of MCC as the filler in Xifaxan tablets of batch 13012 is in dispute.

The Board also considers documents A55-A57 prima facie relevant, because these documents demonstrate that the amount of MCC as the filler in Xifaxan tablets of batch 13012 can be experimentally determined. The patent proprietor argued that these documents lacked relevance, because they refer to analytical methods used in the textile or food industry and thus did not form part of the common general knowledge that the skilled person in the field of galenics could in line with the considerations in G 1/92 (reasons 1.4) apply for determining the amount of MCC in the Xifaxan tablets of batch 13012. The Board finds this objection not convincing, because the the skilled person in the field of galenic could nevertheless retrieve the analytical methods of documents A56 and A57 used in document A55, whereas their application for determining the amount of MCC in the Xifaxan tablets has not been demonstrated to involve undue burden.

Accordingly, the Board has admitted documents A54-A57 into the appeal proceedings under Article 12(4) RPBA.

1.3 Documents A45-A53

Documents A45-A53 were filed by appellant-opponent 2 with the grounds of appeal.

In its communication pursuant to Article 15(1) RPBA the Board explained its preliminary opinion that documents A45-A53 were not to be admitted into the appeal proceedings, because these documents lacked relevance and because their late filing was not justified. No new arguments were submitted in response to the Board's preliminary opinion.

The Board has therefore confirmed its preliminary opinion not to admit documents A45-A53 into the appeal proceedings under Article 12(4).

2. Main request - Novelty

2.1 The finding in the decision under appeal that the Xifaxan tablets of batch 13012 represent prior art under Article 54(2) EPC and have been demonstrated to comprise the polymorph forms alpha and delta of rifaximin in the ratio and amount as defined in claim 1 of the main request, has not been contested during the appeal proceedings. The dispute regarding the requirement of novelty of the subject-matter of claim 1 of the main request with respect to the relevant Xifaxan tablets of batch 13012 thus exclusively concerned the question whether these tablets also anticipated the remaining feature of an amount of filler in the range of 10 wt% to 45 wt%.

2.2 The declaration in document D44 reports that Xifaxan 550 mg tablets as available on the market before the priority date of the patent had been prepared using the filler MCC with a water content of 3.2% in an amount which corresponded to 29.9 wt% of filler in the tablets (see D44: page 1, lines 1-6; pages 2-3, bridging paragraph; page 4, Table 3). Document D44 therefore indicates that the Xifaxan tablets of batch 13012 did indeed comprise an amount of filler as defined in claim 1 of the main request

As explained in section 1.1 above, the declaration in document D44 specifically addresses the amount and nature of the filler present in Xifaxan 550 mg tablets as available on the market before the priority date of the patent. The Board finds no grounds to doubt, that the record for the production of batch 15384 cited in document D44 was in accordance with this declaration representative for the Xifaxan 550 mg tablets available on the market, including the tablets of batch 13012. The patent proprietor's objection that that the declaration in document D44 relies on the record of production for Xifaxan tablets of batch 15384 and therefore lacked relevance regarding the prior use of the tablets of batch 13012 is not therefore not considered convincing.

2.3 According to G 1/92 the composition and internal structure of a product is state of the art, when the product as such is available to the public and can be analysed and reproduced by the skilled person without undue burden (see G 1/92, reasons 1.4 and 2).

The experimental report in document A55 demonstrates that the amount of filler in Xifaxan tablets of batch 13012 could be analysed using methods as described in documents A56 and A57, which were available at the relevant time. Document A55 confirms that using these methods the Xifaxan tablets of batch 13012 were found to comprise a MCC content of 28.2-29.0% on the basis of dry MCC or 29.4-30.1% on the basis of MCC with max. 7% water (see A55, page 9, "Results/Summary table").

The patent proprietor objected that document A55 does not demonstrate that the amount of MCC in the Xifaxan tablets can be determined by the skilled person in the field of galenics without undue burden, because it applied a method for determining the amount of MCC used according to document A56 in the food industry in combination with a method for removing starch as used according to document A57 in the textile industry.

However, as explained in section 1.2 above, the methods of documents A56 and A57 applied in document A55 were nevertheless retrievable to the skilled person in the field of galenics and their application for determining the amount of MCC in the Xifaxan tablets has not been demonstrated to involve undue burden. In view of the availability of these methods the Board considers that the experimental report in document A55 demonstrates that access to the information regarding the amount of MCC in the Xifaxan tablets of batch 1302 was indeed possible and therefore in line with the considerations in G 1/92 part of the state of the art. The conclusion that the skilled person was able to determine the amount of MCC in the Xifaxan tablets of batch 1302 without undue burden using the methods of document A55 is not affected by the circumstance that the suggestion by opponent 2, that the amount of MCC in the Xifaxan tablets could be determined using a combination of Ion Exchange-HPLC and Size Exclusion HPLC, was subsequently not backed up by evidence.

2.4 Accordingly, the Board concludes that the subject-matter of claim 1 of the main request lacks novelty.

3. Auxiliary request 1 - Inventive step

3.1 Closest prior art

The Xifaxan tablets of batch 13012 represented an approved market product. In this context document D8 reports for Germany 6 February 2013 as date of approval of Xifaxan (see D8, section 9). Document D8 describes Xifaxan to comprise rifaximin in polymorphic form alpha (see D8, section 5) and attests Xifaxan tablets a shelf-life of 3 years (see D8, section 6.3).

Document D15 represents the Australian public assessment report for rifaximin of November 2012. The document reports substantially higher bioavailability of rifaximin from form delta as compared to form alpha following administration in dogs (see D15, page 9, Table 3). The document further reports that the currently produced polymorphic form of rifaximin is form alpha, which would according to the provided evidence not convert to other polymorphic forms during the manufacture or storage of Xifaxan tablets (see D15, pages 9-10, bridging section). Under the heading "Assessment of risks" the document observes the need to ensure that the commercial preparation of rifaximin is the poorly absorbed polymorphic form alpha in view of the greater oral bioavailability of other polymorphic forms (see D15, page 21).

The Xifaxan tablets of batch 13012 had been purchased according to document D9 on 20 November 2015. In line with the shelf-life reported in document D8 for Xifaxan tablets in general the pack-inscript of the Xifaxan tablets of batch 13012 shown in document D1 indicates the expiry of these tablets in April 2017.

Document D7 established on the basis of a XRPD pattern as obtained from the Xifaxan tablets of batch 13012 on 17 December 2015 (see D7, page 3, under "Rational") that these tablets comprised the polymorphic forms alpha and delta of rifaximin in a ratio within the range defined in claim 1 of auxiliary request 1 (see D7, page 8, under "Summary").

Whilst the originally contained rifaximin form alpha in the Xifaxan tablets of batch 13012 had thus according to document D7 apparently partially converted to form delta by 17 December 2015, these tablets had at that time not yet expired. As a matter of fact, the post-published document D18 (see page 2, lines 12-18) confirms that Xifaxan tablets of a multitude of batches from different countries have turned out to contain significant amounts of rifaximin form delta after storage and that the known tablets did not prevent the conversion of rifaximin form alpha in form delta during shelf life. Notwithstanding the caution recommended in document D15 regarding rifaximin comprising the more bioavailable form delta, the Xifaxan tablets of batch 13012, which contained on 17 December 2015 rifaximin form alpha and form delta in the ratio as defined in claim 1, still represented an approved market product.

Contrary to the finding in the decision under appeal the Board considers that this approved market product, which had not expired, cannot be disqualified as a realistic starting point for the assessment of inventive step with respect to the method for preparing tablets comprising corresponding amounts of rifaximin form alpha and delta as defined in claim 1 of auxiliary request 1.

3.2 Objective technical problem

The subject-matter of claim 1 of auxiliary request 1 differs from the prior use of the Xifaxan tablets of batch 13012 in the provision of the rifaximin form alpha and form delta before their compression into a tablet instead of the time dependent partial conversion of rifaximin form alpha to form delta that results in tablets originally prepared from rifaximin form alpha.

The claimed method involving the provision of rifaximin form alpha and form delta before their compression into a tablet evidently allows for the advantage of the instant predetermined provision of the tablets comprising these forms of rifaximin in the defined ratio following their compression into tablets with respect to the time dependent partial conversion of rifaximin form alpha to form delta in the Xifaxan tablets of batch 13012.

Starting from the Xifaxan tablets of batch 13012 containing rifaximin form alpha and form delta in the defined ratio the objective technical problem may therefore be seen in the provision of a more convenient and thus improved method for the reproduction of corresponding tablets.

3.3 Assessment of the solution

Faced with the problem of providing a more convenient method for the reproduction of the Xifaxan tablets of batch 13012 containing rifaximin form alpha and form delta with MCC the skilled person would apply the common general knowledge in the field of galenics and take account of convenient methods reported in the prior art for preparing related compositions.

The skilled person would be motivated to indeed seek a more convenient method for reproducing these tablets in view of the inconvenience inherently associated with the time dependent conversion of rifaximin form alpha.

Document D36 represents common general knowledge according to which tablets may be instantly prepared by a dry granulation process involving the dry mixing of the active and auxiliary components, including in particular a binder such as MCC, followed by compressing the ingredients into tablets (see D36, page 261, left column).

Document D28 describes in its example 5 a method for instantly preparing tablets comprising 54 wt% rifaximin of forms alpha and beta in a 85:15 ratio and 33.4 wt% MCC involving the provision of the mixture of these forms alpha and beta which are dry blended with excipients, including the MCC, and subsequently compressed into tablets. Document D28 thus describes the convenient preparation of tablets which in view of their composition are closely related to the Xifaxan tablets of batch 13012 containing rifaximin form alpha and form delta.

The skilled person would thus arrive at the claimed solution by applying the dry granulation process in accordance with the common general knowledge represented in document D36 to a combination of the per se known active components rifaximin form alpha and form delta or by applying the method described in example 5 of document D28 analogously for preparing the Xifaxan tablets of batch 13012 containing rifaximin form alpha and form delta. This solution would therefore seem obvious to the skilled person in view of the prior art.

3.4 Accordingly, the Board concludes that the subject-matter of claim 1 of the auxiliary request lacks an inventive step.

4. Auxiliary requests 2-4 - Inventive step

4.1 Claim 1 of auxiliary request 2 additionally defines with respect to claim 1 of auxiliary request 1 the amounts of the rifaximin and the filler in wt%. As explained in section 2 above these features do no define any additional difference with respect to the closest prior art represented by the Xifaxan tablets of batch 13012 containing rifaximin form alpha and form delta.

In the absence of any additional distinguishing feature being defined in auxiliary request 2 with respect to the closest prior art the Board concludes that auxiliary request 2 does not meet the requirement of inventive step for the same reason as explained for auxiliary request 1.

4.2 Claim 1 of auxiliary request 3 additionally defines with respect to claim 1 of auxiliary request 2 the water content of the filler.

Claim 1 of auxiliary request 4 additionally defines with respect to claim 1 of auxiliary request 1 the water content of the rifaximin.

In as far as the water content of the filler or the amount of water contained by the rifaximin as defined in accordance with auxiliary requests 3 and 4 represents a difference with the Xifaxan tablets of batch 13012, no particular effect has been shown to be associated with these features.

The patent mentions in paragraphs [0090] to [0093] a difference in the disintegration of rifaximin tablets prepared in accordance with example 1 of the patent and tablets comprising a molar ratio of form alpha to form delta higher than 10:1 and a water content of only 1.2 wt%. However, the patent does thereby not indicate any effect that is associated with a difference of the claimed subject-matter with the closest prior art, because the Xifaxan tablets of batch 13012 already contained rifaximin forms alpha and delta in a molar ratio within the claimed range, which is substantially below the 10:1 as mentioned for the comparative tablets in paragraphs [0090] to [0093] of the patent.

Auxiliary requests 3 and 4 are therefore considered to merely provide arbitrary variations with respect to the methods of auxiliary requests 1 and 2. Following the Board's conclusion that the subject-matter of auxiliary requests 1 and 2 was obvious to the skilled person in view of the prior art, the subject-matter of auxiliary requests 3 and 4 would equally seem obvious to the skilled person. Auxiliary requests 3 and 4 therefore lack an inventive step on the same basis as auxiliary requests 1 and 2.