T 1324/21 - Spontaneously forming polymorphs

Key points

• From Derk Lowe's weblog: "The classic story is ritonavir, the anti-HIV medication (now used as a CYP metabolism inhibitor in Paxlovid and other formulations). Eighteen months after FDA approval and the arrival of the drug on the market, a more stable and less soluble polymorph began to take over the world, first noticed as a higher dissolution-test failure rate on the manufacturing line. This extremely unwelcome development precipitated a crisis (couldn’t resist the wording) which was only solved by a great deal of experimentation under severe time pressure, and the whole affair greatly impacted severely ill patients while costing Abbott hundreds of millions of dollars." (https://www.science.org/content/blog-post/stalking-polymorphs) 
• See here for a further review, also discussing patent litigation on polymorphs: https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201410356
• Turning to the present case, claim 1 is directed to a pharmaceutical composition comprising rifaximin in polymorphic form alpha and in polymorphic form delta, and comprising 10 wt% to 45 wt% filler.
• The OD found the claim to be novel, as follows: " Xifaxan tablets of batch 13012, which according to document D9 were purchased before the priority date, had been shown in document D7 to comprise the polymorph forms alpha and delta of rifaximin in the ratio and total amount as defined in claim 1 of the main request. However, it had not been demonstrated that these Xifaxan tablets could be analysed to comprise a relevant amount of filler." 
•  The proprietor argued as follows for inventive step: " The Xifaxan tablets of batch 13012 comprised in addition to rifaximin form alpha also rifaximin form delta. The presence of rifaximin form delta was contrary to the official documentation on the Xifaxan tablets, in particular document D15, according to which only rifaximin form alpha was used for the preparation of the tablets, which would not convert to other forms during manufacture or storage. Document D15 actually recommended 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. The Xifaxan tablets of batch 13012 were therefore defective and unsuitable as starting point for the assessment of inventive step." 
• The Board, on novelty: " 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 [] 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." 
• " 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 " 
• " Accordingly, the Board concludes that the subject-matter of claim 1 of the main request lacks novelty." 
• Auxiliary Request 1 is limited to a method of preparing a tablet comprising " providing (A) rifaximin in polymorphic form alpha and (D) rifaximin in polymorphic form delta"  and compressing.
• The question is whether the public prior use is a suitable starting point for inventive step. " Whilst the originally contained rifaximin form alpha in the Xifaxan tablets of batch 13012 had thus according to document D7 apparently partially [and spontaneously, during storage] converted to form delta by 17 December 2015, these tablets had at that time not yet expired. "
  
• " 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." 
• " the Board concludes that the subject-matter of claim 1 of the auxiliary request lacks an inventive step." 
• The patent is revoked.
• EPO 

The link to the decision is provided after the jump, as well as (an extract of) the decision text.

https://www.epo.org/en/boards-of-appeal/decisions/t211324eu1

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.