Rosuvastatin: is it a “pharmaceutically acceptable salt”?

On 15 July 2015 the District Court for The Hague handed down its decision in Resolution Chemicals v Shionogi and AstraZeneca. This case turned on the validity and scope of protection of Shionogi’s SPC -- in particular, was Resolution Chemicals’ proposed zinc salt of rosuvastatin a “pharmaceutically acceptable salt” as claimed in the basic patent and which would infringe the SPC? The District Court granted a declaration of non-infringement. 

Jan Pot and Mark van Gardingen (both of Brinkhof, which acted for Resolution Chemicals) know how interesting this decision is for our readers and therefore have kindly let us have both the authentic Dutch text of the judgment and an English translation. Their summary of the decision -- without any commentary -- appears below.

Thanks so much, Jan and Mark, for your efforts, which are much appreciated!

Shionogi holds supplementary protection certificate (SPC) 300125 for ‘Rosuvastatinum, if desired in the form of a non-toxic pharmaceutically acceptable salt, in particular the calcium salt’. AstraZeneca is the exclusive licensee for this SPC. The basic patent for the SPC was EP 0 521 471 (“EP 471”), which had expired in 2012. Claim 1 of EP 471 was for “the compound [rosuvastatin, described using its molecular formula] acid or a non-toxic pharmaceutically acceptable salt thereof.” Resolution Chemicals requested the Court to partly nullify the SPC, namely insofar as it extended to more than the calcium and sodium salt of rosuvastatin, and to grant a declaration of non-infringement in relation to its rosuvastatin zinc salt. The case is somewhat unusual in that Resolution Chemicals attacked the validity and scope of protection of the basic patent after its expiration in order to limit (the scope of protection of) the SPC.

The first issue before the court was construction of the term “non-toxic pharmaceutically acceptable salt” as used in claim 1 of EP 471. Resolution Chemicals argued that this term was limited to salts with an alkali metal ion, an alkaline earth metal ion or an ammonium ion by virtue of a definition in paragraph [0007] of the patent, which stated that “the term "a non-toxic pharmaceutically acceptable salt" refers to a salt in which the cation is an alkali metal ion, an alkaline earth metal ion, or an ammonium ion”. As a consequence, rosuvastatin zinc was not within the scope of claim 1. Shionogi and AstraZeneca however contended that para. [0007] should not be considered limiting and that “a non-toxic pharmaceutically acceptable salt” should be understood to include the zinc salt. The Court concluded that the skilled person would read the claim term “non-toxic pharmaceutically acceptable salt” in claim 1 in conjunction with para. [0007], and that the skilled person would construe this paragraph as a limiting definition. The court observed that at other points the specification used non-limiting terms such as “and the like”, whereas para. [0007] used the more restrictive “refers to”. The Court also noted that it was common general knowledge at the priority date that the choice for a particular salt form for a medicinal product matters in terms of therapeutic availability, and that performing a salt screen was for that reason routinely applied. Consequently, the skilled person may presume that the choice for the salts disclosed in paragraph [0007] was a conscious choice by the patentee. The Court therefore ruled that the zinc salt was not within the scope of EP 471.

The second issue was that of added matter. While the patent as granted was limited to rosuvastatin, the original application disclosed and claimed a broad class of compounds using a Markush formula. Resolution contended that the application as filed only offered support for rosuvastatin calcium and rosuvastatin sodium: these were the only salt forms of rosuvastatin disclosed by the examples and it was not permissible to extend this disclosure to other salt forms or to the acid. AstraZeneca and Shionogi claimed that rosuvastatin was the essence of the invention and that it was permissible to claim other salts as well as the acid. After examining the application as filed, the Court came to the conclusion that there was support in the original application not only for sodium and calcium but also for the other salts mentioned in para. [0007]. However, the Court found that there was no direct and unambiguous disclosure in the application for rosuvastatin acid. The Court therefore concluded that the SPC would have to be limited to the salt forms of rosuvastatin in which the cation was an alkali metal ion, an alkaline earth metal ion or an ammonium ion, as there would have been grounds to nullify the basic patent insofar as it had a broader scope.

Having dealt with validity and scope of protection of the basic patent and the SPC, the Court swiftly dealt with infringement. As zinc is neither an alkali metal ion, nor an alkaline earth metal ion, nor an ammonium ion, there was no direct infringement. The Court rejected infringement through equivalence, as zinc would have been a foreseeable alternative at the priority date which are taken into account when construing the claims according to Article 69 EPC. Accordingly, there was no need to discuss whether the zinc salt is “technically” equivalent to the calcium or sodium salt of rosuvastatin (or any of the other salts defined in para. [0007]). Finally, the Court also rejected indirect infringement. Shionogi and AstraZeneca’s indirect infringement argument was based on the premise that the scope of protection extended to rosuvastatin acid, which had already been rejected by the Court on the basis of added matter. The Court did not deal with AstraZeneca’s further argument that the rosuvastatin anions in solution associate with sodium cations present in the gastric fluid, since this argument was raised too late.