In a previous post entitled The salt of the judgment, I reported on an order issued in July 2016 and rejecting a request for preliminary injunction against Biogaran’s generic version of the drug rosuvastatin.
The judgment on the merits has now been issued, so this is an opportunity to go back to this interesting case. The problem with this approach is that finding a good title for a blog post in relation with a given case is difficult enough once, and it is even more difficult the second time. By the time I may get to report on a possible appeal ruling, I am afraid I may run short of salty idioms.
So, yes, everything in this case is about salt, or rather salts.
Claim 1 of the patent at stake (EP0521471, owned by the Japanese pharmaceutical company Shionogi, and licensed to the Swedish group AstraZeneca), on which the SPC is based, reads as follows:
The compound (+)-7-[ 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl)-(3R,5S)dihydroxy-(E)-6-heptenoic acid or a non-toxic pharmaceutically acceptable salt thereof.
The compound in question is rosuvastatin, in its acid or salt form.
The active substance in Biogaran’s generic drug is the zinc salt of rosuvastatin. The zinc salt is not cited in the patent at stake.
As a reminder, the judge in charge of emergency proceedings ruled that the zinc salt of rosuvastatin was in fact excluded from the scope of the patent, when the claim was properly interpreted in view of the description.
Now this preliminary view has been confirmed by the three-judge panel of the Tribunal de grande instance (TGI). As a side note, the judge who issued the interim order (Ms. Courboulay) was not part of this panel.
Here is the relevant part of the judgment (as usual, I took the liberty of cutting excessively long sentences into shorter ones):
[…] [In the patent,] the patentee has mentioned in a clear and precise wording at paragraph  what is meant by “a non-toxic pharmaceutically acceptable salt”, namely “a salt wherein the cation is an alkaline metal ion, an alkaline earth metal ion or an ammonium ion”. [It] does not comprise any indication allowing [the skilled person] to select a salt in another family. [Besides,] the patentee, even if it did not expressly exclude a specific salt, did not, unlike in other paragraphs of the patent, add the expressions “which are not to be considered as limiting”,  […] or “and the like”,  and  […]. [Thus, the skilled person] understands that the salts protected in the patent are defined in a limiting manner as a salt wherein the cation is an alkaline metal ion, an alkaline earth metal ion or an ammonium ion.
Therefore, and as decided by the judge in charge of emergency proceedings, it derives that the non-toxic pharmaceutically acceptable salts protected by claim 1 are salts wherein the cation is an alkaline metal ion, an alkaline earth metal ion or an ammonium ion.
A very interesting example that claim interpretation in view of the description can be used both ways: not only for broadening the scope of protection of the patent beyond what is literally claimed, but also in some situations for restricting said scope.
As a result of this claim interpretation, the necessary conclusion was that Biogaran’s zinc salt of rosuvastatin did not literally infringe the SCP.
Shionogi and AstraZeneca argued that zinc could be considered as an alkaline earth metal at the filing date. They said that the exact classification of zinc was a matter of debate.
However, the court was not convinced. Based on a 1978 dictionary and on Mendeleev’s table, it appeared that zinc could not be considered as an alkaline earth metal.
Another auxiliary argumentation by the plaintiffs was one of contributory infringement: once ingested, the zinc salt of rosuvastatin dissociates, and the anionic active molecule recombines with sodium or hydrogen, to form the sodium salt or the acid form of rosuvastatin. Thus, the zinc salt of rosuvastatin should be considered as an essential means for carrying out the claimed invention.
This bold argument failed – just as it had in the interim proceedings:
[…] The fact that the zinc salt of rosuvastatin, after ingestion, would dissociate in the patient’s body under a neutral acid form may not characterize contributory infringement […]. First, the third party mentioned in article L. 613-4 Code de la propriété intellectuelle [CPI], namely the patient, is not aware of the mechanism of decomposition of the drug within the body, so that he/she does not know under this provision that the ingestion of the drug at stake is intended for implementing the claimed invention. Second, this drug ingestion by the patient is carried out in a private and non-commercial context, so that the patentee’s rights do not extend to such acts.
The first reason mentioned by the court for rejecting this infringement theory is quite convincing. It is true that the patient has absolutely no idea what the drug becomes after ingestion.
The second reason looks much more challengeable on a legal standpoint. Admittedly, the rights conferred by a patent do not extend to acts carried out in a private and non-commercial context (article L 613-5 CPI). But here, the allegedly infringing act is not the ingestion of the drug by the patient, but the sale of the drug to patients, considered as the supply of essential means for implementing the invention to a third party. And article L. 613-4 CPI clearly states that a party benefiting from the exemption of article L. 613-5 CPI (such as a patient) is not regarded as a party authorized to implement the claimed invention for the purpose of the assessment of contributory infringement.
That said, one good reason was certainly enough to throw out Shionogi and AstraZeneca’s auxiliary infringement theory.
In addition to rejecting the plaintiffs’ infringement claims, the court also had to examine the validity of the EP’471 patent.
The interim order had already stated that there was no serious validity challenge. In the judgment now issued by the three-judge panel, the validity of the patent has been confirmed.
The grounds for nullity which were raised were extension of subject-matter, insufficiency of disclosure and lack of inventive step.
Regarding extension of subject-matter, original claim 1 in the application as filed was directed to a compound defined by a Markush formula with five variable groups X, R1, R2, R3 and R4.
Two examples of the application disclosed calcium rosuvastatin and sodium rosuvastatin.
The defendant argued that the acid form of rosuvastatin, on the other hand, was not directly and unambiguously disclosed in the application as originally filed.
But the court was satisfied that claim 1 of the patent was obtainable by the skilled person based on the examples of calcium and sodium rosuvastatin, and on a paragraph of the description which provided a broader definition for group R4 in the general formula, namely: hydrogen (corresponding to an acid form of the molecule), or a lower alkyl group, or a cation capable of forming a non-toxic, pharmaceutically acceptable salt.
What is not explicitly discussed in the court’s reasoning is the fact that the definition of group R4 was restricted to arrive at claim 1 as granted, since the option of a lower alkyl group is no longer covered in the patent.
Turning now to sufficiency of disclosure, Biogaran raised two objections:
- there is no information in the patent how to select or use salts of rosuvastatin other than the exemplified sodium and calcium salts;
- the patent does not sufficiently establish the existence of a therapeutic effect, as it only disclosed an in vitro test, and did not contain any precise indication on a possible dosage regimen.
Regarding the first objection, it is certainly relevant that only certain types of salts were held by the court to be covered by claim 1, namely alkaline metal, alkaline earth metal and ammonium salts. Therefore, it was immaterial for the appraisal of sufficiency that the zinc salt for instance is not discussed in the patent, since this salt is not covered by claim 1.
The court noted that the patent discloses a process for making various salts, and that Biogaran did not demonstrate any difficulty for carrying out the invention with the different forms of rosuvastatin that are claimed.
As for the second objection, the court was satisfied that, since the patent relates to new molecules, an assay comparing the biological activity (namely the activity of inhibition of HMG-CoA reductase) of rosuvastatin to that of the prior art drug mevinoline, is a sufficient disclosure of the therapeutic effect.
Lastly, inventive step.
Biogaran’s argument was based on two prior art documents, Bayer and Beck, which both disclose a broad family of compounds having an HMG-CoA reductase inhibitory activity. Biogaran argued that rosuvastatin can be obtained by way of a selection from the teaching of these documents, and that this selection is arbitrary, since the therapeutic effect of rosuvastatin is the same as that of the other compounds of the broad family explicitly taught in Bayer and Beck.
The court held that this reasoning is based on hindsight and thus impermissible. The court stated in particular that the skilled person would focus on options described as preferred in the prior art, and would thus not study all possible compounds at random. In this case, there was no pointer in the prior art leading the skilled person to rosuvastatin.
CASE REFERENCE: Tribunal de grande instance de Paris, 3ème chambre 2ème section, February 9, 2018, Shionogi Seiyaku Kabushiki Kaisha, AstraZeneca & AstraZeneca UK Ltd v. Biogaran, RG No. 16/13292.