Lawsuits surrounding Leo Pharmaceuticals’ patent EP0679154 directed to calcipotriol monohydrate have been on-going in various European states since 2008. Calcipotriol is a vitamin D3 derivative with an interesting biological activity profile: it is effective against psoriasis, a hyperproliferative skin disease in which immunological and inflammatory processes play an important role and which is essentially characterized in that certain skin cells (keratinocytes) do not stop proliferating and a normal skin structure does not develop. Calcipotriol and some other vitamin D3 derivatives are able to inhibit this proliferative process. Unlike other vitamin D3 derivatives, however, calcipotriol has a lower tendency of inducing calcium-related side effects such as osteoporosis. The original form in which calcipotriol was put on the market was an ointment in which solid calcipotriol in anhydrous form was dissolved in an water-in-oil ointment base. A later patent application of Leo (WO 91/12807) disclosed that calcipotriol could also be used in the form of a suspension cream in an oil-in-water base. Before this prior art background, Leo’s patent EP0679154 protected a crystalline form of calcipotriol which was hitherto not described, i.e. the monohydrate, and was stated to have superior technical properties e.g. in the manufacture of crystal suspension formulations, and superior stability properties.
With the expiration of Leo’s calcipotriol basic patent, Sandoz, a generic manufacturer, started putting two topical calcipotriol preparations on the market, an ointment and a cream. To prepare them Sandoz used the known anhydrous form of calcipotriol, delivered from two external suppliers and therefore believed that no infringement issues should arise. Leo, however, had some of Sandoz’ products analysed by an institute and observed that both of them contained traces of monohydrate.
Hence, a series of infringement/nullity actions concerning calcipotriol monohydrate started from there. The first battlefield was in the UK where Leo successfully obtained a preliminary injunction against Sandoz. Sandoz appealed and at the same time filed revocation actions in Germany, Italy and Sweden. Sandoz also filed invalidity counterclaims in the UK and the Netherlands where Leo had meanwhile started infringement actions. What followed then were some spectacular successes by Leo in the UK (both in summary and in main proceedings and both in the first instance and on appeal) and the Netherlands (in first instance and on summary appeal regarding lack of novelty). Then, however, the tide turned, when the German Federal Patent Court revoked Leo’s patent for lack of inventive step. Italy again was a special case: Leo’s initial request for a preliminary injunction was turned down by the first instance judge, but then allowed on appeal. The patent was then, however, revoked by a panel of the Court of Turine in main proceedings and the injunction lifted. Appeals in Italy (by Leo) and the Netherlands (by Sandoz) are still pending. In Sweden, in turn, Leo succeeded again and Sandoz’ nullity action was dismissed.
The latest battle in this series was fought in Germany before the Federal Court of Justice. Here again Sandoz was successful. Leo’s appeal was dismissed and the patent finally declared null and void for lack of inventive step (decision X ZR 89/09 of May 15, 2012). While the written grounds of the decision have not yet been issued, it may still be of interest to compare the various approaches the courts took when evaluating inventive step in their proceedings. Lack of novelty was also pleaded by Sandoz, but this interesting issue rather deserves a full paper of its own. This blog will therefore exclusively focus on inventive step.
The relevant prior art in these proceedings were the above mentioned Acne use patent (WO 91/12807), a scientific article by Kragballe describing the therapeutic potential of calcipotriol and two other structurally related vitamin D3 derivatives in the treatment of psoriasis, as well as three patent documents disclosing that the vitamin D3 derivatives mentioned in Kragballe and one further therapeutic relevant vitamin D3 derivative, respectively, form crystalline monohydrates when dissolving the active compound in an organic standard solvent such as acetone or methanol and adding water as a non-solvent. In contrast to calcipotriol, however, the other three vitamin D3 derivatives were not described to also form a crystalline anhydrous form (anhydrate).
The first decision on inventive step was rendered by the District Court of the Hague.
This court opined that a skilled person had reason to study other crystalline forms than the anhydrate, because there was a professional interest in the phenomenon of polymorphism. Nevertheless, the court held the patent inventive since it was of the view that the vitamin D3 derivatives disclosed in the three patents presented by Sandoz „differ essentially“ in structure from calcipotriol and a skilled person could therefore not predict whether calcipotriol forms a monohydrate. For the learned reader’s reference, the respective structures are shown in the attached figure (click on link below), and he/she may judge by himself whether they are “closely related” as Sandoz argued or “essentially different”, as the District Court of the Hague held:
The German and the Italian courts at least were of the view that they are closely related and that a skilled person would have tried analogous procedures as disclosed in these documents to obtain such monohydrates, with the hope of improving stability (Italy, Germany 1st instance) and he would have succeeded since the methods taught in Leo’s patent were completely analogous to those disclosed in the other vitamin D3 monohydrate patents (i.e. solution of the vitamin D3 derivative in an organic standard solvent such as acetone or methanol and then addition of water).
In the UK the procedural situation was different: the three vitamin D3 monohydrate patents were not used as main references to oppose inventive step, instead it was argued that it was part of common general knowledge of a skilled person how to make monohydrates. The trial judge, however, was not convinced that this was so and held that the notional skilled person would have tried to make a monohydrate on the evidence, but he/she would not necessarily have succeeded. This decision, which was mainly one on the facts, was upheld by the Court of Appeal.
In Sweden, the Stockholm district court went a completely different way. It held that the object of the patent was to solve a specific foaming problem of a crystal suspension of calcipotriol and that there was no pointer for solving this problem by forming a monohydrate in the prior art. Apparently, the Swedish court was not convinced that a skilled person would have investigated whether calcipotriol forms a monohydrate anyway, e.g. in order to improve the stability of the anhydrous form or because the formation of a foam occurred during a wet ball milling process wherein an aqueous milling fluid was used. The Swedish court also did not consider that the possibility of a spontaneous formation of a hydrate of calcipotriol in an (aqueous) suspension cream, which Sandoz even argued must happen for thermodynamic reasons, as a sufficient motivation for a skilled person to investigate whether such hydrates may form or not.
Turning now to the decision of the Federal Court of Justice in Germany, we will have to wait for the written decision grounds before a full evaluation of the decision can be made. What can already be said now, however, is that the court-appointed expert in Germany, a Professor of pharmaceutical technology, very decidedly took the position that a skilled person who was to formulate an aqueous suspension cream of calcipotriol as disclosed in WO 91/12807 necessarily had to investigate whether the drug remained stable in such a formulation or whether it may form hydrates. He pointed to several textbooks where the need of such investigations was highlighted and where the problems were described that may arise when such investigations are omitted. Such issues included, in particular, the possible spontaneous formation of a less soluble hydrate that might crystallize out in the cream and hence may have a significant impact on the bioavailability of the drug in the final topical preparation. He also was of the opinion that a hydrate, if it existed, would have a higher (physical) stability in an aqueous cream environment than the anhydrate.
The Federal Court of Justice therefore apparently accepted that the skilled person was motivated to investigate the possibility of hydrate formation (as were the Dutch, Italian and UK courts) and, contrary to the UK and Dutch first instance courts, thought that the skilled person investigating the existence of hydrates would also have found monohydrate, possibly since there was no evidence that any other hydrate than the monohydrate existed, since it was not shown that the formation of calcipotriol monohydrate involved any synthetic difficulties, and since the methods taught in the patent to make the monohydrate were completely analogous to those disclosed in the other vitamin D3 monohydrate patents.
This series of lawsuits may also raise the interesting question whether hydrates in general are all that exotic. Sandoz presented textbook evidence showing that approximately 30% of all drug compounds are known to form at least one hydrate. On the other hand, Leo asserted they had conducted a search on vitamin D derivatives in the CAS databank and found that only less than a handful out of more than 600 were reported to form hydrates. This argument was applauded by the first instance court in the Netherlands, but rejected by the German courts and the Italian court expert who rather followed Sandoz’ submission that the fact that only a few vitamin D derivatives were known to form a monohydrate is meaningless, since the formation of hydrates is only tried once the compound itself has drug potential and is therefore further investigated. This was not the case for the 600 vitamin D derivatives listed in the CAS databank, but it happened to be the case for all three vitamin D derivatives discussed in the Kragballe article of 1992.
Thus, while the current state of play is now 4:3 for Leo, the final outcome of this exciting “match” is still open. Now it remains to see how the appeal courts in the Netherlands and in Italy will decide on the appeals pending before them.