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03 Jul 2018

Eli Lilly and Company, ICOS Corporation, and Eli Lilly Danmark A/S (“Eli Lilly”) v. Sandoz A/S (“Sandoz”), the Danish Maritime and Commercial High Court, Case number A-49-17, 15 June 2018

The case concerns infringement of Eli Lilly’s patent DK/EP 1 173 181 T6 (“DK/EP ‘181”) which relates to the use of the active substance Tadalafil in a dosing regime and applications thereof, including for the treatment of sexual dysfunction, wherein Tadalafil is administered up to a maximum of 5 mg Tadalafil per day.

Eli Lilly markets Tadalafil under the trademark CIALIS® in four strengths: 2.5 mg, 5 mg, 10 mg and 20 mg. Tadalafil 10 mg and 20 mg tablets are for use “on demand” whereas 2.5 mg and 5 mg tablets can be used as a “once a day” dosing regimen.

When Sandoz started marketing its generic version of Cialis® in all strengths in Denmark, Eli Lilly filed a request for a preliminary injunction in relation to 2.5 mg, 5 mg and 10 mg tablets. On 15 June 2018, the Danish Maritime and Commercial High Court handed down its decision granting a preliminary injunction against Sandoz’ sale in Denmark of products containing 2.5 mg and 5 mg Tadalafil.

Sandoz’ defense against the preliminary injunction was based on alleged invalidity of DK/EP ‘181. Sandoz argued on several grounds for invalidity: added subject matter, lack of priority, lack of novelty, and lack of inventive step. However, during the proceedings Sandoz limited its defense to only concern inventive step. Accordingly, the case centered on the question whether the patent was obvious to the skilled person.

Sandoz argued that the invention was obvious in view of the patent application WO-A-97/03675 (“Daugan II”) and the known PDE-5 inhibitor Sildenafil (Viagra®).

Based on a thorough analysis of the question of inventive step, the Court found in favor of Eli Lilly, i.e. that Eli Lilly had rendered it probable that DK/EP ‘181 was valid.

The Court defined the objective problem as the provision of a selective, potent tetracyclic derivative as described in Daugan II for the inhibition of PDE5 in the treatment of erectile dysfunction, as well as the provision of an improved dosing regimen.

According to the Court, the skilled person consisted of a team, including a clinician and persons with knowledge about toxicology, pharmacokinetics, urology, and pharmaceutical formulations. The Court agreed with Eli Lilly that the team would be led by a clinician and not a clinical pharmacologist as alleged by Sandoz.

The Court also found that DK/EP ‘181 solves the objective technical problem through the use of a unit dosage comprising 1 to 5 mg Tadalafil for the manufacture of a medicament for administration up to a maximum total dose of 5 mg Tadalafil per day in a method of treating sexual dysfunction in a patient in need thereof.

The Court noted in its decision that in general a routine determination of the optimal dose could not constitute inventive step. However, this was not the case here. The Court found that the specification in claim 10 of a use of a unit dosage comprising 1 to 5 mg Tadalafil up to a maximum total dose of 5 mg daily would not have been obvious to the person skilled in the art in view of Daugan II.

Based on the extensive evidence presented during the proceedings, the Court decided that one could not have determined in advance that the trials would lead to the invention. The Court found that a simplified computer model does not sufficiently describe the complicated conditions in a patient, in which both physical and psychological factors can play a role in relation to the erectile dysfunction.

In view of Viagra®, the skilled person would conclude that the higher the dose used, the better the effect. Moreover, the skilled person would not reduce the dosage in order to decrease the relatively mild side effects, as he would expect this to also reduce the therapeutic effect. The skilled person would therefore not have included 5 mg or less in a dose-response study and would not have tried to develop a daily dosing regimen for a pharmaceutical product for the treatment of sexual dysfunction.

The Court found that DK/EP ‘181 shows the surprising effect that Tadalafil can be used daily and is effective at low doses with a minimum of side effects. This would have been novel for the person skilled in the art in relation to the prior art.

It was concluded that Eli Lilly had rendered it probable that DK/EP ‘181 has inventive step and is valid.
During the proceedings, Sandoz did not contest that if DK/EP ‘181 was valid, it was also infringed by Sandoz’ generic 2.5 mg and 5 mg Tadalafil tablets. Sandoz objected to Eli Lilly’s claim that Sandoz’ 10 mg tablets constituted an indirect infringement of DK/EP ‘181. The Court ruled in favor of Sandoz finding that Eli Lilly had not rendered it probable that sale of Sandoz’ 10 mg tablets constituted an indirect infringement.

Other proceedings across Europe
There are several pending infringement proceedings against other generic companies across Europe. In the UK, Eli Lilly won the case in the first instance, while the patent was found invalid in the second instance for lack of inventive step. Eli Lilly has received permission to appeal to the Supreme Court of the United Kingdom.

A copy of the decision (in Danish) can be read here.

Reported by: Mikkel Vittrup, Peter-Ulrik Plesner and Sara Munch Andersen, Plesner Advokatpartnerselskab, and Pernille Thorsboe, Zacco, who advised Eli Lilly during the PI proceedings in Denmark