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Eli Lilly and Company (Eli Lilly) globally markets its product tadalafil (Cialis®) a PDE5 inhibitor, for use in the treatment of erectile (or sexual) dysfunction as well as for treating the signs and symptoms of benign prostatic hyperplasia.   Tadalafil is available as a tablet in four strengths – 2.5 mg, 5 mg, 10 mg and 20 mg, respectively.   Not surprisingly, worldwide, Eli Lilly has several issued patents covering tadalafil.  One such patent, European Patent No. 1 173 181 T6 (the ‘181 patent), covers a pharmaceutical unit dosage composition comprising 1 to 5 mg of tadalafil that is suitable for oral administration up to a maximum of 5 mg per day.

Over the last several years, there has been significant interest by generic manufacturers in developing a generic version of tadalafil.  As a result, in Europe, the ‘181 patent has already been litigated in several countries and been found to be invalid by courts in the Netherlands, Great Britain (on appeal to the Supreme Court) and Germany.  In Belgium, a nullity action is currently pending (despite the fact that a trial took place a few months ago, the parties are still waiting to receive a judgment).

Sandoz has launched a generic version of tadalafil in a few countries around the world, most recently in Denmark, where the product was made available in all strengths.  As a result, Eli Lilly filed a patent litigation action and a request for preliminary injunction with respect to the 2.5 mg, 5 mg and 10 mg tablets.  On June 15, 2018, the Danish Maritime and Commercial High Court, in Eli Lilly and Company, ICOS Corporation, and Eli Lilly Danmark A/S v. Sandoz A/S found the Danish equivalent of the ‘181 patent valid and issued the injunction.

During the proceeding, Sandoz argued that the preliminary injunction should not be granted because the ‘181 patent was invalid for added subject matter, lack of priority, lack of novelty and lack of inventive step.  However, the main focus of Sandoz’s arguments during the proceeding centered on lack of inventive step.  Specifically, Sandoz argued that the ‘181 patent was obvious in view of WO 97/03675 (Daugen II) and Viagra® (a well known PDG5 inhibitor).  In finding that the ‘181 patent was likely valid, the Court described the objective problem to be solved as providing a selective, potent tetracyclic derivative as described in Daugen II for the inhibition of PDE5 for treating erectile dysfunction as well as providing an improved dosing regimen. According to the Court, the “skilled person” would have consisted of a “team”, namely, a clinician as well as persons with knowledge about toxicology, pharmacokinetics, urology and pharmaceutical formulations.  Eli Lily argued that this team would have been lead by a clinician.  In contrast, Sandoz argued that the team would have been lead by a clinical pharmacologist.

According to the Court, the ‘181 patent solved the problem through the use of a unit dosage comprising 1 to 5 mg of tadalafil in 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.  Specifically, the Court said that the general route of determining the optimal dose of a drug to administer does not in and of itself constitute inventive step.  However, this simply was not the case here.  Instead, the Court found that the recitation in the claims of a unit dose comprising 1 to 5 tadalafil up to a maximum of 5 mg daily did not lack inventive step in view of Daugan II.  Therefore, based on the evidence presented, the Court stated that one could not determine in advance of the clinical trials that a skilled person would have been lead to the claimed invention, and moreover, a computer model could not have sufficiently described the complicated conditions of the patent including the physical and psychological factors that can play a role in erectile dysfunction.  In fact, in view of what was known about Viagra®, the skilled person would have concluded that the higher the dose of tadalafil used the better the effect (in treating sexual dysfunction).  As a result, a skilled person would not have included a 5 mg or less dose in a dose response study and therefore would not have tried to develop a daily dosing regimen for treating sexual dysfunction.  Additionally, the Court found it surprising that tadalafil could be use daily at such an effective low dose with minimum side effects.

This post was written by Lisa Mueller and Verena Simpson of Guardian IP.


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