Tadalafil - Netherlands

On Mar 14, 2018, District Court The Hague handed down its decision in CIALIS® case & revoked Dutch part of EP 1173181 patent for lack of inventive step.

Icos (an Eli Lilly and Company subsidiary) holds EP 1 173 181 B3 (‘EP 181’) entitled: ‘Compositions comprising phosphodiesterase inhibitors for the treatment of sexual dysfunction.’  In the Netherlands, Icos filed a lawsuit against, among others, Teva Nederland BV (a sister company of Teva). In doing so, it essentially sought an infringement ban on EP 181, due to the circumstance that generic tadalafil 5 mg products have been introduced on the market by (among others) Teva Nederland BV from 14 November 2017. Teva sought to revoke the Dutch part of EP 181.

Teva's argument that the conclusions of EP 181 lack inventiveness, comes down in essence to the fact that, in view of the information about tadalafil disclosed in Daugan and given his knowledge about sildenafil (Viagra®), the professional would proceed to further development of tadalafil for the treatment of sexual dysfunctions, by going through different phases of drug development, including dose ranging studies, in which the person skilled in the art would arrive at a dosage within the range of 1 to 5 mg claimed by EP 181 without inventive work.  Teva has argued that the person skilled in the art would have set a maximum safe dose after the Phase I study and that he would have the IC50 value (2-2.5 Nm), half-life (17.5 hours), Tmax ( 2 hours) 14 and Cmax (350 micrograms / l based on a 20mg dose), the molecular weight determined in the laboratory (389.14 g / mol). The dispute then focuses on the question of which doses would be tested in a phase IIb study and whether or not a 5 mg dose would be included. Expert 4 of Teva used graphs to show that calculations show that a 5 mg dose or tadalafil results in a PDE5 activity which is 50 mg dose or sildenafil.

Icos's argument that expert 4, in view of the occasional use of Viagra® known in the state of the art , wrongly assumes that the person skilled in the art at tadalafil would pursue a daily dosing regimen also misses the target. Icos' argument that the person skilled in the art would have no motivation to go to a lower dose of tadalafil, also not expecting the efficacy to be comparable to that of higher doses while at the same time having minimal side effects.

The court after hearing both the parties ruled that the man skilled in the art when starting from the prior art would get to the claimed dosage range in various non-inventive steps. Court held that it is an important objective of the phase IIb study to determine the relationship between dose and efficacy (ie the dose-response relationship) to come. As long as the professional would encounter a plateau, he would not yet have established this dose-response relationship and he would therefore be motivated to carry out research into lower doses (although this may even be compulsory in a regulatory framework). Apart from that, a professional will always strive for the best result, ie an effective dose with as few side effects as possible. It is therefore obvious that even lower doses, including a dose of 5 mg, would have been tested. The phase IIb study would show at the daily dosages that a 10 mg dose would still be as effective as the higher doses tested. It is therefore obvious that even lower doses, including a dose of 5 mg, would have been tested with minimal side effects.

The court thus destroyed the Dutch part of EP’181.

The same patent was also litigated in other jurisdictions .In the United Kingdom, a procedure to destroy (the British) part of EP 181 has been initiated by amongst others, Teva UK Limited and Teva Pharmaceutical Industries Limited. By judgment of 10 August 2016, the High Court stated briefly that, according to Daugan, the skilled person would further develop tadalafil as a medicinal product, but would not have come up with a dosage of 5 mg without inventive work. The High Court therefore found EP 181 to be valid. By judgment of November 1, 2017 however, the Court of Appeal unanimously ruled that this conclusion, as well as conclusions 1 and 10, in the light of Daugan, are invalid because of a lack of inventiveness.

In Germany, a procedure to destroy EP 181 has also been started. The Bundesgerichtshof has destroyed the German part of EP 181 by ruling of October 24, 2017, written statement not yet provided.