Tadalafil - UK

On Mar 27, 2019 The UK Supreme Court ruled in favour of Actavis (Teva) and Mylan in a dosage patent dispute against Eli Lilly over Cialis®.

The dosage patent which is the subject of this appeal is EP(UK) 1173181, which is owned by ICOS and exclusively licensed to Eli Lilly. It relates to the use of tadalafil in a dosage form for the treatment of Erectile Dysfunction (ED). It claims a pharmaceutical dosage form of about 1 to about 5mg of tadalafil in a unit dosage form suitable for oral administration for the treatment of sexual dysfunction, including ED up to a maximum total dose of 5mg per day. Tadalafil is a second in class of phosphodiesterase (PDE) drug. It is another PDE5 inhibitor and operates in essentially the same way as sildenafil. An advantage which tadalafil was found to have over sildenafil was its selectivity; it was able to bind to and inhibit its target PDE5 while having significantly less effect than sildenafil on other PDE families and, in particular, PDE6. This selectivity resulted in less and a smaller number of side effects.

Prior art, Daugan patent, EP 0839040 specifically describes tadalafil. Daugan discloses tadalafil’s potency (ie IC50) against PDE5 as 2 nM. Daugan further discloses that doses of tadalafil will generally be in the range of 0.5mg to 800mg daily for the average adult patient. It gives examples of a tablet containing a 50mg dose of the active ingredient. But the Daugan patent does not discloses an appropriate dosage regime as an oral treatment of ED.  In overturning the decision of Birss J, the Court of Appeal found patent invalid, based on the findings of fact at first instance, that the disclosure in Daugan would have highly motivated a skilled person to pursue tadalafil in clinical trials. Eli Lilly appealed.

The central question in this appeal was whether in the light of the common general knowledge and the Daugan patent as the nearest prior art, the relevant claims in the ‘181 patent were obvious. Specifically, whether it was obvious thing for the skilled team to conduct a further dose ranging study or studies to investigate lower doses and determine the minimum effective dose. Lilly asserted that the essence of the invention is the discovery that tadalafil is effective in treating ED at such a low dose and with minimal side effects. This discovery has allowed the drug to be taken daily (for chronic use) rather than on demand, thus avoiding the need to anticipate when sexual activity might occur. Lilly claims that this is a significant technical advantage as sildenafil by contrast is approved for on-demand use only. Lilly also argued that it was not obvious to try a low dose like 5mg per day as there was no reason to think that it would be effective at that dosage. Lilly further said that to invalidate the claim, it would be necessary to show that at the start of the clinical programme it was obvious to the skilled team that a 5mg/day dose would be safe and effective and also would have the minimal PDE5 related side effects.

Supreme Court considered both the “Windsurfing/Pozzoli” test and the EPO’s “problem/solution approach”, noting that both are glosses on the statutory provisions and that neither should be applied in a mechanistic way. Court further said that the factors which are relevant considerations in the present case include the following (Generics (UK) v Lundbeck):

1.    whether at the priority date something was “obvious to try”;

2.    the routine nature of the research and any established practice of following such research;

3.    the burden and cost of the research programme;

4.    the necessity for and the nature of the value judgments which the skilled team would have in the course of a testing programme;

5.    the existence of alternative or multiple paths of research;

6.    the motive of the skilled person is a relevant consideration;

7.    unexpected or surprising effect;

8.    use of any hindsight, which includes knowledge of the invention, in addressing the statutory question of obviousness;

9.    whether a feature of a claimed invention is an added benefit in a context in which the claimed innovation is obvious for another purpose.

Supreme Court said that the target of the skilled person’s research is in large measure pre-determined. The skilled person would aim for a dose as low as possible consistent with effectiveness. That would normally be the appropriate dosage regime. Court recognized and respected Birss J’s finding of fact that there was no defined standard of minimal efficacy in relation to ED and that this would require the skilled team to make a value judgment. But he also found that it was common general knowledge that regulators were often interested in and could require evidence of the minimum effective dose and that the skilled team would be familiar with multiple dose ranging studies as necessary as a generality. Court said that in its view, the inventiveness of the dosage regime falls to be assessed in that context. Bearing in mind that symmetry, the starting point in the assessment of obviousness in this case is the Daugan patent. One begins therefore with the assumption that the Daugan patent has enabled the skilled person to perform the invention of the use of tadalafil for the treatment of ED. That involves finding the appropriate dosage regime having regard to safety, tolerability and effectiveness. The procedures to achieve that end are familiar and routine as the Court of Appeal found in its judgement. Kitchin LJ gave the leading judgment, in which he adopted a fact specific assessment based on the facts of this case and involving the weighing up of several factors, and Floyd and Lewison LJJ agreed with his reasoning and conclusions. The fact that a 5mg dose was so much lower than the 50mg dose, which was recommended for sildenafil, mentioned in the Daugan patent for tadalafil, and used in the notional skilled team’s Phase IIa tests, is neither here nor there. The lack of an expectation of efficacy at a 5mg dose is a factor of little weight if, as was found, the skilled team would be very likely to study such a dose in the search for a dose response relationship. For the same reason the fact that the effectiveness of tadalafil at a dose of 5mg was a surprise can carry little, if any, weight. Similarly, the finding that there was an important value judgment to be made when the therapeutic plateau was identified at the same time as a marketable dose can bear little weight when there is a finding, which is not tainted by hindsight, that the skilled team would continue their tests.

Lilly also argued that the daily dosing regimen by which a person prescribed tadalafil can take the drug once per day rather than on demand in expectation of sexual activity was enabled by the technical effect of the drug, namely the maintenance of efficacy with minimal side effects, which was not obvious and which justified the patent. Court disagreed for two reasons. First, the judge correctly treated the daily dosing regimen as obvious because it was the result of the inevitable discovery of the half-life of tadalafil in Phase 1 of the tests. Secondly, claims 7 and 10 are not confined to the daily dosing regimen but also cover on demand use of the drug subject to a maximum total dose of 5mg per day. It was obvious to embark on that exercise and carry out tests in a routine way until that appropriate dose was ascertained. Those tests included the completion of the dose-ranging studies which were the purpose of Phase IIb. The fact that tadalafil at the dose of 5mg, while remaining effective as a treatment of ED, also, and unexpectedly, had the additional benefit of reduced side effects was an added benefit which does not prevent the identification of 5mg as the appropriate dose from being obvious. The completion of the Phase IIb dose ranging studies led to the asserted invention. In this case the trial judge’s findings of what would have been the sequence of the tests, which did not depend upon hindsight, included the finding, which the evidence clearly justified, that the team, having found a therapeutic plateau, would be very likely to test lower doses and so come upon the dosage regime which is the subject matter of the patent.

Therefore ‘181 patent is invalid for lacking an inventive step.