Background

The patent under challenge, EP 1 173 181 (the 181 patent), relates to a low dosage of tadalafil for use in the treatment of sexual dysfunction. It is owned by ICOS and exclusively licensed to Eli Lilly.

Tadalafil is sold under the brand name Cialis as a medication for erectile dysfunction (ED). It is a PDE5 inhibitor and works in a similar way to sildenafil (more commonly known as Viagra). Tadalafil was found to be advantageous over sildenafil due to its increased selectivity for PDE5 over other PDE families, which results in fewer side effects. The alleged essence of the 181 patent is the discovery that tadalafil is effective in treating ED at such a low dose and with minimal side effects that it can be taken daily for chronic use rather than on demand. The 181 patent claims doses of 1 – 5 mg up to a maximum dose of 5 mg/day.

However, the use of tadalafil in the treatment of ED has already been disclosed in an earlier patent (the Daugan patent), which was filed by GlaxoSmithKline and later transferred to ICOS. The Daugan patent discloses that doses of tadalafil will generally be in the range of 0.5 mg to 800 mg daily for the average adult patient. It gives examples of a tablet containing a 50 mg dose of the active ingredient. However, Daugan does not purport to set out an appropriate dosage regime as an oral treatment of ED.

In order to clear the way for their own tadalafil generic, Actavis brought revocation proceedings in respect of the 181 patent, which were later combined with related proceedings brought by Teva UK Limited, Teva Pharmaceutical Industries Limited and Generics (UK) Limited (trading as Mylan). Actavis and others argued inter alia that the 181 patent lacked inventive step over the Daugan patent.

Earlier decisions - High Court

At first instance, Actavis argued that it would be obvious for a skilled team given the Daugan patent to take tadalafil forward into a routine pre-clinical and clinical trial programme as an oral treatment for ED at the priority date. Actavis submitted that while costly and time consuming, the programme would involve nothing other than routine work and no inventive effort was required. Lilly responded that the discovery of the dosage regime was the result of expensive and unpredictable research which was entitled to patent protection. Lilly argued that at the start of the programme it was not obvious to try a low dose like 5 mg/day as there was no reason to think that it would be effective at that dosage.

Birss J accepted neither argument in its entirety. Birss J held that it would have been “entirely obvious” for a skilled team given Daugan to take tadalafil forward into a routine pre-clinical and clinical trial programme as an oral treatment of ED at the priority date. Birss J considered that the skilled team would carry out a first dose ranging study using 25, 50 and 100 mg of the drug as part of Phase IIb studies with the expectation of finding a dose response relationship. However, the results would unexpectedly show no difference in efficacy between the three doses, demonstrating an apparent therapeutic plateau.

The critical dispute at this stage was whether in light of those findings it was obvious for the skilled team to conduct a further dose ranging study to investigate lower doses and determine the minimum effective dose. Birss J considered that it was “very likely” that the skilled team would carry out such studies. However, Birss J held that if a 5 mg/day dose of tadalafil was tested, it would not be tested with a reasonable expectation of success. Birss J considered that the discovery that tadalafil at a 5 mg dose was efficacious and had reduced side effects would surprise the team.

Birss J then looked at the programme as a whole and assessed obviousness overall. He concluded that, given Daugan, a 25 mg/day dose of tadalafil was obvious as a treatment for ED but that a 5 mg/day dose was not. Thus, he found the 181 patent to be valid (and infringed).

Earlier decisions - Court of Appeal

The Court of Appeal reached a contrary conclusion and allowed the appeal on the grounds of obviousness.

Kitchin LJ pointed out that Birss J found that the skilled team would “very likely” investigate lower doses of tadalafil after the first or, in the case of on demand dosing, a possible second dose ranging study. Kitchin LJ held that the finding that the skilled team could not predict at the outset that a 5 mg dose would be safe and efficacious was of little weight because at least one purpose of the Phase IIb studies is to understand better the dose-response relationship of the drug and so identify the appropriate dose. Kitchin LJ also held that little weight could be attached to the fact that it was surprising (a) that there was a therapeutic plateau from 10 mg to 100 mg, and (b) that a 5 mg/day dose was efficacious and had reduced side effects as they were the results of a routine trial programme. He also held that the unexpected reduced side effects were a bonus effect which did not cause the 5 mg dose to cease being obvious.

Kitchin LJ concluded that the claimed invention lies at the end of the familiar path through a routine pre-clinical and clinical trial process. Kitchin LJ held that the skilled but non-inventive team would embark on that process with a reasonable expectation of success and in the course of it they would carry out Phase IIb dose ranging studies with the aim of finding out, among other things, the dose response relationship. It is very likely that in doing so they would test a dose of 5 mg/day tadalafil and, if they did so, they would find that it is safe and efficacious. At that point they would have arrived at the claimed invention.

Thus, Kitchin LJ declared the 181 patent lacked inventive step and was invalid.

Supreme Court

ICOS and Lilly appealed the Court of Appeal decision to the Supreme Court. They argued that the Court of Appeal’s approach to inventive step went beyond the requirements of Section 3 of the 1977 UK Patents Act. They argued that Section 3 required the court to ask whether the claimed invention was obvious to the notional skilled but uninventive team at the priority date having regard to the state of the art at that date. They argued that the potential outcome of clinical trials should not form part of the analysis.

Lord Hodge (giving the judgment of the Supreme Court) was not persuaded by Lilly’s arguments. Lord Hodge stated that Lilly’s approach would require the court to disregard the work which a skilled person would carry out after the priority date of Daugan. Lord Hodge held that while the skilled person has no inventive capacity, that does not mean he has no skill to take forward in an uninventive way the teaching of the prior art.

Lord Hodge emphasised that the question of obviousness must be considered on the facts of each case taking into account any particular factors that may be relevant to the circumstances of that case. Lord Hodge then went on to consider ten factors relevant to the case at issue:

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 through to a particular point;
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;
5. the existence of alternative or multiple paths of research;
6. the motive of the skilled person;
7. whether the results of research are unexpected;
8. hindsight;
9. whether a feature of a claimed invention is an added benefit; and
10. the nature of the invention.

Lord Hodge stressed, however, that the relevance of each of these factors and its weight when balanced against other relevant considerations depend on the particular facts of each case.

In the instant case, Lord Hodge agreed with the Court of Appeal that the 181 patent was obvious in view of Daugan. Lord Hodge concluded that the task of the skilled team would be to implement Daugan and that this would involve determining the appropriate dose of tadalafil, which would usually be the lowest effective dose. Lord Hodge held that the pre-clinical and clinical tests involved familiar and routine procedures and normally progressed to the discovery of the dose-response relationship in Phase IIb. In this case, the skilled team would have found the therapeutic plateau and would be very likely to test lower doses and so come upon the dosage regime which is the subject of the patent. Thus, the appeal was dismissed.

Comments

This case highlights that the assessment of inventive step requires a multifactorial approach and depends upon the specific facts of the case. It will be interesting to see how the ten factors identified in this case are applied to future cases.

The court considered the commonly used tests for the assessment of inventive step in the judgement, namely the UK Windsurfing/Pozzoli test and the EPO problem-and-solution approach. The court held that while both approaches focus on the inventive concept put forward in the claims, neither approach should be applied in a mechanistic way. The court stated that both are glosses on the statutory texts and neither requires a literalist approach to the wording of the claims in identifying the inventive concept.

Interestingly, the court held that there is no policy reason why a novel and inventive dosage regime should not be rewarded by a patent. In addition, it was concluded that efficacious drugs discovered by research involving standard pre-clinical and clinical tests should be rewarded with a patent if they meet the statutory tests. Thus, this decision does not close the door on dosage regime patents. However, it is difficult to see how a dosage regime arrived at through routine pre-clinical and clinical tests could be considered inventive in view of this decision.