Supreme Court rules lower dosage regime obvious

The UK Supreme Court on 27 March 2019 handed down its decision in the Actavis v ICOS patent case. The Supreme Court agreed with the Court of Appeal in overruling the first instance decision and ruling that the patent was invalid for lack of inventive step. This is an adverse decision for dosage regime patents and while the Supreme Court stressed that there is no policy reason why a novel and inventive dosage regime should not be rewarded by a patent, this decision reinforces that such patents will be confined to being “an unusual case”.

Background

The case concerns a patent for tadalafil for the treatment of erectile dysfunction (ED). The product in dispute, Lilly’s oral PDE5 inhibitor marketed as Cialis, has had considerable commercial success following the leading product in the field at the patent’s priority date, another orally administered PDE5 inhibitor, sildenafil, marketed as Viagra. Sildenafil was marketed in doses of 25mg, 50mg and 100mg and it was known at the patent’s priority date that broadly its efficacy increased with dose, as did its side effects.

The patent in dispute, EP 1,173,181 (EP181) owned by ICOS and exclusively licensed to Eli Lilly (together referred to as Lilly below), relates to the use of tadalafil in a low dosage form which is said to result in fewer side effects than Viagra. In this way, the invention described in the patent relates to the discovery that tadalafil could be administered at low doses in a clinically effective manner with fewer side effects. More particularly, EP181’s claimed invention was the use of a unit dose of 1 to 5mg of tadalafil for the manufacture of a medicament for administration up to a maximum dose of 5mg per day for the treatment of ED. The claimants (a number of generic companies referred to by reference to Actavis below (the first claimant)), brought proceedings to revoke EP181 and clear the way to market their generic versions of Cialis. Lilly and ICOS counterclaimed for threatened infringement.

The claimants’ revocation claims were based on several grounds including lack of novelty, lack of inventive step and insufficiency. In 2016, Birss J found the patent valid and infringed. When assessing inventive step, the judge found that the 25mg, 50mg and 100mg doses were the doses on which the skilled team would focus initially, although it was also known that a 10mg dose of sildenafil had been shown to be efficacious in trials. As discussed below, none of Birss J’s findings of facts were challenged; but it was his evaluation of such facts that came to be overruled.

Actavis appealed and in November 2017, the Court of Appeal (Lewison, Kitchin and Floyd LJJ) allowed their appeal, finding the patent invalid for lack of inventive step. In their opinion, it would have been obvious to the skilled team, in the light of the prior art, that tadalafil would be a safe and effective treatment for ED with minimal side effects and they would have arrived at the surprisingly low (but effective) dose using routine dose ranging studies. Lilly appealed the decision which has led the Supreme Court to review two issues: first, the English court’s approach to inventive step, in particular the “obvious to try” test; and second, the role of the appellate court in reversing findings under inventive step (a traditionally high hurdle to overcome).

Common general knowledge

Sildenafil was a first in class drug which validated the rationale for trying to treat ED using an oral PDE5 inhibitor. Any other PDE5 inhibitor would be known as a second in class drug. It was also of central importance to Actavis’ case that the motivation for developing a second in class drug would have been very high, and furthermore that such development would have followed a well-established programme of pre-clinical and clinical trials (Phases I, IIa and IIb, III and IV).

The prior art

The prior art for the purposes of obviousness was a patent application known as Daugan. Daugan taught the use of PDE5 inhibitors for the treatment of ED, specifically disclosed tadalafil and its potency of inhibition (IC50) of PDE5 and included by way of example, tablets containing a 50mg dose. It described that doses of tadalafil would generally be in the range of from 0.5 to 800mg daily for the average patient but it did not set out an appropriate dosage regime as an oral treatment for ED. It was not disputed that it would have been obvious for the notional skilled team, given Daugan, to take tadalafil forward into a routine pre-clinical and clinical trial programme as an oral treatment for ED. The Supreme Court appears to place emphasis on the fact that Daugan itself was a patent whose validity was not challenged and that it disclosed and enabled the idea of using tadalafil to treat ED. This appears to weigh not only towards the skilled person being able to follow its teaching, but also towards what the decision refers to as the “balance or symmetry in patent law” leaning towards a monopoly not being justified by its technical contribution.

Obvious to try?

The central question in this case was whether in the light of Daugan and the common general knowledge the invention was obvious.

Actavis had submitted that in light of Daugan it would be obvious at the priority date for the notional skilled team to take tadalafil forward into routine pre-clinical and clinical trials as an oral treatment for ED. In doing so, Actavis said they would arrive at the invention.

Lilly’s response was that the discovery of the dosage regime was the result of costly and unpredictable research which was entitled to patent protection. At the start of the programme it was not obvious to try a low dose such as 5mg per day and there was no reason to think that tadalafil would be effective at that dosage.

Lord Hodge, giving the only judgment with whom the other Justices (Lady Hale, Lord Kerr, Lord Sumption and Lord Briggs) agreed, emphasised that there was a single and uniform test for obviousness. In referring the typical UK approach under Windsurfer/Pozzoli and the EPO’s problem and solution approach, he held that “neither approach should be applied in a mechanistic way”, before later repeating the mantra that “No formula should distract the court from the statutory question”.

In particular, he ran through nine factors which the court should consider when assessing obviousness in such a case.

1. Whether at the priority date something was “obvious to try”, in other words whether it was obvious to undertake a specific piece of research which had a reasonable or fair prospect of success.

2. The routine nature of the research and whether there was any established practice of following such research through to a particular point. As with the other factors, Lord Hodge emphasised that this factor was only one of several and that “it has no primacy and certainly no paramount status as a consideration”.

3. The burden and cost of the research programme.

4. The need for, and the nature of, the value judgments which the skilled team would have made in the course of the research programme. Lord Hodge noted that the cost and effort involved in bringing a drug to market through pre-clinical and clinical trials are “notorious” and that the need to facilitate pharmaceutical research is an important policy consideration, but emphasised that this factor - like the others - was only one of several.

5. The existence of alternative or multiple paths of research as these will often be an indicator that the invention is not obvious. Whilst more than one avenue of research might be obvious, if the skilled team is faced with only one avenue of research it is more likely that the result of that research will be obvious than if they had been faced with a multiplicity of avenues.

6. The motive of the skilled team.

7. The fact that the results of research which the inventor actually carried out are unexpected or surprising as this may point to an inventive step.

8. The courts have repeatedly cautioned against the use of hindsight. Lord Hodge reiterated the risk of a step-by-step analysis that the combination of steps by which the inventor arrived at the invention is ascertained by hindsight knowledge of the invention, but he considered that this warning was not relevant where the steps can readily be ascertained without hindsight.

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.

The Supreme Court concluded that the skilled team’s task in this case was to implement Daugan. Their target would be to ascertain the appropriate dose, which would usually be the lowest effective dose. The pre-clinical and clinical trials involved routine procedures and normally progressed in Phase IIb to the discovery of the dose-response relationship. Birss J’s findings of what would have been the sequence of the tests, which did not depend upon hindsight, included the finding, which was justified on the evidence, that the team, having found a therapeutic plateau, would be very likely to test lower doses and so come upon the dosage regime which was the subject matter of the patent.

On the second substantive issue - ie the reversal of Birss J’s decision - the Supreme Court held that the Court of Appeal was entitled to treat the judge’s failure to appreciate the logical consequences of the finding - that it was very likely that the skilled team would continue the testing - as an error of principle which allowed an appellate court to carry out its own evaluation. As such, the Supreme Court was satisfied that the Court of Appeal was entitled to interfere with Birss J’s assessment of inventive step and to hold that EP181 patent was invalid for lack of inventive step.

Conclusion

The key in this case seemed to be the Court’s recognition of the principle of balance in patent law (ie the extent of the patent monopoly should correspond to and be justified by the actual technical contribution to the art). Lord Hodge commented, in response to interventions from the UK BioIndustry Association and the IP Federation, that he did not construe the judgment of the Court of Appeal as supporting a general proposition that the product of well-established or routine enquiries cannot be inventive. He noted that there is no policy reason why a novel and inventive dosage regime should not be rewarded by a patent, and 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. Nevertheless, here the pre-established (or at least readily foreseeable) target of the skilled team’s tests led the Court to conclude that the claimed invention lacked the necessary inventive step to warrant the grant of a monopoly. It remains to be seen how the lower courts will apply this decision in the future and how soon the “unusual case” of an inventive dosage regime may arise.