In a rare intervention in relation to inventive step, the Court of Appeal has overturned a High Court decision of Mr Justice Birss in relation to ICOS/Lilly's tadalafil 5mg dosage regimen patent. Tadalafil is the generic name of the drug sold under the brand 'Cialis' for the treatment of male erectile dysfunction (ED).
The inventive concept of the patent was stated to be a smaller 5mg dosage of tadalafil, which remained effective but was combined with minimal side effects. However, the appeal court found that there was no invention in a dose that was discovered by virtue of the dose ranging studies carried out as part of routine Phase IIb clinical studies. The patent (EP (UK) 1,173,181) was therefore invalid, and with the Supplementary Protection Certificate for tadalafil also expiring in November, the way became clear for Actavis, Teva and Mylan to launch generic products to compete with Cialis.
Having applied for permission to appeal to the Supreme Court, Lilly made an urgent application in the Patents Court for an interim injunction to stop generic products entering the market, pending any possible appeal. An appeal to the Supreme Court can take some time to resolve (around one to two years from filing the petition to judgment) - if the interim injunction had been granted, this would have meant generic manufacturers would potentially have to factor in the likely timing of an appeal to the Supreme Court when taking steps to clear the way before launch.
In the event, such policy arguments did not impact on the Patents Court's decision refusing to grant an interim injunction. The judge, Mr Justice Henry Carr, concluded that Lilly did not have a realistic prospect of success in a further appeal, as the Court of Appeal had applied the facts, as found by the High Court, to existing and settled principles of law. Further, he would also have been against Lilly on the question of unquantifiable loss (not least as, following the accepted downward price spiral, the patent would expire not long after a period of restored monopoly). In contrast, he accepted that the generic companies would all lose their 'first mover' advantage, outweighing any unquantifiable losses to Lilly.
Whether or not a distinct dosage regime of a known compound can be inventive is an important policy question underlying this litigation. Whilst the Court of Appeal's decision does not rule this out, it did not consider there to be an invention on the facts of this case. The claimed invention lay "at the end of the familiar path through the routine pre-clinical and clinical trials process" and the skilled team would embark on that process with a reasonable expectation of success, and would carry out Phase IIb dose ranging studies, including to find out the dose response relationship. It was very likely that, in doing so, they would test a 5mg daily dose and would find it safe and efficacious.
Trial decision: not obvious
'Daugan', the prior art over which the patent was alleged by Actavis to be obvious, disclosed the use of PDE5 inhibitors to treat ED, and specifically disclosed tadalafil (giving an example of a 50mg dose). However, it did not disclose (specifically) a 5mg daily dose of tadalafil or that such a dose would be an effective treatment for ED.
Mr Justice Birss, in the High Court, found it would have been entirely obvious for a skilled team, on the basis of Daugan, to take tadalafil into a routine pre-clinical and clinical trial programme, and would have investigated on demand and chronic daily dosing. The skilled team would have embarked on a Phase 11a study and then routine Phase IIb dose ranging studies, based on 25, 50 and 100mg initially. However, the question was the extent to which the skilled team would be motivated, as part of the Phase IIb clinical trial, to: (a) investigate whether lower dosages would also display a dose response relationship; and (b) discover the minimum effective dose. Mr Justice Birss's view was that 5mg is a significantly lower dose than 50mg and, even if a test was carried out on a 5mg/day dose, it would not be tested with a reasonable expectation of success and would be the culmination of a series of value judgments.
Court of Appeal decision: obvious
Lord Justice Kitchin acknowledged that it is very easy with hindsight to say something is obvious, but noted that the number of open research avenues was also important. In this case, there were a number of choices including whether to pursue on demand or daily dosing. After Phase 1, Mr Justice Birss found that both avenues would be pursued.
The Court of Appeal found, however, that Mr Justice Birss placed too much emphasis on 5mg being substantially lower than 50mg, meaning 5mg would therefore not be used in the first (or even, in the case of on demand dosing, second) round of a routine dose ranging study, even if it was very likely that it would be subsequently investigated. The very purpose of Phase IIb of a clinical study is to understand the parameters of a given dose response relationship – Lord Justice Floyd stating that "far from being a value judgment, investigating lower doses was something the skilled team would do without further thought". It would not matter that it was not previously known that 5mg was safe and efficacious; instead this stage of the study would continue until complete.
The skilled team's reasonable expectation of success would relate only to the expectation of success in understanding the dose response relationship in question (the objective of the Phase IIb), rather than the effectiveness of a specific dose. Furthermore, it is irrelevant from an obviousness perspective that the result is surprising, since a surprising result does not make routine enquiries inventive.
Lilly is currently seeking permission to appeal to the Supreme Court, but the Patents Court's decision to refuse an interim injunction and, in doing so, its rejection of its attacks on the Court of Appeal's decision will be a setback. Alongside Lord Justice Kitchin, Lord Justices Floyd and Lewison also took the opportunity to express their views in relation to the 'obvious to try' line of cases. In particular, Lord Justice Lewison noted that the Court of Appeal had been "at pains" in previous decisions "to warn against the over-elaboration of the 'obvious to try' line of cases", concluding that in a case involving routine pre-clinical and clinical trials, what would be undertaken as part of that routine, was unlikely to be inventive.