Dosage patent for tadalafil for treatment of male erectile dysfunction held invalid for obviousness on appeal
In order to clear the way for the marketing of their own products Actavis, Teva and Mylan applied to revoke an Icos/ Lilly patent directed at the treatment of sexual dysfunction by the administration of a dose of no more than 5mg tadalafil per day. They argued that it would have been obvious for the skilled team to take tadalafil forward into a routine pre-clinical and clinical trial programme to assess its use as an oral treatment for sexual dysfunction. In the course of that programme, a 5mg daily dose of tadalafil would be used in patients and it would reveal the invention, that a 5mg daily dose is a safe, tolerable and effective treatment.Tadalafil powder dosage
Lilly argued the case was really one of “obvious to try” and that this could only lead to a finding of invalidity if the skilled team would consider that the programme had a fair prospect of success. This they disputed because, at the start of the programme, the skilled team would have had no idea whether or not a 5mg daily dose of tadalafil would be a safe, tolerable and effective treatment of sexual dysfunction, still less that it would be both efficacious and have minimal related side effects.
The trial judge agreed with Lilly that the patent was not invalid for obviousness. He found that the skilled team would embark on the project with a reasonable expectation of success in establishing tadalafil as a safe, tolerable and effective treatment, but it would not have been able to predict that the 5mg / day dose would be effective.
The Court of Appeal held this was not a case in which the skilled team would be faced with a series of parallel avenues of study and would not have any expectation that any one of those avenues would prove fruitful or be more likely to prove fruitful than any other. Nor was it a case where most or even some of the avenues of investigation would not lead to the invention. Instead it was a case where the two possibilities of on demand and daily dosing would both be addressed in light of the earlier routine work, and where each would be very likely to lead the skilled team to the invention.
The judge wrongly attached weight to the fact that a dose of 5mg was considerably less than the 50mg dose (disclosed in the prior art) which would be used in Phase IIa efficacy test, and to the fact that a dose of 5mg would not be chosen for the routine first dose ranging study in Phase IIb. The Court of Appeal noted, however, that the two parts of Phase II clinical trials have different purposes. Phase IIa is designed to provide proof of concept and is generally carried out at one dose selected to be high enough to provide the best chance of showing a positive effect while not causing serious side effects. Phase IIb is carried out at different doses chosen to provide an understanding about the dose response relationship. Although a dose of 5mg would not be chosen for the first study in Phase IIb, the skilled but uninventive team would very likely investigate it thereafter. In the course of this it was very likely that they would test a dose of 5mg tadalafil per day 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.
The judge had therefore fallen into error. If the only thing driving the skilled team to test the 5mg dose was its level of expectation that a 5mg dose might be effective, expectation of success as to efficacy would be highly material. However, phase IIb clinical tests are conducted with a separate objective, namely to identify a dose response. The absence of an expectation of success as to efficacy was, in these particular circumstances, not relevant.
Although the skilled team would be surprised by the result, namely efficacy at 5mg/day, such a finding would be arrived at by the standard, routine enquiries into dose response which are required by Phase IIb clinical trials. It followed that the surprising result, once uncovered, did not make these routine enquiries inventive.
Expectation of success, if relevant at all, should come in before making the decision on what the skilled team would do. If the skilled team had no expectation of success, that might be a reason why they would not undertake the step in question. But having come to the conclusion that they would, there was no further need to examine an expectation of success.