Date: 14 May 2018
By Reuben Jacob
This decision was a reversal of a decision of Mr Justice Birss that the patent concerning tadalifil was valid and infringed. In the course of reaching its decision, the Court of Appeal considered the question of what made an invention “obvious to try”, and found nothing made the claimed dosage regimen of tadalafil inventive, in the light of the prior art.
The question of whether a routine pre-clinical and clinical trial programme had a fair prospect of success was dismissed, as the claimed dosage regime simply equated to the dose at the lower limit of a therapeutic plateau and, therefore, was something that would have been investigated as a matter of routine in Phase IIb dose ranging studies during a clinical trial programme.
Here we consider the Court of Appeal’s reasoning and also report on Eli Lilly’s subsequent failed application for an interim injunction pending further appeal.
The defendants were ICOS Corporation (the registered owner of the patent) and Eli Lilly & Company, the exclusive licensee. We will collectively refer to them as “Lilly”.
The claimants (Acatvis, Teva and Mylan) were seeking to “clear the way” by revoking the patent in order to launch generic tadalafil products. They alleged that the relevant claims of the patent were invalid for lack of novelty over WO 00/53148 (Stoner), which was an international patent application filed by a third party (Merck) and a co-pending patent application. The claimants also argued that all of the relevant claims were obvious in the light of WO 97/03675 (Daugan).
At first instance, Birss J found that claims 2 and 12 lacked novelty in the light of Stoner but that at least claim 7 was valid and would be infringed by the claimants if they were to launch their intended products.
The claimants appealed on a number of grounds; as discussed below, the one that succeeded was that the judge had erred in his assessment of obviousness and should have found nothing inventive in any of the claims, in the light of Daugan.
Court of Appeal’s decision
Lord Justice Kitchin described the submission that the claimed invention was obvious as being, “in the circumstance of this case, a powerful one”. The prior art for the purposes of obviousness was Daugan, an application which had been published before the earliest possible priority date patent.
Daugan taught the use of PDE5 inhibitors for the treatment of ED, specifically disclosed tadalafil and its potency of inhibition (IC50) of PDE5 and described examples of a tablet containing a 50mg dose. It explained that doses of tadalafil would generally be in the range of from 0.5 to 800mg daily for the average adult patient. The disclosure of Daugan and claim 1 of the patent differed in that Daugan did not specifically disclose a tablet containing 5mg of tadalafil, and Daugan differed from Claims 7 and 10 in that it did not disclose that such a dose was an effective treatment for sexual dysfunction.
The claimants argued that it would have been perfectly obvious at the priority date for the skilled team, given Daugan, 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 per day dose of tadalafil would be used in patients and would reveal the invention (i.e. that it was safe, tolerable and effective).
Lilly argued that the claimants’ case was really one of “obvious to try” and could only lead to a finding of invalidity if the skilled team would consider that the programme had a fair prospect of success, which was not the case because, at the start of the programme and given Daugan, the skilled team would have had no idea that a 5mg per day dose of tadalafil would be safe, tolerable or efficacious with minimal PDE5 related side effects when used for ED treatment.
At first instance, Birss J accepted that it would have been entirely routine for a skilled team after reading Daugan to start a pre-clinical and clinical trial programme to find out more about the properties of tadalafil not mentioned in Daugan, such as bioavailability and tissue compartmentalisation. The fact that the skilled team would not be able to accurately predict the outcomes in advance, and might come across unexpected results, would not make the claims inventive.
In reality, after Daugan was published, Lilly did embark on two Phase IIb studies: LVBG, which found that tadalafil administered daily in the dose range of 10-100mg was safe, generally well-tolerated and improved patient’s erectile function and sexual satisfaction; and a subsequent LVBF study, which found that on-demand tadalafil in the dose range of 2-25mg was safe, well-tolerated and improved erectile function. However, on the evidence, Birss J found that it would not have been routine to conduct a dose ranging study which included a 5mg/day dose and, although on the balance of probabilities it was “obvious to try” such a study, there was no reasonable expectation of success. Accordingly, he held that a 5mg daily dose of tadalfil as a treatment for ED was not obvious over Daugan; in particular, claim 7 of the ‘181 patent involved an inventive step.
The claimants submitted it was striking that, despite finding that taking tadalafil forward into a clinical testing programme was “very obvious”, and despite finding that the skilled team would test a dose of 5mg of tadalafil and find it safe and efficacious for the treatment of ED, the judge held that the claimed dosing regimen amounted to an invention. Such a decision, according to the claimants, was “irrational and wrong”.
Kitchin LJ found that
the judge had lost sight of the fact that, on his own findings, the claimed invention lies at the end of the familiar path through the routine pre-clinical and clinical trials’ process.
He explained that the skilled but non-inventive team would have embarked on that journey with a reasonable expectation of success and, along the everyday pathway of research and clinical trials, dose-ranging studies would be performed with the aim of finding out, among other things, the dose response relationship. It was very likely that the skilled but not inventive team would have tested a dose of 5mg tadalafil per day, found that it was safe and efficacious and, at that point of the journey, they would have arrived at the claimed invention. It was irrelevant that such a low dose was surprisingly effective because the result
would be arrived at by the standard, routine enquiries into dose response which are required by Phase IIb clinical trials. The surprising result, once uncovered, does not make these routine enquiries inventive.
Accordingly, the claimants’ appeal was allowed. The court found claims 1, 7 and 10 of the patent were invalid for lack of inventive step and that the judge ought so to have held.
The interim injunction application
Following the court’s decision that the judge had erred in finding that the claimed dosage regimen was inventive, Lilly nevertheless made an application for an interim injunction to restrain the launch of generic tadalafil by Acatvis, Teva and Mylan. As the relevant SPC for tadalafil was due to expire at midnight on Monday 13 November 2017, the application was heard urgently on Friday 10 November 2017.
To succeed in an interim injunction, Lilly would have had to establish that they had a realistic prospect of success on appeal to the Supreme Court. This was a long shot given that Lilly had not even been granted permission to appeal. Lilly attempted to argue that the Court of Appeal had fallen into error on an important point of law (see our discussion below), but in Carr J’s judgment, the Court of Appeal had ruled on the facts as found by the judge applying existing and settled principles of law. Accordingly, he refused to grant the injunction.
The crux of the Court of Appeal’s judgment is routine Phase IIb dose ranging studies. If there is some evidence of efficacy and the patent is a dosing patent, then it would be routine for the skilled team to embark upon a pre-clinical and clinical trial programme, including routine Phase IIb dose ranging studies in larger groups of patients.
Although on the balance of probabilities it was obvious to try a dose ranging study, Birss J had found that there was no reasonable expectation of success, as the skilled team would have to make value judgments along the research pathway.
The judge had allowed himself to become side-tracked at first instance in drawing a distinction between:
In contrast, Kitchin LJ found that this was not a case in which the skilled team would be faced with a series of parallel avenues of study, with no expectation that any one of those avenues would be fruitful or more likely to be fruitful than any other. Instead, it was a case involving two avenues – on demand and daily dosing – and both would reveal tadalafil’s half-life, and each would be very likely to lead the skilled team to the invention.
Lord Justice Floyd, agreeing with Kitchin LJ, said:
“The whole purpose of embarking on the routine Phase IIb dose ranging study was to identify a dose response. The discovery of a plateau indicated that the routine study would have to be repeated at a lower dose, because it was not complete. Completion of the study would inevitably lead the skilled team to test 5 mg/day, whether that dose was still on the plateau, or in a region of the curve where a dose effect is observed. Which it is does not matter, because the result is that the skilled person would at this stage have arrived at a dosing regimen within the claim”.
Not an extension of the “Obvious-to-try” doctrine
Lord Justices Floyd and Lewison warned of the danger in extending the “obvious line of enquiry” principle too far:
“It is important not to let this approach to obviousness extend beyond its proper bounds. There will hardly ever be an invention for which it is not possible to ‘show how it might be arrived at by starting from something known, and taking a series of apparently easy steps’1. Nearly 100 years later, Moulton LJ’s view that this approach was ‘not countenanced by English law’ was said by Jacob LJ2 to be ‘as true today as when it was first said’.
Lord Justice Lewison agreed, and added a few words of his own concerning Lilly’s main argument that an expectation of success was an integral component of an “obvious to try” case: “In my judgment that is not the law - some experiments undertaken without a particular expectation as to the result are obvious”.3
In this particular case, the claimed dosage regime was simply the dose at the lower limit of the therapeutic plateau, which is something that would be investigated as a matter of routine. A patent should not be awarded to the first party that performs an obvious piece of research. The process of research is often quite obvious and produces obvious results, which are quite rightly not patentable. It should not be a goal in life science patent litigation to make the skilled person so witless that they cannot even perform basic research studies and come to a logical conclusion.
Two questions recur in the “obvious to try” case law: Was the invention obvious to try? If so, was it also obvious to succeed? Phrased in such a fashion, it seems like an invention is not obvious to succeed if success cannot be predicted in advance, no matter how obvious to try and how easy the success. However, if we instead consider whether there has been an inventive step, rather than whether the invention would obviously succeed, then success does not have to be predicted in advance, provided that the trial itself did not require any ingenuity or experimentation that would deserve a patent reward.
This means, as Kitchin LJ noted in the present case, that in an “obvious to try” scenario which involves routine research methods that do not deserve a patent reward, we may ask the single and relatively simple question: was it obvious to the skilled but unimaginative addressee in light of the prior art and the common general knowledge to make a product or carry out a process falling within the claim? Unfortunately for the defendants, the answer was yes.
1. per Moulton LJ in British Westinghouse v Braulik (1910) 27 RPC 209 at 
2. Technip France SA’s Patent  RPC 46 at 
3. Quoting Gedeon Richter v Bayer Schering  EWHC 583 (Pat),