Actavis Group PTC EHF, Actavis UK Ltd, Actelion Pharmaceuticals Ltd, Actelion Pharmaceuticals UK Limited, Teva UK Limited, Teva Pharmaceutical Industries Limited & Generics (UK) Limited (Trading as Mylan) v ICOS Corporation & Eli Lilly and Company. England and Wales Patents Court (Birss J), London, UK, 10 August 2016, Neutral Citation Number: [2016] EWHC 1955 (Pat)

The Claimants sought revocation of two patents relating to the active pharmaceutical ingredient tadalafil, which is sold by Eli Lilly as CIALIS® to treat erectile dysfunction and pulmonary arterial hypertension. The Defendants counterclaimed for infringement. The first patent in suit, EP (UK) 1,173,181, which is a dosing regime patent, was found to be valid and infringed, the second, EP (UK) 1,200,092, which concerned a formulation of tadalafil, was found to be invalid for lack of inventive step.

EP 1,173,181 (“EP 181”)
Claim 1 of EP 181 was to “A pharmaceutical unit dosage composition comprising 1 to 5 mg of a compound having the structural formula [XXX] said unit dosage form suitable for oral administration up to a maximum total dose of 5 mg per day”. Claim 7 was an EPC 2000 claim which included the functional technical feature that the tablet is used for treating sexual dysfunction.

Quia timet infringement
Two of the Claimants, Actavis and Mylan, had argued that they had not threatened to infringe the patents as their launch plans were contingent on the patent being held invalid. Considering the case objectively, Birss J. noted that Actavis and Mylan had both applied for marketing authorisations to sell tadalafil which is an expensive and time-consuming process. And subjectively, whilst Actavis and Mylan had indicated their current intentions, no undertaking had been given to abandon the marketing authorisation if the revocation action failed and Actavis’ and Mylan’s intentions could change in the future, especially as a launch at risk can be very profitable. He therefore held that there was a threat to infringe and the Defendants had been justified in bringing their counterclaim for infringement.

Entitlement to priority
Birss rejected two attacks to the entitlement to priority of the relevant claims of EP 181:

The first attack was that the priority document did not disclose tadalafil as the stereochemical description was incorrect and, even if it was disclosed, the disclosure of the document read as a whole was not enabling as it was not clear that the clinical data in the priority document related to tadalafil specifically. Birss J. found that tadalafil was disclosed in the priority document on a proper interpretation of the stereochemistry, but that it was not clear that the clinical data in the patent was in relation to tadalafil.

Nevertheless, the judge found the priority document to contain an enabling disclosure as it was plausible, based on data in the priority document that showed tadalafil was a selective PDE5 inhibitor, that tadalafil would be safe and effective to treat sexual dysfunction. Importantly, when considering the decision of Carr J. in Actavis v Eli Lilly, the judge noted that the test for plausibility is not the same as the test for a reasonable expectation of success in obviousness (although factual considerations which bear on plausibility may have a bearing on obviousness).

The second was that the priority document did not disclose the specific dose claimed in the patent. Birss J found that there was no special law for interpreting sub-ranges over that of the general law on entitlement to priority i.e. whether the claimed invention is directly and unambiguously disclosed in the priority document when considered as a whole in light of the common general knowledge. Interpreting the priority document, a passage which read “one or more 1 to 20 mg dosage forms as needed up to a total dose of…5 to 20 mg/day” disclosed a total daily dose of 5 mg and, combined with the other disclosure in the priority document, disclosed a dosage form of 1 to 5 mg.

Novelty (and legal entitlement to priority)
Given the judge’s finding that EP 181 was entitled to priority, the Claimants’ case on anticipation was based on a novelty only prior disclosure in a patent application referred to as “Stoner”. The Defendants argued that the Claimants had not proved that Stoner was entitled to its priority date (and so it did not qualify as Article 54(3) prior art). This was on the basis that the Claimants had not established that the proper legal formalities had been complied with. Neither party had adduced any evidence relating to the investigation of legal priority – whilst the Claimants had asked the Defendants to admit legal priority as an undisputed fact, the Defendants had made no admission in this respect.

The Judge held that the correct general approach in such circumstances is that legal priority must be established. The party attacking validity will have the burden of proof in establishing legal priority, but “if sufficient evidence is available to support an inference that legal priority exists, an evidential burden will have shifted to the patentee…to call evidence to rebut that inference.” The judge thought that in most cases it would be likely that the Court would be able to infer legal priority where the application is by a third party, by looking at the applicants of the priority document and the application as filed (but cautioned against this being an absolute rule). Birss J. went on to say that should a patentee wish to put forward a positive case why such an inference should not be drawn, it should specifically plead this so that the Court can provide case management directions as to the appropriate steps for the parties to take.

It was therefore considered whether Stoner anticipated EP 181. Stoner disclosed a combination therapy for treating erectile dysfunction comprising of tadalafil and an alpha-adrenergic receptor antagonist at dose ranges which fell within the claims of EP 181. As claim 1 of EP 181 used the term “comprising” it did encompass in its scope combination therapies and the judge held that there was sufficient disclosure. However, the judge did not find that the disclosure was enabled as, whilst tadalafil was disclosed as a selective PDE5 inhibitor and so its effects were plausible (as per the reasoning above for priority), the clinical evidence put forward by the Defendants was that in combination with an alpha-adrenergic receptor antagonist, efficacy of the combination as a treatment for erectile dysfunction was questionable, and the side effects likely to be severe. Therefore the combination therapy in Stoner was not credible. Of note in this respect was that, on the Claimants’ case, the skilled team did not include a prominent role for the clinician, and therefore there was no clinical evidence mentioned in the judgment to support the Claimants’ position.

Obvious to try with a reasonable expectation of success?
The Claimants pleaded that EP 181 was obvious over the prior art “Daugan” which disclosed tadalafil and contained data on its in vitro potency. The tablets disclosed in Daugan contained 50mg of tadalafil, and there was a general teaching that tadalafil could be used in the range of 0.5mg to 800mg daily for the average adult patient. The Claimants argued that starting from Daugan the skilled person would be motivated to undertake routine clinical trials which would ultimately result in it being revealed that a 5mg daily dose is safe, tolerable and effective. In particular 5mg/day is the minimum effective dose which is a standard value to investigate during dose ranging studies in phase IIb clinical trials.

The judge agreed with the Claimants that it would be obvious at the priority date to take tadalafil forward into a routine pre-clinical and clinical trial programme as an oral treatment for male erectile dysfunction at the priority date. However, following on from his detailed examination of the law on what constitutes ‘a reasonable expectation of success’ in the context of whether something is “obvious to try”, Birss J. held that the skilled team testing a 5mg/day dose of tadalafil “would not have a reasonable expectation that it would be useful for erectile dysfunction nor any expectation at all that the drug would produce a clinically relevant effect but with minimal side effects”.

In coming to this decision, the judge distinguished between, on the one hand, routine studies, where stepwise tests are carried out without any expectation of success, without any “value judgments” needing to be made along the way, and merely to obtain necessary results, and on the other hand, other stepwise inventions which do require “value judgments” by the skilled person as to whether or not to carry out particular testing. For example, starting from Daugan it would have been entirely routine to conduct pre-clinical studies to identify the physicochemical properties of tadalafil. The skilled person would not have been able accurately to predict the outcomes in advance, and the results might have been unexpected, but they would not have been inventive based on this alone. In contrast, on the facts of this case it would not have been routine to conduct a dose ranging study encompassing a dose of 5mg/day, and whilst it was, on the balance of probabilities, obvious to try such a study, there was no reasonable expectation that this would have been successful. The relevant claims of EP 181 were therefore found inventive.

EP 1,200,092 (“EP 092”)
Claim 1 of EP 092 was to tadalafil in a “free drug particulate form” where the tadalafil is in solid particles not immediately embedded in a polymeric co-precipitate and at least 90% of the particles have a particle size of less than about 40 microns. Also relevant are claims 8 and 9 which were to pharmaceutical compositions defined by reference to the pharmacokinetic parameters Cmax and AUC(0-24).

Anticipation by inevitable result
The Claimants pleaded that any claims of EP 092 not entitled to priority were anticipated by Oren. The judge found that claims 8 and 9 of EP 092 were not entitled to priority and therefore it was necessary to consider whether Oren provided an anticipatory enabling disclosure. Birss J. held that Oren taught the skilled person to make a formulation containing tadalafil where 90% of the particles had a diameter of 4 microns (d90 of 4 microns) and that an inevitable result of carrying out that teaching would be the Cmax and AUC values in claims 8 and 9. This was because, on the expert evidence, it was highly likely that the product taught in Oren would fall within claims 8 and 9, and on the balance of probabilities this was enough to establish anticipation by an inevitable result – the necessary standard of proof for establishing an inevitable result was not any higher.

A copy of the judgment can be found here.