The UK Supreme Court has upheld the Court of Appeal’s decision that ICOS’s dosage regime patent for tadalafil lacked an inventive step.
Tadalafil is marketed under the brand name Cialis® for the treatment of erectile dysfunction (ED): a competitor to Pfizer’s blockbuster drug sildenafil (Viagra®). The original patent for tadalafil (EP0740668, “Daugan”) disclosed the idea of using certain compounds which are PDE5 inhibitors for the treatment of erectile dysfunction. It specifically described two compounds, one of which was tadalafil, suggesting that doses would generally be in the range of 0.5mg to 800mg daily for the average adult patient. A tablet containing 50mg of the active ingredient was the only specific example given.
ICOS’s dosage regime patent (EP1173181 – “the 181 Patent”) claimed the use of tadalafil up to a maximum dose of just 5mg per day – near the bottom end of the range disclosed in Daugan and much less than the example given in that patent – for the treatment of ED. The patent also disclosed that tadalafil is effective in treating ED at a low 5mg dose, so it can be administered chronically (i.e. taken daily) rather than on demand, and has minimal side effects – a significant advantage over sildenafil, which is approved for on-demand use only and marketed at much higher doses (25mg, 50mg and 100mg).
Actavis began revocation proceedings against the 181 Patent (later combined with proceedings brought by Teva UK Limited and Teva Pharmaceuticals Industries Limited and Generics (UK) Limited) to “clear the way” to market their own generic tadalafil product. ICOS and its exclusive licensee, Eli Lilly and Company, counterclaimed for infringement.
Clearly, the potential for tadalafil to rival sildenafil as an oral PDE5 inhibitor was evident from the Daugan patent, and there was no dispute that at the priority date it was entirely obvious to take tadalafil forward into a routine pre-clinical and clinical trial programme. The question central to the proceedings was whether, in light of Daugan and the common general knowledge, the claims of the 181 Patent were obvious.
Confirming the Court of Appeal’s decision, the Supreme Court held that the claimed low dose of tadalafil was the result of a familiar and routine path of pre-clinical and clinical research, in which each step was likely to follow the outcome of the prior step. The Court reasoned that the target of the skilled person in implementing Daugan would be to ascertain the appropriate dose. Having embarked on Phase IIb dose ranging studies and identified a therapeutic plateau at doses of 10mg and above, the skilled person would very likely test a 5mg dose given that the aim of the dose ranging study is to identify a dose as low as possible consistent with effectiveness.
Neither the fact that the effectiveness of tadalafil at a dose of 5mg was a surprise nor that there was an important value judgement to make when the therapeutic plateau was identified were considered to carry any weight. Since it was found to be “very likely” that the skilled team would continue testing, those discoveries were considered to be the product of a routine trial programme, and the unexpected reduced side effects of the 5mg dose were just a bonus effect which did not make the 5mg dose unobvious.
Hence, the Court’s position was that the skilled person aims for a dose as low as possible consistent with effectiveness. If, as is often the case, this is the appropriate dosage regime, then it is an obvious one, even if it is surprising and has beneficial effects that could not have been predicted.
Does this mean that all dosage regime patents will be found invalid in the UK, because the specified dosing would have been discovered following the standard pathway of required pre-clinical and clinical studies? Not necessarily. The Court stressed that the product of well-established or routine enquiries may in some circumstances still be inventive.
However, it seems likely that dosage patents which claim the product of multiple non-inventive steps, previously deemed inventive because the invention was not directly obtainable from the closest prior art, are now more likely to be considered obvious and therefore invalid.
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