ACTAVIS GROUP PTC EHF v ELI LILLY AND COMPANY

[2016] R.P.C. 12 499 ACTAVIS GROUP PTC EHF v ELI LILLY AND COMPANY PATENTS COURT Carr J.: 6 - 9, 13 and 14 October and 16 November 2015 Patents – Validity – Construction – Medicament for treating ADHD – Swiss form claims – Skilled team – Common general knowledge – Hindsight – Construction – Obviousness – Obvious to try – Fair expectation of success – Insufficiency – Lack of technical contribution – Plausibility – Whether requirement of plausibility required reasonable expectation the drug would work – Whether requirement of plausibility limited to claims of wide scope – Policy considerations – Agrevo obviousness – Priority. H1 This was the trial of an action for revocation of European Patent (UK) No. 0,721,777 (“the Patent”) brought by the claimants, Actavis Group PTC EHF and Actavis (UK) Limited (“Actavis”) with a view to clearing the path for the proposed launch of a generic product which might otherwise infringe. The defendant, Eli Lilly and Company (“Lilly”) was the registered proprietor of the Patent and counterclaimed for threatened infringement. The Patent (which was the subject of a Supplementary Protection Certificate (“SPC”)) had a claimed priority date of 11 January 1995 and concerned a second medical use of atomoxetine (also known as tomoxetine). Claim 1 was in the following terms: “Use of tomoxetine for the manufacture of a medicament for treating attentiondeficit/hyperactivity disorder.” H2 H3 The validity of the Patent was attacked on grounds of lack of inventive step, insufficiency (on the basis of lack of plausibility) and Agrevo obviousness (lack of technical contribution) and there was also a challenge to the claim to priority. It was accepted that the Patent was invalid over intervening prior art if priority was lost. Actavis also ran an obviousness/plausibility “squeeze” argument, alleging that the Patent disclosed no more than a bald assertion that atomoxetine was effective and safe for the treatment of ADHD and that, insofar as the Patent disclosed a theory or principle to support that assertion, that principle was known from the prior art. If the skilled person was unconvinced by the prior art, they would be equally unconvinced by the Patent. Lilly argued that the prior art gave no hint that atomoxetine could be used to treat ADHD. Further, there was no dispute that the commercial embodiment of the Patent, STRATTERA, was a valuable drug in the treatment of ADHD (annual sales in the UK exceeded £10 million), and Lilly argued that this was itself a complete answer to the attacks of insufficiency, Agrevo obviousness and lack of entitlement to priority, which all stood or fell together. It was common ground that the Patent was addressed to a team including a (child and adolescent) psychiatrist with expertise in treating ADHD and a research interest in ADHD, who was interested in the development of new treatments at the priority date. [2016] R.P.C., Issue 7 ß Crown Copyright [2015] EWHC 3294 (Pat), [2016] R.P.C. 12 500 H3 H5 However, there was a dispute as to (i) whether the skilled team would also have included a psychopharmacologist, (ii) if so, whether such person would have been a “basic” or “clinical” psychopharmacologist, and (iii) which member of the team would have taken the leading role. As to common general knowledge, it would appear to have been common ground that, as at the priority date, stimulants had been the first line of treatment for many years but that alternatives including tricyclic antidepressants (“TCAs”) and clonidine (an anti-hypertensive) had been used where stimulants were ineffective or contraindicated. The use of TCAs was known to give rise to a number of problems, namely (a) they were not as efficacious as stimulants, (b) they had a number of unwanted side effects, (c) they were associated with serious cardiac toxicity issues when taken in overdose, and (d) there had been a number of sudden deaths in children taking therapeutic doses of desipramine in the early 1990s. The use of clonidine and other antipsychotics also had drawbacks which were well known. Actavis contended that in the circumstances there was a strong motivation to develop alternative treatments. However, Lilly argued that there was a long felt want for alternatives which was not satisfied until the launch of STRATTERA (which took place in the USA in 2002 and in the UK in 2004). There was a question as to whether there were any relevant differences in common general knowledge as between the UK and the USA as at January 1995. Moreover, there was an issue as to the state of common general knowledge as to the role of neutrotransmitters in ADHD as at the relevant date. Actavis contended that the acute pharmacological action of norepinephrine (“NE”) reuptake inhibition (i.e the inhibition of the process by which the neurotransmitter was taken back up into the presynaptic neuron) was thought to be likely to be responsible for the therapeutic effect of TCAs in ADHD (in the sense of being the initial trigger for that therapeutic effect). Documentary evidence was relied upon as illustrative of this proposition including statements in a chapter by a Dr Shenker in the 1992 edition of Advances in Paediatrics (“Shenker”). Actavis argued that another drug which had that acute pharmacological action would have been expected to result in similar therapeutic efficacy. Lilly submitted, inter alia, that little was known about the role of neurotransmitters in ADHD as at the relevant date and that such information as was common general knowledge pointed away from a simple choice of a selective NE reuptake inhibitor as an alternative to TCAs. The attack on grounds of lack of inventive step was based on prior art publications referred to as “Choinard” and “Zerbe”. Choinard was a “rapid communication” published in the journal Psychopharmacology in 1984 and describing an open-label early phase II clinical trial of atomoxetine in the treatment of ten adults with depression over a six week period. The trial had not involved placebo controls and assessment had been based on clinical interviews conducted by any one of four psychiatrists. Actavis argued that Choinard disclosed that atomoxetine was a selective NE uptake inhibitor. Zerbe was a paper published in 1985 in The Journal of Pharmacology and Experimental Therapeutics and entitled “Clinical Pharmacology of Tomoxetine, a Potential Antidepressant” and described a phase 1 trial in which atomoxetine had been administered to a small number of health volunteers twice a week and the effect of administrating NE, and tyramine (which released NE), on blood pressure was monitored, as well as serotonin uptake. The authors of Zerbe had concluded that atomoxetine was a selective NE reuptake inhibitor with potential use as an antidepressant. Actavis argued, inter alia, that it would have been obvious in the light of Choinard and/or Zerbe to try atomoxetine in the Published by Oxford University Press for the Intellectual Propert (...truncated)