Posted: December 7th, 2015
Actavis Group PTC EHF & Anor v Eli Lilly and Company, High Court of England and Wales (Carr J), London, UK, 16 November 2015, Neutral Citation Number:  EWHC 3294 (Pat)
This was an action by Actavis to “clear the way” in relation to atomoxetine, the first non-stimulant to be approved for the treatment of attention deficit/hyperactivity disorder (ADHD). Atomoxetine is marketed by Lilly under the brand name Strattera and is protected by a second medical use patent and SPC until May 2019.
Actavis argued that the patent was invalid for lack of inventive step and lack of plausibility, (which was argued both as an aspect of insufficiency and so-called Agrevo obviousness i.e. lack of technical contribution). Actavis also argued that the patent was not entitled to priority, in which case both parties agreed the patent would be invalid. Lilly counterclaimed for threatened infringement. Carr J found in Lilly’s favour on all counts; the patent was valid and Actavis had threatened to infringe.
The leading treatment for ADHD at the priority date was Ritalin, a central nervous system stimulant. Second line treatments included tricyclic antidepressants (TCAs). Alternative therapies suffered disadvantages: significant side effects or lack of therapeutic effect. As such, there was significant motivation to develop a new first and/or second line treatment, which was held to have existed for many years. This was a case in which there was a “long felt want” for a new treatment to be developed, notwithstanding that there had been an increased motivation in the lead up to the priority date following the sudden deaths of several patients being treated with TCAs.
There was a significant dispute about the common general knowledge of the skilled team, particularly surrounding what was known about the mechanism of action of the drugs associated with ADHD and the inferences which would be drawn from this knowledge. Actavis argued that although there was a degree of uncertainty concerning the pathophysiology of ADHD at the priority date, it was thought likely that TCAs were effective in the treatment of ADHD because of their role in norepinephrine re-uptake inhibition. Actavis further submitted that because drug development decisions could be made on the basis of the pharmacology of existing drugs, it would have been reasonable for the skilled team to expect another drug exhibiting the same acute pharmacological action to achieve similar therapeutic efficacy.
Lilly presented a more complex picture: although knowledge of the pharmacological actions of drugs would have been useful, it could not be assumed that because the mechanism of action of a drug had been identified, that this was the means by which it worked in ADHD. Furthermore, at the priority date there had been considerable uncertainty about the precise relationship between potentially relevant neurotransmitters and any particular psychiatric disorder.
Carr J agreed with Lilly’s characterisation of the CGK; although the skilled team would consider it reasonable that TCAs were effective in the treatment of ADHD as a result of selective norepinephrine re-uptake inhibition, they would ultimately be aware of the considerable complexity surrounding the contributory causes of ADHD including the possible role of other neurotransmitters and “downstream” factors.
These findings were of particular significance to Carr J’s assessment of inventive step. Actavis argued that this was a case in which the invention would have been obvious to try. The well-established test is whether the skilled team would have had a reasonable expectation of success (see e.g. MedImmune v Novartis  EWCA Civ 1234). The prior art citations, each of which was published more than ten years before the priority date, were reports of small scale clinical trials of atomoxetine as an anti-depressant which disclosed atomoxetine’s capacity for norepinephrine re-uptake inhibition. However, Carr J held that the nature of the clinical trials, including factors such as the limited number of patients involved, the lack of placebo control and the fact that the patients were suffering from depression rather than ADHD would not give the skilled team an expectation of success if they tried atomoxetine in ADHD; they would instead be embarking on a research project with an unpredictable outcome.
As is typical in cases involving patents for second medical uses of known drugs, Lilly faced a squeeze in relation to plausibility between insufficiency and obviousness. It was common ground that atomoxetine was not a well-known drug at the filing date. Furthermore, the patent did not contain in vivo data and claimed a broad range of doses. As such, Actavis argued that the patent amounted to no more than bald assertion. To the extent that the patent disclosed a theory or principle to support the assertion, it should be considered obvious in light of the prior art. Furthermore, Actavis argued that the test for plausibility in relation to sufficiency should mirror that for whether or not an invention is obvious to try i.e. the disclosure in the patent should give the skilled team a basis on which to reasonably expect that the treatment would be successful. Carr J disagreed: “the denial of patent protection based upon the “obvious to try” criterion alone would provide insufficient incentive for research and development in, for example, pharmaceuticals and biotechnology, and would lead to the conclusion that a research program of uncertain outcome would deprive a patent of inventive step. … [In the context of sufficiency] plausibility is only a threshold test. A plausible invention may nonetheless be shown to be insufficient. In my judgment the standard for assessment of plausibility is not the same [as] the standard for assessment of expectation of success in the context of obviousness.”
The test for plausibility in relation to sufficiency, as set out by the Court of Appeal in Regeneron ( EWCA Civ 93), is one of credibility and on the facts of the case, the disclosure of the mechanism of action supported by post-published evidence of therapeutic efficacy was enough to render the claim for atomoxetine as a treatment for ADHD plausible. Therefore, the insufficiency attack failed.
As a result of Carr J’s finding on plausibility, the attack on priority and Agrevo obviousness fell away. The counterclaim for threatened infringement succeeded.
Read the decision here.
Headnote: Steven Willis, Bristows LLP