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Thursday, 24 December 2015

Mr Justice Carr tackles plausibility in Actavis v Lilly ADHD dispute (Part I)

The AmeriKat was distracted
by her 34,000 feet view only a few
 times while reading Mr Justice Carr's
first decision in the Patents Court
Flying to New England Saturday afternoon after a typically busy end of term, the Amerikat could be found snuggled into her window seat devouring judgments that her term-time schedule just would not permit. At the top of her giant stack was the first decision of the brand spanking new specialist Patents Court judge, Mr Justice Carr.  Although the AmeriKat will miss hearing about his latest advocacy adventures and having the opportunity to marvel at how quickly he can assimilate hundreds of pages of expert reports in consultation, she is looking forward to digesting and reporting on Mr Justice Carr's IP judgments for years to come.  And indeed, his decision in Actavis v Eli Lilly [2015] EWHC has not let her down.  So to ensure that the IPKat's dear readers can maximize their time with their families this holiday season, the AmeriKat has summarized the highlights of almost 50 pages of eloquent Carr J prose below.

The commercial picture

It’s a story as old as time. Innovator has a patent for a big product. Generic wants to sell its version of the product. Generic needs to clear a path. Such was the story in Actavis v Lilly. The product at issue was Lilly’s atomoxetine product, sold under the brand name Strattera, which treats ADHD. Strattera was the first non-stimulant approved by the FDA to treat ADHD. In the UK, its sales are in excess of £10 million a year. The product is protected by Lilly’s patent, EP (UK) 0 721 777 (“the Patent”) and a SPC. Actavis stated that it intends to launch its generic product before the expiry of the SPC and therefore brought revocation proceedings to clear the way. Actavis claimed that the Patent lacked:
• an inventive step over two prior art citations;
• plausibility and is therefore insufficient or obvious on the basis it lacked technical contribution. Actavis argued that the Patent made no more than a bald assertion; and
• priority, given the lack of plausibility in the priority document (if property lost Lilly accepted the Patent would be invalid by virtue of intervening prior art).
The skilled addressee

In identifying the skilled addressee, Mr Justice Carr referred to the principles in Catnic v Hill & Smith and Schlumberger [2010] EWCA Civ 819 which stated that the skilled addressee are persons who:
• are likely to have a practical interest in the subject matter;
• have practical knowledge and experience of the kind of work which the invention is intended to be used and experience of that kind of work; and
• whose composition and mind set is founded in reality.
In this case, the skilled person included a clinician (with particular expertise in treating, research in and developing new treatments for ADHD) and a psychopharmacologist. The inclusion of the psychopharmacologist was disputed by the parties (Actavis for/Lilly against). Mr Justice Carr held that because the Patent cited papers that were addressed to a psychopharmacologist and Lilly’s own expert said he would have welcomed such an expert “with open arms”, that was the end of the matter. However, Carr J accepted that the pyschopharmacologist would not have the required knowledge or clinical expertise of ADHD at the priority date.

The common general knowledge

Applying the principles set out in KCI Licensing v Smith & Nephew [2010] EWHC 1487, the judge held that stimulants (e.g. Ritalin) were the “gold standard” in the treatment of ADHD.  However, they had limited duration, requiring multiple dosing with undesirable side effects. Parents were also cautious in their children receiving a controlled substance associated with amphetamine. Second line therapies included tricyclic antidepressants (TCAs) and clonidine. TCAs were well established and effective in ADHD, acting more quickly. However, they were not as effective as stimulants and also carried with them unwanted side effects, including unverified links to a number of sudden deaths in the early 1990s which made clinicians cautious. In light of this, Actavis argued that there was strong motivation to develop alternative treatments at the priority date. Lilly accepted there was a long felt want for alternatives, but none of them had been satisfied until Strattera was launched. Lilly therefore asked the age old patentee question: If it was obvious, why was it not done before?

Mr Justice Carr held that although there was motivation to develop alternative second line treatments to TCAs, it was not as strong as the desire to find alternative stimulants. The motivation to find alternatives to TCAs had existed for many years given the long-standing known drawbacks, but there had been little advance at the priority date.

Mr Justice Carr 
Continuing on, the judge held that pathophysiology (the underlying cause of the symptoms) of ADHD was not well understood, but the emerging view was that ADHD was fundamentally a deficit of impulse control and planning. Actavis argued that it was known that of the neurotransmitters relevant in ADHD, the reuptake blocking of noradrenaline or norepinephrine (“NE”) (where the neurotransmitter is stopped from going back up into the presynaptic neuron causing increased levels of NE in the synapse) was the trigger responsible for therapeutic efficacy of the TCAs in the treatment of ADHD. Therefore, another drug that had this acute pharmacological action would have been expected to result in similar therapeutic efficacy (irrespective of the exact link between the two not being well understood).

Lilly accepted that the idea of NE reuptake inhibition action was a possible explanation of clinical efficacy at the priority date, but it was viewed with scepticism. Further, Actavis’s expert Professor Cowen accepted that there were drugs that were known to affect NE pathways but were not thought to be effective in ADHD. He therefore narrowed his view as expressed in his written report as to how far one could extrapolate NE functionality to therapeutic activity in ADHD.  In cross-examination he accepted there was considerable uncertainty about the precise relationship between potentially relevant neurotransmitters and any particular psychiatric disorder. The contemporaneous literature supported this view in being equivocal as to whether clinical efficacy came from an increase or decrease of NE and whether targeting NE alone would achieve ADHD improvement.

Mr Justice Carr held that the pharmacologist would have knowledge of TCAs as antidepressants and that the action was most likely a result form selective inhibition of NE. However, he or she would have no knowledge of ADHD and would defer to the clinician as to what inferences could be drawn. The skilled clinician would consider that the hypothesis that TCAs had efficacy in the treatment of ADHD as a result of the selective inhibition of NE re-uptake to be reasonable. However, he would consider the position with ADHD to be far more complex. He would not know whether it was desirable to increase or decrease NE in the treatment of ADHD. Actavis’s view of the common general knowledge was essentially, hindsight reasoning. The judge further held that increased selectivity of psychoactive agents would result in less side effects. However, without knowledge of which neurotransmitter(s) are on or off-target, selectivity alone does not provide a clear way forward.

The Patent’s description

The key idea of the Patent – the use of atomoxetine for the manufacture of a medicament for the treatment of ADHD – was introduced at [0001] of the Patent. Atomoxetine is introduced at [0008] as a “well known drug”. It was common ground that this statement was inaccurate as atomoxetine had not obtained regulatory approval for the any condition at the priority date. That paragraph also cites a 1993 paper by Gehlert in Neuroscience Letters which states that the drug is active as a NE reuptake inhibitor and is free from side effects given its selectivity. Lilly argued, and the judge accepted, that the skilled psychopharmacologist would read the Wong citation referenced in Gehlert because Professor Wong was well known in the field; the title of the paper would attract interest and was the only paper that referred to atomoxetine (this is relevant later). The next paragraph states:
“Atomoxetine is a notably safe drug, and its use in ADHD, in both adults and children, is a superior treatment for that disorder because of its improved safety. Further, atomoxetine is effective at relatively low doses, as discussed below, and may safely and effectively be administered once a day. Thus difficulties cause by multiple dosing of patients, particularly children and disorganised adults, are completely avoided.”
This, continued the judge, would be understood to mean that atomoxetine is safer than stimulants and TCAs. However, there was no data provided to support the assertions of safety and efficacy, either at low doses, once a day or at all.

The next two paragraphs provided effective doses in the range of 5mg/day to 100 mg/day, with the most preferred being 20-60mg/day for adults and 10-50 mg/day for children and stated that oral administration was most preferred. Lilly argued that the dose ranges would suggest to the skilled clinician that the drug has been tested in humans. The judge disagreed stating that the ranges were very wide and there was nothing to suggest there was anything unusual about the ranges.

The final paragraphs of the description relate to diagnostic criteria, factors relating to adult ADHD, statements that atomoxetine is effective where there are other disorders in play and is effective in both children and adults. However, there was no data to support the statements of efficacy.

It is all about the reuptake inhibition...or is it?
The Patent's claims

Claim 1 of the Patent is in Swiss form and claims:
“use of tomoxetine for the manufacture of a medicament for treating attention-deficit/hyperactivity disorder.”
Dependent claims 2-4 specify the patient group being an adult, adolescent or a child respectively. In light of Regeneron v Genentech [2013] EWCA 93 and T 609/02 Salk Institute, the judge held that it was settled law that attaining the claimed therapeutic effect is a functional technical feature of the claim. Further, the words “for treating attention deficit/hyperactivity disorder” does not mean that the treatment has to always be successful. For a second medical use claim, what is required that the use is discernibly effective, not that it has to cure all patients (see Teva v Merck [2010] FSR 17).

The law on obviousness

Mr Justice Carr recapped the value of the structured approach in Pozzoli [2007] FSR 37, the additional explanation of principle of the fourth question in Pozzoli in Generics v Lundbeck [2008] EWCA Civ 311 (i.e. the question of obviousness must be considered on the facts of each case, including the motivation to find a solution) and the warning in Technograph [1972] that ex post facto step by step analysis of inventions is to be avoided. The judge added another case to his assessment – that of Ultraframe v Eurocell [2005].  In that case Lord Justice Jacob was considering the issue of claim construction and what the skilled addressee would have understood the claim language to mean. In that decision, Jacob LJ stated that the court needed to get into the mindset, including the knowledge and attitudes, of the skilled team. The judge held that this approach should be equally applied to the assessment of obviousness and is particularly important where the priority date is over two decades before trial when “so much has changed in the state of knowledge in the relevant field and where it is now known that atomoxetine has proved successful in the treatment of ADHD.”

Wise words for any patent
Mr Justice Carr also cautioned against overstating the invention. The question of obviousness concerns the invention specified in the claims, not the invention or extent of disclosure in the specification. To hold otherwise is an error of law made by the lower courts as recognized by the House of Lords in Conor v Angiotech [2008] RPC 28. Although the extent of disclosure of the specification and the absence of experimental data is a matter of relevance to the plausibility of a patent for a claimed therapeutic purpose, this is not the question faced by the court when assessing obviousness.

If it is obvious to the skilled team to try atomoxetine for the claimed therapeutic use, the question is then how optimistic of success it must have been in order for the Patent to lack an inventive step? The judge reiterated the passage on “obvious to try” in Omnipharm v Merial [2011] EWHC 3393 which stated that the test depends on a variety of factors, including whether there was a fair expectation of success based on those factors. In the research-intensive life sciences field, there are particular policy issues which must also be considered. In particular, because there are often numerous avenues to pursue, any particular route that is chosen will be because there is at least some level of hope that it will be worthwhile. This does not mean that such a route is automatically obvious - there has to be an expectation, not just a hope, of success.  To hold otherwise would “deny patent protection in all such cases" and "would act as a significant deterrent to research.” These policy considerations were set out in Medimmune v Novartis [2012] EWCA Civ 1234 and Conor.

The prior art

As stated above, Actavis pursued their obviousness attack via two pieces of prior art – Chouinard and Zerbe. Both pieces of prior art were argued by Actavis to be read along side Wong – the judge agreed. The disclosures were as follows:
• Chouinard is a 1984 rapid communication published in the journal Psychopharmacology which described an open label early phase II clinical trial of atomoxetine for the treatment of ten depressed patients. It states that atomoxetine is a selective inhibitor of NE, citing Wong in support.
• Zerbe is a 1985 paper published in the journal of Pharmacology and Experimental Therapeutics entitled “Clinical Pharmacology of Tomoxetine, a Potential Antidepressant” which describes an early phase I trial. It states that atomoxetine inhibits NE and, again, cites Wong on a number of occasions to support statements that the drug has specific activity as a NE reuptake inhibitor. It concludes that the clinical data indicate that it was safe at all doses, inhibits NE uptake and further clinical trials to investigate it efficacy are warranted. 
 • Wong is a 1982 paper published in the same journal as Zerb entitled “A new Inhibitor of Norepinephrine Uptake Devoid of Affinity for Receptors in Rat Brain” and describes atomoxetine as being a “remarkably specific inhibitor” of NE uptake with potential as an antidepressant. This view is supported by in vitro and in vivo data from studies on rats. It states that although it is “too early to predict whether atomoxetine would be efficacious as an antidepressant, nisoxetine has been found to be effective among a sizable number of depressed patients (unpublished observations).”
Obviousness in light of the prior art

Applying the Pozzoli approach, the difference between Chouinard and Claim 1 of the Patent is that there is no suggestion in Chouinard to use atomoxetine in the manufacture of a medicament for the treatment of ADHD. Would this difference have been obvious in 1995? The judge held that it was not. The Chouinard trial was open-label and therefore not placebo controlled. That means that the assessment of symptoms was based on clinical interviews which introduced variability and bias. Further, the study was on patients with depression, not ADHD, and the side effects described did not provide any information relevant for treating ADHD (e.g., reduced inattentiveness, impulsiveness or overactivity).  Actavis’s experts were equally unenthusiastic about Chouinard and that the disclosure should be treated with a high degree of caution because of the absence of a placebo control. If Chouinard was progressed at all it would be as a phase II trial for depression.

It is more than plausible that
Lilly will be seeing the Court of Appeal
very soon on the issue of plausibility
In relation to Zerbe, an earlier citation, the judge also held that it was not obvious to try atomoxetine for the treatment of ADHD. Lilly’s expert, Professor Hill, observed that the focus of the paper was use of atomoxetine as a potential antidepressant – there was nothing in Zerbe about its use in ADHD or ADHD in general. No conclusions could be drawn about the therapeutic effect in ADHD from Zerbe. Further, the skilled team would have been aware that atomoxetine had not gained regulatory approval for depression. If it was obvious to progress Zerbe further, it would have only been as an antidepressant and not as a new drug for the treatment of ADHD.

Even had it been obvious at the priority date to try atomoxetine for the treatment of ADHD, Mr Justice Carr held that the skilled team would have not had a fair expectation that the drug would be discernibly effective in the treatment of ADHD. This was because Chouinard and Zerbe were both early phase studies with limited numbers of patients, no placebo control and targeted towards depression, rather than ADHD. The use of atomoxetine for the treatment of ADHD would have been an interesting research project, the outcome of which would have been uncertain. Although the judge held that the common general knowledge was that it was reasonable to consider that TCAs were effective in the treatment of ADHD as a result of selective inhibition of NE reuptake, the position was more complex. In particular, it was uncertain whether the efficacy was due to the increase or decrease of NE or whether other neurotransmitters were implicated. Against this background of uncertainty, the skilled team would have not had a fair expectation that atomoxetine would be effective in the treatment of ADHD.

Continued in Part II.

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