New Patents Court judge Mr Justice Henry Carr has explained the tests for inventive step and insufficiency in his decision in a 'clearing the way' action brought by Actavis: Carr J found Eli Lilly's second medical use patent to tomoxetine for treating Attention deficit hyperactivity disorder (ADHD) both inventive and sufficient.
Carr J's decision in Actavis Group PTC EHF & Anr v Eli Lilly and Company  EWHC 3294 (Pat) (16 November 2015) sets out the judge's interpretation of the law on inventive step and insufficiency. Tackling aspects of the law which have appeared unsettled among the Patents Court judges, Carr J made some notable rulings:
- the 'invention' for the purposes of an obviousness challenge is to be defined by the scope of the claims, not by the level of experimental support provided in the specification
- in the context of insufficiency, 'plausibility' is only a threshold test; it is not the same as the standard for assessment of an expectation of success in the context of obviousness
Carr J said that it is the claimed invention that is to be assessed, not the 'invention' as defined by the data provided in the specification. Carr J referred to Conor v Angiotech and Medimmune v Novartis, and to commentary from Professor Sir Hugh Laddie on the "unworkable or irrational" obvious to try test. The consequence was that although supporting data were not provided in Lilly's specification, it was the claimed invention (i.e. efficacy in the treatment of ADHD), which was considered in the assessment of obviousness.
In finding that the patent was also sufficient, the judge tackled the question of whether the concept of plausibility in sufficiency is equivalent to the test for inventive step. He ruled that it is not; plausibility is merely a threshold test. So although Lilly's patent contained no supporting data the claimed invention, in light of the assertions contained in the specification and the references therein, was credible and therefore plausible.
Eli Lilly's European patent no. EP (UK) 721 777 (the Patent) claims (claim 1) the "[u]se of tomoxetine for the manufacture of a medicament for treating attention-deficit/hyperactivity disorder". (Tomoxetine is also known as 'atomoxetine'). This is a Swiss form second medical use type claim. The patent claims a priority date of 11 January 1995. Eli Lilly has obtained an SPC which expires on 26 May 2019. Its atomoxetine medicine for ADHD is marketed under the brand name "Strattera".
Actavis sought revocation of Lilly's patent, alleging that it was invalid for obviousness and insufficiency on the basis that the patent lacked plausibility and lacked technical contribution. Actavis also attacked the priority date of the patent on the basis of lack of plausibility of the document it claimed priority from. Lilly counterclaimed for threatened infringement. Actavis admitted that it had commenced the action in order to clear the way for launch of its generic product, which would otherwise infringe the patent.
The skilled team
There was a dispute as to the composition of the skilled team. The parties agreed that it would include a clinical child and adolescent psychiatrist with expertise in treating ADHD and who was interested in developing new treatments for ADHD at the priority date. The judge found that it would also include a 'basic' psychopharmacologist, but that the psychopharmacologist would need neither clinical experience nor experience in relation to ADHD.
Carr J noted as settled law that in a Swiss form claim, the claimed therapeutic effect is a functional technical feature of the claim (Regeneron v Genentech  EWCA Civ 93 and T 609/02 Salk Institute).
Further, in Warner-Lambert v Actavis EWCA Civ 556, Floyd LJ concluded that the word 'for' in such claims meant 'suitable and intended for' in the sense that such use was known or reasonably foreseeable by the manufacturer. Actavis contended that this requirement of intent would be important and the judge noted that he would return to it when considering validity.
The judge also noted that the words 'for treating ADHD' do not mean that the treatment has to be effective in every patient. This, he said, would never be the case for any medical use claim, as was clear from Aldous LJ's judgment in Bristol-Myers Squibb v Baker Norton  RPC 1 and Floyd J's judgment in Teva v Merck  FSR 17.
Inventive step - the law
Carr J began his assessment of inventive step with the refreshing question: "what must be obvious?"
In addressing this most fundamental of questions, the judge said that it is the claimed invention that is to be assessed, not the 'invention' as defined by the data provided in the specification; one must be careful not to confuse the two:
" It may appear that the answer to this question is so self evident that it is not worth asking. However, it is important not to become confused between the extent of disclosure of the specification and the invention specified in the claims. The appropriate question for the Court to ask itself is whether, in the light of the state of the art, the invention specified in the claims is obvious. A lack of focus on this question was the error of law of the lower courts identified by the House of Lords in Conor v Angiotech  RPC 28. In that case, the invention specified in claim 12 was a stent coated with taxol "for treating or preventing recurrent stenosis". It was argued that this was no more than an assertion, unsupported by experimental data. Lord Hoffman stated at :
"...the invention is the product specified in a claim and the patentee is entitled to have the question of obviousness determined by reference to his claim and not to some vague paraphrase based upon the extent of his disclosure in the description. There is no requirement in the EPC or the statute that the specification must demonstrate by experiment that the invention will work or explain why it will work. As the Dutch court said (at paragraph 4.17):
"... it is not required in the view of the court that experimental data concerning such use of taxol stents in humans and the actual prevention of restenosis be included in the patent to further substantiate [the claim]." "
 Of course, the extent of disclosure of the specification, and the absence of experimental data, is a matter of relevance to the plausibility of the Patent for the claimed therapeutic purpose. However, when considering the cited prior art, the correct question is whether the alleged invention defined in the claim was obvious."
Carr J also had some things to say on the obvious to try doctrine. He referred to Lord Walker's comments in Conor v Angiotech  RPC 28 that, in the forty plus years since Johns-Manville was decided, the volume of, and resources committed to, high tech research had increased enormously. In this context, the judge noted the potential difficulty that may be caused by a mechanistic application of the "obvious to try" approach.
The judge also referred to commentary by Sir Hugh Laddie that the test is "on its face...an unworkable or irrational test". The concern is that the higher the reward one stands to get from a patent, the further the skilled team would be prepared to go to try to achieve the invention and therefore the more likely it was obvious. This "Catch 22" problem, as the judge phrased it, was also referred to by Jacob LJ in the Court of Appeal in Conor v Angiotech ( RPC 20).
Inventive step - assessment
Two challenges of lack of inventive step were made, one based on 'Chouinard' combined with 'Wong', the other based on 'Zerbe' combined with 'Wong'. Carr J accepted the combinations.
Wong described a new racemic molecule as being a competitive, and selective, inhibitor for noradrenaline (NE) uptake in the rat hypothalamus, and as having potential as an antidepressant. The (-) isomer, LY139603 (atomoxetine), was said to be more effective than the racemate or the (+) isomer. All were weak inhibitors of dopamine and serotonin uptake. These NE reuptake inhibitor effects were said to be mirrored in vivo.
Chouinard described an open-label early phase II clinical trial of atomoxetine in the treatment of ten depressed patients over a period of six weeks.
Applying the Pozzoli approach, Carr J noted that the difference between Chouinard and claim 1 of the patent was that there was no suggestion in Chouinard to use atomoxetine in the manufacture of a medicament for the treatment of ADHD.
Actavis' challenge was essentially that there was precedent for using antidepressant drugs, and in particular the TCAs, as a second line of treatment for ADHD. There was a need to replace TCAs (which had been linked with some deaths) and therefore a motivation to try an alternative. Chouinard disclosed that atomoxetine is a selective NE reuptake inhibitor, its disclosure being supported by Wong and credible. The authors of Chouinard were encouraging about the likely efficacy of atomoxetine in treating depression and in the possible avoidance of unwanted side effects as a result of its selectivity. It would be relatively straightforward to perform a basic phase II trial on adults to test atomoxetine in ADHD patients.
Carr J noted an "attractive simplicity" to these arguments but found that they were not supported by the evidence before the court. It was the evidence of Lilly's clinical psychiatrist expert (Professor Hill) that Chouinard would not have been regarded as having any relevance to ADHD and the cross-examination of Actavis' expert witnesses supported this.
It was not therefore obvious to try atomoxetine in the treatment of ADHD on the basis of Chouinard.
Zerbe described the administration of atomoxetine to a small number of healthy human volunteers - i.e. a phase I trial. The authors concluded that atomoxetine is a selective NE reuptake inhibitor at doses which are well tolerated and that it has potential use as an antidepressant.
Again, the evidence of Lilly's clinical psychiatrist (Professor Hill) was that there was nothing in Zerbe that would have been seen as relevant to the treatment of ADHD. Even Actavis' clinical psychiatrist believed that one could draw no conclusions about therapeutic effect in ADHD from Zerbe.
Carr J therefore concluded that the patent was not obvious in light of Zerbe. He also noted that Zerbe had been published ten years before the priority date. Nevertheless, atomoxetine had not gained regulatory approval for depression. In view of these factors, if it was obvious to progress Zerbe further, then this would only be as an antidepressant, not as a drug for the treatment of ADHD.
No fair expectation of success
Carr J also found that, even if it had been obvious at the priority date, either from Chouinard or Zerbe, to try atomoxetine for ADHD, the skilled team would not have had a "fair expectation that this drug would be discernibly effective in such treatment".
The judge explained that the skilled clinician would have considered that the hypothesis that TCAs had efficacy in the treatment of ADHD as a result of selective inhibition of NE reuptake to be a reasonable one. This would lend some support to the idea of trying atomoxetine in ADHD. However, the skilled clinician would also consider the position in relation to ADHD was likely to be more complex, and that a number of other contributory causes were possible. Against this background of uncertainty, the skilled person team would not have had a fair expectation that atomoxetine would be effective in the treatment of ADHD. Carr J noted that again, the oral evidence of Actavis' expert clinician, Dr Steingard, supported this - his comments being "more indicative of an interesting project with uncertain results than of a fair expectation of success".
Sufficiency - the law
Carr J noted that for the purposes of obviousness, the skilled person should be able to make a fair prediction that the alleged invention "will, not might, succeed". Is the same true in relation to sufficiency, or is the standard of plausibility different?
Actavis contended, essentially, that the tests are the same, citing Regeneron and T 609/02 Salk.
Lilly contended that the tests are different. Essentially, Lilly argued that plausibility, in the context of sufficiency, is merely a threshold test restraining excessively broad claim scope, and that it is irrelevant if the invention can, in fact, be performed across the scope of the claim. Lilly relied upon the House of Lords' decision in Conor v Angiotech, the Supreme Court's decision in HGS v Eli Lilly  UKSC 51 and Zymogenetics T 898/05.
The judge rejected Lilly's submission that, in circumstances where an invention can be put into practice, and does in fact work, the imposition of a test for plausibility would be contrary to TRIPS, the EPC or the Patents Act 1977. He said that plausibility has been referred to by courts at the highest level as one factor that should be taken into account in the assessment of industrial application, sufficiency and inventive step, which are all parts of the requirements of the relevant treaties and legislation. However, one must bear in mind that plausibility is not itself an objection to the validity of a patent.
Carr J's conclusion was that the standard for assessment of plausibility is not the same as the standard for assessment of expectation of success in the context of obviousness:
" In my judgment, the policy considerations underlying plausibility for sufficiency are different from those underlying fair expectation of success for obviousness, which indicates that the standard for assessment of plausibility is not the same as assessment of obviousness. For obviousness, a fair expectation of success is required because, in an empirical art, many routes may be obvious to try, without any real idea of whether they will work. 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. The reason why the court requires that the invention of a patent should be plausible is different. It is to exclude speculative patents, based on mere assertion, where there is no real reason to suppose that the assertion is true.
 The cases on which Lilly relies (to which I have referred above) establish that the test of plausibility is a threshold test which is satisfied by a disclosure which is "credible", as opposed to speculative. That disclosure may subsequently be confirmed or refuted by further evidence obtained subsequent to the priority date. If it is subsequently shown that the invention does not work with substantially all of the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution and the patent will be invalid. This indicates why 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."
Sufficiency - assessment
The specification of the patent referred to a paper ('Gehlert'), which the skilled person would read. The skilled person would also read Wong. These papers, said Carr J, would lend support to the statement in the patent's specification that atomoxetine is a selective NE inhibitor.
The specification asserted inter alia that tomoxetine is a safe drug and that its use in ADHD, in both adults and children, is a superior treatment compared with TCAs because of its improved safety. Further, tomoxetine is asserted as being effective at relatively low doses, with effective dose ranges given. No data were provided in the specification in support of the statements to efficacy.
On the evidence before the court, the judge had already concluded that at the priority date, the skilled clinician would have considered that the hypothesis that the TCAs had efficacy in the treatment of ADHD as a result of selective inhibition of NE reuptake was reasonable. It was also reasonable that selectivity would reduce side effects. The position in relation to ADHD would be considered to be more complex than for depression but, said the judge, the skilled person would consider that the invention of the patent was credible, based upon the specification and the common general knowledge. The evidence of Actavis' own experts supported this.
Further, post-published evidence concerning the widespread administration of atomoxetine to ADHD patients had confirmed the disclosure of the patent that it is safe and efficacious for the treatment of this disorder. This was admissible, and important, evidence.
Hence the patent was plausible.
Actavis' challenge of insufficiency in respect of different patient groups also failed. The judge said that there was no reason to think that atomoxetine would be effective to treat ADHD in children and not adults, or vice versa.
Actavis' challenges to priority and of Agrevo obviousness fell with the judge's finding that the patent was plausible.
In the present case, cross examination of the expert witnesses was key to the judge's findings of fact. While Actavis' experts' written evidence supported Actavis' case, the testimony did not bear the scrutiny of cross examination. Carr J did not criticise the witnesses in this regard. He simply said:
"Witnesses often express their views more accurately in the witness box than in written reports, which are carefully scrutinised by lawyers."
In an interesting development, Carr J also noted that Actavis' expert witnesses had made a fundamental error in that they had had a mistaken belief that the patent was an authoritative document. Plainly it was not, and statements made in the patent may well not be supported by evidence when scrutinised. However, the evidence before the court established that if the skilled team had assumed that supporting trials had not been carried out, they would nevertheless have considered the invention plausible.
Lilly's counterclaim for threatened infringement succeeded, Actavis having admitted that it intended to launch in the UK a generic atomoxetine product for the treatment of ADHD before the expiry of Lilly's SPC.
Carr J's conclusions on the law regarding inventive step and sufficiency in Actavis v Lilly offer some welcome clarification.
First, Carr J said that the 'invention' for the purposes of the obviousness challenge is to be defined by the scope of the claims, not by the level of experimental support provided in the specification.
Second, Carr J said that in the context of insufficiency, 'plausibility' is only a threshold test; it is not the same as the standard for assessment of an expectation of success in the context of obviousness.
Upon the evidence before the court, Lilly's position on critical facts was supported whereas Actavis' position was not. Despite this, it would appear to have been the judge's findings on the law which proved critical for the outcome between the parties:
- On obviousness, the judge's conclusions on the law meant that the invention was defined according to the functional technical feature of therapeutic efficacy, not in accordance with the level of supporting data contained in the specification. It was not obvious that that claimed invention (tomoxetine in ADHD) would work, nor would the skilled person have had a 'fair expectation of success'. So the patent was inventive
- On sufficiency, the judge's conclusions on the law meant that the claimed invention was credible and therefore plausible, despite supporting data not being provided. So the patent was not insufficient
Had the judge assessed inventive step by reference to the technical contribution made by the specification, Actavis would seem more likely to have succeeded in its obviousness challenge. Had the judge considered the concept of plausibility to equate to the test for 'fair expectation of success', an obviousness/insufficiency squeeze would seem to come into play - with Actavis succeeding on insufficiency.
Carr J's decision in Actavis v Eli Lilly is the latest in a series of pharmaceutical patent cases in which inventive step and sufficiency have been in issue. Others include Merck v Ono (Birss J, 22 October 2015) and Warner-Lambert v Actavis (10 September 2015). In the Warner-Lambert case an appeal is pending on the question of sufficiency but not, apparently, on inventive step.
In view of Carr J's recent decision, it is to be expected that the Court of Appeal will be asked to rule on the law of both inventive step and sufficiency/plausibility, if not in the Actavis v Eli Lilly case then in the course of time. Nevertheless, Carr J's judgment may justifiably be considered as a positive development for all innovative industries.