Actavis Group PTC EHF & Anor v Eli Lilly and Company

[0001] introduces the key idea of the Patent – the use of atomoxetine for the manufacture of a medicament for the treatment of ADHD. The background to the alleged invention begins at [0002]. The recognition of ADHD as a disease is described in general terms. The specification then refers to the successful use of methylphenidate (Ritalin) to treat ADHD, but emphasises some disadvantages – the requirement to dose several times a day, the possibility of rebound and the side effects of sleeplessness and loss of appetite. Ritalin is referred to as having both noradrenergic and dopaminergic activities.

[0003] refers to the use of TCAs to treat ADHD but states that they have multiple physiological mechanisms and refers to adverse side effects requiring careful supervision. The disadvantages of TCAs were, as I have found, common general knowledge. [0004] explains that the disorder has been recognised in adults. [0005] explains that a safe and convenient treatment for children and adults is desirable, without the disadvantages of methylphenidate.

[0008] introduces atomoxetine, and is of some importance. It describes atomoxetine as “a well known drug”. It was common ground that this statement was inaccurate. Atomoxetine had not received regulatory approval for the treatment of any condition at the priority date, and none of the experts were familiar with it. The paragraph cites a 1993 paper by Gehlert et al. in Neuroscience Letters “for a discussion of the mechanism of tomoxetine’s activity as a norepinephrine reuptake inhibitor”. It then continues:

“Tomoxetine is quite active in that function, and moreover is substantially free of other CNS activities at the concentrations or doses at which it effectively inhibits norepinephrine reuptake. Thus, it is quite free of side effects and is properly considered to be a selective drug.”

Lilly submits that, upon reading Gehlert, the skilled psychopharmacologist would be interested in reading Wong (citation 10) for three reasons – Prof. Wong was well-known in the field; the title of the paper (“A New Inhibitor of Norepinephrine Uptake Devoid of Affinity for Receptors in Rat Brain”) is interesting in this context; and it is the only paper cited that refers to atomoxetine. I accept this submission. Prof. Cowen agreed that if he started with the Patent and followed the reference to Gehlert he would also look at Wong.

[0009] states that:

“Tomoxetine 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, tomoxetine is effective at relatively low doses, as discussed below, and may safely and effectively be administered once a day. Thus difficulties caused by the multiple dosing of patients, particularly children and disorganised adults, are completely avoided.”

This would be understood to mean that atomoxetine is safer than the stimulants and the TCAs. Actavis observes, correctly, that there are no data provided to support the assertions of safety and efficacy, either at low doses / once a day or at all.

Effective doses of atomoxetine are given in [0010], in the range from 5mg/day to 100mg/day, with the most preferred for adults being 20-60mg/day and for children 10-50mg/day. Lilly submits that the fact that dose ranges are given suggests to the skilled clinician that the drug has been tried in humans. I do not accept this inference, as the dose ranges are very wide, and it was not suggested that there was anything unusual about them. [0011] discusses forms of administration, and indicates that the oral form is the most preferred.

[0012] introduces the DSM IV diagnostic criteria which are set out in [0013]. [0014] explains that atomoxetine is effective for treating both recognised components of ADHD. [0015] is concerned with adult ADHD and records the observation that it is heritable. [0016] notes that there is often co-morbidity with ADHD, but that atomoxetine is effective to treat it even where there are other disorders. [0017] records the disturbing nature of the disorder for the person affected and those around them. [0018] records that atomoxetine is effective in the treatment of both children and adults with ADHD. Actavis again observes, correctly, than the Patent does not contain data to support these statements of efficacy.

I have set out claim 1 in the introduction to this judgment. Claims 2-4 specify, respectively, that the patient is an adult, an adolescent or a child. Actavis has pleaded plausibility attacks in respect of particular patient groups and Lilly has sought to reserve the right to amend, following judgment, by deletion of claims, if anything came of this attack. I was not referred to any evidence that was adduced in support of this plea, and the evidence that it was common general knowledge that ADHD in children continues in adults is contrary to any such objection. By the conclusion of the trial, it appeared that this objection to validity was not being pursued, and if it was, I reject it. In my judgment, there is no reason to think that atomoxetine would be effective to treat ADHD in children and not adults, or vice versa.

Interpretation of Swiss form claims

Where, as in this case, a therapeutic application is claimed by means of a Swiss form claim, it is settled law that attaining the claimed therapeutic effect is a functional technical feature of the claim (Regeneron v Genentech [2013] EWCA (Civ) 93, [56]; T 609/02 Salk Institute, [9]).

The history and purpose of Swiss form and EPC 2000 claims was set out by the Court of Appeal in Warner Lambert v Actavis [2015] EWCA Civ 556 at [51]-[68] & [127]. Floyd LJ concluded that the word ‘for’ in such medical use claims meant ‘suitable and intended for’ in the sense that such use was known or reasonably foreseeable by the manufacturer:

“He would understand that the manufacturer who knows (and for this purpose constructive knowledge is enough) or could reasonably foresee that some of his drug will intentionally be used for pain is making use of the patentee's inventive contribution, in the same way as a manufacturer who actively desires that result. In my judgment, therefore, the skilled person would understand that the patentee was using the word “for” in the claim to require that the manufacturer knows (in the above sense) or can reasonably foresee the ultimate intentional use for pain, not that he have that specific intention or desire himself.”

Actavis contends that this element of intention has important consequences when considering plausibility of the Patent, in the context of whether the claimed invention has been sufficiently disclosed and whether the patentee has made the claimed technical contribution. Lilly disagrees, and I will return to this issue when considering these objections to validity.

It is also clear that the words ‘for treating attention deficit/hyperactivity disorder’ do not mean that the treatment has to be successful in every patient. Obviously, as patients respond differently to treatments, this will never be the case for any medical use claim. Aldous LJ stated as follows in Bristol-Myers Squibb v Baker Norton [2001] RPC 1 at [21]:

“The words “for treating cancer” have to be construed in context. The skilled addressee would realise that drugs which were suitable for treatment would not always be successful. However drugs which had no effect were not suitable. The phrase means “suitable for trying to treat cancer”. What is suitable is a question of fact, not one of perception. If the drug has a beneficial effect in the treatment of cancer it will be suitable. If not, it will not be.”

Similarly, in Teva v Merck [2010] FSR 17 at [54] Floyd J (as he then was) held that a second medical use claim requires that the medicament is effective to achieve a new treatment. If it is not discernibly effective, then it is not suitable for that treatment. That did not mean that it had to cure all patients:

“The formulation must produce some discernible effect in the relevant patient class. The claim does not specify any particular degree of effectiveness, beyond the fact that the effect must be shown in a patient who is insufficiently responsive to beta blockers…”

Both parties reminded me of the value of the structured approach as set out in Pozzoli SpA v BDMO SA [2007] FSR 37 at [23]. As to the fourth question in Pozzoli, the parties also cited Generics (UK) Ltd v H Lundbeck A/S [2008] RPC 19 at [24], where Lord Hoffmann approved the following statement of principle of Kitchin J (as he then was):

“The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem which the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.”

Mr Mitcheson also asked me to bear in mind the well known warning about the dangers of an ex post facto step by step analysis of inventions contained in Technograph Printed Circuits Limited v Mills & Rockley [1972] RPC 346 at 362.

To these familiar principles I would add the following: In Ultraframe UK Limited v Eurocell Building Plastics Ltd [2005] RPC 36 at [5]–[7] Jacob LJ considered claim construction and in particular, what a person skilled in the art would have understood the patentee to have used the language of the claim to mean. At [7] he said:

“Before the court gets to the examination room it has to do some swotting: to get into its mind the relevant knowledge of the skilled man. For how a document will be understood depends on the reader.”

The same approach should be applied to the assessment of obviousness. I must get into my mind, when considering the cited prior art, the knowledge and attitudes of the skilled team concerned with the treatment of ADHD in 1995. In some cases this may strengthen the claim of obviousness. A particular step may lack inventiveness because of trends in the field at the priority date, or the recent publication of prior art. In other cases, what may well appear obvious once the solution is known may not have represented the pattern of thought of those in the field at the relevant time.

In the present case, several of the witnesses acknowledged the difficulty of avoiding hindsight, where the priority date was over two decades before the trial date, where 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.

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 [2008] 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 [19]:

“…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.

Assuming that it would have been obvious to the skilled team to try atomoxetine for the claimed therapeutic purpose, the question arises as to how optimistic of success it must have been in order for the Patent to lack inventive step. As in several recent judgments, this is an important issue in the present case.

In Omnipharm Ltd v. Merial [2011] EWHC 3393, Floyd J (as he then was) summarised the position as follows:

“i)

There is but one statutory question: was the invention obvious? It is to be answered by reference to the non-exhaustive list of factors identified by Kitchin J in Generics v Lundbeck, including whether it was obvious to try the invention as a solution to a technical problem, as well as the nature of the invention itself.

ii)

“Obvious to try” is not an independent ground of invalidating a patent under the statute, but one of a variety of factors considered in an overall assessment of inventive step. It must be coupled with a fair expectation of success, the degree of success necessary depending on the other factors present in the individual case.

iii)

Where an invention is claimed plausibly in terms that it would achieve a technical effect, it is correct to ask whether it was obvious that the invention would achieve that effect, and wrong to ask whether the invention might achieve that effect.”

In the context of pharmaceutical and biotechnology inventions, there are particular policy considerations which, depending on the facts, may be of relevance to the requirement of fair expectation of success. This was explained by Kitchin LJ in  Medimmune Ltd v Novartis Pharmaceuticals UK Ltd [2012] EWCA Civ 1234 at [90]:

“One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research.”

Similarly, in Conor, Lord Walker said, in relation to the “obvious to try” approach [47]:

“Johns-Manville was decided over forty years ago, and was concerned with a fairly low-tech process. During the last forty years the volume of high-tech research has increased enormously, especially in the fields of pharmaceuticals and biotechnology. The resources committed to research are enormous, because the potential rewards in world-wide markets are so great. Competition is fierce. In this climate "obvious to try" has tended to take on a life of its own as an important weapon in the armoury of those challenging the validity of a patent.”

The potential difficulty that would be caused by a mechanistic application of the “obvious to try” approach in this context was explained by Professor Sir Hugh Laddie in “Patents - what's invention got to do with it?” (Chapter 6 in Intellectual Property in the New Millennium, p.93):

“The problem can be approached by considering first the concept of 'obvious to try'. The classic statement of this principle is set out in the judgment of the Court of Appeal in Johns-Manville Corporation's Patent. It was said that a development should be treated as obvious if 'the person versed in the art would assess the likelihood of success as sufficient to warrant actual trial'. Statements to similar effect have been made by the EPO.

On its face, this produces an unworkable or irrational test. If the reward for finding a solution to a problem and securing a monopoly for that solution is very high, then it may well be worthwhile for large players to examine all potential avenues to see if one gives the right result, even though the prospects of any one of them succeeding are much less than 50/50. What makes something worth trying is the outcome of a simple risk to reward calculation. Yet, if the reward is very large, the avenues worth trying will be expanded accordingly. So, the more commercially attractive the solution and the more pressing the public clamour for it, the harder it will be to avoid an obviousness attack. In those circumstances a solution which is quite low down a list of alternatives, all of which are more or less worth trying, will fail for obviousness; a consequence which is consistent with the decision in Brugger v Medic-Aid.”

This “Catch 22” problem, inherent for inventors in an empirical art, was also referred to by Jacob LJ in the Court of Appeal in Conor ([2007] RPC 20) at [41]:

“Judge Rich in the US Court of Appeal for the Federal Circuit said (I did not know this when I wrote St Gobain) much the same thing in Tomlinson's Appn (1966) 363 F 2d 928 at 931:

“Slight reflection suggests, we think, that there is usually an element of ‘obviousness to try’ in any research endeavour that is not undertaken with complete blindness but rather with some semblance of a chance of success, and that patentability determinations based on that as the test would not only be contrary to statute but result in a marked deterioration of the whole patent system as an incentive to invest in those efforts and attempts which go by the name of ‘research’.”

Chouinard is a “rapid communication’` published in 1984 in the journal Psychopharmacology. The paper describes an open-label early phase II clinical trial of atomoxetine in the treatment of ten depressed patients over a period of six weeks. The disclosure of Chouinard is summarised in the abstract:

“In a six week open-label study, ten newly admitted depressed patients were treated with tomoxetine, a selective inhibitor of noradrenaline reuptake. After 7 days of drug washout, patients were given an initial dose of 40 mg/day which was gradually increased to a maximum of 70 mg/day (median 50 mg/day). There was a statistically (P<0.001) and clinicallysignificant improvement in the mean symptomatology of the patients measure on the Hamilton Depression Rating Scale. The drug had an early onset of action, a specific effect on mood and no sedative properties”.

In the text which follows, atomoxetine is described as a selective inhibitor of noradrenaline with little affinity for muscarinic, cholinergic, histamine H1, alpha-1 and alpha-2 adrenergic receptors and dopamine receptors, citing Wong 1982. It is said to be the first noradrenaline reuptake inhibitor without affinity for alpha or beta adrenergic receptors of the central nervous system. The text explains that antidepressant activity is suggested because of its action in antagonising apomorphine-induced hypothermia and 6-hydroxydopamine-induced depletion of noradrenaline.

The materials and methods for the phase II study are then set out. The patients received atomoxetine twice a day and eight of the ten patients completed the study. The results are provided on page 127. In terms of adverse effects, the most common were insomnia, constipation and headache. There was also a statistically significant increase in heart rate and all patients showed an increase in fast activity (beta-range), although other EKG measurements were not significantly modified by the drug.

In the discussion, the authors conclude that atomoxetine was found to be an efficacious antidepressant in eight out of the ten patients treated, having a particular effect on mood. Most of the side effects are said to be related to the potentiating effect of atomoxetine on noradrenergic function and its specificity for the noradrenergic system is said to be possibly responsible for its mood-elevating effect and early onset of action – in contrast to other antidepressants which act more slowly because of their indirect action on the noradrenergic system via the serotonin or dopamine pathways.

Zerbe is a paper published in 1985 in The Journal of Pharmacology and Experimental Therapeutics. It is entitled “Clinical Pharmacology of Tomoxetine, a Potential Antidepressant”. It describes the administration of atomoxetine to a small number of healthy human volunteers – i.e. a phase I trial. The abstract explains that atomoxetine selectively inhibits NE and has activity in animal models of depression. Atomoxetine was administered to healthy humans twice a day for a week, and the effect of administrating NE, and tyramine (which releases NE), on blood pressure was measured, as well as serotonin uptake. Changes in blood pressure were correlated with drug levels, but there was no effect on serotonin uptake. The authors conclude that atomoxetine is a selective NE reuptake inhibitor at doses which are well tolerated and that it has potential use as an antidepressant.

Zerbe cites Wong on a number of occasions in the introduction to support the statements that atomoxetine has activity as a NE reuptake inhibitor, has relatively little effect on the reuptake of dopamine or serotonin, and has relatively little affinity for acetylcholine, H₁, alpha-2 and dopamine receptors.

In its introduction Zerbe compares atomoxetine to antidepressants, including desipramine, and describes it as having theoretical advantages to these drugs due to the selectivity of its action, which Zerbe says may result in atomoxetine having fewer cardiovascular side effects.

In the Methods section, the individual dose ranging study involving four volunteers is described first. A study in seven volunteers of repeated doses follows, together with a description of blood “pressor” and serotonin tests. Side effects are recorded for individual doses at the highest level. Some of the volunteers receiving the multiple doses also experienced side effects. Atomoxetine elicited a pressor response in volunteers, but there was no difference in serotonin uptake levels.

The authors conclude that:

“all clinical data indicate that tomoxetine was safe at these doses.”

…

“the effect of tomoxetine in humans, as in animals, appears to be the specific inhibition of NE uptake.”

…

“these early clinical pharmacology studies demonstrate that tomoxetine is well tolerated at doses which can be shown to specifically inhibit NE uptake. According to prevailing theories that increased NE within the central nervous system are effective in treating depression, tomoxetine should be a clinically effective antidepressant at these doses. Considering these observations, further clinical trials to investigate the efficacy of tomoxetine in the treatment of depression are warranted.”

Actavis submits that both Chouinard and Zerbe would be read alongside Wong. I accept this submission, essentially for the same reasons that I concluded that the skilled team would read Gehlert (cited in the Patent) alongside Wong. Wong would be read and understood by the skilled pyschopharmacologist, who I have concluded would be a member of the skilled team.

Wong is entitled “A new Inhibitor of Norepinephrine Uptake Devoid of Affinity for Receptors in Rat Brain” and was published in the same journal as Zerbe. The abstract describes a new racemic molecule, LY135252, as being a competitive inhibitor of noradrenaline uptake in the rat hypothalamus. The (-) isomer, LY139603 (atomoxetine), is said to be more effective than the racemate or the (+) isomer. All are weak inhibitors of dopamine and serotonin uptake. These NE reuptake inhibitor effects are said to be mirrored in vivo. Compared to desipramine and imipramine, atomoxetine is said to be a relatively weak ligand for alpha-1, alpha-2 and beta adrenergic receptors, acetylcholine-muscarinic receptors, histaminergic H1 receptors and the receptors of gamma-aminobutyric acid and benzodiazepines. Thus it is said to be a remarkably specific inhibitor of noradrenaline uptake with potential as an antidepressant. This is supported by in vitro and in vivo data from studies on rats.

The discussion states that:

“Being a selective inhibitor of NE uptake and relatively free of affinity for neurotransmitter receptors, LY139603 would be a useful clinical candidate to elaborate on the monoaminergic theory that has been proposed to explain the therapeutic action of the tricyclic antidepressant drugs”

It concludes that atomoxetine is at least two orders of magnitude more effective in the inhibition of NE uptake than DA or 5-HT. The authors note that the TCAs are all mixed inhibitors of monoamine uptake. The specificity of atomoxetine for NE uptake sites compared to alpha and beta adrenergic receptors is commented on, and its effect is contrasted with that of the TCAs. However, it is it suggested that this is a factor which contributes more to the side effects of the TCAs than to their therapeutic action.

Wong states that, “Although it is too early to predict whether LY139603 [atomoxetine] would be efficacious as an antidepressant, nisoxetine has been found to be effective among a sizable number of depressed patients (unpublished observations)”.

Applying the Pozzoli approach, I have identified the notional skilled team and the relevant common general knowledge. Claim 1 of the Patent does not need to be paraphrased in order to comprehend the inventive concept, and would be understood as I have construed it. 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. The question is whether this difference would have been obvious in 1995.

Mr Mitcheson submits that whether the idea of trying atomoxetine in the treatment of ADHD was obvious is logically prior to the question of whether the skilled team would have a fair expectation of success. I agree.

The case in favour of ‘obvious to try’ may be summarised as follows:

There is an attractive simplicity to these arguments and I have considered them very carefully. However, having heard the evidence and reflected on the views of all the experts, I have reached the conclusion that it was not obvious in the light of Chouinard to try atomoxetine in the treatment of ADHD.

Prof. Hill pointed out that the Chouinard trial was open-label and therefore not placebo controlled. Assessment of symptoms was stated to be based on clinical interviews conducted by one of four psychiatrists and there was likely to be variability, and, in an open trial, varying degrees of inadvertent bias, between the four psychiatrists. Further, without a placebo control, it is difficult to assess the extent to which any perceived improvement was attributable to the effect of the medication, rather than other factors such as positive rater expectancy effects. The study was on a very small number of middle-aged adults with depression rather than ADHD patients, where the primary population was children. The described side effects did not provide any information relevant to treating ADHD, for example reduced inattentiveness, impulsiveness or overactivity. So, when read with interest, Chouinard would not, in the opinion of Prof. Hill, have been regarded as having any relevance to ADHD. In my judgment, he maintained this position during his cross-examination, and I accept his evidence.

During cross-examination, it emerged that Prof. Cowen was equally unenthusiastic about Chouinard. Prof. Cowen thought that Chouinard would be treated with a high degree of caution because of the absence of a placebo control, and that if Chouinard was progressed at all, it would be as a phase II trial for depression:

“Q. It is your position, is it, that you would need to do a placebo controlled trial in depressed patients before you could regard tomoxetine as having established evidence of efficacy as an antidepressant?

A. Yes.

Q. And you cannot draw any conclusions from an open trial with eight patients, given the other drawbacks we have discussed?

A. I think any conclusions is being a little harsh, but I think one would treat the results with a high degree of caution.

Q. And this placebo controlled trial in depressed patients would be the natural next step to take from Chouinard?

A. If you were going to develop the drug further, yes.”

As to whether amoxetine was obvious to try for the treatment of ADHD in the light of Chouinard, Prof. Cowen did not support this suggestion:

“Q. There is nothing to suggest to the skilled psychopharmacologist that this drug should be tried in ADHD, is there?

A. No.”

Dr Steingard was equally cautious about relying on Chouinard:

“A. I would not go that far with a paper like this. I would want to see a comparator study to understand it better, you know, where you had placebo and active agents so I could see the difference between the two groups.

Q. So you just cannot draw ----

A. Maybe I am more careful than that, but I would not make -- I would not take that much from this. I think it is interesting, I thought it was maybe directional, I was interested in EKG stuff, it interested me, but it is not a study that you would rely upon to make any kind of inference for that matter.

Q. Either on safety or efficacy?

A. Right.”

Furthermore, Dr Steingard’s evidence was to the effect that he understood from reading the Patent that atomoxetine would be useful in the treatment of ADHD, and he would not have had this idea at the priority date unless someone else had suggested it to him:

“Q. Indeed. Doctor, I am just trying to establish, I am trying to suggest to you that at the priority date, without knowledge of the patent, you would not be sufficiently interested in a norepinephrine only drug to try it at all?

A. No, if I had been exposed, if somebody walked in my office and said, I have this idea, let me tell you about this agent, what do you think, if that had occurred, I probably would have said I would be interested in taking a look at this.

Q. That is why you say you were interested in the patent when you read it?

A. Yes.”

Mr Tappin points out, correctly, that this evidence reflected Dr Steingard’s personal experience at the priority date, in that he was not part of a team concerned with developing drugs. So he would need to have been given the idea by someone else. On the other hand, Dr Steingard was the main witness called by Actavis to support the case of lack of inventive step, and his evidence on this issue did not persuade me.

Overall, Dr. Steingard agreed with the other experts that it was not obvious in the light of Chouinard to try atomoxetine in the treatment of ADHD:

“Q. So I would suggest to you, doctor, that the notional skilled reader of this paper in 1994 would not think that atomoxetine was a promising agent for ADHD, particularly because of the side effects?

A. Again, I do not think that a report of 25 people in an in-patient unit without a comparator would make you think one way or the other.”

Lilly notes that, although published after Chouinard, Zerbe describes an earlier stage of work, namely a phase 1 trial on healthy human volunteers. I do not accept the submission that Zerbe is therefore worse than Chouinard as a starting point for an obviousness attack – that depends on the contents of its disclosure. I do accept, however, that it is relevant to bear in mind that the Zerbe work was not performed on patients with depression, much less patients with ADHD.

Prof. Hill was clear in his evidence about the limitations of Zerbe. He noted that the whole focus of Zerbe was the use of atomoxetine as a potential antidepressant, and that there was nothing in Zerbe regarding ADHD, or the use of atomoxetine in ADHD. His view was that depression was a very different illness to ADHD. He also observed that Zerbe reported results on a small number of healthy middle-aged adults, rather than ADHD patients (primarily children). In his view, there was nothing in Zerbe that would have been seen as relevant to the treatment of ADHD. During his cross- examination, he summarized his view on the artificial nature of the obviousness argument based on Zerbe:

“A. When I read this paper first, when I was given this paper first of all, I thought why is this being put up? I think, I am trying to capture the amazement as to why this would be relevant; subsequently, of course, I understand the shape of the argument. ”

Prof. Sharp considered that one would not expect to come across an idea for one disease from the pharmacology relating to another, different, condition. Prof. Cowen also believed that one could draw no conclusions about therapeutic effect in ADHD from Zerbe. If one wished to progress Zerbe, the skilled person would want to take it forward into a trial in depressed patients. He was also concerned about the side effects reported in Zerbe.

Dr Steingard also considered that little could be deduced from Zerbe without a further study in depressed patients. In addition, he considered that this paper was outside his expertise, and he would need help from Prof. Cowen.

Having regard to all the evidence, I have reached the conclusion that it was not obvious to try atomoxetine for the treatment of ADHD from Zerbe. I do not think that it was obvious to progress Zerbe at all at the priority date, given that it was published some ten years earlier and the skilled team would be aware that atomoxetine had not gained regulatory approval for depression. If it was obvious to progress it further, then this would only be as an antidepressant, and not as a drug for the treatment of ADHD.

Even if it was obvious at the priority date, either from Chouinard or Zerbe, to try atomoxetine for the treatment of ADHD, I do not consider that the skilled team would have had a fair expectation that this drug would be discernibly effective in such treatment.

I have reached this conclusion based on the expert evidence to which I have referred above. Because Chouinard and Zerbe are both studies on very limited numbers of patients, without any placebo control, and concerned with depression, rather than ADHD, the skilled team would consider that use of atomoxetine in the treatment of a quite different disorder would be a research project, the outcome of which would be unpredictable.

As to the common general knowledge, I have concluded that the skilled clinician would consider that the hypothesis that the TCAs had efficacy in the treatment of ADHD as a result of selective inhibition of NE reuptake was reasonable. That lends some support to the claim that, having had the idea, the skilled team would have a fair expectation that atomoxetine would be effective in the treatment of ADHD. Both Chouinard and Zerbe identify atomoxetine as a selective inhibitor of NE reuptake which may have advantages in the treatment of depression over existing drugs such as the TCAs.

However, I have also concluded that the skilled clinician at the priority date would consider that the position in relation to ADHD was likely to be more complex, and that a number of other contributory causes were possible. I have decided that he would be uncertain as to whether it was desirable to increase or decrease NE in the treatment of ADHD, and uncertain as to whether other neurotransmitters were also implicated. Therefore, he would be uncertain as to which neurotransmitters were “on target” and which “off target” in the treatment of ADHD. Against this background of uncertainty, I do not consider that the skilled team would have a fair expectation that atomoxetine would be effective in the treatment of ADHD.

I consider that the oral evidence of Dr Steingard reflected this degree of doubt, in contrast to his written reports which were rather more optimistic. This is not a criticism of Dr Steingard. Witnesses often express their views more accurately in the witness box than in written reports, which are carefully scrutinised by lawyers. Mr Mitcheson has drawn attention, for example, to the following evidence of Dr Steingard, which, in my judgment, is more indicative of an interesting project with uncertain results than of a fair expectation of success:

Prof. Hill was also very doubtful about the degree of expectation of success, even on the assumption that the psychopharmacologist had advised the clinician that it had been observed in the treatment of depression that TCAs inhibited NE reuptake and had no significant effect on dopamine. He pointed out that, at the time, it was doubted whether effects that had been demonstrated in the treatment of depression, predominantly in adults, applied to ADHD.

Mr Tappin submits that Prof. Hill accepted in cross examination that, if the skilled team had the idea of testing atomoxetine for ADHD from the prior art, then there would be a 50:50 expectation of success, which, he argues, is a reasonable expectation that it would be effective. However Prof. Hill had great difficulty in assuming that the idea was obvious from the prior art, and so, in my view, the enquiry was somewhat artificial. Furthermore, it became apparent that Prof. Hill was using the expression “50:50” to mean that he would have no expectation as to whether the trial would succeed or fail. He summarised his view as follows:

“A. Well, very briefly, the fact that it appears to be a norepinephrine reuptake inhibitor used in depression would not automatically spark in me the idea that it would be useful for the treatment of ADHD in children. It just would not do that. If it did, and I proceeded to a trial, then I would have no expectation either way whether the trial would reveal effectiveness. ”

Shenker was published in 1992 and specifically concerns the mechanism of action of drugs used to treat ADHD. It was not suggested that there had been relevant developments between 1992 and the priority date in relation to the treatment of ADHD and this chapter is a helpful insight into the thinking of the skilled team at the time, in particular in relation to future areas of research in the treatment of ADHD.

Table 3 on page 359 is entitled “Selective Drugs that May be Useful in Behavioural Research on ADHD”. It lists nine different classifications of drugs, which it divides into fifteen categories (“agonist”, “antagonist” etc.”). It gives twenty five examples of selective drugs that could be useful. It makes no mention of any selective NE inhibitor. This provides further support for the conclusion that what is now said to be obvious did not represent the thinking of the notional skilled team at the priority date. It also indicates that there were many possible research pathways to pursue in the treatment of ADHD, and there was uncertainty as to which was most promising.

I have concluded that the motivation to develop alternatives to TCAs for the treatment of ADHD had existed for many years before the priority date, although it had been increased by the unexplained sudden deaths caused by desimaprine. The other drawbacks of TCAs had been known for many years, and yet there had not been much advance in the treatment of ADHD from the early 1980s until the priority date. Strattera, the commercial embodiment of the Patent, has satisfied this need.

Dr Steingard was asked about this during his cross-examination:

“Q. Can you explain why 11 years had elapsed between the publication of Chouinard and the patent and no one has suggested using ADHD for ----

A. I really do not know.

Q. And you are not aware of any suggestion in the prior art to use atomoxetine to treat ADHD between the publication of this document and the patent?

A. I honestly, I really do not know.

Q. Can I suggest to you that it is entirely consistent with the suggestion that it was not obvious to people to do that?

A. I do not even know how to answer that. I am not sure. I mean, if somebody put had this in front of me I would have thought it was an interesting compound, but nobody did put it in front of me.

Q. And that is consistent with this suggestion that it is not obvious to people to try to use this for ADHD from this paper?

A. Yes.”

Evidence of this nature must be kept in perspective. There may be many reasons why prior art was not pursued before the priority date. In the present case, I have found that the motivation to find a TCA alternative increased a few years before the priority date, and this detracts from the weight that can be attributed to this factor. Nonetheless, it does provide some further support for non-obviousness, although I would have reached the same conclusion in the absence of this consideration.

For the purposes of obviousness, the skilled person should be able to make a fair prediction that the alleged invention will, not might, succeed. A question arises as to whether the same is true in relation to sufficiency, or is the standard of “plausibility” different. The parties cited many cases in support of their submissions on this issue. I refer below to those that I regard as the most helpful authorities.

First, Actavis draws attention to the Judgment of Birss J in Hospira UK Ltd v Genentech Inc [2014] EWCA Civ 1094 at [57]-[64]. This passage makes clear that there is a need to balance the requirements for novelty and inventive step with those for sufficiency. If it was required that a patent application contained the results of a clinical trial in order to prove efficacy, that might discourage investment in pharmaceutical research. On the other hand, it would be a recipe for abuse if all that was required to obtain a patent was a proposal, without any basis, to use drug A to treat disease B.

Second, Actavis relies on the Judgment of Kitchin LJ in Regeneron (supra) in particular at [100]-[101]:

“It must therefore be possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim or, put another way, the assertion that the invention will work across the scope of the claim must be plausible or credible. The products and methods within the claim are then tied together by a unifying characteristic or a common principle. If it is possible to make such a prediction then it cannot be said the claim is insufficient simply because the patentee has not demonstrated the invention works in every case.

On the other hand, if it is not possible to make such a prediction or it is shown the prediction is wrong and the invention does not work with substantially all the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution the patentee has made to the art and the claim will be insufficient. It may also be invalid for obviousness, there being no invention in simply providing a class of products or methods which have no technically useful properties or purpose.”

Actavis argues that in the cited passages, Kitchin LJ equated “plausible” and “credible” with a “reasonable prediction the invention will work”. It submits that the words “plausible” and “credible” must be understood accordingly and cannot be treated as meaning anything less robust. Therefore, in Actavis submission, the test for plausibility, in the context of sufficiency, is the same as “reasonable expectation of success” for obviousness.

Third, Actavis relies on [103] of Regeneron, which dealt with sufficiency in the context of a second medical use claim. Kitchin LJ said that the patentee “must show, for example by appropriate experiments, that the product has an effect on a disease process so as to make the claimed therapeutic effect plausible”. He went on to refer to, and adopt, the statement by the TBA in T609/02 Salk at [9], which emphasises that mere assertion of a therapeutic effect may not be enough:

“…It is a well-known fact that proving the suitability of a given compound as an active ingredient in a pharmaceutical composition might require years and very high developmental costs which will only be borne by the industry if it has some form of protective rights. Nonetheless, variously formulated claims to pharmaceutical products have been granted under the EPC, all through the years. The patent system takes account of the intrinsic difficulties for a compound to be officially certified as a drug by not requiring an absolute proof that the compound is approved as a drug before it may be claimed as such. The boards of appeal have accepted that for a sufficient disclosure of a therapeutic application, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported.

Yet, this does not mean that a simple verbal statement in a patent specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se. Showing a pharmaceutical effect in vitro may be sufficient if for the skilled person this observed effect directly and unambiguously reflects such a therapeutic application (T 241/95, OJ EPO 2001, 103, point 4.1.2 of the reasons, see also T 158/96 of 28 October 1998, point 3.5.2 of the reasons) or, as decision T 158/96 also put it, if there is a "clear and accepted established relationship" between the shown physiological activities and the disease (loc. cit.). Once this evidence is available from the patent application, then post-published (so-called) expert evidence (if any) may be taken into account, but only to back up the findings in the patent application in relation to the use of the ingredient as a pharmaceutical, and not to establish sufficiency of disclosure on their own.”

Fourth, Actavis relies on what it describes as the “mental element” of Swiss form claims. In particular, it submits that the technical subject-matter of the claim in the present case is the use of atomoxetine to make a medicament for patients to whom it will be intentionally administered to treat ADHD. The word “for” imports the requirement that the manufacturer knows, or it is reasonably foreseeable, that the product will be used intentionally to treat ADHD. According to Actavis, it must, at least, be reasonably foreseeable from the disclosure of the Patent that atomoxetine will be effective in the treatment of ADHD.

Fifth, Actavis submits that, as a matter of policy, the standard for assessing obviousness and sufficiency should be the same. Patents are granted in return for technical contributions to the art – for the provision to the public of solutions to technical problems. For that reason, Actavis suggests that the general principle underlying the law of both obviousness and insufficiency is that a patent monopoly should correspond to and be justified by the technical contribution to the art.

In support of this argument, Actavis notes that the person who is first to file an application for an invention obtains a patent in preference to someone who files a later application for that invention. But if the first person’s application does not make a technical contribution to the art which justifies the claimed monopoly, then granting him a patent will allow him to steal a march on third parties. The grant of such a patent will not only deprive a later inventor (who in fact provides the public with the solution to the technical problem and the relevant technical teaching) of a patent, it will enable the first person to prevent him from working the technical contribution which he was the first to provide. That would be an abuse of the patent system.

For these reasons, Actavis submitted that the courts and the EPO require it to be possible to make a reasonable prediction that the invention will work, based on the technical teaching of the patent and the CGK, before they will acknowledge that the technical problem has been solved and that the patent provides sufficient disclosure for the skilled person to be enabled to work the invention.

First, Lilly points out in its written submissions that lack of plausibility is not, of itself, a ground of invalidity. It argues that, in circumstances where an invention can be put into practice, and does in fact work, the imposition of a requirement of plausibility would be contrary to TRIPS, the EPC and the 1977 Act.

Lilly submits that the issue of plausibility only arises as a check on over-breadth of claim – for example where a class of compounds was alleged to work for a number of different conditions. That was the context of Regeneron and Salk. Furthermore, Kitchin LJ was applying EPO case-law in relation to plausibility and was not seeking to alter the relevant standard. Nor was he considering whether the standard was the same as reasonable expectation that the invention will work, as in obviousness.

Second, Lilly submits that even if there is a requirement of plausibility when no issue of over-breadth of claim arises, then the threshold for plausibility is a low one. It argues that it is clear from the case-law that the test is a flexible one and each case must be determined on its own facts. It gives the example of a perpetual motion machine, where it will take more to render plausible an invention which appears on its face to run counter to the generally accepted principles of science, than for a development in a well-explored field. It argues that the issue of plausibility is most likely to arise where the patent claims a laundry list of chemical products and/or that such products can treat multiple disease states. In such cases the patent office has more reason to be sceptical that the technical effect really extends across the scope of the (broad) claim. This leads to greater concern that the field of future research will be unduly restricted by the grant of such a patent than in cases where the claims are narrowly framed (as here).

It submits that the hurdle for plausibility must be lower than that for obviousness, and significantly so. Otherwise the patent system would not encourage innovation as it would either be too difficult to satisfy the test for inventive step (because patents would only be awarded for inventions which were “implausible” from the prior art) or it would be too difficult to satisfy the test for plausibility, particularly in the pharmaceutical field where years of testing may be necessary to get clinical approval. Therefore, Lilly suggests that the test for plausibility is merely a filter to stop purely speculative patents, and is not intended to be the flipside of the test for obviousness.

Third, Lilly relies on the decision of the House of Lords in Conor (supra). The issue was lack of inventive step and insufficiency had not been raised as a ground of objection in that case. Nonetheless, Lord Hoffmann considered the extent of disclosure of the patent in the context of (amongst other things) Agrevo/lack of technical contribution at [29]-[37]. Lilly submits that [29]-[32] proceed on the basis that the objection of lack of plausibility applies to speculative patents, whose breadth of claim meant that the alleged invention is inherently improbable. This was the case in Re Prendergast’s Application [2000] RPC 446, which is cited with approval in those paragraphs.

Lilly points out that although the specification in Conor said very little about the details of how or why taxol would be efficacious in preventing restenosis, and offered no proof that this was right, the House of Lords did not regard this as leading to implausibility. Indeed, it was thought unsurprising that implausibility was not argued, as it would have been inconsistent with the ‘obvious to try case’ that was advanced. Lord Hoffman said:

“37.

The Court of Appeal upheld the judgment of Pumfrey J. on the ground that the patent contained no “disclosure” saying that taxol was specially suitable for preventing restenosis. Again, I agree that the description, though offering a theory (its anti-angiogenic properties) as to why taxol would prevent restenosis, did not offer any evidence that this would turn out to be true. If it had not turned out to be true, the patent would have been insufficient. But there is in my opinion no reason as a matter of principle why, if a specification passes the threshold test of disclosing enough to make the invention plausible, the question of obviousness should be subject to a different test according to the amount of evidence which the patentee presents to justify a conclusion that his patent will work.”

There are a number of significant points to be drawn from that paragraph. The fact that the patent offered a theory, but no evidence, that taxol would be effective for the claimed therapeutic purpose, did not render it implausible. A safeguard was that if this turned out to be incorrect, the patent would be invalid for insufficiency. This is why plausibility is referred to as a “threshold test”, which is consistent with its application to purely speculative patents. Furthermore, [37] of Lord Hoffman’s speech does not equate the test of plausibility with the test of obviousness, which would be a very surprising omission if that is what was intended.

Fourth, Lilly submits that the Supreme Court in Human Genome Sciences v Lilly [2011] UKSC 51 also regarded plausibility as a low threshold (in the context of industrial applicability). It referred to the following passage in the speech of Lord Hope:

“149.

In paras 6-8 of its judgment in Zymogenetics the TBA contrasted a product whose structure was given but whose function was undetermined or obscure or only vaguely indicated with one which was “definitely described and plausibly shown to be usable”. In the former case, the granting of a patent might give the patentee unjustified control over others who were actively investigating in that area and who might eventually find ways to exploit it. In the latter, because it was plausibly shown to be “usable”, it might be considered to display concrete benefits. As these benefits are assumed not yet to have been confirmed by research, the exercise that these passages indicate is necessarily one of prediction. That is why the Board used the word “plausibly”. I would not quarrel with Jacob LJ’s comment, after consulting the Shorter Oxford English Dictionary, that the sense that word conveys is that there must be some real reason for supposing that the statement is true: para 111. The important point, however, is that the standard is not any higher than that. Further experiments are not needed if sufficient information is provided in the description, when common general knowledge is taken into account, to show that a positive answer can be given to the question whether a profitable use can readily be identified: ZymoGenetics, para 20.”

In the Zymogenetics case cited by Lord Hope (T 898/05) the Board used two alternative terms for “plausible” – “educated guess” and “reasonably credible” – and all three of these terms were adopted by Lord Neuberger in his summary of the law in HGS at [107](viii). Lilly submit that had the Supreme Court intended plausibility to be a standard akin to obviousness, it would have said so in HGS, and would not have used the “educated guess” language that it adopted.

Fifth, Lilly argues that Lord Neuberger’s judgment also sheds light on the policy underlying the plausibility requirement. The requirement for plausibility acts as a gateway to prevent the filing of speculative patents, whilst at the same time being set at a level which encourages research in the pharmaceutical industry by permitting early filing (see the discussion of the amicus brief of the BIA at [96]-[102], relied on by Lord Neuberger at [130]).

Sixth, Lilly observes that another requirement which prevents speculative patents is that if it is not possible to put the patent into practice without undue experimentation, this renders the patent insufficient. Lilly submits that there is therefore no policy reason why the two requirements of sufficiency and inventiveness should be approached in the same way. If the rationale for doing so is in order to assess whether the patent makes a sufficient technical contribution, then the answer is that the statutory requirements for patentability ensure that.

Seventh, Lilly claims that EPO case law supports its legal submissions. In T 578/06 Ipsen the Board emphasised the need for “substantiated doubts” in order to call into question the plausibility of the patent:

“13.

The board notes that the EPC requires no experimental proof for patentability and considers that the disclosure of experimental data or results in the application as filed and/or post-published evidence is not always required to establish that the claimed subject-matter solves the objective technical problem. This is in particular true in the absence of any formulated substantiated doubt as is the case here.

…

15.

The board re-emphasises in this context however that this case law considers the establishment of plausibility only relevant when examining inventive step if the case at hand allows the substantiation of doubts about the suitability of the claimed invention to solve the technical problem addressed and when it is thus far from straightforward that the claimed invention solves the formulated problem.”

Lilly notes that the origin of the “reasonable prediction” wording is Agrevo. It points out that, as in Regeneron this was another breadth of claim case. It submits that it is apparent from Agrevo that the Board did not consider “reasonable prediction” to be the flip side of obviousness. This is clear from [2.6.3] of the decision, where the Board explained that it is possible for a prediction to be “not obvious, but nevertheless reasonable”. This only makes sense if the hurdle for “reasonableness” is below that of obviousness.

Eighth, Lilly relies on settled EPO practice that evidence obtained after the priority date can be adduced to defend an allegation of insufficiency/lack of support. The utility of later filed evidence is only justified if the plausibility hurdle in the first place is low – if it were high, the later material would add nothing. Thus it is legitimate for the patentee to fill in potential gaps as long as there is some basis in the application.

Ninth, Lilly point out that Under Rule 42(1)(e) EPC a patent is not required to include examples and nor is it a requirement for the invention to actually have been carried out, a point which was emphasised in T 1437/07 Allergan.

I reject Lilly’s submission that, in circumstances where an invention can be put into practice, and does in fact work, the imposition of a test of plausibility would be contrary to TRIPS, the EPC, or the 1977 Act. Susceptibility of industrial application, sufficiency and inventive step are all part of the requirements of the relevant treaties and legislation. Necessarily, it is the task of the courts and the Boards of Appeal of the EPO to interpret these requirements. In so doing, plausibility has been referred to at the highest level as one factor that should be taken into account. Nonetheless it is relevant to bear in mind that plausibility does not form a separate ground of objection to the validity of a patent. Therefore it falls to be considered within the context of the statutory objections to validity, and having regard to their respective purposes.

I also reject Actavis’ submission that the Warner Lambert decision established that plausibility, like obviousness, requires a reasonable expectation that the invention will work. That decision was concerned with the mental element which the manufacturer of the drug, as distinct from the end user, must possess for the purposes of infringement. It did not concern the adequacy of the disclosure of the patent, or its plausibility.

I accept that Regeneron and Salk were concerned with plausibility across the scope of the claims, and the scope of the claims in issue in those cases was very wide. I do not accept that the requirement of plausibility applies only to claims of wide scope. If a claim that a particular drug is useful in the treatment of a particular disease is incredible, then the same consequences should follow as for an implausible claim of wide scope. However, whether an invention is plausible is fact sensitive and will depend upon the nature of the invention, the scope of the claim, the disclosure of the specification and the common general knowledge. Generally, it is likely to be easier, as a matter of fact, to show plausibility for a claim of narrow scope, for example a single drug for a single disease, than for a claim of wide scope, for example a class of drugs for multiple diseases. In the case of the former, less evidence may be required than in the case of the latter.

There is no requirement in the EPC that a patent should contain data or experimental proof to support its claims. The reference in Salk to the provision of experimental tests to support the claimed therapeutic use was by way of example. In respect of claims to therapeutic applications which are of wide scope, such experimental tests may well be required. In the case of narrow claims, they may not be.

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 the standard for assessment of expectation of success in the context of obviousness.

In contrast to the prior art, the Patent discloses for the first time that atomoxetine is effective in the treatment of ADHD. It discloses that the mechanism of action of atomoxetine is as a selective NE reuptake inhibitor, and cites the Gelhert paper in support. I have concluded that, upon reading Gehlert, the skilled psychopharmacologist would also read Wong, which lends further support to the statement that atomoxetine is a selective NE reuptake inhibitor.

I have 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. He would have considered that position in relation to ADHD could be more complex, but that does not detract from the conclusion that the skilled team would consider that the invention of the patent was credible, based on the specification and common general knowledge.

Furthermore, in the present case, post-published evidence concerning the widespread administration of atomoxetine to ADHD patients has confirmed the disclosure of the patent that it is safe and efficacious for the treatment of this disorder. This is admissible, and important, evidence. Subject to the expert evidence, which I consider below, I conclude that the Patent is plausible.

Prof. Cowen considered that the disclosure of the Patent of atomoxetine’s mechanism as a selective NE reuptake inhibitor was backed up by the data in Gehlert and Wong. Similarly, Dr Steingard was in no doubt that the disclosure of the Patent was credible:

“A. The mechanism as a selective norepinephrine inhibitor is backed up by the data in Gehlert and Wong, as you would be told by Professor Cowen, as he explained; correct?

A. Yes.

Q. Based on the disclosure in the patent, including the data in Gehlert and Wong, you would expect it to be safe and effective?

A. We talked about this yesterday. Based on my experience with other compounds, I would have been hopeful that this would have been a drug that as at least comparably effective to the tricyclics because of what I knew about mechanism of action at the time and I would have hoped that it would have been less toxic.

Q. So, you consider the claims to be believable but you would want to see the data or generate your own to support the statements made?

A. Yes, exactly.

Q. And you would expect to get ethical approval to carry out such work based on the disclosure in the patent?

A. Yes.”

This is consistent with the evidence of Profs. Hill and Sharp, who also considered the disclosure of the Patent to be credible. However, I must also consider Mr Tappin’s submission that both of these witnesses made a fundamental error, in that they had a mistaken belief that the Patent was an authoritative document, and that statements would not be made in such a document without underlying evidence. This belief is illustrated by the following cross examination of Prof. Hill:

“Q. Professor, what do you mean by "an authoritative document"?

A. I had never seen a patent document before, ever.

Q. Right.

A. So my first reaction was this is a very short statement, and it tells me it works. Then I think, well, this is a statement that has, I assumed, legal authority, and people are not going to make false statements if they are a large respected company, unless they have got grounds for those statements, so I did take them at face value at that point.

Q. Right. But you are saying even without the assumption that they had grounds to support them, the skilled person would still have considered the statements plausible?

A.

My natural assumption was that they did have grounds.”

Prof. Sharp gave evidence to much the same effect. Their assumptions are wrong. The only sanction for making unsupported statements in a European Patent is that a patent is liable to be invalidated. The fact that a statement appears in a patent does not of itself mean that the statement is supported by undisclosed evidence, or should be taken at face value.

Mr Mitcheson, albeit with little enthusiasm, pointed out that the Priority Document was a US Patent Application, supported by a Declaration from the inventors. He submitted that the statements within it had been declared to be true, to the best of the inventors’ knowledge and belief, and that this justified the trust of Profs. Hill and Sharp in the accuracy of those statements. Mr Tappin disputed that this was the effect of the Declaration. He argued that inventors were merely declaring the truth of the contents of the Declaration, and not of the Patent Application. There is no evidence before me as to the effect of the Declaration, and this is not an issue that I need to resolve. In my judgment, the happenstance that the priority document was a US Application does not mean that statements in the Patent can be accepted on trust. Accordingly, the issue that I have to resolve is whether the evidence of Profs. Hill and Sharp on this issue was inextricably bound up with their mistake, so that I can take no account of their views.

In his first report at [9.4]-[9.8], Prof. Hill referred to the statement in the Patent concerning atomoxetine’s method of action as an NE reuptake inhibitor, by reference to the Gehlert paper. He stated that, “The fact that atomoxetine affects a catecholamine and that catecholamines were implicated in the underlying pathophysiology of ADHD supports the Patent’s statement that atomoxetine is effective in ADHD”. He expressed the view that the Patent would be understood as meaning that atomoxetine is more selective in its effects on NE as compared to the ADHD drugs known at the time, such as stimulants and the TCAs, and therefore that it had reduced side effects. He stated that the skilled person would have assumed that Lilly had undertaken some clinical trials or had some grounds to support the statements made in the Patent. However, he said, “even if this assumption is not made, I believe that the skilled person would have still considered it plausible for the reasons given above.” Therefore, in my judgment, it was clear from his evidence that his mistaken belief was one of several reasons why he considered that the Patent was plausible, and he would have reached the same view without this belief.

Similarly, Prof. Sharp considered differences between the Patent and the prior art in section 8 of his Report and also concluded that Gelhert and Wong provided support for the statement in the Patent that atomoxetine is a selective drug when used at doses which effectively inhibit NE reuptake. It is true that when cross-examined about this section of his report, Prof. Sharp became confused, but this was because he required some time to understand the context in which this section appeared. Like all the other witnesses, Prof. Sharp considered that the disclosure of the Patent was plausible.

I have concluded that the disclosure of the Patent that atomoxetine is effective in the treatment of ADHD is plausible. It is a technical contribution that has proved valuable in the treatment of this serious condition. The prior art lacks this technical contribution. Neither citation makes it obvious to try atomoxetine for the treatment of ADHD. Furthermore, neither citation gives rise to a reasonable expectation that atomoxetine would be effective in the treatment of ADHD. For these reasons, I reject the alleged squeeze between obviousness and insufficiency.

Both of these grounds of invalidity were based on the proposition that the Patent and/or the priority document were not plausible. I did not understand Mr Tappin to suggest that he could succeed on either of these grounds if I rejected the implausibility argument when considering insufficiency. Even if he did suggest this, I reject these grounds of invalidity for the reasons that I have set out when considering sufficiency. The Patent (which is the same in all material respects as the Priority Document) is plausible.

For the reasons set out above, I conclude that the Patent is valid and will dismiss the claim for revocation. The counterclaim for threatened infringement succeeds.