Neutral Citation Number: [2015] EWHC 3294 (Pat) Case No: HP-2014-00027 IN THE HIGH COURT OF JUSTICE CHANCERY DIVISION PATENTS COURT Rolls Buildings 7 Rolls Buildings Fetter Lane London EC4A 1NL Date: 16/11/2015 Before : MR JUSTICE HENRY CARR --------------------Between : (1) ACTAVIS GROUP PTC EHF (2) ACTAVIS UK LIMITED - and – ELI LILLY AND COMPANY
Claimants
Defendant
----------------------------------------MICHAEL TAPPIN QC, ISABEL JAMAL and WILLIAM DUNCAN (instructed by Pinsent Masons LLP) for the Claimants TOM MITCHESON QC and JEREMY HEALD (instructed by Simmons & Simmons LLP) for the Defendant Hearing dates: 6,7,8,9,13 and 14th October 2015 ---------------------
Approved Judgment I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this Judgment and that copies of this version as handed down may be treated as authentic.
............................. MR JUSTICE HENRY CARR
MR JUSTICE HENRY CARR Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
MR JUSTICE HENRY CARR: Introduction 1.
This is the expedited trial of a claim brought by the Claimants (“Actavis”) seeking revocation of EP (UK) 0 721 777 (“the Patent”), the registered proprietor of which is the Defendant (“Lilly”). Lilly has counterclaimed for threatened infringement by Actavis. The Patent claims a priority date of 11 January 1995. Lilly has obtained a Supplementary Protection Certificate which expires on 26 May 2019.
2.
The Patent discloses a second medical use of the drug atomoxetine (also known as tomoxetine). Claim 1 is in Swiss form and claims: “Use of tomoxetine for the manufacture of a medicament for treating attention-deficit/hyperactivity disorder.”
3.
The validity of the patent is challenged on the basis of lack of inventive step in the light of two prior art citations. In addition, Actavis alleges that the disclosure of the Patent lacks plausibility and is therefore insufficient or obvious on the basis of lack of technical contribution. Actavis also challenges entitlement to priority on the basis of lack of plausibility of the Priority Document. Lilly accepts, for the purpose of these proceedings, that the Patent is invalid over intervening prior art if priority is lost. Finally, Actavis submits that there is a squeeze between lack of inventive step and lack of plausibility. It alleges that the Patent makes no more than a bald assertion that atomoxetine is effective and safe for the treatment of ADHD. It claims that insofar as the Patent discloses a theory or principle to support that assertion, such principle was known from the prior art. Accordingly, Actavis submits that if the skilled person was unconvinced by prior art, he/she (hereafter “he”) would be equally unconvinced by the Patent.
4.
In answer to these submissions, Lilly argues that the prior art gives no hint that atomoxetine could be used in the treatment of ADHD. Both prior art citations were published more than a decade before the priority date, and both assert that atomoxetine could be used in the treatment of depression. There is no evidence that this suggestion was acted on before the priority date and the skilled person would view the prior art as paper proposals with no obvious application to ADHD.
5.
As to plausibility, Lilly submits that the Patent contains, for the first time, a disclosure of the utility of atomoxetine for the treatment of ADHD. According to Lilly, this is supported by credible evidence, expressly referred to in the Patent, and the disclosure has been confirmed by the fact that subsequent to the priority date, atomoxetine has proved to be safe and efficacious in the treatment of ADHD. Lilly has been selling atomoxetine in the UK under the brand name “Strattera” for the treatment of ADHD since 2004. Strattera was first authorised for the treatment of ADHD in the USA in 2002 and was the first non-stimulant approved by the FDA to treat this condition. Annual sales of Strattera in the UK are in excess of £10 million. There is no dispute that Stattera is a valuable drug in the treatment of the serious and distressing effects of ADHD. This, says Lilly, is a complete answer to Actavis’ attacks of insufficiency, Agrevo obviousness and lack of entitlement to priority, all of which stand or fall together. Finally, Lilly claims that there is no squeeze, because the prior art fails to disclose or render obvious the invention of the Patent, namely the use of atomoxetine for the treatment of ADHD.
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6.
Actavis Group PTC EHF & anr v Eli Lilly and Co
The Reply and Defence to Counterclaim admits that the Second Claimant intends to launch in the UK a generic atomoxetine product for the treatment of ADHD before the expiry of the SPC. Actavis has commenced this claim in order to clear away for the launch of its generic product, which would otherwise infringe the Patent.
The skilled addressee 7.
It is well established that a patent specification is addressed to those persons likely to have a practical interest in the subject matter of the invention; Catnic v Hill and Smith [1982] RPC 183 at 242 per Lord Diplock. Such persons will have practical knowledge and experience of the kind of work in which the invention is intended to be used. Although the skilled person/team is a hypothetical construct, its composition and mind-set is founded in reality; Schlumberger v Electromagnetic Geoservices [2010] EWCA Civ 819; [2010] RPC 33 at [42] per Jacob LJ.
8.
In the present case, it is common ground that the skilled addressee includes a clinician, and in particular a child and adolescent psychiatrist with expertise in treating ADHD and a research interest in ADHD, who was interested in the development of new treatments for ADHD at the priority date. The primary difference between the parties is whether the skilled addressee would have comprised a team which would also have included a psychopharmacologist, as Actavis submits. Lilly contends that at the priority date, psychopharmacologists did not have experience in ADHD. Professor Peter Hill, who gave evidence on behalf of Lilly, explained that he did not recall the presence of psychopharmacologists on advisory boards to the pharmaceutical industry on which he had sat at the priority date. However, it was pointed out by Professor Philip Cowen, a psychopharmacologist who gave evidence on behalf of Actavis, that pharmacologists and pyschopharmacologists were often employees of drug companies which sponsored advisory boards, and they would contribute during the course of drug development to discussions with clinicians.
9.
In my judgment, a pyschoparmacologist would have been a member of the notional skilled team. [0008] of the Patent cites a paper by Gehlert et al., published in 1993, “for a discussion of the mechanism of tomoxetine’s activity as a norepinephrine reuptake inhibitor”. This paper, together with a paper by Wong et al. which is referenced by Gehlert, is relied upon by Lilly in support of its argument that the disclosure of the Patent is plausible. It was common ground between the experts that these publications are addressed to a psychoparmacologist, whose expertise would be required in order to evaluate their contents. Therefore, such expertise is required by the skilled team to whom the Patent is addressed. Furthermore, Prof. Hill agreed that the skilled team would need someone with knowledge of the pharmacology of the existing drug treatments of ADHD. He said that he would have welcomed a person with knowledge of how drugs worked onto the skilled team “with open arms”.
10.
I accept Prof. Hill’s evidence that psychopharmacologists in 1995 did not have knowledge and experience of ADHD. However, in my judgment, this was not necessary for inclusion in the skilled team, as the required knowledge of ADHD would come from the skilled clinician. However, I consider that this evidence is relevant to the respective roles of the clinician and psychopharmacologist within the skilled team. In the present case I consider that, as of 1995, the clinician would have taken a leading role on the team. Having obtained information about the pharmacology of existing drug treatments for ADHD, it would be for the clinician to
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Actavis Group PTC EHF & anr v Eli Lilly and Co
evaluate the significance of this information on the basis of his knowledge and experience of ADHD. 11.
There is a subsidiary dispute about whether the relevant member of the skilled team would be a “basic” or a “clinical” psychopharmacologist. Prof. Cowen explained that pharmacologists without clinical training, who are sometimes referred to as basic pharmacologists, specialise in the testing of drugs in animal models. They have a deep scientific knowledge of the pharmacological effects of psychotropic drugs, but, unlike clinical psychopharmacologists, do not have clinical experience. Actavis contends that a clinical psychopharmacologist would be a member of the team. I disagree. Given that there were no psychopharmacologists with clinical expertise in ADHD at the priority date, I consider that the expertise of a basic psychopharmacologist would be sufficient for the skilled team.
The witnesses 12.
Each side called eminent technical experts. I have already mentioned Profs. Hill and Cowen. Dr Ronald Steingard is a child psychologist called on behalf of Actavis, and Prof. Trevor Sharp is a psychopharmacologist called on behalf of Lilly. I found the evidence of all the experts most instructive and I am grateful to them for providing it.
Dr Steingard 13.
Dr Steingard is Professor of Psychiatry at the University of Massachusetts Medical School and is the Associate Medical Director of the Child Mind Institute in New York. In January 1995 he was Assistant Professor of Psychiatry at Harvard Medical School, Assistant in Psychiatry and Director of Psychopharmacology in the Department of Psychiatry, Boston Children's Hospital and Research Associate in Psychiatry, Brain Imaging Center, McLean Hospital, Belmont, Massachusetts. He is currently in private practice in New York as an Associate Medical Director and Senior Paediatric Psychopharmacologist. He is also Professor of Psychiatry at University of Massachusetts Medical School, Worcester, Massachusetts.
14.
Lilly accepts that Dr Steingard was trying to assist the Court and makes no personal criticism of him. However, Mr Mitcheson QC submitted that, through no fault of his own, Dr Steingard lacked the necessary experience to put himself properly in the position of the notional skilled clinician. Five points were raised:
15.
First, that he was based in the USA and not the UK, was not exposed to the UK and European field of ADHD, and so was not able to comment on what was common general knowledge in the field at the priority date. I reject this submission. Whilst it is the case that there was a difference in prescribing practice between the UK and the USA, in that it was far more common to treat ADHD with drugs in the USA, UK clinicians were well aware of this in 1995. I do not consider that differences in common general knowledge between the UK and Europe on the one hand, and the USA on the other, are material to this case.
16.
Second, that he was not carrying out research into ADHD at the priority date, having moved his focus to depression. The extent of his involvement in ADHD at the priority date was clarified during cross-examination:
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Actavis Group PTC EHF & anr v Eli Lilly and Co
“Q. And your research at that time was into depression? A.
I still did clinical trial work but I was doing imaging work on depression at the time.
Q.
And the clinical trial work was also concerned with depression?
A.
In 1995 it was principally depression, I think, yes.”
17.
Lilly submits that, in the light of this evidence, Dr Steingard was not in a position to assist the court as to the attitudes of the notional skilled clinician in relation to ADHD at the priority date. I consider that this submission goes too far. Dr Steingard is the joint author of the chapter “Disorders Usually First Diagnosed in Infancy, Childhood or Adolescence” published in The American Psychiatric Press Textbook of Psychiatry, 2nd Ed (1994), which includes a section on ADHD. Nonetheless, when considering areas of disagreement between Prof. Hill and Dr Steingard, I will have regard to the fact that Prof. Hill had more involvement in clinical and research work on ADHD at the priority date than Dr. Steingard.
18.
Third, that he had little practical experience of drug development. I consider that this is a fair point, which I will take account of when considering areas of disagreement between Dr Steingard and Prof. Hill.
19.
Fourth, that he had not sought to read around the subject, confining himself only to the (limited) number of papers sent to him by Pinsent Masons, solicitors for Actavis. I reject this submission. Had Dr. Steingard explored more widely, he would have been criticised for considering matters which were not common general knowledge at the priority date. Dr Steingard considered the material that he and the other experts had exhibited to their reports, which was sufficient.
20.
Finally, that in a case where part of the invention resides in the idea of doing something, and that idea was well known by the time of trial, it can be very difficult to disregard post-acquired knowledge. Lilly submits that in a number of crucial areas, Dr Steingard struggled to put himself in the position of the notional skilled clinician without knowledge of the invention. Lilly further submits that his oral evidence clarified that he was much less enthusiastic about the prior art than might have appeared from his expert reports. I accept these submissions, and will bear them in mind, in particular when considering alleged lack of inventive step.
Professor Hill 21.
Prof. Hill is a Consultant Child and Adolescent Psychiatrist with 40 years’ experience in the psychiatry of the young, and with a special interest in neurodevelopmental disorders, including ADHD. He qualified in medicine and surgery in 1969 from Cambridge University. Subsequently he specialised in child and adolescent psychiatry and has practised in this area since 1975 including at the Maudsley Hospital, Great Ormond Street Hospital for Children and St George’s Hospital and Medical School. He retired from hospital medicine in 2003 (although he continued on an honorary basis until 2012) and since then has run a private clinic in Harley Street treating children and adolescents with complex psychiatric disorders.
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Actavis Group PTC EHF & anr v Eli Lilly and Co
22.
He has received recognition for his contribution in the field of child and adolescent psychiatry and has been awarded Fellowships from each of the Royal College of Psychiatrists (1987), the Royal College of Physicians (1994), and the Royal College of Paediatrics and Child Health (1997). He has also served on a number of academic advisory boards and meetings, including boards concerned with ADHD, during which atomoxetine, amongst other treatments, was discussed. He had had experience of interaction with drug development teams at the priority date.
23.
Actavis alleges that when considering the plausibility of the Patent, Prof. Hill had an erroneous belief that no reputable company would make statements in a patent if it did not have data to support those statements. He considered that, as the Patent was a document which had legal significance and had been examined by the relevant authorities, its statements should be accepted at face value. It is correct that Prof. Hill had this belief. I will consider the significance of this misunderstanding when I come to the issue of plausibility. Actavis is also correct in its submission that Prof. Sharp shared this erroneous belief.
24.
Actavis submits that aspects of Prof. Hill’s evidence changed in a material way between his reports and his cross-examination. I reject this as a criticism of the Professor. During his cross-examination, Prof. Hill accepted a proposition put to him by Counsel, which he later corrected, and I accept his correction. It is inevitable that evidence is expanded and clarified by witnesses during the course of crossexamination, particularly where the same question is asked on more than one occasion.
25.
I consider that Prof. Hill was an excellent expert witness who gave his evidence in a balanced, modest and clear manner.
Professor Cowen and Professor Sharp 26.
It is unnecessary for me to set out the experience of Professors Cowen and Sharp. Both are eminent in their fields. Prof. Cowen is a clinical psychopharmacologist and Prof. Sharp is a basic pyschopharmacologist. For the reasons explained above, I do not consider that the difference between their areas of expertise is relevant. Neither of them had any experience in ADHD at the priority date, and they both explained that they would have deferred to the expertise of the clinician in this area. In my judgment, they both gave their evidence very fairly and insofar as there was any criticism of them (which was very limited) I reject it.
Common general knowledge 27.
I shall apply the legal principles in respect of identification of common general knowledge as set out by Arnold J in KCI Licensing v Smith and Nephew [2010] EWHC 1487 (Pat); [2010] FSR 31 at [105]–[115], which were approved by the Court of Appeal at [2010] EWCA Civ 1260; [2011] FSR 8 at [6]. As would be expected, much of the following was common ground between the experts. There were, however, some important areas of disagreement between the experts which I consider below.
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Actavis Group PTC EHF & anr v Eli Lilly and Co
ADHD 28.
The core symptoms of ADHD include severe and impairing inattentiveness, impulsiveness and over-activity. It is a debilitating condition that can disrupt family care, impede educational achievement and progress, and lead to rejection and exclusion by peers. It was common general knowledge that other conditions often coexisted alongside ADHD, including tic disorders. Whilst ADHD is primarily associated with childhood and adolescence it continues into adulthood, and this was well known by the priority date.
29.
The name and characterisation of the condition has varied over the years but, by the priority date, there were two major diagnostic categorisations: hyperkinetic disorder (ICD-10, 1990) and ADHD (DSM-IV, 1994). ICD-10 was widely used but DSM-IV was also well known. DSM-IV is quoted in the Patent, and is therefore the diagnostic categorisation of relevance to the present case.
30.
DSM-IV provides two lists of nine symptoms relating, respectively, to inattention and hyperactivity-impulsivity. A patient with six or more symptoms from both of these lists will be diagnosed with combined type ADHD whereas a patient with six or more symptoms from only one of the lists will be diagnosed with predominantly inattentive or predominantly hyperactive-impulsive ADHD, as appropriate. Most people exhibit the listed symptoms to some degree and therefore an ADHD diagnosis requires that they are present to a severe degree and cause impairment in more than one setting.
31.
At the priority date there were significant geographical variations in the rate of diagnosis of ADHD. Diagnosis rates in parts of the USA were much higher than in the UK whereas in France ADHD diagnoses were virtually non-existent.
Treatment of ADHD 32.
The leading pharmacological treatments for ADHD at the priority date were the central nervous system stimulants, primarily methylphenidate, sold under the brand name “Ritalin”. Stimulants had been the first line treatment for many years by the priority date, since at least the early 1980s.
33.
Prof. Hill recalls that he selected Ritalin at the priority date in about 90% of the cases in which he prescribed medication. However, Dr Steingard’s evidence, which I accept, was that it was generally thought that there was a significant proportion of patients (between about 20 and 30% - the precise percentage does not matter) who either did not respond to stimulants, or for whom stimulants were inappropriate or intolerable.
34.
Stimulants had the advantage of a rapid and powerful effect but also had a number of disadvantages: a)
the effect was limited in duration to a few hours and therefore multiple dosing was required;
b)
stimulants could cause insomnia; a rebound effect (leaving patients in an irritable state as the drug wears off); and/or suppression of appetite (raising concerns about interference with growth);
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Actavis Group PTC EHF & anr v Eli Lilly and Co
c)
some children did not like taking stimulants because they made them feel “on edge”; and
d)
some parents were concerned about giving their children controlled substances that were associated with amphetamine.
35.
In spite of these disadvantages, stimulants were the “gold standard” for treatment of ADHD at the priority date.
36.
Because of the proportion of cases where stimulants were ineffective or contraindicated, which was not insignificant, a number of other pharmacological treatments had been used by the priority date as second line therapy for the treatment of ADHD. Alternatives included the tricyclic antidepressants (“TCAs”) and clonidine (an antihypertensive).
TCAs 37.
TCAs were antidepressant drugs that were used in the treatment of ADHD. This use of TCAs was very well established by the priority date and they had been used as second line therapy for treating ADHD since at least the early 1980s. TCAs were known to be effective in ADHD even though they were given at lower doses than those used in depression. They were also known to act more quickly in ADHD than in depression.
38.
TCAs were also known to suffer from a number of problems: a)
They were known not to be as efficacious as the stimulants, which was a significant disadvantage.
b)
They had a number of unwanted side effects, including dry mouth, constipation, urinary hesitancy, hypotension and sedation.
c)
They were associated with serious cardiac toxicity issues when taken in overdose. As a result, those taking TCAs were monitored for any cardiac effects.
d)
In the early 1990s a number of sudden deaths had occurred in children taking therapeutic doses of desipramine.
39.
There was some debate about whether these sudden deaths were associated with desipramine alone, or alternatively made clinicians particularly wary of using TCAs generally. I find that the cause of the sudden deaths was uncertain. This made clinicians more cautious about prescribing TCAs for ADHD, although imipramine, as distinct from desipramine, continued to be prescribed by UK clinicians after the priority date, as at the time it was the best available alternative to stimulants.
40.
Both sides rely on these facts for different reasons. Actavis submits that, having regard to the disadvantages of TCAs, there was a strong motivation to develop alternative treatments at the priority date. Lilly submits that there was a long felt want for alternatives to TCAs, which had existed for many years before the priority date and which had not been satisfied until the launch of Strattera, the commercial embodiment of the Patent. Given that the prior art was published more than a decade
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Actavis Group PTC EHF & anr v Eli Lilly and Co
before the priority date, Mr Mitcheson posed the familiar question – if it was obvious, why was it not done before? 41.
My findings on this issue are as follows: First, it is the case that there was a motivation to develop alternative second line treatments to TCAs at the priority date. This motivation was not as strong as the desire to find alternative stimulants without the disadvantages of this class of drugs, but it nonetheless existed. Second, 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 desipramine. The other drawbacks of TCAs had been known for many years, and yet there had been little advance in the treatment of ADHD from the early 1980s until the priority date. I will consider the significance of these findings when reaching my conclusions about inventive step.
Clonidine 42.
It was common ground that clonidine, as well as certain other antipsychotics, were occasionally used at the priority date for the treatment of ADHD. As with TCAs, the drawbacks of antipsychotics were well known.
The underlying pathophysiology of ADHD 43.
It was common ground that the pathophysiology (the underlying cause(s) of the symptoms of the ADHD) was not well understood at the priority date. Prof. Hill identified a number of possible approaches to an understanding of the pathophysiology of ADHD, all of which had produced limited results. I accept his evidence. In summary: a)
the emerging psychological theory at the time was that ADHD was fundamentally a deficit of impulse control and planning and an underfunctioning of the frontal lobes of the brain;
b)
functional brain imaging techniques had begun to be used but were at an early stage;
c)
studies had suggested that there were inherited components to ADHD but it was not known which genes were implicated. Significant advances in understanding the genetic causes of ADHD came after the priority date;
d)
there were no animal models of ADHD that were generally accepted or used in ADHD drug development;
e)
One approach was to analyse neurotransmitter metabolites in body fluids such as urine. These did not necessarily provide an accurate reflection of cerebral neurochemical activity but were nonetheless undertaken in the absence of anything better;
f)
metabolite comparisons between ADHD patients and normal children had not produced a consistent common picture: for example, some showed decreased metabolites whereas others showed no difference or an increase;
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g)
Actavis Group PTC EHF & anr v Eli Lilly and Co
another approach was to consider the mechanism of action of drugs known to be effective in ADHD. There was an important dispute about the level of understanding of the role of particular neurotransmitters in such drugs, which I consider below.
Neurochemistry 44.
Nerve signals in the brain are transmitted by a combination of electrical signals passing along neurons and chemical neurotransmitters passing between neighbouring neurons. Neurotransmitters are released from the presynaptic terminal of a neuron into the synapse (gap) between it and the neighbouring neuron, and bind to specific receptors on the post-synaptic neuron. The anatomy of a neuron is illustrated by the following diagram shown in Prof. Cowen’s first report:
45.
This process continues until the neurotransmitter is either inactivated by enzymatic degradation or taken back up into the presynaptic neuron (“reuptake”). Slowed enzymatic degradation or prevention of uptake will result in the neurotransmitter being present in the synaptic cleft for longer and increase its action at the postsynaptic cell. The following diagram, again shown in Prof. Cowen’s first report, provides an illustration of how these processes work in a norepinephrine (“NE”) neuron, showing the release of NE into the synapse and the NE receptors on the postsynaptic neuron:
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46.
The availability of a given neurotransmitter in the synapse can be altered in a number of ways including slowed enzymatic degradation, prevention of reuptake (“reuptake inhibition”) and through a neurotransmitter releasing agent. The following diagram is an illustration of how a reuptake inhibitor ( ) prevents the reuptake of the neurotransmitter ( ) into the pre-synaptic neuron by binding to the reuptake pump, thus increasing the concentration of the neurotransmitter in the synaptic cleft and the amount of receptor activation ( ).
47.
Prof. Cowen also explained the difference between “non-selective” and “selective” drugs, as used in the treatment of psychiatric disorders. Non-selective drugs had pharmacological actions on several different neurotransmitter receptors and/or uptake sites. Some (or one) of these actions were thought to be involved in mediating the therapeutic effect of the drug, while the others were regarded as producing unwanted or adverse effects. Other drug compounds were relatively selective in the pharmacological target with which they engaged.
48.
The principal neurotransmitters of relevance to this case are:
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49.
Actavis Group PTC EHF & anr v Eli Lilly and Co
a)
dopamine (“DA”);
b)
NE, also known as noradrenaline; and
c)
serotonin, also known as 5-hydroxytryptamine (“5-HT”).
These three neurotransmitters are all monoamines, a group which also includes histamine, epinephrine (also known as adrenaline) and melatonin. DA, NE and epinephrine form a sub-group of the monoamines known as the catecholamines. The effects of NE, DA and 5-HT differ, because they are synthesised by different cells, have differing patterns of innervation (supply of neurons) and interact with specific receptors that have differing distributions across the brain.
The role of neurotransmitters in ADHD 50.
There is a complex and important dispute about the state of common general knowledge at the priority date in relation to this issue. I will summarise each party’s case and then set out my conclusions:
Actavis’ case 51.
There are a number of steps in Actavis’ argument on this issue. First, whilst accepting that an understanding of the pathophysiology of ADHD would clearly have been useful and relevant to drug development, it contends that drug development decisions could still be made based on the pharmacology of existing drugs. Certain examples were provided to illustrate this, by reference to drugs which were trialled or developed in the absence of a clear causal hypothesis about the pathophysiology of the psychiatric condition in question.
52.
Second, Actavis argues that the following was common general knowledge in respect of the acute pharmacological actions of established ADHD treatments at the priority date: a)
Stimulants blocked the reuptake of DA and NE and also caused the release of DA and NE, both of which increased DA and NE levels in the synapses.
b)
TCAs blocked the reuptake of NE and 5-HT, which increased levels of NE and 5-HT in the synapses. TCAs also acted on cholinergic, adrenergic and histaminergic receptors, leading to them being regarded as “pharmacologically dirty”.
c)
However, TCAs did not have any significant acute pharmacological action on dopamine reuptake or dopamine receptors.
53.
Prof. Hill did not accept that all this was common general knowledge. However, Actavis submits that the skilled team would include a psychopharmacologist who would know about the pharmacology of these drugs and would pass this on to the clinician, to the extent that he did not already know this information.
54.
Third, Actavis argues that it was common general knowledge that the acute NE reuptake blocking effect was the trigger responsible for the therapeutic efficacy of
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TCAs in the treatment of ADHD. It relies on Dr Steingard’s evidence that this was the prevailing view at the priority date. 55.
It submits that Dr Steingard’s opinion was corroborated by the following documentary evidence, which it suggests is illustrative of the common general knowledge: a)
Table 2 in the review article “Neurobiology of Attention Deficit Disorder with Hyperactivity: Where have we come in 50 years?” Zametkin et al, American Academy of Child Adolescent Psychiatry 1987 (“Zametkin”). This table, reproduced in certain textbooks, attributed the efficacy of TCAs in ADHD to their action on NE, not DA;
b)
The statement in the 1990 textbook “Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis” Dupaul et al, that TCAs “are slower-acting medications that have been shown to produce behavioural effects similar to those of the stimulants with ADHD children. This is presumably due to their agonistic effects on the noradrenergic system as obtained with the CNS stimulants. ”
c)
The comment by Dr Gross in his 1973 paper “Imipramine in the Treatment of Minimal Brain Dysfunction in Children” that: “Both amphetamines and methylphenidate are known to enhance the available pool of norepinephrine in the brain…” so “it was thought that other medications which also increase the levels of available norepinephrine in the brain might also be effective.”
d)
The statements in a chapter by Dr Shenker published in the 1992 edition of “Advances in Paediatrics” (“Shenker”) that: “The reduced efficacy of imipramine and desipramine compared to the stimulants is of special interest because these antidepressants are much less potent at inhibiting uptake of DA than they are at inhibiting NE reuptake in vitro (1000 and 10000 fold less potent respectively). Selectivity of these two antidepressants for noradrenergic vs dopaminergic systems is retained in vivo. It has been hypothesised that imipramine and desipramine are not as effective as d-amphetamine in ADHD because, unlike d-amphetamine, they lack the ability to potentiate dopaminergic activity.” and
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“the evidence that selective inhibition of NE uptake by tricyclic antidepressants does not produce full therapeutic effects has been mentioned” (e)
The statement in Biederman et al “A Double Blind Placebo Controlled Study of Desipramine in the Treatment of ADD” published in 1989 that: “Since DMI [desipramine] has a powerful and selective inhibitory effect on the neuronal uptake of norepinephrine and alters its metabolism and effects on adrenergic receptors in the mammalian brain, these findings may suggest that the somewhat delayed antiADDH effects of DMI, like its anti-depressant effects, may relate to the drug’s actions on this central neurotransmitter system by actions partly shared with those of the stimulants.”
56.
Actavis submits that, given what was thought about the pathophysiology of ADHD (i.e. that DA and NE were involved in the pathophysiology), and given that the stimulants also inhibited the reuptake of NE and DA, there were good reasons for the belief that the therapeutically relevant pharmacological action of the TCAs was NE reuptake inhibition. Furthermore, it suggests that: a)
5-HT was not thought to be relevant to the pathophysiology of ADHD and that the 5-HT reuptake inhibition action of the TCAs was not thought to be responsible for their therapeutic efficacy;
b)
the skilled team would not think that the acute effects of the TCAs on the cholinergic, histaminergic or adrenergic receptors were responsible for therapeutic efficacy, as these acute pharmacological effects were responsible for a number of the unwanted side effects of the TCAs.
57.
Accordingly, Mr Tappin asks, forensically, what acute pharmacological effects other than the NE reuptake blockade could be responsible for the therapeutic effects of the TCAs on ADHD?
58.
Fifth, Actavis accepts that the skilled team would not have known how the acute pharmacological action of the TCAs actually resulted in therapeutic efficacy in ADHD. In other words, the skilled team would not know what the downstream events caused by the relevant acute pharmacological action (e.g. the cascade of signalling changes) were, or how those downstream events caused therapeutic efficacy. Nonetheless, it submits that it was still possible to have a reasonable expectation that another NE reuptake inhibitor would have a therapeutic effect in ADHD, for the following reason.
59.
It argues that the evidence showed that, where a drug affects a particular acute target (which gives rise to its therapeutic efficacy – either directly, or indirectly by downstream events), another drug affecting the same acute target in the same way would generally be expected to give rise to similar downstream events and (therefore) a similar therapeutic effect. Applying this logic to ADHD, Actavis submits that the
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acute pharmacological action of NE reuptake inhibition was thought likely to be responsible for the therapeutic effect of the TCAs in ADHD (in the sense of being the initial trigger for that therapeutic effect). Another drug which had that acute pharmacological action would have been expected to result in similar therapeutic efficacy. Accordingly, the fact that the steps between the acute action of NE reuptake inhibition and therapeutic efficacy in ADHD were not well understood was, for the purposes of this case, irrelevant. Lilly’s case 60.
As might be expected, Lilly presents a very different picture of the common general knowledge at the priority date about the role of neurotransmitters in ADHD.
61.
First, regarding the mechanism of action of drugs associated with the treatment of ADHD, Lilly relies on Prof. Hill’s evidence that the picture was confused at the priority date: a)
methylphenidate and dextroamphetamine were generally thought to affect neurotransmission by DA and NE;
b)
pemoline was generally thought to affect DA neurotransmission; and
c)
the TCAs (which were not as effective as the stimulants) were thought to affect NE, 5-HT and DA neurotransmission by blocking reuptake (not causing release) and had a range of effects on other neurotransmitter systems (including histamine and acetylcholine).
62.
The acute pharmacological effect of methylphenidate and dextroamphetamine (stimulants) was to increase DA levels by a combination of release and reuptake inhibition and NE to some extent. However, the overall picture of their effect was complicated by the fact that ADHD patients were observed to have lower-than-normal excretion of NE metabolites and that the stimulants reduced these levels even further.
63.
As to clonidine, the position, according to Lilly, was again complex. It was known to have two acute pharmacological effects on NE: it would decrease NE release presynaptically and increase the activity of the post-synaptic receptor. As a general matter, predicting in advance its overall effect would be difficult. However, at the doses at which it was given in ADHD it was common general knowledge that its overall effect was to decrease NE levels. Dr Steingard had expressed this view shortly before the priority date and he accepted during cross-examination that the skilled person’s view would accord with what he had written. This was contrary to Actavis’ case that it would have been common general knowledge that TCAs, like clonidine, were effective as a result of an increase in NE levels.
64.
Lilly therefore submits that although knowledge of the acute pharmacological actions of effective drugs would have been useful, it could not be assumed that because the pharmacological mechanism of each of these drugs had been identified, that that was the means by which they worked in ADHD.
65.
Second, Lilly submits that common general knowledge regarding the role of neurotransmitters in ADHD was limited, but could be summarised as follows:
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Actavis Group PTC EHF & anr v Eli Lilly and Co
a)
ADHD was suspected to involve some abnormality in neurotransmission, particularly the catecholamines and especially DA and NE;
b)
it was highly likely that several neurotransmitter systems were involved;
c)
it was not known whether one or other of these pathways played a more important role;
d)
the available evidence undermined a single-neurotransmitter hypothesis and the skilled clinician would have thought that more than one neurotransmitter system was involved;
e)
there was a theory that NE had a role to play, but it was not known whether it went up or down. Similarly it was common clinical knowledge that dopamine appeared to be part of the disorder; and
f)
theories regarding the underlying role of neurotransmitters existed but none were known to be correct and none were generally accepted.
Third, Lilly acknowledges that the psychopharmacologist (who I have decided would be on the skilled team) would believe as a matter of generality that TCAs were thought to inhibit reuptake of NE (and 5-HT) rather than all of NE, 5-HT and DA. Nevertheless it suggests that their ultimate mechanism of action was much less clear. Lilly accepts that the idea that the NE reuptake inhibition action of the TCAs was a possible explanation of their clinical efficacy and that this idea had been put forward by various authors before the priority date. However, Prof. Hill’s evidence was that this idea was viewed with some scepticism as it did not explain why the TCAs worked on different timescales and at different doses in ADHD when compared to depression. He summarised his position as follows: “A. You see, it is very difficult, because I do not think then we thought that reuptake inhibition was a sufficient explanation for anything; and subsequently, of course, you know, that has been proved right, but we did not know that at the time; but we were suspicious of it, we were sceptical of it. That is my difficulty. I wish I could give you a fully formed formulation of how we thought tricyclics were working, but we could not; we did not know, but it looked different.”
67.
Fourth, Lilly submits that the skilled psychopharmacologist would need input from the skilled clinician as to what the on-target effects were in ADHD before the reduction of off-target effects could be addressed. However, common general knowledge as to what was on-target and what was off-target was very limited.
68.
Fifth, Lilly addresses Prof. Cowen’s evidence in his first report at [39] that: “where there was evidence that drugs found to be active in the treatment of the symptoms of psychiatric disease in humans affected a particular neurotransmitter, the skilled psychopharmacologist would expect that another drug affecting
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the same neurotransmitter pathway could also have a therapeutic effect on the symptoms of that disease”. 69.
This formed an important part of Actavis’ case, but Lilly submits that Prof. Cowen narrowed this approach considerably in cross-examination. It is correct that Prof. Cowen accepted that there were drugs that were known to affect NE pathways which were not thought to be effective in ADHD. In the light of this, Prof. Cowen qualified his view on how far inferences about therapeutic activity could be drawn between drugs in this context, and even whether NE drugs could accurately be described as a class. Prof. Cowen also accepted that there was considerable uncertainty about the precise relationship between potentially relevant neurotransmitters and any particular psychiatric disorder insofar as the same drug might be useful in different conditions.
70.
Sixth, Lilly relies on a number publications to support Prof. Hill’s view as to the limited knowledge as to the role of neurotransmitters in ADHD at the priority date. I shall focus primarily on the Zametkin review article. The discussion (amongst other hypotheses) of the “Noradrenergic Hypothesis”on Page 3 of Zametkin states that: “Support for a noradrenergic hypothesis (leaving aside the issue of over or underactivity) comes from several areas. Drugs ameliorating ADDH often alter MHPG. That dextroamphetamine reduces the urinary excretion of MHPG has now been demonstrated by three independent laboratories (Brown et al., 1981; Shekim et al., 1977, 1979; Zametkin et al., 1984). Moreover, the significant reduction in urinary MHPG after desipramine, which is moderately efficacious in ADDH, also implicates the noradrenergic system (Donnelly et al., 1986).”
71.
Lilly points out that whilst that discussion suggests a role for NE in the amelioration of ADDH, it is equivocal as to whether efficacy comes from an increase or decrease in NE, which reflected uncertainty arising from the analysis of metabolites in body fluids.
72.
Lilly also relies on Table 2 on page 4, which was reproduced in, amongst other publications, Shenker. Mianserin is included in the same section as the TCAs in the NE row, but is said to be minimally effective in the treatment of ADHD. It also refers to Pages 4 and 6 of Zametkin; “Thus, changing noradrenergic function might be necessary, but it is not a sufficient condition for improvement in ADDH.” … “It is clear by now that the array of effective agents has put to rest any single transmitter hypothesis”
73.
Lilly submits that this tends to refute the hypothesis that targeting NE alone would achieve ADHD improvement, and suggests that no single neurotransmitter hypothesis was generally accepted as responsible for efficacy in the treatment of ADHD.
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Actavis Group PTC EHF & anr v Eli Lilly and Co
Next, Lilly refers to page 7 of Zametkin: “Although few new pharmacodynamic studies seem useful at this time, trials of a combination of dopaminergic and noradrenergic agents, e.g., sinemet plus desipramine, might demonstrate much greater efficacy than either one alone, supporting roles for both neurotransmitters.”
75.
Lilly submits that this points away from a simple choice of a selective NE reuptake inhibitor as an alternative to the TCAs.
76.
Lilly reinforces this submission by reference to a number of chapters in textbooks published before the priority date, which, it suggests, show similar doubts as to the validity of the NE reuptake hypothesis as the cause of efficacy of the TCAs in the treatment of ADHD, and confusion over the results of the metabolite urinary tests. Overall, Lilly submits that these passages support Prof. Hill’s evidence that very little was understood about the role of neurotransmitters in ADHD at the priority date.
Assessment 77.
Having set out the parties’ submissions on this issue at some length, I can summarise my findings as follows: a)
The skilled pharmacologist would have knowledge of TCAs as antidepressants and would advise the skilled clinician that the acute pharmological action of TCAs was most likely to result from selective inhibition of NE reuptake. However, the pharmacologist would have no knowledge of ADHD, and would defer to the clinician as to what inferences could be drawn from this information
b)
The skilled clinician would consider the hypothesis that TCAs had efficacy in the treatment of ADHD as a result of selective inhibition of NE reuptake to be reasonable. However, he would consider that the position in ADHD could be far more complex, and that a number of other contributory causes were possible. He would not consider that it was possible to ignore “downstream” events. He would not consider that the steps between the acute action of NE reuptake inhibition and therapeutic efficacy in ADHD were irrelevant. 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
c)
I accept the thrust of Prof. Hill’s evidence that the simple picture presented on behalf of Actavis was, essentially, hindsight reasoning, and the position at the time was far less clear.
d)
These conclusions, in my judgment, are amply supported by the passages from the textbooks and other articles to which I have referred, which are illustrative of common general knowledge.
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Selectivity as a drug development goal 78.
Actavis submits that there was a general interest in selective psychoactive drugs at the priority date because in general terms, the more selective the drug (i.e. the more reduced the “off-target” effects) the better the side effect and safety profile will be. This point was made by Dr Cobb in “Practical Problems in Clinical Psychiatry” Hawton and Cowen (1992): “A guiding concept in the search for new psychoactive agents has been increasing the selectivity of the drugs for their actions on single neurotransmitter systems.”
79.
In general terms, I accept this. It was a reasonable hypothesis that increased selectivity would result in less side effects. However without clear knowledge of which neurotransmitter(s) are on or off-target (and I have found that the common general knowledge lacked such clarity in respect of ADHD), it does not provide a clear way forward. It all depends on what is meant by off-target, and focussing on one neurotransmitter might have been thought to lead to efficacy losses.
The Patent The Description 80.
[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.
81.
[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.
82.
[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
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reuptake. Thus, it is quite free of side effects and is properly considered to be a selective drug.” 83.
Lilly submits that, upon reading Gehlert, the skilled psychopharmacologist would be interested in reading Wong (citation 10) for three reasons – Prof. Wong was wellknown 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.
84.
[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.”
85.
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.
86.
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.
87.
[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.
The claims 88.
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
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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 89.
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]).
90.
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.”
91.
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.
92.
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.”
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Actavis Group PTC EHF & anr v Eli Lilly and Co
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…”
Obviousness – the law General Principles 94.
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.”
95.
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.
96.
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.”
97.
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.
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98.
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
What must be obvious? 99.
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].” ”
100.
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.
Obvious to try/fair prospect of success 101.
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.
102.
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 nonexhaustive list of factors identified by Kitchin J in
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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.
103.
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.”
104.
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
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weapon in the armoury of those challenging the validity of a patent.” 105.
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.”
106.
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’.”
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The cited prior art Chouinard 107.
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 clinically significant 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”.
108.
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.
109.
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.
110.
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 111.
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
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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. 112.
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.
113.
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.
114.
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.
115.
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.”
Wong 116.
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
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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. 117.
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.
118.
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.
119.
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)”.
Obviousness in the light of Chouinard 120.
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.
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Was it obvious from Chouinard to try atomoxetine in the treatment of ADHD? 121.
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.
122.
The case in favour of ‘obvious to try’ may be summarised as follows: a)
there was precedent for using antidepressant drugs, and in particular the TCAs, as a second line treatment for ADHD;
b)
at the priority date, there was a need for a replacement for the TCAs as a second line treatment for ADHD and therefore there was motivation to try an alternative;
c)
therefore, the skilled team would be interested in finding new treatments for ADHD and would read Chouinard with this interest in mind;
d)
Chouinard discloses that atomoxetine is a selective NE reuptake inhibitor. Its disclosure is supported by Wong, and is credible. The skilled pharmacologist would advise the skilled clinician that the acute pharmacological action of the TCAs was to block the reuptake of NE;
e)
the authors of Chouinard are cautiously encouraging about the likely efficacy of atomoxetine in the treatment of depression, and its possible avoidance of unwanted side effects as a result of its selectivity;
f)
it would have been relatively straightforward to perform a basic phase II trial on adults to test atomoxetine in ADHD patients.
123.
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.
124.
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.
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125.
Actavis Group PTC EHF & anr v Eli Lilly and Co
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?
126.
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.
127.
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.”
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128.
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.”
129.
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.
130.
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 inpatient unit without a comparator would make you think one way or the other.”
Obviousness in the light of Zerbe 131.
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.
132.
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
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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. ” 133.
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.
134.
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.
135.
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.
Fair expectation of success 136.
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.
137.
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.
138.
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, if it had the idea, the skilled team would have a fair expectation that atomoxetine would be effective in the treatment of ADHD. Both
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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. 139.
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.
140.
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:
141.
a)
“you might consider” a single transmitter
b)
“conceptually thinking about where else I might think about applications of an agent of this kind of property…are there other things that this might be useful for?”;
c)
“If I were looking for something that might take the place of the tricyclics, I might be interested in this”;
d)
“theoretically I think I would have been interested in taking a look at it”;
e)
“if someone had approached me and said would you be interested in doing a trial and I have the funding to do this, I might be interested”;
f)
“Once somebody said this was available and it is an interesting agent, I would think about it. I was not out there looking for these sorts of things, that is for sure”;
g)
“you have an idea, a hypothesis, you have an idea of a story about why you might be interested in something”;
h)
“it would have been easier to use a drug that was available on the marketplace, unless I was approached by somebody to say we are looking to develop this compound and I want to conduct a trial of it, which I was part of at some point in my life”.
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
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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. 142.
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. ”
Other factors Future direction of research as of 1995 143.
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.
144.
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.
Longfelt want 145.
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.
146.
Dr Steingard was asked about this during his cross-examination:
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“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 ----
147.
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.
Insufficiency 148.
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.
Actavis’ submissions 149.
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.
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150.
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.”
151.
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.
152.
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
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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.” 153.
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.
154.
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.
155.
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.
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156.
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
Lilly’s submissions 157.
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.
158.
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.
159.
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).
160.
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.
161.
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
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in Re Prendergast’s Application [2000] RPC 446, which is cited with approval in those paragraphs. 162.
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.”
163.
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.
164.
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
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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.” 165.
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.
166.
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]).
167.
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.
168.
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. …
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Actavis Group PTC EHF & anr v Eli Lilly and Co
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.”
169.
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.
170.
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.
171.
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.
Assessment 172.
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.
173.
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.
174.
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
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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. 175.
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.
176.
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.
177.
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 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.
Plausibility – application to the facts 178.
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.
179.
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
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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. 180.
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.
The expert evidence 181.
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?
182.
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:
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“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.”
183.
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.
184.
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.
185.
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
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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. 186.
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.
The alleged squeeze between obviousness and insufficiency 187.
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.
Agrevo Obviousness/loss of priority 188.
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.
Conclusion 189.
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.
