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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.
MR JUSTICE HENRY CARR
Approved Judgment
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
MR JUSTICE HENRY CARR
Approved Judgment
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:
MR JUSTICE HENRY CARR
Approved Judgment
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.
MR JUSTICE HENRY CARR
Approved Judgment
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.
MR JUSTICE HENRY CARR
Approved Judgment
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);
MR JUSTICE HENRY CARR
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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
MR JUSTICE HENRY CARR
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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;
MR JUSTICE HENRY CARR
Approved Judgment
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:
MR JUSTICE HENRY CARR
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Actavis Group PTC EHF & anr v Eli Lilly and Co
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:
MR JUSTICE HENRY CARR
Approved Judgment
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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Actavis Group PTC EHF & anr v Eli Lilly and Co
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
“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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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:
MR JUSTICE HENRY CARR
Approved Judgment
66.
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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
MR JUSTICE HENRY CARR
Approved Judgment
74.
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 re-uptake 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.
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
89.
Interpretation of Swiss form claims
90.
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]).
91.
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.”
92.
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.
93.
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.”
MR JUSTICE HENRY CARR
Approved Judgment
94.
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
95.
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.”
96.
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.
97.
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.”
98.
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.
MR JUSTICE HENRY CARR
Approved Judgment
99.
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?
100.
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].” ”
101.
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
102.
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.
103.
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
104.
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.”
105.
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
MR JUSTICE HENRY CARR
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Actavis Group PTC EHF & anr v Eli Lilly and Co
weapon in the armoury of those challenging the validity of a
patent.”
106.
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.”
107.
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’.”
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
The cited prior art
Chouinard
108.
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”.
109.
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.
110.
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.
111.
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
112.
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
113.
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.
114.
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.
115.
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.
116.
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
117.
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
MR JUSTICE HENRY CARR
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Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
118.
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.
119.
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.
120.
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
121.
Applying the Pozzoli approach, I have identified the notional skilled team and the
relevant common general knowledge. Claim 1 of the Patent does not need to be
paraphrased in order to comprehend the inventive concept, and would be understood
as I have construed it. The difference between Chouinard and claim 1 of the Patent is
that there is no suggestion in Chouinard to use atomoxetine in the manufacture of a
medicament for the treatment of ADHD. The question is whether this difference
would have been obvious in 1995.
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
Was it obvious from Chouinard to try atomoxetine in the treatment of ADHD?
122.
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.
123.
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.
124.
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.
125.
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.
MR JUSTICE HENRY CARR
Approved Judgment
126.
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?
127.
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.
128.
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.”
MR JUSTICE HENRY CARR
Approved Judgment
129.
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.”
130.
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.
131.
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
132.
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.
133.
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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. ”
134.
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.
135.
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.
136.
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
137.
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.
138.
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.
139.
As to the common general knowledge, I have concluded that the skilled clinician
would consider that the hypothesis that the TCAs had efficacy in the treatment of
ADHD as a result of selective inhibition of NE reuptake was reasonable. That lends
some support to the claim that, having had the idea, the skilled team would have a fair
expectation that atomoxetine would be effective in the treatment of ADHD. Both
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
140.
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.
141.
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:
142.
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
MR JUSTICE HENRY CARR
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Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
143.
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
144.
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.
145.
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
146.
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.
147.
Dr Steingard was asked about this during his cross-examination:
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
“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 ----
148.
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
149.
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
150.
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.
MR JUSTICE HENRY CARR
Approved Judgment
151.
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.”
152.
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.
153.
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.”
154.
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.
155.
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.
156.
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.
MR JUSTICE HENRY CARR
Approved Judgment
157.
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
158.
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.
159.
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.
160.
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).
161.
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.
162.
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
in Re Prendergast’s Application [2000] RPC 446, which is cited with approval in
those paragraphs.
163.
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.”
164.
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.
165.
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.”
166.
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.
167.
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]).
168.
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.
169.
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.
…
MR JUSTICE HENRY CARR
Approved Judgment
15.
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.”
170.
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.
171.
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.
172.
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
173.
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.
174.
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.
175.
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
176.
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.
177.
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.
178.
The cases on which Lilly relies (to which I have referred above) establish that the test
of plausibility is a threshold test which is satisfied by a disclosure which is “credible”,
as opposed to speculative. That disclosure may subsequently be confirmed or refuted
by further evidence obtained subsequent to the priority date. If it is subsequently
shown that the invention does not work with substantially all of the products or
methods falling within the scope of the claim then the scope of the monopoly will
exceed the technical contribution and the patent will be invalid. This indicates why
plausibility is only a threshold test. A plausible invention may nonetheless be shown
to be insufficient. In my judgment the standard for assessment of plausibility is not
the same the standard for assessment of expectation of success in the context of
obviousness.
Plausibility – application to the facts
179.
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.
180.
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
MR JUSTICE HENRY CARR
Approved Judgment
Actavis Group PTC EHF & anr v Eli Lilly and Co
selectivity would reduce side effects. He would have considered that position in
relation to ADHD could be more complex, but that does not detract from the
conclusion that the skilled team would consider that the invention of the patent was
credible, based on the specification and common general knowledge.
181.
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
182.
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?
183.
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:
MR JUSTICE HENRY CARR
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Actavis Group PTC EHF & anr v Eli Lilly and Co
“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.”
184.
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.
185.
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.
186.
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
MR JUSTICE HENRY CARR
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Actavis Group PTC EHF & anr v Eli Lilly and Co
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.
187.
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
188.
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
189.
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
190.
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.