Hilary
Term
[2019] UKSC 15
On appeal from: [2017] EWCA Civ 1671
JUDGMENT
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Actavis
Group PTC EHF and others (Respondents) v ICOS Corporation and another
(Appellants)
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before
Lady Hale, President
Lord Kerr
Lord Sumption
Lord Hodge
Lord Briggs
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JUDGMENT GIVEN ON
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27 March 2019
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Heard on 19 and 20 November 2018
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Appellants
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Respondents
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Andrew Waugh QC
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Adrian Speck QC
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Thomas Mitcheson QC
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Mark Chacksfield
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Katherine Moggridge
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Thomas Jones
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(Instructed by Allen
& Overy LLP)
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(Instructed by see
below for details)
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Intervener (3)
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(written
submissions)
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Myles Jelf
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Annsley Merelle Ward
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Alan Johnson
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(Instructed by
Bristows LLP)
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Intervener (4)
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(written
submissions)
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Nicole Jadeja
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(Instructed by
Fieldfisher)
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Appellants:
(1) ICOS Corporation
(2) Eli Lilly & Company
Respondents:
(1) Actavis Group PTC EHF Pinsent
Masons LLP (London)
(2) Actavis UK Ltd Bird
& Bird LLP
(3) Teva UK Ltd Pinsent
Masons LLP (London)
(4) Teva Pharmaceutical Industries Ltd Pinsent
Masons LLP (London)
(5) Generics (UK) Ltd (t/a Mylan) Taylor
Wessing LLP
Interveners: (written submissions)
(1) Medicines for Europe Pinsent
Masons LLP (London)
(2) British Generic Manufacturers Association Pinsent
Masons LLP (London)
(3) The
IP Federation Bristows
LLP
(4) UK BioIndustry Association Fieldfisher
LORD HODGE: (with whom
Lady Hale, Lord Kerr, Lord Sumption and Lord Briggs agree)
1.
This appeal concerns the application of the test of obviousness under
section 3 of the Patents Act 1977 to a dosage patent. In summary, a patent,
whose validity is not challenged, identified a compound as an efficacious
treatment but did not identify an optimal dosage regime. A pharmaceutical
company, which had acquired the patent, conducted extensive research into
ascertaining the optimal dosage of the compound. It discovered a dose which not
only was safe and effective but also, unexpectedly, could be administered in a new
and beneficial manner, because of both the half-life of the compound and its
minimal side effects at that dose. A number of generic drug manufacturers
challenge the validity of the dosage patent on the basis that it involves no
inventive step.
2.
The appeal raises two principal questions. The first relates to the
application of the obviousness test to a dosage patent and the second is
concerned with whether the Court of Appeal was entitled to reverse the judgment
of the judge at first instance on that question in the circumstances of this
case.
The patent under challenge
3.
The dosage patent which is the subject of this appeal is EP(UK)
1,173,181 (“the 181 patent”). It is owned by ICOS and exclusively licensed to
Eli Lilly (collectively “Lilly”). It relates to the use of tadalafil in a
dosage form for the treatment of sexual dysfunction. It was filed on 26 April
2000 and claims priority from US application no 60/132036P filed on 30 April
1999. It was granted on 15 October 2003. The form of the 181 patent is a B3
specification following centralised amendments made in the European Patent
Office (“EPO”) on 25 March 2015.
4.
The claimants, who are the respondents in this appeal, raised
proceedings to revoke the 181 patent and Lilly defended the claim and
counterclaimed that the claimants were threatening to infringe its patent. The
earlier phases of this litigation involved challenges to the 181 patent based
on (a) priority, (b) added matter, (c) lack of novelty, (d) obviousness and (e)
insufficiency. Of those challenges, the principal matter of contention is
obviousness. The claimants’ challenges on priority, added matter and lack of
novelty arise only if this court upholds the appeal by Lilly against the Court
of Appeal’s finding of obviousness.
Factual background
5.
Erectile dysfunction (“ED”) is a common medical condition which affects
approximately 50% of the male population between the ages of 40 and 70. It is
caused by a number of disorders, both physiological and psychological.
Unsurprisingly, the discovery of a drug to treat ED, called sildenafil, which
was and is sold under the brand name VIAGRA, proved to be a very great
commercial success.
6.
The drug, which is the subject of the patent in dispute, is called
tadalafil. Tadalafil is the generic name for a drug which is sold under the
brand name CIALIS for the treatment of ED and benign prostatic hyperplasia, and
under the brand name ADCIRCA for the treatment of pulmonary arterial
hypertension. CIALIS has also enjoyed great commercial success. In 2014
worldwide sales amounted to about $2.29 billion and UK sales amounted to about
$99m. In that year UK sales of ADCIRCA amounted to about $1m.
Technical background
7.
I derive my summary of the technical background from the judgment of
Kitchin LJ, who wrote the leading judgment in the Court of Appeal [2017] EWCA Civ 1671; [2018] RPC 7, and the findings of the trial judge, Birss J [2016] EWHC 1955 (Pat).
8.
The penis contains smooth muscle. When in its normal resting state, the
smooth muscle contracts and so restricts the arteries supplying blood to the
penis. When an erection is triggered, the smooth muscle relaxes and no longer
restricts the supply of arterial blood, causing the penis to become tumescent.
The smooth muscle relaxation which leads to the erection results from a cascade
of complex biochemical reactions within the body. Sexual stimulation causes the
release of the neurotransmitter nitric oxide (“NO”) which enters the smooth
muscle cells where it leads to an increase in the production of a second
molecule, cyclic guanosine-3’, 5’-monophosphate (“cGMP”). cGMP in turn binds to
and activates an enzyme which regulates the activity of other intracellular
proteins and leads to the relaxation of the smooth muscle. An increase in the
intracellular level of cGMP, through NO production, therefore promotes smooth
muscle relaxation, while a decrease in the intracellular level of cGMP tends to
cause the smooth muscle to return to its ordinary contracted state.
9.
The intracellular concentrations of cGMP and another second molecule,
cyclic adenosine-3’,5’-monophosphate (“cAMP”), are regulated by a class of
enzymes known as cyclic nucleotide phosphodiesterases (“PDEs”). By the priority
date in 1999 at least six PDE families had been identified. It was known that
the PDE family most prevalent in the penis was PDE5. This binds cGMP and
hydrolyses it to its non-cyclic form GMP, so leading to a reduction in smooth
muscle relaxation and the prevention of penile tumescence.
10.
It is necessary to mention also the concept of potency. Potency is the
amount of the drug required to produce a defined biological effect of given
intensity. Potency can be measured as the concentration or dose of a drug
required to produce 50% of the drug’s maximal effect (EC50 or ED50)
as depicted by a graded dose-response curve. In the context of a drug that
inhibits the action of another substance, potency can be expressed as the
concentration of a drug required to inhibit a given biological process by half,
ie the in vitro concentration of the drug which is required for 50% inhibition
(IC50). A higher potency drug will have a lower concentration
because less drug will be required to achieve the same effect. As Kitchin LJ
illustrated in paras 17 and 18 of his judgment the dose-response curve of a
drug is illustrated graphically as a sigmoid (or S-shaped) curve with a flat or
gently inclined base at which increasing doses are slow to manifest a
significant effect, a steep central part at which increasing doses have an
increasing effect, and a plateau at the top at which increasing doses have no
increased effect.
11.
The minimum effective dose is the smallest dose in the dose-response
curve at which a clinically relevant effect can be seen. The concept of the
minimum effective dose would be known to the skilled team, who would be aware that
regulators could ask for it to be identified. But they would also know that it
is not always required.
12.
The trial judge found that it had not been established that the skilled
team would always seek to identify the minimum effective dose for a given drug.
It might be sufficient to know that the minimum effective dose was somewhere in
a range. In the context of ED, there was no agreed definition of a minimum
clinically relevant effect and this had a bearing on the judge’s reasoning in
relation to obviousness. Identification of the minimum effective dose depends
on a value judgment, as the skilled team would know. The primary task of the
skilled team was and is to make safe, tolerable and effective medicines.
Sildenafil and tadalafil
13.
Sildenafil was marketed as an orally administered PDE5 inhibitor, which
prevented PDE5 from hydrolysing cGMP to the inactive GMP. cGMP levels remain
elevated as a result and this promotes smooth muscle relaxation. This leads to
greater arterial blood flow into the penis when it is stimulated and results in
penile tumescence.
14.
A disadvantage of sildenafil was its effect on other PDE families and,
in particular, PDE6 which was associated with known visual side effects.
Sildenafil was also associated with normally mild and transient side effects
including flushing, headache and dyspepsia, which were thought to be related to
its mode of action as a PDE5 inhibitor. Sildenafil was known to be administered
on demand with an onset of action of about one hour and a half-life of about
four hours. It was marketed at doses of 25mg, 50mg and 100mg. It was known that
broadly efficacy increased with dose and so did side effects. Those were the
doses upon which a skilled team would focus although it was also known that a
10mg dose of sildenafil had been investigated in trials and shown to be
efficacious.
15.
Sildenafil was a first in class drug which validated the rationale for
trying to treat ED using an oral PDE5 inhibitor. Any other PDE5 inhibitor for
ED would be known as a second in class drug. A clinical pharmacologist would
have an enhanced expectation that a second in class drug would be efficacious.
But the idea of investigating chronic dosing of a drug for ED was not part of
the common general knowledge.
16.
Tadalafil is a second in class drug. It is another PDE5 inhibitor and
operates in essentially the same way as sildenafil. An advantage which
tadalafil was found to have over sildenafil was its selectivity; it was able to
bind to and inhibit its target PDE5 while having significantly less effect than
sildenafil on other PDE families and, in particular, PDE6. This selectivity
resulted in less and a smaller number of side effects.
The skilled team
17.
The parties agreed that the notional skilled team, by reference to which
the question of the obviousness of the patent in dispute would be assessed,
would include a clinical pharmacologist with experience in pharmacokinetics and
a clinician specialising in urology. Both were important and would work
together. The clinical pharmacologist would take the lead in the quantification
of doses and the dose response. The clinician would take the lead when
assessing the clinical significance of an effect, whether a desired effect or a
side effect. The clinical pharmacologist would be primarily responsible for
selecting the doses to be tried in the dose ranging study, with input from the
clinician.
The phases of clinical research
18.
It was of central importance to the case of obviousness which the
claimants presented that clinical research into a new medicine follows a standard
pathway of four phases. The judge set out this pathway in paras 76-81 of his
judgment and below I draw heavily on Kitchin LJ’s summary of that exposition.
19.
A new drug, identified through appropriate in vitro testing and
pre-clinical animal studies, is taken forward into human tests. The first of such
tests are known as Phase I and they are carried out on healthy volunteers to
test safety rather than efficacy. The tests provide pharmacokinetic information
and allow an assessment of bio-availability. If these tests are positive, the
next step is to move the drug into Phase II.
20.
Phase II studies are generally carried out in two stages, Phase IIa and
Phase IIb. Phase IIa, which consists of what are sometimes known as “go, no-go”
studies, provides proof of concept. The studies are generally carried out at
one dose, selected to be high enough to give the drug the best chance of
showing a positive effect on the disease, albeit not too high to risk serious
side effects.
21.
Phase IIb involves testing a range of doses to show the effect of the
dose. In the judge’s words, the idea is that the highest dose will show a
larger clinical effect than the smallest dose. The obviousness challenge in
this case focuses on what the hypothetical skilled team would do in this phase
of clinical research.
22.
If the decision after Phase II is positive, the next phase is Phase III.
This is a large scale clinical trial designed to generate data to support an
application for regulatory approval. Phase IV studies take place after
regulatory approval and are not relevant to the issues arising in this appeal.
The Daugan patent
23.
Glaxo filed an application for a patent which was published on 6
February 1997 and led to patent EP 0 839 040 (“the Daugan patent” or “Daugan”).
Glaxo did not take forward the research to implement the Daugan patent but
transferred it to ICOS. The Daugan patent discloses the idea of using certain
compounds which are PDE5 inhibitors for the treatment of ED. It specifically
describes two compounds, A and B. Compound A is tadalafil. Daugan discloses
tadalafil’s (and Compound B’s) potency (ie IC50) against PDE5 as 2
nM. Daugan discloses that doses of Compounds A and B will generally be in the
range of 0.5mg to 800mg daily for the average adult patient. It gives examples
of a tablet containing a 50mg dose of the active ingredient. But the Daugan
patent does not purport to set out an appropriate dosage regime as an oral
treatment of ED.
24.
It is not disputed that at the priority date it was entirely obvious for
the notional skilled team, given the Daugan patent, to set out taking tadalafil
forward into a routine pre-clinical and clinical trial programme as an oral
treatment for ED. The statements in Daugan and the huge success of sildenafil
as an oral PDE5 inhibitor made it very obvious. Tadalafil would be an
attractive potential second in class medicine to develop because Daugan teaches
that it has a promising IC50 against PDE5. It is more potent than
sildenafil, which has an IC50 of about 3 or 3.9 nM. The trial judge
found that the skilled team would understand the limitations of in vitro IC50
data and would know that there could be all sorts of factors such as
bioavailability and tissue compartmentalisation which might limit tadalafil’s
clinical utility. But he found that that would not deter the skilled team from
embarking on a routine pre-clinical and clinical trial programme.
25.
The central question in this appeal is whether in the light of the
common general knowledge which I have summarised in paras 8-16 and 18-22 above
and the Daugan patent as the nearest prior art, the relevant claims in the 181
patent were obvious. I therefore turn to the 181 patent.
The 181 patent
26.
The 181 patent is a dosage patent. In the specification (para 1) it
refers for priority to the provisional patent application to the US Patent and
Trademark Office Serial no 60/132036, which was filed on 30 April 1999. It
asserts (para 2) that the invention relates to a highly selective PDE enzyme
inhibitor and to its use in a pharmaceutical unit dosage form. In particular it
relates to a potent inhibitor of PDE5 that is useful for the treatment of
sexual dysfunction. In its description of the background of the invention, it
refers to VIAGRA, its lack of selectivity for PDE6 and its side effects (para
4). It refers in para 7 to the Daugan patent and its disclosures. It asserts
(para 8) that the applicants have discovered that tadalafil (which it described
as “compound (I)”) “can be administered in a unit dose that provides an
effective treatment without the side effects associated with the presently
marketed PDE5 inhibitor, sildenafil. Prior to the present invention such side
effects were considered inherent to the inhibition of PDE5.” It continues (para
9) that clinical studies revealed that the product is effective with a reduced
tendency to cause flushing and, unexpectedly, can be administered with
clinically insignificant side effects associated with the combined effects of a
PDE5 inhibitor and an organic nitrate.
27.
In its summary of the invention (paras 11-15) it discloses a
pharmaceutical dosage form for human pharmaceutical use of about 1 to about 5mg
of tadalafil in a unit dosage form suitable for oral administration for the
treatment of sexual dysfunction, including ED up to a maximum total dose of 5mg
per day.
28.
The relevant claims are as follows. Claim 1 asserts “A pharmaceutical
unit dosage composition comprising 1 to 5mg of a compound having [the
illustrated structural formula of tadalafil] said unit dosage form suitable for
oral administration up to a maximum total dose of 5mg per day”. Claims 2 and 3
assert dosage forms comprising 2.5mg and 5mg of the compound respectively.
Claim 6 states: “the dosage form of any one of claims 1 through 3 for use in
treating a condition where inhibition of PDE5 is desirable.” Claim 7 refers to
the dosage form of claim 6 “wherein the condition is a sexual dysfunction”. It
is a claim for a purpose-limited product, known as an EPC 2000 claim, which,
since 2011, the European Patent Office (“EPO”) issues in place of “Swiss-form
claims”, and claim 8 refers to the sexual dysfunction of ED. Claim 10 is a
Swiss-form claim which, as is well-known, is a purpose-limited process claim,
giving a monopoly for “the use of compound X in the manufacture of a medicament
for the treatment of indication Y”. It is in the following terms:
“10. Use of a unit dose
containing 1 to 5mg of a compound having the structure [of tadalafil] for the
manufacture of a medicament for administration up to a maximum total dose of
5mg of said compound per day in a method of treating sexual dysfunction in a
patient in need thereof.”
29.
Kitchin LJ in his judgment (para 46) observed that the purpose-limited
claim 7 is dependent on claim 6 and claim 1 and construed it as manifesting an
intention that the maximum dose per day constituted part of the purpose
limitation of the claim. He also interpreted claims 7 and 10 as being directed
to the treatment of sexual dysfunction by the administration of a dose of no
more than 5mg tadalafil per day. The claimed invention is the application of
the discovery that sexual dysfunction may be treated by administering such a
dose and with minimal side effects (paras 50-52). The claimants do not
challenge those findings.
30.
Lilly asserts that the essence of the invention is the discovery that
tadalafil is effective in treating ED at such a low dose and with minimal side
effects. This discovery has allowed the drug to be taken daily (for chronic
use) rather than on demand, thus avoiding the need to anticipate when sexual
activity might occur. This is, Lilly claims, a significant technical advantage
as sildenafil by contrast is approved for on-demand use only.
Obviousness: the claimants’ challenge and Lilly’s answer
31.
Before Birss J the claimants submitted that it would be obvious for a
skilled team given the Daugan patent to take tadalafil forward into a routine
pre-clinical and clinical trial programme as an oral treatment for ED at the
priority date. While costly and time-consuming, the programme would involve
nothing other than routine work and no inventive effort was required. In the
course of the programme to establish tadalafil as a safe, tolerable and
effective treatment for ED, a 5mg dose would be one of the doses used on
patients as it was obvious to ascertain the lowest dose at which the drug was
effective. Standard dose-ranging studies would lead to the claims in the 181
patent. The programme would reveal the invention without any inventive step.
The fact that the 5mg per day dosage has a surprising beneficial property of
minimal side effects was simply a bonus which did not make the dosage regime an
invention.
32.
Lilly’s response was first that the discovery of the dosage regime was
the result of expensive and unpredictable research which was entitled to patent
protection. Secondly, at the start of the programme it was not obvious to try a
low dose like 5mg per day as there was no reason to think that it would be
effective at that dosage. To invalidate the claim, it would be necessary to
show that at the start of the programme it was obvious to the skilled team that
a 5mg/day dose would be safe and effective and also would have the minimal PDE5
related side effects. Lilly referred to the EPO’s problem and solution approach
and sought to apply it to the facts of the case.
33.
Birss J accepted neither approach in its entirety. He analysed the
obviousness case by concentrating on claim 7. He reminded himself that the test
for obviousness is a single and relatively simple question of fact. It is a
question of fact to be decided by detailed technical arguments and evidence
concerning the particular facts and circumstances, a task with which wide
generalisations do not assist. He accepted that some experiments which were
undertaken without a particular expectation as to the result were obvious. When
considering pre-clinical and clinical research it may be necessary to consider
a step-wise series of tests which the skilled team would undertake. But even if
each of those steps were obvious, one must avoid the risk of hindsight by
standing back and looking at the facts as a whole. The fact that routine tests
have uncertain results does not on its own turn those results into an
invention. Similarly, the fact that, before the pre-clinical, Phase I and Phase
IIa tests had been performed, one cannot say what particular doses will be
tested in a Phase IIb test does not of itself make those doses inventive if
some of them are found to work. He referred to the statement by Kitchin J in Generics
(UK) Ltd v H Lundbeck A/S [2007] RPC 32, which I set out in para 63 below,
and identified as relevant factors in his assessment of obviousness in this
case the following: motive, multiple avenues, the effort involved and the
expectation of success, the occurrence of unexpected and surprising results and
the need for and nature of value judgments which have to be made in carrying
out the project.
34.
The judge’s findings of fact were based principally on the evidence of
(i) Mr Gary Muirhead a consultant to the pharmaceutical industry, whom the
claimants called and who had worked for Pfizer on the development of drugs,
including sildenafil, (ii) Dr Jay Saoud, whom Lilly called and who had over 25
years of experience in clinical development, pharmacokinetics and statistical
analysis in industry, academia and contract research organisations and (iii) Dr
Gerald Brock, whom Lilly called and who is a practising clinical urologist with
extensive clinical, academic and advisory experience in matters concerning
treatments for ED.
35.
In his careful assessment of their evidence Birss J held, at paras 287
et seq, that it would have been “entirely obvious” for a skilled team given
Daugan to set out to take tadalafil forward into a routine pre-clinical and
clinical trial programme as an oral treatment for ED at the priority date. The
Phase I studies would produce results which would lead the skilled team to
design and undertake the Phase IIa “go no-go” study of a single 50mg dose of
tadalafil in a relatively small group of patients. They would embark on that
study with a reasonable expectation that the drug would be safe, tolerable and
effective at that dose. Turning to the Phase IIb studies, Birss J concluded
that the first dose ranging study would be of on demand dosing using 25, 50 and
100mg of the drug. He did not accept Mr Muirhead’s suggestion that a 5mg dose
would be included in this first study. The skilled team’s expectations would be
that they would hope that the study would show a dose response relationship.
But the results would not be what the team expected because they would show no
difference in efficacy between the three doses, demonstrating an apparent
therapeutic plateau.
36.
The critical dispute at this stage was whether in the light of those
findings it was an obvious thing for the skilled team to conduct a further dose
ranging study or studies to investigate lower doses and determine the minimum
effective dose. Birss J did not accept the claimants’ case that it was. He held
that the skilled team would be well aware that there was no defined standard of
minimal efficacy in relation to ED and that it would require a value judgement
to characterise a minimum effective dose. He concluded (para 327) that it was
not inevitable that the skilled team would investigate lower doses after
discovering the therapeutic plateau because they had found a dose (at least
25mg) which was safe, tolerable and effective and thus had secured the prime
objective of the programme; but he held that it was “very likely” that they
would. A skilled team would be familiar with multiple dose ranging studies as
necessary as a generality.
37.
If the skilled team carried out a further dose ranging study they would
have included 5mg and 10mg doses. They would not have any expectation that the
minimum effective dose was substantially lower than 25mg or that they would
find a dose below 25mg at which there was a clinically relevant effect with
reduced side effects. The discovery that at a 5mg dose tadalafil was
efficacious and had reduced side effects would surprise the team. The
investigation of chronic daily dosing in addition to on demand dosing would
follow the similar pattern but the initial study would probably include a 10mg
dose. The team’s expectation would be the same.
38.
Having conducted this step-by-step analysis, Birss J then looked at the
programme as a whole and assessed obviousness overall. He concluded that, given
Daugan, a 25mg/day dose of tadalafil was obvious as a treatment for ED but that
a 5mg daily dose was not. In para 343 he summarised his reasons in these terms:
“i) In terms of motives to
find a solution to the problem the patent addresses, the skilled team would be
highly motivated by Daugan and the success of sildenafil to investigate
tadalafil as a treatment for [ED].
ii) As for possible avenues
of research, overall tadalafil would be obvious to investigate. In terms of
doses however, 5mg/day is a significantly lower dose than the 50mg dose
exemplified in the Daugan prior art and the marketed doses of sildenafil. It is
also significantly lower than the 50mg dose which would be chosen for the first
test of efficacy at Phase IIa. It would not be chosen in the routine first dose
ranging study. The team would not have anticipated daily dosing as something to
be studied from the outset but once the half-life was discovered it is likely
that daily dosing would be included.
iii) In terms of effort,
overall the programme would involve very substantial resources of time, money
and people but it would be pursued. However, by the time the idea of
investigating lower doses presents itself, the team would have established
safe, tolerable and effective doses of tadalafil at 25mg on demand and 10mg for
daily dosing. At that stage the impetus to investigate lower doses would be
reduced but not eliminated.
iv) Expectations of success
can be considered overall and in relation to particular studies. Overall the
team would embark on the project with a reasonable expectation of success in
establishing tadalafil as a safe, tolerable and effective treatment for [ED].
However, the claimants failed to prove that efficacy at 5mg tadalafil was predictable
or worth considering by the skilled team based on the properties of tadalafil
as compared to sildenafil. The team would know that in principle there would be
a minimum effective dose for tadalafil but would also know that its definition
depends on a value judgment made by the team. In relation to the dose ranging
studies, the team would conduct them hoping for a dose response. Following
discovery of a plateau starting at 25mg or 10mg, there would very likely be a
subsequent dose ranging study which included 5mg. The team would include a 5mg
dose in this study hoping to see a dose response but that does not mean they
would have a reasonable expectation that 5mg would produce a clinically
relevant effect at all nor one with minimal side effects. Assuming a 5mg/day
dose of tadalafil was tested, it would not be tested with a reasonable
expectation of success.
v) Considering unexpected
or surprising results, the position is as follows. The path to a 5mg dose
requires the discovery of new information such as the half-life and the IC50
vs PDE6. That information would inevitably be found in any clinical programme.
The path includes an important result which is unexpected even if it is not
actually surprising, ie the plateau in the dose response from 10 to 100mg.
There is also a surprising result: the existence of a useful effect with
reduced side effects. The claimed 5mg/day dose has that property.
vi) A number of value
judgments would be required of a skilled team in a programme which reaches the
claimed invention. One is to define the level of clinical effect to be regarded
as relevant. Another is to embark on investigating daily dosing. An important
value judgment is what to do when an unexpected plateau in the dose response
has been identified as the same time as a marketable dose.”
39.
He therefore concluded that claim 7 of the 181 patent involves an
inventive step.
40.
The Court of Appeal reached a contrary conclusion and allowed the appeal
on the ground that claims 1, 7 and 10 were invalid for lack of inventive step.
41.
In the leading judgment, Kitchin LJ addressed the claimants’ case that,
in the light of Daugan, it was obvious to take tadalafil forward into routine
pre-clinical and clinical trial programme to assess its use as an oral
treatment for sexual dysfunction. The claimants argued that nearly all dosage
regimes in a Swiss-form claim will be obvious: Actavis UK Ltd v Merck &
Co Inc [2008] EWCA Civ 444; [2009] 1 WLR 1186, Jacob LJ at para 32. A 5mg
daily dose would be used in patients in the course of that programme and would
reveal that it was a safe, tolerable and effective treatment. In other words,
it would reveal the invention. The alleged invention was merely the product of
standard practice in a routine clinical trials’ process and the purpose of
Phase IIb studies was to provide an understanding of the dose response
relationship. Lilly’s answer was that at the start of the programme it was not
obvious to try a 5mg dose because the skilled team would have no idea if it
would be a safe, tolerable and effective treatment. The skilled team had to
make a series of value judgements in order to arrive at the invention and would
have had no expectation that the 5mg dose would be efficacious or that it would
have reduced side effects.
42.
Kitchin LJ stated, at paras 131-135, that it was not the law that
investigations into appropriate dosage regimes cannot yield patentable
inventions and that Jacob LJ had not suggested otherwise in Actavis v Merck.
The statutory task of the court was to have regard to all the relevant circumstances
in order to answer the single question: “was it obvious to the skilled but
unimaginative addressee in light of the prior art and the common general
knowledge to make a product or carry out a process falling within the claim?”
He affirmed that the judge would have had this well in mind. Accordingly, where
no question of principle was involved, an appellate court had to be very
cautious in differing from a judge’s evaluation.
43.
Nonetheless, he held that claim 1 was invalid for obviousness. It had no
purpose limitation and encompassed a unit dosage composition comprising 1mg to
5mg of tadalafil which was suitable for administration up to a maximum
total dose of 5mg per day but which was intended and was in fact used for
administration of a higher per day total dose. On the judge’s findings, given
Daugan, it was obvious to develop such a composition and the judge should have
so found. I do not understand Lilly to challenge this finding in this appeal.
Instead, the battleground relates to claims 7 and 10.
44.
In relation to those claims, the debate in the Court of Appeal appears
to have focussed on the notional skilled team’s approach to the Phase II trial.
Kitchin LJ recorded Lilly’s case that, having carried out the initial Phase IIb
study, which would have found the 25mg dose on demand to be safe and
efficacious, the skilled team needed to go no further but if they chose to do
so, would test a 10mg dose before deciding whether to go further and test a 5mg
dose. The skilled team also had to decide whether to test daily dosing. There
were therefore various possible avenues of research, involving value judgements
and it was not inevitable that the skilled team would investigate lower doses.
45.
Kitchin LJ accepted that it was relevant to consider whether the skilled
team, starting with Daugan, would be faced with various possible avenues of
research. He recognized that the skilled team would be faced with choices when
embarking on Phase II studies, including how to proceed with the dose ranging
studies and whether to study on demand or daily dosing. But in relation to the
latter decision, he pointed out that the judge had found that the Phase I trial
would have revealed the half-life of tadalafil and that the team would have
decided to pursue both on demand and daily dosing in Phase II. In relation to
the former decision, Kitchin LJ pointed out that the judge had found that the
team would very likely investigate the 5mg dose of tadalafil after the
first or, in the case of on demand dosing, a possible second dose ranging
study. This finding was supported by the purpose of dose ranging studies, which
was to ascertain the dose response relationship of the drug, and the fact that,
so long as the study showed the IC50 remaining on the upper
therapeutic plateau, that dose response relationship had not been found.
Further, it was consistent with the evidence of the expert clinical
pharmacologists, Mr Muirhead and Dr Saoud, and Kitchin LJ quoted the latter’s
evidence on cross-examination that, having discovered the therapeutic plateau,
it was a “no brainer” to test a lower dose and that the skilled team would have
done so. Kitchin LJ therefore rejected the idea that the skilled team would
have been faced with a series of parallel avenues of studies and would have no
expectation that any one of them would prove fruitful. Further, the team would
have addressed both on demand and daily dosing and each avenue of inquiry would
be very likely to lead the team to the invention.
46.
Kitchin LJ held that the judge should not have attached weight to the
fact that a 5mg dose was considerably less than the 50mg dose which would have
been used in Phase IIa, because the Phase IIb tests were carried out for a
different purpose, that is to ascertain the dose response relationship. Nor
should the judge have attached weight to the conclusion that a 5mg dose would
not be tested in the first Phase IIb study because he had also found that the
team would very likely investigate it afterwards: the impetus to investigate
lower doses would have remained because the purpose of the Phase IIb study had
not been fulfilled. The finding that the skilled team could not predict at the
outset that a 5mg dose would be safe and efficacious was of little weight
because at least one of the purposes of the Phase IIb studies is to understand
better the dose-response relationship of the drug and so identify the
appropriate dose for the target population. Similarly the judge was wrong to
attach weight to the conclusion that the team would not have an expectation of
success when testing the 5mg dose: the judge had held that the team were very
likely to test the 5mg dose as part of the dose ranging study but it was hard
to see why they would have done so unless they had a reasonable expectation
that it would assist them better to understand the dose response relationship.
47.
Kitchin LJ also held that little weight could be attached to the fact
that it was surprising (a) that there was a therapeutic plateau from 10mg to
100mg, and (b) that a 5mg per day dose was efficacious and had reduced side
effects. While the discovery of a surprising or unexpected technical effect may
be suggestive of invention, in this case the discovery of the therapeutic
plateau and the efficacy of the 5mg dose was the product of a routine trial
programme and the unexpected reduced side effects of the 5mg dose was a bonus
effect which did not cause the 5mg dose to cease to be obvious. He also
concluded that the value judgments to which the judge referred in para 343(vi)
of his judgment (para 38 above) provided no effective support for the judge’s
conclusion in the face of his critical finding that it was very likely that the
team would test the 5mg dose.
48.
Kitchin LJ summarised his conclusions in this way, at para 152:
“Drawing the threads together, I
am satisfied that Mr Speck has made good his criticisms of the judge’s
reasoning. The judge has lost sight of the fact that, on his own findings, the
claimed invention lies at the end of the familiar path through the routine
pre-clinical and clinical trials’ process. The skilled but non-inventive team
would embark on that process with a reasonable expectation of success and in
the course of it they would carry out Phase IIb dose ranging studies with the
aim of finding out, among other things, the dose response relationship. It is
very likely that in so doing they would test a dose of 5mg tadalafil per day
and, if they did so, they would find that it is safe and efficacious. At that
point they would have arrived at the claimed invention. In my judgment claims 7
and 10 are therefore invalid.”
49.
Floyd and Lewison LJJ issued concurring judgments to which I will refer
in the discussion below.
50.
Mr Waugh’s challenge to the judgment of the Court of Appeal can be
boiled down to one central submission: the statutory question in section 3 of
the 1977 Act is whether the claimed invention was obvious at the priority date.
This straightforward approach to the assessment of obviousness, he submitted,
required the court to look at the invention set out in the relevant claim or
claims of the patent and ask itself whether that asserted invention was obvious
to the notional skilled but uninventive team at the priority date having regard
to the state of the art at that date. Therefore, the question which the Court
of Appeal should have asked was whether at the priority date, before the
skilled team embarked on its investigation, it was obvious in the light of
Daugan, and without knowledge of the alleged invention, that a 5mg per day dose
of tadalafil would be a safe and effective treatment, with minimal side
effects, for sexual dysfunction. The Court of Appeal erred by not adopting that
approach and instead by holding that the invention was obvious, because the
claimed invention was the product of a familiar and routine path of
pre-clinical and clinical research, in which each step was likely to follow the
outcome of the prior step. This erroneous approach failed to address the
question whether it was obvious to try that low dose because there was a reasonable
expectation of success at the outset. It was also in conflict with the approach
of the EPO which adopted a problem-and-solution analysis. Costly and
time-consuming research which led to an unexpected technical effect will be
patentable, whether such work is routine or not. The Court of Appeal, which
accepted the trial judge’s findings of fact, was not entitled to overrule his
analysis.
51.
Mr Speck sought to answer this case by making seven propositions. They
were, first, that patent law is concerned with technical information which is
of use industrially. A technical contribution is the difference between what a
skilled person is enabled to do (a) in light of the state of the art and (b)
with the teaching of the patent. Secondly, there was a symmetry or balance in
the patent system which required an enabling disclosure, in other words a
technical contribution, as the basis of a patent. Thirdly, the fundamental
principle underlying the grant of a monopoly through a patent is that the
monopoly must be commensurate with that technical contribution. The monopoly
cannot cover that which the skilled person is already able to do or make,
including obvious modifications or additions to the state of the art. Those he
described as “the skilled person’s repertoire”. Fourthly, if all that a skilled
person discovers is more information about products or processes that are
already within that notional person’s repertoire, there is no basis for the
grant of a patent because that information does not add to the products or
processes which the skilled person can make or do. Fifthly, the principle
advanced by Lilly, that it is not permissible to take into account information
not known at the priority date, is contrary to the basic scheme of patent law.
Sixthly, if that principle were correct, it would apply whether or not the
research revealed an unexpected benefit. Seventhly, patent law excludes from
consideration information which is routinely ascertained using routine methods
as part of the state of the art and using them for a routine purpose towards a
routine end: in this case the implementation of the Daugan patent.
Discussion
i) The approach to
obviousness
52.
I am not persuaded that the law adopts the extreme position of either
submission. Lilly’s approach would require the court to disregard the work
which a skilled person would carry out after the priority date in order to
implement the teaching of the Daugan patent. That approach, as Mr Speck
submitted, is contrary to the basic scheme of patent law. Actavis’s approach in
its reliance on “the skilled person’s repertoire”, in other words on what the
skilled person could already do, cannot be a general test for obviousness as it
would render irrelevant many of the factors to which the courts have had regard
in the assessment of obviousness, some of which I mention below.
53.
Since the enactment of the 1623 Statute of Monopolies, which prohibited
the grant of a monopoly by the Crown but in section VI created an exception for
a patent for “the sole working or making of any manner of new Manufactures … to
the true and first Inventor and Inventors of such Manufactures …”, the purpose
of a grant of a patent has been to encourage innovation. The monopoly granted
by the patent rewards the inventor by enabling him or her to charge a higher
price than would have been possible if there had been competition. The “patent
bargain” is this: the inventor obtains a monopoly in return for disclosing the
invention and dedicating it to the public for use after the monopoly has
expired. Lord Mansfield stated the point with his characteristic succinctness
in Liardet v Johnson (1778):
“The condition of giving
encouragement is this: that you must specify upon record your invention in such
a way as shall teach an artist, when your term is out, to make it - and to make
it as well by your directions: for then at the end of the term, the public
shall have benefit of it. The inventor has the benefit during the term, and the
public have the benefit after …”
(quoted in Hulme, “On the History of Patent Law” (1902) 18
LQR 280, 285 and cited by Lord Sumption in the leading judgment in Generics
(UK) Ltd (trading as Mylan) v Warner-Lambert Co LLC [2018] UKSC 56; [2019] Bus LR 360, para 17).
54.
This overarching principle has survived the amendment of UK patent law
after accession to the European Patent Convention. The EPO Technical Board of
Appeal has confirmed the principle in, for example, its decision of 12
September 1995 in Agrevo/Triazoles (Case T-939/92) [1996] EPOR 171, para
2.4.2 in which it stated:
“it has for long been a generally
accepted legal principle that the extent of the patent monopoly should
correspond to and be justified by the technical contribution to the art. …
[T]his general legal principle was applied in relation to the extent of the
patent protection that was justified by reference to the requirements of
articles 83 and 84 EPC, the same legal principle also governs the decision that
is required to be made under article 56 EPC, for everything falling within a
valid claim has to be inventive.”
See also EXXON/Fuel Oils (Case T-409/91) [1994] OJ
EPO 653 at paras 3.3 and 3.4. Articles 83 and 84 of the EPC are concerned with
the sufficiency of the disclosure of the invention in the patent application
and the support which the description gives to the claims in that application.
Section 14(3) and (5) of the 1977 Act correspond to those requirements. Article
56 of the EPO is concerned with the inventive step and provides:
“An invention shall be considered
as involving an inventive step if, having regard to the state of the art, it is
not obvious to a person skilled in the art. …”
Section 3 of the 1977 Act, which I set out below,
corresponds to this requirement.
55.
As is well-known, section 130(7) of the 1977 Act declares that specified
sections of the 1977 Act “are so framed as to have, as nearly as practicable,
the same effects in the United Kingdom as the corresponding provisions of the
European Patent Convention, the Community Patent Convention and the Patent Co-operation
Treaty have in the territories to which those Conventions apply”. Those
sections include the sections which govern (a) the principal conditions of
validity, that is to say novelty (section 2), inventive step (section 3),
capability of industrial application (section 4) sufficiency of disclosure and
the support of the claim by the description in the patent application (section
14(3) and (5)), and (b) the power of the court to revoke a patent on
application, on grounds which include that the invention is not a patentable
invention (which is a reference via section 1 to inter alia sections 2, 3 and
4) and inadequate disclosure in the patent application to enable the skilled
person to perform the invention (section 72(1)).
56.
It is also well established in the jurisprudence of courts in the United
Kingdom that our courts, although not bound to do so, should normally follow
the settled jurisprudence of the EPO (especially decisions of its Enlarged
Board of Appeal) on the interpretation of the European Patent Convention in the
interests of uniformity, especially when the question is one of principle: Merrell
Dow Pharmaceuticals Inc v H N Norton & Co Ltd [1996] RPC 76, 82 per
Lord Hoffmann; Gale’s Application [1991] RPC 305, 322 per Nicholls LJ; Actavis
UK Ltd v Merck & Co Inc [2009] 1 WLR 1186, paras 45-48 per Jacob LJ; Conor
Medsystems Inc v Angiotech Pharmaceuticals Inc [2008] UKHL 49; [2008] 4 All ER 621, para 3 per Lord Hoffmann; Generics (UK) Ltd v H Lundbeck A/S
[2009] UKHL 12; [2009] 2 All ER 955, para 35 per Lord Walker of Gestingthorpe; Dr
Reddy’s Laboratories (UK) Ltd v Eli Lilly and Co Ltd [2010] RPC 9, para 102
per Lord Neuberger of Abbotsbury MR; Eli Lilly and Co v Human Genome
Sciences Inc [2011] UKSC 51; [2012] 1 All ER 1154; [2012] RPC 6, paras
83-87 per Lord Neuberger.
57.
The general principle that the extent of the patent monopoly should
correspond to and be justified by the actual technical contribution to the art
is thus part of the jurisprudence of both the EPO and the UK courts and, as
Lord Sumption observed in Generics v Warner-Lambert (above), para 17,
“the principal conditions of validity, novelty, inventive step, industrial
application and sufficiency are all, in one way or another, directed to
satisfying the principle thus expressed”. There is therefore a balance or
symmetry in patent law, as Mr Speck submitted.
58.
This case is concerned with the condition which requires there to be an
inventive step. Section 3 of the 1977 Act provides:
“An invention shall be taken to
involve an inventive step if it is not obvious to a person skilled in the art,
having regard to any matter which forms part of the state of the art by virtue
only of section 2(2) above (and disregarding section 2(3) above).”
Section 2(2) provides:
“The state of the art in the case
of an invention shall be taken to comprise all matter (whether a product, a
process, information about either, or anything else) which has at any time
before the priority date of that invention been made available to the public
(whether in the United Kingdom or elsewhere) by written or oral description, by
use or in any other way.”
These statutory provisions mandate the court to assess
whether an invention is obvious by having regard to the state of the art at the
priority date of the invention. If the invention is not obvious to the skilled
person at that date, section 3 deems the invention to involve an inventive
step.
59.
The notional skilled person, while having the compendious knowledge of
the state of the art which section 2(2) requires, has no inventive capacity.
But that does not mean that the skilled person has no skill to take forward in
an uninventive way the teaching of the prior art. In this case the notional
skilled team comprises the clinical pharmacologist and the clinician
specialising in urology (para 17 above). That notional team is treated as
exercising the professional skills of its members in responding to the teaching
of the Daugan patent. It follows that uninventive steps which the skilled team
would take after the priority date to implement the Daugan patent are not
excluded from consideration in assessing the obviousness of the alleged
invention at the priority date.
60.
In addressing the statutory question of obviousness in section 3 of the
1977 Act it is common for English courts to adopt the so-called Windsurfing/Pozzoli
structure which asks these questions:
“(1) (a) Identify the
notional ‘person skilled in the art’;
(b) Identify the relevant
common general knowledge of that person;
(2) Identify the inventive
concept of the claim in question or if that cannot readily be done, construe
it;
(3) Identify what, if any,
differences exist between the matter cited as forming part of the ‘state of the
art’ and the inventive concept of the claim or the claim as construed;
(4) Viewed without any
knowledge of the alleged invention as claimed, do those differences constitute
steps which would have been obvious to the person skilled in the art or do they
require any degree of invention?”
(Pozzoli SPA v BDMO SA [2007] EWCA Civ 588; [2007] FSR 37, para 23 per Jacob LJ). The fourth question is the statutory question
and the first three questions or tasks, the second and third of which involve
knowledge and consideration of the invention, are a means of disciplining the
court’s approach to that fourth question: DSM NV’s Patent [2001] RPC 35,
para 55 per Neuberger J; Actavis UK Ltd v Novartis AG [2010] EWCA Civ 82; [2010] FSR 18, para 21 per Jacob LJ. In this case the trial judge adopted
the Pozzoli approach. There is no dispute about the first question. Mr
Waugh emphasises the focus of the second question on the wording of the claim,
as I shall discuss below.
61.
An alternative approach which the EPO often adopts, is the so called
“problem-and-solution approach”. The EPO has described the approach in these
terms:
“the Boards of Appeal consistently
decide the issue of obviousness on the basis of an objective assessment of the
technical results achieved by the claimed subject-matter, compared with the
results obtained according to the state of the art. It is then assumed that the
inventor did in fact seek to achieve these results and, therefore, these
results are taken to be the basis for defining the technical problem (or, in
other words, the objective) of the claimed invention. … The next step is then
to decide whether the state of the art suggested the claimed solution of this
technical problem in the way proposed by the patent in suit …”
(Agrevo/Triazoles
(above) para 2.4.3)
The test is helpfully summarised in the EPO’s Guidelines
for Examination in the EPO (November 2017) (Part G - Chapter VII) para 5:
“Problem-and-solution approach
In order to assess inventive step
in an objective and predictable manner, the so-called ‘problem-and-solution
approach’ should be applied. Thus deviation from this approach should be
exceptional.
In the problem-and-solution
approach there are three main stages:
(i) determining the
‘closest prior art’,
(ii) establishing the
‘objective technical problem’ to be solved, and
(iii) considering whether or
not the claimed invention, starting from the closest prior art and the
objective technical problem, would have been obvious to the skilled person.”
Again, Mr Waugh urges the application of this approach
because of the emphasis which, he submits, it places on the terms of the claim.
62.
While both approaches focus on the inventive concept put forward in the
claims, neither approach should be applied in a mechanistic way. Both are
glosses on the text of section 3 of the 1977 Act and article 56 of the EPC and
neither require a literalist approach to the wording of the claim in
identifying the inventive concept.
63.
In Conor Medsystems Inc v Angiotech Pharmaceuticals Inc [2008] UKHL 49; [2008] RPC 28; [2008] 4 All ER 621, at para 42 Lord Hoffmann endorsed
the fact-specific approach which Kitchin J set out in Generics (UK) Ltd v H
Lundbeck [2007] RPC 32, para 72 where he stated:
“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 the patent addresses, the number and extent of the possible
avenues of research, the effort involved in pursuing them and the expectation
of success.”
Kitchin J’s list of factors is illustrative and not exhaustive.
Another factor which needs to be considered in the present case is the
routineness of the research. Much of the interest and controversy which the
Court of Appeal’s judgment has generated relates to how people have understood
or misunderstood the significance which that court has attached to the routine
nature of the pre-clinical and clinical research which I have described. Again,
I discuss this below (paras 102-104).
64.
Factors which are relevant considerations in the present case include
the following.
65.
First, it is relevant to consider whether at the priority date something
was “obvious to try”, in other words whether it was obvious to undertake a
specific piece of research which had a reasonable or fair prospect of success: Conor
v Angiotech (above) para 42 per Lord Hoffmann; MedImmune Ltd v Novartis
Pharmaceuticals UK Ltd [2012] EWCA Civ 1234; [2013] RPC 27, paras 90 and 91
per Kitchin LJ. In many cases the consideration that there is a likelihood of
success which is sufficient to warrant an actual trial is an important pointer
to obviousness. But as Kitchin LJ said in Novartis AG v Generics (UK) Ltd [2012] EWCA Civ 1623, para 55, there is no requirement that it is manifest that a test
ought to work; that would impose a straightjacket which would preclude a
finding of obviousness in a case where the results of an entirely routine test
are unpredictable. As Birss J observed in this case (para 276), some
experiments which are undertaken without any particular expectation as to
result are obvious. The relevance of the “obvious to try” consideration and its
weight when balanced against other relevant considerations depend on the
particular facts of the case.
66.
Secondly, it follows that the routine nature of the research and any
established practice of following such research through to a particular point
may be a relevant consideration which is weighed against the consideration that
the claimed process or product was not obvious to try at the outset of a
research programme. Again, it is only one of several factors to be weighed in
the assessment and it has no primacy and certainly no paramount status as a
consideration.
67.
Thirdly, the burden and cost of the research programme is relevant. But
the weight to be attached to this factor will vary depending on the particular
circumstances. This appeal concerns a pharmaceutical patent claiming as an
invention a dosage regime. The cost and effort involved in bringing a drug to
market through pre-clinical and clinical trials are notorious. Mr Waugh
referred to the extrajudicial writing of Sir Hugh Laddie, “Patents - what’s
invention got to do with it?” (in Intellectual property in the new
millennium: essays in honour of William R Cornish (2004), p 91 et seq), in
which he stated, at p 92:
“In this field it is apparent
that, without patents, few new products would be marketed. The expense in
producing a new pharmaceutical is in the research and development stage.
Normally, once it has been discovered and given regulatory approval, the
manufacture of a new pharmaceutical will be comparatively cheap and its
replication by competitors easy. Without the protection of patents, there will
be no ability to recoup the cost of the research and development, let alone
fund such activities in the future. No private company is going to enter this
business unless it can see a reasonable prospect of obtaining a return on
investment.”
The need to facilitate expensive pharmaceutical research is
an important policy consideration for legislators and others involved in
intellectual property law. It was a factor behind the creation of the
Swiss-form claim and the EPC 2000 claim as well as the supplementary protection
certificate regime under Regulation (EC) 469/2009, which is available after
market authorisation to give the patent owner the protection of the patent for
up to 15 years, and the data exclusivity regime which Directive 2001/83/EC
(article 10) and Regulation (EC) 726/2004 (article 14), which may confer ten
years of exclusive marketing protection against competition from generic manufacturers.
But the effort involved in research is only one of several factors which may be
relevant to the answer to the statutory question of obviousness.
68.
Fourthly, the necessity for and the nature of the value judgments which
the skilled team would have in the course of a testing programme are relevant
considerations as both the trial judge and the Court of Appeal held.
69.
Fifthly, the existence of alternative or multiple paths of research will
often be an indicator that the invention contained in the claim or claims was
not obvious. If the notional skilled person is faced with only one avenue of
research, a “one way street”, it is more likely that the result of his or her
research is obvious than if he or she were faced with a multiplicity of
different avenues. But it is necessary to bear in mind the possibility that
more than one avenue of research may be obvious. In Brugger v Medic-Aid Ltd
(No 2) [1996] RPC 635, 661, Laddie J stated:
“[I]f a particular route is an
obvious one to take or try, it is not rendered any less obvious from a
technical point of view merely because there are a number, and perhaps a large
number, of other obvious routes as well.”
I agree. As a result, the need to make value judgments on
how to proceed in the course of a research programme is not necessarily a
pointer against obviousness.
70.
Sixthly, the motive of the skilled person is a relevant consideration.
The notional skilled person is not assumed to undertake technical trials for
the sake of doing so but rather because he or she has some end in mind. It is
not sufficient that a skilled person could undertake a particular trial; one
may wish to ask whether in the circumstances he or she would be motivated to do
so. The absence of a motive to take the allegedly inventive step makes an
argument of obviousness more difficult. In Agrevo/Triazoles (above),
para 2.4.2, the Technical Board of Appeal of the EPO, having referred to the
principle that the extent of the patent monopoly should correspond to and be
justified by the technical contribution to the art (see para 54 above) made the
point in these terms:
“Moreover, in the Board’s
judgment, it follows from this same legal principle that the answer to the
question what a skilled person would have done in the light of the state of the
art depends in large measure on the technical result he had set out to achieve.
In other words, the notional ‘person skilled in the art’ is not to be assumed
to seek to perform a particular act without some concrete technical reason: he
must, rather, be assumed to act not out of idle curiosity but with some
specific technical purpose in mind.”
This forms the basis of the EPO’s problem-and-solution
approach to obviousness which I have quoted in para 61 above.
71.
Seventhly, the fact that the results of research which the inventor
actually carried out are unexpected or surprising is a relevant consideration
as it may point to an inventive step, at least in so far as it suggests that a
test was not obvious to try or otherwise the absence of a known target of the
research which would make it less likely that the skilled person would conduct
a test.
72.
Eighthly, the courts have repeatedly emphasised that one must not use
hindsight, which includes knowledge of the invention, in addressing the
statutory question of obviousness. That is expressly stated in the fourth of
the Windsurfing/Pozzoli questions. Where the pattern of the research
programme which the notional skilled person would undertake can clearly be
foreseen, it may be legitimate to take a step by step analysis. In Gedeon
Richter plc v Bayer Schering Pharma AG [2011] EWHC 583 (Pat); [2011] Bus LR D153, Floyd J stated (para 114):
“I think that the guiding
principle must be that one has to look at each putative step which the skilled
person is required to take and decide whether it was obvious. Even then one has
to step back and ask an overall question as to whether the step by step
analysis, performed after the event, may not in fact prove to be unrealistic or
driven by hindsight.”
The obvious danger of a step by step analysis is that the
combination of steps by which the inventor arrived at his invention is
ascertained by hindsight knowledge of a successful invention. Lord Diplock
warned against this in Technograph Printed Circuits Ltd v Mills &
Rockley (Electronics) Ltd [1972] RPC 346, 362, a warning which judges have
reiterated in later cases. I am not persuaded by Mr Speck’s suggestion that Technograph
is concerned only with a case in which a step by step approach was constructed
by counsel on cross-examination in the absence of evidence of routine steps of
research. The case contains a wider warning against the use of hindsight and
has been interpreted as doing so. I agree with Birss J’s analysis in Hospira
UK Ltd v Genentech Inc [2014] EWHC 3857 (Pat), para 240, where he stated:
“The particular point made in Technograph
was that it was wrong to find an invention was obvious if it was only arrived
at after a series of steps which involve the cumulative application of
hindsight. In some circumstances success at each step in a chain is a necessary
predicate for the next one and it is only the hindsight knowledge of the
invention as the target which could motivate a skilled person to take each step
without knowledge about the next one. In a situation like that, Technograph
is important.”
But the Technograph warning has no bearing in a case
in which the steps which the notional skilled person would take can readily be
ascertained without the taint of hindsight.
73.
Ninthly, it is necessary to consider whether a feature of a claimed
invention is an added benefit in a context in which the claimed innovation is
obvious for another purpose. In Hallen & Co v Brabantia (UK) Ltd
[1991] RPC 195 the Court of Appeal was concerned with an alleged selection
patent for a self-pulling corkscrew which had a helix coated with
polytetrafluoroethylene (PTFE) which was a known friction-reducing material. At
the priority date PTFE had been used for several years to coat the helix of a
twin-lever type corkscrew to aid its penetration into the cork. The PTFE-coated
helix had this effect also on the self-pulling corkscrew, a fact which was
obvious at the priority date. The PTFE coat when applied to a self-pulling
corkscrew also had a non-obvious benefit of making a striking improvement in
the extraction of the cork. The trial judge, Aldous J, held that the patent was
invalid on the ground of obviousness because it was obvious to select the
features of the claim for the first purpose notwithstanding that it was not
obvious for the other purpose: [1989] RPC 307, 326-327. The Court of Appeal
agreed with the judge, holding (pp 215-216) that it was self-evident that a
PTFE coating would improve the penetration by any corkscrew and that the
“golden bonus” or added benefit of the dramatic improvement in extraction of
the cork would not found a valid patent as the claimed innovation was obvious
for another purpose. Mr Waugh does not challenge this principle but submits
that the 181 patent does not involve such an added benefit.
ii) Dosage patents
74.
The courts are enjoined to have regard to all the relevant facts of
particular case in assessing whether an alleged invention is obvious. One of
those facts is the nature of the invention. A tenth consideration, therefore,
is that here we are concerned with a dosage patent with a Swiss-form claim and
an EPC 2000 claim. The possibility that a dosage patent with such claims may be
valid has been recognized both by the EPO and in the United Kingdom courts.
75.
In decision Abbott Respiratory LLC/Dosage regime (G 0002/08) EP:BA:2010:G000208.20100219
the Enlarged Board of Appeal of the EPO decided that, when it was already
known to use a medicament to treat a particular illness, it was possible to
obtain a patent for a new and inventive dosage regime for that medicament to
treat that illness. In so finding the Enlarged Board decided (a) that the dosage
patent did not breach the prohibition against the patenting of medical
treatment in article 53(c) of the EPC and (b) that a novel dosage regime for
the treatment of the same illness could be a specific use under article 54(5)
of the European Patent Convention. Recognizing the risks of undue prolongation
of patent rights, the Enlarged Board confirmed that “the whole body of
jurisprudence relating to the assessment of novelty and inventive step
generally also applies”. In relation to the assessment of obviousness this
included consideration whether the dosage regime caused a new technical effect
(para 6.3). The EPO has therefore not sanctioned any relaxation of the tests of
obviousness in relation to dosage patents.
76.
In the United Kingdom the Court of Appeal addressed the question of
dosage patents in Actavis UK Ltd v Merck & Co Inc [2009] 1 WLR 1186.
The case concerned an application to revoke a patent which included a
Swiss-form claim for the use of a specified dose of a known and already
patented substance, finasteride, in the treatment of androgenic alopecia. The
Court of Appeal reversed the trial judge’s revocation of the patent, holding
(para 29) that there was no policy reason why a novel non-obvious dosage
regime, which was the product of expensive and unpredictable research, should
not be rewarded with a patent of a Swiss-form claim. Jacob LJ, who delivered
the judgment of the court, added this significant qualification (para 32):
“So holding is far from saying
that in general just specifying a new dosage regime in a Swiss-form claim can
give rise to a valid patent. On the contrary nearly always such dosage regimes
will be obvious - it is standard practice to investigate appropriate dosage
regimes. Only in an unusual case such as the present (where, see below,
treatment for the condition with the substance had ceased to be worth
investigating with any dosage regime) could specifying a dosage regime as part
of the therapeutic use confer validity on an otherwise invalid claim.”
77.
The reason for this qualification is no mystery. The target of the
skilled person’s research is in large measure pre-determined. As Jacob LJ
stated (para 109), the skilled person would aim for a dose as low as possible
consistent with effectiveness. That would normally be the appropriate dosage
regime. I recognize and respect Birss J’s finding of fact that there was no
defined standard of minimal efficacy in relation to ED and that this would
require the skilled team to make a value judgment (para 36 above). But he also
found that it was common general knowledge that regulators were often
interested in and could require evidence of the minimum effective dose (para 83
of his judgment) and that the skilled team would be familiar with multiple dose
ranging studies as necessary as a generality (para 327 of his judgment). In my
view, the inventiveness of the dosage regime falls to be assessed in that
context.
iii) The role of the appellate court
78.
Finally, before addressing directly the question whether the Court of
Appeal was entitled to reverse Birss J’s finding of non-obviousness, I remind
myself of the limits of an appellate court’s power to overturn the evaluation
of a trial judge in this field. Where inferences from findings of primary fact
involve an evaluation of numerous factors, the appropriateness of an
intervention by an appellate court will depend on variables including the
nature of the evaluation, the standing and experience of the fact-finding judge
or tribunal, and the extent to which the judge or tribunal had to assess oral
evidence: South Cone Inc v Bessant, In re Reef Trade Mark
[2002] EWCA Civ 763; [2003] RPC 5, paras 25-28 per Robert Walker LJ.
79.
An experienced patent judge faced with a challenge to a patent on the
ground of obviousness, and who has heard oral evidence including cross-examination,
carries out an evaluation of all the relevant factors, none of which alone is
decisive but each of which must be weighed in the balance in reaching a
conclusion. In Biogen Inc v Medeva plc [1997] RPC 1, 45, Lord Hoffmann
emphasised the need for appellate caution in reversing the judge’s evaluation
of the facts where the application of a legal standard involved no question of
principle but was simply a matter of degree. He held that it would be wrong to
interfere with the judge’s assessment if no question of principle were
involved.
80.
What is a question of principle in this context? An error of principle
is not confined to an error as to the law but extends to certain types of error
in the application of a legal standard to the facts in an evaluation of those
facts. What is the nature of such an evaluative error? In this case we are not
concerned with any challenge to the trial judge’s conclusions of primary fact
but with the correctness of the judge’s evaluation of the facts which he has
found, in which he weighs a number of different factors against each other.
This evaluative process is often a matter of degree upon which different judges
can legitimately differ and an appellate court ought not to interfere unless it
is satisfied that the judge’s conclusion is outside the bounds within which
reasonable disagreement is possible: Assicurazioni Generali SpA v Arab
Insurance Group (Practice Note) [2002] EWCA Civ 1642; [2003] 1 WLR 577,
paras 14-17 per Clarke LJ, a statement which the House of Lords approved in Datec
Electronic Holdings Ltd v United Parcels Service Ltd [2007] UKHL 23; [2007] 1 WLR 1325, para 46 per Lord Mance.
81.
Thus, in the absence of a legal error by the trial judge, which might be
asking the wrong question, failing to take account of relevant matters, or
taking into account irrelevant matters, the Court of Appeal would be justified
in differing from a trial judge’s assessment of obviousness if the appellate
court were to reach the view that the judge’s conclusion was outside the bounds
within which reasonable disagreement is possible. It must be satisfied that the
trial judge was wrong: see, by way of analogy, In re B (A Child) (Care
Proceedings Threshold Criteria) [2013] UKSC 33; [2013] 1 WLR 1911, paras
90-93 per Lord Neuberger, para 203 per Lady Hale.
iv) Were claims 7 and 10 of the 181 patent obvious?
82.
The patent bargain which Lord Mansfield described and the EPO has used
as an overarching principle (paras 53 and 54 above) underpins and creates a
symmetry between the various provisions of the 1977 Act which govern the
validity of a patent (para 55 above).
83.
Bearing in mind that symmetry, the starting point in the assessment of
obviousness in this case is the Daugan patent. Its validity is not contested.
Indeed, Lilly’s case assumes its validity. But to be valid it must both
disclose and enable. It must disclose the invention, that is that tadalafil may
be used as a PDE5 inhibitor for the treatment of ED, to the notional skilled
person who uses common general knowledge in construing the patent. It must also
enable the notional skilled person to perform the invention using the disclosed
matter, common general knowledge, and that person’s uninventive skill in making
trial and error experiments. In Synthon BV v SmithKline Beecham plc
[2005] UKHL 59; [2006] 1 All ER 685, the House of Lords addressed and
distinguished the concepts of disclosure and enablement in the context of a
challenge to the validity of a patent on the ground of lack of novelty because
of anticipation by a prior patent application under section 2(3). But their
Lordships’ discussion of the need for both disclosure and enablement is equally
relevant to the validity of a patent under sections 14(3) and 72(1)(c) as Lord
Hoffmann stated at para 27 and Lord Walker at paras 63 and 64. One begins
therefore with the assumption that the Daugan patent has enabled the skilled
person to perform the invention of the use of tadalafil for the treatment of
ED. The notional skilled person’s task is to implement the ex hypothesi valid
patent. That involves finding the appropriate dosage regime having regard to
safety, tolerability and effectiveness. The procedures to achieve that end are
familiar and routine. In my view it is important to see the Court of Appeal’s
discussion of familiar routine research in this case in this context (paras
102-104 below).
84.
In assessing whether the Court of Appeal was entitled to reject the
trial judge’s evaluation it is important to recognize that the Court of Appeal
did not reverse any of Birss J’s findings of primary fact. Both courts accepted
that it was obvious for the skilled team to pursue the pre-clinical and
clinical research in order to implement Daugan. Motive was clearly present. It
was not in dispute that the target of that research was to identify the
appropriate dosage regime for tadalafil in the treatment of ED. It was accepted
that the skilled team were looking for a dose response relationship and that
they would know that, as a generality, multiple dose ranging studies were
necessary. There was no challenge to the finding that the discovery of a
therapeutic plateau between 25mg and 100mg doses would have surprised the
skilled team. Birss J, without relying on hindsight, held that it was “very
likely” that the skilled team would research further by testing doses of 10mg
and 5mg. That finding was amply justified as both Mr Muirhead and Lilly’s
expert, Dr Saoud, agreed that the skilled team would not stop the dose ranging
studies when they had revealed that therapeutic plateau. Indeed, as Kitchin LJ
recorded, Dr Saoud accepted that the decision to test the lower doses,
including the 5mg dose, was “a no brainer”. In short, the skilled team, having
embarked on the Phase IIb tests, would have continued their search for a dose
response relationship, because the purpose of the Phase IIb study had not been
fulfilled.
85.
The Court of Appeal was correct to attach significance to this central
finding because it undermined several of the factors which Birss J placed in the
balance as pointing to non-obviousness in para 343 of his judgment. The fact
that a 5mg dose was so much lower than the 50mg dose, which was recommended for
sildenafil, mentioned in the Daugan patent for tadalafil, and used in the
notional skilled team’s Phase IIa tests, is neither here nor there. The lack of
an expectation of efficacy at a 5mg dose is a factor of little weight if, as
was found, the skilled team would be very likely to study such a dose in the
search for a dose response relationship. For the same reason the fact that the
effectiveness of tadalafil at a dose of 5mg was a surprise can carry little, if
any, weight. Similarly, the finding that there was an important value judgment
to be made when the therapeutic plateau was identified at the same time as a
marketable dose can bear little weight when there is a finding, which is not
tainted by hindsight, that the skilled team would continue their tests.
86.
I consider that the Court of Appeal was entitled to treat the judge’s
failure to appreciate the logical consequences of the finding - that it was
very likely that the skilled team would continue the testing - as an error of
principle which allowed an appellate court to carry out its own evaluation.
87.
Lilly also argues that the daily dosing regime by which a person
prescribed tadalafil can take the drug once per day rather than on demand in
expectation of sexual activity was enabled by the technical effect of the drug,
namely the maintenance of efficacy with minimal side effects, which was not
obvious and which justified the patent. I disagree for two reasons. First, the
judge correctly treated the daily dosing regime as obvious because it was the
result of the inevitable discovery of the half-life of tadalafil in Phase 1 of
the tests. Secondly, claims 7 and 10 are not confined to the daily dosing
regime but also cover on demand use of the drug subject to a maximum total dose
of 5mg per day. That is fatal to this argument. The inventive concept by which
a patentee seeks to justify his or her monopoly must apply to all embodiments
falling within the claims which are said to have independent validity. In Brugger
v Medic-Aid Ltd (No 2) [1996] RPC 635, 656 Laddie J stated:
“It is not legitimate to define
the inventive step as something narrower than the scope of the relevant claims.
In particular it is not legitimate to identify a narrow sub-group of
embodiments falling within the claim and which have certain technical
advantages and then to define the inventive step in terms which apply to that
sub-group but not the rest of the claim.”
I agree. A similar rule applies in the EPO’s
problem-and-solution approach in the requirement that the identified problem
must be covered by all embodiments of the claim: see for example (Cognis IP
Management GmBH / Satuarated dicarboxylic acids) (Case T-1014/07) EP:BA:2012:T101407.20120702,
para 5. The daily dosing regime is not a factor which pointed against
obviousness.
88.
Standing back from the step by step analysis, it is clear that the
skilled team was engaged in the familiar and routine testing of a drug to
establish the appropriate dosage regime for tadalafil in order to implement the
teaching of the Daugan patent. That target was never in doubt. It was obvious
to embark on that exercise and carry out tests in a routine way until that
appropriate dose was ascertained. Those tests included the completion of the
dose-ranging studies which were the purpose of Phase IIb. The fact that
tadalafil at the dose of 5mg, while remaining effective as a treatment of ED,
also, and unexpectedly, had the additional benefit of reduced side effects was
an added benefit which does not prevent the identification of 5mg as the
appropriate dose from being obvious. The completion of the Phase IIb dose
ranging studies led to the asserted invention.
89.
Mr Waugh also submits (a) that the Court of Appeal lost sight of the
requirement that obviousness must be assessed by reference to the subject
matter of the relevant claims - a dose of tadalafil of between 1mg and 5mgs for
oral administration up to a maximum total dose of 5mg per day for the treatment
of sexual dysfunction - and not a loose paraphrase of what the claim or the
process by which the dose is discovered, and (b) that the Court of Appeal’s
approach conflicts with the problem-and-solution approach which the EPO adopts.
90.
In support of the first submission, he refers to the statement of
Kitchin LJ in MedImmune Ltd v Novartis (above), para 93, that the court
must answer a relatively simple question of fact: was it obvious to the skilled
but unimaginative addressee to make a product or carry out a process falling
within the claim (emphasis added). He also refers to Lord Hoffmann’s
statement in Conor v Angiotech (above) para 19, that the patentee is
entitled to have the question of obviousness determined by reference to his
claim and not a vague paraphrase based upon the extent of his disclosure.
91.
I am not persuaded that, in the context of a dosage patent, it is
necessary for the skilled team to identify in advance of the Phase IIb tests
the specific dose which is the subject of the claim. Were it otherwise, many,
if not most, dosage regimes would be patentable, whether the results of the
tests were surprising or not, simply because the precise doses which ultimately
are specified in the claim may not be sufficiently foreseeable. In my view, the
MedImmune requirement is met if the step by step approach, without the
benefit of hindsight, demonstrates that the skilled team would be very likely
to pursue the tests to the point at which they would ascertain the product or
process falling within the claims.
92.
Conor v Angiotech does not assist Lilly in this context. In that
case the relevant claim of the patent taught the use of a stent coated with
taxol in the prevention or treatment of recurrent stenosis, or restenosis,
which is the constriction of an arterial channel after the insertion of a
stent. Conor, which challenged the patent on the ground of obviousness and not
on the ground of insufficiency, sought to argue by reference to the patent’s
specification that the patent taught no more than that taxol was worth trying.
The House of Lords rejected this challenge, directed attention to the terms of
the claim, as section 125 of the 1997 Act requires, rather than the
specification, and held that the specification supported that claim. The case
is not authority for the proposition that, in all circumstances, obviousness
must be assessed by reference to the precise wording of the claim.
93.
In relation to the second submission, that the Court of Appeal’s
approach was in conflict with the EPO’s problem and solution approach, it is
important to recall Jacob LJ’s words in Actavis v Novartis (above) (para
26) that no-one has ever suggested that the problem-and-solution approach is
the only way to go about considering obviousness. Like the Windsurfing/Pozzoli
approach, it provides a structured approach which may assist in avoiding the
dangers of hindsight and may be more helpful in some cases than in others. No
formula should distract the court from the statutory question: Generics (UK)
Ltd v Daiichi Pharmaceutical Co Ltd [2009] EWCA Civ 646; [2009] RPC 23,
para 17 per Jacob LJ.
94.
Further, there is considerable room for judgment and disagreement on the
formulation of the objective technical problem to be solved. The EPO’s Guidelines
for Examination state (Part G - Chapter VII, para 5.2):
“In the context of the
problem-and-solution approach, the technical problem means the aim and task of
modifying or adapting the closest prior art to provide the technical effects
that the invention provides over the closest prior art. The technical problem
thus defined is often referred to as the ‘objective technical problem’.
The objective technical problem
derived in this way may not be what the applicant presented as ‘the problem’ in
his application. The latter may require reformulation, since the objective
technical problem is based on objectively established facts, in particular
appearing in the prior art revealed in the course of the proceedings, which may
be different from the prior art of which the applicant was actually aware at
the time the application was filed. In particular, the prior art cited in the
search report may put the invention in an entirely different perspective from
that apparent from reading the application only.”
The Guidelines recognize the difficulty which a court or
tribunal faces in formulating the objective technical problem and state:
“It is noted that the objective
technical problem must be so formulated as not to contain pointers to the
technical solution, since including part of a technical solution offered by an
invention in the statement of the problem must, when the state of the art is
assessed in terms of that problem, necessarily result in an ex post facto view
being taken of inventive activity (see T-229/85, [OJ 1987, 237]). …
The expression ‘technical problem’
should be interpreted broadly; it does not necessarily imply that the technical
solution is an improvement to the prior art. Thus the problem could be simply
to seek an alternative to a known device or process which provides the same or
similar effects or is more cost-effective.”
95.
The Guidelines continue in para 5.3 to discuss the “could-would
approach”, which the EPO adopts in the problem-and-solution approach, stating:
“the point is not whether the
skilled person could have arrived at the invention by adapting or modifying the
closest prior art, but whether he would have done so because the prior
art incited him to do so in the hope of solving the objective technical problem
or in expectation of some improvement or advantage (see T-2/83) …
When an invention requires various
steps to arrive at the complete solution of the technical problem, it should
nevertheless be regarded as obvious if the technical problem to be solved leads
the skilled person to the solution in a step-by-step manner and each individual
step is obvious in the light of what has already been accomplished and of the
residual task still to be solved (see T-623/97 and T-558/00).”
96.
I am not persuaded that the problem-and-solution approach would
necessarily give a different answer from that of the Court of Appeal. The
closest prior art is the Daugan patent and the well-established procedures of
pre-clinical and clinical testing. The problem posed by Daugan was the
identification of an appropriate dosage regime. The EPO approach to assessing
the obviousness of the claimed invention would then be to apply the
“could-would approach”, which means asking not whether the skilled person could
have carried out the invention, but whether he would have done so in the hope
of solving the underlying technical problem or in the expectation of some
improvement or advantage: T-2/83 OJ 1984 265 (Rider/Simethicone tablet),
para 7; T-1014/07 (above) paras 7 and 8. The tangible evidence which reveals
why the skilled team would have been prompted to come upon the asserted
invention is that (a) the team would not have completed the dose-ranging
studies which Phase IIb requires if it had stopped after the initial
dose-ranging studies which revealed the therapeutic plateau and (b) Dr Saoud’s
evidence that it was a “no brainer” to go on with the tests. The judge’s
finding that the skilled team would not have had an expectation of
effectiveness at a 5mg dose does not militate against the conclusion that the
team would have investigated that dose in the course of a sequence of tests
which had as its purpose the solution of the underlying technical problem,
which the implementation of the Daugan patent entailed.
Foreign judgments
97.
The court heard submissions about the judgments of the courts of other
countries which are signatories of the EPC on parallel revocation proceedings
against the 181 patent. The claimants founded principally on the judgments in
the Netherlands and Germany, in which in each case the national court revoked
the patent on the ground of obviousness. We were also referred to judgments
from other jurisdictions concerning the same patent, including Belgium and
Portugal, which upheld the obviousness challenge, and Denmark, Poland and the
Czech Republic, which reached a different view. I do not find the judgments
particularly helpful. While consistency of approach between the domestic courts
of the signatory states to the EPC on matters of principle is desirable, we are
not bound by the judgments of other national courts and it is possible that
national courts applying the same law may come to different conclusions for
various reasons: Conor v Angiotech (above) para 3 per Lord Hoffmann; Dr
Reddy’s Laboratories (UK) Ltd v Eli Lilly (above) paras 79-82 per Jacob LJ,
para 92 per Lord Neuberger MR; Actavis UK Ltd v Eli Lilly & Co
[2017] UKSC 48; [2017] RPC 21, para 52 per Lord Neuberger.
98.
The Dutch District Court of the Hague in Teva Pharmaceuticals Europe
BV v ICOS Corpn (14 March 2018) held the patent to be invalid as obvious
over Daugan and in its judgment referred in some detail to the decisions of
Birss J and the Court of Appeal in this case. The court treated as important
the objective of the Phase IIb test and Dr Saoud’s evidence in the English
proceedings (para 4.22). The court recorded (para 4.24) that it had not used
the problem-and-solution approach but that if it had, the outcome would
probably not have been different: if one adopted ICOS’s formulation of the
problem as “providing an improved dosing regime” the skilled team, having
ascertained the half-life of tadalafil, would have tested doses during the dose
ranging studies that enabled safe and effective daily use.
99.
The German Federal Patent Court in its judgment in Hexal AG v ICOS
Corpn of 24 October 2017 analysed the problem in the problem-and-solution
approach to be to provide dosages of tadalafil for effective treatment of
sexual dysfunction and stated that the skilled team would conduct dose-finding
studies as part of “the standard repertoire in [their] field of activity”. It
considered and disagreed with the judgment of Birss J on the significance of
the unexpected reduction in side effects, which in German case law would be
treated as a bonus effect.
100.
One can draw some support from judicial decisions in other national
courts which reach the same conclusion as one has come to. But it is necessary
to recognize not only that the first instance decisions in the Netherlands and
Germany are the subject of appeals but also that the evidence led before
different courts in parallel proceedings may differ and, even when the same
evidence is led, each court’s findings of fact based on that evidence may not
be the same. For example, the German court attached weight to evidence (a) that
sildenafil was effective at a 5mg dose and the skilled person would infer from
that that tadalafil would be more effective at low dosages because of its IC50
value (a finding which supported the conclusion that the skilled team had a
reasonable expectation of success in a test at that level) and (b) that it was
customary to start dose-ranging studies with very low initial doses and
increase the doses if tolerated. Neither of those findings was made in the
English proceedings. Similarly, the Dutch court in its analysis of the Phase
IIb studies accepted a mathematical calculation which Teva’s expert, Dr Cohen,
advanced in those proceedings which was similar to the “three factors point”
which the claimants put on cross examination to Dr Saoud in the English
proceedings but which Dr Saoud accepted only as “a paper exercise” and Birss J
rejected as the thinking of the skilled team (paras 297-303 of his judgment).
It is also necessary to observe, as Mr Waugh pointed out, that there was also a
judgment in favour of Lilly on obviousness in Australia, which is not a
signatory of the European Patent Convention.
101.
Because of the differences in the evidence led, the manner by which it
is tested, and the differing findings to which that evidence gives rise, one
may derive support from the approach to the question and methods of reasoning
of other national courts but should never rely uncritically on the outcome.
Interventions, selection patents and “improvement” patents
102.
In this appeal the court had the benefit of interventions from the IP
Federation, Medicines for Europe, the British Generic Manufacturers Association,
and the UK BioIndustry Association. The first intervener represents the views
of a wide range of UK industry on policy and practice in relation to
intellectual property rights. The second and third interveners represent the
interests of a range of manufacturers of generic drugs. The fourth intervener
is a national trade association for innovative enterprises in the bioscience
sector of the UK economy. Several interveners advocated that obviousness be
approached by a fact specific assessment on a case by case basis, an approach
which is consistent with my approach in this judgment, and resisted the
recognition of any one factor as being of overriding importance, whether it be
the cost and effort which pre-clinical and clinical trials entail, or the
standardised and sometimes routine nature of such tests.
103.
The UK BioIndustry Association asked for guidance on the relevance in
the assessment of obviousness of (a) the reasonable expectation of success as a
factor and (b) the problem-and-solution approach of the EPO. It expressed
concern that the judgment of the Court of Appeal might support the view that
empirical research in the field of bioscience would not be seen as inventive in
so far as the methods of research were well-established. The IP Federation
similarly expressed concern about a perceived risk that people might
extrapolate from statements in the Court of Appeal’s judgments that the result
of routine investigations cannot lead to a valid patent claim. It expressed a
particular concern about the breadth of the statement by Lewison LJ (in para
180): “in a case which involves routine pre-clinical and clinical trials, what
would be undertaken as part of that routine is unlikely to be innovative”. Its
concern was that a simplistic adoption of this phrase as a blanket test without
regard to the facts of the specific case would be contrary to the fundamental
principles of patent law. I do not interpret the Court of Appeal’s judgments,
including Lewison LJ’s statement which I have quoted, as supporting such an
extrapolation. Kitchin LJ gave the leading judgment, in which he adopted a fact
specific assessment based on the facts of this case and involving the weighing
up of several factors, and Floyd and Lewison LJJ agreed with his reasoning and
conclusions. I do not construe the judgments of the Court of Appeal as
supporting any general proposition that the product of well-established or
routine enquiries cannot be inventive. If that had been what the experienced
judges had said, I would have respectfully disagreed. But it is not. As Jacob
LJ stated in Actavis v Merck (above) para 29, there is no policy reason
why a novel and inventive dosage regime should not be rewarded by a patent. A
fortiori, efficacious drugs discovered by research involving standard pre-clinical
and clinical tests should be rewarded with a patent if they meet the statutory
tests (para 54 above).
104.
Mr Waugh in his reply attacks Mr Speck’s proposition that nothing which
was already within the skilled person’s repertoire could be inventive. He
suggests that such a proposition would undermine the so-called selection
patents and improvement patents. But because I do not accept Mr Speck’s
submission on the skilled person’s repertoire in this broad formulation, this
judgment does not militate against selection patents or improvement patents.
Selection patents are patentable as involving an inventive step if the
selection is not arbitrary and is justified by a hitherto unknown technical
effect (Agrevo/Triazoles (above) para 2.5.3) or, in other words, when
they make a real, novel and non-obvious technical advance (Dr Reddy’s
Laboratories (above) para 50 per Jacob LJ; para 104 per Lord Neuberger MR).
“Improvement” in the context of the law of patents is “in the most technical
sense … an invention which comes within the claims of an earlier patent but
contains a further inventive step”: Buchanan v Alba Diagnostics Ltd
[2004] UKHL 5; 2004 SC (HL) 9; [2004] RPC 34, para 32 per Lord Hoffmann. The
use of well-known research tests of itself does not render such selections and
improvements obvious.
Summary
105.
The balance or symmetry in patent law and the pre-established or at
least readily foreseeable target of the skilled team’s tests hold the key to
the resolution of this dispute. The Daugan patent is ex hypothesi valid and it
is not in dispute that it discloses an invention - that is the use of tadalafil
in the treatment of ED - in a manner which enables the skilled person to
perform it as section 14(3) of the 1977 Act requires. The task which the
notional skilled team would undertake was that of implementing Daugan. The
target of the skilled team would be to ascertain the appropriate dose, which
would usually be the lowest effective dose. The skilled team would know of that
target from the outset of its research. The pre-clinical and clinical tests
involved familiar and routine procedures and normally progressed to the
discovery of the dose-response relationship in Phase IIb. In this case the
trial judge’s findings of what would have been the sequence of the tests, which
did not depend upon hindsight, included the finding, which the evidence clearly
justified, that the team, having found a therapeutic plateau, would be very
likely to test lower doses and so come upon the dosage regime which is the
subject matter of the patent. For the reasons which I have given above, I am
satisfied that the Court of Appeal was entitled to interfere with the trial
judge’s assessment of obviousness and to hold that the 181 patent was invalid
for lacking an inventive step.
The claimants’ other challenges
106.
Having reached that conclusion, it is not necessary to address the
claimants’ alternative arguments for revocation on the grounds of
non-disclosure by the priority document, anticipation, and added matter.
Conclusion
107.
I would dismiss the appeal.
