Strand, London, WC2A 2LL
B e f o r e :
|Cipla Limited and others||Claimants|
|Glaxo Group Limited||Defendant|
Mark Chacksfield (instructed by Taylor Wessing, Sanderson Lumber, Roiter Zucker and Mr Campbell Forsyth) for the Claimants
Andrew Waugh QC and Justin Turner (instructed by Simmons & Simmons)
for the Defendant
Hearing dates: 13-16, 19, 20, 22, 23 January 2004
Crown Copyright ©
Mr Justice Pumfrey:
The patent in suit
'Asthma is a condition characterised by variable, reversible obstruction of the airways which is caused by a complex inflammatory process within the lungs. In most cases, this process is initiated and maintained by the inhalation of antigens by sensitive atopic individuals (extrinsic asthma). However, in some patients it is caused by other mechanisms which at present are poorly understood but do not involve an allergic process (intrinsic asthma). The disease has therefore two components, spasm of the bronchial (or breathing) tubes and inflammation or swelling of the breathing tubes.'
'It has been recognised that asthma may be treated by using both a bronchodilator for immediate relief and a prophylactic anti-inflammatory corticosteroid to treat the underlying inflammation. Such combination therapy directed at the two main underlying events in the lung (i.e. relief of spasm in the breathing tubes and treatment of inflammation in the breathing tubes) using a combination of salbutamol and beclomethasone has previously been proposed (Ventide, Glaxo Group trade mark), but suffers a number of disadvantages in view of the above-mentioned short duration of action exhibited by salbutamol. Thus the need for a 4-hourly dosing regimen may discourage effective patient compliance and also renders the product less than satisfactory in the treatment of nocturnal asthma since the bronchodilator may not remain effective for the duration of the night, leading to impaired sleep for asthmatics troubled by nocturnal cough, breathlessness and wheeze.
The present invention is based on the concept of a novel combination therapy which has markedly greater efficiency and duration of bronchodilator action than previously known combinations and which permits the establishment of a twice daily (bis in diem - b.i.d.) dosing regimen with consequent substantial benefits in, for example, the treatment of asthma, particularly nocturnal asthma.'
'We have found these two compounds to be particularly compatible and complementary in their activity and thus highly effective in the treatment of asthma and other respiratory disorders.'
'Pharmaceutical compositions comprising effective amounts of salmeterol (and/or a physiologically acceptable salt thereof) and fluticasone propionate as a combined preparation for simultaneous or sequential administration by inhalation in the treatment of respiratory disorders.'
The pleaded case
i) UK Patent GB 2,088,877 'androstane 17 ß-carbothioates'. This discloses fluticasone propionate and does not call for further consideration.
ii) UK Patent GB 2,140,800 'Phenethanolamine derivatives' discloses salmeterol and again does not call for further consideration. For reasons that I shall give below, salmeterol was part of the common general knowledge at the priority date.
iii) "Salmeterol, a long acting inhaled ß2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients" Ullman & Svedmyr, Thorax 1988; 43:674-678 ('Ullman & Svedmyr (1988)').
iv) "The effect of inhaled fluticasone propionate (FP), a new potent corticosteroid" Bauer & al European Respiratory Journal 1988, 1 (Suppl 2): 201S ('Bauer & al (1988)').
v) "A comparison of the tolerance and systemic effects of fluticasone propionate (FP) and beclomethasone dipropionate (BDP) in healthy volunteers" Harding & al European Respiratory Journal 1988, 1 (Suppl 2) 196S. ('Harding (1988)')
vi) "Fixed dose combination therapy in asthma. The positive case for future therapy" Ruffin, Mechanisms in Asthma: Pharmacology, Physiology and Management 1988, 427. ('Ruffin (1988)')
vii) "Glaxo's R&D progressing on target" SCRIP No. 1411, 12 May 1989.
viii) "UK Pharma companies' R&D assessed" SCRIP No.1435, 4 August 1989.
ix) The matter made available to the public by the prior use from 1983 of the VENTIDE inhaler to which I have already referred, together with its ABPI data sheet compendium entry for 1988-9 ('the VENTIDE data sheet').
x) "The Drug Therapy of Asthma: Directions for the 21st Century" by Barnes in Directions for new anti-asthma drugs ed O'Donnell & Persson; Agents and Actions / Supplements 23 (1988) ('Barnes (1988)').
xi) The common general knowledge in the art.
The addressee of the specification: the common general knowledge
'[The court] has to arrive as closely as it can at the mental attitude of a well-instructed representative of the class to whom the Specification is addressed, and no more. In other words, in the performance of this part of its task it has to ask itself what ought fairly to be considered to be the state of knowledge in the trade or profession at the date of the patent with respect to the matters in question, and if any facts or documents are such that in ordinary probability they would not be known to competent members of such trade or profession they ought not to be taken, either for or against the public on the one hand, or the inventor on the other, as forming part of public general knowledge.'
'On the other hand, common general knowledge is a different concept [sc. from public knowledge] derived from a commonsense approach to the practical question of what would in fact be known to an appropriately skilled addressee - the sort of man, good at his job, that could be found in real life.
As regards scientific papers generally, it was said by Luxmoore, J. in British Acoustic Films (53 R.P.C., 221, at 250):
"In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art.: in other words, when it becomes part of their common stock of knowledge relating to the art."
And a little later, distinguishing between what has been written and what has been used, he said:
"It is certainly difficult to appreciate how the use of something which has in fact never been used in a particular art can ever be held to be common general knowledge in the art."
Those passages have often been quoted, and there has not been cited to us any case in which they have been criticised. We accept them as correctly stating in general the law on this point, though reserving for further consideration whether the words "accepted without question" may not be putting the position rather high: for the purposes of this case we are disposed, without wishing too put forward any full definition, to substitute the words "generally regarded as a good basis for further action".'
'Invention can lie in finding out that that which those in the art thought ought not be done, ought to be done. From the point of view of the purpose of patent law it would be odd if there were not patent incentive for those who investigate the prejudices of the prior art.'
'...Common general knowledge has both positive and negative aspects. I have so far considered under this topic, as is customary, only positive aspects of the knowledge with which the skilled addressee is to be imbued. In my view in certain cases (and I believe this to be one of them), negative aspects of knowledge must in approximation to reality play their part. At the priority date of the patent, I believe that such was the "mindset" within the vacuum cleaner industry, no notional, right-thinking addressee would ever have considered the viability of purifying dirt-laden air from a vacuum cleaning operation, other than by means of using a bag [alone] or bag and final filter. For present purposes, the addressee is nonetheless deemed to have been presented with (in effect) three items of prior art wherein it is proposed to clean dirt-laden air by means not of bags but by cyclonic action alone. He is also assumed to take some interest in them however inimical the proposals may be to his likely way of thinking at the time. In terms of its impact on the issue of obviousness, I believe that this negative thinking which as Mr Kitchin suggested amounted to prejudice, would at least have caused the addressee to regard modification to any of these prior art proposals with considerable reserve if not overt scepticism. This likelihood must, I consider, be given due weight. In my view of the matter, I cannot think that any of the cited prior art would ex facie be likely to have led the addressee at the relevant date with any enthusiasm to effect the often substantial changes which would bring these proposals within a claim of the patent...my view in this regard is bolstered (but not precipitated) by Mr Dyson's evidence of what actually happened when he tried to interest the industry in Dyson I.'
'The vacuum-cleaner industry was functionally deaf and blind to any technology which did not involve a replaceable bag. The fact that the handicap was entirely economically determined made it if anything more entrenched. The industrial perception of need was consequently, in the judge's happy coinage, bagridden. It is entirely in accordance with what we know about innovation that this commercial mindset will have played a part in setting the notional skilled addressee's mental horizon, making a true inventor of the individual who was able to lift his eyes above the horizon and see a bag-free machine.'
'It is not good enough to show that a matter was known to some but not to others and in particular it is not good enough to show that knowledge (or a prejudice) was confined to one or a limited class of suggested exemplars of the skilled man.'
The legal approach to obviousness
3. 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).
2.-(1) An invention shall be taken to be new if it does not form part of the state of the art.
(2) 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.
'When any piece of prior art is considered for the purposes of an obviousness attack, the question asked is "what would the skilled addressee think and do on the basis of this disclosure?" He will consider the disclosure in the light of the common general knowledge and it may be that in some cases he will also think it obvious to supplement the disclosure by consulting other readily accessible publicly available information. This will be particularly likely where the pleaded prior art encourages him to do so because it expressly cross-refers to other material. However, I do not think it is limited to cases where there is an express cross-reference. For example if a piece of prior art directs the skilled worker to use a member of a class of ingredients for a particular purpose and it would be obvious to him where and how to find details of member of that class, then he will do so and that act of pulling in other information is itself an obvious consequence of the disclosure in the prior art.'
'There are, we think, four steps which require to be taken in answering the jury question. The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter [forming part of the state of the art] and the alleged invention. Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention.'
'Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of all the relevant prior art and of the facts of the nature and success of chlorpromazine, directly be led as a matter of course to try the - CF3 substitution in the "2" position in place of the - C1 atom in chlorpromazine or in any other body which, apart from the - CF3 substitution, has the other characteristics of the formula of claim 1, in the expectation that it might well produce a useful alternative to or better drug than chlorpromazine or a body useful for any other purpose?'
'I come now to the other branch of the argument on obviousness based on the Smith paper. Sir Lionel at first based himself on Gillette Safety Razor Co. v Anglo American Trading Co. (1913) 30 RPC 465 at 480, but it turned out on examination of this case that it did not bear out the proposition for which he was contending, namely, that anyone having the Smith paper before him was "entitled" to take the cyanide [molecule] of formula VIII and reduce it to form a basic [molecule] which would then fall within claim 1 and that claim 1 was therefore invalid. This argument is, in my judgment, fallacious, because it ignores the fact that the invention may well lie in the idea of taking the step in question. Why should anyone want to take this step unless he had first appreciated that such a step might give him a useful product? There is nothing in the Smith paper to suggest that reduction of formula VIII would have a useful anti-oxidant or, still less, a useful drug, and it is in my judgment not obvious to take the step in question unless and until it has been conceived that the idea of doing so might lead to a useful result. Of course, once one has the idea of doing so it is perfectly obvious how to do it, but that is not the material question.'
'When deciding whether a claimed invention is obvious, it is often necessary to decide whether a particular avenue of research leading to the invention was obvious. In such circumstances the extent of the different avenues of research and the perceived chances of any one of them providing a successful result can be relevant to the decision whether the invention claimed was obvious. Whether the subject matter was obvious may depend upon whether it was obvious to try in the circumstances of that particular case and in those circumstances it will be necessary to take into account the expectation of achieving a good result. But that does not mean that in every case the decision whether a claimed invention was obvious can be determined by deciding whether there was a reasonable expectation that a person might get a good result from trying a particular avenue of research. Each case depends upon the invention and the surrounding facts. No formula should be substituted for the words of the statute. In every case the Court has to weigh up the evidence and decide whether the invention was obvious. This is the statutory task'
i) Determine the 'closest prior art'. Only the closest prior art may be relied on, for the reason that any argument of obviousness based on more distant prior art will necessarily be weaker. This limits the investigation of obviousness in a manner which is no doubt acceptable in what is, after all, a body primarily concerned with granting patents, and refusing only those that it can be confident would not survive in the courts of the Contracting states, but it is not necessarily always compatible with the Convention, which requires the invention not to be obvious over 'the state of the art'. Thus a single reference is normally considered.
ii) Establish the technical problem to be solved. The technical problem is ascertained by a study of the patent against the background of the closest prior art. The EPO requires every invention to be a solution to a technical problem which is to be ascertained from the specification itself, which ought to contain a statement of the problem. The problem must not be formulated ex post facto, nor in a manner that points towards the alleged invention.
iii) Decide whether the solution to the problem provided by the claimed invention is obvious, starting from the closest prior art. In arriving at this decision, it is legitimate to take into account unpredictable advantages of the patented solution, but the advantages must be related to the distinguishing features of the invention, and must be possessed by everything falling within the claim. They are irrelevant in so-called 'one-way street' inventions, where the invention represents the way forward from the closest prior art that the skilled person would naturally adopt.
'6. In reconsidering the case, the Opposition Division will have to:
(i) determine the most relevant piece of prior art, whether it be citation (1) or (3) or possibly a new document;
(ii) define the object of the invention on the basis of an objective analysis considering the difference or surplus of the results of the invention (effect) beyond such most relevant art;
(iii) satisfy itself that the so defined object will be achieved by the solution of the invention;
(iv) Assess whether in the light of such object, such solution involved an inventive step, taking into account the prior art.'
ß-agonist and steroid therapy at the priority date: the common general knowledge
....In aerosol form, the so-called bronchodilator drug quickly and directly relaxes the constricted airways. Unfortunately, the effects of such drugs in this form only last for up to six hours, which is not enough to keep the airways relaxed during the whole night.
To circumvent these problems, Glaxo introduced the popular bronchodilator drug, salbutamol, in a special tablet form. Taken by mouth, it releases controlled amounts of the drug over a period of 12 hours. This can be useful for children, patients who suffer from nocturnal asthma and those who cannot cope with inhaler devices.
Now, however, Glaxo is developing a new drug which is closely related to salbutamol. Called salmeterol, it is longer-acting and twice as potent as salbutamol. After inhalation, it can protect against an asthmatic attack for up to 12 hours - right through the night, avoiding those early-morning attacks. The drug is still going through the last stages of clinical trials; Glaxo predicts that the first application for a product licence will be made about the end of 1989.
But drugs that relax the airways only alleviate the symptoms of asthma; they have no effect on actually treating the disease itself. Patients often think they are getting better because they can control acute asthmatic attacks with bronchodilators. In fact, such drugs divert attention from the underlying pathology of the disease and, without appropriate restorative treatment, there can be progressive damage to the airways. Doctors fear these long-acting bronchodilators may lull patients into a false sense of security.
There are, fortunately, drugs that can prevent this airway inflammation. In England the two most widely used drugs are corticosteroids and cromoglycate, both of which can be inhaled and have a direct action on the lungs. The steroids have an additional effect of helping to resolve the inflammation as well as simply preventing it. What these drugs do not do is to treat the symptoms of asthma - the tightening of the airways and the breathing difficulties. 'This', said Professor Peter Barnes, head of the department of thoracic medicine at the Cardiothoracic Institute, 'is why patients tend to give up taking steroids or cromoglycate, despite the fact that they have been prescribed. Patients just don't feel they are working.'
According to Dr Clive Page at King's College in London, one of the big problems about long-acting bronchodilator drugs is that patients taking them will never notice if their asthma is getting worse. 'More frequent use of the shorter-acting drugs is a sign that airway damage is increasing. If the long-acting salmeterol provides protection against an asthmatic attack for 12 hours, patients may have no indication as to the state of their airways.'
He stresses the need for regular therapy with steroids or cromoglycate, even if the patient is feeling well. It can take up to three months before any improvement of the airway damage might be seen. 'After all,' he said 'when people have high blood pressure they don't wait until they have suffered from an embolism or thrombosis before taking treatment for hypertension. It is the same with asthma. We need to help the airway to repair even if asthmatic attacks are becoming less frequent.
Professor Barnes is also optimistic and confirms an increasing use of the inhaled anti-inflammatory steroids. He thinks that Britain is ahead of most other countries in educating asthmatics: 'If handled carefully, Glaxo's new drug will be excellent. But we must not be complacent about continued education for asthmatic patients and rigorous adherence to appropriate prophylactic treatment.'
'Peter Barnes anticipated that one dose of salmeterol will be essentially the same as repeated doses of salbutamol. This may or may not be the case. Salmeterol and salbutamol do have a dramatically different profile in terms of their duration of action. It appears that after treatment with salmeterol the effects are very long lasting and it may be that twice-a-day treatment will give you a true 24-h cover, whereas with four-times-a-day salbutamol, by the time the next dose is due the effect of the salbutamol is effectively no longer there. I think it may be that the compound will prove itself one way or the other, but I think it will be very interesting to see whether in fact salmeterol does behave just like a long-acting salbutamol or whether it has a little something extra.'
'I would anticipate that virtually everyone with an interest would have read the Thorax paper. I do not think many people were aware of it through its development phases. I was, because I had a consultancy with Astra at that time, and I knew what they were developing and I knew what the opposition was developing, but I do not think many people -- but the asthma doctors would be aware of it in 1989 with the Svedmyr paper, yes.'
'the beta2 stimulant, salmeterol and the anti-inflammatory steroid, fluticasone, are the resultant product candidates from research to improve salbutamol (Ventolin) and beclomethasone dipropionate (Beclovent/Becotide).'
The common general knowledge as to the treatment of asthma
'Two issues drove it, but I do not know if I can speak for others about which was the relatively most important. Certainly one of the most important was driving that understanding that you needed to take inhaled steroids. There was a secondary driving force that there was an increasing concern about the correctness of taking regular bronchodilators. I think it is apparent from some of the data that I was able to unearth to help me recall what I was thinking at that time that we were certainly teaching very widely at that time that there should be a move towards regular use of inhaled steroids and that bronchodilators should be moving to being an "as required" treatment, not something which was taken regularly.
A ß2 agonist such as salbutamol 100-200 µg or terbutaline 250-500 µg) should be used as required rather than regularly [my emphasis].
(2) Inhaled anti-inflammatory agents
Patients who need to inhale a bronchodilator more than once daily or who have night time symptoms require regular inhaled anti-inflammatory drugs. Options include corticosteroids, sodium cromoglycate...Inhaled steroids are the drugs of choice and should be started at a dose of beclomethasone dipropionate or budenoside 100-400 µg twice daily...
(3) High doses of inhaled steroids
If control (as judged by symptoms, increased use of inhaled ß2 agonists and peak expiratory flow) is not achieved compliance should be questioned and inhaler techniques checked...
(4) Additional bronchodilators
If adequate control of symptoms is not achieved with inhaled steroids 2 mg each day and standard does of inhaled ß2 agonstis (such as salbutamol 200 µg or terbutaline 500 µg four times daily) a trial of the addition of inhaled ipratropium bromide, oral bronchodilators or high doses of inhaled bronchodilators may be considered.
Oral ß2-agonists and xanthines should not be used as first line drugs. The main indication is the presence of symptoms, often at night, which are not controlled by high does of antiinflammatory drugs and standard does of inhaled ß2-agonists.
'...The adverse effect of regular bronchodilator inhalation occurred not only among subjects who used a bronchodilator as sole treatment ((2 were better and 10 were worse during regular bronchodilator treatment) but also among those who took inhaled corticosteroids (14 were better and 29 were worse). Thus, regular inhalation of a betasympathomimetic agent was associated with deterioration of asthma control in the majority of subjects. The trends to use of regular, high doses or longer acting inhaled betasympathomimetic treatment may be an important causal factor in the worldwide increase in morbidity from asthma.'
'Whether or not this change in bronchial hyperresponsiveness is important can be resolved only by a large clinical trial in which asthmatic patients are randomised into groups receiving either beta agonists for regular inhalation or beta agonists to be inhaled sparingly. Earlier studies found slightly better peak flow and FEV1 values in patients taking regular beta agonists and led to the recommendation that the first line of treatment for the ambulatory patient is regular inhaled beta agonists.[The paper referred to is a 1987 publication by Rebuck and Chapman.] The sample size in these studies has been too small, however, to detect any long term benefit or disadvantage of regular inhaled ß agonists, such as a change in the number of severe asthmatic episodes and admissions to hospital. Until such a study has been reported it seems prudent to avoid using regular high doses of inhaled beta agonists and to reserve these for symptomatic treatment. Symptoms necessitating frequent use of inhaled beta agonists should be seen as indicating a need to start or increase prophylaxis with inhaled corticosteroids or cromoglycate.'
Q. Can you help my Lord, If everybody thought that regular beta 2 agonist therapy was to be avoided, why did not anybody from the floor say, "Look, you are missing a fundamental point about combinations. Combinations require regular therapy. That must be bad"? Nobody said it. A. I think they were concentrating, if I remember correctly, on the combination of an inhaled steroid and beta agonist, and there were so many other things that occupied the discussion like compliance and whether this does improve compliance, that nobody thought that it was appropriate or necessary to talk about regular low dose beta agonist, which in those days, and as I said, I did not really think there was major concern clinically. There were other things about the combination which were very, very much more discussion-worthy than discussing the regular beta agonist part of that therapy.
Q. I am sorry, I cannot not equate you having no problem with regular. A. I did have a problem with regular, but I did not think it was a major problem.
'Failure to respond to inhaled therapy is related to both poor inhaler technique and poor drug compliance. Amongst a group of "resistant" asthmatics regular prophylactic therapy is clearly necessary, but only two-thirds of patients with chronic asthma admit to regular ß2-agonist and less than one-half to regular use of inhaled steroids (these figures relate to self-reported compliance and will undoubtedly overestimate true compliance).'
"Airway hyperresponsiveness that characterizes bronchial asthma has two distinct components: an increased sensitivity of the airway as reflected by a leftward shift of the dose-response curve...as well as excessive airway narrowing as evidenced by an exaggerated or absent maximal response plateau. ...This latter component of the airway hyperresponsiveness has been considered by some investigators to be 'the most hazardous feature of airway hyperresponsiveness' as patients are still at risk of undergoing bronchoconstriction, even if the airway sensitivity is shifted. It is therefore of considerable importance that in contrast to glucocorticosteroids, neither regular use of short-acting bronchodilators...or the long acting bronchodilator salmeterol protect against excessive airway narrowing, leading some investigators to conclude that 'the insufficient efficacy against this component of airway hyperresponsiveness of monotherapy with long-acting agonists is a drawback in the treatment of asthma.
Against this background, it is relevant to ask why should any clinician prescribe regular ß-agonist therapy? The British Thoracic Society guidelines for the treatment of chronic asthma specifically recommends that ß-agonist should be used as required rather than regularly, and suggests that patients who need to inhale a bronchodilator more than once daily require inhaled anti-inflammatory drugs. In this regime, therefore, there appears to be no place for regular inhaled ß-agonists. The choice for prescribers has become more complicated since the arrival of the longer-acting ß-agonists such as salmeterol and formoterol, with the implication that their prolonged bronchodilator effect might be sufficient in itself to control asthmatic symptoms; indeed, the 'symptomatic control' argument may have some validity in the short-term, but the evidence presented here suggests that their long-term regular use is undesirable. A case has been made for an anti-inflammatory effect of salmeterol in man...; when scrutinized, however, this appears to be a functional antagonist rather than a true anti-inflammatory effect...and subsequent detailed histological and lavage studies on the effects of regular salmeterol treatment do not support an anti-inflammatory action. The debate amongst specialists, and the publicity given to the postulated 'anti-inflammatory' effects of salmeterol must have confused general practitioners and others not directly involved, and indeed may have led to some believing that inhaled long-acting ß-agonists might be a panacea for asthma, with consequential and regrettable under-use of inhaled corticosteroids or cromoglycate.
The Committee on Safety of Medicines concur that the case for the anti-inflammatory effects of ß-agonist has not been made. We suggest, therefore, that the use of regular inhaled ß-agonist has no place in treatment regimes for asthma, and is indeed potentially hazardous."
Over the past five years, there has been substantial debate about inhaled ß-agonists as a class of treatment. In this study, despite a more than fivefold difference in the amount of ß-agonist administered (9.3 puffs vs. 1.6 puffs per day) there was no clinically significant difference in asthma control between the treatment groups, indicating that patients with mild asthma should receive inhaled albuterol on an as-needed basis only; this approach also reduces the costs of medication. On the other hand, if, in an individual case, a patient with mild asthma and his or her physician perceive that scheduled treatment is beneficial, our results indicate that this practice will not be detrimental in this population.
They also make the following observation earlier in the paper, which is of some interest:
'Over the past five years, health professionals have been concerned about potential deleterious effects of inhaled ß-agonists on asthma control. In part because of concern about potential adverse effects of regular ß-agonist use, most current guidelines for the management of asthma recommend their use on an as-needed basis only, even though there is no sound clinical evidence on which to base this recommendation, [my emphasis] Our study provides reassurance about the use of inhaled albuterol by clearly demonstrating, in patients with mild asthma, that its regular use is not associated with a deleterious effect on asthma control. At the same time, however, in this group of patients with mild asthma we were unable to demonstrate any additional beneficial effect of regularly scheduled treatment with inhaled albuterol beyond that achieved with albuterol used on an as-needed basis only.'
In other words, their conclusion is that regular therapy does no harm in patients with mild asthma, but does no good either.
Other aspects of ß-agonists
Obviousness: the prior use of Ventide
'Asthmatic patients who routinely take three to four inhalations a day from both a Ventolin and a Becotide aerosol should find life a little easier from now on. Allen and Hanburys has combined the two into one product that goes under the composite name of Ventide. The new aerosol is intended only for patients who are stabilised on both drugs as it provides the standard dose of each (100 µg salbutamol plus 50 µg beclomethasone dipropionate) in every inhalation. It shouldn't be used for first line treatment or for acute attacks, and patients in danger of acute bronchospasm may need to carry a Ventolin inhaler as well.
But the advantage of Ventide, say Allen and Hanburys, is that it should improve compliance, especially with the Becotide component. Because the corticosteroid inhaler doesn't have an instant effect, some patients stop taking it or use it only intermittently, they say.
Previously it's been suggested that patients who need both drugs should use the Ventolin inhaler first as this would fully dilate the bronchioles for receiving the corticosteroid. But later studies have shown the sequence of administration to be unimportant, the company says.'
'The safety of these two drugs given separately, is well established. As Clark (1974) points out "It has been shown that most asthmatic patients are under-treated and that this is a particular problem with corticosteroids. As inhaled steroids can usually treat successfully patients with chronic asthma, the fixed combination may ensure better treatment as many patients omit to use inhaled [beclomethasone dipropionate] because they do not perceive any immediate advantage. This leads to significant under-treatment".'
In the part of the report entitled 'Justification of prescribing information' the following passage appears:
'Ventide Inhaler, Ventide Rotacaps and Ventide-Disks are therefore provided for those patients who require regular doses of both drugs for treatment of their reversible airways obstruction. Ventide is not intended for use as a first-line treatment but is for use once the need for inhaled corticosteroid therapy has been established and my be particularly useful in patients for whom compliance is a problem.'
Again, the conclusion of this report is significant:
'Ventide-Disks will, like Ventide Inhaler, provide for chronic asthmatics a convenient single presentation of two drugs, both of which are necessary for the optimum control of their condition. The safety of these two drugs, already in wide concurrent use by such patients, is clear. The danger of inhaled steroid stems not from overdosage but from under-dosage. There is a very real possibility that the patient who needs bronchodilator and steroid treatment for good control of their asthma will, if prescribed regularly the two drugs separately, favour salbutamol inhaler which gives immediate relief, but allow the beclomethasone dipropionate inhaler to lapse because it does not appear to him to be providing an obvious benefit. Such asthmatics are clearly at risk; if their condition is of sufficient severity to necessitate steroid therapy, it is essential that such therapy should be continuous. In this patient group combination therapy may be preferred.
Studies reported show that the management of asthmatic patients is the same whether salbutamol and beclomethasone dipropionate are administered from the same or separate inhalers. In addition, the acute bronchodilator effects of salbutamol are the same whether administered from a standard salbutamol inhaler or from an inhaler also containing beclomethasone dipropionate.
Ventide Inhaler and Ventide disks are specially provided for those patients who require regular doses of both drugs. It is not intended for use as a first-line treatment but is for use once the need for inhaled corticosteroid therapy has been established.'
[of the Justifications passage]Q. Do you stand by that? A. I think at the time, 1988, for Ventide and the way in which Ventide was being used in some countries it was a reasonable statement.
Q. And the United Kingdom? A. And for the United Kingdom.
Q. Would you read the Conclusion? A. I have read it.
Q. Again, presumably you stand by that, as of the time this was written?
A. I stand by that in terms of the patient population for whom this was directed, which was primarily patients...we saw this as an option for patients who are already taking Ventide, and certainly you point out the UK. The UK usage of Ventide was really very small. This product was primarily directed at some other markets in the world, notably Latin America, where this was a popular product. [I have made a small emendation to the transcript by inserting the marks of omission, which correspond to the sense of the answer.]
Dr Crompton was also constrained to agree that they were logical:
Q. Could you read under "Conclusion," on page 26, the first paragraph? (Pause for reading) A. I have read the first paragraph.
Q. Are you suggesting that there is anything illogical about the Glaxo justification for a new Ventide product? A. All I can assume is that Dr. Palmer was using as much persuasion as he could to allow the new formulation in the diskhaler to be marketed.
Q. Do you see anything wrong with the reasoning? A. No, I do not see anything wrong with the reasoning. It is just when you try and put it into clinical practice, it just falls down.
Q. Why does it fall down for the people for whom compliance is a problem? A. In this particular instance, it is paediatric and we have a problem there with letting loose children with a diskhaler without supervision. If they have got supervision, there should not be a problem with compliance because their parents will make sure that they use it.
Q. Some parents will. It is not just paediatric; it is VentideDisks and Ventide-Disks paediatric, so it is ----A. Sorry?
Q. There is nothing illogical in the reasoning? A. No, there is nothing illogical in the reasoning.
Q....The suitable cases to whom you believed Ventide had a role, can you just expand on the suitable cases? A. Yes. I think those people who were having problems with their compliance with medication. That is the first grouping. Ventide was a useful agent in that situation where what we could do would be to give them the inhaled corticosteroid preparation as well as their beta agonist, and they would take it because they could feel the immediate benefit of taking the Ventolin, the beta agonist, and therefore would take this material because they felt an immediate benefit and so they were happy and we were happy because they were taking inhaled corticosteroid at some level to prevent problems; so that they are a group of people principally who have problems with compliance. There are a group of people as well whom we found that they would get confused if there were a large number of different inhalers for them to take or different sorts of medication during the daytime. If we could achieve a balance of control of their symptoms by the regular use of a combination preparation, and in this instance we are talking about Ventide, then we had another group of people in whom we would have a more successful outcome.
'If you have to make compromises, you should think about giving combinations of inhaled steroids and beta agonists. The patients will take the drug because they get immediate symptom relief, but the important thing is you actually get the useful drug into the patients.'
'Many asthmatics require regular therapy with an inhaled ß2-receptor agonist and an inhaled corticosteroid to achieve control of their symptoms. The use of these two agents affords relief of bronchospasm, suppression of inflammation and hyper-reactivity and prevention of ß2-adrenoceptor tolerance. Salbutamol and beclamethasone dipropionate are frequently used concomitantly and a combination inhaler of the two has now been developed. This form of treatment may aid patient compliance since it is recognized that compliance decreases as the number of different medications increases. Two studies have shown that the combination inhaler is as effective as the same two agents from different inhalers.
This study was designed to compare the clinical effects of regular inhalations of salbutamol and beclomethasone dipropionate used simultaneously from a combination inhaler with regular inhalations of the same agents used sequentially from separate inhalers. An attempt was also made to assess patient compliance.
In conclusion, this study has confirmed the efficacy of the combination inhaler as an alternative to the separate inhalers used sequentially. However, a ß2-agonist inhaler should also be supplied to patients for treatment of breakthrough symptoms in order to avoid over-use of the (combination) inhaled corticosteroid. The combination could not be shown to improve patient compliance in this study, in which there was good compliance throughout in both treatment groups-a reflection perhaps of the close supervision which forms part of any clinical trial.'
'Q. You would have checked it. A. I perhaps would not have checked it as I should have done because of the quality of the journal and the circumstances in which the study was allowed to take place.
Q. Well, wait a minute, doctor. You knew that your name was going to go on a paper in which there was an investigation as to compliance between regular salbutamol and Ventide. You must have known that. A. Yes. The second author of the paper is Dr. Pover who to Ventide is the James Palmer to Seretide. It was her baby and Dr. McDonald's salary came via Dr. Pover from Allen & Hanburys. Therefore, although we were not asked to do this because we would not get further funding in that type of way, it seemed appropriate at that time that I should allow that paper to be written. I did not check the last draft. I would not have allowed that first paragraph and I would certainly not have allowed the last sentence which actually shows how scientifically worthy this paper is.
Q. But you---
A. The last sentence says---
MR. JUSTICE PUMFREY: Just wait a moment.
A. The combination could not be shown to improve patient compliance. It was sent off to the Current Medical Research opinion. I think Allen & Hanburys paid for this publication. If I can be flippant, it is kind of Dal Negro.'
The reference to Dal Negro is to Dal Negro & al (1983) 'Chronic Airways Obstruction - Responsiveness to combined pressurized salbutamol-beclomethasone dispropionate (Ventolin Flogo)' Clinical Trials Journal 20:366, a paper criticised heavily by Dr Crompton, which reports a trial of Ventide in cases of chronic obstructive pulmonary disease.
MR. WATSON: If it was your view that Ventide was irrational, what were you doing putting your name to a paper which is investigating Ventide as against regular salbutamol? A. I think I have almost answered that with my Lord. I allowed the paper, or the investigation, to be performed in the unit.
Q. But why if it was irrational, doctor? A. Perhaps in the hope that it would be shown that it was not as good as regular therapy.
Q. Are you really saying that on oath? A. No. I did not have any views one way or the other. I was not terribly interested. I was not interested in the paper. As I said, had I been interested in the paper, I would not have allowed the last sentence to say "this combination could not be shown" which is not really a thing that you put in a scientific paper.
Q. Do I understand it that you did not have the view in 1988 that Ventide was an irrational product? A. I did have the view it was an irrational product - I did.
Q. I am asking how you can square up a paper which was comparing Ventide with regular salbutamol when you believed Ventide was irrational and, as I understand your evidence, you believed regular salbutamol therapy was not the best therapy. A. That is correct.
Q. So why are you putting your name to it? A. Because it was important for Dr. McDonald to have a name other than Dr. Pover on, because I am sure it was for her benefit. I admit that that is the paper and that is my name and that is what is written in it, but I did not believe it.
Q. Doctor, I find this rather strange. Are your professional standards such that you will allow your name to go forward to help another colleague if you do not believe in the science of the paper? A. I do not think so.
Q. So you did believe in this as being an ethical and proper trial to be carried out. A. It was a proper and ethical trial to be carried out. I just do not believe what actually was written by Dr. Pover and Dr. McDonald, and it is my fault for not checking.
Q. Are you saying that despite your name as the senior man on the paper, are you disagreeing with that first sentence in the introduction? A. "Many asthmatics require regular therapy", yes.
Q. Presumably that was the view of at least one of the other authors. A. Dr. Pover.
Q. A reasonable physician? A. An employee of Allen & Hanburys.
Q. So Allen & Hanburys were approaching it on the basis that many asthmatics required regular therapy with beta agonists? A. I assume so.
Q. You see, lower on the page, it says, talking of the combination: "This form of treatment may aid patient compliance since it is recognised that compliance decreases as the number of different medications increases." You would stand by that? A. Yes, with non-asthma medications. I think most of the references are to tablets taken by people with hypertension and other diseases. I am not sure, but I think that is it.
Q. Again, you are putting your name to a statement that a combination product for asthma might aid patient compliance. That was something that you believed. A. This paper suggests that I believed .... Well, it does not suggest. My name is on that paper and that is written on that paper, and all I can say is yes.'
Q. You say in your evidence -- this is what I am testing - it was just obvious to update Ventide. A. I absolutely think it was. If you have got a steroid, a ß agonist in one inhaler, and suddenly a longer acting one comes along that is twice daily -- another steroid that comes along that is more potent and twice daily, and we already know from Dr. Crompton's evidence and others that the biggest problems with Ventide was the fact that it was not necessarily the combination of the best bronchodilator in terms of the frequency of administration with the steroid -- it is like falling off a log. I really do not see that there is a big issue about it.
This answer was given during the course of a cross-examination about a paper of Professor Page's, Page (1987) 'Developments in Asthma: a view of current research'. (Scrip Bookshop, London). He had classified anti-asthma drugs into symptomatic bronchodilators, prophylactics and anti-inflammatories. In a diagram on page 20, he identifies the ß2-agonists as falling within the first class, along with other families of drugs, and the glucocorticoids as being the only family of drugs falling within both the prophylactic and anti-inflammatory classes. Underneath, he places a box stretching across all three classes, and puts the words 'What's needed!' in the box. He says this:
'Our understanding of asthma is now at a crossroads; despite many pharmacological and technological advances, the unfortunate fact remains that many asthmatics are not diagnosed early enough, do not understand the seriousness of their disease, and many with continuing symptoms are inadequately treated. The stage has clearly been reached where a major challenge in this area of medicine is the more effective use of existing anti-asthma treatments, a task involving an enormous amount of education directed at patients and general physicians alike. In particular, education must highlight the fact that asthma is a chronic inflammatory disease rather than a reversible airways disease. Furthermore, it needs emphasising that asthma is a disease requiring constant monitoring and much wider usage of anti-asthma drugs aimed at reducing airways inflammation and bronchial hyperreactivity, rather than increased usage of symptomatic treatment as is occurring currently. Although it is inevitable that some patients will remain non-compliant, the goal should be earlier diagnosis and treatment with prophylactics before patients have established inflammation to resolve with glucocorticosteroids. To try and overcome the compliance problem associated with taking prophylactics regularly (where no immediate clinical relief is evident), a prophylactic having symptomatic properties in the same molecule is needed.'
'MR. WATSON: From the background that you are aware of, that pharmaceuticals which are taken concurrently are often combined for convenience, from the background ---- A. Sorry combined?
Q. Into one pill, ampoule, injection or whatever. From the background that in asthma there were at least three combination products, what I am suggesting to you is that the concept of combining the new steroid with the new ß2-agonist was self-evident. What was not self-evident is whether it would be a commercial success and/or whether it would be safe. Do you agree? A. Correct.
Q. Of course, the way to establish safety would be in a clinical trial. You might have to do animal studies first. A. In clinical trials, yes.
Q. The way to find out whether the combination would be safe would be routine clinical trials. A. Routine?
Q. Clinical trials. A. There would have to be pre-marketing clinical trials, would there not?
Q. Yes. That is where the commercial decision comes in as to whether you are going to invest in this combination. That may be where Dr. Palmer was to be commended because he had the faith, that commercially it was going to be a winner. A. In spite of the opinion of others, yes.
'Fixed combinations have been used before eg. Salbutamol/beclomethasone dipropionate (Ventide) and have received a very mixed reception from the medical profession. However the problem of compliance, particularly with inhaled steroids, has lead [sic] clinicians to recently re-appraise the need for such products in selected patients. A fixed combination treatment of salmeterol with beclomethasone dipropionate (BDP) or salmeterol with fluticasone propionate will fulfil such a need by combining a long lasting bronchodilator with a steroid in a twice-daily treatment.' (October 1989)
'There is increasing evidence that underlying the symptoms of asthma is airway inflammation and that, in many cases, treatment with both a bronchodilator and an inhaled steroid provides the most appropriate prophylactic therapy. To aid patient compliance, there is an increasing medical recognition of the need for bronchodilator/corticosteroid combination products to treat all aspects of the disease.' (June 1990)
Unless these extracts contain some inventive insight at the priority date, the patent must be invalid, because I consider that the problem of compliance has, on the evidence, always been a problem.
Ullman & Svedmyr (1988)
Barnes (1988) and Ruffin (1988)
Many different therapeutic approaches to the treatment of asthma may be possible, yet there have been few new drugs. ß2-adrenoceptor agonists are by far the most effective bronchodilator drugs and lead to rapid symptomatic relief. It is difficult to imagine how these drugs could be improved, apart from a longer duration of action when given by inhalation, since they antagonise bronchoconstriction irrespective of cause, are virtually devoid of side-effects and over-dosage does not cause problems. Similarly, inhaled corticosteroids are extremely effective as chronic treatment in asthma and suppress the underlying inflammatory process. It follows that a combination of inhaled steroids and ß-receptor agonists is required and combined inhalers would seem to be a sensible development, since they will improve the compliance of inhaled steroids (which is poor because of the lack of immediate bronchodilator effect). Future developments in asthma therapy should be directed towards the inflammatory mechanism and perhaps more specific therapy may one day be developed. The possibility of developing a "cure" for asthma seems remote, but when more is known about the genetic abnormalities of asthma it may be possible to search for such a therapy.
Q. So if Glaxo came along and said, "We have thought for the first time of making a combined product of salmeterol and BDP", you would have to say, "No, you have not. That was suggested by Professor Barnes"?
A. Putting it that way, I have got to agree, I suppose.
The SCRIP citations
MR. WATSON: You are in a pharmaceutical company other than Glaxo. My Lord is absolutely right. If you were unconstrained by patent rights, you would love to have access to those two products which Glaxo saw as potentially major products, would you not? A. I suppose so. I find it a bit extremely difficult to put myself into that position which I have never been in, and I will never will be, but I suppose I would.
Q. If you were given rights to those products, you would be looking at various ways in which they could be marketed. A. Of course.
Q. And a way which would occur to you as a potential way to market them would be as combinations. Just hear me out: you would then have to decide would that be safe, would it be efficacious, would it be a good seller. But the idea of combining two products which are taken concurrently in itself is hardly novel. You would agree with that? A. Yes.
Q. The difficult decision is whether it is going to be commercial. A. Or safe.
Q. Or safe. A. That means commercial, yes.
'Whether or not there was a synergy demonstrated by experiments conducted after the date of the patent cannot help show obviousness or non-obviousness. Nor can the amended claim be better if only the components of the amended claim (as opposed to the unamended claim) can be shown to demonstrate synergy. The patent does not draw any such distinction and it would be quite wrong for later-acquired knowledge to be used to justify the amended claim.'
'The Defendant's position is that the Patent provides the person skilled in the art with the information necessary to produce a combination which is, in fact, highly effective and is particularly complementary and compatible, whereas at the priority date the skilled person would not have seen any benefit in making something falling within the claim. Thus it is of assistance to the court to understand that the combination of salmeterol and fluticasone is a very real contribution to the art and that there has indeed been an inventive step.'
The conclusion does not, in my view, follow from the premises. There was no-one else to make the invention except the patentee of salmeterol. There cannot, therefore, have been any reaction in the art involving salmeterol in response either to Ventide or to any other matter falling to be taken into account as forming part of the state of the art at the priority date. Subsequent history can throw no light at all upon the skilled person's view at the priority date. In my judgment, claim 1 was a very good, obvious therapy at the priority date. Because I cannot see any probative value in the exercise, I have not gone into the subsequent investigations of the combination of claim 1 with a view to demonstrating synergy. I should merely record an impression that if there is synergy, it is slight and controversial, and that the value of the combination lies in the very advantageous properties of its components, together with the guarantee of compliance, as the patent itself suggests.
Glaxo's internal history
Q. That is very different, doctor. That is very different. I quite understand that once you have the concept of a combination product, you have got to test it. You have got to find whether you can formulate it and you have got to test whether in fact surprisingly one affects the other, even though they are taken concurrently in man when they are put in a joint formulation. But that is all down the road. The concept of making the combination is one that the marketing department make. The scientist then goes and works out whether it can be done. The clinician works out whether it can be used effectively and safely. A. No, in this case it is not correct because this is 1990. In '88 and '89, the concept of regular beta agonist therapy was controversial. As we have heard, the concept of twice a day longer duration of action of drug was controversial, so it was not immediately apparent that putting together a long-acting beta agonist with an inhaled steroid was the right thing to do.
Q. It was apparent that it was something that needed to be investigated. A. It was apparent to me that it was something that needed to be investigated.
Q. And apparent to the marketing department and apparent to anybody with experience in creating line extensions of successful products?
A. It gets to the issue of what was going on in '88 and '89. I worked extremely closely with the marketing team in terms of thinking about what we did, but getting to the point of deciding this was the right thing to do was not apparent because of all the controversies that we have actually talked about.
'Professor Page was involved in wide ranging discussions on GSK core strategies in the respiratory area of the most sensitive nature, which included GSK current thinking on anti inflammatory and bronchodilator medicines. As such, Professor Page would be involved in discussions of the most sensitive nature regarding GSK's views on the role of the above in the management of asthma and other chronic respiratory diseases. As mentioned previously, much of the CEDD's current efforts in the asthma area revolve around the identification of the next generation successors to Seretide/Advair.
7. I thought it was inappropriate for Professor Page to continue to be involved in meetings of opinion leaders at which a number of highly confidential developments would be discussed (including GSK's respiratory portfolio and pipeline development projects, including developments relating to Seretide) while he was, in the very same week, assisting Cipla with their action to revoke the Seretide patent. Neither Malcolm Johnson nor David Waters nor anybody else working on the case had been aware of Professor Page's special role in our ongoing research.
8. In my view Professor Page had put himself into a position in which he had a clear conflict of interest. I telephoned him to know how upset I was about this and to say that I did not think it was appropriate for him to attend the opinion leaders meeting on 22 and 23 January or continue in this role.'