‘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.’
‘[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.’
‘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.’
‘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 - CF 3 substitution in the “2” position in place of the - C1 atom in chlorpromazine or in any other body which, apart from the - CF 3 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’
‘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.’
‘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 beta 2 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 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 FEV 1 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 β 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.’
‘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 β 2-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 β-agonist therapy? The British Thoracic Society guidelines for the treatment of chronic asthma specifically recommends that β-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 β-agonists. The choice for prescribers has become more complicated since the arrival of the longer-acting β-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 β-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 β-agonist has not been made. We suggest, therefore, that the use of regular inhaled β-agonist has no place in treatment regimes for asthma, and is indeed potentially hazardous.”
‘Over the past five years, health professionals have been concerned about potential deleterious effects of inhaled β-agonists on asthma control. In part because of concern about potential adverse effects of regular β-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.’
‘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”.’
‘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.’
‘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.’
‘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.’
“This form of treatment may aid patient compliance since it is recognised that compliance decreases as the number of different medications increases.”
‘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.’
‘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.’
‘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.’