Cipla Ltd. & Ors v Glaxo Group Ltd.

Mr Justice Pumfrey:

Introduction

1. This judgment is given in four actions to revoke UK patent 2 235 627 which stands in the name of Glaxo Group Limited (“Glaxo”). The claimants in the four actions are Cipla Limited and Neolab Limited (HC03 C00429), Generics (UK) Limited (HC03 C02619), IVAX Pharmaceuticals (UK) Limited (HC03 C03055) and Arrow Generics Limited (HC03 C03946). Each of the claimants is engaged in the manufacture or sale of generic pharmaceuticals and was separately represented in the proceedings until a comparatively late stage, when all instructed a single leading counsel for the purpose of the conduct of the trial.

2. Although the grounds of invalidity relied on by each of the claimants did not traverse exactly the same ground in each case, on 17 December 2003 I ordered that all four claimants should serve a consolidated statement of the Grounds of Invalidity relied on, and this was done on 30 December 2003, a further ground of invalidity being added by amendment on 13 January 2004.

3. When the four actions came on for trial, Dr Costello and Professor Page gave evidence first. They had been instructed by Cipla Limited and Neolab Limited. Although the actions had not been consolidated, an order had been made that the evidence in one should stand as the evidence in the others, and Mr Watson QC indicated that Professor Kay, who had been instructed by Generics (UK) Limited and Ivax Pharmaceuticals (UK) Limited, would not be called. Dr Auty and Dr MitchellHeggs gave evidence on matters not covered by the other two experts. Expert evidence was given by Dr Crompton and Professor Johnson for Glaxo, who also called Dr Palmer (the named inventor), Professor Partridge, and Professor Ruffin (witnesses of fact).

4. Dr Rapeport, a senior manager with Glaxo, was also cross-examined on his witness statement which related not to the issues in the case but to a very unsatisfactory incident which occurred shortly before the trial. I shall deal with that matter at the conclusion of this judgment.

The issues

5. In general terms, the patent in suit relates to an asthma treatment consisting of an inhaler that administers simultaneous doses of two drugs, salmeterol and fluticasone propionate. Salmeterol is a β2-agonist and fluticasone propionate a steroid suitable for administration by inhalation. The only issue in this case was whether this combination of β2-agonist and steroid was obvious to include in an inhaler at the priority date. A number of citations were relied on, but the principal basis for the allegation of obviousness turned out to be a previous combined inhaler containing salbutamol (a β2-agonist) and beclomethasone dipropionate (a steroid) sold by Glaxo well before the priority date under the name ‘Ventide’ which was established to form part of the common general knowledge of the skilled person. Two publications, “Fixed dose combination therapy in asthma. The positive case for future therapy” by Ruffin in Mechanisms in Asthma: Pharmacology, Physiology and Management 1988, 427-435 (Ruffin (1988)) and “The Drug Therapy of Asthma: Directions for the 21st Century” by Barnes, published in “Directions for New anti-Asthma Drugs”, Agents and Actions supplements, Volume 23, 293-313 (Barnes (1988)) were also particularly relied on.

6. The principal argument relied on by Glaxo to repel what appeared on the surface to be a strong argument of obviousness was that there existed at the priority date such a prejudice in the relevant art against regular β2-agonist therapy and to combination therapy by inhalation for asthma, that the combination claimed could not at the date be said to be obvious to the skilled person, albeit that Ventide was still on sale. In support of the contention that there was invention here, Glaxo also pointed to the enormous success of inhalers according to the invention which are sold under the mark ‘Seretide’: it is common ground that they have effected a very important change in prescribing practice and that Seretide is by all accounts a very successful treatment, both medically and commercially. It is one of GlaxoSmithKline’s best-selling drugs.

7. The question of the extent of the prejudice against regular β2-agonists and against combination therapies occupied most of the hearing. A large number of articles in the scientific press and elsewhere were referred to, and in order to keep some order in my discussion of them I use the conventional method of reference, that is Author’s name (year) with a letter following the year if there is more than one publication by that author in that year.

Some history

8. I shall return to the history of asthma treatments in greater detail below, but the principal milestones in modern asthma therapy down to the priority date in 1989 are as follows. Treatment of asthma by inhaled β-adrenoreceptor agonists, or β-agonists, can be traced back to a report of the treatment of asthma by the use of inhaled adrenaline at Guy’s well before the second World War. Administration of a β-agonist relieves the symptoms of asthma by relaxing the bronchial smooth muscle and so opening the airways. β-agonists act on the so-called β receptors on the walls of smooth muscle cells to affect the biochemical processes within the cell. There are at least two types of β receptors in human tissue. Adrenaline acts on the β receptors in the bronchial smooth muscle to relax it, but acts on the cardiac receptors to increase heart rate. Notwithstanding this undesirable effect β-agonists entered clinical practice after the introduction in the 1950’s of the pressurised metered-dose inhaler, which permitted an accurately metered dose of the drug to be administered via the airways directly to the affected muscle. The first drug to be widely used in this manner was the non-selective β-agonist isoprenaline, and its undisciplined use in the 1960’s is suspected to have caused an increase in the number of asthma deaths during that decade. In 1967 the Committee on the Safety of Medicines issued a warning to all doctors that there might be a link between the observed increase in asthma deaths and the overuse of isoprenaline-containing inhalers. Sales of the inhalers fell and so did the asthma death rate.

9. Salbutamol was one of the first β-agonists to be selective in its activity. It did not target the β₁ receptors in cardiac tissue, but selected the β₂ receptors of the bronchial smooth muscle. It accordingly gave symptomatic relief against an asthmatic attack but had much less effect upon the heart. Salbutamol and terbutaline, another β₂-agonist, were very well established by 1989 in the symptomatic treatment of asthma. It should be noted that some physicians certainly thought that regular (that is, non-symptomatic) use of bronchodilators was undesirable for a number of reasons. I shall return to this topic below.

10. While this development in the symptomatic treatment of asthma was going on, it came to be appreciated that asthma is in fact an inflammatory disease. Glucocorticosteroids are of course important anti-inflammatory drugs and their use in the treatment of asthma had started in the 1950’s. The available drugs at that time, prednisolone and hydrocortisone, had problems for long term therapy unless used in very low doses because of their side-effects. In the early 1970’s beclomethasone diproprionate (‘BDP’) was introduced and it became apparent very rapidly that inhaled BDP was a valuable asthma therapy.

11. BDP was administered either four times or twice daily (‘b.i.d.’, the accepted abbreviation for bis in diem). Compliance with a four-times-daily schedule was difficult for some patients, the more so as treatment with a steroid did not relieve immediate symptoms. I shall deal with the problems of compliance in greater detail below. It is sufficient to observe that compliance with a twice-per-day regimen is obviously easier for the patient, if only because the inhaler did not have to be carried about but could be left next to the toothpaste tube.

12. At this stage also, it should be noted that salbutamol alone was a comparatively short-acting β2-agonist, and would not suffice for overnight symptomatic treatment. There is no doubt that by 1989 many patients were prescribed BDP twice daily and instructed to use their salbutamol inhaler only when necessary to alleviate symptoms of bronchoconstriction.

The patent in suit

13. The patent is entitled ‘Inhalation medicaments for treating respiratory disorders’, and the invention is said to relate to the use of a bronchodilator drug in combination with a steroidal anti-inflammatory drug for the treatment of respiratory disorders such as asthma. The nature of this unpleasant condition is then briefly described in outline in terms that certainly represent the general understanding of the condition at the priority date:

‘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.’

14. At page 2 line 23 the patent starts its discussion of Ventide. It points out that salbutamol has ‘usually a four to six hour duration of action, which is too short either to control nocturnal asthma or for convenient maintenance of the disease in some patients. Having referred to BDP (page 1 line 31) the specification observes that the benefits of reduced inflammation may not be immediately apparent. There follows this important passage:

‘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.’

15. Having identified salmeterol and fluticasone propionate as the bronchodilator and steroid respectively, the specification observes that

‘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.’

16. No data are given in support of this assertion. It does not appear that any clinical trials had in fact been performed at this stage. There are no data offered in support of any other property of the combination, the specification concerning itself only with the manner in which the metered dose inhalers containing the combination are to be manufactured. There is, in my view, force in the claimants’ contention that the only teaching of the document is that the two drugs should be combined in an inhaler, for subsequent clinical trial.

17. There was a minor dispute about the precise import of the words ‘compatible and complementary’ in this passage. In context, it is plain that they refer to the effects just described: that is, treatment of the underlying inflammation by the steroid and of the constriction of the airways by the bronchodilator. There was a suggestion that they also suggested that there was some kind of ‘synergistic’ effect between the two active ingredients. I do not think that they do indicate that there is such an effect, but in any event I shall consider the question of synergy below.

18. Claim 1 of the patent in suit is to

‘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.’

19. Only this claim is said to possess independent validity. It will be seen at once that where simultaneous administration is concerned it covers an inhaler adapted to administer appropriate doses of the two active ingredients. It also appears to cover the provision of two inhalers packaged together to provide sequential administration. The words ‘for ... sequential administration’ will normally be taken to mean only ‘suitable for’ such administration, and since the claim is not limited to any particular dosage regime, it potentially covers two inhalers used as required. Since this was certainly obvious at the priority date, Mr Waugh QC for Glaxo was content, if necessary, for the words ‘or sequential’ to be removed by amendment. Without such an amendment, the claim is only partially valid. The question is whether what remains is obvious.

20. The patent claims priority from two applications and it was not disputed that it is entitled to a priority date of 8 September 1989, unless the words ‘compatible and complementary’ introduce a suggestion that there are ‘surprising synergistic or other advantages or interactions’. If they do, the claimants contend that the patent is insufficient and loses priority, since there is no suggestion of any such interaction in the priority documents. So far as loss of priority is concerned, the point is a bad one. The invention (whose scope is to be ascertained from the claim) is not in any way defined by reference to any synergistic effect. It covers combinations where there is no synergistic effect, if that is possible, and combinations where there is such an effect. The failure to refer to such an effect in the priority documents cannot mean that their disclosure does not support the invention claimed in the patent. In any event, only one further relevant publication would have been let in, and this was abandoned by Mr Watson QC for the claimants.

21. Apart from the foregoing, no substantial questions of construction arise. I can turn to the obviousness of the invention.

The pleaded case

22. Ten matters forming part of the state of the art at the priority date are pleaded:

i) UK Patent GB 2,088,877 ‘androstane 17 β-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 β₂ 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

23. As I have indicated above, the specification discloses a proposed new drug formulation. The active ingredients are known, and it seems to me that the specification is plainly addressed to a pharmaceutical manufacturer with an interest in marketing an inhaler. In Catnic v Hill & Smith [1982] RPC 183 at 242, Lord Diplock described the addressee of the specification as the person ‘likely to have a practical interest in the invention’. It is of course well settled that this practical interest may involve a collection of skills and knowledge that would not normally be found in a single individual, and such cases are often described as ones in which the addressee of the specification is a team. In this case the addressee is making metered dose inhalers with a view to clinical trial and, if the clinical trial is successful, ultimate sale. It includes clinical pharmacologists and formulation specialists, and obviously it consults with physicians. I do not accept the contention that the patent is addressed to physicians alone. Physicians lack all the skills necessary to make a workable product: but they will advise the manufacturer as to the appropriateness of the proposed product in clinical practice.

24. In this case, the discussion has centred on the knowledge and prejudices to be imputed to the notional clinical member of the team. The skilled person is a legal construct, related no doubt to the reasonable man and other similar personifications of legal criteria. It is through his eyes that the specification must be read and he provides the touchstone for obviousness and insufficiency of description. There are technologies where no great knowledge is to be attributed to the skilled man, and others (such as genetic engineering) where to attribute an unrealistically low level of attainment to the skilled man would prejudice industrial development. There are two classic statements. The first is that of Fletcher Moulton LJ in British Ore Concentrate Syndicate Ltd v Minerals Separation Ltd (1909) 26 RPC 124, 138:

‘[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.’

25. The second is in General Tire v Firestone [1972] RPC 457 at 482:

‘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”.’

26. Laddie J has described the difference between the ‘plodding unerring perceptiveness of all things obvious [of] the notional skilled man and the personal characteristics of real workers in the field’ at length in Pfizer Ltd’s Patent [2001] FSR 201, paragraphs 62 ff. As he says, the skilled person has no idiosyncratic preferences or dislikes, but he does possess the preferences or dislikes that may be objectively identified as characteristic of the real workers in the field.

27. Invention may lie in overcoming the preconceptions of the skilled person in a particular field of technology. As Jacob J put it in Union Carbide v BP Chemicals [1998] RPC 1, 13:

‘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.’

28. A good example is to be found in the Dyson vacuum cleaner case, Dyson Appliances Ltd v Hoover Ltd [2002] RPC 22, [2001] EWCA Civ 1440. The judge had held that

‘...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.’

29. In the Court of Appeal, Sedley LJ put it this way:

‘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.’

30. Such a prejudice may be a merely commercial one (‘this device won’t sell’) or it may be a technical one (‘this won’t work and it is not worth bothering with’). A twenty-year monopoly is conferred for overcoming a prejudice of the second kind, but not for overcoming a commercial prejudice (see Hallen v Brabantia [1989] RPC 307 (Aldous J)). A technical prejudice must be general: it is not enough that some persons actually engaged in the art at the material time labour under a particular prejudice if a substantial number of others do not. A prejudice which is insufficiently widespread for it properly to be regarded as commonly shared will not, in my view, be attributed to the notional skilled person. As Jacob J put it in Union Carbide v BP (above at page 16):

‘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.’

31. This is the obverse of the distinction between the common general knowledge and that which is known only to some who enjoy advantages that it would be unfair to attribute to every person working in the field (see, for example, Beloit v Valmet [1997] RPC 489 (CA)).

32. At the same time, the skilled man should not be taken to represent some sort of lowest common denominator of persons actually engaged in the field, possessed only of the knowledge and prejudices that all of them can be said to possess. The common knowledge of different groups employed on the same tasks in different organisations is likely to be different, for the reasons mentioned by Aldous J in Beloit. It is unlikely that the expert witnesses will be truly representative of the skilled person, as not only may they be too well qualified but they will come to the case with personal prejudices or preferences that must be discounted: see for example the discussion of the question whether there was a bias in favour of or against d.c. and a.c. coupled amplifiers in PCME Ltd v Goyen Controls Co UK Ltd [1999] FSR 801 at paragraph 61, and in the passage in Pfizer to which I have referred.

The legal approach to obviousness

33. The statutory provision, following Article 56 EPC, is:

Inventive step

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).

34. The state of the art is defined in section 2(2) as follows:

Novelty

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.

(3) ...

35. These provisions do not permit what is sometimes called the mosaicing of individual documents or prior uses said to form part of the state of the art, unless it can be shown that the skilled person, confronted with a particular citation, would turn to some other citation to supplement the information provided by the first. Such cases are not common, and the problem most frequently arises when the patent in suit itself makes assumptions about what its disclosure enables a skilled man to do. To take an example, one might consider a prior use consisting of the sale of a particular pharmaceutical preparation. The defendant says that the nature of the active ingredient can be ascertained by analysis of the preparation. Whether that active ingredient forms part of the state of the art depends upon identifying the experimental techniques available to the skilled person. The use of such techniques may involve reference to books and journals, and the explanation of the results may require reference to particular publications. If it can be shown that this analysis is the kind of analysis that would be normally performed, then it is part of the common general knowledge even if only a fraction of the material can be ascertained without reference to the books. Laddie J gives a further example in paragraph 66 of his judgment in Pfizer:

‘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.’

36. The analysis whether an invention is obvious in the light of the state of the art proceeds, therefore, on the basis of the individual citations, read alone in the light of the common general knowledge. An approach very frequently adopted is set out in the much-cited passage in the judgment of the Court of Appeal in Windsurfing International v Tabur Marine [1985] RPC 59:

‘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.’

37. The High Court of Australia has detected a shift in what it calls the Grundnorm in English law relating to obviousness in a case cited by Glaxo in the present case, AB Hässle v Alphapharm [2002] HCA 59, 194 ALR 485, a shift said to be exemplified by the observation of Laddie J that the skilled person ‘is assumed to have read and understood all the available prior art’ (see Cairnstores v AB Hässle [2002] EWHC 309 (Ch) at [94]). That statement of Laddie J is, with respect, only concerned with the point decided in Windsurfing International v Tabur Marine [1985] RPC 59 at 71, that the skilled man is to be assumed to take an interest in the prior art cited, and thus that obscurity of a citation is not to be counted against it. To allow documents to be discounted on the ground of obscurity will run against the policy of the law that any person must be free to enter a library and exploit what he finds there, provided that he exercises no invention in that exploitation.

38. On the basis of the decision of the High Court in the Alphapharm case, I was asked to approach the final Windsurfing question in this case on the basis of the reformulation of the so-called Cripps question by Graham J in Olin Mathieson Chemical Corp v Biorex Laboratories Ltd [1970] RPC 157, as follows (with the emphasis favoured by their Honours):

‘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?’

39. This formulation is derived from the ‘Cripps question’ (Sharp & Dohme v Boots Pure Drug Co Ltd 45 RPC 154) but it is not identical to it. Graham J’ s formulation contains an implicit definition of the word ‘obvious’. Graham J says that he used the words ‘led directly as a matter of course to try’ to incorporate the meaning of the word ‘obvious’. It omits any reference to the therapeutic quality of the compounds, because the claim with which Graham J was concerned was not limited by any therapeutic effect.

40. It is worth noting that Graham J in his judgment approached the words ‘in the expectation that it might well’ as follows:

‘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.’

41. It seems to me clear that Graham J’s question was formulated in the light of the particular case before him. Had the evidence been that the notional research team would, in following a strategy dictated by the common general knowledge, investigate either the direct - CF₃ substitution at the 2 position or (less likely) the reduction of Smith’s formula VIII the question formulated in the manner set out above might have been misleading, because the substitution might be considered to have been part of an obvious course of action, without any expectation of success at all. I say ‘might’ because there will certainly come a point where the result of an entirely rational strategy of investigation based exclusively on the common general knowledge cannot be considered obvious. It is a question of fact in every case. Both the Scylla of considering nothing obvious except that to which the skilled man is driven and the Charybdis of considering every invention obvious that can be decomposed into a sequence of obvious steps must be avoided. The former is unfair to industry because it stifles natural development. The latter is unfair to inventors and not countenanced by English patent law (see British Westinghouse v Braulik 27 RPC 209 at 230 (Fletcher Moulton LJ) Non-Drip Measure Co Ltd v Stranger’s Ltd (1943) 60 RPC 135 at 142 (Lord Russell) and Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] RPC 346 at 362 (Lord Diplock). The problem with the Cripps question, and with its various reformulations, is that it tends to obscure the actual question, which is whether the invention was obvious or not. The form propounded by Graham J is, with respect, open to a number of further objections if it is separated from the facts of the particular case. The first is that it seems to assume that if there are a large number of obvious steps that might be taken in the light of a particular citation, some of them will not be obvious because they would not be suggested to be carried out directly: they may only be carried out if the ones tried earlier fail. That is unacceptable: the obviousness of an invention cannot depend upon the order in which the various courses of action obvious in the light of a particular citation are attempted - see Brugger v Medic-Aid Ltd [1996] RPC 635 at 660-1 (Laddie J). Second, the import of the final italicised phrase is unclear. Is something a priori obvious as a possible course of action necessarily to be rejected on the ground that the notional skilled man has only a modest hope that it will produce something useful?

42. In my judgment, evidence that the skilled person will be led to try something because there is a reasonable expectation that it will produce a useful result establishes one possible route to a possible finding of obviousness. But if it is obvious to try that thing for other reasons, there need be no superadded requirement that there should also be some expectation of success. This was made clear in the decision of the Court of Appeal in Norton Healthcare v Beecham Group plc CA 19 June 1997 (unrep) where Aldous LJ said:

‘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’

43. Mr Waugh submitted that if English law did not in every case require consideration of the prospect of success of a particular step (he put it as high, I think, as requiring the expectation of a good result) it was out of step not only with the law of Australia exemplified in AR Hässle v Alphapharm which I have discussed above but also with the law as applied in the EPO. To support this submission, he referred to the long discussion of obviousness in the C.I.P.A. Guide to the Patents Acts, paragraphs 3.21, 3.33-4 and to the ‘Case Law of the EPO’ at I.D.6 paragraphs 6.1 and 6.2. The approach of the EPO to the question of obviousness is highly structured. It has three stages:

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.

44. The whole methodology is encapsulated in the decision of Technical Board of Appeal 3.3.1 in T 31/84 MILES/Test Device. The Board remitted an opposition to the Opposition Division for re-examination on the basis of a new claim 1, with the following direction:

‘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.’

45. I am not persuaded that this is substantially different from the Windsurfing approach, subject to one qualification. The EPO will consider obviousness on the basis of the closest prior art only. Every pleaded starting point, however remote, needs to be considered in coming to a conclusion on obviousness in the domestic context, but I suspect that the need to concentrate on the ‘best’ citation has a result that is not much different. When one reaches the final step (the last Windsurfing step seems to be the same) the factors to be taken into account in assessing obviousness are not, so far as I can see, much different. The summaries of decisions contained in the ‘Case Law of the Boards of Appeal’, sections 6.1-2 clearly indicate the wide variety of factors that the EPO consider relevant to an assessment of obviousness. Interestingly, the question of the expectation of success seems to be considered particularly relevant where the course of action in question is long and consists of much labour, and understandably it is in the field of genetic engineering and biotechnology that the question becomes important (see section 6.2). Obviousness is a question of fact, a so-called ‘jury question’, and I see no basis for the suggestion that UK law is out of step with the principles applied in the EPO.

46. I propose to analyse the question of obviousness along Windsurfing lines. Before I do so I must consider the common general knowledge in the art, and the question of the prejudices from which it is contended that the skilled person suffered.

β-agonist and steroid therapy at the priority date: the common general knowledge

47. I have discussed the skilled team above. The claimants contend that the following matters formed part of the common general knowledge at the priority date.

48. Asthma has two aspects, bronchospasm and bronchial inflammation. Both require to be treated. This is obviously common general knowledge, and it forms the basis of the dispute as to the correct therapy to which I shall come.

49. Bronchospasm is treated by a bronchodilator. By 1989 the leading class of bronchodilators were the β₂-agonists of which the most popular was salbutamol. There is no doubt that during this period it was prescribed both for regular and for symptomatic (p.r.n.) use. It had the particular shortcoming to which I have referred, that it had a comparatively short duration of action, and thus could not protect against nocturnal asthma.

50. By 1989, it was generally known that Glaxo had developed a new β₂-agonist called salmeterol which was in clinical trials. Its main point of interest was that it had a considerably longer duration of action than salbutamol. It had been the subject of conferences and even a press article quoting Professor Page (who gave evidence for the claimants) in the Independent in April 1989:

....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.’

51. I have quoted this article at length because it describes in a digestible form two of the matters causing concern to asthma specialists. The first is compliance with steroid therapy, and the second is the masking of a deteriorating condition of the airways by the use of bronchodilators. It is obvious that two kinds of bronchodilators will have this effect: long acting compounds, as the article describes, but also short acting compounds taken regularly rather than in response to the onset of an attack.

52. The new material had been discussed at a conference in November 1987 the proceedings of which were published in 1989 under the title ‘Allergy and asthma, new trends and approaches to therapy’ attended by representatives of Glaxo, one of whom, a Mr Coleman, is reported as having said this:

‘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.’

53. The last sentence is some coat-trailing for an anti-inflammatory effect that it was hoped would be exhibited by the compound. In fact, I believe that no clinically significant effect that cannot be ascribed to its longer-lasting bronchodilator effect has been convincingly demonstrated, and the suggestion that there was such an effect is disputed by Professor Page, who considered that the claim should not have been made. But the importance of salmeterol was immediately appreciated by the physicians who were interested in this field. I am also satisfied that while they were all aware of it, they were not confident of the place, if any, it would finally occupy in the armamentarium.

54. There are other pre-launch publications that need to be considered. Salmeterol was recognised as a very important drug for Glaxo and thus it was covered in the business press as well. The publications are as follows.

55. Ullman & Svedmyr (1988) ‘Salmeterol, a new long acting inhaled β₂ adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients’ Thorax 43: 674-678. This document is pleaded. It describes the attractive feature of salmeterol, that is, its long acting nature as appearing to be ‘an important therapeutic advance’. It also contains a warning about the risk that regular therapy with the drug might produce a rebound increase in bronchial reactivity and notes also the risk of tachyphylaxis (i.e. a decrease in response to a given dose over time). The evidence goes a long way towards showing that this paper was common general knowledge in itself, as Dr Crompton accepted:

‘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.’

56. There was some suggestion that Ullman & Svedmyr (1988) was only suggesting the use of salmeterol once per day, in the evening, for the control of nocturnal symptoms. This is obviously wrong. The reference to ‘maintenance treatment’ is clearly a reference to more frequent use, and the whole is plainly concerned with the use of the drug at all times of the day and night. It is to be noted that those of Ullman & Svedmyr (1988)’s patients who were on steroids were kept on steroids for the duration of the trial.

57. Ullmann & Svedmyr (1988) refer to four further papers, of which the most important is Bradshaw & al (1987) below. I consider that the extent to which a skilled person can be expected to follow cross-references depends on a number of factors. On the face of it, he should be taken to follow immediate citations, but obviously he cannot be taken to undertake a citation hunt, following every lead in every paper, or there would be no end to it. This, however, is a direct citation on the central properties of salmeterol, and I think that he should be taken to follow it, although Dr Crompton did not, in fact, do so, being insufficiently interested.

58. Bradshaw & al (1987) ‘The Design of Salmeterol, a long-acting selective β₂ Adrenoceptor Agonist’ British Journal of Pharmacology 92: 590P. This paper is not pleaded. It describes the design of the salmeterol molecule in response to the need ‘for a longer acting inhaled bronchodilator for maintenance treatment of the disease and to control nocturnal asthma’. This is one of a number of early papers originating with Glaxo that appear to have been presented at a meeting of the British Pharmacological Society in September 1987.

59. SCRIP No 1177 (February 1987) observes that products highlighted by the analysts include ‘salmeterol, a long-acting beta₂-agonist for asthma; and the steroids, fluticasone and cloticasone, believed by Bell Lawrie to be in Phase III clinical trials for dermatological uses; Greenwell Montagu analysts speculate that Glaxo may also develop these steroids for use in asthma.’ By SCRIP no 1184 (4 March 1987) the news had hardened as a result of an extensive presentation by Glaxo:

‘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).’

60. SCRIP No 1243 contains a report of the meeting of the British Pharmacological Society at which Bradshaw & al (1987) was presented. By April 1988, SCRIP No 1301 is reporting that both salmeterol and fluticasone propionate are in Phase III clinical trials as aerosol formulations. Dr Costello said that there was a great deal of excitement about the drug in the field, and it was known to rival manufacturers.

61. The 1987 conference was two years before the priority date of the patent in suit (September 1989) and in the two years that followed it is clear that salmeterol became a molecule of great interest. I conclude that salmeterol was certainly part of the common general knowledge by the priority date. Although it had not emerged from clinical trials, it was clearly a molecule of great importance and accordingly of interest to any skilled person as a sound basis for further development.

62. The next matter is the treatment of the underlying inflammation. Again, there is no doubt that it was generally accepted that bronchial inflammation in asthma should be treated with an anti-inflammatory agent, and that the most popular class of anti-inflammatory agents for this purpose was the inhaled corticosteroids. Beclomethasone dipropionate (Becotide inhaler) was one of the most successful, at least in the United Kingdom.

The common general knowledge as to the treatment of asthma

63. In 1989, the correct treatment of asthma was a matter of considerable debate. There is no doubt that the claimed combination contemplates regular treatment by inhalation, at least once per day (I take this from the reference to nocturnal asthma) and most likely twice per day. Glaxo contend that regular use of a β₂-agonist was so strongly disapproved of by physicians in this field that it was a real barrier to the acceptance of any therapy involving regular administration of a β₂-agonist.

64. At the outset, it should be noted that salbutamol was at all material times sold as suitable for use in regular therapy. There was some explanation of this, centred on the regulatory difficulty in changing the ‘package insert’, but I agree with the observation that if regular therapy with β₂-agonists was perceived to be really harmful this would have been changed. This, however, is only a straw in the wind, and the substantial question is what the notional specialist physician, who forms part of the addressees of the specification for this purpose, thought.

65. First, it is necessary to consider therapy using β₂-agonists alone. I have no doubt that at the priority date specialist physicians considered that treatment with β₂-agonist alone was normally inappropriate except in the mildest cases. There is a fundamental problem in the treatment of asthma with β₂-agonists. This is that the underlying inflammation is not treated, and may consequently deteriorate to the point at which the inhaled β₂-agonist will not provide symptomatic relief. Certainly, I think that by the priority date it was thought by specialists in the field that the best mode of treatment was based upon the regular use of steroids together with symptomatic relief using β₂-agonists.

66. It is this fact that explains why there was a controversy as to the correctness of prescribing the drug for regular administration. I think that the overall position is well described by Professor Partridge, who was involved in the preparation of the Guidelines for the management of asthma in adults that were published in the BMJ in 1990. The Guidelines were presented under the auspices of the British Thoracic Society, the Research Unit of the Royal College of Physicians, the King’s Fund Centre and the National Asthma Campaign. Prof. Partridge put it this way:

‘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.

67. Thus Professor Page and Dr Costello (both of whom gave evidence for the claimants) doubted the usefulness of regular β₂-agonist therapy in general and regular salmeterol treatment in particular in their paper ‘Why β-agonists should not be used regularly’ Respiratory Medicine (1992) 86, 477-479. This paper is concerned both with use of the drugs in monotherapy and with their use in combination with steroid therapy, although there is no doubt that some of their reasons for not using β-agonists regularly can relate only to monotherapy.

68. The ‘Guidelines for management of asthma in adults: I-chronic persistent asthma’ (1990) BMJ 301:651-653 represent the direction in which professional thought was moving at the priority date. The guidelines divide the treatment of asthma into a number of steps, with patients starting treatment at a step most appropriate to the severity of their condition. The steps are:

(1) Bronchodilators

A β₂ 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 β₂ 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 β₂ 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 β₂-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 β₂-agonists.

69. There was considerable discussion of the guidelines. I think that it is plain that they deprecate regular treatment with β₂-agonists at an early stage, although the description of stage 4 suggests a use of the β₂-agonist that has become in effect regular, the rate of symptomatic use making the distinction from regular use difficult to draw. The reference to night time symptoms certainly suggests the use of the β₂-agonist prophylactically at night time. The publication of the guidelines more or less coincided with the publication of Sears & al (1990) Lancet 326: 521, an important paper. The message of this paper is that regular use of β₂-agonists, whether or not in combination with inhaled corticosteroids, involves an increased risk over their symptomatic use:

‘...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.’

70. Dr Palmer, the sole inventor of the patent in suit, put the point at its highest when he referred, somewhat hyperbolically, to a ‘gathering storm’ in the period 1988-9. He referred to three publications, ‘the Tattersfield paper, the Crane paper on Fenoterol and then an editorial in Thorax...’. Taking these in reverse order, the Thorax editorial (a paper by Mitchell published in February 1989) was concerned in particular with enhanced bronchial hyperresponsiveness and tachyphylaxis caused by regular, as opposed to symptomatic, use of β₂-agonists. It points out that that the population of asthma sufferers is large and that small effects can be of great significance and concludes as follows:

‘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 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.’

71. The Crane paper on fenoterol is Crane & al. (1989) ‘Prescribed Fenoterol and Death from Asthma in New Zealand 1981-83: Case-controlled Study’ Lancet 1:917. Fenoterol is a short-acting β₂-agonist less selective than salbutamol, and the hypothesis advanced in the paper is that ‘the use of fenoterol by MDI [metered dose inhaler] increases the risk of death in severe asthma’. The Tattersfield paper is (I think) Vathenen & al. (1988) ‘Rebound Increase in bronchial Responsiveness after Treatment with inhaled Terbutaline’ Lancet 1: 554. This was one of a trio of papers, with Kerrebijn & al. (1987) ‘Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma’ J Allergy Clin Immunol 79: 653 and Kraan & al (1985) ‘Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline’ J Allergy Clin Immunol 76: 628. The summary of this paper concludes that ‘budesonide [a corticosteroid] improves bronchial hyperreactiviy, possibly by a dampening of late allergic reactions, whereas treatment with terbutaline [a β₂-agonist] may lead to a temporary increase of bronchial hyperreactivity, possibly as a result of β-receptor desensitization.’

72. I formed the clear view that there was increasing concern about the use of β₂-agonists throughout the 1980’s. My impression is that Crane & al (1989) and rather more importantly Sears & al (1990) had a significant effect on the attitude of some consulting physicians to the use of β₂-agonists. The position adopted by the Guidelines represented the logical culmination of such developments down to their publication in 1990.

73. However, I am inclined to regard the Guidelines as representing the culmination of one line of thought only. That this is the case is demonstrated by a number of factors. First, none of the papers excited a worry about regular low dose use of β₂-agonists. There are two instances of ‘for and against’ pairs of papers in this case. The first is Lindsay (1988) ‘Fixed dose combination therapy in the treatment of asthma-the case against it’ and Ruffin (1988) ‘Fixed dose combination therapy in asthma. The positive case for future therapy’ in ‘Mechanisms in Asthma: Pharmacology, Physiology and Management’ 421 and 427. Ruffin (1988) is cited against the patent. These papers were prepared for a conference that took place in Australia. I shall return to Ruffin (1988) in its place, but for present purposes it is necessary only to note that Ruffin is supporting treatment using a combination inhaler containing a β₂-agonist and a steroid. If the steroid is to be administered regularly, necessarily so too will the β₂-agonist be. The proceedings of the conference do not record this objection being raised. Dr Crompton was cross-examined on this:

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 hope I am not detecting a change in emphasis, and correct me. Are you saying that as of ‘87 that you did not have a problem with the regular use of beta agonists? A. I did not have a problem in that I did not think it was clinically relevant in terms of use regular, four times daily, of conventional doses, irrespective of the alerts that had come to my mind because of the three papers that we were discussing. I thought it was bad medicine to give regular therapy if the patients did not need regular therapy, and that is why I suggested to all my patients that they should take their beta agonist on demand rather than regularly.

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.

74. This is not, I think, evidence of a widespread unwillingness among the relevant class of physicians to contemplate regular therapy with β₂-agonists. In fact, the point goes further. There is no doubt that in 1987 regular therapy with β₂-agonists was being employed in the United Kingdom Thus, Cochrane (1987a) ‘Inhaled Steroids and their use in the treatment of asthma’ Bronchus 2: 3: 8 observes that ‘a recent survey of two general practices in London has suggested that in the UK, at least, there is now a move to use regular prophylactic therapy earlier in the treatment of asthma, and that in 75% of the mild to moderate asthma patients the second-line drugs after regular inhaled bronchodilators are inhaled corticosteroids (two-thirds) and disodium cromoglycate (one-third).’ In his ‘Colour Atlas of Asthma’ published in 1989, Dr Cochrane proposes a number of algorithms for assessment of the treatment of various classes of asthma, three of which involve regular inhaled β₂-agonist therapy, albeit in two of those classes the regular regimen is preceded by inhaled corticosteroids. Dr Costello, who gave evidence, had proposed something rather similar in his book.

75. In his paper Cochrane (1987b) ‘The difficult chronic asthmatic’ British Journal of Diseases of the Chest 81: 313 Dr Cochrane had made the following observation:

‘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 β₂-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).’

76. Professor Barnes wrote the paper that I allowed to be cited by a late amendment, Barnes (1988) ‘The drug therapy of asthma: directions for the 21st century’ in Directions for New Anti-Asthma Drugs, Agents and Actions supplements 23: 293. He remarks that inhaled corticosteroids ‘should probably be introduced much earlier in the management of asthma and β-adrenoceptor agonists, which have no effect on the inflammatory response, should be used for symptomatic control as required’.

77. None of these publications, nor Dr Crompton’s evidence that I have quoted above, suggests that there was a general refusal to use regular β₂-agonist therapy. Dr Mitchell-Heggs gave evidence, entirely credible, that he was prescribing regular β₂-agonists with inhaled corticosteroids in 1989. The facts are far more consistent with there being no uniformity of view in the profession, but that one view was in 1989 becoming more dominant.

78. Objectively, the later history of this matter does not support the view that there was any general prejudice against regular therapy with β₂-agonists. There is clear evidence of regular therapy with β₂-agonists well after the priority date. Even Sears & al (1990), described by Dr Crompton as having poured fuel on the embers of a debate that had been smouldering, should not be regarded as having completely turned the general view of the profession. Dr Sears’ views on regular β₂-agonist therapy and similar views expressed by Professor Page in the Lancet were criticised in the letters pages by (inter alios) representatives of the Glaxo group for generalising from the results for fenoterol to all β₂-agonists.

79. The existence of a spectrum of opinion, and of prescribing practice, is also shown by the succession of publications on which Professor Page was cross-examined. Page & Costello (1992) ‘(2) Why β-agonists should not be used regularly’ Respiratory Medicine 86: 477 is one member of the second pair of deliberately controversial papers. The other is Twentyman & Higenbottam (1992) ‘(1) β-agonists can be used safely and beneficially in asthma’ Respiratory Medicine 86: 471, the pair of papers being published under the heading ‘Controversies in respiratory medicine: regular inhaled β-agonists - clear clinical benefit or a hazard to health?’. These two papers come to conflicting conclusions even on the basic question whether the studies (including Kerrebijn & al (1987), Kraan & al (1985) and Vathenen & al (1988)) do in fact show that regular administration of β-agonists does increase bronchial responsiveness. Twentyman & Higenbottam (1992) say it does not: Page & Costello (1992) say that it does. I cannot resolve this dispute, but it was even in 1992 a dispute.

80. There is in Page & Costello (1992) a passage suggesting that it is necessary to take a more nuanced view of the opinions of the relevant physicians than merely to attribute an outright dismissal of regular β-agonist therapy:

“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.”

81. This passage is primarily aimed at monotherapy with β-agonists. Basing itself on the Guidelines recommendation that patients who inhale a β-agonist more than once per day are in need of anti-inflammatory drugs, it points out that there should be no scope for regular therapy with β-agonists at all: they should only be used as required, and only in the short term. Long term regular use is undesirable, because it shows a failure to control the underlying inflammation with anti-inflammatories. This passage was employed to suggest that the article is not only concerned with monotherapy (which is true) but that it was evidence of a firm objection among physicians that regular therapy was unacceptable. I would draw precisely the opposite conclusion. The article has a polemic aspect, and I do not believe it would be necessary if regular therapy with β-agonists were not an established feature of the clinical scene, whether in combination with steroid therapy or as a monotherapy.

82. The last part of the passage I have quoted above represents a real fear that did arise after the introduction of salmeterol in 1990. It had been claimed that salmeterol had anti-inflammatory properties, and it was feared that GP’s would be discouraged from prescribing inhaled corticosteroids as well. Dr Costello gave unchallenged evidence that Glaxo changed their patient information to reflect this concern.

83. It is difficult to get over the conclusions of the article by Drazen & al. (1996) ‘Comparison of regularly scheduled with as-need use of albuterol [salbutamol] in mild asthma’ New England Journal of Medicine 335: 841:

Over the past five years, there has been substantial debate about inhaled β-agonists as a class of treatment. In this study, despite a more than fivefold difference in the amount of β-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 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.’

In other words, their conclusion is that regular therapy does no harm in patients with mild asthma, but does no good either.

84. There are a number of other factors that suggest that this was a continuing dispute, with strong positions being taken on each side, albeit that the majority may well have been opposed to regular β-agonist therapy. For example, the Committee of the Safety of Medicines did not set up their working party to investigate the literature on β-agonists until about 1991 (the only reference to this I can find is in the transcript of the ‘Public Eye’ television programme transmitted on 31 May 1991), and it seems that the FDA in the United States did not convene a meeting to consider the question until late 1991. I am satisfied that I should not ascribe any rooted objection to regular therapy to the skilled person when I work out his relevant characteristics. He or she might well view the possibility critically, but this would be a matter that could be resolved by clinical trial. Dr Crompton was too willing to attribute his own views, genuinely held and for good reasons, to all practitioners in the art, and he was, I think, too reluctant to accept that others might not hold those views, or hold them less dogmatically.

85. Mr Waugh QC was inclined to suggest that the only class of physicians whose views should be attributed to the skilled man were those at the forefront of asthma research and so those who entertained most doubt about regular β₂-agonist therapy and about combination therapy. This approach is not consistent with the evidence. The patentees cast their net much more widely (see paragraph 104 below) and I am satisfied that any drug company would want to have an idea of what the general approach to a particular therapy was, if it could.

Other aspects of β-agonists

86. I have referred to the fact that bronchial hyperreactivity on the rebound was mentioned as a possible problem in the published literature. Dr Crompton did not attach any clinical significance to it. Tachyphylaxis I have also referred to: there was little evidence about it and it cannot have been a genuine issue at the date. There was some attempt to turn various theories about the action of β-agonists into aspects of the common general knowledge, such as their effect on mast cells, or Professor Page’s theory relating to the ‘asthma paradox’ in Page (1991) ‘One explanation of the asthma paradox: inhibition of natural anti-inflammatory mechanism by β₂-agonists’ Lancet 337: 717. Professor Page was obviously very doubtful about the risks of β₂-agonists and this article emphasises in particular the risks of monotherapy, but this is unsurprising given that asthma morbidity and mortality rates were still increasing, although the disease was in principle preventable. It was never shown that this kind of scientific speculation could ever have formed part of the common general knowledge of the addressee.

87. Finally, I should turn to the problem of masking. There is no doubt that regular use of a β-agonist tends to mask the frequency of attacks. Thus, regular use makes it more difficult for the prescriber to satisfy him- or herself that the correct dosage of anti-inflammatories is being administered. This prevents the frequency of inhaler use from being used as a marker for disease progression. This is undoubtedly true, but (at least with short-acting β-agonists) nocturnal symptoms and breathlessness are also useful. I think that this was common general knowledge at the date. Nonetheless, the importance of this problem is most important when a β-agonist is administered as a monotherapy.

88. I have dealt at length with the common general knowledge at the date because it is crucial to the proper approach to the question of obviousness, to which I now turn. As I have indicated, each of the matters relied on as a starting point for the allegation of obviousness must be considered individually. The first matter is the prior use of Ventide.

Obviousness: the prior use of Ventide

89. Ventide is a combination of salbutamol and beclomethasone dipropionate in a metered dose inhaler. It was launched in 1983, and by 1989 it was selling 250,000 units a year. It was far from being a front-line treatment for asthma, and I do not think that any of the witnesses had any affection for it, although Dr Mitchell-Heggs saw a use for it and prescribed it. The reason that Ventide was prescribed was to overcome compliance problems, which I must now discuss. Although this is a topic which falls naturally into the common general knowledge, it is best considered in the context of this particular product.

90. The problem of compliance is a well recognised one. It is difficult for the prescriber to persuade certain patients to take their medicine, particularly when the medicine does not have an obvious effect. Thus, when Ventide was launched in 1983, GP magazine carried a piece of ‘advertorial’:

‘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.’

91. The claimants’ evidence in chief indicated that compliance was indeed a problem, and that a solution was a combination inhaler. Dr Auty, who was with Fisons at the relevant time, said that prescribing both corticosteroid and β-adrenoceptor stimulant was known to have benefits, as is common ground. He identifies the problem of compliance, and observes that some patients would think that only the β₂-agonist was working, and would not take the corticosteroid as prescribed. He says that the problem of achieving compliance with the corticosteroid regimen was of particular concern in the treatment of asthmatics. He says that Ventide was a very well known product, and that although well received, there were two criticisms of it. First, that the frequency of dosing (3-4 times per day) was dictated by the duration of action of the β₂-agonist component and the salbutamol element was insufficient to last through the night. Second, it was not possible to give the individual patient that patient’s ideal dose of both components. He expresses the view that it was the view amongst a large part of the field, especially practising clinicians, that better compliance with an imperfect dosage regimen was preferable than poor compliance withan individually tailored regimen. Dr Costello said that although he did not like Ventide, GP’s would use it ‘to get steroids into patients’.

92. This is confirmed by Glaxo’s own documents. In 1988, Dr Palmer, the inventor of the patent in suit, wrote a ‘Clinical Expert Report’ to the Medicines Control Agency in support of the extension of the Ventide product licence to disks and disks (paediatric) for use in so-called diskhalers. This is a regulatory document, and can safely be taken to express an honest view. Under the heading ‘Combined Therapy’ he 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.’

93. Dr Palmer stood by these statements, as was inevitable:

[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.

94. There was some consistency among the witnesses as to the circumstances in which Ventide might be used, although it would not be used as a first-line therapy. Dr Costello, who did not like it, said that it might be used by GP’s to get steroids into patients, and Dr Mitchell-Heggs explained in his witness statement that compliance was a real problem. In cross-examination he identified two groups of patients who drew advantage from the use of the combination therapy:

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.

95. In his report, Dr Crompton had described Ventide as an irrational product. He accepted under cross-examination that its use in an attempt to improve compliance was not irrational. To use combination products for such a purpose had been suggested by others. For example, Ruffin (1988) is a report of a paper delivered at a conference. Included is a report of the ensuing discussion, during which Dr Barnes is reported as having said

‘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.’

96. Finally, Dr Crompton was himself a co-author of a paper, McDonald & al (1988) ‘Evaluation of the combination inhaler of salbutamol and beclomethasone dipropionate in the management of asthma’ Current Medical Research and Opinion 11;2:116. It is necessary only to consider the Introduction and a concluding paragraph.

‘Many asthmatics require regular therapy with an inhaled β₂-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 β₂-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 β₂-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.’

97. The evidence from Dr Crompton as to this is, first, that it was done as a favour to Glaxo:

‘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.

98. The evidence that follows demonstrates, I am afraid, what happens to the reliability of publications when a particular department is beholden to a sponsor of its research. After an intervention by me caused by my failure to understand Dr Crompton’s reply, the cross-examination resumed:

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.’

99. There is no reason for Dr Crompton to put his name to a paper supporting a treatment that he considers irrational unless either he was negligent in permitting his name to be added to the paper or he felt sufficient pressure, professional and financial, to override his scientific doubts. I do not think he was negligent, and against my better judgment I found myself in sympathy with him in the circumstances in which he appears to have found himself. I feel deep unease at the fact that funding considerations can have this effect on those who appear to be conducting disinterested research. What this evidence does convince me of is that there was no reason to suppose that there was any relevant prejudice against either combination products or regular β₂-agonist therapy.

100. Against this background, two answers are relied on by the claimants as encapsulating the case of obviousness over Ventide. The first is that of Professor Page. He is the Professor of Pharmacology at King’s, and he is not a clinician. He has, however, had a long experience of asthma therapy, and has published very extensively about it. He said this:

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 β 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 β₂-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.’

101. Professor Page was challenged on his evidence that the ‘updating’ of Ventide was obvious. He had not suggested it in his article. In fact, his article looks further into the future. As the extract above makes clear, he is talking about not the combination of two separate drugs having respectively prophylactic and symptomatic effects, but the design of a single molecule with both these qualities. Such a molecule would be open to the criticisms advanced against the combination.

102. Dr Crompton’s answer followed a challenge by Mr Waugh QC to Mr Watson’s use of the word ‘obvious’ in a question:

‘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 β₂-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.

103. In the light of the whole of the evidence, I think this series of answers contains the right approach. The combination was an obvious combination, as a combination. It was not obvious that it would be safe, or that it would represent any advance on what had gone before. Whether this would be the case depended upon the outcome of clinical trials which was not foreseeable, although it was a reasonable prediction for the skilled man having regard to the known properties of salmeterol (which was part of the common general knowledge at the date) and any steroid previously used for prophylactic therapy that the combination would be both safe and efficacious. Any skilled person would find fluticasone propionate in looking for up-to-the-date members of the class of steroids as candidates for incorporation in his new Ventide. A. good reason for such a combination is the need to ensure compliance. The ‘prejudice’ discussed at such length above was, in fact, a doubt relating to questions that could only be resolved by clinical trial. This extends to such matters as the significance of the long-acting effects of salmeterol. The skilled man would understand this: and accordingly the combination was entirely obvious in the light of the prior manufacture, use and sale of Ventide and the publication of the various data associated with that preparation.

104. That salmeterol would be the obvious substitution for salbutamol follows from the most basic consideration, that a drug that only needs to be taken twice a day will encourage compliance. That this was the case appears to be the universal message of the evidence. It is also Glaxo’s internal view of the justification for the product:

‘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.

105. The foregoing findings are sufficient to dispose of this case, but the claimants put their case of obviousness on a selection of the citations to which I have referred in paragraph 22 above.

Ullman & Svedmyr (1988)

106. The case on Ullman & Svedmyr (1988) adds nothing to the case on Ventide, once it is accepted that the paper is common general knowledge.

Barnes (1988) and Ruffin (1988)

107. The case on Dr Barnes’s article (Barnes (1988)) is rather more straightforward. Dr Barnes is an acknowledged expert in this field. This article was introduced by late amendment, Mr Watson saying that he did not wish to advance any case on the basis of evidence in chief. Thus, all the evidence on this citation comes from Glaxo. The article concludes:

Many different therapeutic approaches to the treatment of asthma may be possible, yet there have been few new drugs. β₂-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 β-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.

108. It may be observed that elsewhere in the article Dr Barnes advocates the reduction in the use of β-agonists to use for symptomatic control as required. It must be accepted that nonetheless this is a clear general instruction to use combination inhalers, which by the priority date included as one of a limited number of available combinations salmeterol and an inhaled corticosteroid. Dr Crompton accepted this. A flavour of the cross-examination is to be obtained from this exchange, when it was being put that a combination of salmeterol and beclomethasone dipropionate is obvious in the light of this disclosure:

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.

109. The message from Dr Barnes in Ruffin (1988) is to the same effect and, it seems to me, equally clear. The only real objection that can be advanced to this argument of obviousness is the prejudice alleged to exist that I have considered. I conclude that on the basis of this publication also, the patent is invalid for obviousness.

The SCRIP citations

110. The case on these publications is in substance the contention that the patent is invalid in the light of Ullman & Svedmyr (1988). They add little to the case overall. The evidence relied on has two aspects: the exchange that I have set out in paragraph 102 above and the fact that combinations were common general knowledge as a possible way of presenting drugs with complementary effect, even if Ventide is not part of the common general knowledge:

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.

111. I confess that absent any strong prejudice against regular therapy with β-agonists I would consider that this was, in fact, sufficient to make the invention of the patent in suit obvious, but manifestly the case is stronger on the footing of the Ventide prior use.

112. In the result the invention of the patent in suit is obvious. The claimants’ case is, in my view, overwhelmingly strong. This is a decision arrived at on what I believe to be a conventional approach, and I have not felt it necessary to examine the effect of the interesting decision of the Privy Council in Ancare New Zealand Limited’s Patent [2003] RPC 8 (page 139). Had I considered that scientific opinion was wholly out of accord with what was being done in the market, it would have been necessary to do so. I do not read this case as throwing any doubt on the proposition that invention may lie in overcoming a prejudice in the art.

Synergy

113. It is sometimes thought that a patent may be saved from a finding of obviousness if a combination otherwise obvious has some unexpected advantage, and, in particular, an advantage caused by an unpredictable cooperation between the elements of the combination. I do not consider that such an approach is in general justified. There is a limited class of cases in which the patentee has identified an advantageous feature possessed by some members only of a class otherwise old or obvious, has described the advantageous effect in his specification and has limited his claim to the members of the class possessing this advantageous feature. Such a claim may be justified on the basis of what is called selection. Unexpected bonus effects not described in the specification cannot form the basis for a valid claim of this kind. I think that the matter is described with complete correctness by Jacob J in Richardson-Vicks’ Patent [1995] RPC 568 at 581:

‘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.’

114. If a synergistic effect is to be relied on, it must be possessed by everything covered by the claim, and it must be described in the specification. No effect is described in the present specification that is not the natural prediction from the properties of the two components of the combination. Although there was some considerable evidence in the case intended to show synergy between the elements of this combination, Mr Waugh QC rightly abandoned any reliance on synergy per se as justifying a finding of non-obviousness (see paragraph 152 of his closing skeleton argument). Instead, he refers to the real, great, success of Seretide as demonstrating that a prejudice had indeed been overcome.

115. This argument is hopeless. At all material times down to the priority date, salmeterol was protected by patent. The question of any commercial use of the combination product was thus under the control of the patentees and subject to the satisfactory completion of the clinical trial process. But Mr Waugh QC puts the point:

‘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

116. It was on this issue that Dr Palmer, the inventor, gave evidence. Mr Watson QC cross-examined him on the basis that the invention of the patent in suit was what Glaxo call a ‘line extension’, that is, a further presentation of existing active ingredients which may provide the basis for further patent protection. No doubt there was something in this, but in this case I did not regard this evidence as helpful. It has to be remembered that a perfectly valid patent may be written by a person who does not stir from his armchair, thinks it is all obvious and does no experiments to confirm his hunch. I suspect he may even be permitted to invent the experiments, provided they work and give the promised result. Because the assessment of obviousness has to be objective, there is always a risk in paying too much attention to what the patentee does. I have myself found it of assistance when, for example, the experts suggest that a particular course of action is the obvious one to try first, and it appears that that is what the patentee indeed did. There was no evidence of that kind here. Of course, what Glaxo record internally may for example reflect on the alleged prejudice against β₂-agonist regular therapy, and I have taken that into account. It is also true that Mr Watson QC suggested to Dr Palmer the evidence that so far as he was concerned, the question was essentially a marketing one:

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.

117. Even were I to accept Mr Watson’s suggestion that for Glaxo the idea of the combination (the line extension) is essentially a marketing concept in this case, it is of limited assistance in deciding the objective question. While therefore I consider that there is some force in it I prefer to leave it out of account in coming to my decision on obviousness.

The witnesses

118. Much of this judgment has concentrated on the evidence of Dr Crompton, and to a somewhat lesser extent that of Professor Page, Dr Auty and Dr Costello. I should make it clear that Dr Crompton and Professor Page were both on the dogmatic side, so much so in Dr Crompton’s case that I have felt it necessary to criticise his evidence in specific respects. Dr Costello and Dr Auty were, if I may put it this way, more objective. There is one final matter to which I should refer.

119. In his first report, Professor Page referred to the good relations that subsisted between him and Glaxo. In his reply report, he reveals that he was telephoned by Dr Garth Rapeport, who is rather grandiloquently described as the ‘Senior Vice President, Centre of Excellence for Drug Discovery, Respiratory and Inflammatory Diseases’ at GlaxoSmithKline. It is accepted that he telephoned Professor Page and informed him that he was disappointed with his involvement in the case. He said that Professor Page could no longer expect Glaxo to be friends with him and that Glaxo could no longer fund his research activities beyond the existing research grants. Professor Page told Dr Rapeport that he was expressing only his genuinely-held views.

120. Dr Rapeport was very upset that Professor Page had not told him of his involvement in the case. As he puts it:

‘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.’

121. No apology was proffered by Glaxo for this. Dr Rapeport attended at my insistence, and he offered an apology in the witness box. I have seriously considered whether to refer this matter to the Attorney-General with a view to proceedings for contempt of court. I have decided not to do so. My reasons, put shortly, are that Dr Rapeport acted on his own initiative, and that his reasons for his action were silly. There was no conflict of interest. Dr Rapeport said that Professor Page would be treated in future on the same basis as any other eminent academic with interests in respiratory medicine, and I am content to leave the matter there. I wish it to be clearly understood that expert witnesses are relied on by the court to express a disinterested view. Any pressure, and any act which may have the effect of placing pressure, on a witness may be a contempt of court and dealt with accordingly. If the witness’s actions have genuinely created a risk of the disclosure of confidential information, or if there is genuinely a conflict of interest, then the matter must be dealt with in open court on the application of the party which considers itself to be wronged.