Mr Justice Pumfrey :
Introduction
- This is an action for the revocation of European Patent (UK) 706376 which is in respect of an invention entitled "Anti-Angiogenic Compositions and Methods of Use". The Defendants are the registered proprietors of the patent. I shall refer to them as "Angiotech". The Claimant, Conor Medsystems Inc. ("Conor"), is a manufacturer of stents used in coronary angioplasty.
- The patent is exclusively licensed to the well-known manufacturer of stents, Boston Scientific ("Boston").
- As they now appear, the claims of the patent relate to a stent coated with polymer loaded with the drug taxol. Boston's taxol-eluting stent is called the "Taxus" stent. The patent claims priority from 19th July 1993. Before further considering it, I will sketch out an introduction to the use of stents in angioplasty at the priority date, although each of these matters will have to be revisited in more detail when I come to consider the common general knowledge in the art.
- Coronary heart disease is caused by a narrowing or blockage of the coronary arteries, whose task is to supply the heart muscle with blood. Arterial walls have three layers: a thin inner layer called the intima; a middle layer called the media, which consists of muscle; and an outer layer called the adventitia, which is a loose layer of connective tissue. The normal cause of arterial narrowing is atherosclerosis, in which a gradual build-up of fatty material in the inner layer of the artery wall takes place. This build-up of fatty material is followed by a deposit of fibrous tissue which produces a plaque protruding into the channel of the artery. The narrowing caused by the plaque is called a stenosis. The channel of the artery is referred to as the lumen, and as the lumen becomes progressively narrowed, the heart muscle becomes deprived of blood when demands are made of it, for example during exercise. The patient may then complain of angina, which is typically a crushing or constricting sensation in the chest and which may spread elsewhere, for example in the left arm or neck. If the protective fibrous cap on the surface over the fat-laden core of the plaque (the so-called atheroma) breaks, the platelets in the bloodstream adhere to the roughened exposed surface and a blood-clot forms. Any angina may worsen and, if the lumen of the artery is suddenly closed off, blood-flow ceases and the heart muscle dies, resulting in a heart attack.
- By the mid 1980s, there were three ways of treating coronary heart disease: drugs, coronary bypass surgery and angioplasty. Drugs may be used to relieve the symptoms of angina by relaxing the muscle of the artery wall, which improves the supply of blood to the heart muscle. They may also be used to make the heart beat less forcefully, so reducing its workload. Clot-dissolving drugs may be used, as may anti-platelet drugs, which reduce the tendency of the platelets to adhere to the plaques. (Platelets are specialised cells responsible for clotting.) If drugs alone are insufficient, and there is narrowing and blockage in several arteries, the patient may undergo coronary artery bypass surgery, in which vessels from elsewhere in the patient's body are used to bypass the problem by connecting them round the blockage. This surgery can relieve angina and may be successful for many years if the grafts remain open. Angioplasty is a technique originally developed in the early 1960s, but whose application to the coronary arteries became possible after the development of a balloon which, when inflated, was strong enough to dilate an arterial stenosis in a coronary artery. One Andreas Grüntzig developed a catheter with a relatively non-elastic sausage-shaped balloon near its tip. The catheter had two channels: one for introducing a guide-wire along which the balloon catheter could be passed and the other carrying fluid at a high pressure (between 6 and 12 bar) to inflate the balloon. The catheter is inserted in one of the main arteries, normally in the groin or in the arm, and manoeuvred to the site of the stenosis by the operator, who observes its progress using radiological techniques.
- The first percutaneous angioplasty was performed in 1977. The idea is that, once the wire is in place and the balloon passed into position along it, the balloon is then inflated so as to expand the lumen at the point of the stenosis. The procedure was and is successful, and in many cases relieves the patient of the burden of a bypass operation. It has low morbidity, rapid recovery time, and is repeatable. It is minimally invasive and does not require a general anaesthetic. It appears to have rapidly gained ground in the 1980s and by the middle of that decade had become widely accepted as an alternative to bypass surgery.
- By the mid 1980s it was becoming clear that there were problems associated with balloon angioplasty. Two in particular are important. The first, acute closure, took place in between 5% and 10% of patients. It occurred as the catheter was withdrawn. Without quick reaction by the operator, backed up if need be by emergency bypass surgery, acute closure would be fatal to the patient. The other problem is the gradual closure of the lumen, known as restenosis. Restenosis occurs in 33% to 50% (or possibly more) of patients. It normally takes place within six months following the angioplasty procedure, and is likely to re-occur at the same sort of rate among patients who had second and subsequent angioplasties. There is no doubt that restenosis was and remains a serious problem with the balloon angioplasty procedure.
- The attempt to deal with this problem has passed through a number of stages. The first was the employment of coronary stents. Stents are devices inserted into the diseased artery at the point at which the balloon expanded to open the lumen. They act as scaffolding to hold the artery open. The desirability of stenting had been obvious from the early days of balloon angioplasty, but real success only came with the use of stents that were themselves held on the balloon and expanded with it so as to be automatically placed in the right position during the procedure. A number of expandable core stents were developed from the mid 1980s onwards and were used from the late 1980s to see if they might reduce restenosis – they are obviously useful in preventing acute closure. Nonetheless, patients who had received a stent still suffered restenosis, and the reduction in restenosis rates was investigated. Two studies suggested that there was still a very significant rate of restenosis in patients receiving a balloon expandable stent in angioplasty.
- The claims of the patent in suit – but little of its description – are concerned with a stent coated with a polymeric carrier containing the drug taxol. Although the priority date of the patent is 1993, the Boston Scientific stents, which have been approved for use since 2004, correspond to this description and, on the evidence, exhibit a very much better rate of restenosis than do bare-metal stents. Taxol is a powerful inhibitor of cellular division, and in outline the mode of operation of the stent is that the taxol is eluted from the polymer coating and restrains the proliferation of tissue which results in restenosis.
- The question in this action is whether the patent in suit is obvious in the light of three separate publications: PCT application number WO 91/12779 ("Wolff"), PCT application number WO 93/11120 ("Kopia") and an abstract of a paper by Katsuda et al, page 446 of the International Atherosclerosis Society Poster Sessions Abstract Book from 8th International Symposium on Atherosclerosis, Rome, 9-13 October 1988 ("Katsuda").
- In order properly to undertake this investigation it is necessary both to identify the addressee of the specification and the common general knowledge that is to be imputed to him. Both questions were the subject of lively controversy, and in order to explain that controversy it is convenient first to describe the patent in suit.
The Patent
- The patent is a very lengthy document, containing some 37 pages of description and 34 pages of figures. Very little of it is about restenosis and stents.
- The technical field of the invention is said (page 2 line 5) to relate to
"compositions and methods for treating cancer and other angiogenic-dependent diseases, and more specifically, to compositions comprising anti-angiogenic factors and polymeric carriers, stents which have been coated with such compositions, as well as methods for utilizing these stents and compositions."
"Angiogenesis" is the term employed to refer to the growth of blood vessels. The basic idea, as expressed in this paragraph, is to inhibit the growth of tissue by preventing the formation of blood vessels. The background of the invention is described, in a lengthy passage from page 2 line 11 to page 3 line 29, in terms of cancerous tumours. A passage of some importance is at page 3 lines 13 to 21, as follows:
"A related problem to tumor formation is the development of cancerous blockages which inhibit the flow of material through body passageways, such as the bile ducts, trachea, esophagus, vasculatures and urethra. One device, the stent, has been developed in order to open passageways which have been blocked by tumors or other substances. Representative examples of common stents include the Wallstent, Strecker stent, Gianturco stent and the Palmaz stent. The major problem with stents, however, is that they do not prevent the ingrowth of tumor or inflammatory material through the interstices of the stent. If this material reaches the inside of a stent and compromises the stent lumen, it may result in blockage of the body passageway into which it has been inserted. In addition, presence of a stent in the body may induce reactive or inflammatory tissue (e.g. blood vessels, fibroplasts, white blood cells) to enter the stent lumen, resulting in partial or complete closure of the stent."
The patent then sets out at page 3 line 30 what is described as a summary of the invention. This is no longer an accurate description of the passage which follows, since very extensive amendments to the claims have been permitted by the EPO. Since the various formalities relating to amendment had not been completed before the trial of the action before me, I made an order amending the patent in the same way as had been authorised by the EPO. In the result, it will be observed that at many places in the body of the specification the word "invention" has been replaced by the word "disclosure", since much of the descriptive matter has become irrelevant to the granted claims, other than as background or as statements of technical fact relating to related matters.
- As amended, the passage at page 3 lines 32-39 accurately sets out the concept underlying the invention claimed by claims 1 to 12 as amended:
"Briefly stated, the present disclosure relates to anti-angiogenic compositions, as well as methods and devices which utilize such compositions for the treatment of cancer and other angiogenesis-dependent diseases. Compositions are disclosed (hereinafter referred to as "anti-angiogenic compositions") comprising (a) an anti-angiogenic factor and (b) a polymeric carrier. Molecules which are utilized within the scope of the present invention as anti-angiogenic factors are taxol, taxol analogues and taxol derivatives. Similarly, a wide variety of polymeric carriers may be utilized . . ."
- Stenting is described at page 3 line 48 as follows:
"According to the present invention, there is provided a stent in accordance with claim 1. Within other aspects of the present invention, such stents are provided for use in a method of expanding the lumen of a body passageway, comprising inserting a stent into the passageway, the stent having a generally tubular structure, the surface of the structure being coated with an anti-angiogenic composition as described above, such that the passageway is expanded. Within various embodiments of the invention, such methods include eliminating biliary obstructions, comprising inserting a biliary stent into a biliary passageway: eliminating urethral obstructions, comprising inserting a urethral stent into a urethra; eliminating esophageal obstructions, comprising inserting an esophageal stent into an esophagus and eliminating tracheal/bronchial obstructions, comprising inserting a tracheal/bronchial stent into the trachea or bronchi. In each of these embodiments, the stent has a generally tubular structure, the surface of which is coated with an anti-angiogenic composition as described above."
Then, after dealing with corneal neovascularisation after cancer surgery, a method of manufacturing a medicament for treating arthritis is disclosed. A similar passage to that which I have already quoted above is set out at page 4 lines 12-19, but specifying taxol, and, with that introduction, the specification turns to a brief description of the drawings, which precedes in the usual way the detailed description of the invention.
- The detailed description begins with a description of an assay for suitable anti-angiogenic compounds. The claim now being limited to taxol, this is of importance only to understanding the manner in which the claims are constructed, since they refer to the "CAM" assay. This assay, which is described in detail later on in the specification, is an assay to determine whether a particular compound inhibits vascular growth in vivo. The assay is simple enough: it utilizes the vascularisation of a chick embryo as it grows within the shell. The specification turns to compositions comprising an anti-angiogenic compound and a polymeric carrier at page 6 line 3, a passage in which taxol is not distinguished from other materials of this description. Taxol is again discussed at page 6 line 24, where it is described in more detail:
"Taxol is a highly derivatized diterpenoid . . . which has been obtained from the harvested and dried bark of Taxus brevifolia (Pacific Yew) and Taxomyces Andreanae an[d] Endophytic Fungus of the Pacific Yew . . . Generally, taxol acts to stabilize microtubular structures by binding tubulin to form abnormal mitotic spindles. "Taxol" (which should be understood herein to include analogues and derivatives of taxol such as, for example, baccatin and taxotere) may be readily prepared utilizing techniques known to those skilled in the art . . . or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St Louis, Missouri . . ."
- It is not necessary to deal with the discussions of Suramin and Tissue Inhibitor of Metalloproteinases-1 or Plasminogen Activator Inhibitor, which follow the passage relating to taxol. At page 6 line 52 the specification states that "a wide variety of other anti-angiogenic factors may also be utilized within the context of the present disclosure". Two of these materials in particular are to be noted – Methotrexate (page 7 line 2) and Heparin (page 7 line 4). The evidence was that Methotrexate was not positive in the CAM assay, a fact which had been established by tests carried out by the Patentees. It had also been shown (along with Heparin) not to prevent restenosis in a study in pigs using drug-eluting stents carried out by Cox some two years previously.
- The nature of the polymeric carrier is described at page 7 line 37, from which it will be seen immediately that a huge range of different polymers is within the Patentees' contemplation. At page 7 line 55 there is some indication of the manner in which a polymeric carrier is to be selected, but the directions given are so general as to throw the skilled reader back onto the relevant common general knowledge:
"Preferably, anti-angiogenic compositions for use in the present invention (which comprise one or more anti-angiogenic factors, and the polymeric carrier) are fashioned in a manner appropriate to the intended use. Within preferred aspects of the present invention, the anti-angiogenic composition should be biocompatible, and release one or more anti-angiogenic factors over a period of several weeks to months. In addition, anti-angiogenic compositions of the present invention should preferably be stable for several months and capable of being produced and maintained under sterile conditions."
- A number of other presentations are also discussed. They are polymer spheres or microspheres; sprayable nano-particles; paste or gel; or films. Having regard to the field of application of the present invention, it comes as something of a surprise to find that the first application of the invention is in arterial embolization: that is, the obstruction of a blood vessel to prevent the supply of blood to a tumour. The field of application of this technique is stated to be wide and it is discussed in detail in the passage from page 8 line 33 to page 10 line 25, where the disclosure then turns to the use of anti-angiogenic compositions as coatings for stents.
- The specification describes stents in a general way, and sets out a number of relevant US patents. It describes coating the stents with both anti-angiogenic compositions (i.e. polymer/drug compositions) and anti-angiogenic factors themselves. Again, the directions are very general:
"Within preferred embodiments of the invention, the composition should firmly adhere to the stent during storage and at the time of insertion, and should not be dislodged from the stent when the diameter is expanded from its collapsed size to its full expansion size. The anti-angiogenic composition should also preferably not degrade during storage, prior to insertion, or when warmed to body temperature after expansion inside the body. In addition, it should preferably coat the stent smoothly and evenly, with a uniform distribution of angiogenesis inhibitor, while not changing the stent contour. Within preferred embodiments of the invention, the anti-angiogenic composition should provide a uniform, predictable, prolonged release of the anti-angiogenic factor into the tissue surrounding the stent once it has been deployed. For vascular stents, in addition to the above properties, the composition should not render the stents thrombogenic (causing blood clots to form), or cause significant turbulence in blood flow (more than the stent itself would be expected to cause if it was uncoated)."
- The use of expandable stents in the lumens of a variety of body passageways for the purpose of eliminating obstruction is described. The first example is the biliary system, in which the troublesome obstructions described are all tumour-induced. The same goes for the examples given of the use of the stent in the oesophagus, the trachea, the bronchi and the urethra. Finally, at page 12 line 32 is the comparatively brief passage which describes the invention so far as it has found application in therapy:
"Within another embodiment of the disclosure, methods are provided for eliminating vascular obstructions, comprising inserting a vascular stent into a blood vessel, the stent having a generally tubular structure, the surface of the structure being coated with an anti-angiogenic composition as described above, such that the vascular obstruction is eliminated. Briefly, stents may be placed in a wide array of blood vessels, both arteries and veins, to prevent recurrent stenosis at the site of failed angioplasties, to treat narrowings that would likely fail if treated with angioplasty, and to treat post surgical narrowings (e.g. dialysis graft stenosis). Representative examples of suitable sites include the iliac, renal and coronary arteries, the superior vena cava, and in dialysis grafts."
- There is some general teaching of the mode of operation of the anti-angiogenic compositions at page 14 line 22, a short passage which observes that the compositions block the stimulatory effects of angiogenesis promoters, reducing endothelial cell division, decreasing endothelial cell migration and impairing the activity of the proteolytic enzymes secreted by the endothelium. It was suggested before me that this was a general teaching relating to the compositions of the invention, and that it was therefore appropriate not to amend this passage. On reflection, I am satisfied that this is incorrect. This short passage is in the context of a long section of the specification, extending from page 13 line 47 to page 14 line 44, which is concerned exclusively with the cornea. This passage seems to me to relate to the corneal endothelium alone.
- After a brief diversion into hypertrophic scars and keloids, the specification returns to the eye at page 15 line 10 with a discussion of neovascular glaucoma, followed by diabetic retinopathy and retrolental fibroblasia. The specification turns then to rheumatoid arthritis and the coating of vascular grafts. There is no further discussion of the use of stents.
- A very extensive set of examples is provided between pages 17 and 37. Example 2 describes the CAM assay and the employment of that assay in assessing taxol. The conclusion in relation to taxol is that it clearly inhibits angiogenesis by arresting endothelial cells in mitosis. Example 7 describes the use of biliary stents in rats to inhibit tumour in-growth, without stating what the anti-angiogenic factor employed was. Taxol is used as the exemplar for the manufacture of microspheres in example 8 and for the manufacture of a stent coating in example 9. The use of the CAM assay in assessing the release of taxol from microspheres is discussed in example 12 and its use in polymeric films in example 13. It is the anti-angiogenesis factor employed in example 15 (assessment of a taxol-loaded paste in the CAM assay) and in example 16 (use of a taxol-loaded paste to inhibit tumour growth and tumour angiogenesis in mice). In example 17 the effect of the taxol-loaded paste in another mouse tumour model is assessed. Example 18 describes the use of films loaded with 5% taxol for use in surgery. The idea is that during resection of a tumour the film may be used to protect adjacent organs from inadvertent contamination by cancer cells, and possibly left in situ to provide continued protection. Finally, example 19 is concerned with the treatment of rheumatoid arthritis using taxol-loaded microspheres. This is a summary, but I believe a sufficient summary, which shows that there is no example of the use of taxol-coated stents for the inhibition of restenosis at angioplasty sites.
- Three claims of the specification as amended are alleged to have independent validity. It is convenient to set them out here.
"1. A stent for expanding the lumen of a body passageway, comprising a generally tubular structure coated with a composition comprising an anti-angiogenic factor and a polymeric carrier, the factor being anti-angiogenic by the CAM assay, and wherein said anti-angiogenic factor is taxol, or an analogue or derivative thereof.
…..
6. A stent according to any one of claims 1 to 5 wherein said stent is a vascular stent.
…..
[11. A stent according to any one of claims 1 to 5 for treating narrowing of a body passageway.]
12. A stent according to claim 11 for treating or preventing recurrent stenosis."
- It is common ground that taxol is in fact anti-angiogenic by the CAM assay. Those words therefore do not add anything to claim 1 if for any reason it is obvious to employ taxol on a stent suitable for expanding the lumen of a body passageway. Nor has it been suggested that success in the CAM assay is either necessary or sufficient for a material to be suitable for preventing restenosis. So far as claim 6 is concerned, it is, I think, assumed by both parties that it is possible to identify vascular stents as a particular class of stent, and it seems to me that claim 12 adds nothing to claim 6 as a matter of inventive concept, although the word "recurrent" is perhaps not what was intended: I read claim 12 as stating that the stent must be suitable for treatment or prevention of stenosis. That is what taxol-coated stents are sold for.
- One final observation needs to be made. I have summarised the disclosure of the patent in the foregoing paragraphs, and, as I have indicated, the disclosure in respect of taxol-eluting vascular stents is slight. Conor submit that the inventive concept of the patent must reside in the idea of seeking to treat or prevent restenosis by coating a stent with a taxol/polymer composition. This is the full scope of the disclosure. It is submitted that the specification does not show that this concept works at all or to any particular extent. Nor is the suitability of any particular polymer or any particular amount of taxol demonstrated. It follows that the skilled person to whom ex hypothesi the idea is new is left with the task of assessing one or more taxol/polymer combinations, to determine the extent to which that combination is effective to prevent restenosis. Conor do not suggest that the specification is insufficient in this respect, but say that the disclosure is a disclosure merely of the idea of using a taxol-eluting stent. They rely upon a passage in the cross-examination of Professor Cumberland (transcript 515 to 517) in which Professor Cumberland accepted that the specification contained no data as to the efficacy of any of the compounds disclosed, did not address the question whether any of the compounds disclosed inhibited the proliferation of smooth muscle cells (believed to be the main mechanism of restenosis), did not deal with possible side-effects in otherwise healthy tissue, did not address the question of dosage, and did not address the length of time for which a taxol-containing product should remain in the location in question. Nor was the fact that a compound was anti-angiogenic of any assistance in concluding whether or not the compound would actually work to inhibit the proliferation of smooth muscle cells.
- To this extent, therefore, I conclude that the disclosure is indeed speculative. The reason was provided by Dr Hunter's evidence. At the priority date, the Patentees had neither made nor tested any taxol-eluting stent for the prevention of restenosis in percutaneous transluminal coronary angioplasty. By December 1994, work had been done on the use of coated stents for the purpose of treating cancerous blockages, but the evaluation of the usefulness of stents in prevention of arterial restenosis was just being initiated. A document dated August 1995 reveals that by that date no in vivo studies had been performed, and it appears from the evidence that the first such studies were performed somewhat later than this.
- It is a fundamental principle that the disclosure of a specification to the skilled man at the relevant date is not to be assessed by reference to the work that the patentee had in fact done towards arriving at the invention claimed in the claims. It is entirely legitimate for a patentee to write a complete specification, experiments and all, without leaving his armchair, but he runs the risk of a finding of insufficiency if he gets anything wrong. Other inventions may be fully disclosed as working embodiments, even if only the underlying concept is disclosed – see, for example, Hickton's Patent Syndicate v. Patents and Machines Improvements Co Ltd (1909) 26 RPC 339. In this case, I draw some comfort in my assessment of the disclosure of the specification from the knowledge that in fact the Patentee had done none of the work which would turn the idea of using taxol in a polymer coating on a stent into a product that could be tested and shown to prevent restenosis.
- The conceptual nature of the disclosure has a particular consequence in the identification of the attributes to be imputed to the skilled addressee of the patent. Obviously, the patent is addressed to a manufacturer who wants to make coated stents for preventing restenosis, and it was assumed throughout the trial that the bare stent, together with the ability to coat it, must be viewed as part of the common general knowledge of the addressee. I heard evidence from two representative members of the notional team from both parties. One of the members of the team was an interventional cardiologist and the other a person familiar with the kind of drugs which would pass the CAM assay, in other words, cancer drugs. It was common ground, given the nature of the prior publications, that the same team provides the eyes through which the disclosure of the prior publications is to be ascertained. This may not always be the case, because a patent representing an entirely fresh departure may call for skills not required hitherto in the art. This is not such a case.
Validity - the Law
- This is a case in which obviousness is alleged. The approach to obviousness set out in Windsurfing International v. Tabur Marine [1985] RPC 59 was accepted by both parties as an appropriate method for approaching the question of obviousness on the facts here. As sometimes happens, the case of obviousness on the documents appears at first sight to be strong, and the Patentees rely upon a number of secondary indications of non-obviousness. The principal indication of this sort is acceptance by the art, by which I mean that the Patentees say that taxol-eluting stents have been rapidly and widely accepted in cardiovascular medicine as an improvement upon the bare stents which preceded them, because they have been shown by trials substantially to reduce the rate of restenosis. Implicit in such a plea is, of course, the contention that if it had all been so obvious, it would have been done earlier. Chronology becomes a significant issue.
- In most cases of obviousness, the primary evidence of obviousness comes from the expert witnesses. The question whether the difference between the inventive concept of the patent in suit and the state of the art represents an obvious step is one upon which their evidence is crucial. Nevertheless, from other facts an inference of non-obviousness may be drawn. History may be decisive, but it is important to place the history in its context. Thus in Vickers Sons & Co Ltd v. Siddell (1890) 7 RPC 292, 304, Lord Herschell said:
"If the apparatus be valuable by reason of its simplicity, there is a danger of being misled by that very simplicity into the belief that no invention was needed to produce it. But experience has shown that not a few inventions, some of which have revolutionised the industries of this country, have been of so simple a character that when once they were made known it was difficult to understand how the idea had been so long in presenting itself, or not to believe that they must have been obvious to everyone."
- Others have drawn attention to the echo of Milton's description of the invention of gunpowder by Satan in this and other passages elsewhere. Of course mere acceptance by the trade is not logically probative of non-obviousness. That this is so was recognised in Longbottom v. Shaw (1891) RPC 333, where Lord Herschell said this:
"Great reliance is placed upon the fact that when this patent was taken out and frames were made in accordance with it there was a large demand for them. It is said that at all events in the experience of certain houses dealing largely in these matters, the new apparatus, as it is called, of the plaintiff superseded the one formerly in use. My lords, I do not dispute that that is a matter to be taken into consideration; but again, it is obvious that it cannot be regarded in any sense as conclusive. I think that its value depends very much upon certain other circumstances. If nothing be shown beyond the fact that the new arrangement results in an improvement, and that this improvement causes a demand for an apparatus made in accordance with the patent, I think it is of very little importance. If it were shown that the defects which this apparatus is designed to remedy, or does remedy, were defects which had been felt, and the knowledge of which had come to the public so that there was a demand for a new apparatus which did not possess these defects, and if it were shown that that demand had lasted for a considerable time, so that men's minds were likely to have been engaged upon a mode of remedying those defects, and they were not remedied until the apparatus was devised for which the patent is taken out, no doubt that would have afforded considerable evidence that the adaptation or arrangement of the patentee was not obvious, inasmuch as you would then have a demand for some considerable time not met although known, and the fact that it was not met for a considerable time though known would indicate that the mode by which it was ultimately met could not have been so obvious as otherwise might have been supposed. Therefore, in that way, the demand for an improved article might become a very material circumstance. But it appears to me that the elements which would make it very material are altogether wanting in the present case. We have here no evidence that the defects, though they existed, seriously pressed upon those who used this apparatus, and that they had indicated a desire for a machine which was free from those defects. There is no evidence that men's minds had been applied to the removal of these defects, which in some cases has been thought a very material circumstance."
The principle so stated has long been familiar. Commercial success of a new invention may be attributable to factors having nothing to do with the technical merit of the invention. The identification of those factors can in many cases render the proper assessment of a case of commercial success disproportionately difficult, and in Molnlycke AB v. Procter & Gamble Ltd [1994] RPC 49 Sir Donald Nicholls V-C emphasised at page 112 line 40 that the investigation of obviousness is essentially objective:
"Under the statutory code (which is further confirmed in its completeness by sections 74 and 72) the criterion for deciding whether or not the claimed invention involves an inventive step is wholly objective. It is an objective criterion defined in statutory terms, that is to say whether the step was obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art as defined in section 2(2). We do not consider that it assists to ask whether "the patent discloses something sufficiently inventive to deserve the grant of a monopoly". Nor is it useful to extract from older judgments expressions such as "that scintilla of invention necessary to support a patent". The statute has laid down what the criterion is to be: it is a qualitative not a quantitative test. The warning against coining phrases given by the Court of Appeal in General Tyre and Rubber Co v. Firestone Tyre and Rubber Co Ltd [1972] RPC 457 at 497-498 is even more apt under the 1977 Act. (See also the rejection of semantic arguments by the Court of Appeal in Hallen v. Brabantia [1991] RPC 195 and 211-212.)
The Act requires the court to make a finding of fact as to what was, at the priority date, included in the state of the art and then to find again as a fact whether, having regard to that state of the art, the alleged inventive step would be obvious to a person skilled in the art.
In applying the statutory criteria in making these findings the court will almost invariably require the assistance of expert evidence. The primary evidence will be that of properly qualified expert witnesses who will say whether or not in their opinions the relevant step would have been obvious to a skilled man having regard to the state of the art. All other evidence is secondary to that primary evidence. In the past, evidential criteria may have been useful to help to elucidate the approach to the common law to the question of inventiveness. Now there is a statutory definition, evidential criteria do not form part of the formulation of the question to be decided.
In the nature of things, the expert witnesses and the court are considering the question of obviousness in the light of hindsight. It is this which may make the court's task difficult. What with hindsight seems plain and obvious, often was not so seen at the time. It is for this reason that contemporary events can be of evidential assistance when testing the experts' primary evidence. For instance, many people may have been industriously searching for a solution to the problem for some years without hitting upon the allegedly obvious invention. When this type of evidence is adduced, the court can quickly find itself caught up in an investigation of what was or was not obvious to certain identified individuals at certain dates during the history of the development of the product or process involved. This gives rise to complications because the state of the knowledge of these individuals, though skilled, may not correspond to the statutory definition of the state of the art. A particular inventor may have been unaware of some aspect of the state of the art as defined in section 2(2), and may therefore have genuinely taken what was actually an inventive step, but nevertheless be unable to claim a patentable invention since the step was, in the terms of the statute, obvious. Further, this type of evidence invites the court to speculate whether particular individuals were of an inventive disposition, because the earlier making of the same invention by another or others does not necessarily mean that at the later date the invention was obvious. Yet again, evidence of the commercial success of the invention can lead into an investigation of the reasons for the success; there may be commercial reasons for this success unrelated to whether the invention was or was not obvious in the past.
Secondary evidence of this type has its place and the importance, or weight, to be attached to it will vary from case to case. However, such evidence must be kept firmly in its place. It must not be permitted, by reason of its volume and complexity, to obscure the fact that it is no more than an aid in assessing the primary evidence."
- History is what real people actually did. The assessment of obviousness is a test against the legal construct known as the hypothetical skilled person, and this means that appeals to commercial success make the unstated assumption that enough people in the art to be representative are under consideration. At the same time, when assessing the attributes of the skilled person, it is essential to try to reflect, to the extent that the evidence permits, the actual ordinary skills of the real-life contemporaries of the skilled man at the priority date. The point of the objection of obviousness is to prevent the too-ready grant of patents from hampering them in the ordinary technical development that must take place in an industry. While, therefore, I am bound by the propositions set out by Sir Donald Nicholls V-C above, I am also obliged to remember the observations of Hoffmann LJ in STEP v. Emson [1993] RPC 513 at 519 line 23, where he said:
"The words "obvious" and "inventive step" involve questions of fact and degree which must be answered in accordance with the general policy of the Patents Act to reward and encourage inventors without inhibiting improvements of existing technology by others. The question is therefore whether in accordance with this policy the patent discloses something sufficiently inventive to deserve the grant of a monopoly."
- To an inappropriately defined skilled man, nothing may be obvious or everything may be obvious. The most difficult part of any obviousness case is the attribution of the relevant skill and knowledge to the notional addressee of the patent. When the common general knowledge is identified, the height of the bar is set. Normally, there are two main inputs. The first is the inference that one can draw from the other allegations that are made in the case. Thus, the agreement by the parties that the specification is sufficient will give a substantial indication of the degree of skill and knowledge to be attributed to the skilled addressee. The other input is the expert evidence as to the common general knowledge. It is perhaps a surprising feature of the passage that I have quoted from Molnlycke that the Vice-Chancellor does not refer expressly to the common general knowledge and to the light that may be thrown on the level of skill and the common general knowledge by the contemporary history. It was for this purpose that Laddie J seems to have employed the evidence of commercial success and long-felt want in Haberman v. Jackel [1999] FSR 683. This is the leading modern case on commercial success, and although Laddie J does not refer to any of the authorities apart from the short passage to which I have referred in STEP v. Emson (above), he suggests in [32] that "some insight into the thinking of those in the art at the priority date can be provided by evidence of commercial success". In approaching this question he lists a number of factors that may be relevant, accepting that there may be others as well. The list (which I have somewhat abbreviated) is as follows:
"(a) What was the problem which the patented development addressed? Although sometimes a development may be the obvious solution to another problem, that is not frequently the case.
(b) How long had that problem existed?
(c) How significant was the problem seen to be? A problem which was viewed in the trade as trivial might not have generated much in the way of efforts to find a solution. So an extended period during which no solution was proposed (or proposed as a commercial proposition) would throw little light on whether, technically, it was obvious. Such an extended period of inactivity may demonstrate no more than that those in the trade did not believe that finding a solution was commercially worth the effort. The fact, if it be one, that they had miscalculated the commercial benefits to be achieved by the solution says little about its technical obviousness and it is only the latter which counts. On the other hand evidence which suggests that those in the art were aware of the problem and had been trying to find a solution will assist the patentee.
(d) How widely known was the problem and how many were likely to be seeking a solution? Where the problem was widely known to many in the relevant art, the greater the prospect of it being solved quickly.
(e) What prior art would have been likely to be known to all or most of those who would have been expected to be involved in finding a solution? A development may be obvious over a piece of esoteric prior art of which most in the trade would have been ignorant. If that is so, commercial success over other, less relevant, prior art will have much reduced significance.
(f) What other solutions were put forward in the period leading up to the publication of the patentee's development? This overlaps with other factors. For example, it illustrates that others in the art were aware of the problem and were seeking a solution. But it is also of relevance in that it may indicate that the patentee's development was not what would have occurred to the relevant workers. This factor must be treated with care. As has been said on more than one occasion, there may be more than one obvious route around a technical problem. The existence of alternatives does not prevent each of them from being obvious. On the other hand where the patentee's development would have been expected to be at the forefront of solutions to be found yet it was not and other, more expensive or complex or less satisfactory, solutions were employed instead, then this may suggest that the ex post facto assessment that the solution was at the forefront of possibilities is wrong.
(g) To what extent were there factors which would have held back the exploitation of the solution even if it was technically obvious? For example, it may be that the materials or equipment necessary to exploit the solution were only available belatedly or their cost was so high as to act as a commercial deterrent. On the other hand if the necessary materials and apparatus were readily available at reasonable cost, a lengthy period during which the solution was not proposed is a factor which is consistent with lack of obviousness.
(h) How well has the patentee's development been received? Once the product or process was put into commercial operation, to what extent was it a commercial success? In looking at this, it is legitimate to have regard not only to the success indicated by exploitation by the patentee and his licensees but also to the commercial success achieved by infringers. Furthermore, the number of infringers may reflect on some of the other factors set out above. . . .
(i) To what extent can it be shown that the whole or much of the commercial success is due to the technical merits of the development, i.e. because it solves the problem? Success which is largely attributable to other factors, such as the commercial power of the patentee or his licensee, extensive advertising focusing on features which have nothing to do with the [invention], branding or other technical features of the product or process, says nothing about the value of the invention."
- This list starts with the basic question, what was the problem? (b), (c), (d), (e) and (f) are really concerned with the wider question, why was the invention not made earlier? (g), (h) and (i) are concerned with commercial success. Mere delay while all the building-blocks of an invention are known in the art is a familiar secondary indication of non-obviousness, which requires no special treatment. There is a temptation, which was not avoided in the submissions addressed to me in the present case, to turn this list of factors into a checklist. I do not find this particularly helpful, preferring to identify those collateral matters which logically go towards fulfilling the Molnlycke task of testing the experts' primary evidence.
- I have spent more time on this issue than normally would be justified because it formed an important plank in the Patentees' case. I wish to make two further observations. The first is that it is essential to remember that the objection of obviousness is available even when the invention is not anticipated. This proposition may be trite, but it is important to guard against the suggestion that lack of anticipation is in itself an indication of non-obviousness in the technically objective sense. It is not. The second is that inventions may be obvious even though the art missed them. That is a corollary of my first observation. It is absurd to suggest that everything objectively obvious at the priority date should have been done or contemplated either then or at any time thereafter. Patents should not be granted for things that have been obvious for a long time.
- With that introduction, I can turn to the witnesses.
The Witnesses
- The Claimant called Professor Rogers and Professor Lemoine as experts, respectively, on interventional cardiology and on chemotherapeutic agents for use in cancer. Both of them were accused of being poor witnesses and of being unqualified to give the evidence that they gave. That, at least, is my reading of the submissions advanced by the Patentees. So far as Professor Lemoine was concerned, the submission is clearly made that he had no basis upon which "to assist the court on the key issues in this case". Professor Rogers was accused of taking "unmeritorious verbal points on papers as they were put to him".
- I should record that Professor Rogers is an Associate Professor of Medicine at the Harvard Medical School, the Director of the Cardiac Catheterisation Laboratory and the Director of the Experimental Cardiovascular Interventional Laboratory at Brigham and Women's Hospital, Boston, Massachusetts. He was an extremely expert interventional cardiologist. In fact, the main objection to his evidence was merely that he was starting up in the field at the priority date, and the criticism is based entirely upon his refusal to accept the main point upon which the Patentees rely. As Mr Waugh QC's written submissions put it:
"Being able to speak of the common general knowledge and, in particular, the expectations of those skilled in the art derives from [his] actual experience in practice. In this case, a crucial part of the perspective of the skilled person at the priority date was experience of the failure over a period of years in the art to find a solution to restenosis. Hindsight was unavoidable for such a witness."
- On the contrary, I found Professor Rogers a helpful witness who convincingly rejected the repeated suggestion (it was put to him three times) that his opinions were tainted by his current knowledge of the success of taxol and of the Patentees' stent. A short history of his involvement in the field is as follows. From 1991 to 1994 he was a trainee in cardiology, and in 1992-3 he was training in interventional cardiology and doing basic research in a laboratory. He first implanted a stent in 1993, and at the same time was instructing students in cardiovascular and pulmonary pathophysiology, giving his first talk at a national meeting in 1991. He acted as a principal investigator in animal studies in relation to intravascular stents for the first time in 1991-2.
- Professor Lemoine, who is the Professor of Molecular Pathology and the Director of the Cancer Research UK Clinical Centre at St Bartholomew's and the London Institute of Cancer was, I thought, a very good witness. At the priority date, he was an honorary consultant in oncology at the Hammersmith. He was challenged on his experience, but explained that although he was not on the wards, as he put it, administering the agents, he took part in the selection of appropriate protocols, audit meetings looking at outcome data for efficacy of drugs and their toxicity, and this was both a routine part of his departmental business and also an important element in oncology practice. As a clinical histo-pathologist, he is particularly concerned with the toxicity of the drugs with which the patients are treated, and he also taught. I thought that an attack on a clinical histo-pathologist who is also a professor of molecular pathology and director of a leading cancer treatment centre, on the footing that he knew nothing of the toxicity of the drugs which were being administered in that centre, was surprising. Professor Lemoine was, in my judgment, qualified to give the evidence which he did.
- No such criticisms are made by the Claimant of the Patentees' experts, Professor Cumberland and Professor Calvert. Professor Cumberland is an extremely experienced interventional cardiologist. He is now Consultant in Cardiac Intervention at the Northern General Hospital in Sheffield. He was Founder Chairman of the British Coronary Angioplasty Group and a member of its council from 1987 to 1991. He was a consultant cardiovascular radiologist at the Northern General Hospital from 1975 to 1994 and Consultant in Cardiovascular Studies at the San Francisco Heart Institute from 1988 to 1994. He has always had an interest in the problems of restenosis.
- Professor Calvert is a consultant oncologist and became Professor of Medical Oncology at the University of Newcastle in 1989, a position which he occupied until 2002. He is evidently an extremely skilled and experienced oncologist.
- I should also refer to Professor Karsch, who was a witness of fact. Professor Karsch holds the Chair of Cardiology at the University of Bristol and is an associate director of the Cardiology Department at the Bristol Royal Infirmary. He is also the Professor of Cardiology at the University of Tuebingen. Professor Karsch gave factual evidence about his use of taxol in the treatment of restenosis before the priority date. I shall deal with his evidence in more detail in its place.
Background – Restenosis
- I have outlined the history of the use of stents as an adjunct to percutaneous balloon angioplasty in paragraphs 6ff. of this judgment. It is now necessary to turn to the background in a little more detail.
- Restenosis is rarely life-threatening. By the early 1990s, it was understood that restenosis was different in nature from atherosclerosis, which is a naturally occurring disease. Restenosis is a response to the injury caused by the angioplasty. In their respective reports, Professor Rogers and Professor Cumberland deal with the nature of restenosis in some detail. The following is my summary.
- Balloon angioplasty possesses very substantial advantages as a means of treating coronary heart disease. Compared with bypass surgery, it has the advantages of low morbidity, rapid recovery time and repeatability. It is minimally invasive and does not require a general anaesthetic. Restenosis is the main chronic problem of balloon angioplasty and it occurs within weeks or months of the procedure, and almost always within the first six months, in between 33% and 50% or more of patients. It seldom results in sudden closure of the artery and so is seldom immediately dangerous, but it means that repeat procedures are often necessary because of the return of the patient's symptoms (for example, angina). Curiously, the incidence of repeat restenosis is about the same as the original restenosis and the phenomenon was generally viewed amongst clinicians as, in Professor Cumberland's words, the "Achilles' heel" of angioplasty.
- Between the mid 1980s and the mid 1990s, a number of approaches to the problem of restenosis were considered. Obviously, these expedients were not considered in a vacuum: at the same time there was much investigation of the mechanism of restenosis, and my impression is that to a certain extent different techniques reflected an improving understanding of the mechanism responsible for the phenomenon. Certainly, it seems by 1990 that it was a dominant theory that restenosis was an example of a healing response to the injury caused by angioplasty. At an early stage, probably by the early 1980s, it was recognised that restenosis was associated with the rapid proliferation and growth of the smooth muscle cells of the intima, the innermost part of the blood vessel wall. A phrase for this is "neointimal hyperplasia". Professor Cumberland gives a rather detailed description of the mechanism for the proliferation of smooth muscle cells in paragraphs 4.9 to 4.12 of his report, and it will be observed that the essential problem is cell proliferation. The extent of cell proliferation determines the seriousness of the restenosis.
- A number of proposals were made in the 1980s to reduce or prevent restenosis. So far as mechanical devices were concerned, the most important was the stent; many others are described in a paper entitled "Crackers, Breakers, Stretchers, Drillers, Scrapers, Shavers, Burners, Welders and Melters – the Future Treatment of Atherosclerotic Coronary Heart Disease? A Clinical-Morphologic Assessment" by Waller, exhibited to Professor Cumberland's report. Stents are in effect small metal scaffolds intended to hold the artery open at the angioplasty site. The first coronary stents were implanted in about 1985 in Europe and rather later in the United States. The stents were either self-expanding (the Wallstent) or balloon-expanded (Gianturco-Roubin, Palmaz-Schatz and Wiktor). The latter stents were placed over the angioplasty balloon and expanded by it during the angioplasty procedure. Stents greatly reduced the incidence of acute closure. The first stent approved for use in the United States was the Gianturco-Roubin stent, approved in mid-1993. European experience predated this substantially, and in any event trials had been going on for some years. It is clear that the use of stents for the purpose of reducing the risk of acute closure was part of the common general knowledge in the field of interventional cardiology by 1993.
- Soon after stents were introduced, evidence of restenosis in stented patients became available. Stent-induced restenosis happened at about the same time as restenosis after balloon dilatation alone, and was thought to be similar in nature to restenosis post-balloon angioplasty. It was certainly associated with excessive neointimal hyperplasia. It appears that there was some evidence that in-stent restenosis was less common than restenosis following balloon angioplasty alone, but according to Professor Cumberland the truth of this proposition became apparent only when extensive random trials had been completed in late 1993. The rate of in-stent restenosis was lower than the rate of restenosis in patients not receiving stents, but was still very substantial. So far as the published results of the studies are concerned, these cannot have formed part of the common general knowledge at the date. Nonetheless, it is plain that the fact of restenosis following stent implantation was well known in the field.
- The problem of restenosis, whether following simple balloon angioplasty or in-stent, was also being approached from a pharmaceutical direction. The work done in the early 1990s was associated with, among other things, a better understanding of the molecular biology of the cell. There was much work done on molecular-biologically-based agents, such as locally delivered anti- sense nucleotides. The purpose of this sophisticated technique, which is a way of inhibiting the expression of mRNA, was to target the synthesis of proteins known to cause cell division and growth. The target was thus proliferation of the cells. Other pharmacological approaches were investigated as well.
- In summary, therefore, the problem of restenosis was a problem that had been identified in the early years of balloon angioplasty. Stenting had begun in about 1985 and the first reported instance of restenosis appears, as I understand it, in a paper by Sigwart in about 1988. The whole position is reviewed in a paper entitled "Pharmacological Approaches to the Prevention of Restenosis following Angioplasty – the Search for the Holy Grail?" by Herrman and others from the Catheterisation Laboratory at the Thorax Centre of Erasmus University in Rotterdam, an acknowledged leading centre for investigation. This paper reports the use of anti-thrombotic, anti-platelet, anti-proliferative, anti-inflammatory, calcium-channel-blocking and lipid-lowering drugs, as well as the newer molecular biological approach to which I have already referred. Mr Waugh QC, who appeared on behalf of the Patentees, was inclined to put great weight upon the characterisation of the search as being the search for the Holy Grail, a phrase which appears to be used in the sense of something that does not exist, a chimera. I have found the paper extremely instructive and helpful. Table 2 of the paper identifies in summary form the potential targets for drugs and a list of the appropriate drugs for preventing restenosis. The targets are identified as thrombosis, cell proliferation, inflammation, coronary vasospasm and lipid regulators, and specimen active agents are identified for each. Being a review paper, not all its contents, and certainly not the contents of the papers to which it refers, could by any stretch of the imagination be viewed as part of the common general knowledge in the strict sense, but no doubt a paper of this description, originating in one of the leading research institutes concerned with the problem, would be the first point of call for the skilled man seeking to familiarise himself with the pharmacological background. Of particular interest is section 3.3 of the paper, which is concerned with anti-proliferative agents. I think it was established that at least the opening paragraph of this section does reflect the common general knowledge at the priority date:
"After the disruptive action of balloon dilatation, smooth muscle cells respond by proliferation. Cell characteristics shift from the contractile to the synthetic phenotype, which results in an intracellular matrix deposition. Since one of the key features of restenosis is the uncontrolled proliferation of vascular smooth muscle cells, anti-proliferative agents have been considered as an attractive concept."
- The discussion of the various pharmaceuticals with which the reviewed papers are concerned is summary and there is little discussion of modes of administration. It is plain that certain of the agents are administered systemically, while others are administered locally: so far as the cytostatic agents are concerned, work on locally administered doxorubicin, in rabbits, systemic vincristine 0.075 mg/kg and dactinomycin 0.015 mg/kg, cyclosporine 15 mg/kg and locally delivered methotrexate. The final report is of a paper by Cox (1991) concerning the effect of stents, respectively uncoated, coated with heparin, coated with methotrexate, and coated with a mixture of the two. This section of the paper concludes that "the results reported so far suggest that there seems to be no role for cytostatic agents in the prevention of restenosis in human coronary vessels". Notwithstanding this, research into anti-proliferatives generally was one class of work that was still being pursued at the priority date. The mode of delivery might be either systemic or local, and, where local, a number of methods of local drug delivery had been suggested. Thus there had been proposals for drug-eluting stents, porous balloon catheters for the local direct administration of the agent as a liquid, and the wrapping of polymers round the outside of arteries (although it is not clear to me how this last mode of delivery is of any particular interest to an interventional cardiologist concerned with balloon angioplasty). Professor Cumberland accepted that systemic delivery was largely unsuccessful and, from about 1990, interest appears to have veered towards local delivery. He accepted that by 1993 the thinking was that local delivery of a small quantity of drug might prove effective with manageable side-effects. He was also satisfied that the concept of the drug-eluting stent was well known in research circles, presentations being made at the major meetings. The Claimant submits that the common general knowledge in relation to classes of drugs and methods of delivery included the following:
a) Bare metal stents were available for use with balloon angioplasty in the treatment of atherosclerosis. There were problems with the deliverability of stents in coronary arteries.
b) Restenosis was known to occur as a result both of balloon angioplasty and of stenting.
c) Restenosis was known to be caused by (inter alia) the proliferation of smooth muscle cells.
d) Research was known to be directed (inter alia) into local delivery of anti-proliferative drugs.
e) One form of delivery being contemplated was in the form of a drug-eluting stent. Dosage levels of drugs to be used on drug-eluting stents were of orders of magnitude lower than those used for systemic administration.
f) The concept of using a polymer coating on the stent as a vehicle for drug delivery was well known.
- I think this is right, and I can turn to the question of the state of pharmaceutical knowledge of the skilled addressee. It is common ground between the parties that the skills of at least the interventional cardiologist element and the pharmaceutical element of the skilled addressee are complementary. The way it is put in criticising the evidence given by Professor Lemoine was that "Professor Lemoine was not the kind of medical oncologist or pharmacologist the skilled person would consult to obtain information on the profiles of various agents". The parties were agreed, therefore, that a reference to a person knowledgeable in this class of agents was a legitimate approach both to the qualities of the skilled person and also for the purpose of elucidating the disclosure of the specification. Nonetheless, the common general knowledge of this person is best discussed in its context.
- With that introduction, therefore, I can turn to the cited prior art.
Wolff
- Wolff was published on 5th September 1991. This is about two years before the priority date of the patent in suit. Wolff was employed by Medtronic, a company engaged heavily in this class of research. It is entitled "Intralumenal Drug Eluting Prosthesis". Wolff is concerned with intravascular stents, as its title suggests. The patent begins with a statement that the invention relates to methods of lessening restenosis of body lumens, and to prostheses for delivering drugs to treat said restenosis, and turns immediately to a description of the related art. This description is important for the context of the disclosure of the invention. After describing restenosis, the patent continues at page 1 line 16 with a description of intravascular stents. At page 1 line 24 it is observed that the initial data from clinical stent implants shows that they do not significantly reduce the amount of restenosis. It turns then to a discussion of pharmacologic attempts to reduce the amount of restenosis and observes that all of those attempts have dealt with the systemic delivery of drugs via oral or intravascular introduction. It concisely states the objection to systemic administration at page 1 line 33:
"For drug delivery, it has been recognised for a long period of time that pills and injections may not be the best mode of administration. It is very difficult with these types of administration to get constant drug delivery. Through repeated doses, these drugs often cycle through concentration peaks and valleys, resulting in time periods of toxicity and ineffectiveness. Thus, localised drug treatment is warranted."
- The summary of the invention which follows first proposes stents typically for use in the lumen of part of the vascular system and continues (page 2 line 23):
"The prostheses of the invention include at least one drug which will release from the device at a controlled rate to supply the drug where needed without the overkill of systemic delivery. The prostheses include means for fixing the device in the lumen where desired. The prostheses may be completely biodegradable or may be bioabsorbable in whole or in part such that the prostheses will be completely incorporated into the lumen wall as a result of tissue growth, i.e. endothelialisation. Alternatively, the prostheses may be biostable in which case the drug is diffused out from the biostable materials in which it is incorporated."
One of the possible prostheses designed is a conventional metal stent, and with conventional metal stents it is stated that the invention requires a drug-carrying coating overlying at least a portion of the metal. The introduction to the suitable drugs is given at page 3 line 7 as follows:
"The drugs in the prosthesis may be of any type which would be useful in treating the lumen. In order to prevent restenosis in blood vessels, migration and subsequent proliferation of smooth muscle cells must be checked. Platelet aggregation and adhesion can be controlled with antiplatelets and anticoagulants. Growth factor and receptor blockers and antagonists may be used to limit the normal repair response.
The current invention contemplates the usage of any prosthesis which elutes drugs locally to treat a lumen in need of repair. Controlled release, via a bioabsorbable polymer, offers to maintain the drug level within the desired therapeutic range for the duration of the treatment."
- There follows a lengthy discussion of the mechanism of restenosis, and at page 7 line 19 a passage entitled "Prevention of Restenosis" contains that part of the disclosure about which the debate has concentrated. The passage begins with the statement that in order to prevent restenosis, one must stop the proliferation of smooth muscle cells. It is pointed out that this is a biochemical process which cannot be treated mechanically, and it sets out five hypotheses as to how to stop restenosis biochemically. The first of the five hypotheses is to reduce the adhesion and aggregation of the platelets at the arterial injury site. It is observed that this hypothesis is directly related to the formation of thrombus, and on page 8 at line 9 two different ways to prevent the adhesion and aggregation of platelets are described. These are the use of an antiplatelet agent and the use of anticoagulants, of which examples are given. The remaining four hypotheses are all, as it is said, closely related. They are said to deal with blocking restenosis during the massive cell migration and replication cycle. In contrast to item 1, they are said to address the growth factors that are produced from sources other than platelets. The central passage at page 9 line 11 describes these agents as follows:
"There are several types of drugs that interrupt cell replication. Antimitotics (cytotoxic agents) work directly to prevent cell mitosis (replication), whereas antimetabolites prevent deoxyribose nucleic acid (DNA) synthesis, thus preventing replication. The action of the antimitotics and antimetabolites are so similar, they will be grouped into one category. This category will be known as the anti-replicate drugs.
Anti-replicate drugs include among others: Methotrexate, Azathioprine, Vincristine, VinBlastine, Fluorouracil, Adriamycin and Mutamycin. The target systemic molarity desired with methotrexate is on the order of 10-6 M with a range of between 10-3 to 10-8 Molar. Locally, the molarity of the drug may be highly variable, which is one of the great disadvantages in systemic administration of the drug. When drugs are delivered locally via the prosthesis of the invention, they may be at therapeutic levels at the diseased site while at the lower limits of detectability in the bloodstream. So little drug is required for effective local treatment of a lumen that the drug may not be detectable in blood samples."
- The argument of obviousness is simple enough. The difference between the disclosure of Wolff and the inventive concept of the patent in suit is the use of taxol in a drug-eluting stent. The pharmaceuticals listed in Wolff are each known for the treatment of cancer and are drugs which inhibit or prevent the replication of cells. They are all toxic. The Claimant's case is that if in 1992 an interventional cardiologist wished, in the light of the disclosure of Wolff, to select an anti-replicate drug to use on a stent to conduct research into restenosis, he would consult with an oncologist or someone familiar with cancer drugs, because the anti-replicate drugs listed on page 9 of Wolff were commonly used in the treatment of cancer. If asked for a recommendation for other "anti-replicate" drugs, paclitaxel (taxol) is one that would be recommended.
- In summary, therefore, the Claimant's case is that it is sufficient for the purposes of invalidating the claims of the patent in suit that the interventional cardiologist, in consultation with someone of skill and experience in the field of anti-mitotic drugs of one sort or another, would see paclitaxel (taxol) as worth experimentation. The Patentees' case is that the properties of taxol are such that the skilled person would not think that it was suitable for local administration in a drug-eluting stent. The Patentees' contentions centre on the toxic character of taxol. It is therefore necessary at this point to deal with a particular question which has vexed this case. Is it sufficient for Conor to show that taxol is an obvious candidate for testing on a drug-eluting stent in addition to the material specifically identified in Wolff, or is it necessary to show that taxol is an obvious, or the obvious, material to use in a drug-eluting stent for administration to human beings? Put another way, is the patent vulnerable only if it can be shown that the skilled person would have an expectation of success sufficient to induce him to incorporate taxol in a drug-eluting stent, or is it sufficient that without any expectation of success he would test or screen taxol?
- In my judgment, this question is to be answered by assessing the contribution to the art disclosed by the specification. For the reasons that I have given above, I am satisfied that the disclosure of the specification is that taxol may be incorporated in a stent. It does not suggest that such a stent would be safe or that such a stent would work to prevent restenosis. I think it is fair to say that the sum of the disclosure of the specification is that taxol should be incorporated in a drug-eluting coating on a stent with a view to seeing whether it works to prevent restenosis and whether it is safe. If it is obvious to the skilled person that taxol should be incorporated in a drug-eluting coating on a stent with a view to seeing whether it prevents restenosis and is safe, then the claim is invalid, the specification having made no contribution to the art. It is obviously preferable to identify the correct question before assessing the evidence. In this case, the profound difference between the parties as to the nature of the inventive step has led them to identify as relevant very different factors.
- Mr Waugh QC submitted that an expectation of success is a relevant factor in assessing the question of obviousness. As a broad proposition that is probably always true, but the question to be asked is: success in what? He points to the judgment of Goff LJ in Hickman v. Andrews [1983] RPC 147 at 189:
"There is another preliminary question and that is what the expert is supposed to be doing. It cannot be that he is to look to the whole store of his imaginary knowledge and see if it is obvious to turn something therein to better account. He must, I think, have some definite object in view."
Mr Waugh submits that the "definite object in view" in this case is the treatment or prevention of restenosis. He refers also to the judgment of Aldous LJ in Lilly Icos LLC v. Pfizer Ltd [2002] EWCA Civ 1, [2002] IP&T 244, where at [57] the following was said:
"Mr Young is correct that when considering what is obvious it cannot be assumed that the skilled person would try every possible permutation or carry out extensive research (see Hallen Co v Brabantia (UK) Ltd [1991] RPC 195 at 212). What would have been obvious will depend on all the circumstances. As I said in Norton Healthcare Ltd v. Beecham Group plc (19 June 1997, unreported) –
'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.' "
Whether one approaches the question from Goff LJ's "definite object in view" or from Aldous LJ's "Successful result", the preliminary question is: what is the result we are talking about, and what is the success relevant to this particular claim?
- The claim is to a physical device, that is, to a stent upon which is a drug-eluting coating loaded with taxol and optionally with other active ingredients as well. If, as I consider is the case here, the specification provides directions to make such a stent, but provides no data or other material suggesting that such a stent is in fact suitable for the treatment of restenosis, then success in preventing restenosis is not, in my view, a relevant consideration when assessing the obviousness of constructing such a stent. I accept immediately that there must be some motive making such a stent: but a sufficient motive is the testing of such a stent to see if it has potential in the treatment of restenosis. In the present case, therefore, I reject Mr Waugh's contention that the definite object in view is the treatment or prevention of restenosis. The object in view is the testing of a taxol-loaded stent to see if it is of any use in the treatment or prevention of restenosis: that is all the specification provides.
- In my judgment, therefore, in this case obviousness will be established if on balance the evidence shows that the skilled man would consider taxol to be worth testing to see what its properties were. If the skilled man would reject taxol a priori even from a test, then the position is otherwise. There is no doubt that Professor Calvert was of this view. In cross-examination he was asked directly whether he would or would not have said "I strongly advise you not to start" and his answer was that that is the advice which he would give. If, therefore, I accept his response as the response that should be attributed to the skilled addressee, the invention is not obvious. I turn to what was known of taxol both as a matter of common general knowledge and as would be revealed in the published material to a skilled person who had been pointed in its direction.
Taxol
- By 1993, paclitaxel was an agent well known to oncologists. In December 1992 it had received its first approval from the FDA for the treatment of ovarian cancer, having been in development first by the National Cancer Institute and secondly by Bristol Myers Squibb for about 20 years. It is a complex molecule and was originally extracted from the bark of the Pacific Yew. Its mode of action was understood to be the stabilisation of microtubules in the cell, preventing spindle formation and mitosis. Essentially, it prevented cancerous cells from dividing. The process of mitosis is described in detail by Professor Lemoine in his exhibit NRL2 in paragraphs 1 to 5. He sets out in paragraphs 10 to 16 of this primer the oncologist's understanding of the classes of chemotherapeutic drugs for cancer. Essentially all of the information in the primer, and more, is found in the entry for taxol which he extracts from the 4th edition of "Cancer – Principles and Practice of Oncology", referred to at trial as "De Vita". By 1993, taxol was produced by a semi-synthetic route from an associated compound called 10-deacetyl baccatin III found in the leaves of another yew species. This semi-synthetic route made taxol much less scarce than it had been when extracted from the bark of the Pacific Yew, and the drug was, for reasons given by Professor Lemoine, a drug of great interest. It had, from the point of view of the clinical oncologist, a number of problems.
- It was extremely insoluble in water. This makes systemic administration difficult. The problem of insolubility was overcome by dissolving the drug in cremophor, which is a non-ionic surfactant. Taxol is itself toxic, but in clinical studies showed in addition a wide range of hypersensitivity reactions including, as De Vita suggests, hypotension, bronchospasm, dyspnoea, urticaria, abdominal and extremity pain, and diaphoresis. De Vita attributes these reactions to the cremophor vehicle. It also notes that "other toxicities that have been observed with taxol include nausea and vomiting, mucositis, total body alopecia, and rare local venous toxicity. Cardiac effects include bradycardia and rare instances of atrioventricular block, ventricular tachycardia and myocardial infarction". In chapter 63 of De Vita it is noted that it has been recommended that continuous ECG monitoring accompany the use of taxol and taxatere. It is possible to multiply the examples of references, but it seems to me that it is wrong to go too deeply into the publications. Cardiac toxicity is in fact referred to in a number of articles: "Cardiac Disturbances during the Administration of Taxol" by Rowinsky and others, published in 1991 in the Journal of Clinical Oncology and the report of the Phase Two trial of taxol in the Journal of the National Cancer Institute by Holmes and others, also 1991, are examples.
- The evidence of greatest importance is that given not by the interventional cardiologists, but by the oncologists. The hypothesis is that the cardiologist consults with the oncologist to decide what is worth testing in the light of the disclosure of Wolff. Professor Rogers' evidence was not entirely satisfactory on this point. Professor Rogers gave evidence in paragraph 37 of his initial report that if he or another investigator wanted to choose an "anti-replicate drug" to conduct research and to coat its stents following what is disclosed by Wolff, he would approach an oncologist who would provide him not only with a list, but also with what he described as relevant insight into properties, mechanisms of action, toxicity, etc. He did, however, give evidence as to the obviousness of including taxol in such a list without having obtained that sort of information, whether from Professor Lemoine or elsewhere. He was acquainted with the use of taxol in 1993, because he had seen it in use. That is not, in my view, sufficient for a complete assessment of candidates for stents in these circumstances, but I am not sure that this matters. It is agreed on all sides that the important information must be obtained from the oncologists, and so the assessment is first of the evidence of Professor Calvert and that of Professor Lemoine. Professor Lemoine concentrated on anti-mitotics because that is what he was told to do. Vincristine, vinblastine, fluorouracil, adriamycin and mutamycin fall into two categories (at least): antimetabolites and anti-mitotics. So if the question which it is proper to put as of the priority date is to update the list in Wolff to reflect the most up-to-date knowledge, then paclitaxel will be on the list, but perhaps with others, although the cross-examination of Professor Lemoine did not suggest any other agents that might be suitable. Professor Calvert gave evidence that he would have strongly advised against the use of any anti-replicate drug at all to treat restenosis. He took the list from Wolff which I have set out above and observed that it is a list to which not much thought has been given. He says that several of the drugs would be unsuitable for use on a stent, among which he includes vincristine and vinblastine. I accept his evidence to the extent that he suggests that these compounds may be unsuitable for use on the stent, but I observe that vinblastine (along with doxorubicin, adriamycin, tamoxifen and fluorouracil) is expressly listed in the patent in suit itself as being an additional ingredient of the anti-angiogenic composition for use in the invention of claim 1 as amended (see page 7 line 31). Methotrexate is disclosed as an anti-angiogenic factor for use on stents in the patent in suit also, and one cannot avoid the impression that the disclosure of Wolff and that of the patent in suit in this respect are not very dissimilar. Be that as it may, however, there is the basic question that I have already outlined above: would the skilled person test, and if so, what would he test, and does it include taxol, or would he either reject all anti-replicates out of hand or, having thought of taxol, would he nonetheless reject it?
- The most cogent reason for rejecting even a test out of hand lies, it seems to me, in the inherent toxicities of the materials with which Wolff and the patent in suit are concerned. Professor Calvert's objection to the use of anti-proliferatives in general and taxol in particular may be summarised as follows. All these materials have systemic side-effects and local toxicity; and taxol has been shown to cause hypersensitive reactions, cardiac disturbances, and is intrinsically in any event toxic and lacking a long-term safety profile. This objection seems to me to be cogent, and I would accept it, were it not for the fact that anti-replicate drugs had already been tried both systemically and locally for restenosis at the priority date. I have already quoted the "Holy Grail" paper above in this respect. Professor Calvert put his position particularly clearly during cross-examination at page 706 line 6:
"I have spent most of my career trying new things in patients with cancer, so I am not reluctant to try something new, but I was trying to put myself in the position of this particular application. If you have something old which is safe, which you think would do the job just as well, then I would be against trying something new."
- Professor Calvert is talking there about methotrexate, but his cross-examination in respect of the other materials expressly listed in the Wolff paper (see pages 704-709 and again at 710-11) reveals that in the art there was a willingness both to use toxic materials systemically and also to use toxic materials such as doxorubicin locally by means of infusion catheters. Professor Karsch was using infusion-catheter administered taxol. Accordingly, systemic effects in consequence of the administration of toxic materials is not, submits Mr Thorley QC for the Claimant, a disincentive in the art: a consideration reinforced by the reflection that the amount of agent on an eluting stent will be tiny compared with the amount that needs to be administered in order to get a suitable concentration at this site. Indeed, Professor Calvert did agree that the likelihood of serious systemic side-effects from a small amount on a drug-eluting stent must be, as he put it, very low.
- Local effects may be a different matter. The proximity of a stent loaded with such a toxic material to even a small area of tissue could rationally be a disincentive to the use of such a material. Professor Rogers took the view that the inevitable toxicity would have to be assessed in trials. Professor Calvert also accepted that it would be necessary, if the problem were to be properly assessed, to determine whether there was a "window" between a therapeutic effect and a toxic effect which was dose-dependant. I think he accepted that the existence or otherwise of such a window could not be determined without trials.
- I turn now to the particular factors affecting taxol. For this purpose, the skilled person is to be taken to have thought of taxol, but will be employing the common general knowledge to see whether it should be rejected out of hand. The first concern is hypersensitivity. The literature up to 1993 is unclear as to whether hypersensitivity is to be attributed to the taxol or to the cremophor vehicle in which it is dissolved. Professor Calvert accepted that as at 1992, the date of a paper by Rowinsky, the state of knowledge was that it was not known whether taxol of itself could cause hypersensitivity reactions. That these reactions were likely to have been caused by the cremophor was certainly a widely held view. The purpose of cremophor, of course, is to dissolve taxol for administration by infusion. It would not be present in a drug-eluting stent. I accept that it is much more likely than not that a hypersensitivity reaction is not dose-dependant, but that it may be associated with a triggering threshold.
- Next, cardiac disturbances. This is obviously a matter of importance. However, cardiac disturbances had been seen in taxol's clinical trials, which were all concerned with systemic administration of the pharmaceuticals. There is simply no material upon which it can be said that taxol in the sort of quantities that would be associated with a stent would be a risk, even when in close proximity to the heart. Nonetheless, it seems to me as a matter of common sense that this is a matter that would weigh with the skilled person. Professor Rogers expressed the view that these results would flag up something which would have to be watched for in clinical and pre-clinical trials of a notional taxol-containing drug-eluting stent. Professor Rogers had in fact done pre-clinical work for Boston Scientific in respect of their taxol-containing stent, and had not been asked to watch out for cardiac effects. His view was that most cardiologists would have thought that cardiac events would have been unlikely to result from the local delivery of very small amounts of taxol over a number of weeks. Professor Calvert agreed that, at least on the basis of a paper in 1991 by Rowinsky, the cause of the cardiac disturbances was not clear.
- Long-term safety is the next matter which weighs against taxol in Professor Calvert's evidence. Under cross-examination, Professor Lemoine expressed the view that the nature of the toxicology exhibited by a particular agent depends upon dosage. He took the view that low-dose toxicity of taxol had never been investigated in the literature. This appears to be correct. It is undoubtedly something which must be considered both in pre-clinical testing and in clinical trials.
- Finally, there remain the systemic side-effects of the administration of taxol. In cross-examination Professor Calvert accepted that once microgram quantities of taxol on a drug-eluting stent are considered, the possibility of systemic side-effects is something that one would want to test for, but not something that would prevent one from embarking on a project. He expressed the view that the likelihood of serious systemic side-effects from a small amount on a drug-eluting stent must be very low.
- Both parties rely upon secondary indications: the Claimant upon technical indications of obviousness and the Patentees, as I have discussed above, on both technical and commercial indications of non-obviousness. I start with the Claimant's case. The Claimant criticises Professor Calvert not for his knowledge of taxol, but for what they submit is an excessive caution. They rely upon six matters in particular. In order they are, first, the experience of Professor Karsch. Professor Karsch was seeking to identify drugs which might be effective in stopping proliferation of smooth muscle cells in 1992. He went to his oncology colleagues: they suggested he use taxol. They warned him of the cardiac, hypersensitivity and other local and systemic effects potentially associated with the systemic use of paclitaxel identified by Professor Calvert. However, he says, in the course of their discussions, when it was explained that it was contemplated that extremely small doses of paclitaxel would be used, several orders of magnitude lower than the sort of doses that were being contemplated for use in the treatment of cancer in humans, the oncology and pharmacology colleagues agreed that the doses proposed were most likely to be well below the threshold levels at which those effects would be apparent, and encouraged him to proceed with his work on paclitaxel. This he did. The result was a paper dealing with certain of the qualities of locally administered paclitaxel using a porous balloon.
- In fact, it became quite apparent from his cross-examination that Professor Karsch was extremely sceptical about the value of stents, whether drug-eluting or not, in the treatment of long-term restenosis. In cross-examination he accepted that it was and always had been one of his concerns that "despite continuing advancement in anti-proliferative drug-eluting stents technology since the first studies heralding the effect of sirolimus [rapamycin] to reduce in-stent restenosis, there is still disquiet regarding the use of anti-mitotic agents in areas where healing is essential". I have not hitherto mentioned sirolimus. It is an antibiotic which is used apparently as successfully as taxol in drug-eluting stents. Evidently, it is not covered by the patent in suit.
- Professor Karsch was accordingly in a position to say that his group had first used paclitaxel as a potential treatment for restenosis in 1992. On this, he was not challenged. I should add that Mr Waugh QC's submission that a drug-eluting stent was not obvious to Professor Karsch in 1993 is completely unsupported by any evidence or cross-examination. It is plain that he did not like drug-eluting stents, but that is a different matter.
- The next matter to which I must refer is a particular paper which I have mentioned above, that by Sollott and others, including Professor Rowinsky. This reports the administration of taxol to prevent vascular small muscle cell proliferation and restenosis following balloon angioplasty in a rat model. The paper, though published comfortably after the priority date, went for publication in March 1994 (8 months after the priority date) and must be reporting work done round about the priority date, and before publication of the application. Professor Rowinsky did not evidently feel any conclusive reluctance to employ taxol and it is notable that this paper itself recommends sustained release delivery systems on stents as a likely way forward.
- Then there is the Kopia application. This is pleaded prior art, but for present purposes it is only necessary to note that the application proposes a drug delivery method for the purpose (among other things) of delivering taxol to the site of post-angioplasty restenosis. So the Claimant suggests that at least the authors of Kopia were not perturbed by the supposed risks inherent in the use of taxol. Finally, Angiotech's own internal documents do not record any concerns about taxol's toxicity before the priority date.
- Two other matters are relied upon by Mr Thorley QC as indications that taxol is not so worrying as Professor Calvert feared. These are the work done by Professor Rogers for Boston Scientific, in which he was not asked to monitor for cardiac effects or other side-effects of taxol, and also a patent application from well past the priority date, from a group of which Professor Calvert was a member, relating to the use of another anti-proliferative (lometrexol) for diseases of abnormal cell proliferation, including restenosis. This application lists taxol as one of the agents which can be combined with lometrexol. I think that at best these matters can be viewed as straws in the wind and I do not attach any particular weight to them.
Commercial Success
- Commercial success is relied on as the antidote to hindsight. There is no doubt that in the present case the invention has enjoyed substantial commercial success: the taxol-containing stent was licensed for use in 2005. It was of course licensed after an exhaustive set of pre-clinical and clinical trials, including toxicity studies, none of which had been performed before the priority date. I am satisfied on the evidence that the commercial success of the product is due to the technical qualities of the drug-eluting stent. The commercial success of the stent is substantial. It is called the Taxus stent, and studies thus far performed reveal a stent which is a considerable improvement upon the bare-metal stents which have preceded it. The other drug-eluting stent, to which I have already referred above, contains rapamycin (sirolimus) and is called the Cypher stent. It too has achieved a corresponding stent success. Professor Rogers and Professor Cumberland both use both stents. Professor Rogers prefers Cypher and it appears that Professor Cumberland may prefer Taxus. But it seems to be more-or-less common ground that these stents represent a real advance. They are not, as I understand the evidence (particularly the evidence of Professor Karsch), the answer to restenosis, but I have little doubt that they do represent such an advance.
- At the priority date, there were a number of groups working on the problem of restenosis, and the rapamycin-eluting stent forms the subject matter of a patent seeking priority from 9th January 1992, which concentrates upon vascular restenosis and exhibits experimental results demonstrating the potential utility of rapamycin in prevention of hyper-proliferation at the site of damage to the vascular wall. This patent was published five days before the priority date of the patent in suit, but it has no direct impact upon the question of obviousness of the patent in suit. It is, however, another demonstration of the widespread desire in the art for a technique for dealing with the problem of restenosis, and of the use of drug-eluting stents.
- It seems to me that it is plain that there was a current of thought in the art which considered that drug-eluting stents with anti-proliferatives was the way to go. Certainly, this was not the only line of attack and, by the time of the publication of Wolff, it appears that certain of the agents selected (particularly heparin and methotrexate) did not work. In this connection, it is interesting to note that the Patentees took the view, prior to the amendments which I allowed, that methotrexate was a suitable material, at least for the purposes of experimentation.
- I do not find in these factors, together with the ultimate commercial success of taxol, any answer to the contention that administration of anti-proliferatives by drug-eluting stent was known and that taxol, whose action as an anti-proliferative was well understood, was a natural candidate for a test at some stage before the priority date. This contention is, as I have indicated, supported by contemporaneous events, in particular by the Sollott paper and by Professor Karsch's activities with locally administered taxol.
- There are a number of matters relied upon by Mr Waugh QC as contemporary indications of non-obviousness. The first is Medtronic's own developments. Medtronic is the assignee of Wolff and can be safely assumed to do what is obvious in the light of that disclosure. They again pursued heparin-coated stents as their "central and primary" effort. They worked also on an anti-sense oligonucleotide, and failed with both. The evidence was that the polymer-coated stent failed because the polymer was unacceptably inflammatory. The heparin-coated stent contained no polymer, and was aimed at thrombin formation: a significant problem, as Dr Muller's evidence makes clear. So the Medtronic story is of limited assistance, save to demonstrate that drug-eluting stents were common general knowledge by 1993.
- Dr Muller also gives evidence relating to the Medtronic history. He gives evidence of a collaboration group centred on Medtronic, but involving other centres (the Mayo Clinic, the University of Michigan and the Thorax Centre in Rotterdam). He says this:
"The drugs that we considered included methotrexate, heparin, doxorubicin, colchicine, thiol protease inhibitor and angiopeptin. Essentially the idea was to use drugs that had failed systemically to prevent restenosis . . . "
Dr Muller had tried colchicine with a polymer, but that killed three minipigs. He tried dexamethasone (an anti-inflammatory) and hirulog (an anti-coagulant), but exterior of the artery in a polymer matrix. As he put it, his idea was "to work through a lot of different classes of drugs". He would not have homed in on anti-proliferatives. Aware of paclitaxel, he did not consider it because of his experience with colchicine.
- Finally, I must take into account the benign nature of restenosis. It is not worth putting patients at risk, but this is what tests prevent.
- Balancing the foregoing factors is not straightforward. In my judgment, the key to the solution of the problem lies in the correct identification of the appropriate approach to the test for obviousness. For the reasons that I have endeavoured to explain, I consider that the appropriate test is whether it was obvious to test taxol at all. The specification giving no indication of any likelihood of success, and giving no indication as to toxicity, side-effects or indeed efficacy, it is wrong in principle to permit such considerations to weigh against the obviousness of testing taxol. So I conclude that the claims were obvious.
Kopia
- Kopia is a publication made just a month before the priority date of the patent in suit. It is, like the patent, a long document and its subject matter is a general technique for the delivery of therapeutic agents to their required sites of action within the body. The concept of Kopia may be summarised as the provision of a site-specific molecular fragment to which is attached the drug required to be administered. The idea is explained on page 2 at line 8:
"Drugs that prevent or reduce the proliferation of pathological cell types are essential to the treatment and control of various diseases involving undesirable or uncontrolled cell proliferation. But anti-proliferatives, by definition, must be toxic to certain cell types. It is often not feasible to administer these drugs systemically, because the amounts needed to control the diseased cell types may be toxic or deadly to the patient's normal cells. This difficulty could be circumvented by administering anti-proliferative agents directly to the site of the undesired cell proliferation. A mechanism is also needed for retaining anti-proliferative agents at the disease site, so that they may effectively control the proliferation of undesired cells, while being restrained from migrating and damaging normal cell types."
At page 2 line 35, the first application for the technique is identified as post-angioplasty restenosis, and the anti-proliferative agents which are proposed for use with the technique of the invention are heparin (page 3 line 31), colchicine (page 4 line 21) and certain other agents (page 5 line 7). Further on in the document a section entitled "Treatment of Specific Diseases or Pathological Conditions by Direct Delivery of Therapeutically Active Substances" again starts with post-angioplasty reocclusion and restenosis. The disclosure here is rather different in that the compounds of the invention useful for treatment of post-angioplasty restenosis comprise anti-proliferative agents such as heparin, hirudin, colchicine, vinca alkaloids, taxol and derivatives thereof. The construction of a molecule involving colchicine attached to two lipophilic tails acid-cleavable from the active molecule is then described.
- Conor identify the difference between the disclosure of Kopia and that of the patent in suit as lying essentially in the mode of local delivery of taxol for the treatment of post-angioplasty restenosis. Kopia uses chemical means and the patent in suit uses physical means. There is no doubt, in my judgment, that one of the teachings of Kopia is to use taxol to treat restenosis when delivered locally. This was accepted by Professor Cumberland in cross-examination.
- Kopia gives no detailed information which enables the reader to satisfy himself that taxol will either work or satisfy any safety requirements, but in this it is not to be distinguished from the patent in suit. For this reason it incidentally supports my view that taxol was an obvious candidate for testing in the context of the Wolff disclosure, but that is by the way. It clearly teaches local administration of taxol and so the only question is whether drug-eluting stents were common general knowledge for the purpose of delivering anti-proliferatives to an angioplasty site to prevent future restenosis.
- If, as I have concluded, it is obvious to test taxol using Wolff's drug-eluting stent, then I think it is obvious to see if taxol works by any mode of delivery which comprises part of the common general knowledge. After all, Kopia is primarily concerned with the mode of delivery. Since Kopia contains a direct teaching to deliver taxol to the angioplasty site, the arguments reviewed above in relation to the obviousness of testing taxol in the context of the Wolff disclosure lose much of their force. I think that Kopia renders the invention obvious. In coming to this conclusion, I do not ignore the fact that Kopia describes taxol as one among many anti-proliferatives capable of being delivered by its novel method of delivery to an angioplasty site. What matters is the classification of taxol as one of that class of drugs. It is obvious to test those drugs to see if any of them have a prospect of working.
Katsuda
- Katsuda discloses in vitro work demonstrating the effect of taxol and dimethyl sulphoxide (DMSO) in the inhibition of proliferation of smooth muscle cells in the intima of an artery. The message of the publication is that taxol prevents mitogenic (i.e. cell-division) stimulation by growth factors. The context is atherosclerosis.
- Katsuda is accordingly another teaching that taxol may be a promising material in dealing with smooth muscle cell proliferation. I do not consider that the question of obviousness in the light of Katsuda is substantially different from the question of obviousness in the light of Kopia, given that both teach the use of taxol for this purpose. The teaching of Kopia is, perhaps, somewhat more developed in the sense that taxol is identified as a drug suitable for local administration at a site for the purpose of preventing future restenosis, and to that extent perhaps Katsuda is less compelling. But the other arguments against obviousness must, I think, be approached in the same way as they must be approached in the context of Kopia. I feel slightly more doubt about Katsuda, but I think it does render the claims obvious.
Conclusion
- The patent is invalid for obviousness in the light of the citations pleaded and must be revoked.
