“[4] 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. [5] 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. [6] 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. [7] 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. [8] 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.”
“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.”
“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, for treating narrowing of a body passageway, for treating or preventing recurrent stenosis.” comprising a generally tubular structure coated with for treating or preventing recurrent stenosis.”
“Technical field The present invention relates generally 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”
“[13] “’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 11 to 3 39, in terms of cancerous tumours. A passage of some importance is at page 313-21, 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 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. [14] As amended, the passage at page 332-39 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 . . .’ [15] Stenting is described at page 3 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 412-19, 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. [16] 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 3, a passage in which taxol is not distinguished from other materials of this description. Taxol is again discussed at page 6 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 . . .” [17] 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 52 the specification states that “a wide variety of other anti-angiogenic factors may also be utilized within the context of the present disclosure”
‘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.’ [19] 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 33 to page 10 25, where the disclosure then turns to the use of anti-angiogenic compositions as coatings for stents. [20] 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).’ [21] 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 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.’ [22] There is some general teaching of the mode of operation of the anti-angiogenic compositions at page 14 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. ….. This passage seems to me to relate to the corneal endothelium alone. [23] After a brief diversion into hypertrophic scars and keloids, the specification returns to the eye at page 15 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. [24] 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.” ‘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.’ ‘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 . . .’ ‘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.’ ‘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 . . .” ‘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.’ ‘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).’ ‘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.’
“[26] 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.”
“you do not put something in your mental toolkit unless you have a good sense that it works.”
“[53] 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.”
“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.”
“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.” [58] 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 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.”
“… anti angiogenic factors should be understood to include any protein, peptide, chemical or other molecule which acts to inhibit vascular growth.”
“A wide variety of anti-angiogenic factors may also be used with the context of the present inventiondisclosure. Representative example include [there then follows a long list of compounds or in some cases classes of compound]”
“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.”
“Analysis of various agents for anti-angiogenic activity.”
“if the skilled man would reject taxol a priori even from a test, then the position (i.e. obviousness) would be otherwise”
“It is enough that the person versed in the art would assess the likelihood of success as sufficient to warrant actual trial”
“Slight reflection suggests, we think, that there is usually an element of ‘obviousness to try’ in any research endeavour that is not undertaken with complete blindness but rather with some semblance of a chance of success, and that patentability determinations based on that as the test would not only be contrary to statute but result in a marked deterioration of the whole patent system as an incentive to invest in those efforts and attempts which go by the name of ‘research’.”
“I have endeavoured to refrain from coining a definition of ‘obviousness’ which counsel may be tempted to cite in subsequent cases relating to different types of claims.”
“Patent law can too easily be bedevilled by linguistics and the citation of a plethora of cases about inventions of different kinds. The correctness of a decision upon an issue of obviousness does not depend upon whether or not the decider has paraphrased the words of the Act in some particular verbal formula. I doubt whether there is any verbal formula which is appropriate to all classes of claims.”
“An invention shall be considered as involving an inventive step, if, having regard to the state of the art, it is not obvious to a person skilled in the art” (Art 56 EPC). In the end the question is simply “was the invention obvious?”
“[64] 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. [65] 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.”
“The results reported so far suggests that there seems to be no role for cytostatic agents in the prevention of restenosis in human coronary vessels”
“[54] ….Notwithstanding this [i.e. the passage I have just quoted], research into anti-proliferatives generally was one class of work that was still being pursued at the priority date. ”
“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.”