“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.”
“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.”
“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.”
“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”
“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.”
“(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.”
“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.”
“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.”
“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.”
“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 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.”
“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 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.’ ”
“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.”
“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 . . . ”
“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.”