“immediate release” and “controlled release”
“The prevailing attitude in the opioid field at the Priority Date can be summarised as follows. The gold standard compound for the alleviation of severe pain was morphine. Morphine suffered from the prevalent view that its use would inevitably lead to addiction. Mu agonists, by their association with morphine, were considered likely to carry the same dependence liability. Consequently, the use of mu agonist opioids was restricted predominantly to the palliation of acute pain and cancer pain. Exhaustive efforts had been expended over the course of many decades in the search for analgesics that constituted an improvement over morphine. Agonists at the kappa and delta receptors were attracting a great deal of interest as they offered a potential route into analgesics that might not have resulted in dependency. Finally, substance P antagonists were a very promising area of development due to the striking results obtained in pre-clinical and animal testing.”
"Pharmaceutics: the science of dosage form design"
“an acrylic resin matrix selected so that the formulation provides pH-independent dissolution characteristics.”
“It has now been surprisingly discovered that the presently claimed controlled release oxycodone formulations acceptably control pain over a substantially narrower, approximately four-fold (10 to 40 mg every 12 hours – around the- clock dosing) in approximately 90% of patients. This is in sharp contrast to the approximately eight-fold range required for approximately 90% of patients for opioid analgesics in general.”
“Despite the fact that both controlled-release oxycodone and controlled release morphine administered every 12 hours around-the-clock possess qualitatively comparable clinical pharmacokinetic characteristics, the oxycodone formulations of the presently claimed invention can be used over approximately 1/2 the dosage range as compared to commercially available controlled release morphine formulations (such as MS Contin®) to control 90% of patients with significant pain.”
“The present matrix may be any matrix that affords in vitro, dissolution rates of oxycodone within the narrow ranges required, except an acrylic resin matrix being selected so that the formulation provides pH-independent dissolution characteristics. Preferably the matrix is a controlled release matrix, although normal release matrices having a coating that controls the release of the drug may be used. Suitable materials for inclusion in a controlled release matrix are (a) Hydrophilic polymers, such as gums, cellulose ethers, acrylic resins and protein derived materials….”
“[0041] As an alternative to a controlled release matrix, the present matrix may be a normal release matrix having a coat that controls the release of the drug. In particularly preferred embodiments of this aspect of the invention, the present dosage form comprises film coated spheroids containing active ingredient and a non-water soluble spheronising agent. The term spheroid is known in the pharmaceutical art and means a spherical granule having a diameter of between 0.5 mm and 2.5 mm especially between 0.5 mm and 2 mm.”
“The present solid, controlled release, oral dosage form may also be prepared, in the form of film coated spheroids, by (a) blending a mixture comprising oxycodone or a oxycodone salt and a non-water soluble spheronising agent, (b) extruding the blended mixture to give an extrudate, (c) spheronising the extrudate until spheroids are formed, and (d) coating the spheroids with a film coat.”
“34. “Purposive construction” does not mean that one is extending or going beyond the definition of the technical matter for which the patentee seeks protection in the claims. The question is always what the person skilled in the art would have understood the patentee to be using the language of the claim to mean. And for this purpose, the language he has chosen is usually of critical importance. The conventions of word meaning and syntax enable us to express our meanings with great accuracy and subtlety and the skilled man will ordinarily assume that the patentee has chosen his language accordingly. As a number of judges have pointed out, the specification is a unilateral document in words of the patentee’s own choosing. Furthermore, the words will usually have been chosen upon skilled advice. The specification is not a document inter rusticos for which broad allowances must be made. On the other hand, it must be recognised that the patentee is trying to describe something which, at any rate in his opinion, is new; which has not existed before and of which there may be no generally accepted definition. There will be occasions upon which it will be obvious to the skilled man that the patentee must in some respect have departed from conventional use of language or included in his description of the invention some element which he did not mean to be essential. But one would not expect that to happen very often.”
“The film coat is chosen so as to achieve, in combination with the other ingredients, the in-vitro release rate outlined above...”
“In the present specification, "substantially independent of pH" means that the difference, at any given time, between the amount of oxycodone released at, e.g., pH 1.6, and the amount released at any other pH, e.g., pH 7.2 (when measured in vitro using the USP Paddle Method at 100 rpm in 900 ml aqueous buffer), is 10% (by weight) or less. The amounts released being, in all cases, a mean of at least three experiments.”
“added technical teaching” and “intermediate generalisation”
“The present matrix may be any matrix that affords in vitro, dissolution rates of oxycodone within the narrow ranges required, except an acrylic resin matrix being selected so that the formulation provides pH-independent dissolution characteristics. …. Suitable materials for inclusion in a controlled release matrix are (a) Hydrophilic polymers, such as gums, cellulose ethers, acrylic resins and protein derived materials….”
“The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.”
“It has never been easy to differentiate between common general knowledge and that which is known by some. It has become particularly difficult with the modern ability to circulate and retrieve information. Employees of some companies, with the use of libraries and patent departments, will become aware of information soon after it is published in a whole variety of documents; whereas others, without such advantages, may never do so until that information is accepted generally and put into practice. The notional skilled addressee is the ordinary man who may not have the advantages that some employees of large companies may have. The information in a patent specification is addressed to such a man and must contain sufficient details for him to understand and apply the invention. It will only lack an inventive step if it is obvious to such a man. It follows that evidence that a fact is known or even well-known to a witness does not establish that that fact forms part of the common general knowledge. Neither does it follow that it will form part of the common general knowledge if it is recorded in a document. As stated by the Court of Appeal in General Tire & Rubber Co. v. Firestone Tyre & Rubber Co. Ltd. [1972] R.P.C. 457, at page 482, line 33: "The two classes of documents which call for consideration in relation to common general knowledge in the instant case were individual patent specifications and widely read publications'. As to the former, it is clear that individual patent specifications and their contents do not normally form part of the relevant common general knowledge, though there may be specifications which are so well known amongst those versed in the art that upon evidence of that state of affairs they form part of such knowledge, and also there may occasionally be particular industries (such as that of colour photography) in which the evidence may show that all specifications form part of the relevant knowledge. As regards scientific papers generally, it was said by Luxmoore, J. in British Acoustic Films (53 R.P.C. 221 at 250): "In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art." And a little later, distinguishing between what has been written and what has been used, he said: "It is certainly difficult to appreciate how the use of something which has in fact never been used in a particular art can ever be held to be common general knowledge in the art." Those passages have often been quoted, and there has not been cited to us any case in which they have been criticised. We accept them as correctly stating in general the law on this point, though reserving for further consideration whether the words 'accepted without question' may not be putting the position rather high: for the purposes of this case we are disposed, without wishing to put forward any full definition, to substitute the words 'generally regarded as a good basis for further action'.” "The two classes of documents which call for consideration in relation to common general knowledge in the instant case were individual patent specifications and widely read publications'. As to the former, it is clear that individual patent specifications and their contents do not normally form part of the relevant common general knowledge, though there may be specifications which are so well known amongst those versed in the art that upon evidence of that state of affairs they form part of such knowledge, and also there may occasionally be particular industries (such as that of colour photography) in which the evidence may show that all specifications form part of the relevant knowledge. As regards scientific papers generally, it was said by Luxmoore, J. in British Acoustic Films (53 R.P.C. 221 at 250): "In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art." And a little later, distinguishing between what has been written and what has been used, he said: "It is certainly difficult to appreciate how the use of something which has in fact never been used in a particular art can ever be held to be common general knowledge in the art." Those passages have often been quoted, and there has not been cited to us any case in which they have been criticised. We accept them as correctly stating in general the law on this point, though reserving for further consideration whether the words 'accepted without question' may not be putting the position rather high: for the purposes of this case we are disposed, without wishing to put forward any full definition, to substitute the words 'generally regarded as a good basis for further action'.”
“ I can readily accept that, faced with a disclosure which forms part of the state of the art, it may be obvious for the skilled person to seek to acquire further information before he embarks on the problem to which the patent provides a solution. But that does not make all such information part of the common general knowledge. The distinction is a fine one but it may be important. If information is part of the common general knowledge then it forms part of the stock of knowledge which will inform and guide the skilled person’s approach to the problem from the outset. It may, for example, affect the steps it will be obvious for him to take, including the nature and extent of any literature search.”
“a controlled-release formulation of an alternative strong opioid was an obvious thing to make to substitute where necessary, for example, with morphine intolerant patients, for controlled-release morphine which was the drug of choice for palliative care…. We say it was simply a straightforward choice to say, well, if I cannot treat a patient with controlled-release morphine, it would be very convenient and helpful to be able to treat that patient with a controlled-release alternative opioid as to which oxycodone is an obvious example and therefore is an obvious example to make into a controlled-release formulation.”
“If a patient is predisposed to side effects, the simpler titration approach afforded by morphine and hydromorphone, which have a short half-life, warrants selection of one of these drugs (and because it has recently become available in tablet and elixir form, potentially oxycodone as well). For other patients, the drug can be morphine, hydromorphone, oxycodone, or either levorphanol or methadone”
“It has been observed that when desiring to control the release of some highly water soluble pharmacologically active ingredients, for example oxycodone, from conventional controlled release tablet matrices, a delay or gradual release of such material can be difficult to achieve. However, when such highly water soluble pharmacologically active material such as oxycodone is incorporated into the matrix system of the present invention, a controlled release of the material is clearly observable.”
“Professor, assume that a formulator had made up example 2B using oxycodone hydrochloride. If he found that the dissolution characteristics were not what he wanted, he could easily adjust the formulation to vary those characteristics. That is what Oshlack teaches, is it not? A. The formulation would have to be changed to change the dissolution characteristics, that is correct. Q. And the teaching of Oshlack is that you can readily do that with those components that it puts in. Do you want me to show you the passages? A. I do, yes. Q. It is the first five paragraphs under "Summary of the Invention" on page 3 and the last paragraph before the heading "Description of Preferred Embodiments" on page 4. Just cast your eye over those. (Pause) A. Yes, it does appear to suggest what you are saying, yes.”
“Having read the 104 Application, the Clinician would approach a formulator to produce a controlled release formulation of oxycodone. The Clinician would ask the formulator to prepare a formulation suitable for dosing at the same frequency as MST Continus i.e. once every 12 hours. He would also ask the formulator to prepare a dose independent formulation, i.e formulations that give the same release profile when different dosages of oxycodone were used e.g. 10, 20 & 30 mg dosages. ”