Mr Justice Floyd :
- These two actions started life as actions by ratiopharm GmbH ("ratiopharm" – for some reason it does not dignify itself with a capital letter) and Sandoz Limited ("Sandoz") to revoke two patents, European Patent (UK) Nos. 722730 and 1258246 in the name of Napp Pharmaceutical Holdings Limited ("Napp"), and for declarations of non-infringement in respect of pharmaceutical products which ratiopharm and Sandoz wished to market in the United Kingdom. Napp responded in both cases with a counterclaim for infringement, asserting that the patents were both valid and infringed. The declaratory proceedings thus became unnecessary and fell away. The case is now a conventional patent action brought by Napp against each of ratiopharm and Sandoz, and was so treated at the trial. Napp opened the case and called its evidence first.
- This judgment is divided into the following main sections:
- The two patents in suit, which I will refer to by their last three digits, 730 and 246, are concerned with a known opioid pain killer (analgesic) oxycodone. They have a priority date in 1991. The patents are not concerned with the discovery of the drug – that occurred in 1916, and it has been in clinical use in from 1917. Instead the patents are concerned with a formulation of the drug which achieves slow release. The case is perhaps unusual, in that there was nothing to prevent the manufacture of a slow release version of the drug for many years before 1991.
- ratiopharm and Sandoz deny infringement on a number of grounds, most of which depend on the proper construction of the claims.
- Validity of both patents is attacked on the basis of added matter. Certain of the added matter attacks are met by an application to amend. The application to amend is not opposed. The application is conditional in the case of 730, but unconditional in respect of 246. The amendments to 246 do not affect the scope of the claims.
- Validity of both patents is also attacked on the ground of obviousness. The principal attack is over common general knowledge alone. There are also attacks based on two specific citations, referred to as Oshlack and Goldie.
- Both sides have taken too many points, probably revealing that neither considered they had the "killer" blow described by Jacob LJ in Corus UK Ltd v Qualchem  EWCA Civ 1177 at . The case is indeed a finely balanced one. The result is that the reader is subjected to a long judgment, for which I apologise.
- This case is concerned with formulations of oxycodone for oral administration. There are two main types of oral drug delivery system for present purposes: "immediate release" and "controlled release". In immediate release systems the drug is intended to be released rapidly and completely when it reaches the stomach. In controlled release systems, the rate of the drug release is controlled. These systems may be either delayed release systems, in which the release of the drug is held up altogether for a period, or extended (or sustained) release systems in which the drug is released more slowly from the dosage form than in immediate release in order to provide a longer period of therapeutic effectiveness. The case is concerned with the latter type of release.
- Drugs have a so-called "pharmacokinetic profile". This is the graph of the concentration of the drug in plasma or serum as a function of time after administration. The concentration first reaches a peak, which must be below the maximum safe concentration, and then tails off. After a time, the concentration falls below the minimum therapeutic concentration and the drug ceases to exert its effect. A typical pharmacokinetic profile for an immediate release system looks like this:
- The difference in plasma levels between the maximum safe concentration and the minimum effective concentration is called the therapeutic range. Pharmacokinetics, the science of the kinetics of how drugs reach the bloodstream, is to be distinguished from pharmacodynamics. Pharmacodynamics is concerned with the patient's response to the drug.
- The object of a sustained release system is to create a flattened pharmacokinetic profile, so that the plasma concentration remains within the therapeutic range for longer in consequence of a single dose. This has the obvious advantage in terms of convenience, in that the patient does not have to take repeated doses to keep the plasma level within the therapeutic range. It also means that there is less fluctuation in the plasma concentration.
- At the priority date of the patent there were a number of well known formulation methods for achieving sustained release versions of a drug.
- One method of creating a controlled release version of a drug would be to use a controlled release matrix. The active drug is embedded into a pharmaceutical excipient which provides a matrix into which water can diffuse. The behaviour is determined by the characteristics of the excipient and of the drug.
- An alternative method is to use a so called reservoir system. Here the drug is surrounded by a barrier which controls the release of the drug. This can be achieved by coating so called non-pareil sugar beads with the drug, and adding the barrier on top, and in a variety of other ways.
- Opioid analgesics are substances that have an affinity for opioid receptors. The term opioids includes (i) opiates - the naturally occurring alkaloids which are found in the opium poppy (which include morphine and codeine); (ii) semi-synthetic opioids – substances chemically derived from the natural opiates, including heroin, dihydromorphone, dihydrocodeine, oxycodone and others; (iii) fully synthetic opioids from several chemical classes, including pethidine, fentanyl, methadone, and others and (iv) the opioid peptides.
- Opioids can be classified pharmacologically according to their efficacy, that is to say their ability to activate the opioid receptors. Full agonists have high efficacy and therefore fully activate the receptor, leading to the highest biological effect. Partial agonists have reduced efficacy, and may have an antagonistic effect on the efficacy of a full agonist which is present.
- Opioids were also classified as either "weak" or "strong" according to the severity of pain they were used to alleviate. Weak opioids were used to alleviate mild to moderate pain, whereas strong opioids were used for moderate to severe pain.
- By 1991 the WHO had classified drugs according to a sequential ladder containing three stages. A patient should not be progressed to the next step on the ladder until it proves impossible to relieve pain with appropriate doses of drugs on the previous step. Patients suffering low levels of pain (step 1) should use non-opioid analgesics (paracetamol or aspirin). Those suffering from mild to moderate pain (step 2) should take a weak opioid. Those suffering moderate to severe pain (step 3) should take a strong opioid.
- The drug of choice for severe pain, the highest step on the ladder, was morphine. The potency of other drugs for the relief of severe pain is given in terms of their potency relative to morphine.
- At the priority date there were considered to be three principal types of opioid receptor, identified by the Greek letters, mu kappa and delta: The mu receptor is activated by morphine, which is therefore considered a mu agonist. The majority of clinically available opioid analgesics were mu agonists.
- Mu agonists as a class suffer from a number of potential side effects. These include nausea, vomiting, itching, somnolence, constipation and respiratory depression.
- Mu agonists also suffered from a perception that they give rise to addiction and dependence. This is in fact a false perception at least in so far as it relates to acute pain, as the controlled therapeutic use of these agents is in fact perfectly safe. Because of their extensive use in terminal illness, morphine and similar agents also have an association with dying. These and other matters had led researchers into looking for drugs with equivalent analgesic effect, but with fewer side effects, or some distinct advantage over morphine. At the priority date there was widespread scepticism amongst opioid pharmacologists that the goal of separating analgesic potency from dependence liability was in fact achievable. Nevertheless research into the kappa and delta agonists continued, as did research into non-opioid analgesics including those active at substance P receptors. Dr McKnight summarised the position in 1991 in a paragraph of his first report on which he was not challenged:
"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."
- For a small percentage of patients the side effects of morphine prove intolerable. At the priority date there was a need for alternative analgesia for these patients. One approach in those circumstances would be to prescribe a drug as chemically different as possible to morphine. This was an approach advocated by a leading expert in the field at the time, Dr Twycross, in the textbook Twycross & Lack: Symptom Control in Far Advanced Cancer: Pain Relief, published in 1983. The WHO Guidelines on Cancer Pain Relief published in 1986 also recommend the use of a "chemically distinct" alternative, and list methadone, pethidine and buprenorphine as alternatives "in the hope that this will not again cause the unwanted effect".
- Nevertheless it was well known that the side effect profile of the drug could vary from patient to patient. Thus an individual suffering intolerable side effects with one mu agonist would not necessarily do so with another, even if chemically similar. Whether a lower incidence of side effects would be obtained was of course entirely unpredictable.
- It is common ground that oxycodone was a known opioid mu agonist at the priority date. The extent to which it would have been recognised as a suitable alternative to morphine for oral administration for the treatment of moderate to severe pain is the subject of serious contention. I consider this in more depth later in this judgment.
- Napp called Dr McKnight and Professors Power and Aulton. ratiopharm/Sandoz called Professors McQuay, Bennett and Davis.
- Professor Ian Power is Head of Anaesthesia, Critical Care and Pain Medicine at the University of Edinburgh. Prior to that, he was senior lecturer and consultant anaesthetist at Cardiff, University of Wales College of Medicine and then an associate professor and specialist at the Royal North Shore Hospital in Sydney, Australia. In addition to his academic duties, he is also a practising consultant anaesthetist and pain specialist.
- Mr Silverleaf QC, who appeared for ratiopharm and Sandoz, suggested that Professor Power was an enthusiastic fan and advocate of Oxycontin, and I should be wary of accepting his views as objective ones. I did not understand this as a suggestion that Professor Power was doing anything other than expressing his genuinely held views. I will of course have to weigh his evidence against the other oral and documentary evidence in the case, to the extent that it is relevant.
- Dr Alexander McKnight is a pharmacologist. From 1984 to 1990 he was engaged in drug discovery research for Merck Sharpe & Dohme, establishing models for receptor targets, including the receptors for "substance P" as a possible target for a non-opioid analgesic. In 1990 he became Head of Pharmacology at the Parke-Davis Neuroscience Research Centre in Cambridge, again in the field of drug discovery, including research in the field of analgesia.
- Professor Michael Aulton was, until he retired in April 2006, Professor of Pharmaceutical Technology at the Leicester School of Pharmacy and de Montford University. He held that post for 13 years. Prior to that he was a member of staff at the School of Pharmacy from 1971. His research concentrated mainly on pharmaceutical preparations in solid dosage forms. He is the author of one of the leading publications in the field of pharmaceutics: "Pharmaceutics: the science of dosage form design". He is a highly respected figure in his field. At times I felt he became a little flustered in the course of his cross examination, but on the whole I still found his evidence helpful.
- Professor Henry McQuay is the Nuffield Professor of Clinical Anaesthetics at the University of Oxford. He has been an Honorary Consultant at the Pain Relief Unit in Oxford and he is an Honorary Civilian Consultant to the Army -- Pain.
- Professor Michael Bennett is the Professor of Palliative Medicine at Lancaster University. He has only held that post since October 2007 and is the first holder of the post which is a joint appointment between Lancaster University and St John's Hospice, Lancaster. For the 11 years prior to taking up that appointment Professor Bennett was a consultant and senior clinical lecturer in palliative medicine at St Gemma's Hospice in Leeds.
- Professor Stanley Davis is Emeritus Professor of Pharmacy at the University of Nottingham. He has held senior posts in pharmacy and pharmaceutics at the University of Aston in Birmingham, taking up a professorship at Nottingham in 1975. At Nottingham he ran a large research group specialising in the study of novel drug delivery systems including controlled-release formulations for human use. Mr Silverleaf said that Professor Davis held Professor Aulton in such high regard that he did not do himself justice in the witness box. I did not detect that his evidence was affected by professional courtesy in this way. The issues on which he was disinclined to differ with Professor Aulton were over the use of terminology. What this showed was that the terms in question did not have a rigid accepted meaning in the field.
- Somewhat refreshingly, apart from the point made about Professor Power that I have already dealt with, neither side had any criticism of the way in which the experts gave their evidence. Napp has a complaint about the way in which the experts were instructed by ratiopharm/Sandoz on the issues of common general knowledge and obviousness, but that is another matter. Mr Silverleaf, in his skeleton and in opening the case, trailed a potential inconsistency between Professor Aulton's evidence and the way he had expressed himself in his textbook. I was not impressed by this point at that time, or when it came to be put to Professor Aulton in cross examination.
- With certain exceptions to which I will have to return in the context of the objection of added matter, the disclosure of 730 and 246 is substantially the same. That is because 246 was divided out of 730. For the purposes of introducing the case it is sufficient to review the contents of 730.
- The 730 patent explains at  that the variability of daily dosage required to control pain with an opioid analgesic in 90% of patients is approximately eight-fold. The consequence is that the time taken to titrate the patient to the appropriate dose is unacceptably long. Titration is the process of arriving at the correct minimum dose to relieve pain in the patient. At  the patent claims that
"[a]n opioid analgesic which acceptably controls pain over a substantially narrower daily dosage range would, therefore, substantially improve the efficiency and quality of pain management"
- Having set out a list of objects of the invention, a list which includes "substantially reducing the time and resources needed to titrate patients … on opioid analgesics", the 730 patent includes at  a consistory clause substantially in the form of claim 1. That claim is to a controlled release matrix of oxycodone defined by a mean plasma concentration profile. The claim specifically excludes:
"an acrylic resin matrix selected so that the formulation provides pH-independent dissolution characteristics."
- The "Detailed Description" starts with a claim at  that:
"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."
- At  there is a reference to morphine and its 12-hourly controlled release version MST Continus. The specification points out:
"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."
- ratiopharm/Sandoz' case was that the advantages of smaller dosage range and ease of titration were not made out in practice. I will return to this topic, and its relevance, under "Oxycodone after the priority date" below.
- The specification claims that an advantage of the present composition
"which releases oxycodone at a rate that is substantially independent of pH, is that the dose is evenly released throughout the intestinal tract"
The skilled person would understand that the varying acidity/alkalinity of different parts of the intestinal tract would affect release rate unless the composition provided pH independent release: see .
- At  the 730 patent deals with the matrix:
"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…."
- There are two things to note here. Firstly, the specification is introducing, instead of a controlled release matrix, a film-coated, normal release matrix. These formulations are the subject of claim 6 and claims dependent thereon, and are discussed in more detail later in the specification. Secondly it should be noted that, consistently with the disclaimer from claim 1, the specification excludes pH independent acrylic resin matrix formulations, whilst still teaching that acrylic resins are suitable for controlled release matrices. This passage is important in relation to the objection of added matter.
- At  and following the 730 patent gives more detail about the film coated embodiment:
" 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."
- This last sentence is of importance, because ratiopharm/Sandoz rely on it to argue that the term "spheroids" in the claim is limited to granules, which alternative term they say has a particular, narrow meaning. The patent continues
" The spheronising agent may be any pharmaceutically acceptable material that, together with the active ingredient, can be spheronised to form spheroids. Microcrystalline cellulose is preferred.
 In addition to the active ingredient and spheronising agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxy propyl cellulose, are preferred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
 The spheroids are preferably film[-]coated with a material that permits release of the oxycodone (or salt) at a controlled rate in an aqueous medium. The film coat is chosen so as to achieve, in combination with the other ingredients, the in-vitro release rate outlined above (between 12.5% and 42.5% (by wt) release after 1 hour, etc.)."
- ratiopharm/Sandoz point out that these paragraphs distinguish between spheronising agents and binders. The requirement for a spheronising agent is another disputed issue on infringement. The last sentence of  indicates that other ingredients, in addition to the film coat, may be responsible for the release rate.
- The manufacture of film coated spheroids is taken up again at :
"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."
- The skilled person would recognise this as the process of extrusion/spheronisation. This is relevant to the argument about whether the claims extend to products made by processes other than extrusion/spheronisation, and in particular whether they can extend to processes where a non-pareil bead is taken as the starting point.
- The Examples in the patents are all of controlled release matrix formulations: there is no example of a coated spheroid.
The claims in issue
- A large number of claims are put in issue. I have attached as Annex 1 to this judgment the relevant claims of 730 and 246. Despite taking this convenient course, it is important that the relevant phrases in the claims are not construed in isolation, as in some cases there is interaction with other features which must be taken into account.
- The principles applicable to the correct construction of a patent claim are well settled, and were not really in dispute. The task for the court is to determine what the person skilled in the art would have understood the patentee to have been using the language of the claim to mean: see per Lord Hoffmann in Kirin Amgen v TKT  RPC 9 -.
- I was reminded by Mr Silverleaf of the wider context in which Lord Hoffmann had explained the correct approach to construction in Kirin Amgen, particularly at :
"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."
- I will, of course, have considerations such as this well in mind, where they arise.
"(a) oxycodone salt in an amount equivalent to 10 to 160 mg of the oxycodone hydrochloride salt (b) a matrix incorporating said oxycodone salt (c) a coating on said matrix controlling the release of said oxycodone salt" (Claim 1 of 246)
- This phrase raises the first of three points which are all concerned with the location of the film coating. I take this one first because Mr Silverleaf focussed his argument on it – perhaps understandably, as it is the one where his argument is strongest. All three points arise because the alleged infringement has an external layer containing some 20% of the drug which releases immediately. It is common ground that the release of the remaining 80% is controlled by the film coating.
- The phrase also raises the question of what is meant by "matrix" here. I will deal with that point separately later.
- Both parties made submissions about the precise syntax and grammar of the claims, as well as relying on more general considerations. ratiopharm/Sandoz submit:
i) that the oxycodone salt being referred to must mean all the oxycodone salt in the formulation. Thus all the oxycodone salt in the formulation must be within the film coating. If there is a layer of oxycodone outside the film coating, then there is no infringement;
ii) that "said oxycodone salt" in feature (c) refers back to the "matrix incorporating said oxycodone salt" in feature (b) and to the amount of the oxycodone salt in feature (a). The amount of oxycodone salt is the amount comprised in the formulation. By this process of reasoning the coating is required to control the release of all the oxycodone in the formulation. It cannot do this if some of the oxycodone is on the outside;
iii) that to construe the claim as wide enough to include the case where there is an immediate release layer on the outside would be allow it to include embodiments which would or might have a material effect on the way the invention works. They rely, by way of example, on the statement in both patents at  that the oxycodone releases "evenly throughout the gastrointestinal tract". Accordingly there is a sound purpose in limiting the claim to its grammatical meaning.
- Napp submits:
i) that the claim requirement is satisfied if the coating controls the release of such oxycodone as is beneath the coating. In other words you cannot avoid infringement by placing some of the oxycodone outside the coating;
ii) that reading features (a), (b) and (c) in claim 1 of 246 together, one is concerned only with the oxycodone within the matrix covered by the coating, not all the oxycodone in the dosage form. Provided the quantity of oxycodone within the matrix is within the range specified in feature (a), there is infringement, even if there is more oxycodone on the outside;
iii) that the use of an immediate release layer external to the controlled release formulation was a common general knowledge approach to improving the initial rate of release of the drug – a sort of booster shot before the controlled release kicks in. It is common ground that it remains accurate to describe such a combined formulation as a "controlled release formulation". Napp submits that it would be technically surprising to the skilled reader if the patentee had chosen to exclude this well known mechanism.
iv) that the skilled person would understand from the disclosure of 246 at  that other ingredients such as an external immediate release layer could contribute to the release rate. That passage states:
"The film coat is chosen so as to achieve, in combination with the other ingredients, the in-vitro release rate outlined above..."
- I have been referred to a decision dated April 27th 2007 of the Düsseldorf District Court in an action on the German designations of the patents in suit against Cimex AG, the manufacturers of the pills that are alleged to infringe in the present case. In that decision, Judges Grabinski, Klepsch and Thelen refused an interim injunction, relying on some of the points made by ratiopharm/Sandoz here. Moreover on August 19th 2008, the Mannheim District Court (Judges Kircher, Lehmeyer and Lembach) reached a conclusion to the same effect. Those decisions are of considerable persuasive authority, but as will be seen, I have not felt able to go quite as far as they have gone in certain respects.
- The oxycodone dosage defined in (a) is, it seems to me, the total amount of oxycodone in the formulation. It is to be noted that it is a range, with an upper and lower limit. I do not think it is possible to read this, as Napp contends, as relating only to the amount of oxycodone in the matrix. If the matrix were to contain 160 mg oxycodone hydrochloride equivalent (i.e. the upper limit), and a further 20 mg was present in an external layer, the dosage form as a whole would be outside the claim, even though the amount of oxycodone in the matrix was within the limits. It would not be an "oxycodone dosage form… comprising (a) oxycodone salt in an amount equivalent to 10 mg to 160 mg of the oxycodone hydrochloride salt".
- Thus, when the claim requires at (b) that the matrix should incorporate "said oxycodone salt", the natural reading is that it contains the oxycodone in the dose, that is to say all of it. And when it says it has a "coating on said matrix", the natural reading is again that it coats all the oxycodone in the formulation.
- On balance, I prefer ratiopharm/Sandoz' submissions. Neither the passage in the specification at , nor knowledge of immediate release booster layers (which I accept the skilled person would have had) would lead the skilled person to conclude that the patentee was seeking to include formulations where a significant part of the oxycodone was outside the film coating:
i)  comes immediately after  which describes other ingredients, such as spheronising agent and binder, which are present in addition to the film coating, and contained within it.  would not lead the skilled person to contemplate other ingredients external to the film coating;
ii) an immediate release booster coating is but one example of a case where the oxycodone is not all contained inside the film coating. There is no basis for focusing exclusively on such a construction when trying to understand the claim. If the claim is wide enough to let in such coatings it is difficult to see what its limits would be. If the claim were to be interpreted in that broad way, as long as some of the oxycodone is within the film coating, the vast majority could be on the outside of the film, with its release controlled in another way. The skilled person would conclude that there was good reason for the limitation that requires the oxycodone to be on the inside of the coating.
iii) The passage at  helps ratiopharm/Sandoz very indirectly: one should not do anything to cause uneven release. But it is fair to say that the passage is not really focussing on the precise point at issue. I would have reached the same conclusion without that passage.
iv) Where there are technical reasons both for and against giving a claim something other than its conventional meaning, as there are here, I should hesitate before assuming that a different meaning is intended.
- I conclude that claim 1 of 246 requires all the oxycodone to be within the film coating.
"film coating which controls the release of the oxycodone salt" (claim 4 of 246)
- Claim 4 is directed to the spheroid embodiment discussed at . It is dependent on claim 1. So a patent lawyer would be surprised by a conclusion that a structure which did not infringe claim 1 because it had oxycodone outside the controlled release coating, could infringe claim 4.
- Claim 4 is very poorly drafted, as it makes no attempt to correlate the features it introduces to the features of the claims on which it is dependent. One embodiment which it would apparently cover is that in which all the oxycodone in the dose is enclosed within spheroids. In claim 4, only "an analgesically effective amount" has to be within the spheroids, as compared with the large dose range of claim 1. Thus claim 4 covers the case where some of the dose is within spheroids, and the rest could be outside the spheroid's film coating. But even if that arrangement were adopted, the dependency on claim 1 would mean that there would have to be a coating controlling the release of all the oxycodone. So claim 4 is no wider than claim 1 in the relevant respect.
"film coating which controls the release of the oxycodone or oxycodone salt" (claim 6 of 730),
- Thus far, my decision on this trilogy of points is in conformity with that of my German colleagues. It is on this third point that I have not been able to follow them.
- Claim 6 of 730 is an independent claim. Mr Silverleaf's case is plainly weaker here, because, unlike claim 1 of 246, the language of the claim does not clearly place the total amount of oxycodone in the dose inside the coating. The oxycodone or salt referred to in feature (b) is simply whatever oxycodone is within the spheroids, not all the oxycodone in the formulation.
- Napp says that the literal meaning includes the case where not all the oxycodone is within the spheroids. I agree. There is no reason in principle why a skilled person might not nevertheless understand a narrower meaning. But, as I have held, there are technical reasons both for and against departing from the conventional meaning. Here this approach helps Napp and not ratiopharm/Sandoz. I cannot see a firm enough basis in the specification for reading the claims as narrowly as ratiopharm/Sandoz would wish me to.
- The German decision to which I have referred attaches importance to the fact that the claim refers to "the" oxycodone. In the end, however, I am unpersuaded that the skilled person would hang so much on the use of the definite article, when the reference back can only be to the oxycodone within the spheroids, not all the oxycodone in the dose.
- Accordingly I hold that claim 6 of 730 does not contain a requirement that all the oxycodone is within the spheroids.
"A matrix incorporating said oxycodone salt" (claim 1 of 246)
- This is the additional point on this phrase which I have mentioned: what are the requirements of the "matrix" in claim 1 of 246?
- It would be clear to the skilled reader that the matrix in this case is not a controlled release matrix. The matrix is required to hold the oxycodone and be able to release it on administration.
- Mr Silverleaf argued that the matrix material must form a self-standing structure which holds or contains the active ingredient, and that was so whether the matrix is one which limits the rate of release, or whether it is one where the rate of release is controlled by other means.
- I do not think that the word "matrix" in this context is calling for anything as sophisticated as Mr Silverleaf contends. The matrix required for this feature of the claim is constrained only by the requirement that it must hold the oxycodone and must allow its release to be controlled by the coating.
"Spheroids" and "spheronising agent" (claim 6 of 730, claim 4 of 246)
- The specifications of both patents describe the process of extrusion/spheronisation. In this process, drug and excipients are passed through an extruder to produce cylindrical pieces of material. Whilst still in a plastic state, the cylindrical sections are placed in a second device which rounds the cylinders into spheroidal shapes. In this context, a spheronisation agent is a material chosen to give the mass of material the right degree of plasticity when it is extruded to allow the second stage of the process to take place in an optimum way.
- Extrusion/spheronisation is but one way in which to make a spheroid. Spheroids can be made by rotor-granulation, a process which does not involve converting a cylinder into a sphere, but in which the spheroids are formed from a mass of powdered material.
- There was much debate at the trial about how the terms "spheronisation" and "spheroid" had been used in particular publications. These struck me as somewhat isolated examples. I believe the skilled person would take the meaning of "spheronising agent" and "spheroid" principally from the patents themselves.
- The patents say (e.g. 730 at ) that:
"the spheronisation agent may be any pharmaceutically acceptable material that, together with the active ingredient, can be spheronised to form spheroids".
- The patents further say (e.g. 730 at ) that:
"the term spheroid is a term known in the pharmaceutical art and means a spherical granule".
- The first point is what is meant by "spheroid". There was no real dispute that as a matter of ordinary language the term "spheroid" simply meant a generally spherical particle. The dispute, such as it was, was as to whether the patent was using the term in a narrower sense in consequence of the reference to a "granule". A granule is an aggregated particle made up of smaller particles.
- In my judgment the skilled reader would have no reason to think that the term "granule" was being used in any particularly limited sense. He would know that a wide range of processes exist for arriving at a spheroidal particle by agglomerating smaller particles. He would have no reason to suppose that the patentee wanted to exclude any of them.
- The second point is what is meant by "spheronising agent". Napp submits that a spheronising agent is anything that will assist in the process of making a spheroid.
- ratiopharm/Sandoz submit that the term, in its purest form, refers to materials such as microcrystalline cellulose, which are incorporated to give the material the correct degree of plasticity in an extrusion/spheronisation process. They submit that, at its widest, the term is limited to agents which have assisted in making a sphere out of something that is not a sphere. If the process has started with a sphere, it makes no sense to speak of any ingredients which are used after that point as spheronising agents. Just about anything you choose after that point will fit Napp's definition.
- The difficulty of construction arises because this is a product, not a process claim. In that connection it is somewhat odd that the claim to spheroids includes a requirement for a spheronising agent – it is rather like saying that a pot of tea includes a tea-making agent. Whatever role is inherent in the definition of that term, it will have been fully performed by the time that one has a product. To put it bluntly: if you have succeeded in obtaining spheroids, why should it matter how you got there?
- The problem for Napp is that some meaning has to be given to the term. It cannot be the case that one can assume that a spheronising agent is present just because a spheroid has been made. Something more must be meant. Hence both sides' submissions involve, in different degree, an assessment of the purpose which the agent has fulfilled in the process. Although this is unusual for a product claim, it seems inescapable in the present case.
- On the whole, I prefer ratiopharm/Sandoz' submission. I think the claim is using the term "spheronising agent" in the sense of an agent which has enabled the excipients to form into a sphere. I do not think it can properly apply to materials which are added once the sphere has already been formed. I reach that conclusion primarily because, on the alternative construction, the result is that the claim extends to a whole host of materials which the skilled person would never dream of calling spheronising agents, as they have played no significant role in formation of the sphere. Moreover Napp did not give any example of a case where an excipient present in the spheroid would not also have assisted in the process of making of the spheroid.
The in vitro dissolution parameters (claim 9 of 730, claim 1 of 246)
- These claims include requirements as to dissolution rates when measured by the United States Pharmacopoeia("USP") Paddle Method. The patents identify the USP Paddle Method as that described e.g. in U.S. Pharmacopeia XXII (1990): see 730 at ; 246 at .
- Some claims (e.g. claim 9 of 730 and claim 9 of 246) also include a requirement that the dissolution rate be "independent of pH" or "substantially pH independent". "[s]ubstantially independent of pH" is defined at  in 730 and  in 246 in the following terms:
"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." (emphasis supplied)
- Measurement of dissolution by the USP Paddle Method as a function of time is a necessarily destructive process. It follows that, to carry out the test for pH independence of the dissolution rate, three tablets are required for each pH at which a timed set of measurements is taken. The timed measurements at a given pH are taken by sampling the solution at different time points: so only one tablet is necessary for a set.
- The USP Paddle Method contains two relevant sections, 711 and 724. Both sections cross-refer to an "individual monograph", which is intended to refer to a drug monograph which specifies a dissolution rate to be measured by this method. In context, the skilled person would understand this as referring to the Patents.
- Section 711 is headed "Dissolution". It describes two pieces of apparatus. "Apparatus 2" is the Paddle Method which the patents direct the reader to use. Most of the details of the apparatus and procedure do not matter. It is sufficient to note that the reader is directed to place a single tablet in the apparatus, and to extract specimens of the solution at the specified time intervals. He is directed to perform the analysis as directed in the monograph and to repeat the test with "additional dosage forms". Section 711 has an acceptance table with a series of staged tests, through which the experimenter has to proceed until the tests conform to the criterion. The number of dosage forms tested at each stage is 6.
- Section 724 is concerned with drug release requirements, and contains the appropriate alternative acceptance table for controlled release requirements when using the USP apparatus described in 711. Again there are three stages to the acceptance criteria. Level 1 requires the testing of 6 tablets: to pass at this level no individual value may fall outside each of the stated ranges. Level 2 requires a further 6 tablets to be tested and the average of 12 thus tested to be within the stated ranges. In addition, Level 2 imposes further requirements: none is to be more than 10% outside each of the stated ranges. Level 3 tests a further 12 tablets, averages all 24 and imposes further requirements still.
- The issue which arises is whether, in carrying out the USP Paddle Method for the purposes of testing infringement, it is legitimate to look at the results for a single tablet, or whether there is a further requirement that the batch from which the tablet comes has to comply with the acceptance criteria in the USP.
- ratiopharm/Sandoz argue that the whole of the test procedure and the acceptance test method must be carried out in order to determine infringement of the absolute requirements. For pH dependence, three such experiments must be carried out. They argue that the fact that the measurements of relative dissolution rates at different values of pH are required to be averages of three experiments means that the reader would assume that the same would apply to the absolute dissolution rates. They also argue that section 711 of the USP expressly directs the procedure to be repeated.
- I think the short answer to this point is that, so far as absolute dissolution rate is concerned, the relevant claims are directed to dosage forms, not batches of products. The claim is not drafted to a batch of tablets or capsules conforming to a release rate determined by the USP Paddle Method. The claims are directed to a dosage form on its own. I do not believe that in those circumstances the skilled reader would think he was being directed to anything other than the experimental procedure in the USP. He knows that he can carry out the procedure once and only once on a single dosage form. The direction in the USP to repeat the procedure is only appropriate if one is concerned with conformity of a batch. It would have no relevance to the task of testing a single dose.
- The principle thus expressed has to give way to a limited extent to accommodate the fact that the average of three experiments is required for pH independence. I do not think that the skilled person would understand that he was being directed to repeat the batch acceptance experiment three times, nor was any reason suggested why the patents should require more extensive testing than even the USP requires for this purpose.
- The pH independence testing is essentially concerned to establish that the result obtained for absolute dissolution rate does not differ depending on the pH tested. One tablet is needed for each pH value tested (there were four in the experiments). So to come to a conclusion about pH independence one would need 12 tablets. If those tablets turn out not to conform to the patents' test for pH independence, then there will be no infringement: but such a finding will not negate the conclusion about the absolution dissolution requirement. They are separate and independent requirements.
- It is not alleged that claim 1 of 730 is infringed. Apart from this all the claims in the Appendix need to be considered.
The Cimex product
- The Cimex product which is accused of infringement is a tablet which contains, embedded in excipients, small particles made up of a number of layers. A cross section of a particle showing the layers is shown below.
- The Core is bought in by Cimex. It is made from sugar crystals which are built on with liquid glucose and corn starch in a standard coating vessel from which they are taken and dried. The Inner Layer is made up of oxycodone hydrochloride (83 wt%), hydroxypropylmethyl cellulose (HPMC, about 8 wt%) and talc/macrogol (about 9 wt%). It is sprayed onto the cores in a fluid bed processor.
- The Polymer Layer contains ethyl cellulose, hydroxypropylcellulose and propylene glycol. It is accepted by ratiopharm/Sandoz that the Polymer Layer controls the release of the oxycodone hydrochloride in the Inner Layer.
- The Outer Layer contains about 96 wt% oxycodone hydrochloride and about 4 wt% HPMC. About 20% of the total weight of oxycodone hydrochloride in the dosage form is in the Outer Layer.
Infringement – spheroid and spheronising agent
- ratiopharm/Sandoz contend that the Cimex particles are not granules, and therefore are not spheroids within the definition in the patents. On the approach I have taken to construction, the particles are granules. They are agglomerates of smaller particles, albeit including a large central particle as the Core.
- Napp contends that the HPMC in the Inner Layer is the "spheronising agent". In my judgment the HPMC is not a spheronising agent as that term is used in the Patents. The skilled person would understand the function of the HPMC to be that of a binder or matrix for release of the drug at a rate controlled by the Polymer Layer. The Cimex particle neither requires nor uses a spheronising agent.
- It follows that claim 6 of 730 is not infringed. As all the remaining claims of 730 are dependent on claims 1 or 6, and claim 1 is not alleged to be infringed, it follows that there is no infringement of 730.
- It follows also that claim 4 of 246 is not infringed.
Infringement – oxycodone outside release layer
- On the view which I have come to as to the correct construction of 246, claims 1 and 4 are not infringed because there is a significant amount of oxycodone the release of which is not controlled by the Polymer Layer. As all the claims of 246 are directly or indirectly dependent on claim 1, it follows that the Cimex product does not infringe any claim of 246.
- The corresponding argument does not apply to claim 6 of 730. On the view which I have taken of the proper construction of that claim, the relevant phrase does not provide an answer to infringement.
Infringement – matrix
- The oxycodone is held within the HPMC. In my judgment it is held within a matrix, as that term is used in the claim. Moreover I consider that there is infringement even on the narrower basis contended for by ratiopharm/Sandoz. The evidence establishes that the normal release matrix in the Cimex tablets had structural integrity. Accordingly this point does not provide a separate ground of non-infringement of claim 1 of 246.
Infringement – in vitro dissolution rates
- On the view which I have come to on construction, the in vitro dissolution rates do not provide a separate ground of non-infringement of claim 1 of 246. A fairly modest percentage (some 7%) of the Cimex tablets tested had dissolution rates which fell within the ranges in claim 1 of 246.
- There was a further dispute as to whether Napp had successfully proved that the Cimex tablets showed pH independent behaviour. This was not a point which was given much prominence in the evidence. Mr Silverleaf contended that not enough infringing tablets had been tested to enable one to have an average of three experiments on tablets which satisfy the absolute dissolution criterion at each pH value tested. He was correct, but I do not think this is the right question. Firstly, I do not think it is necessary for this purpose that all the tablets should be those which satisfy the absolute dissolution criterion. That conclusion follows from my conclusion that the absolute and relative requirements are independent of each other. Secondly, even if it is necessary only to test "infringing" tablets, I think the results of Napp's experiments are sufficient to show on the balance of probabilities that the release rate of these tablets is substantially independent of pH. From the evidence there is, it is unlikely that further tests would have revealed a dependence on pH. It follows that there is no separate non-infringement point arising on claim 9 of 730 or claim 9 of 246.
Conclusion on infringement
- Those points are sufficient for me to reach a conclusion that the action must fail. Neither claim 6 of 730 nor claim 1 of 246 is infringed. The remaining claims are either not asserted or narrower in scope. Nevertheless, I should go on to decide the remaining issues, in case a higher court takes a different view.
Added Matter - law
- The law of added matter is summarised by Kitchin J in European Central Bank v. Document Security Systems  EWHC 600 at - (approved on appeal –  EWCA Civ 192 at ):
" The test for added matter was explained by Aldous J in Bonzel v. Intervention Ltd  R.P.C. 553 at 574:
"The decision as to whether there was an extension of disclosure must be made on a comparison of the two documents read through the eyes of a skilled addressee. The task of the Court is threefold:
(a) To ascertain through the eyes of the skilled addressee what is disclosed, both explicitly and implicitly in the application.
(b) To do the same in respect of the patent as granted.
(c) To compare the two disclosures and decide whether any subject matter relevant to the invention has been added whether by deletion or addition.
The comparison is strict in the sense that subject matter will be added unless such matter is clearly and unambiguously disclosed in the application either explicitly or implicitly."
 A number of points emerge from this formulation which have a particular bearing on the present case and merit a little elaboration. First, it requires the court to construe both the original application and specification to determine what they disclose. For this purpose the claims form part of the disclosure (s.130(3) of the Act), though clearly not everything which falls within the scope of the claims is necessarily disclosed.
 Fifth, the issue is whether subject matter relevant to the invention has been added. In case G1/93, Advanced Semiconductor Products, the Enlarged Board of Appeal of the EPO stated (at paragraph  of its reasons) that the idea underlying Art. 123(2) is that an applicant should not be allowed to improve his position by adding subject matter not disclosed in the application as filed, which would give him an unwarranted advantage and could be damaging to the legal security of third parties relying on the content of the original application. At paragraph  it explained that whether an added feature which limits the scope of protection is contrary to Art 123(2) must be determined from all the circumstances. If it provides a technical contribution to the subject matter of the claimed invention then it would give an unwarranted advantage to the patentee. If, on the other hand, the feature merely excludes protection for part of the subject matter of the claimed invention as covered by the application as filed, the adding of such a feature cannot reasonably be considered to give any unwarranted advantage to the applicant. Nor does it adversely affect the interests of third parties."
- A specific question arises in this case about whether a disclaimer introduced into the disclosure and claims amounts to added matter ("an undisclosed disclaimer"). Subject to the question of intermediate generalisation, there is of course no objection in principle to a disclaimer of subject matter which properly finds basis in the original document. The circumstances in which a disclaimer which does not find its original basis in the application for the patent, and which therefore potentially adds subject matter, were considered by the Enlarged Board of Appeals of the European Patent Office in PPG Industries Case G0001/03. In that case the Enlarged Board was asked in substance (a) whether an amendment to a claim by the introduction of a disclaimer was always unallowable under Article 123(2) EPC if neither the disclaimer nor the subject matter excluded by it have a basis in the application as filed and (b) if not, what were the criteria to be applied in order to determine whether or not a disclaimer is allowable.
- The Enlarged Board answered the first question in the negative. It defined a number of circumstances in which a disclaimer which had the effect of adding matter could nevertheless be allowed. These were (a) to restore novelty in the light of matter forming part of the state of the art by virtue of Article 54(3) and (4) (deemed publications available for novelty only attacks); (b) to restore novelty against a so-called "accidental anticipation"; (c) to disclaim matter which is unpatentable for non-technical reasons.
- The rationale behind the exception in favour of disclaimers of matter forming part of the state of the art by virtue of article 54 (3) (deemed publication) is set out in paragraph 2.1.3 of the decision
"For the interpretation of Article 123 (2) EPC … the purpose of a disclaimer excluding a conflict in applications is merely to take account of the fact that different applicants are entitled to patents in respect of different aspects of inventive subject matter and not to change the given technical teaching. The disclaimer splits the invention as a whole in two parts: in respect of the identical part, it preserves the rights of the first applicant; for the rest, disclosed for the first time in the later application it attributes the right to the second applicant. This approach restricts the effects of Article 54 (3) EPC to resolving the problem of double patenting.
"Such a disclaimer, only excluding subject-matter for legal reasons, is required to give effect to Article 54 (3) EPC and has no bearing on the technical information in the application. It is, therefore, not in contravention to Article 123 (2) EPC. "
- The Board held that the same rationale applied in the case of an accidental anticipation under Article 54(2), that is to say a novelty destroying disclosure from a technically remote field of use. Excluding such subject matter did not affect the technical teaching of the patent: see paragraph 2.2, even although the subject matter of the disclaimer was not present in the application as filed. Nevertheless the Board held that the disclaimer should remove no more than is necessary either to restore novelty or disclaim excluded subject matter a minimalist test.
- The Enlarged Board also pointed to certain classes of case where a disclaimer would be prohibited. A disclaimer which was or became relevant for the assessment of inventive step could not be permitted: paragraph 2.3. Similarly, undisclosed disclaimers to eliminate non-working embodiments would also not be allowed as these would allow specifications to be rendered sufficient after the date on which they were required to be so: see paragraph 2.5. Any undisclosed disclaimer which had the effect of making a technical contribution would also not be allowed: see paragraph 2.6.
- In the present case each of the patents was granted on a divisional application. 730 is a divisional from the original PCT application and 246 is a divisional from 730. Where a divisional application is filed, it is necessary for the patent office to ensure that there is no double patenting, by ensuring that the divisional patent does not contain claims which cover the same subject matter as a parent.
- Napp argues that the case of divisional applications represents a further class of case where an undisclosed disclaimer may be permissible as merely excluding part of the subject matter of the patent, rather than adding to the technical teaching of the patent. Napp says that the logic of the other exceptions to the rule identified in G1/03 applies to the case of divisional applications.
- Insofar as this argument seeks to create a general exception for disclaimers introduced in divisional applications, I reject it. The filing of a divisional application with a disclaimer which is not based on the original disclosure is not analogous to the cases where the Enlarged Board has held that disclaimers may be permissible. Those cases are concerned with amendments made necessary by different types of subject matter forming part of the state of the art, or being excluded from patentability for non-technical reasons. These matters will define the scope of the necessary disclaimer, and make it possible to apply the Board's minimalist test. In the case of a divisional application, the applicant is not disclaiming subject matter which forms part of the state of the art or which is otherwise excluded from patentability for non-technical reasons, he is merely seeking to make his claims different from those in the parent application. He can do this is a variety of ways, but it is not easy to see how one would apply a minimalist test to any of them.
- If this further general category of exception were to be created, the applicant for a patent would be able to achieve, by filing a divisional application, an unwarranted advantage that he would not have been able to achieve by amending the parent patent.
- Nevertheless, the test for added subject matter remains that set out in the Convention and the Act. The reason that disclaimers of accidental and deemed anticipations do not offend is that they do not add subject matter relevant to the invention. If a disclaimer introduced by a divisional application does not add subject matter relevant to the invention, but merely excludes subject matter from protection, then it too will not offend against the provision.
Added Matter - facts
- There are broadly two added matter points which I shall call the "acrylic resin point" and the "spheroids point".
The acrylic resin point
- The original pleading of the acrylic resin point was the subject of trenchant (and justified) criticism by Mr Carr QC (who appeared for Napp) in his opening. As a result, Mr Silverleaf offered to explain the point further by amendment of the pleading. In the absence of substantive objection from Napp, I allowed the amendments at the beginning of the trial. As so amended, the acrylic resin point has two aspects. The first aspect ("the disclaimer point") is that there had been a disclaimer in '730 which is of a kind which is not permissible according to EPO Case Law. The second aspect of the point is a more conventional added matter attack. There are two parts to this as well: "added technical teaching" and "intermediate generalisation". I will deal first with the disclosure of the PCT application and the 730 patent.
The disclosure of the PCT about acrylic resins
- At page 9 line 11 the PCT discloses that the "present composition … releases oxycodone at a rate which is substantially independent of pH". The PCT discloses the following at page 9 line 25:
"The present matrix may be any matrix that affords in vitro dissolution rates of oxycodone within the narrow ranges required and that releases the oxycodone in a pH independent manner. 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…."
- Thus, in this passage, an acrylic resin is said to produce pH independent release. At page 11 line 14 a preferred embodiment is said to be 5-25% acrylic resin and 8-40% aliphatic alcohol by weight of the dosage form. The ratio of the acrylic resin to the aliphatic alcohol is said to determine to a considerable extent the release rate. Eudragit RS-PM was said to be a particularly preferred form of acrylic resin.
- The Examples are said to illustrate various aspects of the invention. Those using acrylic resins are Examples 1-6, 11 and 12. Examples 1, 2, 5 and 6 use Eudragit RS-PM; Examples 3-4 use Eudragit RS 30D and Triacetin; Examples 11 and 12 use Eudragit L-100-55. Examples 5 and 6 show how the tablets produced in accordance with Examples 1 and 2 release at different pH values.
- Eudragit RS-PM is a non water-soluble polymer, sold as a powder, which the skilled person would understand as giving pH-independent release. Eudragit RS-30D is the same polymer sold as a 30% aqueous dispersion also giving pH independent release. Eudragit L-100-55 is a pH dependent polymer which would remain undissolved in the acidic stomach, but which would dissolve at pHs above 5.5. Whether a given polymer gives a pH independent or dependent release in a formulation may depend on the other ingredients present and what controls the rate-determining step. Example 12 therefore presents a puzzle: but the skilled person would need more information before confirming, in the face of the rest of the disclosure, that Example 12 was pH independent. Mr Silverleaf so submitted in paragraph 124 of his closing submissions. I accept that submission.
- Accordingly the skilled person reading the PCT as a whole would understand that he should choose a matrix which releases oxycodone in a pH independent manner. He is taught that acrylic resins such as Eudragit RS-PM can achieve release in that manner. He would expect the examples which used acrylic resin to achieve pH independent release but there would be a question mark over Example 12.
The disclosure of 730 about acrylic resins
- The relevant disclosure of 730 is as follows. Firstly the skilled person would note at  that
"Granted European Patent No 0 576 643, based on [the PCT] from which the instant application is a divisional, forms the basis for the disclaimer in independent claim 1"
- From the cross reference, the skilled person would be able to note that granted EP (UK) 0 576 643 contains claims which are specifically limited by reference to the use in the matrix of an acrylic resin that is selected to provide pH-independent release characteristics.
- Secondly the skilled person would note that claim 1 claims inter alia
"a controlled release dosage matrix, other than an acrylic resin matrix selected so that the formulation provides pH-independent characteristics"
This is the disclaimer referred to in .
- Thirdly the skilled person would note the disclosure at  that the present composition releases oxycodone at a rate that is substantially independent of pH.
- Fourthly the skilled person would note the disclosure at  that:
"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…."
- Finally the skilled person would note that the Examples used acrylic polymers, and that Examples 5 and 6 showed how the tablets of Examples 1 and 2 released as a function of pH. He would note that Example 12 appeared to have ingredients designed to give pH dependent release, but he would need more information to be sure.
- ratiopharm/Sandoz contend that  teaches that acrylic resins for use in the invention must be those which achieve pH dependent release. They say that is the only way to make sense of the two highlighted passages, one excluding pH independent acrylic resins, and the other including acrylic resins generally. They say the latter must be read subject to the former, yielding a teaching to use only acrylic resins which provide pH dependent formulations.
- Napp submits that so to read  is to divorce it from the remaining context. Firstly, it ignores  which says that the compositions are pH independent. Secondly, it ignores the fact that Examples 1 and 2 use an acrylic polymer which would be recognised as giving pH independent release. Thirdly, it ignores the fact that the skilled person is given an explanation for the disclaimer, namely that pH-independent acrylic matrices are the subject of a separate patent from which the present patent is a divisional.
- In my judgment the skilled person would read 730 as teaching that acrylic resins were suitable materials to use for achieving pH-independent release, but that the combined effect of  and the disclaimer was that these materials were not claimed. I do not think that he would derive from the general disclosure any technical teaching about pH-dependent acrylic resins.
- Mr Silverleaf argued that the combined effect of the general disclosures now provided a background against which Example 12 would be understood as an example of a pH-dependent matrix, whereas previously it would have been less clear that this was so. However, as I have reached the conclusion that the general description does not provide any technical teaching about pH dependent matrices, there is no basis for reading Example 12 in a different light.
- The disclaimer point is pleaded in the following way:
2. The matter disclosed in the specification of the '730 Patent extends beyond that disclosed in PCT Application WO 93/10765 filed on 25 November 1992 (hereinafter "the PCT').
(a) The '730 patent contains an impermissible disclaimer, which is prohibited by the case law of the EPO, and in particular Case G0001/03.
1. The PCT discloses that acrylic resins are suitable materials for inclusion in a controlled release matrix formulation of the invention (page 9 line 31).
2. The '730 patent discloses that "the matrix may be any matrix…except an acrylic resin matrix being selected so that the formulation provides pH independent dissolution characteristics"(). Claim 1 of the 730 patent claims a "controlled release dosage matrix, other than an acrylic resin matrix selected so that the formulation provides ph-independent dissolution characteristics".
3. This amounts to a disclaimer which is not disclosed in the PCT.
4. The disclaimer is not made to restore novelty by delimiting a claim against the state of the art under article 54 (3) and (4) EPC or against an accidental anticipation under article 54(2) EPC, nor to disclaim subject-matter which is excluded from patentability for non-technical reasons. Accordingly it is impermissible.
- This is a short-cut argument. It rests on the proposition that the only undisclosed disclaimers which are allowable are those identified in G1/03. It is correct to say that the disclaimer does not fall into any of the categories identified in G1/03. But, as I have held, the correct question is whether 730 adds subject matter relevant to the invention. If the effect of the disclosure of 730 is not to add subject matter relevant to the invention at all, then the fact that it includes a disclaimer does not make it do so. Thus I do not think that this short-cut to the solution works.
- As I have construed the disclaimer it could not possibly confer on Napp any unwarranted advantage. The exclusion of pH-independent acrylic resins is not to distinguish any matter which forms part of the state of the art. If a prior disclosure of such resins were to surface in the future, Napp could not argue any inventive difference over it – the patent still identifies such resins as being suitable and part of Napp's invention. No matter relating to the invention has been added. I therefore reject this disclaimer point.
The conventional added matter attack
- ratiopharm/Sandoz' alternative argument and conventional added matter attack is pleaded as follows:
(b) Further or alternatively, parts of the specification and/or claims of the '730 Patent are not disclosed clearly and unambiguously in the PCT and are relevant for the assessment of inventive step and/or provide a technical contribution.
(1) The PCT discloses that the matrix made in accordance with the invention may be any matrix … that releases the oxycodone in a pH-independent manner (page 9 line 25). The materials which are said to be suitable for providing this matrix include acrylic resins (page 9 line 32). A particularly preferred acrylic resin is said to be Eudragit RS-PM (page 11 line 17), and Eudragit RS-PM resins are used in Examples 1 and 2 which are said to be examples of the invention. The skilled reader of the PCT would understand from this that the formulations in examples 1 and 2 use the specified acrylic resins to provide a matrix which releases oxycodone in a pH independent manner.
(2) The '730 patent discloses that the matrix made in accordance with the invention may be any matrix … except an acrylic matrix being selected so that the formulation provides pH-independent dissolution characteristics (). Eudragit RS. resins are used in Examples 1 and 2 which are said to be examples of the invention. The skilled reader of the '730 patent would understand from this that the formulations in Examples 1 and 2 use the specified acrylic resins to provide a matrix which releases oxycodone in a manner which is not pH-independent. This is a different disclosure to that of the PCT and amounts to added matter which provides a technical contribution.
(3) Further or alternatively, if the PCT discloses matrices that release oxycodone in both a pH-independent manner and a manner which is not pH-independent, the '730 patent discloses an allegedly inventive selection by claiming a matrix selected so as to exclude both an acrylic resin matrix and a matrix which provides ph-independent dissolution characteristics. Neither this selection nor its technical significance are disclosed in the PCT and it amounts to an impermissible intermediate generalisation.
- Having considered the disclosure of the PCT and the 730 Patent above, I can deal with the point raised by paragraphs (1) and (2) above quite shortly. I do not accept that the skilled reader of the 730 patent would understand from the passages referred to that the formulations in Examples 1 and 2 use the specified acrylic resins to provide a matrix which releases oxycodone in a manner which is not pH-independent. That conclusion, it seems to me, is contrary to  and to the technical content of Examples 1 and 2 themselves. No point about Example 12 is pleaded, but I have already held that there was no change to the teaching of that example. This "added technical contribution" attack therefore fails.
- I can deal equally shortly with the intermediate generalisation. Firstly, the plea is premised on the basis that the PCT discloses both a pH-independent and a pH-dependent acrylic resin. In my judgment the disclosure of the PCT is limited to pH-independent matrices. Secondly I do not think that 730 disclosed an inventive selection of a matrix selected so as to exclude an acrylic resin which is pH independent. The skilled person would understand the exclusion of pH-independent acrylic matrices as having no inventive or technical significance. The intermediate generalisation point fails as well.
- I was referred to the decision of the Opposition Division of the EPO in the present case, which is the subject of appeal. I agree with the Opposition Division that the reasoning of G1/03 cannot be directly transferred to the present case. I have differed with them on the question of whether 730 contains a disclosure relevant to the invention which is not in the PCT. Whilst I have given the decision its appropriate consideration, I was not in the end persuaded by its reasoning.
The spheroids point
- The above analysis does not exhaust all ratiopharm/Sandoz's added matter points. As I indicated above, there is another point altogether about spheroids. It is pleaded (against 730) in the following way
"(a) Claim 6 of the Patent claims and discloses as an alternative to a controlled release matrix, controlled release oxycodone formulations comprising (a) spheroids containing oxycodone and a spheronising agent wherein (b) each spheroid is coated with a film coating which controls the release of the oxycodone. Such disclosure is not limited to any particular type of spheroid composition or matrix nor is it limited to any particular type or class of spheronising agent.
(b) The 730 Application discloses as an alternative to a controlled release matrix, film coated spheroids containing oxycodone and a spheronising agent wherein the latter is non-water soluble. Alternatively insofar as the 730 Application discloses film coated spheroids containing oxycodone and a spheronising agent without express limitation as to the type or class of spheronising agent, the spheroid composition is itself a controlled release matrix having the characteristics set out in claim 3(b) thereof."
- The relevant passage in the description of 730A at page 5 lines 27-34 states that
"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 spheronising agent may be any pharmaceutically acceptable material that together with the active ingredient can be spheronised to form spheroids. Microcrystalline cellulose is preferred."
- Identical words appear at  and  of 730 itself.
- Claim 6 of 730 reads as follows:
A controlled release oxycodone formulation for administration to human patients, comprising:
(a) an analgesically effective amount of spheroids comprising oxycodone or a salt thereof and a spheronising agent;
(b) each spheroid being coated with a film coating which controls the release of the oxycodone or oxycodone salt at a controlled rate in an aqueous medium.
- As Kitchin J pointed out in ECB at , not everything which is claimed is disclosed. In particular I can see no disclosure in claim 6 which is not present in the passages I have cited from the application. Indeed, as Mr Carr submitted, it seems to me that a claim which is not limited "to any particular type of spheroid composition or matrix" or "any particular type or class of spheronising agent" is entirely in accordance with that disclosure. So this further added matter point fails as well.
Obviousness – Law
- A patent is liable to be revoked under section 72(1)(a) if the invention to which it relates is not a patentable invention. If the invention does not "involve an inventive step", it is not patentable. By section 3, an invention is to be taken to involve an inventive step if it is not obvious to a person skilled in the art having regard to any matter which formed part of the state of the art. I will follow the structured approach explained most recently by Jacob LJ in Pozzoli v BDMO SA,  EWCA Civ 588;  FSR 37 at .
"In the result I would restate the Windsurfing questions thus:
(1) (a) Identify the notional "person skilled in the art"
(b) Identify the relevant common general knowledge of that person;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the "state of the art" and the inventive concept of the claim or the claim as construed;
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?"
- In Conor v Angiotech  UKHL 49;  RPC 28 at  Lord Hoffmann approved the following statement by Kitchin J in Generics (UK) Ltd v H Lundbeck A/S  RPC 32 at :
"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."
- The rules of pleading in patent actions require a party to identify the matter in the state of the art which is relied on to support of an attack on the ground of obviousness: see CPD Part 63 PD 11.3(1) and 11.4(1). Notwithstanding that provision, it has been the practice for allegations of obviousness to include a plea founded on nothing other than "common general knowledge". Sometimes, as here, these allegations reach trial without any further particularisation of the plea, except to the extent that the plea has been explained by the expert evidence adduced in support of it. I consider that the time has come when the matter which is said to be common general knowledge ought to receive some more formal exposition in advance of the expert evidence stage. Apart from anything else, the Pozzoli approach, which depends on identifying a difference between matter alleged to form part of the state of the art and the inventive concept, cannot begin to be applied without adequate particularisation of the starting point.
- There are a number of things to note about the plea of obviousness based on common general knowledge. The first is self-evident: it is that it is essential that the starting point for the plea is indeed established to be common general knowledge. If the matter alleged to be common general knowledge is not established as such then the result is just the same as if a documentary starting point is not shown to have been published before the priority date: the attack based on it is likely to fail.
- The second point is that it is important to be precise about what it is that is asserted to be common general knowledge. For example, in the present case it is admitted that "the existence of oxycodone" was common general knowledge. But the dispute here is not about whether a skilled person knew about oxycodone. The real dispute is about what oxycodone was used for. If the skilled person has not used oxycodone as an alternative to morphine for oral administration for moderate to severe pain, it becomes difficult to argue that it would occur to him to use oxycodone in the course of deciding on a controlled release formulation for use in such circumstances.
- Thirdly, it is vital to have in mind the requirements for matter to be part of the common general knowledge. In Beloit Technologies Inc v Valmet Paper Machinery Inc  RPC 489 at pages 494-495, Aldous LJ put it in this way:
"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.  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'."
- Fourthly, allegations of obviousness in the light of common general knowledge alone need to be treated with a certain amount of care. They can be favoured by parties attacking the patent because the starting point is not obviously encumbered with inconvenient details of the kind found in documentary disclosures, such as misleading directions or distracting context. It is vitally important to make sure that the whole picture presented by the common general knowledge is considered, and not a partial one.
- Finally, the common general knowledge does not include knowledge which does not inform the skilled person's approach from the outset. As Kitchin J said in Generics (UK) v Daiichi Pharmaceutical  EWHC 2413 (Pat):
" 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."
Whether knowledge is common and general depends on the considerations explained by Aldous LJ in Beloit. If information does not satisfy that criterion, it does not become common general knowledge by postulating a set of steps that the skilled team might take to find it if they had already embarked on an attempt to solve a particular problem. That is not to say that it is illegitimate, in assessing an obviousness attack, to take account of material which would inevitably be found and treated as reliable in consequence of a step or steps which it is obvious to take. If the material so found is such as would be accepted, then it may assist in showing obviousness of a further step. But what it cannot be used for is in support of an argument that the series of steps being undertaken were obvious from the start.
- As numerous claims are in issue, no one formulation of the inventive concept will do. For the purposes of the obviousness attack based on common general knowledge, it will be sufficient to consider the inventive concept, in general terms, as a 12 hourly controlled release formulation of oxycodone. For the other attacks it is necessary to consider individual claims. I will deal separately with the inventive concepts of those claims below.
The Skilled Addressee
- The patents are addressed to a drug development team, most likely in a pharmaceutical company. There is no dispute, obviously, that such a team would include a skilled formulator. The parties are also agreed that the team would include a clinician, although there is some argument about the nature of the role that such a clinician would normally be expected to play. There is a further dispute about the relevance of the evidence of Dr McKnight, who is a pharmacologist.
- ratiopharm/Sandoz submitted that the clinician's role would include making suggestions as to types of controlled release formulation for the drug company to develop. Napp submitted that such a role was unrealistic. Napp pointed out that Professor Power explained that he did not get involved in making such suggestions. Professor McQuay explained that he had never approached a pharmaceutical company suggesting a new formulation in that way, although a drug company had once approached him in relation to a project in relation to papaveretum.
- I have no doubt that the skilled team would have on it, or have access to the skills of, a clinician. Such a team would ask the clinician to advise it on such matters as prescribing practices in relation to known drugs. I also have no doubt that the team's interaction with the clinician would be two-way. Were a clinician to have the idea for a new controlled release formulation of a drug, I have no doubt that he would communicate it to the drug company.
- The evidence does show that it would be unusual for a clinician in hospital practice to approach a pharmaceutical company in this way, although there is at least one example of that happening in this case. I think the explanation is that the drug companies can be relied on to follow prescribing practices closely, and to see the opportunities that exist for new controlled release formulations for themselves.
- Mr Silverleaf did not press very strongly the notion that the team should not include a pharmacologist. In my judgment the team would need access to the services of a pharmacologist. As the evidence progressed it became clear that the skilled team developing such a formulation would need to know as much as possible about the pharmacokinetic and pharmacodynamic properties of the drug, input which the pharmacologist might be able to provide. Mr Silverleaf's objection to Dr McKnight was not so much the fact that he was a pharmacologist but that he had approached his evidence from the wider perspective of drug research generally, rather than the narrower perspective of doing research into controlled-release formulations of known drugs.
- The relevance of Dr McKnight's evidence about drug research generally needs to be considered in its proper place. For present purposes it is enough to record that I have no doubt that the skilled team would have access to the services of a pharmacologist.
Obviousness over common general knowledge
- ratiopharm/Sandoz' case of obviousness over the common general knowledge is very simply put. I quote Mr Silverleaf's opening speech:
"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."
- An absolutely crucial link in this case is the proposition that oxycodone would be perceived as a substitute analgesic for patients receiving morphine. Mr Silverleaf faintly suggested in his reply speech that he could get home if he failed on his main attack with an argument that it was obvious to make a controlled release version of oxycodone even if it was perceived as a weak opioid. But that case was never put to Napp's witnesses, and so it would be unfair to Napp to consider it further.
What was the common general knowledge about oxycodone?
- It was undoubtedly common general knowledge at the priority date that morphine was available in a controlled release version for treating patients with moderate to severe pain. The dispute centres on what was known about oxycodone. At the priority date oxycodone was a known opioid with a potency greater than or equal to that of morphine. Despite the length of time for which it had been in clinical use, its availability was far from being universal.
- At the priority date oxycodone was available in the United States and perhaps other countries as a combination therapy consisting of the drug co-formulated with aspirin or paracetamol. Examples of these products were Percodan and Percocet tablets, the former being a co-formulation with aspirin and the latter with paracetamol. From 1983 there was also a capsule formulation called Tylox which included the hydrochloride and terephthalate salts of oxycodone in combination with paracetamol. The thinking behind these combination products was that the side effects of aspirin and paracetamol placed a limit on the dosage of such drugs. A small dose of oxycodone in combination with the aspirin or paracetamol was seen as supplementing the analgesia available with aspirin or paracetamol by a different pharmacologic route. These formulations were limited in use to mild to moderate pain, as one could not increase the dose without encountering the toxic side effects of excessive administration of the co-drug. All these matters were part of the common general knowledge, widely recorded in text books and other publications.
- In the United Kingdom no oral formulation of oxycodone was available. For some years before 1991 oxycodone in the form of its pectinate salt had been available as a rectal suppository called Proladone for use with patients who could not swallow. Even this formulation had been withdrawn from general supply by 1991. The suppositories were available as a special order from Boots who maintained stocks of it. Nevertheless the use of oxycodone in this way was widely known and accepted and formed part of the common general knowledge.
- Dr. McKnight told me in his written evidence that, at the priority date, oxycodone was generally considered suitable only for patients with mild to moderate pain, co-formulated with an analgesic or NSAID such as paracetamol or aspirin. He said that the drug was perceived as a weak opioid suitable for mild to moderate pain. When found in the combination products, oxycodone was classed as a weak opioid, suitable for Step 2 on the WHO ladder. Little was known about the pharmacology of oxycodone, and it was seldom used in comparative animal testing before the priority date.
- Dr McKnight's cross-examination proceeded on the basis that if one was looking for an alternative to morphine for morphine intolerant patients he would look for and find clinical studies comparing the known opioids with morphine to see which ones were likely to be useful. However no such studies were put to Dr McKnight, and, as I shall show, none was part of the common general knowledge. His later acceptance that oxycodone would be one among a number of candidates for consideration for development into a controlled release formulation has, it seems to me, to be seen in that light, as well as in the light of his earlier written evidence which was not directly challenged.
- Professor Power considered that a majority of specialists in 1991 considered oxycodone to be a weak to medium strength analgesic. In his view, in 1991, the most common use of oxycodone was in products where it was combined with weak analgesics such as paracetamol which were not, to his knowledge, in use in the UK. He had no personal experience of the clinical use of oxycodone in 1991 and he believed that the majority of clinicians would have been in the same position. Compounds that were in clinical use in 1991 as alternatives to morphine included diamorphine and methadone. He remembered the Boots oxycodone suppository, but did not think that this was ever a widely used product.
- Professor Power first encountered oxycodone on taking up an appointment in Australia in 1994. He wondered how Australian clinicians had managed to keep it such a secret. On returning to the UK in 2000 he found that his colleagues still had little experience of the use of oxycodone.
- Professor McQuay said that he had relied on a number of textbooks and review articles to support his views about the common general knowledge in 1991. I will have to return to these materials and others in due course. In paragraph 51 and following of his first report he gave his clinician's view of a long list of strong opioids. These included partial agonists like buprenorphine and butorphanol, which he pointed out had a ceiling effect on their efficacy and were therefore used at low to intermediate doses.
- As to oxycodone, Professor McQuay explained that it was available in the UK as a suppository as an alternative to injections, although he did not explain what injections these would have been. Some hospices used the suppositories as an alternative to oral administration of morphine when that became difficult. He said that in Finland oxycodone was used as an alternative to morphine for post-operative pain.
- Professor McQuay is correct that oxycodone was available in Finland. In his first report he did not refer to any specific material to support this use. ratiopharm/Sandoz put a May 1990 paper by Kalso and Vainio from the Journal of Clinical Pharmacology and Therapeutics to Professor Power in cross examination. The authors reported that
"Oxycodone hydrochloride .. is a semi-synthetic narcotic analgesic agent that has been in clinical use since 1917 and that is considered to be comparable to morphine in its pharmacologic actions. The administration of 10 to 15 mg of oxycodone hydrochloride intramuscularly has been reported to be equal to 10 mg of morphine intramuscularly, and both drugs have a duration of 3-4 hours. The oral bioavailability of oxycodone hydrochloride is 50% or more. The clinical impression is that it is as effective as morphine but with fewer side effects. At the moment oxycodone hydrochloride is available for oral use only as 5 mg tablets or in combination with other analgesic agents and has therefore been used only for mild to moderate pain. Few studies of the efficacy of oxycodone hydrochloride have been done in patients with severe cancer pain and no studies exist of its pharmacokinetics." Emphasis added.
- In their "Results" section Kalso and Vainio reported that both oxycodone and morphine hydrochloride effectively relieved cancer pain with both intravenous and oral administration. They suggested that they had observed hallucinations only to occur with morphine.
- In the course of his cross examination, Professor McQuay identified this paper as having caused a change in thinking about oxycodone. He said that
"eyebrows went up when people realised that this drug was misclassified … by all of us because it came in these …. combination with paracetamol and aspirin. So we were just wrong. You know that this drug actually was a strong drug, as we now know. I think that Clinical Pharmacology and Therapeutics paper was very important in opening people's eyes why."
- When Kalso and Vainio was put to Professor Power in cross-examination he explained that he had not read it, although he did accept later that he was aware of some of the Finnish work. As ratiopharm/Sandoz had not notified him that this was a paper on which he might be cross examined, he was asked to read it overnight. When the paper was put to him again the following day, it was not suggested to him that its contents were part of the common general knowledge, or that it had changed people's thinking in the way Professor McQuay suggests. The cross examination was concerned only with what the authors had found about morphine and oxycodone.
- In a number of answers in cross-examination Professor McQuay referred to an increase in interest in oxycodone prior to 1991 at conferences, seminars and in publications. At one point Professor McQuay referred to a "tsunami of evidence coming out of Finland for their use". This did not accord with Professor Power's recollection at all. He said that in all the research meetings that he went to in the 1980s and before the priority date, he never heard of any research on oxycodone. At that time he was attending just about every analgesic research meeting he could.
- I conclude that either Professor Power or Professor McQuay must be mistaken as to the date. No material evidencing any such upsurge in interest is before me. If there had been such an upsurge before the priority date, I would have expected some of that material to have been made available to the court. It was not.
- I think that that the reason for this conflict between the professors is that Professor McQuay had known Dr Kalso since 1984 and co-authored a paper with her in 1991. He would have known more about the work on and use of oxycodone in Finland through this route than would ordinary clinicians without the benefit of such a connection.
- It is not accepted by Napp that Kalso and Vainio, or indeed the use of oxycodone in Finland, formed part of the common general knowledge. I do not think that the evidence comes anywhere near establishing that either of these matters formed part of the common general knowledge. This finding plays an important role in this case, given the heavy reliance which Professor McQuay placed on the Finnish material in support of ratiopharm/Sandoz's argument about obviousness over the common general knowledge.
- Nevertheless I should also consider the other documentary evidence originally relied on by Professor McQuay as establishing the common general knowledge. I have assembled them in chronological order.
- Twycross and Lack "Symptom Control in Far Advanced Cancer: Pain Relief" was published in 1983 and so antedates the patents in suit by some eight years. Twycross was at this stage an honorary lecturer at Oxford University and a consultant at the Churchill Hospital, whilst Lack was a consultant in hospice care at a hospital in Connecticut USA: so the book obviously has UK and US input. In its classification of analgesics in Table 6.3 it classified oxycodone as a weak narcotic agonist, with a footnote referring to another section for a comment. The comment reads
"Until recently, oxycodone was available in the USA only in combination with other drugs. Thus although oxycodone could be characterized as a strong narcotic, possibly as potent as morphine, it has been used in the USA as a weak narcotic by virtue of the small content in available tablets. Dose increase has also been limited by aspirin toxicity"
- Table 8.7 includes a reference to an unbranded syrup of oxycodone hydrochloride at 1mg/ml. Both the comment above and the Table appear in the chapter concerned with "Weak narcotic agents". Twycross and Lack's recommendations for alternatives to morphine are listed in Table 6.6, part of a general chapter on "Analgesics". They are papaveretum, phenazocine, hydromorphone and oxymorphone. Oxycodone is listed in the same table as a weak narcotic alternative to codeine.
- As I mentioned earlier, it is this book which recommends a drug which is as chemically distinct as possible from morphine for those patients who are intolerant to morphine. Examples of alternatives are given as phenazocine and hydromorphone, dipipanone, dextromoramide and pethidine. There is no section on oxycodone in the chapter "Alternative strong narcotic agents", although there are sections on many other agents.
- The WHO Guidelines on Cancer Pain Relief published in 1986 was obviously a highly influential document. It contains, as Table 3, a list of alternatives to morphine: methadone, pethidine, buprenorphine, standardized opium, hydromorphone and levorphanol. Oxycodone is not included, either in this list or elsewhere in Table 3 (even as a weak opioid). The alternative strong opioids discussed in the text are methadone, pethidine and buprenorphine. The problem of accumulation with methadone is noted. Both pethidine and buprenorphine are said not to be complete alternatives to morphine. The text also points out that in some countries methadone, pethidine and levorphanol may not be available. In those circumstances it is said that standardized opium (which is essentially diluted morphine), hydromorphine and levorphanol "should be satisfactory".
- The American Pain Society published a guide called "Principles of Analgesic Use in the Treatment of Acute Pain and Chronic Cancer Pain" in 1989. Oxycodone is listed in Table 2 which is entitled "Opioid analgesics Commonly Used for Mild to Moderate Pain". It is listed as a morphine-like agonist. The comment section says "... many preparations include acetaminophen which limits dose…". Table 3, headed "Opioid Analgesics Commonly used for Severe Pain" lists six morphine-like agonists as well as a number of mixed agonist-antagonists and a partial agonist. The morphine-like agonists include hydromorphone, methadone and levorphanol, noting an accumulation problem with the last two. The guidance recommends that the clinician become familiar with several strong opioids, pointing out that all the morphine-like agonists in Table 3(a) (which does not include oxycodone) provide similar qualities of analgesia and similar qualities and frequency of side effects. It recommends selecting an alternative to morphine where there is a limiting adverse effect of morphine. Oxycodone is mentioned as a supplement to non-opioids, where it is described in inverted commas as "weak". The guide goes on to explain that if more analgesia is required than can be provided with aspirin or an NSAID, morphine, hydromorphone, levorphanol or methadone should be used.
- Also published in 1989 was "Textbook of Pain" edited by Wall and Melzack. Wall was at University College London and Melzack was at McGill University in Canada. Chapter 48 is edited by Twycross (already mentioned) and Professor McQuay. Table 48.6 has a table of "Opioids by mouth, approximate equivalence to oral morphine sulphate". Oxycodone is listed in the table, but only by reference to the drugs Percodan, Percocet and Tylox, the combination products. In the text, under "Prescriber or Institution preference" it is pointed out that in the USA hydromorphone is widely used, whereas in Britain phenazocine is commonly used. Levorphanol is also mentioned. Not surprisingly, Napp placed considerable weight on the fact that Professor McQuay made no mention of oxycodone in this apparently international review.
- Bonica et al "The Management of Pain" (2nd Edition 1990) is an American textbook. This has a table (24-15) which lists oxycodone amongst the "potent opioid analgesics". The entry for oxycodone has the comment "used orally in combination with aspirin or acetaminophen". Acetaminophen is another name for paracetamol. The plasma half-life is said not to be known. There is a reference to Percodan, Percocet and Tylox. When it came to considering alternatives to morphine, it mentioned methadone as "the best alternative in patients who have intolerance to the standard agent" i.e. morphine. Levorphanol was said to be "another effective alternative to morphine". Also mentioned are meperidine, heroin, pentazocine, nalbuphine, butorphanol, and buprenorphine. Oxycodone is not mentioned in this context.
- The British National Formulary for September 1991 merely explains that oxycodone is used in the form of (special order) suppositories for the control of pain in terminal care.
- That completes a review of the materials put forward in Professor McQuay's report. They do not provide any support for the view that oxycodone was perceived as an alternative to morphine. Some additional materials were put to Professor Power in cross-examination.
- The first of these was "Analgesic Studies of Codeine and Oxycodone in Patients with Cancer. II. Comparisons of Intramuscular Oxycodone with Intramuscular Morphine and Codeine" by Beaver and a group from the Sloane-Kettering Cancer Research Institute and the Department of Pharmacology at Cornell University. The article was published in the Journal of Pharmacology and Experimental Therapeutics in 1978. It refers to an earlier paper by the same principal author which is presumably the first in this series. The paper was not established to be common general knowledge. Indeed, this was another paper that Professor Power had not read at the time he was first cross-examined on it. In any event Beaver does not show oxycodone to be a practical alternative to morphine for oral use for the treatment of moderate to severe pain.
- A paper by Ada Rogers was published in Virginia Medical in April 1989. Ada Rogers is a nurse based in New York who had been a co-author of the Beaver article in 1978. Table 2 lists oxycodone by reference to Percocet and Percodan.
- The next article is "Pharmacologic Approaches to the Control of Cancer Pain" by Portenoy, also of the Sloane Kettering Cancer Centre and Cornell University. This was published in the Journal of Psychosocial Oncology in 1990. There was no evidence that this publication was one regularly read by those skilled in this art, or that this paper formed part of the common general knowledge. Table 2A lists a large number of "morphine-like agonists", including oral oxycodone. At page 89 the author states that "In the United States, the "strong" opioids include morphine, methadone, hydromorphone, meperidine (considered to be strong when given parenterally), levorphanol and oxycodone (when it is not combined with another analgesic)." In Table 2B oxycodone is said to be available without a co-analgesic and it notes "Higher doses used for severe pain or tolerant patients." In discussing the stepwise approach to analgesia, the author says:
"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"
- This is a somewhat tentative suggestion of oxycodone. Even if it were established that this was a generally read publication, the statement that oxycodone was "potentially" selectable does not strike one as providing a sound basis for action. One would have no way of knowing how it would compare with other drugs which had been regularly used for that purpose in terms of side effects when substituted for morphine. Moreover the statement that oxycodone had recently become available without co-drug in elixir form seems to conflict with Twycross & Lack. I have surprisingly little evidence as to what the tablet form was or how widely it was available. Professor McQuay did not know it had been available before the priority date until shortly before the trial.
- Later in the text, Portenoy points out that "Refractory side effects mandate a switch to an alternative drug, route of administration or analgesic approach". He makes no specific recommendations for alternatives to morphine in these specific circumstances.
- ratiopharm/Sandoz placed some reliance on a short contribution by Ada Rogers of the Sloane-Kettering Centre in the Journal of Pain & Symptom Management published in October 1991. The article is entitled "The underutilization of oxycodone". It reports a case study on a patient receiving 45 mg of morphine by mouth every four hours and who had previously been receiving oxycodone and paracetamol tablets (5mg and 325 mg). The patient was experiencing side effects and was switched to oxycodone elixir and paracetamol elixir (30mg and 650 mg). Oxycodone elixir is said to have been recently introduced. It was reported that several patients had a similar experience.
- This particular paper by Nurse Rogers was first mentioned by Professor McQuay in the course of his cross examination and was identified by him in re-examination. It was never put to Professor Power. The title of the article is supportive of a general lack of appreciation of oxycodone as an alternative to morphine. Moreover the oxycodone therapy recommended was still not a single drug therapy, which might be thought to maintain the view that oxycodone on its own was not thought to be a direct substitute for morphine. As the paper was not put to Professor Power, I did not have the benefit of his views on it. In any case, as the paper is by no means established to be common general knowledge, I do not think it provides any support for ratiopharm/Sandoz' case.
- It is significant that after the priority date Glare & Walsh, two well respected physicians and authors in this field, wrote to the Journal of Palliative Medicine pointing out that oxycodone was usually classified as a weak opioid analgesic because the dose could not be increased above 10 mg every four hours due to the risk of toxicity by increasing the doses of the co-drugs. They pointed out that "little was known about the pharmacology of oxycodone" and that "few studies had looked at the analgesic efficacy of higher doses" but that "it may be as effective as morphine with fewer side effects". It pointed out that there were no relative potency data for the two drugs when administered orally. They were currently undertaking studies themselves. They suggested that single-entity oxycodone should be re-classified as a strong opioid analgesic.
- Given that this document post-dates the priority date, I think it is powerful evidence that before the priority date oxycodone was generally perceived as a weak opioid analgesic. Moreover it is strong support for the fact that relatively little was known about it as a single entity oral dosage form in 1991.
- I conclude that the majority of those clinicians who had experience of oxycodone would regard it as a co-drug administered with aspirin or paracetamol to give additional analgesia by another mechanism. They would know that it was a potent opioid. I consider that most clinicians would have no practical experience of the use of oxycodone as an opioid alternative to morphine in 1991. Such use did not form part of the common general knowledge.
The difference between the common general knowledge and the inventive concept
- For this purpose it is sufficient to say that the principal difference between the inventive concepts of all the claims relied on and the common general knowledge is the provision of a controlled release version of oxycodone.
Were the differences obvious without the benefit of hindsight?
- I have to admit that I approached this case, at the outset, with a notion that it would be surprising if a controlled release version of a known drug turned out to be inventive. After all, controlled release technology is a technology of potentially universal application. If a drug is being taken four times a day over an extended period, it is potentially more convenient to take it at less frequent intervals. The motivation to do so might be thought to be automatic. The means of achieving the goal are available. Unless there is some specific technical difficulty to overcome (and none is suggested here), why does making a controlled release version of a known analgesic warrant a patent?
- As the case progressed, however, I appreciated that this was, for whatever reason, not the way in which the case for obviousness was advanced. Moreover I began, as I listened to the evidence, to nurture doubts about whether a case presented in the way I had originally conceived would necessarily have succeeded. It may be, for example, that absent a perception of oxycodone as an alternative to morphine for moderate to severe pain, it simply would not have occurred to the skilled team to make controlled release versions. Oxycodone in its traditional role as a co-drug might not be thought suitable for controlled release. I just do not know: certainly no witness said that he would think in that way. It should not be assumed that the task of preparing a controlled release version of a drug is a trivial one. A skilled team would not routinely make controlled release versions of known drugs in the absence of a proper rationale. It may be that it is unrealistic to suppose that the ordinary advantages of controlled release will always amount to a sufficient rationale.
- The case of obviousness which Napp was called upon to meet was set out very clearly in the evidence of Professor McQuay and in Mr Silverleaf's opening. This was that the skilled team approaching matters in 1991 would perceive a need for an alternative therapy to morphine for those patients who were showing intolerable side effects to it. Just as MST Continus, the controlled release version of morphine, was a useful therapy for those patients who could tolerate morphine, a controlled release version of an alternative to morphine would be useful for those patients who could not. In putting their case in that way ratiopharm/Sandoz gained the advantage of a clear rationale, but took on the burden of showing that oxycodone would be perceived as a practical alternative to morphine at the priority date.
- There are two matters which would be in the background to any research or development work in this area. Firstly, in seeking to find an alternative to controlled release morphine, the skilled team would not be limited to existing drugs. Although research into agonists which act on receptors other than the mu-receptor was on the wane, this avenue cannot be regarded as shut off. Secondly, the approach of seeking out an alternative drug which is as chemically different as possible to morphine would also recommend itself to the skilled team, particularly as such an approach might eliminate the side effect problem rather than rely on inter-patient variability. These considerations apply equally to all the obviousness attacks, and operate as a brake on too ready an assumption that the skilled team would necessarily choose the route of seeking out a known drug as a solution to this problem.
- In support of ratiopharm/Sandoz' case based on common general knowledge, Professor McQuay suggested that he would make a shortlist of known drugs which would fulfil this role. On this list he would include hydromorphone, oxycodone and levorphanol. He would exclude methadone on the grounds of its risk of accumulation, and others on other grounds.
- I have considerable doubt about whether Professor McQuay would have included oxycodone on such a list in 1991. That the average clinician member of the skilled team would have done so at the start of such a project seems highly unlikely. My doubts about the position of Professor McQuay stem partly from his own contemporaneous writing. I have already mentioned his chapter in Wall and Melzack's Textbook of Pain (1989). A number of other papers of which he was an author were put to him, none of which discussed oxycodone as an alternative to morphine, although their contexts would have provided an opportunity to do so. One of the papers cites the Kalso and Vainio paper, yet does not make the suggestion of oxycodone as an alternative. Professor McQuay's explanation was that this was simply because oxycodone was not available to British clinicians, and so there was no point in discussing it. But Professor McQuay had discussed other drugs which were not available. I think the reason he did not include oxycodone on the list is that he personally had no experience of using it. In that respect he was no different from the vast majority of clinicians. I fail to see how oxycodone finds its way onto his list for the purposes of these proceedings, but did not when he was compiling such lists around the priority date.
- I have explained in some detail what I consider to have been the state of common general knowledge about oxycodone in 1991. The average clinician would not put oxycodone on a list of alternatives to morphine for a development into a controlled release product. He simply did not know enough about its oral administration or clinical performance in comparison to morphine to make that judgment.
- Professor Davis (the formulator called by ratiopharm/Sandoz) gave evidence that, given the similarities between oxycodone and morphine and the fact that a successful controlled release version of MST Continus was on the market, a controlled release version of oxycodone would be "well worth trying". This evidence was, however, given on the basis that he had been asked to develop such a formulation. He did not explain how he would have come up with the idea if he had not been asked. I therefore did not find his evidence to be of any real value in support of the case of obviousness over common general knowledge. Moreover it is clear that the information which he gathered about the similarities between the two drugs was gathered in consequence of his being asked to consider the development of an oxycodone formulation.
- I should refer to two other matters. The first is a letter ("the Twycross letter") dated September 27th 1990 from Dr Twycross to a Dr Miller who was Medical Director of Napp. The letter recommends that Napp consider developing an ordinary and a slow release version of oxycodone as an alternative to morphine. He describes oxycodone as an "exciting alternative agent". The basis for his recommendation is a pair of articles attached to his letter "together with anecdotal evidence from Vittorio Ventafridda's group". It is not clear from the evidence what those other papers were. Dr Twycross explains that in addition to the data in the two papers, Dr Vainio herself has observed two interesting phenomena, namely that a patient who appeared to be hyperalgesic when receiving morphine did not so appear on oxycodone and that patients on oxycodone do not hallucinate.
- ratiopharm/Sandoz attached considerable importance to the Twycross letter in support of their case. I do not consider that it provides any support at all. It is accepted that the Twycross letter is a private communication: it does not form part of the state of the art. Dr Twycross was a very distinguished and, according to the evidence, a somewhat idiosyncratic figure in this field. He was basing his suggestion on material which is wholly different from that relied upon as the starting point for the obviousness attack in the present case. Although the two papers have not been identified, it is clear that they were neither Oshlack nor Goldie (which were both Napp documents) and not "papers" in the real sense. It appears that they did not include the Kalso & Vainio 1990 paper which Dr Miller had to obtain subsequently. They were probably other Finnish papers, but there was no evidence as to their contents. In addition to whatever was contained in the attached papers, he relied on personal communications from two research groups working in the field, neither of which are pleaded here. None of these was part of the common general knowledge, if indeed they were published at all. It is not even clear that the letter would support an allegation of obviousness over the materials to which Dr Twycross refers: given his pre-eminence in the field he is probably not representative of the person skilled in the art. It is not necessary for me to decide whether there is anything in that allegation of obviousness, although I suspect it would have failed as being based on an illegitimate "mosaic" of materials of the kind which is not permissible in patent law.
- For my part I think the Twycross letter, if anything, helps Napp rather than ratiopharm/Sandoz. Why would Dr Twycross write a letter to Napp to inform Napp of matters such as these if they were already obvious in the light of common general knowledge? His description of oxycodone as an "exciting alternative agent" shows that Dr Twycross had started to view oxycodone in a wholly different light from that which it was viewed by the majority of clinicians, namely as an alternative to morphine. The picture of oxycodone as an exciting alternative agent is not the one which emerges from the common general knowledge.
- The second matter is that according to research done by Napp in 1986, oxycodone pectinate suppositories were the commonest replacement therapy for morphine in patients who could not swallow. Again, I do not think this helps ratiopharm/Sandoz. Such use would not make the clinician view oral dosage forms of oxycodone as a direct replacement for oral morphine.
- I conclude that it would not occur to a skilled team in 1991 to place oxycodone on a list of potential alternatives to morphine for making into an oral controlled release formulation.
- Even if oxycodone were to be mentioned in this circumstance, I consider that too little was known about its clinical performance in comparison to morphine as an oral analgesic to make it an obvious choice for further development in those circumstances. Many of the publications to which reference has already been made refer to this lack of data: the Glare and Walsh paper being a clear example.
Conclusion on obviousness over the common general knowledge
- I conclude that the inventive concept of the claims was not obvious in the light of the common general knowledge.
Obviousness over Oshlack
Disclosure of Oshlack
- Oshlack was published on 20th January 1988. It is entitled "Controlled release bases for pharmaceuticals." The essence of what is disclosed is that by using a combination of a higher aliphatic alcohol and an acrylic resin, the release of an active ingredient from a controlled release matrix can be varied over a period of time from 5 hours to as much as 24 hours (see page 3 lines 34-39).
- At page 4 lines 14-18 the specification says this:
"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."
- The specification also explains at page 4 lines 29-34 that it is possible to exert a degree of control over the release rate by varying the proportions of the ingredients.
- Oshlack contains four detailed examples of the use of the combination of aliphatic alcohol and acrylic resin, providing in vitro dissolution data for each with different proportions of the two principal ingredients. The four active ingredients are aminophylline (a bronchodilator), propranolol (a beta blocker), and the two analgesics, morphine sulphate and oxycodone.
- Example II is the oxycodone example. Oxycodone is introduced simply as a "narcotic analgesic". The example states that "it was desired to produce an oxycodone controlled release tablet which would show a controlled gradual release of active material over an approximate 9-10 hour period."
- Example II describes two formulations: one incorporating no acrylic resin, and one in which part of the stearyl alcohol used in the first has been replaced with acrylic resin. Both contain 9.2 mg of oxycodone. The release of the oxycodone in vitro in simulated gastric fluid for one hour followed by simulated intestinal fluid is shown to be duly extended (complete dissolution moving from 5 to 9 hours). This is described by the author as "potentiation of the control of release of the oxycodone". Potentiation is a word sometimes used in connection with a supra-additive or synergistic effect. But the skilled person in this instance would see that there was no attempt to establish such an effect and would assume that the word was being used in the sense of achieving a further degree of control.
- Example 4 relates to morphine which is introduced as "very effective for pain relief and in the care of terminal cancer". The example is of two tablets, each containing 30 mg of morphine sulphate.
- There is a dispute between the experts as to whether the skilled reader would regard the direction in Oshlack to use oxycodone as a direction to use that ingredient in the form of a free base or a salt. I agree there is some doubt about it, but I believe the skilled person considering the document would readily conclude that it was a soluble salt and not the free base. Even if he nurtured some lurking doubt, he could readily discover that the free base is virtually insoluble and unsuitable for use in a pharmaceutical in that form.
Oshlack - enablement
- Quite apart from the question of what Oshlack discloses, Napp raises a question as to what it enables. It is common ground that the skilled formulator carrying out Example II of Oshlack with the hydrochloride salt, would discover that the release rate was too fast for a twice daily dose. According to such evidence as there is, this oxycodone salt in this formulation was all released in 4 hours.
- Professor Aulton was cross-examined on the issue of enablement:
"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."
- I did not understand Professor Aulton to have accepted anything going beyond the disclosure of the document. I therefore do not think that it is established on the evidence that the teaching of Example IIB of Oshlack, coupled with the general teaching in the document to which Professor Aulton was referred, is adequate to enable the skilled person to make anything other than a four hour controlled release formulation using Oshlack's ingredients.
- I should make it clear here that I am considering enablement in the sense of a person who is seeking to make Oshlack's invention work. It was essential to Oshlack's idea to use the aliphatic alcohol/acrylic polymer combination. I do not treat this finding as in any sense foreclosing a finding of obviousness of the claims of the patents in suit in the light of the document (although it obviously does not set the inquiry off to a promising start). That will depend on other evidence.
The differences between Oshlack and the inventive concept
- As Mr Silverleaf correctly pointed out, starting from Oshlack gave him the advantage (as compared with his common general knowledge case) that he was starting from a document which disclosed the use of oxycodone. Moreover it discloses the use of oxycodone as a single agent in a controlled release formulation.
- As compared with the enabled disclosure of Oshlack, the differences with the inventive concepts of the various claims in issue would appear to be that each claim relied on requires at least one of the following features:
i) the provision at steady state after 12 hourly dosing of maximum and minimum plasma concentrations within ranges;
ii) a film coated spheroid formulation;
iii) an in vitro release rate by USP Paddle Method (still releasing after 4 hours);
iv) a coating controlling release.
Were the differences between Oshlack and these inventive concepts obvious?
- It is at this stage that it is particularly important to avoid hindsight.
- Oshlack is a document aimed at a formulator. Its disclosure is concerned far more with the novel controlled release matrix than with the identity of the drugs released by it. In that respect it is different to the patent in suit which includes information about the clinical performance of the drug. I gained the very clear impression that it was not the sort of document which any of the clinicians who gave evidence would be accustomed to reading or which would much influence their thinking. Nor do I think it is a document which would influence the thinking of a pharmacologist.
- Professor Davis, ratiopharm/Sandoz' formulation expert, gave evidence in his report that Oshlack would be regarded as a rather unexciting document. His view was that the combination of a hydrophilic and a hydrophobic polymer as a controlled release matrix was part of the common general knowledge. The combination of a higher aliphatic alcohol (hydrophobic) with an acrylic resin (hydrophilic) "would not have been thought of as a major advance". He would not have been impressed by the reference to potentiation in the absence of supporting data. He goes on to point out that there is no data in Oshlack comparing the controlled release formulations of morphine and propranolol with commercially available versions of those drugs of which the formulator would be aware.
- Having reached that conclusion, Professor Davis relates that he was then asked by those instructing him to consider the formulator's approach "if he had been requested in 1991 to develop an oral controlled release formulation of oxycodone suitable for delivering pain relief over a period of 12 hours in the light of 104A." It is unfortunate that he was asked this question. It would have been preferable to have asked him what he would have done in the light of the document, particularly in the light of his conclusion that he found it rather unexciting.
- I think the evidence establishes nevertheless that the skilled person would have carried out the example involving oxycodone in order to test Oshlack's hypothesis that an aliphatic alcohol can be used in such formulations in place of a polymer. There would have been no invention in taking that step. He would have discovered that he could get a controlled release version of oxycodone in this way, although the release would have been very rapid if he used the hydrochloride salt, as he probably would. I am also satisfied that there would have been no invention involved in carrying out the example with a slightly larger dose of oxycodone (so as to bring the dose up to the 10 mg bottom limit of some of the claims). That is not, however, enough to bring the skilled person within any of the claims of either patent. It would not provide a 12 hour dosage which would keep the plasma levels within the ranges, or the USP dissolution rate which requires release to continue after 4 hours, or a film coated or spheroid formulation.
- Professor Davis suggests that the discovery that the release rates obtained by Example IIB of Oshlack were too fast might lead the formulator to try different acrylic polymers or to use some other combination of alcohol and acrylic polymer. He observed that the amount of lactose used in Example IIB of Oshlack seemed rather high, and that he might experiment with that as well. Alternatively he might turn to a different technology such as a different type of matrix, a reservoir or osmotic pump. He accepted that this was in the nature of a development program, although he did not accept that it could be properly categorised as "research".
- I have no doubt that a skilled person with sufficient motivation to produce a controlled release version of oxycodone could have constructed a development program to do so at the priority date. The evidence shows clearly that controlled release technology enabled the skilled formulator to make a fairly confident prediction that he could make a twelve hour version of any drug unless it had rather unusual properties. An example cited by Professor Aulton was the case of a drug which already absorbed so slowly that a controlled release version would not make sense. Extremely high solubility would be another problem. Another example would be where the dose size necessary would make the controlled release version look like a horse pill. But within these very broad limits most things were possible, even if the work involved in most cases would be far from trivial.
- I think the question of obviousness over this document, at least of the wider claims, thus boils down to a very simple question. Would the skilled team having read Oshlack be sufficiently motivated by it (or by Oshlack and common general knowledge) to embark on the development program described by Professor Davis so as to arrive at a 12 hourly controlled release oral dosage form of oxycodone?
- Napp's submissions on obviousness over Oshlack are as follows. It argues that Oshlack does nothing to change the skilled team's perception of oxycodone as a drug. Unless one approached Oshlack with a pre-formed determination to make a controlled release version of oxycodone, one would see no purpose in taking its disclosure further. In fact the skilled person would approach Oshlack with the common general knowledge view of oxycodone, a weak opioid used as a co-drug for mild to moderate pain. In Oshlack, oxycodone would be seen as a drug chosen as an example for testing Oshlack's new base, rather than as the jumping off point for development of that particular drug. Oshlack's idea of using an alcohol and a polymer would be seen as a disappointing one.
- ratiopharm/Sandoz rely on the evidence that Professor McQuay gave in his report:
"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. "
- It seemed to me that this evidence was based on the premise that the skilled clinician approaches Oshlack with the understanding that oxycodone is in all relevant respects an alternative to morphine. This, after all, was Professor McQuay's position. I can entirely understand such a clinician having the reaction to Oshlack that Professor McQuay describes. As Professor McQuay said, it would tell the clinician that the formulator should be able to achieve the objective of an alternative to MST Continus with oxycodone as the active ingredient. On making that request, I have no doubt that the formulator would eventually respond with something to meet the brief, although, from the evidence, the formulator would find Oshlack more of a hindrance than a help.
- It is significant that Professor McQuay did not give any convincing reason why the skilled team would get the idea of a controlled release oxycodone alternative to MST Continus from the disclosure of Oshlack itself. Although both morphine and oxycodone are referred to within the confines of this document, there is no attempt to relate one to the other or to present them as alternatives. There was one passage of cross examination where Professor McQuay appeared to suggest that what was said about morphine in Example IV at page 9 line 30 also applied to oxycodone (Transcript page 632), but I am unable to accept that suggestion as a proper reading of the document.
- Professor Power was cross-examined on the basis that he was a palliative care physician in a territory where oxycodone was available, such as North America or Australia (although, as I have said, it was not established that oxycodone was available in single active oral form in Australia before the priority date). Although the assumption was originally put as one involving only knowledge of the existence of oxycodone and its half-life, it was clear that Professor Power thought that he was being asked to assume experience of its use in palliative care as well. The following passage is what then occurred:
Q. Can we concentrate on oxycodone just for the moment? The context in which I have asked you to put yourself is one where oxycodone and morphine would be the drugs of interest to you as a palliative care physician. Right?
Q. You already have controlled-release morphine.
Q. When you look at this document, it is of interest to you because it provides the possibility of a controlled-release oxycodone formulation giving extended therapeutic activity.
A. If the claims of extension of time are correct, yes.
Q. So you would take this to a formulator and say, "Can you make me up something that will give me extended release oxycodone over 12 hours?" You would ask the formulator whether, on the basis of this, it could be done because this is a formulation patent, is it not?
A. Yes. You are proposing a clinician, such as myself, working in palliative care, would see this and then find a formulator and say, "Can I have some of this, please?"
A. I have put myself in the position you have suggested, in Australia, working as a palliative care physician. That is just not the way most drugs are developed now with a clinician suddenly fronting up the front door of a manufacturer.
Q. I understand that. I also understand that you have not personally been involved in this process. What I am saying to you is, if you were in that situation and you were given this document, it would be of sufficient interest to you to say, "I would like a formulator to see if he can make this up for me."
A. So a palliative care physician who uses oxycodone, who has seen this and has an intimate relationship with a drug company ----
Q. Let me put it to you like this. You have available to you the opportunity to do that.
A. Yes. I wonder how many people are in that situation.
Q. I am not asking you to consider that. I am asking you to consider what you would do if you were in that situation.
A. With all these fortunate circumstances coming into place?
Q. Make those assumptions.
A. This is a bit like accidents happening because all the holes line up in the cheese, but ----
Q. Could you just make these assumptions, professor.
A. If you had all these assumptions lined up, then I think you would, yes.
- I put to one side the question of whether it is common for drugs to be developed in consequence of suggestions from the physician. As I have held, the skilled team includes access to the opinions of clinicians. However Professor Power was, as I understood the cross-examination, also being asked to assume that the clinician was one who had experience of using oxycodone in palliative care. I do not think it is justified to assume that the skilled person has such experience. Such experience would have been exceptional rather than common in 1991.
- As I have held, at the priority date oxycodone was not perceived, as a matter of common general knowledge, as an alternative to morphine in palliative care. Thus, the clinician reading Oshlack would not see Example II of Oshlack as providing him with an alternative to MST Continus. In my judgment, Oshlack would not prompt the clinician to make the request which Professor McQuay describes, or that which was suggested to Professor Power. Example II would be explored to the extent necessary to test Oshlack's invention, but no further. There is nothing in Oshlack to alter the skilled team's perception of oxycodone as a drug.
- Accordingly I do not think that Professor McQuay's evidence, or Professor Power's cross-examination carries ratiopharm/Sandoz home. Absent the suggestion from the clinician to launch a development program based on Oshlack, the evidence does not persuade me that the skilled team would take the project further than an investigation of Oshlack's new base. The evidence does not establish that such an investigation would lead the skilled team to a product within the claims.
- None of the claims is obvious over Oshlack.
Obviousness over Goldie
- Goldie is entitled "Controlled release hydromorphone composition". As its title suggests, it is concerned with hydromorphone not oxycodone.
- Accordingly, the principal difference between the disclosure of Goldie and the inventive concept is the identity of the active ingredient in the controlled release formulation.
- Professor McQuay's evidence was that, as hydromorphone was one of the three alternatives to morphine on his list, he would say to himself "well, if you could do this with hydromorphone, you could do this with oxycodone". His evidence in cross examination was very clearly on the basis that, for someone who had already selected oxycodone as an alternative to morphine, Goldie would lead to the suggestion that a controlled release version of oxycodone could be achieved.
- The evidence also established that one could not simply take a formulation developed for one active ingredient and assume it would work for another. Just as with Oshlack, so also with Goldie there would be a need to embark on some development work to establish a 12 hour formulation for oxycodone if one started from the hydromorphone formulation in Goldie. The starting point might be simply to try oxycodone in the Goldie formulation, but one would have no idea whether that would work.
- I think ratiopharm/Sandoz' case of obviousness over this document suffers from the same problems as that based on the common general knowledge. Unless the skilled team perceives oxycodone as a morphine-equivalent, one does not extract from Goldie any hint that one should do for oxycodone what one has done for hydromorphone. The necessary work is not so trivial that one can say it would be embarked on in the absence of an obvious rationale. Just as the case on common general knowledge fails because the skilled person does not see a controlled release oxycodone as an alternative to MST Continus, so also the case on Goldie fails because the skilled person does not see oxycodone as a substitute for hydromorphone in the examples of Goldie.
Controlled release oxycodone after the priority date
- I have outlined the advantages alleged for controlled release oxycodone in discussing the disclosure of the patents. Professor Bennett acknowledged that it formed "a valuable weapon in the armoury of the pain management clinician working in palliative care or otherwise", but he disagreed with Professor Power as to the existence of any titration advantage.
- Professor Power based his support for the conclusion on his own experience, and the fact that the data sheets for the two drugs indicate a clear difference in favour of oxycodone. Professor Bennett pointed to the lack of published studies to support the advantage. A published meta-analysis by Reid and others stated that the authors "found no clinically important differences between the analgesic efficacy or the adverse effect profile of oxycodone as compared with morphine." The paper does not specifically address a comparison of time to titration. A paper by Mucci LeRusso and others found no statistical difference between the time to titrate between the two controlled release drugs.
- The evidence does suggest that equivalent pain can be managed with oxycodone with a smaller range of doses than with morphine. However, in the end I was unpersuaded that the advantage claimed for oxycodone over morphine in terms of time to titrate to the correct dose had been shown to exist in practice. That is not to say that professor Power does not genuinely believe this to be so. None of this, however, helps ratiopharm/Sandoz to establish obviousness.
The application to amend
- The condition on which the application to amend 730 was dependent (invalidity) has not arisen. If it had, I would have allowed the amendment, as it is not opposed. The main effect of the amendment is to delete claims 1-5, which were not alleged to be infringed.
- The application to amend 246 is not opposed and is allowed.
- Neither 730 nor 246 is infringed by the Cimex tablets.
- Neither patent is invalid for added matter or obviousness.
- The condition on which the amendments to 730 were applied for has not arisen. The amendments to 246 are allowed.
- I will hand down this judgment at 10.30 on 16th December 2008. There is no need for any party to attend. I will adjourn at that time any application of which I am advised by 4.30 on the previous day. If an agreed minute of order cannot be agreed the action should be restored for further argument at the earliest convenient date.
Relevant claims of 730
1. A controlled release oxycodone formulation for oral administration to human patients, comprising:
(a) oxycodone salt in an amount equivalent to 10 mg to 160 mg of the oxycodone hydrochloride salt, and
(b) a controlled release dosage matrix, other than an acrylic resin matrix selected so that the formulation provides pH-independent dissolution characteristics,
(c) wherein said formulation provides, at steady state after repeated administration at 12-hour intervals, a mean maximum plasma concentration of oxycodone of 6 to 240 ng/ml at 2 to 4.5 hours after administration and a mean minimum plasma concentration of oxycodone of 3 to 120 ng/ml at 10 to 14 hours after administration.
6. A controlled release oxycodone formulation for administration to human patients, comprising:
(a) an analgesically effective amount of spheroids comprising oxycodone or a salt thereof and a spheronising agent;
(b) each spheroid being coated with a film coating which controls the release of the oxycodone or oxycodone salt at a controlled rate in an aqueous medium.
7. The controlled release oxycodone formulation of claim 6, comprising: an analgesically effective amount of spheroids comprising oxycodone salt and a spheronising agent, such that the total dosage of oxycodone salt in said dosage form is from 10 to 160 mg.
9. A controlled release dosage formulation according to any one of the preceding claims, whereby said dosage formulation provides an in-vitro dissolution of the dosage form, when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37°C, between 12.5% and 42.5% (by wt) oxycodone released after 1 hour, between 25% and 55% (by wt) oxycodone released after 2 hours, between 45% and 75% (by wt) oxycodone released after 4 hours and between 55% and 85% (by wt) oxycodone released after 6 hours, the in vitro release rate being independent of pH, wherein at steady state after repeated administration at 12-hour intervals, a mean maximum plasma concentration of oxycodone of 6 to 240 ng/ml is obtained in vivo at 2 to 4.5 hours after administration, and a mean minimum plasma concentration of 3 to 120 ng/ml is obtained in vivo at 10 to 14 hours after administration.
11. Use of a controlled release oxycodone formulation as defined in any one of the claims 1-10, containing oxycodone salt in an amount equivalent to 10 mg to 160 mg of the hydrochloride salt, for the manufacture of a medicament, said medicament when used at multiple 12-hour intervals in human patients, providing at steady state:
(a) a mean maximum plasma concentration of oxycodone of 6 to 240 ng/ml at 2 to 4.5 hours after administration;
(b) a mean minimum plasma concentration of oxycodone of 3 to 120 ng/ml at 10 to 14 hours after administration; and
(c) pain relief in substantially all human patients for at least 12 hours.
12. The use of claim 11, said formulation containing 10 to 40 mg oxycodone salt, and said medicament providing at steady state:
(a) a mean maximum plasma concentration of oxycodone of 6 to 60 ng/ml at 2 to 4.5 hours after administration;
(b) a mean minimum plasma concentration of oxycodone of 3 to 30 ng/ml at 10 to 14 hours after administration; and
(c) pain relief in at least 90% of all human patients for at least 12 hours.
13. The use of a formulation of claims 11 and 12, wherein the medicament is designed for application to a patient suffering from moderate or severe chronic pain.
14. The use of a formulation of claims 11 and 12, wherein the medicament is designed for application to a patient suffering from postoperative pain.
Relevant claims of 246
1. A controlled release oxycodone dosage form for oral administration to human patients, comprising:
(a) oxycodone salt in an amount equivalent to 10 mg to 160 mg of the oxycodone hydrochloride salt;
(b) a matrix incorporating said oxycodone salt;
(c) a coating on said matrix controlling the release of said oxycodone salt;
(d) wherein said dosage form has an in vitro dissolution rate, when measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37 °C, between 12.5 % and 42.5 % (by weight) oxycodone salt released after 1 hour, between 25 % and 55 % (by weight) oxycodone salt released after 2 hours, between 45 % and 75 % (by weight) oxycodone salt released after 4 hours and between 55 % and 85 % (by weight) oxycodone salt released after 6 hours.
4. The controlled release oxycodone dosage form of any one of claims 1 to 3 comprising:
(a) an analgesically effective amount of spheroids comprising oxycodone salt and a spheronising agent;
(b) each spheroid being coated with a film coating which controls the release of the oxycodone salt at a controlled rate in an aqueous medium.
9. The controlled release oxycodone dosage form of claims 1 to 8, wherein said in vitro release rate is substantially pH-independent, at pH 1.6 and pH 7.2.
16. Use of a controlled release oxycodone dosage form as defined in any one of the preceding claims, for the manufacture of a medicament, said medicament when used at multiple 12-hour intervals in human patients, providing at steady state:
(a) a mean maximum plasma concentration of oxycodone of 6 to 240 ng/ml at 2 to 4.5 hours after administration;
(b) a mean minimum plasma concentration of oxycodone of 3 to 120 ng/ml at 10 to 14 hours after administration; and
(c) pain relief in substantially all human patients for at least 12 hours.
17. Use of a controlled release oxycodone dosage form as defined in any one of the preceding claims, for the manufacture of a medicament, said formulation containing 10 to 40 mg oxycodone salt, and said medicament when used at multiple 12-hour intervals in human patients, providing at steady state:
(a) a mean maximum plasma concentration of oxycodone of 6 to 60 ng/ml at 2 to 4.5 hours after administration;
(b) a mean minimum plasma concentration of oxycodone of 3 to 30 ng/ml at 10 to 14 hours after administration; and
(c) pain relief in approximately 90% of all human patients for at least 12 hours.
18. The use of claims 16 and 17, wherein the medicament is for application to a patient suffering from moderate to severe chronic pain.
19. The use of claims 16 and 17, wherein the medicament is for application to a patient suffering from postoperative pain.