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IN THE HIGH COURT OF JUSTICE
||Royal Courts of Justice
Strand, London, WC2A 2LL
B e f o r e :
THE HON. MR JUSTICE BIRSS
|| ACCORD HEALTHCARE LIMITED
||- and -
||MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH
Adrian Speck QC and Lindsay Lane (instructed by Taylor Wessing) for the Claimant
Charlotte May QC and Mark Chacksfield (instructed by Bristows) for the Defendant
Hearing dates: 23rd, 24th, 26th November 2015
HTML VERSION OF JUDGMENT
Crown Copyright ©
Mr Justice Birss:
- This is a case concerning patent EP (UK) 2 046 332, entitled "Concentrated Methotrexate Solutions". The patent claims the use of a formulation of methotrexate with a concentration of about 50 mg/ml for the treatment of individuals with inflammatory autoimmune diseases by subcutaneous injection. The point of the invention is that known concentrations of methotrexate used for this indication were at a lower level (no more than 25 mg/ml) and so by using a higher concentration of the drug, the injection volume can be reduced and so the injection will be less painful.
- The patent has a priority date of 21st July 2006. The patent was originally filed and granted in the German language. The English translation is agreed.
- The proprietor of the patent is the defendant, medac. The company writes its name with a lower case "m". In this judgment I will use the lower case form of the name unless the word appears at the start of a sentence. Medac is a privately owned German company which promotes the development and marketing of therapeutics in malignant diseases, particularly therapeutics for use in treating cancer and autoimmune diseases. This patent protects medac's Metoject® syringe and pen products. These were launched in the UK in 2008 and are now widely used in the treatment of rheumatoid arthritis (RA) and related inflammatory conditions.
- The claimant in this action is Accord, a generic company. It is seeking to clear the way in order to launch its own 50 mg/ml injectable product. Accord claims that the patent is invalid; medac contends that the patent is valid.
- Claims 1, 13, 15 and 27 have been asserted as independently valid by medac. They are as follows:
Claim 1: Use of methotrexate for the production of a medicament to be administered subcutaneously for the treatment of inflammatory autoimmune diseases, wherein the methotrexate is present in a pharmaceutically acceptable solvent at a concentration of about 50 mg/ml.
Claim 13: Use according to claim 7, wherein the ready-made syringe contains a dosage of 5 to 40 mg, in particular 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20.0, 22.5, 25.0, 27.5, 30.0, 32.5, 35.0, 37.5 or 40.0 mg, of methotrexate.
Claim 15: Methotrexate for use in the treatment of inflammatory autoimmune diseases, wherein the methotrexate is to be administered subcutaneously and the methotrexate is present in a pharmaceutically acceptable solvent at a concentration of about 50 mg/ml.
Claim 27: Methotrexate for use according to claim 21, wherein the ready-made syringe contains a dosage of 5 to 40 mg, in particular 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20.0, 22.5, 25.0, 27.5, 30.0, 32.5, 35.0, 37.5, or 40.0 mg, of methotrexate.
- Claims 13 and 27 are dependent on intermediate claims (7 and 21) between claims 1 to 13 and 15 to 27 respectively. Those intermediate claims provide that the concentrated methotrexate solution is contained in a ready-made syringe.
- Claims 1 and 13 are Swiss form claims, claims 15 and 27 are purpose limited product claims (EPC 2000). Nothing turns on this and no issues of claim construction arise in this case.
- The issues are:
i) Obviousness in the light of:
a) The common general knowledge alone;
b) A paper "Methotrexaat buiten de kliniek" by Jansen et al. (1999) Pharmaceutisch Weekblad, Volume 134, No 46, p1592 (Jansen). The original language of the paper is Dutch. There is an agreed translation;
c) A letter "Tolerance of parenteral, higher dose methotrexate in children with juvenile chronic arthritis" by Russo and Katsicas (2000) Clinical and Experimental Rheumatology, Volume 18, No 3, p425, (Russo);
d) The fact that the patent encompasses embodiments which make no technical contribution. This is directed to claims 1 and 15 which provide no limitation on volume. Accord argues that some of the products within the claim offer no pain reduction advantage over the prior art and therefore the claim encompasses embodiments which make no technical contribution.
ii) Insufficiency. The argument is that the patent does not render it plausible that the claimed concentration could be safely administered to patients. This is a squeeze on inventive step.
- Accord called two experts: a clinician and a formulator. Medac called an expert clinician only.
- Accord called Dr Andrew Östör as its expert clinician. Dr Östör is a Consultant Rheumatologist and Director of the Clinical Research Unit at Addenbrooke's Hospital in Cambridge. He is an Associate Lecturer in the Faculty of Clinical Medicine at the University of Cambridge. He is also a Fellow of the Royal College of Physicians in London and Edinburgh respectively.
- Accord called Dr Peter Rue as its expert formulator. Dr Rue is a Visiting Professorial Fellow to the Department of Pharmacy of the University of Aston in Birmingham. He also currently acts as a commercial pharmaceutical consultant. He has many years of experience working in formulation and development in industry. His experience includes having worked as Head of the Pharmaceutical Development Department at Glaxo Research and Development from 1990 to 1995.
- Medac called Professor Ulf Müller-Ladner as its expert. Prof Müller-Ladner is currently Director of the Department of Rheumatology and Clinical Immunology at the Kerckhoff Clinic in Bad Nauheim. He is also Professor of Internal Medicine and Rheumatology at the Justus Liebig University Giessen and President of the German Society of Rheumatology for the year 2015-2016. Prof Müller-Ladner has previously worked with medac in a number of capacities, including as a consultant and as a member of its research advisory board. He has also acted as an expert witness for medac in a US action in respect of a related patent to EP 2 046 332 (US Patent No.8 664 231). Prof Müller-Ladner is a native German speaker but gave his evidence in English.
- Each witness gave their oral evidence fairly, aiming to assist the court. The parties made detailed submissions about aspects of each witness's evidence but they are best dealt with in context.
The person skilled in the art
- One of the important disputes in this case concerns the identity of the person skilled in the art. Accord submitted that the skilled person is a team consisting of a clinician, specialising in the field of inflammatory autoimmune diseases such as RA, and a formulator. The team may also include a nurse and a pharmacist although these latter two are not the focus of the controversy. Medac submitted that the skilled person is the clinician alone. The identity of the clinician following medac's approach is the same as Accord's. The major issue is about the position of the formulator. Accord submits it is plain from the patent itself that it is directed to a team consisting of a clinician and a formulator. So the skilled person is such a team.
- Looking ahead to medac's case on obviousness, it makes the following submissions. Medac argues that the formulator would only be brought into a team at the instigation of the clinician, that it would not be obvious to the clinician to think there was any need to produce a new formulation of subcutaneous methotrexate and so the clinician would not approach a formulator at all. Therefore it is unfair to define the team as a team consisting of a clinician and a formulator from the outset. To do so is to fall into the trap identified by the Court of Appeal in Schlumberger v EMGS  EWCA Civ 819 in that it may involve hindsight to postulate a team consisting of two distinct disciplines which had not been put together in reality before the priority date. The fact that, given the patent, one would put the two disciplines together into a team in order to implement the teaching does not mean that that team is the correct person skilled in the art for the purposes of obviousness. Medac also contends that the way in which Accord put its case in evidence was on the basis that impetus came from the clinician and so it is not legitimate to allow Accord to change its case in closing after the evidence had been heard.
- Starting with the general law: a patent is directed to those persons likely to have a practical interest in the subject matter (see e.g. Medimmune v Novartis  EWCA Civ 1234 at paragraphs 72 and 76). In appropriate cases the skilled person can be a team.
- Schlumberger shows that the skilled person in the context of obviousness is not necessarily the same as the skilled person from the point of view of reading and implementing the patent. In paragraphs 55 and 63 of his judgment in Schlumberger Jacob LJ (with whom Sullivan and Waller LJ agreed) explained that while it was generally true that the same person/team would be considered for both purposes, it was not necessarily so as a matter of law.
- What are the legal principles which govern the question ofwhether the skilled person or skilled team are the same for both purposes or not? The court in Schlumberger identified the following aspects as relevant. First, if an invention brought together two disparate fields and was therefore "art changing", then the identities of the person/team from the two different perspectives may be different (Jacob LJ paragraphs 55 and 64). Second, (paragraph 65) the court explained that a key question is generally – what problem was the patentee trying to solve? That leads one to consider the art in which the problem lay. It is the notional team in that art which is relevant. Third, you cannot assume that a person in one field would know what was known by a person in another field, proof is required (paragraph 70). Fourth, and importantly in my judgment, the skills (and mind sets) of real persons or teams in the art are what matter when one is constructing the notional skilled person/team to whom the invention must be obvious if the patent is to be found invalid (paragraph 42).
- The evidence of both Dr Östör and Dr Rue was that the skilled person was a team consisting of a clinician and a formulator. Prof Müller-Ladner's evidence was that the patent was addressed primarily to a clinician and that they would be able to call on the expertise of other people such as formulators and pharmacologists.
- On the question of the person to whom the patent is addressed, in my judgment Accord is correct and I prefer the evidence of Dr Östör and Dr Rue on the issue. The document itself is not directed to a clinician alone who may or may not choose to involve a formulator. It is directed to a team in which the clinician and the formulator are working together. Formulation is at the heart of the matter. The invention is the use of a new dosage form of a known drug (methotrexate) to treat diseases it is already indicated for (RA and other diseases) using a known mode of administration (subcutaneous). The new dosage form is a formulation of the drug in a solvent at a particular concentration (about 50 mg/ml). The patent is plainly addressed to such a team in a pharmaceutical manufacturer. After all that is where formulators work and that is where these new dosage forms come from. Prof Müller-Ladner accepted in cross-examination that the patent is directed to industry. It is common ground that the clinician will be someone with experience of treating patients, but for the purposes of considering this patent, they will work with the formulator.
- Turning to the question of the skilled person/team for the purposes of obviousness, I will address the factors mentioned in Schlumberger. I am satisfied that such teams existed in reality irrespective of the patent. Prof Müller-Ladner accepted that there were companies which might wish to make methotrexate products to compete with those already on the market and accepted that a skilled team working in industry would typically include a formulator and a clinician. Therefore the existence of such a team is not an assumption, it is based on the evidence. Moreover this is not a case in which the invention is "art changing" or has brought together two disparate fields.
- Consideration of the problem(s) which the invention aims to solve raises a number of issues. The patent is directed to the problem of pain. The problem to be solved described in the document is pain on subcutaneous injection caused by a relatively large volume of drug being injected. The solution is a higher concentration of methotrexate which therefore permits a lower volume to be used for a given dose. Another aspect of the problem advanced by the patentee at trial (albeit not mentioned in the patent) is a concern about possible side effects due to the higher concentration deterring the skilled person from going forwards or at least meaning that there was not a sufficient expectation of success in the testing which would be required to make the invention obvious. Finally another aspect of the patentee's case is that the skilled person would not think there was a problem to solve at all. Taking these issues into account does not mean that the skilled person/team should be considered as a clinician alone rather than a team.
- Of course it is true that clinicians treating patients did not do that in a team with a formulator and so another real skilled person/team would be a clinician on their own (or in a team with a nurse). If the invention is obvious to that skilled person/team then the patent will be invalid. However I conclude that it is also legitimate to consider the issues of inventive step from the point of view of a skilled team comprising a clinician and a formulator. It is not an exercise in hindsight to look at the matter that way. For the patent to be valid, the invention must not be obvious to such a team.
- Standing back, there is really nothing surprising about this conclusion. Since such real teams existed, it would be wrong in principle if a patent was upheld when the invention was obvious to such a team. Real persons skilled in the art are entitled to make obvious developments without fear of infringing patents.
- I reject the submission that it was not open to Accord to put its case about the skilled team in the manner it did. Both Accord's witnesses gave evidence based on the same skilled team comprising a clinician and a formulator, and both gave evidence on the basis that the initial impetus comes from the clinician. That position has not changed. I would agree that a case based on the formulator deciding to do something without an impetus coming from the clinician in the team would be a change but, whether or not Accord made such a submission, it is not the argument I am considering.
- The clinician in the team would be a consultant level rheumatologist. They would have been at medical school for six years with four years general medical training and three to six years specialist training at registrar level. They would have significant experience in treating patients.
- The characteristics of the skilled formulator were not addressed in detail. The focus of Dr Rue's experience with formulation was on tablets but he also had experience of injectable formulations. His experience formulating injectable dosage forms was much less than his experience with tablets but, given that tablets are by far the most common dosage form, this is not surprising. I am satisfied he is in a position to help the court in relation to the thinking of a skilled formulator asked to make an injectable formulation. In my judgment the skilled formulator would be someone with experience in developing injectable formulations (including subcutaneous) albeit in the context of developing dosage forms in general.
- The point about a nurse in the team arises in this way. At the priority date, in both the UK and Germany, the doctor would prescribe subcutaneous methotrexate to a patient and a pharmacy would dispense it. However there was a difference between the two countries in how the drug was administered. In Germany it was (and is today) the doctor who administered subcutaneous methotrexate whereas in the UK this task was and is carried out by nurses, sometimes specialist nurses. There was also self-administration by patients in both Germany and the UK. Thus Prof Müller-Ladner had extensive experience with the administration of subcutaneous methotrexate whereas Dr Östör did not. Moreover while Prof Müller-Ladner therefore was directly familiar with the injectable methotrexate products available on the market in 2006, Dr Östör did not know what the pharmacists would dispense to fulfil a prescription he would have written for subcutaneous methotrexate. Consistently with this, Dr Östör did not know what concentrations of methotrexate were being administered to patients at that time. So although I do not believe anything actually turns on it, it seems to me that if one is considering a skilled team in the UK which is concerned with administration it will include a nurse whereas a similar team in Germany will not.
Common general knowledge
- Rheumatoid arthritis is a systemic inflammatory autoimmune disease that predominantly affects the organs of the locomotor system that provide form, support, stability and movement to the body – although it can also affect a number of other organs including the lungs, heart, eyes, skin and blood vessels. Whilst the symptoms of RA vary widely with regard to type, severity and rate of progression, its clinical diagnosis requires at least four of the following to be satisfied (the American College of Rheumatology criteria):
i) Morning stiffness;
ii) Arthritis (soft tissue swelling or fluid) of at least three joints;
iii) Arthritis of hand joints;
iv) Symmetrical arthritis;
v) Rheumatoid nodules;
vi) Abnormal amounts of serum rheumatoid factor; and
vii) Radiographic changes in the joint.
- Established RA is characterised by abnormally shaped wrists, fingers and toes caused by inflammation of the synovial membrane of the relevant joints and secondary damage to the joint cartilage and underlying bone. The causes of the condition are unknown, but one of the theories (amongst several others) is that an infectious agent triggers the generation of antibodies against the synovial membrane, resulting in inflammation, pain, stiffness and potentially damage to the cartilage and bone associated with the affected joints. In the UK, RA affects around 690,000 patients.
- At the priority date a number of options were available for the treatment of RA and other rheumatic diseases. Of the conventional disease modifying anti-rheumatic drugs (referred to as 'DMARDs'), methotrexate was the most common first choice treatment, usually in combination with non-steroidal anti-inflammatory drugs ('NSAIDs'). At the beginning of treatment low-dose steroids may also have been used.
- If methotrexate was found not to be effective, or not to be tolerated, then the physician would usually attempt to treat the patient with one or more of the other major DMARDs (e.g. sulfasalazine, hydroxychloroquine or leflunomide) alone or in combination.
- If none of the DMARDs was found to be effective and tolerable then the physician would use one of the then newer biological disease modifying anti-rheumatic agents ('biologics'), such as rituximab, adalimumab, infliximab (antibody products), abatacept or etanercept (fusion protein products). These were second line therapies due to their higher cost, and were used where the first line therapies (such as methotrexate) proved ineffective or not tolerated.
- Methotrexate is a potent cytotoxic drug that was developed in the 1950s for cancer chemotherapy. It was soon discovered, however, that it had a beneficial effect in the treatment of psoriasis and RA at much lower doses, probably owing to its anti-inflammatory and immunomodulatory properties.
- In the treatment of cancer, at the priority date methotrexate was frequently used in doses of up to several grams, diluted in saline and given by intravenous (IV) infusion. Such doses constituted an aggressive, short term therapy, which could not be sustained long term. In oncology treatment, chemotherapy is usually given over a relatively short period (of around 6 months) in cycles typically with 3 – 4 week gaps between treatments to enable the body to recover from the side effects. The skilled clinician concerned with RA would have known that methotrexate was used as a cytotoxic drug in much higher doses than for the treatment of RA. I doubt they would have known the exact dosage or precise details of a typical treatment regime, but nothing turns on that.
- The treatment of RA is usually a life-long treatment. One common approach was to start a patient on an initial dose of 7.5 mg or 10 mg weekly and then titrate the dose upwards to a maximum of 25 mg/week. This was the highest dose typically regarded as safe. A higher 30 mg/week dose was used occasionally but was very rare. Another approach, more common in Germany, was to start treatment more aggressively using a higher dose of 15 to 20 mg weekly. Following either approach, if the patient could not tolerate the higher doses, the dose would be reduced to the lowest tolerable effective dose. For most patients on long-term therapy, once the disease had been brought under control, again the dose was reduced to the lowest possible dose that remained effective; normally in the range of about 15 to 20 mg/week.
- In the UK by 2006 methotrexate was generally administered for the treatment of RA (and other inflammatory autoimmune diseases) in oral tablet form, as it had been in the past. Tablets are cheap, convenient and simple to manufacture, transport and store. The use of parenteral administration, particularly subcutaneous, was growing but subcutaneous administration of methotrexate was not authorised in the UK at the time. It was prescribed off-label. Dr Östör estimated that about 5% of British RA patients received subcutaneous methotrexate at the priority date. In evidence was a detailed 2004 guideline document from the Royal College of Nursing concerning administering subcutaneous methotrexate for RA and JCA (as to JCA see below). The 2004 guideline demonstrates that subcutaneous administration was undertaken and also shows that methotrexate had to be handled appropriately and with real care given its cytotoxic nature.
- In Germany in 2006 there were two subcutaneous methotrexate products with marketing authorisations for RA and Prof Müller-Ladner estimated that about one third of his patients received methotrexate in that form.
- In practice by 2006 the main approach to parenteral methotrexate administration was subcutaneous. One reason for using parenteral administration of a drug instead of oral tablets is because parenteral administration bypasses the first pass metabolism and usually results in a higher bioavailability of a drug. With methotrexate in particular parenteral administration reduced the variability within and between patients due to variable absorption of methotrexate in the intestine. Another reason for parenteral administration of methotrexate was gastric intolerance experienced by some patients taking the tablets. Amongst parenteral routes, subcutaneous injections have a number of advantages. They are less invasive than the intravenous route and cause less pain than intramuscular injections. Patients can also self-administer subcutaneous injections (a well known example is the insulin taken by insulin dependent diabetics).
- The mechanism of action of methotrexate in the treatment of RA was not understood at the priority date (indeed, it is still not understood today), although several mechanisms had been proposed. The skilled team would not have known the details of all the various theories, but would have been aware that the mechanism of action was unknown and the subject of ongoing research.
- As a drug, methotrexate, in common with other anti-proliferatives, was known to be associated with a wide range of potentially serious side effects. Methotrexate was known to be a very toxic compound, intended to kill tumour cells in the body. It was known to be capable of inducing severe side effects including mucositis (inflammation and ulceration of the mucous membranes in the mouth and gastrointestinal tract), nausea and vomiting, diarrhoea, tissue necrosis, bone marrow suppression, alopecia, anaemia, problems with blood clotting and teratogenicity (the disruption of the development of an embryo or foetus, often leading to death or deformation).
- However there are important differences in the thinking of the skilled person about the side effects depending on whether one is concerned with cancer treatment or RA. Cancer can represent an immediate threat to the life of the patient. RA cannot be cured and requires regular treatment throughout a patient's lifetime. It may shorten the lifespan of the patient but RA is not terminal in the sense that cancer can be. Therefore whereas physicians and patients dealing with cancer are prepared to deal with the risk and occurrence of what can be significant side effects, RA physicians were less willing to put their patients at risk of significant side effects.
- On the other hand, and importantly, the significant side effects mentioned above are most severe when methotrexate is used in the very high chemotherapy doses. The doses are orders of magnitude larger than the doses used in RA. RA patients receiving methotrexate can still experience serious side effects and the skilled team would have been aware that there were reported instances of patients having died from low dose methotrexate treatments due to the weekly dose being given on a daily basis as a result of tragic mistakes by staff. Well known side effects of methotrexate for RA included dizziness, nausea, hair loss, mucositis and dermatological side effects but listing them in this way and focussing on the patient deaths is capable of giving the wrong impression. Dr Östör characterised the drug in the context of RA as "pretty benign". Dr Östör's evidence was not that methotrexate was at all risk free but he used this expression to explain why he did not accept the manner in which medac's case was put, placing such emphasis on side effects. Prof Müller-Ladner did not agree with that characterisation but (for reasons which are given below) I preferred Dr Östör's evidence on this to that of Prof Müller-Ladner.
- Another important feature of side effects is whether they are systemic or local in nature. If an effect has a systemic cause then in general it will not matter how the drug is delivered (orally by tablets or parenterally). What matters is the overall dose. Whereas if a side effect is local, then the site at which the drug is delivered and the mode of delivery matters. Dr Östör explained that methotrexate does not cause an injection site reaction, erythema, inflammation or redness and overall was well suited for subcutaneous therapy.
- The fact that a side effect is skin related does not mean it has a local cause. Some of the dermatological side effects associated with methotrexate are systemic. Moreover the deaths caused by the tragic mistakes in administering methotrexate daily instead of weekly were systemic in nature.
- The side effects were generally dose dependent in a given patient but between patients the dose response was unpredictable and that is why it was common practice to start patients on a low dose and then titrate upwards in stages to the maximum level that could be tolerated, subsequently reducing the dose again once the disease was under control.
- Dr Östör gave evidence that at the priority date around one third of patients discontinued treatment within a year due to intolerance but this was based on a retrospective survey conducted years afterwards and he accepted he could not say it was known at the relevant time. I find that, in general, in 2006 patient compliance with methotrexate treatment in RA was regarded as good. So long as the side effects remained modest, patients would generally tolerate these provided that they also experienced improvement in their symptoms. Where patients experienced more severe side effects, then they could be switched to a different treatment or to a lower dose of methotrexate (providing that efficacy was maintained).
- There was a dispute about the common general knowledge relating to pain associated with methotrexate injections. There is no doubt that in general injections hurt and there is no doubt that injection pain in general can be due to a number of different factors, including the size and shape of the needle, the injection technique, the injection volume and its formulation. The specific issues relating to pain with subcutaneous methotrexate administration are best addressed in context below.
- At the priority date there were a number of oral tablet formulations available for methotrexate. There were also subcutaneous injectable methotrexate formulations available in both the UK and Germany. This included prefilled methotrexate syringes. They were not licensed for the treatment of RA in the UK but in Germany there were subcutaneous formulations licensed for RA.
- RA is an inflammatory autoimmune disease and the claims are not limited to RA. The other inflammatory autoimmune disease which plays a role in this case is juvenile chronic arthritis (JCA), also known as juvenile idiopathic arthritis (JIA). This disease has similar symptoms to RA but is a different disease. It is treated the same way. Notably children are able to tolerate somewhat higher doses of methotrexate that adults, probably due to their faster metabolism. Weekly doses of 25 mg and even 30 mg of methotrexate are more common in children with JCA/JIA than in adults with RA.
- Issues relating to the common general knowledge of the skilled formulator in the team are best dealt with in context.
- At paragraph 1, the patent states that the present invention relates to the "use of methotrexate in the production of a subcutaneously administered medicament for the treatment of inflammatory autoimmune diseases, wherein the methotrexate is present in a pharmaceutically acceptable solvent at a concentration of about 50 mg/ml." Paragraph 2 identifies methotrexate as a folic acid antagonist. Paragraph 3 notes that methotrexate has previously been used to treat breast cancer and leukaemia in children as a result of its effectiveness as a cytostatic agent and has also been used to treat psoriasis, which can accompany RA. Paragraph 5 notes that disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, have a disease modifying effect in RA.
- Paragraph 6 explains that, when used to treat RA as opposed to treating cancer, methotrexate is administered in significantly lower doses, which can be up to 1,000 times lower than doses used in chemotherapy. In Germany a dosage range of 5.0 to 30.0 mg per week is identified as common, while doses of up to 40.0 mg per week are apparently routinely administered in other European countries. Paragraph 6 then emphasises that "It is extremely important that methotrexate only be administered once a week."
- Paragraph 7 identifies that methotrexate can be administered orally and parenterally. Parenteral administration is said to be more commonly used because methotrexate, when orally ingested in tablet form, can be absorbed by the patient in an unreliable way. This is undesirable in a dosage-dependent therapy, where a sufficient degree of accuracy needs to be guaranteed. The remainder of paragraph 7 together with paragraph 8 emphasises the desirability of ready-made syringes for parenteral administration of methotrexate because of the difficulties and restrictions around handling and preparing medicaments containing cytostatics. Paragraph 9 notes that there are two products known from the prior art which are ready-made syringes for parenteral administration containing methotrexate solution at a concentration of up to 25 mg/ml. These are Lantarel® produced by Wyeth and Metex® produced by medac. The Lantarel® product with the concentration 25 mg/ml is said not to be approved for subcutaneous application. Paragraph 10 goes on to say that the subcutaneous administration of methotrexate for the treatment of RA has been described in a number of publications, including Jansen.
- Paragraphs 11 and 12 set out the problem that the patent is trying to solve, namely the need for "pharmaceutical formulations of methotrexate which can be administered to the patient, including children, as easily and pain-free as possible, while providing good bioavailability, over a long period of time at regular intervals, in particular weekly, which therefore leads to a high degree of patient compliance". In addition, the medicament should allow for self-administration by the patient. Paragraphs 13 and 14 explain that the disadvantages of the prior art can be overcome by using the claimed invention. Paragraph 15 states that the first embodiment of the invention relates to the use of methotrexate which is present in a pharmaceutically acceptable solvent at a concentration of "about 50 mg/ml" for subcutaneous administration for the treatment of inflammatory autoimmune diseases. Further embodiments of the invention are set out between paragraphs 16 to 34.
- Within these further embodiments, paragraphs 24 and 25 are worth noting. Paragraph 24 explains that, although the provision of methotrexate solutions in ready-made syringes has had a positive impact on patient compliance, the existing products approved for subcutaneous application have the disadvantage that potentially large amounts of liquid have to be injected under the patient's skin. This could be as much as 3 ml, if the patient uses the existing 10 mg/ml formulation and requires a weekly dose of 30 mg. The requirement that the patient be subjected to such large volume injections is described as being "often hard to convey to the patient, in particular children, which leads to a reduced patient compliance." The patent states at paragraph 25 that this problem is solved by highly concentrated formulations of methotrexate, where a concentration of 50 mg/ml would only require 0.6 ml of liquid in order to administer a 30 mg weekly dose.
- There are two examples in the patent, at paragraphs 35 to 41, which set out methods of preparing formulations of a methotrexate solution with a concentration of 50 mg/ml.
- The patent consists of 28 claims in total. As noted above, only claims 1, 13, 15 and 27 are said to be independently valid. There are no arguments about claim construction.
- Section 3 of the Patents Act 1977 (based on Art 56 EPC) provides:
"An invention shall 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…"
- It is convenient to assess inventive step using the structured approach set out by the Court of Appeal in Pozzoli SpA v BDMO SA  EWCA Civ 588. The key, statutory step is the fourth one, that is: viewed without any knowledge of the alleged invention as claimed, do the differences between the prior art and the claimed invention constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?
- The analysis is a multifactorial one, having regard to all of the relevant circumstances, as Kitchin J (as he was then) put it in the much cited passage from Generics v Lundbeck  RPC 32 at paragraph 72, approved in Conor v Angiotech  UKHL 49.
- In Medimmune Kitchin LJ explained that in cases involving a question of whether something is "obvious to try", that is only one of the considerations which it may be appropriate to take into account (paragraph 92). When considering "obvious to try" the Court of Appeal in Teva v Leo  EWCA 779 emphasised the expectations of the skilled person. For example, the fact that something might work is not enough and nor would be performing a test simply on the basis of a hope that it will succeed (see also Conor). The Court of Appeal in Teva v Leo also emphasised the importance of assessing the question of obviousness by reference to what real-life skilled people would think and do.
- In the end however the task of the court is to evaluate the evidence against a single statutory test expressed in simple terms whose meaning is not necessarily made much clearer by elaborate judicial exposition (Medimmune, paragraph 95).
- Medac referred to the point addressed by Floyd J (as he then was) in Dr Reddy's Laboratories v Eli Lilly  EWHC 2345 (Pat) at paragraph 170. There the judge observed that there can be a risk in focussing too much on the disclosure of any particular document and losing sight of the whole common general knowledge. Medac submitted that while the law requires that the pleaded prior art be notionally read with interest by the skilled person, that person does not approach it on the assumption that that particular document (out of all the others directed to the same problem) in fact contains pointers towards the solution, and an unnatural focus on it may lead to an unbalanced analysis and hindsight. I agree with that submission. The key issue is that the skilled person does not approach a document on the assumption described. To do so would indeed involve hindsight.
- Finally I will mention secondary evidence. An important part of medac's argument was to ask the rhetorical question – if it was obvious, why was it not done before? It was common ground that while this is a form of secondary evidence, as compared to the primary evidence being the reasons given by the experts for their opinions, such secondary evidence has its place and in a proper case can be powerful.
- In arguing their case relating to obviousness each side put a different starting point first. Accord started with its case over common general knowledge alone, then referred to Jansen and Russo. Medac started with its case over Jansen and then focussed on Russo and common general knowledge alone. I will start with Russo.
Obviousness over Russo
- Russo is a letter published in the journal Clinical and Experimental Rheumatology in 2000. The letter reports the results of a small study concerning the tolerance of parenteral higher dose methotrexate in children with JCA. Higher dose parenteral methotrexate is compared to lower dose oral methotrexate. The study compares 20 children given the higher parenteral dose and 124 on the oral dose. The mean age of the children treated with the parenteral dose was about 10 ½ years old and the mean duration of their disease was about 3 ½ years. The mean higher dose was 23.25 mg/m2 per week. They had all been on low dose oral methotrexate for a year on average beforehand.
- The letter reports positive results. The letter recognises that the observations are based on a retrospective study but explains that nevertheless the data shows that higher dose parenteral methotrexate is safe and is not associated with more frequent side effects that lower dose oral administration, at least in the first year of treatment. Further prospective studies will be undertaken.
- Russo only refers to "parenteral" administration and does not specify whether that relates to intramuscular and/or subcutaneous administration. In my judgment the skilled team reading Russo at the priority date would see the reference to "parenteral" as covering either mode (they would not think it meant intravenous or intrathecal). It would be entirely obvious to any skilled reader to consider what is disclosed by Russo as applicable to subcutaneous or intramuscular administration or both. If the skilled team thought about it in any more detail they might consider that the work actually reported most likely involved some intramuscular administration (the title of reference 1 in the letter refers to intramuscular methotrexate and following up the references bears that out) but this does not alter the fact that subcutaneous administration is obvious over Russo.
- A relevant aspect of Russo is what is said about side effects and in particular, given the issues in this case, what is said about pain. The results table reports the various side effects experienced by both groups. "Pain at injection site" is reported in four out of the twenty children on the higher parenteral dose (i.e. 20%). In the text the paper mentions the various side effects, including the fact that four patients reported pain and states that "No patient needed to permanently discontinue the drug due to side effects". The text also mentions that the parenteral methotrexate group experienced a much lower occurrence of complaints related to the gastro-intestinal (GI) system whereas for the oral methotrexate, 19 (15%) of patients had to permanently discontinue the treatment due to side effects, of whom 17 experienced side effects related to GI intolerance.
- The skilled team and the common general knowledge have been identified above. The difference between Russo and claim 1 is that while Russo does describe the use of a methotrexate medicament to be administered parenterally for the treatment of an inflammatory autoimmune disease (JCA/JIA), it does not disclose a concentration of the parenteral methotrexate and does not single out subcutaneous administration.
- Accord submits that the invention would be obvious to a skilled team over Russo. It would be obvious for the team to create a subcutaneous methotrexate formulation in the light of Russo. A subcutaneous formulation of 50 mg/ml methotrexate would be nothing more than the product of routine optimisation by the skilled team and so claim 1 is obvious. If claim 1 is obvious so too are the other claims. The limitation to ready made syringes and to the doses listed in claim 13 adds nothing. Claims 15 and 27 fall for the same reasons.
- Medac does not agree. It submits that claim 1 would not be obvious. Its arguments are as follows. The clinician would not be motivated to ask the formulator to do anything at all. If the clinician wanted a methotrexate formulation for subcutaneous administration then there were already such products available on the market and no need to create another. If the formulator was asked to prepare methotrexate for subcutaneous administration, it was not obvious to arrive at a 50 mg/ml concentration. Injection volumes in the range from about 0.5 ml to 1 ml, 1.5 ml or even 2 ml were standard for subcutaneous administration. Two key steps in Accord's case are incorrect. First that it was obvious that reducing the injection volume below 1 ml would reduce pain and second that the skilled formulator would target a volume of 0.5 ml. The first proposition is now known to be true as a fact today and is the reason why the invention has been very successful but Accord failed to establish it was known or obvious at the priority date. The second proposition was based on a personal preference of Dr Rue and was not established to represent the thinking of the ordinary and uninventive skilled formulator. Even if a 50 mg/ml subcutaneous methotrexate formulation was contemplated, the skilled person would be put off by a concern about side effects caused by the increase in concentration over what were then the highest known subcutaneous concentrations of methotrexate, at 25 mg/ml. At most the formulation would have to be tested but there would be no basis for a fair or reasonable expectation of success. Moreover secondary factors matter. Russo was published in a well read and respected journal six years before the priority date. If there was ever a case in which to ask the question – if the invention was obvious why was it not done before? – this is such a case. Medac submits there is no satisfactory answer to that question from Accord.
- In addition to engaging with medac on the facts, Accord submits that the point on side effects is not open to medac or, if accepted, leads to insufficiency because the patent says nothing at all about side effects. Not only is there no data showing that 50 mg/ml subcutaneous methotrexate is safe, there is no discussion of the point at all. So if that is an aspect of the problem to be solved for the purposes of inventive step, the patent does not render the claimed solution plausible.
- Turning to the evidence, I will address Dr Östör, Dr Rue and Prof Müller-Ladner in sequence.
- In his written report Dr Östör's evidence was that it would be obvious for a clinician reading Russo to prompt the team to embark on creating a parenteral formulation of methotrexate not just for JCA but for inflammatory autoimmune diseases generally (in particular including RA). Subcutaneous administration would be obvious. The clinician would understand Russo to teach that, at the doses described, parenteral methotrexate does not have more frequent side effects and appears better tolerated than low doses of oral methotrexate. They would ask the formulator to prepare a suitable methotrexate formulation for subcutaneous use. The mention of 20% of patients experiencing pain would lead the clinician to ask the formulator to see if a subcutaneous dosage form could be prepared that minimises pain.
- In cross-examination Dr Östör accepted that he did not know what volumes and concentrations were in use (off-label) in the UK at the priority date and that it did not occur to him at the time that the approach to subcutaneous administration of methotrexate for RA in the UK which existed at that time (2006) was not the optimal solution from the point of view of pain or discomfort, and accepted that this would be a fair reflection of the position of the skilled clinician at the priority date. This acceptance was a key aspect of medac's submission that the skilled clinician would not be motivated to ask the formulator to optimise a formulation. Medac submits it would have been thought to be already optimal.
- As to the level of pain reported in Russo, medac put to Dr Östör that it was low, his answer was that it was "lowish". There was a debate about the duration of the study in Russo in the context of the significance of the pain reported but I was not convinced anything significant turned on the duration point. Dr Östör accepted, as Russo states in terms, that the pain was not bad enough for those patients to stop treatment in the context of the study.
- In terms of patient compliance and any problem due to pain, as I have mentioned already Dr Östör accepted that his evidence about what the position was in 2006 had been based on a later published study looking back in time.
- As to concern about side effects, Dr Östör's evidence about a 50 mg/ml formulation of methotrexate was that concern about side effects would not deter the skilled team. He maintained that evidence in cross-examination. He maintained that an important distinction was between systemic and local side effects. So, for example, 2.5 ml of 10 mg/ml drug and 1 ml of 25 mg/ml drug provide the same dose and have the same risk of systemic side effects.
- Dr Östör explained that given an increase in concentration, the side effects which might be relevant would be local side effects but that the skilled clinician would have no specific concerns about local side effects of subcutaneous methotrexate. He thought the risk of local side effects described in Prof Müller-Ladner's expert's report was a purely academic and theoretical possibility. Dr Östör said that given the experience at lower concentrations, in all likelihood 50 mg/ml would be safe.
- Medac submitted that Dr Östör's evidence about the likely safety of 50 mg/ml subcutaneous methotrexate was based on knowledge of a point of detail within an SmPC for a form of methotrexate called Abitrexate. That SmPC in particular bears writing in Hebrew and medac submitted it was not established to be part of the common general knowledge in the UK at the relevant time. I agree the Abitrexate SmPC was not part of the common general knowledge and knowledge of its content cannot be relied on. But the main reason for Dr Östör's view was his experience that the subcutaneous methotrexate he prescribed was administered safely. I have considered whether the fact that Dr Östör did not know at the time what the concentrations administered actually were has any impact on this. In my judgment it does not. It is clear that the concentrations used in the UK will in all likelihood have been in the 7.5-25 mg/ml range. A clinician who wanted to know at the time would simply have asked the pharmacist or nurse.
- Dr Rue's evidence was from the perspective of a formulator asked to prepare a subcutaneous methotrexate formulation. He thought the formulator would do so and would proceed as follows. The formulator would readily identify methotrexate products on the market in 2006. One of the pieces of information a formulator would wish to know was the solubility limit of methotrexate. The information from the products on the UK market would show that injectable methotrexate solutions were available in solutions including the following: 2.5 mg/ml, 7.5 mg/ml, 25 mg/ml and 100 mg/ml (Hospira and Wockhardt UK Ltd). As I have said, in the UK the parenteral products were indicated for cancer and psoriasis. They were not indicated for RA or any other disease within the claims.
- Dr Rue's evidence was that part of the formulator's common general knowledge was that a smaller injection volume caused less pain. The formulator would optimise the injection volume on that basis and it was obvious to prepare the smallest injection volume possible that was still practical. Dr Rue would target a volume of 0.5 ml. The average parenteral dose described in Russo is 23.25 mg/m2. That equates to a dose of about 26 mg (based on the appropriate average body surface area). To deliver 26 mg in 0.5 ml one would use a concentration of 52 mg/ml. The claim is to about 50 mg/ml. Therefore the claim is obvious.
- Dr Rue also exhibited a paper by Jorgensen published in 1996 (Jorgensen et al Pain Assessment of Subcutaneous Injections The Annals of Pharmacotherapy 1996 July/August, Vol 30 p729). This paper was not said to be common general knowledge but it bore out Dr Rue's view that as a matter of fact increasing injection volume from 0.5 ml to 1 ml increases pain significantly.
- It was pointed out to Dr Rue in cross-examination that while the standard formulation text books he exhibited supported his view that subcutaneous injection volumes were usually in the range between about 0.5 ml to 2 ml, they did not contain any statement that reducing the volume within that range reduced pain nor did they refer to a target of 0.5 ml. Dr Rue accepted that the textbooks did not contain those statements. However he maintained his opinion on those issues as representative of the views of the skilled formulator.
- Medac submitted that Dr Rue did not have any relevant experience about subcutaneous administration and that what emerged in cross-examination was that the basis for his opinion about injection volumes generally and a 0.5 ml target in particular was work done at another department in Glaxo while he was there. I am satisfied that Dr Rue's actual experience was sufficient to put him in a position to give cogent evidence about injection volumes. Moreover he was entitled to have regard to what he was aware of about what happened at the other Glaxo department as support for his opinion. It was clearly Dr Rue's honestly held opinion that pain is reduced by smaller volumes and that a target of 0.5 ml was representative of the thinking of a skilled formulator concerned with a subcutaneous formulation. He expressed that view well aware that the particular point he was making was not set out in the general text books he cited.
- Prof Müller-Ladner's written evidence was that the skilled clinician would have no particular desire to change the existing concentrations of methotrexate. The professor routinely used 10 mg/ml in 2006. Secondly even if the skilled person considered injection pain to be a problem, there was no reason to focus on the volume of methotrexate. Pain could be caused by a number of aspects (the size and shape of needle itself, and injection technique). Third and importantly, if the skilled team did think of an increased concentration of methotrexate, they would have serious concerns about the risk of side effects due to the toxic nature of methotrexate. The skilled person would be concerned that there was a threshold concentration of methotrexate above which RA patients could not tolerate methotrexate subcutaneously but it could not be predicted in advance what this "invisible barrier" or "red line" would be. So even if a 50 mg/ml formulation was tested, it could not be predicted that it was safe. This is particularly so given the limited blood supply to the subcutaneous layer compared to other tissue such as the muscle targeted with intramuscular injections.
- In cross-examination Prof Müller-Ladner's evidence was quite different. He agreed it was obviously desirable to optimise an injection product like this one, which is going to be given regularly to patients over an extended period of time, in effect for a lifetime. It was not necessarily the case that the injections always hurt but he agreed that while some patients reported that it did not hurt, some patients given subcutaneous methotrexate injections complained to him about the pain of the injection. The pain depended on a number of factors but one of them was volume.
- Prof Müller-Ladner accepted that Russo showed that the number of patients reporting pain was "significant", by which I understood him not to refer to statistical significance (nor to the level of pain itself) but to be an indication that the occurrence of the side effect was regarded as noteworthy by the authors.
- Prof Müller-Ladner agreed that it was fair for a formulator to consider optimising for pain and he also agreed that if the skilled team did optimise the volume, they would produce a product at around 50 mg/ml. Accord placed particular emphasis on that evidence.
- Prof Müller-Ladner said he would not disagree with Dr Rue's evidence that 0.5 ml would be considered to be good by the skilled formulator. That latter evidence arose as follows. Counsel for Accord put to Prof Müller-Ladner that 0.5 ml would be considered good from the point of view of pain. The professor agreed, nevertheless, as medac emphasised, he said that it was not the only volume that was possible and convenient. Medac submitted this was an important qualification and that it meant in effect that the professor did not agree that it was obvious for a formulator to optimise the volume to 0.5 ml bearing in mind pain. I do not accept that. Prof Müller-Ladner fully understood the importance of the 0.5 ml volume in this case. In cross-examination the professor had fair opportunities to say if he thought targeting 0.5 ml was not obvious but he did not. A fair summary of Prof Müller-Ladner's view about volumes was that 0.5 ml was one obvious volume but not the only one. Somewhat higher volumes were also obvious.
- Medac also submitted that it was not put to Prof Müller-Ladner that starting from an injection volume of 1 ml, it was common general knowledge or obvious that reducing the volume down from there to 0.5 ml would reduce the pain experienced by the patient. The distinction is between the idea that reducing a volume from (say) 3ml down to something in the range 0.5 ml – 1.5 ml would be expected to reduce pain (which was common ground) and the idea that reducing a volume already within the range down to 0.5 ml would be expected to reduce pain. The latter is something medac contends was not obvious and is what medac contends was not put. The point applies whatever the upper bound of the range is, i.e. regardless of whether the range is 0.5 - 1 ml; 0.5 - 1.5 ml; or 0.5 - 2 ml. The significance of the numerical difference between 1 ml and 0.5 ml in the context of this dispute is that with the highest typical dose of 25 mg, you do not need a 50 mg/ml concentration to produce a volume of 1 ml. 25 mg/ml will suffice. So if 1 ml was targeted instead of 0.5 ml medac says the skilled person would not come up with a 50 mg/ml concentration. I do not accept medac's submission about what was put to Prof Müller-Ladner. It was clearly put to the professor that it was obviously desirable to optimise the injection volume in order to minimise pain and further that the clinician would want as low a millilitre quantity as possible so that the product could be administered more easily. Prof Müller-Ladner agreed with this.
- On the issue of side effects, the tenor of Prof Müller-Ladner's evidence can be seen on the issue of Lyell's syndrome. Prof Müller-Ladner's written reports placed significant emphasis on the risk of severe dermatological side effects, particularly a life threatening condition known as toxic epidermal necrolysis or Lyell's syndrome. This is a very severe toxic skin necrosis which is often fatal. It has been associated with methotrexate but it is very rare indeed and, importantly in the context of this case, it has a systemic cause. Dr Östör explained that in his experience it was "incredible – you know one in a million". More generally Dr Östör explained there was vast experience of using methotrexate for autoimmune inflammatory disease, starting in 1985, with hundreds of thousands perhaps millions of patients. In his view actual local reactions were very uncommon and completely distinct from systemic potential side effects. I found this aspect of Dr Östör's evidence credible and convincing. In my judgment Prof Müller-Ladner's written evidence, which placed such emphasis on side effects such as skin necrosis being associated with methotrexate, was exaggerated.
- On the general issue of local side effects, Dr Östör's characterisation of methotrexate as "pretty benign" was put to Prof Müller-Ladner in cross-examination. He was not prepared to go that far and pointed out that "benign" is a relative term, but he did agree that 25 mg/ml methotrexate was safe and had no major problems. When cross-examined about a concentration of 50 mg/ml, the professor maintained a number of times that the skilled clinician would have a safety concern which would put them off from trying it. Accord emphasised that when Prof Müller-Ladner was asked specifically about how a concern about toxicity on the part of a skilled person seeking to optimise injection volume would be taken into account, the professor said that he would not be deterred, he would just be cautious and concerned, and accepted that he would be aware that you needed to verify that the formulation was not toxic. Accord submitted, rightly, that this evidence was much closer to Dr Östör's opinion on the topic than the professor's written evidence. Medac submitted that those answers had to be seen in the light of the other oral evidence the professor gave, which I have mentioned already, that the skilled clinician would have a safety concern which would put them off from trying 50 mg/ml. Medac's counsel provided a list of references to the relevant parts of the transcript.
- In considering the rival submissions about Prof Müller-Ladner's evidence, I think an important point is that the answers he gave on which Accord rely were clear and involved no misunderstanding on his part. They were not a mistake. In my judgment those answers reflected his truly held opinion. To the extent that they differ from the other statements medac rely on, the answers qualify those other statements. In other words the cross-examination as a whole revealed that Prof Müller-Ladner's opinion was not reflected by the words used in his report. He had a serious concern about risk of local side effects with increasing concentration. A higher concentration such as 50 mg/ml needed to be tested before it was used but he did not positively expect 50 mg/ml to be unsafe and would not be deterred by this concern from optimising.
- A key part of the written report prepared by Prof Müller-Ladner for the US proceedings was his view about the risk of local side effects caused by such a high concentration of methotrexate. That US evidence is similar to his written evidence here but in the US it is expressed even more strongly. His US evidence was that local side effects would be expected (my emphasis) using concentrated methotrexate (which means >30 mg/ml) and that the safety of concentrated methotrexate was unexpected. In cross-examination Prof Müller-Ladner suggested that the difference between the US evidence and his evidence here was due to the use of a second language. I reject that. Prof Müller-Ladner was an accomplished English speaker and the difference is not only in the word "would" in his US report but in the whole tenor of the evidence given. The difference between the way Prof Müller-Ladner expressed himself in writing in his US report and his answers given in cross-examination here bears out why cross-examination of experts is an important tool in patent disputes. Like his written evidence here, Prof Müller-Ladner's written evidence on side effects in the US report was exaggerated.
- Overall, on the issue of the skilled person's thinking about risks associated with side effects, there was not so much between Dr Östör and Prof Müller-Ladner's evidence in cross-examination. Nevertheless, to the extent the two experts differed on side effects, I preferred Dr Östör. In particular I do not accept that concern about a so called "invisible barrier" represents the thinking of the skilled clinician.
- I find that a skilled team reading Russo in 2006 would set about producing a formulation of subcutaneous methotrexate for use as a treatment for inflammatory autoimmune diseases such as JCA and RA. The clinician member of the team would ask the formulator to do that. The impetus would come from the clinician reading Russo as part of the team. The fact that formulations existed on the market already would not deter the team from aiming to produce their own.
- It was obvious for the formulator to optimise such a putative formulation with respect to pain. The express reference in Russo is in itself a sufficient impetus to the skilled team to think about pain. Although there are other issues which can be addressed overall when considering pain (such as the needle shape and injection technique), from the point of view of the skilled formulator, it would be wholly obvious to optimise injection volume with that in mind.
- The fact that Russo also states that none of the side effects led to any patient permanently discontinuing the drug does not make it any less obvious for the team to consider pain. The skilled reader would think pain was significant enough for the authors to draw attention to it. Moreover the skilled team would know that the patients would be given subcutaneous methotrexate weekly for a very long time. The fact that the pain reported by Russo was not sufficient to lead to a problem with patient compliance in Russo would not lead the skilled team to leave pain to one side.
- I accept Dr Rue's evidence about targeting small volumes like 0.5 ml. Medac did not call an expert formulator to give evidence to contradict Dr Rue's opinion and I am satisfied his views represent those of the skilled person. I find that it was common general knowledge that larger volumes cause more pain than smaller volumes both in general and in the context of comparing the likely pain caused by 1 ml as opposed to 0.5 ml. It was obvious to target a small volume like 0.5 ml.
- The skilled team would find out what products were on the market. They include products in which the injection volume would be greater than 2 ml. The ready to use syringe of the Lantarel product for a 20 mg dose had an injection volume of 2.67 ml. It was made using a 7.5 mg/ml concentration of drug. That volume is materially larger than the widest range regarded as normal for subcutaneous injection and would be seen as such. A likely problem of pain with such an injection volume would also be obvious.
- I am sure it would be obvious to the skilled clinician in the team given Russo to ask the formulator to optimise with regard to pain. The significance of Dr Östör's evidence seems to me to be that without the prompt of reading something like Russo or a prompt to find out what was actually being administered in the UK, a UK based clinician acting on their own, and not part of the skilled team, would have no reason to think of embarking on a project to optimise a formulation of methotrexate for pain.
- In the context of injection volumes, the higher doses of methotrexate obviously are the ones to consider. One obvious one to consider would be 25 mg. The aim would be to produce a solution of methotrexate at a sufficient concentration to provide a 25 mg dose (or 26 mg using the numbers in Russo precisely) with an injection volume of 0.5 ml. The formulator would know from publicly available information that with those values there is no problem of solubility and would produce such a dosage form, in a suitable isotonic form for injection, without difficulty. The concentration of methotrexate produced would be about 50 mg/ml.
- I have addressed the common general knowledge of methotrexate as a cytotoxic agent above. The skilled team would know that the drug is cytotoxic and therefore has to be treated with real care. In doses orders of magnitude higher than the ones relevant to this case it is a dangerous drug. When considering side effects of the optimised formulation, systemic effects would not be a concern at all because the dose is unchanged. The issue would be the possible risk of local toxicity. Although the relative risk of local toxicity would be expected to increase as concentration increases, the absolute magnitude of that risk would be very low. The correct way to characterise the attitude of the skilled team to local toxicity is as follows. The existence of a risk of local side effects is not frivolous. There is some evidence from medac's internal letters of doctors asking questions about it. The team would know that methotrexate had been administered in a subcutaneous fashion without problems. One known side effect of methotrexate is a rash.
- The concentrations actually used in the UK to administer off-label prescribed subcutaneous methotrexate in 2006 will in all likelihood have been in the range 7.5 mg/ml to 25 mg/ml. If the skilled team in the UK were at all concerned about side effects they would readily find out what was done in practice from a nurse or pharmacy. Thus in the UK the team would find out that the drug had been administered safely at these concentrations, up to 25 mg/ml. As regards administration in Germany (which a UK team would know did occur) the same concentrations would be applicable. The team's expectation would be that 50 mg/ml would be safe but they would know the product would have to be tested. They would have a high expectation of success. They would conduct simple tests (perhaps in a small animal study) with a view to verifying that it was safe. "Verifying" is an appropriate way to characterise the approach. The word verify was accepted by Prof Müller-Ladner and also appears in a medac internal document in the same context.
- For these reasons there is a powerful case that claim 1 (and therefore all the other claims) are obvious over Russo. It does not involve an undue focus on the document (c.f. Dr Reddy's). I turn to consider the "secondary" indications, starting with the question emphasised by medac: that if it really was obvious it would have been done before; and then dealing with other matters.
- Medac's main case is this: The 25 mg/ml formulation for methotrexate has been available since 1995. Subcutaneous administration was well established by at least 2000. The years leading up to the priority date were a period of intense focus on RA as a result of the new biologics. Yet the invention was not made until medac did the work leading up to the patent. A 50 mg/ml solution of methotrexate can be readily produced and so the absence of any such thing in intervening years is evidence that it was not obvious to produce it. Moreover medac's own 50 mg/ml product launched after the priority date has been conspicuously successful and become popular. That popularity is down to the lower pain of injection caused by the small volume. Considering Russo itself, it was published in 2000, six years before the priority date in a widely read journal. So many skilled clinicians will have read it, and yet, again, the invention was not made.
- In evaluating this argument I start with the position in Germany. By 2006 there were two suppliers of subcutaneous methotrexate formulations with licences for RA: medac and Wyeth. Medac's product had a 10 mg/ml concentration and Wyeth's was 25 mg/ml. In Germany as in the UK the normal dose range was 10 mg to 25 mg. A 25 mg dose made up using the medac product would have a volume of 2.5 ml. It was clear from Prof Müller-Ladner's oral evidence and parts of his US written evidence that this happened in practice. It is also clear in the evidence that pain caused by injection volume of subcutaneous methotrexate was a recognised problem in Germany. Prof Müller-Ladner knew about it and sometimes he would split the dose into two injections in order to avoid the pain problem. His US evidence about the existence of a long felt need is based on the same point. The thrust of this part of his US report was that those working in the field had a long felt need for concentrated (>30 mg/ml) methotrexate for RA because of the injection volume problem but positively expected it to be locally toxic. That long felt need was met when a safe concentrated subcutaneous methotrexate formulation was produced.
- In addition to the evidence of Prof Müller-Ladner, I refer to internal documents from medac. There is an internal medac email dated 27th April 2005 and also a later document dated 18th December 2007. Based on these documents I infer that clinicians with whom medac was in contact, I presume in Germany, wanted methotrexate at higher concentrations as a result of the pain caused by injection volume, particularly in children.
- Therefore, whatever the reason why no 50 mg/ml product was produced in Germany before 2006 actually was, it was not because thinking of a higher concentration/lower injection volume was not obvious. Nor am I persuaded that it did not emerge due to a fear of side effects. Probably the art was just more focussed on the new biologic agents. Also important, in my judgment, is that despite the large size of the methotrexate market by volume, it is still a generic medicine. Margins will be tight. The evidence did not address the commercial factors either way and so one is left to speculate, but I would not be at all surprised if it only became commercially attractive to go to the time, trouble and cost of producing a 50 mg/ml product, verifying its safety, and getting authorisation once subcutaneous administration became very well established on a large scale, which was towards the priority date. However whatever the reason was, as I have said, it is not because the idea of a higher concentration product was not obvious.
- Turning to the UK, the position here was that by 2006 the subcutaneous approach was common general knowledge. Nevertheless by that time there was still no licensed subcutaneous methotrexate product for RA. It represented only 5% of prescriptions and was prescribed off label. So subcutaneous administration was much less popular in the UK at the time than in Germany. Moreover I infer that the practicalities of subcutaneous administration were not and had not been focussed on in as much detail by clinicians in the UK as in Germany. As evidence of the position in the UK, Dr Östör's testimony shows that doctors were not aware of a problem of pain here, I infer because they were not the ones administering the drug. Therefore whatever the reason why no 50 mg/ml product was produced in the UK before 2006 actually was, it was not because clinicians had the opportunity to see a problem in practice but missed the obvious solution. They were not in a position to encounter the problem at all. Neither side called a nurse, and I will draw no inference either way about their actual knowledge.
- Thinking about Russo, it was in a well read journal and I infer it was read by some skilled clinicians at the time but it is clear the art did develop somewhat between 2000 and 2006, although the extent of that development was not addressed in detail. No evidence was called from anyone who actually did read the paper at the time. Neither expert said they remembered actually reading it and as a document it was not established to be common general knowledge. The fact that no-one apparently took it forward in 2000 does not prove that the invention was not obvious in 2006.
- Separately medac submitted that one can infer Accord's legal team conducted major literature searches. We know that both Dr Östör and Dr Rue did so. Nevertheless there were no papers in evidence stating that 25 mg/ml was not already optimal, none suggesting pain was a significant issue (except Russo) or caused a problem with compliance (Russo did not) and none suggesting the injection volumes were high. Nor were there any textbooks or review articles suggesting that the common general knowledge was that optimal injection size was 0.5 ml. These submissions about the state of the documents are all correct. Nevertheless I have mentioned the evidence of Prof Müller-Ladner and from medac's documents about what doctors familiar with actually injecting subcutaneous methotrexate did and thought in Germany. Also I carefully considered Dr Rue's evidence about 0.5 ml in its context above.
Obviousness over Russo – conclusion
- Medac's submissions about secondary evidence are legitimate points which carry weight overall. Calling them "secondary" might give the wrong impression since arguments of this kind can be decisive in a proper case. I have considered them carefully, and the weight to be attached to them. However in the end I conclude that the invention is obvious over Russo. They are not strong enough to overcome what is a powerful obviousness case over Russo. I conclude that all the claims lack inventive step.
Obviousness over Jansen
- There is no need to consider the case over Jansen in detail. The paper was published in 1999. It provides a clear proposal to use subcutaneous administration of methotrexate for RA. The differences between Jansen and Russo are these. Jansen does not mention pain at all. In fact Jansen goes further and makes two important statements. First it states that delivery in ready-made syringes is "comfortable and safe". Second it states that volumes to be administered are between 0.2 ml and 1.2 ml (corresponding to doses of 5 mg to 30 mg) and that "these small quantities are very well suited to subcutaneous and intramuscular administration". Medac submits these teach away from the invention. The other major difference between Jansen and Russo is that the journal in which Jansen was published was in the Dutch language and not widely read. Accord submits this means the secondary evidence arguments related to Russo cannot apply to Jansen.
- In my judgment Accord's case over Jansen is not as strong as its case over Russo and so there is no point in considering it further. On the evidence as it came out before me, if the invention is not obvious over Russo then it will not be obvious over Jansen.
Obviousness over common general knowledge alone
- I am not satisfied that the invention is obvious based on the common general knowledge alone attack relied on by Accord. That is because the relevant common general knowledge must be that in the UK (see Arnold J in Generics (UK) v Warner Lambert  EWHC 2548 (Pat) at paragraphs 123-124) and in the UK the skilled clinician was unaware as a matter of common general knowledge what concentrations were being administered subcutaneously to patients and was unaware, without prompting, of any particular issue of pain arising from the subcutaneous administration. There is therefore nothing to provide an impetus to the skilled team to think about the issue at all.
- Before leaving the argument based on common general knowledge alone, I will mention the words of Floyd J (as he then was) in ratiopharm v Napp  EWHC 3070 (Pat) at paragraphs 155-159 and in particular the passage at paragraph 158 which warns that such attacks need to be scrutinised with care since they can be favoured by parties because the starting point is not obviously encumbered by inconvenient details of the kind found in documentary disclosures. I respectfully agree with Floyd J. Since it seems to me that this case provides a good example of the problems identified in ratiopharm I will add a few words of my own.
- Normally the person attacking validity will rely on a particular concrete document or well defined prior use as a starting point. The fact that such a concrete item of prior art may be part of the common general knowledge is not the point. That is different from an attack based on common general knowledge alone.
- Many inventions involve a combination of known features. However a combination of features, all of which individually were common general knowledge, can give rise to a valid patent claim if that combination is new and non-obvious. Patent trials are inevitably ex post facto and a key problem is to identify and avoid hindsight. Combinations of features can pose a particularly acute hindsight problem. The thing about concrete items of prior art, whether they are prior published documents or prior used products or processes, is that whatever combination of features that concrete prior art consists of, is not one which was created with hindsight knowledge of the invention.
- The problem with arguments over common general knowledge alone is that the combination of features relied on is always and necessarily one created with hindsight knowledge of the invention, and worse, is one which the person attacking validity has not been able to find as a pre-existing combination in the concrete prior art. If they had they would have relied on that concrete prior art. Either the combination has not been made in the concrete prior art at all or it only appears with additional inconvenient details. If an invention is not obvious over the concrete prior art which is relied on, the court is entitled to be sceptical that an argument that it is nevertheless obvious over common general knowledge alone is correct.
- The problem is illustrated in this case. Sometimes an invention belongs to a field which is not well documented but in this case Accord did not lack possible starting points. It has pleaded two documents and could easily have pleaded others, such as the existing SmPCs for subcutaneous methotrexate. However the documents contain what might have been thought of as "inconvenient" details. Russo does not mention subcutaneous administration by name and is aimed at JCA rather than RA. Russo is also a small study and was published six years before the priority date. Jansen does mention subcutaneous and is for RA but it does not mention pain and contains the two statements referred to above which medac relies on. That the "inconvenient" details in Russo have not led to a finding of non-obviousness is not the point. To invent as a starting point in the prior art an amalgam of the best bits of the two cited documents while leaving out the inconvenient aspects, which is in effect what the argument was, created a combination which did not hitherto exist.
Obviousness – no technical benefit
- Accord accepts that the no technical benefit argument would not invalidate the higher doses in claim 13. I am not satisfied that if the claims had been otherwise valid, the lack of technical benefit argument would justify revoking any claims. The argument is about the lower doses covered by the claims. The argument depends on an issue of fact, whether the painfulness of injections gets any less as the volume is reduced below 0.5 ml, so that there comes a point somewhere in the range of doses at which a concentration of 50 mg/ml does not make the injection any less painful than the known injections for that dose. I am not satisfied that the factual premise for this argument is made out. In other words on the evidence I find that it is more likely than not that the reduction in pain caused by reducing injection volume continues to reduce as volume reduces below 0.5 ml. No lower limit was established and so there is no basis on which to find that the lower reaches of claim 13 do not confer a technical benefit.
- On my findings on obviousness the insufficiency argument does not arise. However I do agree with Accord that if the argument about side effects had materially contributed to a finding that the claims involve an inventive step then the claims would have been insufficient because the patent does not make that invention plausible.
- For the law on plausibility relating to sufficiency I will refer to the Court of Appeal in Regeneron v Genentech  RPC 28 at paragraphs 95-103, Lilly v HGS  UKSC 51 and the recent judgment of Henry Carr J in Actavis v Lilly  EWHC 3294 (Pat).
- The problem for medac is that the patent says nothing at all about side effects. Medac referred to Actavis as authority for the proposition that the law does not require a patent to contain experimental data in order for the plausibility test to be satisfied. The judge so held and I respectfully agree. However Actavis can be distinguished from this case because in Actavis although there was no experimental data the patent did contain information and reasoning on the issue. It was that reasoning which the judge held made it plausible that the drug would have utility as a treatment for the disease (see paragraphs 178-181). The judge was not talking about a patent which contained no reference to the issue at all. In the present case there is no experimental data nor is there any reasoning or information at all addressed to side effects. There is nothing on which a skilled reader could base a view about the credibility of whether 50 mg/ml subcutaneous methotrexate does or does not have a side effect problem.
- Prof Müller-Ladner explained in his evidence that he regarded the invention as plausible because the holder of the patent, medac, was a well respected pharmaceutical company. Medac relied on this evidence. It is not relevant. As a matter of law, the identity of the inventor or patentee cannot have anything to do with sufficiency in general and plausibility in particular. The issue is an objective legal standard. It is based on the technical disclosure only. In that respect it may differ from consideration of an item of prior art. In some (unusual) cases the identity of the author of an item of prior art may be relevant to what the skilled person does with it.
- Both Dr Rue and Dr Östör were asked about plausibility. When asked about the matter in an unqualified way they said it was plausible, but that was because they thought the invention was obvious. When asked on the correct basis, essentially from the point of view of a skilled person who was sufficiently concerned about side effects that a test of 50 mg/ml was not obvious to try with the appropriate expectation of success, the most Dr Östör said was that it could work. That is not enough.
- This case illustrates why in a proper case there can be a squeeze between plausibility for insufficiency and obviousness. There is no squeeze concerning pain due to injection volume. If it was not obvious to a skilled person to make a 25 mg dose using a 50 mg/ml concentration in a 0.5 ml volume in order to reduce pain, such a finding would not reveal a sufficiency problem not least because the patent explains that the reduced volume reduces pain. However the position with side effects is different. If it was not obvious to administer a 25 mg dose using a 50 mg/ml concentration in a 0.5 ml volume subcutaneously because of a concern about the risk of side effects, then the patent does not give such a skilled person any comfort at all about that risk. If that skilled person would not administer the formulation to treat RA due to the risk, they would still not do it after reading the patent, and the claim to the use of that formulation would be insufficient.
- I find that patent EP 2 046 332 (UK) is invalid for obviousness over Russo. It will be revoked.
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