Accord Healthcare Ltd v Medac Gesellschaft Für Klinische Spezialpräparate Mbh [2016] EWHC 24 (Pat) (13 January 2016)
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`8/29/17, 4*38 PM
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`You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Accord Healthcare Ltd v
`Medac Gesellschaft Für Klinische Spezialpräparate Mbh [2016] EWHC 24 (Pat) (13 January 2016)
`URL: http://www.bailii.org/ew/cases/EWHC/Patents/2016/24.html
`Cite as: [2016] EWHC 24 (Pat)
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`IN THE HIGH COURT OF JUSTICE
`CHANCERY DIVISION
`PATENTS COURT
`
`Neutral Citation Number: [2016] EWHC 24 (Pat)
`Case No: HP-2014-000011
`
`Royal Courts of Justice
`Strand, London, WC2A 2LL
`13/01/2016
`
`B e f o r e :
`THE HON. MR JUSTICE BIRSS
`____________________
`Between:
`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
`____________________
`
`Defendant
`
`Claimant
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`Accord Healthcare Ltd v Medac Gesellschaft Für Klinische Spezialpräparate Mbh [2016] EWHC 24 (Pat) (13 January 2016)
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`8/29/17, 4*38 PM
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`HTML VERSION OF JUDGMENT​
`____________________
`Crown Copyright ©
`
`Mr Justice Birss:
`Introduction
`1. 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.
`2. 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.
`3. 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.
`4. 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.
`The issues
`5. 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
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`Accord Healthcare Ltd v Medac Gesellschaft Für Klinische Spezialpräparate Mbh [2016] EWHC 24 (Pat) (13 January 2016)
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`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.
`6. 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.
`7. 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.
`8. 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.
`The witnesses
`9. Accord called two experts: a clinician and a formulator. Medac called an expert clinician only.
`10. 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.
`11. 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.
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`Accord Healthcare Ltd v Medac Gesellschaft Für Klinische Spezialpräparate Mbh [2016] EWHC 24 (Pat) (13 January 2016)
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`12. 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.
`13. 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
`14. 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.
`15. 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 [2010] 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.
`16. 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 [2012] EWCA Civ 1234 at paragraphs 72 and 76).
`In appropriate cases the skilled person can be a team.
`17. 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.
`18. 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
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`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).
`19. 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.
`20. 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.
`21. 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.
`22. 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.
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`23. 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.
`24. 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.
`25. 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.
`26. 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.
`27. 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.
`28. 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
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`29. 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.
`30. 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.
`31. 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.
`32. 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.
`33. 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.
`34. 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.
`35. In the treatment of cancer, at the priority date methotrexate was frequently used in doses of up to
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`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.
`36. 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.
`37. 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.
`38. 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.
`39. 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).
`40. 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.
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`41. 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).
`42. 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.
`43. 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.
`44. 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.
`45. 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.
`46. 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.
`47. 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
`
`http://www.bailii.org/ew/cases/EWHC/Patents/2016/24.html
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`Page 9 of 24
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`Page 9 of 24
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`KOIOS Exhibit 1042
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`

`

`Accord Healthcare Ltd v Medac Gesellschaft Für Klinische Spezialpräparate Mbh [2016] EWHC 24 (Pat) (13 January 2016)
`
`8/29/17, 4*38 PM
`
`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).
`48. 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.
`49. 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.
`50. RA is an inflammatory autoimmune disease and the claims are not limited to RA.