Canada: Medac's 'Second Medical Use' Metoject PEN Patent Found Invalid

Last Updated: April 22 2016
Article by Elwin Morgan

Medac's patent to methotrexate for subcutaneous administration for the treatment of inflammatory autoimmune diseases (including rheumatoid arthritis (RA)), has been found invalid.

Birss J's 13 January 2016 decision (Accord Healthcare Limited v Medac Gessellschaft für Klinishe Spezialpräparate mbH [2016] EWHC 24 (Pat)) includes interesting guidance on the composition of the skilled team, what constitutes 'common general knowledge', the role of plausibility in the context of a squeeze between obviousness and sufficiency, and the usefulness of cross-examination in patent cases.


Methotrexate has been used as a chemotherapeutic agent in cancer as far back as the 1950s. It was later approved for the treatment of psoriasis and rheumatoid arthritis (RA). In 2006 in the UK, no product was approved for subcutaneous (i.e. below the skin) administration for inflammatory autoimmune diseases. However, approved formulations were available in the UK for intravenous administration for cancer and were being used 'off-label' for the treatment of RA and other inflammatory autoimmune diseases. In Germany, there were two approved subcutaneous methotrexate formulations for RA.

Medac's European patent number EP (UK) 2 046 332 (the Patent), with a July 2006 priority date, was granted with claims in Swiss form and EPC 2000 form to methotrexate for subcutaneous administration for the treatment of inflammatory autoimmune diseases, wherein the concentration of methotrexate is about 50mg/ml. Although this is not stated in the Patents Court's decision, the authors understand that the Patent offered protection for Medac's Metoject ® PEN single use syringe.

In a 'clearing the way' action, Accord sought revocation of the Patent on the grounds of obviousness and insufficiency. Central to the dispute were issues regarding the composition of the team skilled in the art and its common general knowledge.

The skilled team

Accord contended that the Patent was addressed to a team consisting of a clinician specialising in the field of inflammatory autoimmune diseases, and a formulator.

In contrast, Medac contended that prior to the making of the invention in issue (and so for the consideration of Accord's obviousness challenge), the skilled 'team' would not include a formulator. Medac argued "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". In consequence, argued Medac, to bring the skilled formulator into the team from the outset would fall foul of the hindsight trap identified by the Court of Appeal in Schlumberger v EMGS  [2010] EWCA Civ 819.

Starting with the general law, Birss J noted:

a patent is directed to those persons likely to have a practical interest in the subject matter, and that in appropriate cases, the skilled person can be a team.

The judge then considered the legal principles identified in Schlumberger as relevant when considering whether the skilled team is the same for both the purpose of obviousness and the purpose of reading and implementing the patent (i.e. sufficiency):

First, if an invention brought together two disparate fields and [is] therefore "art changing", then the identities of the person/team from the two different perspectives may be different... Second, ... 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. ... 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.

Birss J's view was that the present case was not one in which the invention was "art changing", and it was "not an exercise in hindsight" to consider the issues of inventive step from the point of view of a skilled team which comprised a formulator. Addressing a new formulation of the drug using a known mode of administration, the Patent was addressed to a team in the pharmaceutical sector as "that is where formulators work and that is where these new dosage forms come from".

Indeed, Medac's expert witness, Professor Müller-Ladner, a clinician, accepted during cross-examination "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".

One further noteworthy point on the skilled team was its identity in the UK compared with in Germany. The evidence established that in Germany it was the doctor who administered subcutaneous methotrexate (or the patient), whereas in the UK it was a nurse (or the patient). Consequently, in the UK the skilled team would include a nurse.

Lack of inventive step

The law

On the 'obvious to try' doctrine, Birss J noted the Court of Appeal's decision in Teva v Leo [2015] EWCA Civ 779 - The Teva v Leo case is discussed in our article here. He noted that the Court of Appeal "emphasised the question of obviousness by reference to what real-life people would think and do".

Medac cited Dr Reddy's Laboratories v Eli Lilly [2008] EWHC 2345 (Pat), in which the judge (Floyd J) "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". Birss J accepted Medac's submission 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".

Obviousness over Russo

'Russo' was a letter published in the Journal of Clinical and Experimental Rheumatology, in 2000. It reported the results of a small study into the tolerance of parenteral (i.e. not involving the gastrointestinal tract) doses of methotrexate in 20 children with juvenile chronic arthritis, versus 124 children orally dosed. Parenteral administration (of a higher dose) was associated with fewer side effects and complaints relating to the gastro-intestinal system relative to the orally administered (lower dose) control group. 20% of the experimental cohort reported "pain at injection site".

Russo did not specify whether the parenteral administration (by injection) was subcutaneous (i.e. under the skin) or intramuscular. The judge found that it would have been obvious to the skilled person that the disclosure was applicable to either or both.

Birss J noted that the differences between Russo and claim 1 of the Patent were that Russo did not disclose a concentration of parenteral methotrexate and that it did not single out subcutaneous administration.

Accord contended that it was obvious over Russo for the skilled team to create a subcutaneous formulation of 50ng/ml methotrexate using nothing more than routine optimisation. Accord's expert witness, Dr Rue, a formulator, gave evidence that a part of the common general knowledge of the skilled formulator was that smaller injection volumes caused less pain, and that a target of 0.5ml was representative of the thinking of the skilled formulator regarding subcutaneous formulation. The average parenteral dose described in Russo being 23.25mg/m2, Accord argued that this equated to a dose of 26mg based on average body surface area. Delivery of 26mg of methotrexate in 0.5ml would require a starting concentration of 52mg/ml; therefore the claim to 50mg/ml was obvious.

Medac argued that i) the skilled clinician would have had no need or desire to change the existing concentration of methotrexate from the existing concentrations used, ii) there was no reason to focus on the volume administered, and iii) if the skilled team had thought to increase the concentration of methotrexate, they would have had serious concerns about side effects associated with such a high dose.

The judge preferred Accord's case, concluding that:

  • The skilled team reading Russo in 2006 would gain from that document impetus to set about producing a formulation of subcutaneous methotrexate for use as a treatment for inflammatory auto-immune diseases. The fact that other formulations existed would not deter the team from producing their own, and the express reference to pain in Russo would make optimisation for that purpose obvious.
  • It was obvious to target a small volume like 0.5ml. Medac did not put in expert evidence from a formulator, and in the absence of evidence to contradict the opinion of Accord's expert witness Dr Rue, the judge was satisfied that Dr Rue's views represented those of the skilled formulator.
  • The skilled team would not be put off this approach by concerns about side effects. In this context the judge's conclusions regarding the expert evidence of the parties' skilled clinicians were key. Noting a difference between the way Medac's Professor Müller-Ladner expressed himself in his written report and his answers given in cross-examination, the judge said that this "bears out why cross examination of experts is an important tool in patent disputes". In particular, Professor Müller-Ladner's emphasis in his written evidence on possible side effects was exaggerated and the cross-examination, as a whole, revealed that Professor Müller-Ladner's opinion was not reflected by the words used in his report. Overall, there was "not so much" between Accord's expert witness Dr Östör and Professor Müller-Ladner's evidence in cross-examination. To the extent the two experts differed on side effects, the judge preferred Dr Östör, whose evidence was that concern about side effects would not deter the skilled team.

The result of this analysis was that Accord's case that the patent was obvious over Russo was "powerful" and was not overcome by arguments of long-felt want made by Medac. The judge's comments in this context are also noteworthy:

...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.

Obviousness over Jansen

'Jansen' was a paper was published in 1999. It proposed the use of subcutaneous administration of methotrexate for RA. The judge noted that differences with Russo included that it did not mention pain, and that it taught the use of 0.2-1.2ml injection volume, corresponding to 5mg-30mg methotrexate. Birss J was of the view that if the invention was not obvious over Russo then it was not obvious over Jansen, but he did not otherwise reach a conclusion on the obviousness challenge based on Jansen.

Obviousness over common general knowledge

Accord also challenged the validity of the Patent on the basis of obviousness over common general knowledge alone.

Following Generics (UK) v Warner-Lambert [2015] EWHC 2548 (Pat) (Arnold J), Birss J noted that the relevant common general knowledge for this purpose must be that in the UK.

In the UK, Birss J had found that the clinician member of the skilled team was unaware of the concentrations of methotrexate being administered subcutaneously and of the fact that there would be an issue with regard to pain in relation to such an administration. Consequently, he considered that there was "nothing to provide an impetus to the skilled team to think about the issue at all".

The judge had noted that the skilled team may also include a nurse (and a pharmacist) and that this was not the subject of controversy in the litigation. Neither side called a nurse. The judge said that he drew "no inference either way about their actual knowledge".

Citing Ratiopharm v Napp [2008] EWHC 3070 (Pat) (Floyd J), Birss J warned of the dangers associated with attacks of obviousness over the common general knowledge alone, which are not restricted or limited by inconvenient details. Of this, Birss J said:

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.

Obviousness - no technical benefit

Accord also challenged the validity of the patent based on lack of technical benefit but the judge was not satisfied that the factual premise for the challenge was made out:

...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 0.5ml. No lower limit was established and so there is no basis on which to find that the lower reaches of claim13 do not confer a technical benefit.


Accord contended that if Medac's argument that the skilled person would have been put off attempting a high concentration/low volume formulation by concern about side effects succeeded, then the claims were insufficient because the patent did not make that invention plausible.

The judge noted that the "problem" for Medac in this context was that the patent did not mention side effects. However, as Medac had not succeeded, based on its side effects argument, in successfully defending the obviousness challenge, Accord's insufficiency squeeze fell away.

More generally, Birss J made some interesting points on the law relating to sufficiency. Citing Regeneron v Genentech [2013] EWCA Civ 93, HGS v Eli Lilly [2011] UKSC 51 and the recent judgment of Henry Carr J in Actavis v Lilly [2015] EWHC 3294 (Pat) ( our article on Actavis v Lilly is available here), he said:

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 ... 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.

...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.

Concluding Comments

In the UK, the skilled team was found to include a nurse. Birss J commented that he did not believe that anything turned on this and that it was not the subject of controversy in the litigation; neither side called a nurse and he drew "no inference either way about their actual knowledge".

However, the judge found that based upon the common general knowledge alone, the clinician member of the skilled team in the UK, who would not usually administer methotrexate injections, would lack the necessary impetus to think about the issue of pain in the context of subcutaneous injection, and that accordingly the challenge to inventive step based upon the common general knowledge failed.

With this background, it may be queried whether the evidence of a nurse member of the skilled team would have established impetus (or lack of it). Should Medac succeed in an appeal, such evidence could potentially be relevant to Accord's (so far) unsuccessful challenges.

In light of the distinction between the composition of the skilled team in the UK compared with that in Germany, it would also seem possible that in Germany, the outcome of an obviousness challenge based upon the common general knowledge alone could be different. This is because the skilled team in Germany would comprise a clinician who personally administered subcutaneous methotrexate to patients for the treatment of RA, and so who would be personally aware of the problem of associated pain.

The Accord v Medac case therefore illustrates the importance for litigants of adopting a multi-layered strategy which enables the other party's case to be refuted even if the primary strategy is unsuccessful. Having failed in its primary case regarding the composition of the skilled team, Medac had not submitted evidence from an expert formulator which could be used to contradict the evidence upon which Accord relied. Accord, on the other hand, had not submitted evidence from a nurse, which might have supported its challenge of obviousness over common general knowledge alone.

One further point of note arising from Birss J's decision concerns his comments on the role of plausibility in a squeeze between challenges of obviousness and insufficiency. Although the comments are most likely obiter, patentees should be wary of relying on arguments in support of inventive step for which there is neither data nor reasoning in the patent specification in support.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on

Click to Login as an existing user or Register so you can print this article.

In association with
Related Video
Up-coming Events Search
Font Size:
Mondaq on Twitter
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
Email Address
Company Name
Confirm Password
Mondaq Topics -- Select your Interests
 Law Performance
 Law Practice
 Media & IT
 Real Estate
 Wealth Mgt
Asia Pacific
European Union
Latin America
Middle East
United States
Worldwide Updates
Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:
  • To allow you to personalize the Mondaq websites you are visiting.
  • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our information providers who provide information free for your use.
  • Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.
    If you do not want us to provide your name and email address you may opt out by clicking here
    If you do not wish to receive any future announcements of products and services offered by Mondaq you may opt out by clicking here

    Terms & Conditions and Privacy Statement (the Website) is owned and managed by Mondaq Ltd and as a user you are granted a non-exclusive, revocable license to access the Website under its terms and conditions of use. Your use of the Website constitutes your agreement to the following terms and conditions of use. Mondaq Ltd may terminate your use of the Website if you are in breach of these terms and conditions or if Mondaq Ltd decides to terminate your license of use for whatever reason.

    Use of

    You may use the Website but are required to register as a user if you wish to read the full text of the content and articles available (the Content). You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these terms & conditions or with the prior written consent of Mondaq Ltd. You may not use electronic or other means to extract details or information about’s content, users or contributors in order to offer them any services or products which compete directly or indirectly with Mondaq Ltd’s services and products.


    Mondaq Ltd and/or its respective suppliers make no representations about the suitability of the information contained in the documents and related graphics published on this server for any purpose. All such documents and related graphics are provided "as is" without warranty of any kind. Mondaq Ltd and/or its respective suppliers hereby disclaim all warranties and conditions with regard to this information, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. In no event shall Mondaq Ltd and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use or performance of information available from this server.

    The documents and related graphics published on this server could include technical inaccuracies or typographical errors. Changes are periodically added to the information herein. Mondaq Ltd and/or its respective suppliers may make improvements and/or changes in the product(s) and/or the program(s) described herein at any time.


    Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:

    • To allow you to personalize the Mondaq websites you are visiting.
    • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
    • To produce demographic feedback for our information providers who provide information free for your use.

    Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.

    Information Collection and Use

    We require site users to register with Mondaq (and its affiliate sites) to view the free information on the site. We also collect information from our users at several different points on the websites: this is so that we can customise the sites according to individual usage, provide 'session-aware' functionality, and ensure that content is acquired and developed appropriately. This gives us an overall picture of our user profiles, which in turn shows to our Editorial Contributors the type of person they are reaching by posting articles on Mondaq (and its affiliate sites) – meaning more free content for registered users.

    We are only able to provide the material on the Mondaq (and its affiliate sites) site free to site visitors because we can pass on information about the pages that users are viewing and the personal information users provide to us (e.g. email addresses) to reputable contributing firms such as law firms who author those pages. We do not sell or rent information to anyone else other than the authors of those pages, who may change from time to time. Should you wish us not to disclose your details to any of these parties, please tick the box above or tick the box marked "Opt out of Registration Information Disclosure" on the Your Profile page. We and our author organisations may only contact you via email or other means if you allow us to do so. Users can opt out of contact when they register on the site, or send an email to with “no disclosure” in the subject heading

    Mondaq News Alerts

    In order to receive Mondaq News Alerts, users have to complete a separate registration form. This is a personalised service where users choose regions and topics of interest and we send it only to those users who have requested it. Users can stop receiving these Alerts by going to the Mondaq News Alerts page and deselecting all interest areas. In the same way users can amend their personal preferences to add or remove subject areas.


    A cookie is a small text file written to a user’s hard drive that contains an identifying user number. The cookies do not contain any personal information about users. We use the cookie so users do not have to log in every time they use the service and the cookie will automatically expire if you do not visit the Mondaq website (or its affiliate sites) for 12 months. We also use the cookie to personalise a user's experience of the site (for example to show information specific to a user's region). As the Mondaq sites are fully personalised and cookies are essential to its core technology the site will function unpredictably with browsers that do not support cookies - or where cookies are disabled (in these circumstances we advise you to attempt to locate the information you require elsewhere on the web). However if you are concerned about the presence of a Mondaq cookie on your machine you can also choose to expire the cookie immediately (remove it) by selecting the 'Log Off' menu option as the last thing you do when you use the site.

    Some of our business partners may use cookies on our site (for example, advertisers). However, we have no access to or control over these cookies and we are not aware of any at present that do so.

    Log Files

    We use IP addresses to analyse trends, administer the site, track movement, and gather broad demographic information for aggregate use. IP addresses are not linked to personally identifiable information.


    This web site contains links to other sites. Please be aware that Mondaq (or its affiliate sites) are not responsible for the privacy practices of such other sites. We encourage our users to be aware when they leave our site and to read the privacy statements of these third party sites. This privacy statement applies solely to information collected by this Web site.

    Surveys & Contests

    From time-to-time our site requests information from users via surveys or contests. Participation in these surveys or contests is completely voluntary and the user therefore has a choice whether or not to disclose any information requested. Information requested may include contact information (such as name and delivery address), and demographic information (such as postcode, age level). Contact information will be used to notify the winners and award prizes. Survey information will be used for purposes of monitoring or improving the functionality of the site.


    If a user elects to use our referral service for informing a friend about our site, we ask them for the friend’s name and email address. Mondaq stores this information and may contact the friend to invite them to register with Mondaq, but they will not be contacted more than once. The friend may contact Mondaq to request the removal of this information from our database.


    From time to time Mondaq may send you emails promoting Mondaq services including new services. You may opt out of receiving such emails by clicking below.

    *** If you do not wish to receive any future announcements of services offered by Mondaq you may opt out by clicking here .


    This website takes every reasonable precaution to protect our users’ information. When users submit sensitive information via the website, your information is protected using firewalls and other security technology. If you have any questions about the security at our website, you can send an email to

    Correcting/Updating Personal Information

    If a user’s personally identifiable information changes (such as postcode), or if a user no longer desires our service, we will endeavour to provide a way to correct, update or remove that user’s personal data provided to us. This can usually be done at the “Your Profile” page or by sending an email to

    Notification of Changes

    If we decide to change our Terms & Conditions or Privacy Policy, we will post those changes on our site so our users are always aware of what information we collect, how we use it, and under what circumstances, if any, we disclose it. If at any point we decide to use personally identifiable information in a manner different from that stated at the time it was collected, we will notify users by way of an email. Users will have a choice as to whether or not we use their information in this different manner. We will use information in accordance with the privacy policy under which the information was collected.

    How to contact Mondaq

    You can contact us with comments or queries at

    If for some reason you believe Mondaq Ltd. has not adhered to these principles, please notify us by e-mail at and we will use commercially reasonable efforts to determine and correct the problem promptly.

    By clicking Register you state you have read and agree to our Terms and Conditions