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.

Background

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.

Insufficiency

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.