01 March 2016

Patents Court finds methotrexate patent invalid for lack of inventive step

This article was written by David Nickless, Managing Associate

The Patents Court has decided that medac’s patent relating to the use of methotrexate for subcutaneous administration in the treatment of rheumatoid arthritis (EP (UK) 2046332) is invalid for obviousness. Based on the prior art cited by Accord, the skilled team would have recognised that methotrexate could be administered by subcutaneous or intramuscular administration, and would optimise the concentration during formulation to minimise side effects.

Background

Accord sought revocation of the Patent, which protects medac's Metoject® syringe and pen products (widely used in the treatment of rheumatoid arthritis (RA) and related inflammatory conditions). The Patent covered the use of methotrexate for subcutaneous administration in the treatment of inflammatory autoimmune diseases, wherein the methotrexate is administered in a pharmaceutically acceptable solvent at a concentration of about 50mg/ml.

Accord attacked the Patent on a number of grounds including:

  • obviousness over a number of prior art citations, 

  • Agrevo-type obviousness based on the assertion that the claims of the Patent made no technical contribution, and 

  • insufficiency because, it was alleged, the Patent did not render it plausible that the claimed concentration could be safely administered to patients. The insufficiency attack was run as a squeeze on inventive step.

Obviousness

The Court found the Patent was obvious over a prior art citation (‘Russo’) which referred only to “parenteral” administration of methotrexate and reported a study in which several patients reported pain at the injection site, but did not indicate the methotrexate concentration in the injected fluid. Birss J concluded that the skilled person would obviously recognise the reference to “parenteral” administration as applicable to subcutaneous or intramuscular administration, or both. Furthermore, while Russo did not disclose a particular methotrexate concentration, it would be obvious to the skilled clinician in the team given Russo to ask the formulator to optimise with regard to pain, and such routine optimisation would lead to a concentration of about 50mg/ml, which was the concentration claimed.

medac relied on a number of pieces of secondary evidence to support its non-obviousness position. Most notably, Russo had been published 6 years before the priority date so why, asked medac, had no one come up with this ‘obvious formulation’ prior to the Patent?  The Judge was not persuaded by such arguments for a number of reasons: 

  • methotrexate was a generic medicine and so there was likely to be little commercial incentive for future development, 

  • most methotrexate in the UK before the priority date was administered orally so there was little appreciation of the pain problems associated with administration by injection, and

  • finally, in order for a “why had it not been done before?” position to have weight, the patentee would need to show that Russo had been read and its content appreciated by the skilled person, who had nevertheless not pursued the route taken by the inventors. 

Accord also ran an argument of obviousness over common general knowledge, a claim which drew a warning from the Judge on attacks based on CGK alone:

"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"

Insufficiency

Following the finding of obviousness over Russo, the insufficiency case became moot. However, the Judge confirmed 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. The Patent contained no experimental data nor any reasoning or information at all addressed to side effects. There was 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.

The Judge concluded by underlining the potential effectiveness of the obviousness/insufficiency plausibility squeeze when deployed correctly:

"This case illustrates why in a proper case there can be a squeeze between plausibility for insufficiency and obviousness … 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."

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