More pain for Warner-Lambert and their pregabalin patent
The long-awaited UK Supreme Court decision concerning Warner-Lambert’s Lyrica® patent was handed down last month.
In summary, the Supreme Court dismissed Warner-Lambert’s appeal and upheld that the patent did not sufficiently disclose the claimed medical uses i.e. all pain including peripheral and neuropathic pain. They also found that the claims were not even sufficient in respect of neuropathic pain in dependent claim 3.
They also found that even if the claims had been found valid, they would not have been infringed by Actavis and Mylan’s activities and that the post-trial amendment to try to limit the claims to the treatment of peripheral neuropathic pain was an abuse of process.
The Supreme Court is known for being pro-patentee, but this decision was a departure from that and appears, at first glance, to set the bar higher for medical use claims. This decision provides important guidance on the role of plausibility in the test for sufficiency and how infringement of European Swiss-type claims (the old medical use claim format) is assessed in the UK.
Claim 1 of the patent is directed towards pregabalin for the treatment of pain using a European Swiss-type claim. Dependent claim 3 was limited to the treatment of neuropathic pain.
It was known that neuropathic pain can be categorised into peripheral and central neuropathic pain. The patent only exemplified the use of pregabalin in a rat model, which the Court of Appeal viewed only to be linked to peripheral neuropathic pain. It was later confirmed (after the filing date) that pregabalin is effective in treating both peripheral and central neuropathic pain.
Actavis manufactures Lecaent, a pregabalin generic and brought proceedings for revocation along with Mylan in the UK.
Warner-Lambert then brought UK infringement proceedings against Actavis later that year.
The High Court at first instance ruled that claims 1 and 3 were insufficient, and even if valid, were not infringed. The Court of Appeal upheld these findings and also found that a post-trial amendment filed by Warner-Lambert after the High Court decision to limit the claim 3 to the treatment of peripheral neuropathic pain was an abuse of process.
The role of plausibility in the test for sufficiency
Sufficiency requires that the patent discloses the invention clearly and completely enough for it to be performed by the skilled person – essentially, in return for a patent the patentee needs to give full public disclosure of their invention.
The case law has developed over the years to categorise sufficiency into two main types:
- Enablement – the patent must enable the skilled person to carry out the invention. This aspect of sufficiency was recently dealt with by the UK Court of Appeal in Regeneron v Kymab where they found that the patent was enabled and sufficiently disclosed despite the methods provided in the application being unworkable at the time of the invention. The Court of Appeal afforded the skilled person with considerable time and expertise to find a workable method in that case. Thus, an unworkable method is not an immediate bar to patentability in respect of the enablement aspect of sufficiency.
- Entire scope – the patent must also enable the skilled person to work the invention across its entire scope without an undue burden. It must also be plausible to a skilled person for the data provided in the application, that the invention would work across its entire scope e.g. in the case of a broad medical use claim to a class of diseases if the drug’s mechanism of action is applicable to that broad class of diseases. The Warner-Lambert case dealt with this aspect of sufficiency.
In recent years, the EPO has raised an increasing number of plausibility objections to the claims concerning this second aspect of sufficiency with some decisions seemingly raising the threshold for plausibility (e.g. the Dasatinib decision – T0488/16).
In the Warner-Lambert case, the Court of Appeal found that it was implausible that pregabalin would be effective at treating any type of pain (claim 1) or central neuropathic pain (in respect of claim 3) based on the data in the application showing a mouse model of inflammatory pain. The treatment of peripheral neuropathic pain was found plausible because there was a sufficient unifying mechanistic link between inflammatory pain and peripheral neuropathic pain because both types of pain have a central sensitisation component. The Court noted that while the data was not predictive, it at least rendered its efficacy in treating that type of claim as plausible.
The Supreme Court paid close attention to the EPO Board of Appeal decision T609/02 (Salk Institute) and held by a slim majority that the disclosure supported claims so far as they extend to inflammatory pain but not to any kind of neuropathic pain. Interestingly, dependent claim 2 was directed to the treatment of inflammatory pain but does not appear to have been asserted.
In T609/02, the EPO Board of Appeal held that the specification must disclose the suitability of the drug for the claimed therapeutic application. Clinical trials were not deemed necessary but a mere assertion of efficacy was not enough. In vitro data that provides a direct link to the disease in question is also sufficient.
Warner-Lambert argued that it is necessary to disclose reasons why the claimed effect is plausible only when the skilled person reading the patent would be sceptical about it in the absence of such a disclosure (so-called negative plausibility).
Lord Sumption in the Supreme Court disagreed because it would mean that if nothing was known either for or against the claimed therapeutic effect, no disclosure need be made in support of it. Thus, the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true (so-called positive plausibility). However, not all the Supreme Court judges agreed with this approach.
On the aspect of plausibility across the whole scope of the claim, Lord Sumption in the Supreme Court viewed that where a feature of a claim is an assertion of therapeutic efficacy for a given condition, a monopoly is being claimed for the process of manufacturing the compound for the treatment of that condition. This does not mean that it must work for all patients suffering from that condition, or work on every occasion when it is applied by way of treatment. But, it does mean that where the condition identified embraces a number of different pathologies, and the claim is construed as asserting efficacy of the product for each of them, the assertion must be plausible in relation to them all.
While this appears a straightforward test, it has difficulties particularly for diseases having potentially many distinct (and as yet potentially unknown) underlying mechanisms of pathology.
It is important to note that the Warner-Lambert case involved a second medical use claim and the Supreme Court appeared to restrict the plausibility test to second medical use claims. Thus, it remains to be seen how a first medical use claim might fare before the Supreme Court.
In assessing the plausibility of the Warner-Lambert claims, the Supreme Court disagreed with the Court of Appeal that the specification sufficiently disclosed the use of pregabalin for the treatment of peripheral neuropathic pain. Thus, while the Court of Appeal had found that the use of pregabalin for the treatment of peripheral neuropathic pain (but not central neuropathic pain) was sufficiently disclosed, the Supreme Court disagreed and found that the use of pregabalin for any type (peripheral or central) of neuropathic pain was not sufficiently disclosed.
The Supreme Court reasoned that the rat models used to obtain the data provided in the specification were only relevant to inflammatory pain.
Inflammatory pain is an immune-pathology resulting from an activation and dysregulation of the immune system, whereas neuropathic pain occurs following dysfunction or injury of nerve fibres and is characterised by the lack of conversion of nociceptive stimuli into electrical impulses, which can be caused by an altered sensitivity of the peripheral and central nervous system or by damage of the peripheral nerve tissue.
The patentee argued that peripheral neuropathic pain and inflammation are unified by “central sensitisation”, which is the process by which chronic pain signals in the periphery (from inflammatory or neurological causes) sensitize the CNS to pain, leading to pain hypersensitivity. Thus, the data in the application using models of inflammatory pain was relevant to peripheral neuropathic pain via this unifying principle.
However, Lord Sumption argued that just because central sensitisation may be involved in both peripheral neuropathic pain and inflammatory pain, does not prove that they have a common metabolic mechanism.
Lord Sumption further reasoned that the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true. They reasoned that the specification said nothing about neuropathic pain of any kind. Also, the specification did not refer to central sensitisation as a mechanism of action of the drug, so there was nothing to suggest, even as a hypothesis, that pregabalin works with peripheral neuropathic pain by blocking central sensitisation. Also, the while the specification provided mouse models that could be used to test for efficacy of the drug in peripheral neuropathic pain, it did not directly suggest doing so.
This test seems to go beyond that applied by the EPO in requiring there to be an explicit disclosure of a mechanism of action of a claimed therapeutic effect that is predictive across the claim scope. The EPO would likely view that if it was known that the mouse models in the specification could be used to test for efficacy of the drug in peripheral neuropathic pain, then the therapeutic effect is derivable from the specification and sufficiently disclosed.
The patentee should, however, be careful about any claim amendment to a disease category for which there is little mention in the specification.
It is also worth noting that Lord Hodge and Lord Mance also of the Supreme Court disagreed with the approach taken by Lord Sumption, viewing it as imposing too high a threshold and imposing a burden on the patentee which the EPO Board of Appeal case law does not justify.
Therefore, despite the negative decision, the test for sufficiency in the UK appears far from settled since it is difficult to reconcile the differing views of the Judges in the Supreme Court.
Abuse of process
The Supreme Court also agreed with the lower courts that Warner-Lambert’s post-trial amendment limiting claim 3 to peripheral neuropathic pain was an abuse of process.
Therefore, it is important that any claim amendments are put forward as early in the proceedings as possible to avoid them being disallowed for an abuse of process.
In any case, it is unlikely that this amendment would have saved their case in this instance in view of the Supreme Court’s position on sufficiency.
Infringement of Swiss-type claims
The action for infringement was brought on the basis of claim 1 and 3. The Court of Appeal found these claims to both lack sufficiency, but Lord Justice Floyd still considered the issue of infringement in obiter, particularly the proper interpretation of Swiss-form medical use claims.
Lord Justice Floyd particularly provided a clear test by which infringement of Swiss-type claims by a generic could be assessed. The court should assess whether the alleged infringer knew or could foresee that at least some of the prescriptions written generically for the claimed drug for the claimed indication would, in fact, be fulfilled with the generic. The absence of the claimed indication from the label (“skinny label”) could not “conceivably be sufficient to negative the intention” and so would result in infringement. Instead, where the manufacturer has “taken all reasonable steps within his power to prevent the consequences occurring”, this would be sufficient to negative the intention and not result in infringement.
Warner-Lambert also appealed this point to the Supreme Court. The Supreme Court dismissed by majority Warner-Lambert’s appeal on this point.
Particularly, Lord Sumption, together with Lord Reed, Lord Hodge and Lord Briggs, found that if claims 1 and 3 had been valid, they would not have been infringed, but differed in their reasons.
Lord Sumption and Lord Reed agreed that the intention of the alleged infringer is irrelevant and that the sole criterion of infringement is whether the product as it emerges from the manufacturing process, including any labelling or accompanying leaflet, is presented as suitable for the uses which enjoy patent protection. Lord Hodge and Lord Briggs preferred the view of Mr Justice Arnold at first instance that the test is whether the alleged infringer subjectively intended to target the patent-protected market.
Therefore, the Court of Appeal’s test was not followed. As with the issue of sufficiency, despite the negative decision, the test for infringement of Swiss-type medial use claims in the UK appears far from settled since it is difficult to reconcile the differing views of the Judges in the Supreme Court.
In summary, Warner-Lambert’s patent claims 1 and 3 were found invalid for lack of sufficiency, and even if they were valid, were found not infringed. This is despite pregabalin being confirmed to be effective in treating both central and peripheral neuropathic pain and becoming a blockbuster drug.
It will remain to be seen in future case law how the UK-IPO and UK Courts interpret and follow this decision. Since the Judges in the Supreme Court could not reach agreement on the test for sufficiency and infringement in respect of Swiss-type claims, this will not be an easy job. However, it does mean that there is scope for arguing that the test of Lord Sumption, particularly in respect of sufficiency is too strict and not in line with EPO Board of Appeal case law.