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Matthew Royle

Matthew Royle, Ph.D.

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Paul England

Paul England, DPhil

高级专业支持律师

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作者
Matthew Royle

Matthew Royle, Ph.D.

合伙人

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Paul England

Paul England, DPhil

高级专业支持律师

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2019年1月31日

Plausibility of second medical use patents: pregabalin in the Supreme Court

  • Briefing

Supreme Court decisions about patent law are relatively rare and usually significant. The latest such decision, Warner-Lambert v Mylan & Actavis [2018] UKSC 56, which was handed down by the court on 14 November 2018, is no exception.

The decision concerns a number of issues, the most important of which are the direct infringement of Swiss-form second medical use patent claims (direct infringement) and the role of plausibility in assessing validity on the grounds of insufficiency.

This article explains the plausibility part of the decision.

How did the Warner-Lambert case arise?

Actavis markets a generic pregabalin product under the brand name Lecaent, which was launched in February 2015. Lecaent was marketed under a "skinny label", which means that some possible indications are carved out of the Summary of Product Characteristics (SmPC) of the product. In this case the SmPC and the Patient Information Leaflet included in the packet state that the conditions for which Lecaent is indicated are epilepsy and generalized anxiety disorder only, for which patent protection has expired.

Warner-Lambert owns a patent, for which the relevant claims in this case are 1 and 3, in the following 'Swiss-form' (that is, 'the use of X in the preparation of a medicament for treating Y'):

  • Use of (S)-3-(aminomethyl)-5-methylhexanoic acid [which is to say 'pregabalin'] or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treating pain.

  • Use according to Claim 1 wherein the pain is neuropathic pain.

Actavis, together with Mylan, claimed the revocation of the Warner-Lambert patent, and – despite the treatment of pain being carved out on the skinny label – claimed against Actavis for infringement of Claims 1 and 3.

The lower instance and Supreme Court decisions in summary

At first instance, Arnold J held that none of the claims of the patent were obvious, but that claims 1 and 3, as well as other claims, were invalid on the ground of insufficiency; the claims were not plausible across their scope. The judge also held that, if claims 1 and 3 were valid, Actavis's activities with Lecaent would not infringe those claims either directly or indirectly.

The Court of Appeal dismissed appeals by both parties, upholding the first instance decision. That decision was then appealed to the Supreme Court, which heard the case in February 2018. By the time the case reached the Supreme Court, the issues left to be resolved were the test for infringement of a second medical use claim and the test for insufficiency based on lack of plausibility, in particular with regards to claim 3.

On the issue of plausibility, Lord Sumption (giving the leading judgment for the whole court) has upheld the lower courts' decisions that the patent did not plausibly support the treatment of central neuropathic pain. He also leads the majority in holding that the patent did not plausibly support any kind of neuropathic pain, thereby allowing Mylan and Actavis's cross-appeal. The claims alleged to be infringed were therefore invalid as insufficient.

What is neuropathic pain, as claimed?

There were a number of types of pain that were considered in the Warner-Lambert case, some of which were specific conditions leading to pain and others were broader classes of pain. The following classes of pain were particularly important:

  • Inflammatory pain - this is a type of nociceptive pain, where the body responds to an injury by releasing chemical mediators which increase the sensitivity of nociceptors, causing pain both at the site of the injury or in the surrounding area. Inflammatory pain resolves with the treatment of the underlying cause.
  • Neuropathic pain (which features in claim 3) - unlike inflammatory pain, this is pathological, being caused by damage to the nervous system itself. Also unlike inflammatory pain, neuropathic pain can last for years or even for life. There are two types of neuropathic pain: peripheral neuropathic pain, which arises from damage or dysfunction of the peripheral nervous system; and central neuropathic pain, which is rarer and arises from damage or dysfunction of the central nervous system.

The Supreme Court in Warner-Lambert unanimously agreed with both the first instance judge and the Court of Appeal that the meaning of 'neuropathic pain' in claim 3 of the patent should be construed to cover central neuropathic pain and peripheral neuropathic pain.

Why is there a plausibility test?

Patents raise a policy issue: to what extent should it be demonstrated in the patent at the time of filing that the claimed invention works? To deal with this issue the UK courts and the Boards of Appeal of the European Patent Office have developed the requirement of plausibility – to be patentable claims must make a technical contribution which is at least plausible. This has been described by the UK courts as a base-line or 'threshold test' of patentability.

Depending on the context, falling below the threshold will render the patent invalid as obvious or insufficient (or perhaps lacking industrial applicability). In the context of second medical use claims, the plausibility concept touches on the particular practical difficulty of demonstrating therapeutic efficacy at the stage when the patent application must in practice be made; typically long before the results of any clinical trials are available. How much information about the claimed therapeutic use should be disclosed and to what level of proof must it be shown to work? This is the question addressed by the Supreme Court in the context of insufficiency.

How high is the plausibility threshold?

The Court of Appeal in Warner-Lambert, had thought that the threshold was not only low, but that the test could be satisfied by a "prediction … based on the slimmest of evidence". Lord Sumption disagrees with this. The test is relatively undemanding, but it cannot be deprived of all meaning, the judge says, or reduced to little more than a test of good faith (as he thinks the Court of Appeal does). Indeed, if the threshold were as low as suggested by the Court of Appeal, Lord Sumption states, it would be unlikely to serve even the limited purpose of barring speculative or 'armchair claims'.

Lord Sumption instead explains that plausibility is inevitably influenced by the legal context. But in the present case, he makes a number of points of guidance:

  • First, the proposition that a product is efficacious for the treatment of a given condition must be plausible.
  • Second, it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion.
  • But, third, the claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason - reasonable scientific grounds are disclosed for expecting that it might well work.
  • Fourth, although the patent needn't prove the assertion that the product works for the claimed purpose, there must be something that causes the skilled person to think there is a reasonable prospect that the assertion will prove to be true.
  • Fifth, that reasonable prospect must be based on "a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se."
  • But, sixth, the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning.
  • Finally, sufficiency is a characteristic of the disclosure, although the disclosure may be supplemented or explained by the common general knowledge of the skilled person.

Apparently in contradiction to Lord Sumption's fifth point, however, the judgment of Lord Mance expresses concern that there is a real risk that the test described by Lord Sumption would amount to, or be understood as, involving a requirement to establish a prima facie case on the material contained in the specification. In Lord Mance's opinion, the EPO authorities do not put the standard so high.

While they certainly reject speculative or wide-ranging unsubstantiated claims, he says, they accept as sufficient a tailored claim which appears scientifically possible, even though it cannot be said to be even prima facie established, without for example testing or assays according to the state of the art. Only if a person skilled in the art would have significant doubts about the workability of the invention would it, in such a case, fail for insufficiency of disclosure. Thus, in Lord Mance's view, Lord Sumption had put the test of plausibility too high.

Similarly, Lord Hodge appears to differ from Lord Sumption by stating that a patent does not need to disclose experimental evidence of plausibility unless there is an allegation, supported by sufficient evidence, that the invention does not work. In fairness to Lord Sumption, this is not what he says. In fact, his sixth point listed above makes clear that experimental evidence is not needed.

The pre-clinical data in the Warner-Lambert patent

In his judgment, Lord Sumption looks at what had been established by the judge at first instance about the empirical data disclosed in the patent in support of the Warner-Lambert patent claims. The empirical data in the patent consisted of references to a number of pre-clinical animal models used to test drugs for various kinds of pain:

  • The most significant of these animal models was the rat paw formalin test. This test models inflammatory pain. The patent records that the test results showed pregabalin to be effective in treating inflammatory pain. There is also no statement in the patent that it is effective to treat neuropathic pain.
  • Next is the carrageenin test, which also models inflammatory pain. The Patent specification again records that test results showed pregabalin to be effective in treating this pain.
  • The post-operative pain model tests for pain responses following surgery. Like the other tests, nothing in the literature suggests that this model could be used to predict efficacy for neuropathic pain.
  • The patent specification refers to two well-known models for peripheral neuropathy, the Bennett model and the Kim and Chung model, but no data is presented from either model.

Analysis of the pre-clinical data

It followed, in the unanimous view of the Supreme Court, that the experimental data in the specification was predictive of efficacy against inflammatory pain. But, there was no experimental data or a priori reasoning to make it plausible that pregabalin is effective for the treatment of central neuropathic pain.

Furthermore, the skilled person would not have considered there was any reasonable basis for thinking that an anticonvulsant like pregabalin, known to be effective for the treatment of epilepsy, would for that reason alone be effective for treating neuropathic pain.

Warner-Lambert's appeal

A key point of appeal by Warner-Lambert was that claim 3 should be construed to cover only peripheral neuropathic pain and that there is a relevant unifying principle underlying this form of pain and inflammatory pain called central sensitisation, a well-known concept at the priority date.

However, and importantly for the case, whilst the experts were agreed that central sensitisation is common to inflammatory pain and peripheral neuropathic pain, it was not known to be causative of either. However, as stated above, the Supreme Court held that neuropathic pain in claim 3 of the patent should be construed to cover central neuropathic pain and peripheral neuropathic pain and, on the evidence, efficacy of pregabalin against central neuropathic pain was not plausible.

In their appeal, however, Warner-Lambert also argued that Court of Appeal had been wrong to say that it had to be demonstrated across the whole scope of the claim. But, Lord Sumption, on behalf of court, rejected this argument on the basis that plausibility is one element of sufficiency and the same principles apply as to sufficiency generally. This meant, where the claim is said to exceed the disclosed contribution to the art, it is of the essence that the specification must justify the full extent of the claim to the requisite standard.

Where a feature of the 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 the efficacy of the product for each of them, the assertion must be plausible in relation to them all.

The cross-appeal

Actavis and Mylan submitted a cross-appeal submitting that the disclosure of the patent did not make plausible the manufacture of pregabalin for the treatment of neuropathic pain of any kind, including peripheral neuropathic pain which Arnold J and the Court of Appeal had held was "just plausible".

Lord Sumption comments that Arnold J's conclusions about peripheral neuropathic pain from the data presented in the Warner-Lambert patent was based entirely on the common general knowledge that central sensitisation was "involved" in both inflammatory and peripheral neuropathic pain. The first instance judge concluded from this that it was "possible" that a drug which the specification showed to be effective for the first would also be effective for the second, although, as he admitted, "this would not necessarily be the case".

Lord Sumption says this is a logical non-sequitur. The reason for seeking a unifying principle embracing neuropathic as well as inflammatory pain is that the unifying principle may suggest a common cause or metabolic mechanism embracing both, whose operation may be affected by the drug. That might in turn suggest that a drug which was effective for one condition might also be effective for the other.

But, in this case, neither the specification nor the common general knowledge supplied any reason for supposing this. In particular, there was nothing to suggest, even as a hypothesis, that pregabalin works to treat peripheral neuropathic pain by blocking central sensitisation. There was also simply an absence of any evidence that Pregabalin acted on central sensitisation at all.

It was not, in the majority view, enough to justify a monopoly that it is "possible" a priori that a drug which was effective for inflammatory pain would also be effective for neuropathic pain, without any reason to suppose that the possibility had some scientific basis or that it was more than speculative. As Lord Sumption puts it: "Everything is possible that is not impossible, but 'not impossible' is very far from being an acceptable test for sufficiency. Plausibility may be easy to demonstrate, but it calls for more than that".

What does Warner-Lambert change?

There is a debate about whether the EPO case law only requires plausibility to be demonstrated if the therapeutic effect in a second medical use patent is inherently implausible. The majority of the Supreme Court think not. Lord Sumption, for the majority, says if this were correct then 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. This, he says, would be an odd result and contrary to the policy considerations of plausibility.

Instead, the majority adopts a positive requirement to show plausibility, their concern being that the Court of Appeal in this case set the bar too low; suggesting that plausibility is little more than a test of good faith. Instead, there must be something that causes the skilled person to think there is a reasonable prospect that the assertion will prove to be true, in the sense that plausibility must be based on some predictive data, or a priori reasoning. Lord Sumption, also says a reasonable prospect must be based on "a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se."

The minority of judges – Mance and Hodge – think this is putting the test too high. It risks, in their judgement, involving a requirement to establish a prima facie case on the material in the specification. This is not, in their view, supported by the EPO authorities.

Another issue raised by this discussion, given that the decision is focussed on second medical use claims, is whether the plausibility bar now set in English law by the majority is the same for other forms of claim, in particular per se claims. We know from earlier English authorities that plausibility applies to these claims too. The difference with a per se claim, is that there must simply be a plausible technical effect or contribution of some kind – any kind - rather than for the specific treatment of a condition.

Given the generality of a per se claim, is there the same need to disclosure material amounting to a "reasonable prospect" that such an effect is true? The principle that the Supreme Court was trying to apply was that the monopoly must be commensurate with the technical contribution. This is fact specific but in per se claims is likely to be the molecule itself. In English law this question may be more properly dealt with as a question of industrial applicability. In any case, the issue is likely to come up again quite quickly.

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