No pain, no gain: Plausibility in Warner-Lambert v Actavis

The dust has started to settle following the Supreme Court decision in Warner-Lambert v Actavis [2018] UKSC 56 handed down recently (IPKat post here). Much of the commentary has focused on the infringement aspect of the decision. In this first of IPKat's follow-up posts, this Kat delves deeper into the court's take on the issue of plausibility.

The plausibility of second medical use inventions - why is it necessary?

In the Supreme Court decision, Lord Sumption began his discussion of plausibility by considering the problem raised by determining the sufficiency of Swiss-style second medical use claims.

"Section 14 of the Patents Act and the corresponding provisions of the EPC assume that an invention will be sufficiently disclosed if the specification enables it to be “performed”. In the case of a patent for a new product or process, that assumption is almost always correct. But the assumption is not correct in the case of a second use patent. The invention is not the compound or the process of its manufacture. The skilled person already knows how to make the product from the prior art disclosed in the original patent. The invention consists in the new purpose for which the product is to be manufactured. If sections 14(3) and 72(1)(c) are read literally and as an exhaustive statement of the requirement of sufficiency, all that needs to be disclosed is the new purpose, which is enough to enable it to be administered to a patient suffering from the relevant condition. The skilled person does not need to know how or why the invention works in order to replicate it. The result would be that the knowledge which made the identification of the new purpose inventive need not be disclosed at all."

Thus, reasoned Lord Sumption, if only the classical insufficiency test is applied, a patent could be obtained for a second medical use on a wholly speculative basis, by an “arm-chair inventor”. The plausibility test is designed to prevent this. According to the plausibility test, a skilled person must not only be able to perform the claimed invention, but it must be plausible to a skilled person, at the filing date, that the invention works.
An armchair inventor
Lord Sumption then reviewed the UK case law and the Technical Boards of Appeal (TBA) of the EPO cases dealing with plausibility. Of crucial importance to the case in question was Lord Sumption's interpretation of Salk Institute (T 609/02). In this decision, the Board of Appeal (BoA) held that the specification must disclose the suitability of the drug for the claimed therapeutic application. Clinical trials were deemed not necessary, but a mere assertion of efficacy was not enough. In vitro tests could suffice if the skilled person would know that the in vitro effect shown has a direct mechanistic bearing on the disease in question.

Positive and negative plausibility

Warner-Lambert argued that the lessons to be taken from T 609/02 were that it is necessary for the patentee to disclose reasons regarding the claimed therapeutic effect as plausible only when the skilled person reading the patent would be skeptical about it in the absence of such a disclosure ("negative plausibility").  However, Lord Sumption thought that, whilst this reading was consistent with the turns of phrase in the case, "it would have been a strange thing for the Technical Board of Appeal to have meant". This was because it would be inconsistent with the whole reason behind the necessity of the plausibility test: "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". Lord Sumption thus interpreted the principle laid down by T 609/02 as being that "the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true" (paragraph 36) ("positive plausibility").

Lord Sumption's reading of T 609/02 was key to how he decided on the appropriate requirements for plausibility. However, other judges voiced some concern with the reasoning.

Following the standard interpretation of T 609/02 as requiring negative plausibility, does it follow that in a case where nothing is known either for or against a claimed effect, no disclosure need be made in support of it? Some would argue that, on the contrary, that in the empirical sciences completely new assertions (i.e.those lacking any evidence either way for their truth) must be backed-up with some form of empirical evidence before they are considered remotely plausible.  In fact, the more disconnected an assertion is with that which has gone before, the greater the need for evidence. Negative plausibility thus may not enable someone to claim something for which there is no evidence whatsoever. Lord Sumption's interpretation of the EPO approach to plausibility is therefore controversial.

Plausible over the entire scope of the claim?

In their appeal to the Supreme Court, Warner-Lambert took issue with the Court of Appeal’s requirement that plausibility must be demonstrated for everything falling within the scope of the claim. Lord Sumption roundly rejected this argument:

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.

This appears to provide a clear test as to the meaning of "the entire scope" of a second medical use patent. For example, if you claim a composition for use in the treatment of cancer, this must be plausible for breast cancer, lung cancer, pancreatic and all other types of cancer.

However, it could be argued that the distinction is perhaps not quite as clear as it first appears. If a patent specification provides data demonstrating that a drug only works in 95% of patients suffering from HIV infection, following the Supreme Court's reasoning, it is sufficiently disclosed for a drug for use in the treatment of HIV infection. However, the reason the treatment does not work in the 100% of HIV patients will be due to differences in the underlying pathology of the disease, the mechanisms of which have just not been identified.

By contrast, if a patent specification only provides data showing that a drug works with respect to patients shown to have HIV-1 infection (e.g. representing 95% of HIV infections) but is not sufficiently disclosed with respect to the treatment of HIV-2, it is not enabled across the entire scope of a claim to a drug for use in the treatment of HIV.  The patent would only be sufficiently disclosed for a drug use in the treatment of HIV-1.

The only difference between the former and latter examples is that in the latter the reason for the drug not working in all patients (95% of patients versus HIV-1 but not HIV-2 infected individuals) is known. It can be asked therefore, whether there is a distinction between a treatment that only treats a proportion of patients suffering from a condition and a treatment that only treats a sub-type of patients suffering where the condition? (except that the sub-type has been identified).

Personalized medicine takes these issues to the extreme. In personalized medicine, conditions can be said to embrace an ever increasing number of causative pathologies, potentially each unique to an individual. Whilst this is an extreme example, it demonstrates that achieving plausibility for the use of a drug to treat a disease having potentially many distinct (and as yet potentially unknown) underlying mechanisms of pathology may not be a trivial task. It also raises the question of how the plausibility test should be applied when the the distinct causative pathologies are identified after the filing date for a patent application.

What about first medical use claims?

Lord Sumption appears to restrict the plausibility test to second medical use claims. This seems to be because he believes the invention underlying a first medical use patent to be the provision of the compound, as opposed to it use in a treatment. However, an inventor could make a new (but e.g. obvious) compound and speculatively claim from the comfort of their armchair that it could be used to any number of diseases. Following Lord Sumption's logic for the need for the plausibility test, should the specification of a patent claiming a first medical use also be required to make the assertion plausible to all conditions falling under the scope of the claim? Particularly, if in a hypothetical world, the patent in suit was the first to disclose pregabalin, and included a broad claim to the use of pregabalin in the treatment of pain, would this be deemed sufficiently disclosed? 

A question of pain

Returning to the case in question, Lord Sumption disagreed with the Court of Appeal that the specification sufficiently disclosed the use of pregabalin for the treatment of peripheral neuropathic pain. Lord Sumption, applying his test for plausibility, reasoned that the rat models used to obtain the data provided in the specification were only relevant to inflammatory pain.

Inflammatory pain is an immuno-pathology resulting from activation and dysregulation of the immune system. Neuropathic pain occurs following dysfunction or injury of nerve fibres and is characterised by the lack of conversion of nociceptive stimuli into electrical impulses. It can be caused by an altered sensitivity of the peripheral and central nervous system or by damage of peripheral nerve tissue.

Arguments had been presented in court that the data provided using models of inflammatory pain provided in the specification, were relevant to peripheral neuropathic pain because peripheral neuropathic pain and inflammatory pain share the unifying principle of "central sensitization". Central sensitization is the process by which chronic pain signals in the periphery (from inflammatory of neurological causes) sensitize the central nervous system to pain, leading to pain hypersensitivity.

However, Lord Sumption argued that just because central sensitization may be involved in both peripheral neuropathic pain and inflammatory pain “does not prove that they have a common cause” and “does not suggest that there may be a common metabolic mechanism at work”. [the phrase "metabolic mechanism" is quoted from the TBA law, but does not make sense in this context; "common mechanism of action" may have been a better choice of phrase].

Lord Sumption disagreed with the Court of Appeal that the plausibility test could be satisfied by “the slimmest of evidence” from which a therapeutic effect could be plausibly predicted. Lord Sumption instead identified the principle as being that “the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true”. Given that the specification in the present case says nothing about neuropathic pain of any kind. Furthermore, the specification did not refer to the central sensitization as a mechanism of action of the drug, "there is nothing to suggest, even as a hypothesis, that pregabalin works with peripheral neuropathic pain by blocking central sensitisation". Additionally, whilst the specification provides mouse models that may be used to test for the efficacy of a drug in peripheral neuropathic pain, it does not directly suggest doing so.

Lord Sumption thus ruled that the requirement for plausibility was not satisfied, as the specification did not provide a full disclosure of its contribution to the art: "The disclosure did not contribute any knowledge of the art capable of justifying a claim to a monopoly of the manufacture of pregabalin for the treatment of neuropathic pain of any kind".

By requiring explicit disclosure of a mechanism of action of a claimed therapeutic effect that is predictive across the entire scope of the claim, Lord Sumption therefore arguably establishes a prima facie test for the plausibility of the therapeutic efficacy of a composition. This test seems to go beyond that usually applied by the EPO, in that positive reasoning is required as to why the claimed effect is plausible given the data provided in the specification. 

Lord Hodge and Lord Mance 

Lord Hodge and Lord Mance disagreed with the approach taken by Lord Sumption on the issue of plausibility. Lord Mance argued that Lord Sumption's analysis "imposes too high a threshold, and imposes a burden on a patentee which the case law of the Board of Appeal of the EPO does not justify". Particularly, the requirement for the specification to disclose some reasoning for supposing the implied assertion of efficacy in the claim is true "risks being read as a requirement that the plausibility of the claim must appear to be established prima facie through scientifically cogent reasoning".  

Has the right balance been struck?

The disagreement among the Judges on whether negative or positive plausibility should be the test for second medical use claims, has been reflected in the responses to the decision since it was handed down. There are diverging opinions as to whether the Supreme Court (and particularly Lord Sumption) places the bar for plausibility too high. Is the requirement for positive reasons for the plausibility of a claimed therapeutic effect necessary to prevent speculative inventors obtaining unfair monopolies? Would the EPO's test for negative plausibility have ensured that the right bargain had been struct between the patentee and the state?

In the follow-up next post on the case, IPKat will look at the court's reasoning on the issue of infringement.
No pain, no gain: Plausibility in Warner-Lambert v Actavis No pain, no gain: Plausibility in Warner-Lambert v Actavis Reviewed by Rose Hughes on Monday, November 26, 2018 Rating: 5

4 comments:

Anonymous said...

How terrible it is that an inventor should need to provide positive evidence of actually having invented something prior to being awarded a monopoly for 20 years that can stymie any R&D in that area! I think that some perspective is needed here. It is still a very low bar - there just need be some tangible reasoning disclosed. The other route would constitute a charter for trolling...

Anonymous said...

The question relating to an HIV treatment is interesting.

To my mind, if an application claims a drug for treating HIV and doesn't acknowledge the existence of the two different types of HIV or differentiate between the efficacy of the drug for the two different types then the application is insufficient for both types of HIV. This is extremely basic information that has to be included in a patent application. In the absence of this information the skilled person would likely consider the specification to be extremely deficient and would not consider anything disclosed therein to be plausible (even if it actually works).

This, again, is a very low bar that could be overcome by a simple paragraph stating "There are two types of HIV: HIV-1 and HIV-2, these are believed to have different underlying pathologies. It is currently believed that the drug is effective in treatment of both types."

Anonymous said...

Interesting summary - thanks. Is there an authority for saying "Following the STANDARD INTERPRETATION of T 609/02 as requiring negative plausibility" and "Would THE EPO'S TEST FOR NEGATIVE PLAUSIBILITY have ensured that the right bargain had been struct between the patentee and the state" (my emphasis)? I'm not sure most EPO practitioners would characterise the approach of the EPO in this way. Personally, I think the EPO tends to require what this summary calls "positive plausibility", although there are of course variations between Divisions and Boards.

I like plausibility said...

If one would follow Warner-Lambert’s line of argumentation it would boil down to, in case of a first or further medical indication, that by merely alleging some medical effect without the faintest proof of it, be it empirical or not, a patent should be granted. This is anything but reasonable.

I cannot see that the standard interpretation of T 609/02 is requiring “negative plausibility”, the contrary seems true. If as an applicant you allege some medical effect, you have the onus of proof.

For the disclosure to be sufficient in this matter, it is important for the applicant/proprietor to show that at the priority/filing date the originally filed documents render it plausible that the patent is solving the problem stated, i.e. to be effective in the treatment of a given illness or to have the desired effect on the metabolism.

T 609/02 is only one of a long list of decisions relating to plausibility in case of medical uses. T 488/16 (dasatinib) is another decision of the same kind. See also T 866/08, T 1050/12 or T 1255/11.

The only valid plausibility is a “positive plausibility”. It is only if plausibility is positively given at the priority/filing date that post-published documents can be taken into account. This seems plainly logical and it is difficult to see anything controversial in it.

When disclosing plausibility, it does not mean that plausibility at filing should only be required in case of a second medical use. It applies as well to a first medical use. I would simply say that it is even more important in a second medical use that the pathology treated is different and that there is a least some reasonable likelihood, that it works.

A patent can only be granted if there is a contribution to the existing art. And this has to be demonstrated at priority/filing, hence the quest for plausibility. That not every pharmaceutical has a positive effect on a human body is a mystery which might never be solved, but it has at least to be made plausible.

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