Plausibility after pregabalin – how much information must a patent disclose?

Plausibility has been increasingly important in life sciences patent prosecution and litigation in recent years, including in the UK Supreme Court. Due to the growing significance of second medical use claims in biopharma innovation, rights holders should ensure that they properly understand this complex area

In order to obtain a patent for an invention, it is necessary to meet the following statutory validity requirements:

  • The invention must be novel or new compared with the prior art.
  • It must contain an inventive step, which is not obvious over the prior art.
  • It must be enabled across its scope (ie, it must describe to a skilled person how to perform everything covered by the patent claims).

In addition, the invention must have an industrial application.

In recent years, UK patent law has taken its lead from EPO case law in developing a non-statutory threshold step to validity that underlies all of the statutory requirements. This step is to first ask whether a patent discloses a plausible technical contribution. But what is the mark of plausibility; how high is the threshold? This question has real implications for the amount of information that must be provided in a patent application (particularly in the pharmaceutical and biologic fields) and therefore the optimum time for filing. This plausibility threshold was the subject of the recent UK Supreme Court case Warner-Lambert Company LLC v Generics (UK) Ltd ([2018] UKSC 56 (14 November 2018)). This article discusses the rationale for plausibility and the impact of Warner-Lambert, including within the EPO context.

Applicant’s dilemma

At the heart of the patent system is a public contract or ‘patent bargain’. This essentially offers patentees 20 years of market exclusivity for their inventions in exchange for the publication of the associated technology for the benefit of the wider R&D community. Exclusivity is also necessary, it is argued, in order to charge the premium prices necessary to recoup investment (the cost of developing even a successful small-molecule product can be more than $1 billion). Further, the European patent system works on a first-to-file basis. Therefore, given that the innovator pharmaceutical and therapeutic biological industry is highly competitive in many areas of disease, drug companies want to file patent applications as early as possible to avoid being beaten to exclusivity by their rivals or having prior art published which would destroy the novelty of their invention.

This system creates tension between the commercial pressure to file patent applications as soon as possible and the public policy of providing enough information on an invention to justify the exclusivity that a patent brings. This is known as the ‘applicant’s dilemma’ – in other words, how much information must be made available in a patent to enable an application to be filed as soon as possible without running the risk of failing to disclose enough information to satisfy the patent bargain? In theory, the information provided could be anything from mere speculation to full clinical trial data. This question is not answered by the traditional statutory requirements of novelty, inventive step, sufficiency and industrial application. Instead, plausibility has become pervasive as a common threshold which underlies these requirements and serves to answer this question.

Plausiblity threshold

The policy behind the plausibility threshold has been explained by UK judges in the particular context of second medical use claims in which efficacy as a particular therapy is claimed. These judges have reasoned that plausibility provides a balance between:

  • a demand that a patent specification must contain the results of a clinical trial in order to prove efficacy; and
  • the argument that if a patent contains only a mere proposal, it has not made a contribution to the art (and thus failed the patent bargain).

The problem with the first proposition is that although the existence of a patent (or application) may facilitate investment in a clinical trial that might not otherwise take place, this means that the patent must be applied for before the results are known. Thus, a rule which demands clinical results first risks the publication of such results destroying the invention’s novelty. The problem with the second proposition is that it would be a recipe for abuse if all that was required to obtain a patent was a proposal, without any basis, to use drug A to treat disease B:

Patent law seeks to address these factors balancing the requirements for sufficiency of disclosure against the rules of novelty and inventive step. But the conventional sufficiency test of asking whether the claimed invention works, does not help. The treatment does work but what if the patent does not say so?

For these reasons the idea of ‘plausibility’ as part of the law of sufficiency of disclosure has been developed both in the EPO… and the UK… The term ‘plausibility’ has been coined to characterise what it is that a patent specification must provide in order to be sufficient, short of full clinical proof of efficacy (Hospira UK Ltd v Genentech Inc [2014] EWHC 1094 (Pat) (10 April 2014)).

This rationale is not limited to second medical use cases, but also covers per se claims to a product. According to EPO Boards of Appeal case law, a chemical compound is not patentable merely because it potentially enriches chemistry. In such cases, just as in second medical use claims, some indication of the technical effect or contribution of the claimed invention is needed. This indication must manifest itself in:

  • a valuable property (in the widest sense);
  • an effect; or
  • an increase in the potency of an effect.

Further, such effect must be plausible (T 0488/16, Dasatinib/BRISTOL-MYERS SQUIBB, 1 February 2017 (unpublished)).

Warner-Lambert pregabalin case

Aside from the infringement case in Warner-Lambert, which was based on Actavis’s launch of the generic pregabalin in February 2015, Actavis – together with Mylan – claimed the revocation of the Warner-Lambert patent claims shown in Table 1.

At first instance, Justice Arnold held that none of the patent’s claims were obvious, but that Claims 1 and 3, among others, were invalid on the ground of insufficiency, specifically because they were not plausible across their scope. The Court of Appeal upheld the first-instance decision. An appeal of that decision was subsequently filed with the Supreme Court. This included a challenge to the test being used for insufficiency, which was based on lack of plausibility. On the issue of plausibility, Lord Sumption (giving the leading judgment for the whole court) upheld the lower courts’ decisions that the patent did not plausibly support the treatment of central neuropathic pain. He also led the majority in overturning the Court of Appeal by holding that the patent did not plausibly support any kind of neuropathic pain. The claims alleged to be infringed were therefore invalid due to insufficiency.

Table 1. Warner-Lambert patent claims

Generic Actavis product

Pregabalin (under the brand name Lecaent)

‘Skinny labelʼ

The summary of product characteristics and the patient information leaflet included in the packet state that the only conditions for which Lecaent is indicated are epilepsy and generalised anxiety disorder, for which patent protection has expired.

Relevant Warner-Lambert patent claims

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

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

Guidelines for demonstrating plausibility

In Warner-Lambert the Supreme Court explained what plausibility requires in the context of patent claims to the second medical use of pregabalin for treating pain. Before the case reached the Supreme Court, the Court of Appeal had held not only that the threshold was low, but also that the test could be satisfied by a “prediction… based on the slimmest of evidence”. Lord Sumption in the Supreme Court disagreed with this, stating that while the test is relatively undemanding, it cannot be deprived of all meaning or reduced to little more than a test of good faith. In Lord Sumption’s view, the Court of Appeal’s approach would be unlikely to serve even the limited purpose of barring speculative or so-called ‘armchair’ claims. With the support of the majority of the Supreme Court, Lord Sumption instead set out seven guidelines relevant to deciding plausibility in this case (Table 2).

According to the minority (ie, Lords Mance and Hodge), Lord Sumption set the test of plausibility too high. Lord Mance expressed concern that there was a real risk that the test could amount to, or be understood as, requiring a prima facie case to be established on the material contained in the specification. In his view, this outcome would not be supported by the EPO authorities to which the Supreme Court was referred in the case. According to Lord Mance, although the authorities reject speculative or wide-ranging unsubstantiated claims, they also accept as sufficient tailored claims which appear scientifically possible but have not been even prima facie established, without – for example – conducting testing or assays according to the state of the art. In Lord Mance’s view, following the EPO authorities should mean that the workability of an invention will fail for insufficiency of disclosure only if a person skilled in the art would have significant doubts. Similarly, Lord Hodge differed from Lord Sumption by stating that a patent need not disclose experimental evidence of plausibility unless there is an allegation, supported by sufficient evidence, that the invention does not work. In other words, the Supreme Court minority held that EPO case law requires plausibility to be demonstrated only if the therapeutic effect in a second medical use patent is inherently implausible.

Lord Sumption, for the majority, held that if this were correct, no disclosure would need to be made in support of a claimed therapeutic effect if nothing was known either for or against it. According to Lord Sumption, this would be an odd result, which would contravene the policy considerations of plausibility. Instead, the majority adopted a positive requirement for the patent to show plausibility – there must be something that causes a skilled person to think that 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.

Table 2. Deciding plausibility

1

The proposition that a product is efficacious for the treatment of a given condition must be plausible.

2

It is not made plausible by a bare assertion to that effect; the disclosure of a mere possibility that it will work is no better than a bare assertion.

3

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.

4

Although the patent need not prove the assertion that the product works for the claimed purpose, there must be something that causes a skilled person to think there is a reasonable prospect that the assertion will prove to be true.

5

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.

6

The effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning.

7

Sufficiency is a characteristic of the disclosure, although the disclosure may be supplemented or explained by the common general knowledge of the skilled person.

Applying principles to facts

Lord Sumption looked at what the first-instance judge had established about the empirical data disclosed in the patent in support of the Warner-Lambert patent claims. This consisted of references to numerous pre-clinical animal models used to test drugs for various kinds of pain (Table 3). It followed from these, in the Supreme Court’s unanimous view, that the experimental data in the specification was predictive of efficacy against inflammatory pain. However, there was no experimental data or a priori reasoning that pregabalin would be effective for treating central neuropathic pain. Further, a skilled person would not have considered that there was any reasonable basis for thinking that an anti-convulsant such as pregabalin – which is known to be effective for treating epilepsy – would for that reason alone be effective for treating central neuropathic pain.

The Supreme Court also examined whether it was plausible on the basis of the patent that pregabalin would be effective against any neuropathic pain (peripheral or central). Lord Sumption noted that 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 Warner-Lambert had been right in arguing that pregabalin works to treat peripheral neuropathic pain by blocking central sensitisation. There was also an absence of any evidence that pregabalin acts on central sensitisation at all. In the majority view, it was insufficient to justify a monopoly that it was possible a priori that a drug that is effective for inflammatory pain would also be effective for neuropathic pain without any reason to suppose that this possibility had some scientific basis or was more than speculative. As Lord Sumption put 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.”

Table 3. Pre-clinical animal models

Test result

Meaning

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 no statement in the patent that pregabalin is effective in treating neuropathic pain.

The carrageenin test

This test also models inflammatory pain. The patent specification records that test results showed pregabalin to be effective in treating this pain.

The post-operative pain model

This model tests for pain responses following surgery. Like the other tests, nothing in the literature suggests that it could be used to predict efficacy for neuropathic pain.

The Bennett model and the Kim and Chung model

The patent specification refers to these as two well-known models for peripheral neuropathy; however, no data from either model is presented.

Is EPO and UK approach to threshold different?

Much of the debate in the Supreme Court focused on whether the approach set out by Lord Sumption, for the majority, was in keeping with the EPO authorities. One of the key decisions referred to in this respect was T 609/02 AP-1 complex/SALK INSTITUTE (unpublished, 27 October 2004). In this case, the board stated that under Article 83 of the European Patent Convention, unless a product’s suitability for the claimed therapeutic application is already known to a skilled person at a patent’s priority date, the application must disclose this. However, in the case of purpose-limited medicinal use patents, the board recognised that definitive evidence of a therapeutic effect will not be available until clinical trials have been carried out and that, because these must be disclosed, a patent application must first be made:

For a sufficient disclosure of a therapeutic application, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement in a patent specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has 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. Showing a pharmaceutical effect in vitro may be sufficient if for the skilled person this observed effect directly and unambiguously reflects such a therapeutic application (T 241/95 Serotonin receptor/ELI LILLY [2001] OJ EPO 103 (14 June 2000)) or, …if there is a ‘clear and accepted established relationship’ between the shown physiological activities and the disease (T 158/96 Obsessive-compulsive-disorder/PFIZER (unpublished, 28 October 1998).

In the context of pharmaceuticals, a mere assertion or speculation that a compound is suitable for treating a particular disease is insufficient at the EPO, as in the United Kingdom, to render an invention plausible. Conversely, in vitro tests – which cannot be reproduced in humans or animals – may suffice, as may experimental tests showing that a claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease. Again, apparently as in the United Kingdom, plausibility can also be demonstrated in a specification without experimental evidence if no substantiated doubt about a theoretical case exists for the invention’s efficacy. This was the case in T 0578/06 IPSEN/Pancreatic cells (unpublished, 29 June 2011), which concerned a compound for extending the functional life of pancreatic islet cells. In this case, although the patent had contained no experimental data supporting the drug’s claimed therapeutic effect, it had contained a technical explanation of the drug’s effect and an experimental methodology by which this could be verified.

The EPO’s two dasatanib decisions (ie, Dasatinib/BRISTOL-MYERS SQUIBB T 0488/16 (unpublished, 1 February 2017) and Dasatinib in the treatment of CML/BRISTOL T 0950/13 (unpublished, 3 February 2017)), illustrate how the approach of the EPO Boards of Appeal has been applied in practice. In particular, despite being similar in fact, the result of these respective cases was that the claims at issue fell on either side of the plausibility threshold.

Not plausible: claim to dasatinib (T 0488/16) T 0488/16

concerned the per se compound claims to pregabalin in EP1,169,038, titled “Cyclic protein tyrosine kinase inhibitors” (PTKs) (Table 4). The board stated that the application as filed contained no evidence that any of the compounds that fell within the scope of the generic formulas, let alone dasatinib, would be active as an inhibitor for any of the specific PTKs. There was merely an assertion that “Compounds described in the following Examples have been tested in one or more of these assays and have shown activity”. No individual values or range of values were given and no information as to whether the observed activity would be suitable for the diseases and disorders was listed. Specifically, there was no evidence provided as at the date of filing that dasatinib was a suitably active PTK inhibitor, let alone an inhibitor for PTKs associated with cancer treatment. There was also no evidence at the date of filing that a skilled person possessed common general knowledge, which made it plausible that the compounds of the invention, in particular dasatinib, could be expected to show PTK inhibitory activity. The board also stated that “structural similarity of small molecules does not necessarily imply similar function. Their activity is in general unpredictable and even minor structural changes can disrupt activity”.

In this case, no established structure-activity relationship existed that, in the complete absence of any verifiable data in the application, would make it plausible that dasatinib was a PTK inhibitor (Table 4).

Table 4. Claims to dasatinib

 

T 0488/16

T 0950/13

Form of claim in issue

Per se, compound: dasatnib or salts thereof.

Second medical use: dasatinib in the oral treatment of cancer, wherein the cancer is CML.

Ground of invalidity alleged

Obviousness under Article 56 of the European Patent Convention.

Insufficiency under Article 83 of the European Patent Convention.

Evidence of function in the patent as filed

It is merely asserted that compounds described in the examples were tested in the assays mentioned and showed activity.

No individual values or range of values are given and no information as to whether the observed activity would be suitable for the diseases and disorders is listed.

No evidence to show that dasatinib would be active as an inhibitor for any of the specific PTKs is named.

Evidence of inhibitory activity of other PTKs by dasatinib.

Common general knowledge

No common general knowledge which made it plausible that the compounds of the invention – in particular, dasatinib – could be expected to show PTK inhibitory activity.

No established structure-activity relationship existed.

BRC-ABL PTK inhibition is seen as an effective way to treat CML.

Imatinib, an analogue of dasatinib, is a PTK inhibitor and has been used successfully in the treatment of CML.

Plausibility

Not plausible

Plausible

Post-published evidence

Not admissible

Admissible: confirmed the PTK inhibitory activity of dasatinib and its suitability for the oral treatment of CML.

Plausible: claim to dasatinib second medical use (T 0950/13)

T 0950/13 concerned claims to dasatinib in the manufacture of a medicament for (and for use in) the oral treatment of chronic myelogenous leukemia (CML). Although the application as filed claimed a generic group of compounds for this purpose, the only compound identified in the description as preferred was dasatinib. In the absence of experimental evidence for dasatinib’s BRC-ABL PTK activity, the board accepted the applicant’s argument that it would be part of a skilled person’s common general knowledge that they could test dasatinib for BRC-ABL PTK inhibition. Further, given that the application disclosed evidence of inhibitory activity of other PTKs by dasatinib, it could not be said that there were a priori serious doubts that it should also be able to inhibit BRC-ABL PTK, regardless of whether such a result was surprising. It then followed that the functional equivalence of dasatinib to imatinib as a BRC-ABL PTK inhibitor in the application satisfied the TBA that it was suitable in the treatment of CML. There were no a priori reasons why a skilled person would regard this concept as incredible or implausible. As a result, the relevant claims were held to be plausible (Table 4).

Lessons from pregabalin and dasatinib cases

Does EPO treat plausibility differently from Supreme Court?

In T 0950/13 the board restated the principle seen in SALK that for second medical use patent claims to be sufficient, under Article 83, it must be possible to show that:

  • both the content of the patent as filed and the common general knowledge as at the filing date would enable a skilled person to prepare the claimed compound; and
  • the claimed treatment could be achieved in a reliable and reproducible manner.

This requires:

  • the applicant to provide suitable evidence of the claimed therapeutic effect; or
  • such evidence to be derivable from the prior art or common general knowledge.

The board agreed with the applicant that it is not always necessary to disclose experimental results to demonstrate sufficiency if the application discloses at least a plausible technical concept, without substantial doubts, as to why it can be put into practice. Post-published evidence may be considered, but only to back up the findings in the application in relation to the use of the compound as a pharmaceutical. On this basis, it is difficult to distinguish the EPO requirements for plausibility from the positive requirements set out by the Supreme Court when it says that plausibility must be based on some predictive data or a priori reasoning. However, how these principles for setting the plausibility threshold in future cases will be applied will depend on the facts of each case.

Are per se and second medical use claims treated in the same way?

A per se claim simply requires a plausible technical effect or contribution of some kind, rather than the specific treatment of a condition. Given the generality of per se claims, does the same need to demonstrate plausibility exist? The two dasatnib cases – one of which concerned a per se claim and one which concerned a second medical use claim – suggest that it does. The per se claim in T 0488/16 failed because it disclosed neither plausible experimental evidence nor a plausible technical concept – the same criteria used in T 0950/13.

Is the plausibility test the same under Article 56 and Article 83?

As the Supreme Court did not comment on this issue in Warner-Lambert, the position under English law remains unclear. However, the dasatinib cases give a clue to another issue as:

  • the plausibility of the per se claims was dealt with under the inventive step requirement (Article 56); and
  • the second medical use case was dealt with as a matter of insufficiency (Article 83).

The EPO Boards of Appeal took this approach because once a claimed therapeutic application of a second medical use has been demonstrated to be plausible, as a threshold step, it is then necessary to show that the therapeutic use actually works as a matter of sufficiency. This sufficiency step is not required for per se claims; rather, it is necessary to prove only that the compound claimed can be made (ie, there is a technical contribution for the purpose of assessing inventive step using the EPO’s problem-and-solution approach). The difference between these two forms of claim is not therefore the plausibility analysis, but rather the further requirement of sufficiency.

In this respect, the Supreme Court agreed that the plausibility tests for Article 56 and Article 83 are the same:

The claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason, ie not just because there was an abstract possibility that it would work but because reasonable scientific grounds were disclosed for expecting that it might well work. The disclosure of those grounds marks the difference between a speculation and a contribution to the art. This is in substance what the Technical Board of Appeal has held in the context of article 56... In my opinion, there is no reason to apply a lower standard of plausibility when the sufficiency of disclosure arises in the context of EPC articles 83…. In both contexts, the test has the same purpose.

Action plan

Some understanding of plausibility is increasingly important in filing for biopharma patents. Some key issues to consider include the following:

  • When filed, patent applications must contain enough information to cross a minimum threshold.
  • The threshold is that the patent, together with any common general knowledge of a skilled reader to whom it is addressed, must disclose a plausible technical contribution.
  • A mere assertion or speculation that a compound is suitable for a particular purpose does not show that it is plausible.
  • The Supreme Court’s Warner-Lambert decision provides seven guidelines on what is required to show plausibility, which are particularly applicable for second medical use patents.
  • In essence, the Supreme Court has held that plausibility must be based on either:
    • some predictive data in the patent, together with the prior art and common general knowledge;
    • a priori reasoning; or
    • both of the above.
  • There is no significant difference between the Supreme Court’s approach to plausibility and that of the EPO.


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