Summary

Existing medicinal products are attractive options for development for new medical uses.  Although the granting of patents for second medical uses is well established in Europe, few cases have been litigated in national courts.  In 2018, the UK Supreme Court decided a case on validity and infringement of a second medical use patent in Warner-Lambert v Mylan and Actavis[1].  Here, I take a look at Warner-Lambert’s second medical use patent, the commercial context and development of the litigation, the Court’s finding of invalidity and the Court’s views on infringement.  As the decision may weaken existing second medical use patents, I will provide suggestions for new points to look for in patent due diligence.  I will also consider the wider impact of the decision.

Warner-Lambert’s second medical use patent

Warner-Lambert’s second medical use patent to pregabalin for the treatment of pain was granted by the European Patent Office (EPO).  At the time the patent was granted, the only approved claim format for second medical uses was the so-called “Swiss-type” claim directed to “use of substance X in the preparation of a medicament for treating indication Y”.  Warner-Lambert’s patent claims were therefore of the Swiss-type.

Warner-Lambert had an earlier-filed patent for the active compound, which expired in 2013.  Pfizer (parent company of Warner-Lambert) had data exclusivity in Europe in respect of its marketed pregabalin product Lyrica® which expired in 2014.

The expiry of the compound patent and data exclusivity focussed the attention of generic competitors on Warner-Lambert’s second medical use patent, and this has since been litigated in several European jurisdictions.

Commercial context and development of the litigation in the UK

Until 2015, Lyrica® was the only pregabalin product on the market in the UK.  There was a significant market for pregabalin in the treatment of epilepsy and generalised anxiety disorder, which fell under Warner-Lambert’s earlier patent for the active compound.  These indications account for about 30% of the pregabalin market in the UK.  Treatment of pain, particularly neuropathic pain, the subject of the second medical use patent, accounts for the remaining 70% of the market. 

Warner-Lambert asserted its second medical use patent against Actavis, which started marketing a generic version of pregabalin in the UK in 2015.  Actavis’s product was marketed with a “skinny label” which identified only the indications for which patent protection had expired.  However, Pfizer feared that the generic pregabalin might be used to fulfil the pain market.  This is because it is normal practice for doctors to prescribe a drug by reference to its International Non-proprietary Name (INN), and prescriptions usually do not identify the indication.  Thus, pharmacists who dispense drugs against a prescription will generally not know the indication for which the drug has been prescribed.

In interim proceedings, the High Court granted to Pfizer an order compelling National Health Service England (NHSE) to issue central guidance to prescribers and pharmacists requiring medical doctors to identify Pfizer’s branded drug Lyrica® when prescribing pregabalin for pain[2].  For non-infringing indications, pregabalin would continue to be prescribed by reference to its INN.

Meanwhile, Mylan and Actavis had sought revocation of the second medical use patent, and the cases were combined at the High Court[3].  Both the High Court, and subsequently the Court of Appeal, held the patent to be invalid.  The Supreme Court, dismissing Warner-Lambert’s appeal, has confirmed the finding of invalidity; and also found that even if key patent claims had been valid, they would not have been infringed by Actavis. 

Plausibility and second medical use

The finding of invalidity of Warner-Lambert’s second medical use patent arose because the patent was deemed not to meet the legal requirements for a sufficient disclosure.

Patent statutes require a patent to disclose the invention in a manner sufficiently clear and complete for it to be performed by a skilled practitioner.  Pregabalin is in fact useful for treating all forms of pain, and a description of how pregabalin may be made, and its administration for pain, would therefore on the face of it meet the statutory requirement for a sufficient disclosure.  Earlier legal decisions make the situation more complex though. The issue before the Court was whether, for a sufficient disclosure, the patent would also need to make it plausible that pregabalin would be effective for treating pain.

The concept of a “plausibility” test originally arose at the EPO in order to prohibit speculative claiming.  The UK Supreme Court has now approved this principle as requiring disclosure in the patent of more than mere assertion that a known compound is effective for the claimed medical use.  The lead judgment identified in the EPO and UK case law the “fundamental principle” that the patentee must not only make but disclose a contribution to the art.  For a second medical use claim, that disclosure must demonstrate the discovery that the active agent can be expected to work.  Subsequent data may supplement this, but only if the therapeutic effect is plausible in the light of the disclosure in the patent. 

As for the stringency of the plausibility requirement, the majority view of the Court was that disclosure of a mere possibility of efficacy would not be enough, but the disclosure of reasonable scientific grounds for expecting that a medication might work may suffice.  If the condition identified in a second medical use claim embraces a number of different pathologies, the disclosure should make plausible the efficacy of the product to treat them all. 

The Court was unanimous in finding that the experiments disclosed in Warner-Lambert’s patent did not render plausible the treatment of central neuropathic pain.  By a majority, the Court held that efficacy in the treatment of peripheral neuropathic pain was not plausible, but dissenting opinions considered the Court to have set the plausibility bar too high, and would have found in favour of the patentee.

The Supreme Court’s plausibility test is binding on future decisions of the High Court and Court of Appeal.  The High Court has recently applied the test in Eli Lilly v Genentech[4], finding key patent claims to be insufficient because it was not plausible from the content of the application as filed that the antibody defined in the claims would have therapeutic efficacy against psoriasis.

Due diligence for second medical use patents

Other second medical use patents could now be more vulnerable to revocation in the UK on the grounds of lack of plausibility following the Supreme Court judgment.  Due diligence should consider the following issues:

Whether the patent specification discloses reasonable scientific grounds for why the active agent can be expected to be effective.  A strong patent would disclose such grounds in relation to all therapeutic areas covered by a second medical use claim. 

Whether the Examples of a patent specification include experimental data which show an effect of the active agent on the disease to be treated, or on a biological mechanism specifically involved in that disease.  A strong patent would typically disclose a range of different types of experimental evidence.  In vitro testing may be adequate, although this may need to be supported with an explanation for why the test results would predict clinical efficacy.

Where the experimental examples are limited, a patent may rely on a priori reasoning to support efficacy.  For example, the specification may point to some property of the product which would lead the skilled person to expect that it might well produce the claimed therapeutic effect.  In practice, a strong patent may include a combination of experimental data and reasoning for why the data would support efficacy across the full scope of the claim.

Whether the patent claims include claims defining subtypes of the condition to be treated. A strong patent would typically include such claims, which may more easily satisfy the plausibility requirement and could potentially be enforced even if the broadest claim was found to be invalid. Ideally, the most commercially important subtypes of the condition to be treated would be specifically identified in the claims.

These considerations will also apply at the stage of drafting new patent applications for new second medical use inventions.

Infringement of Swiss-type claims

As the Supreme Court had found Warner-Lambert’s patent to be invalid, its opinion on the correct test for infringement of Swiss-type second medical use claims is not binding. 

Swiss-type claims are considered to protect the process of “manufacture” of a medicine containing the specified active agent only insofar as that process is undertaken “for” treating the specified indication.  The High Court and Court of Appeal found that the intention of the manufacturer of a generic medicine was relevant to infringement, either on a subjective basis or on the basis of reasonable foreseeability that the product will intentionally be used for the patented indication.  By a majority view, the Supreme Court disagreed, emphasising the importance of the “outward presentation” of the generic product, particularly whether the patient information leaflet carves out the patented indication.  A test of intention on behalf of the manufacturer would be unfair to downstream parties including distributors and pharmacists who could unwittingly incur liability for dealing in infringing products.  A test based on the outward presentation of the product would be less likely to deter downstream parties from legitimate dealings in generic medicines.  However, greater legal certainty would come at a cost for innovators, and a minority view of the Court preferred a test of subjective intent for this reason.

Actavis’s generic pregabalin product did not refer to the treatment of pain in its patient information leaflet, or in its packaging, and would not have infringed Warner-Lambert’s second medical use patent under the “outward presentation” test. However, considerable efforts had been made to limit the use of the generic product in treating the patented indication, and these may have been relevant in the finding of non-infringement.

Impact of decision on infringement of second medical use patents

The divergence of opinions expressed by the Justices of the Court shows that the law is not settled.  Further judgments will be required to establish binding law on the correct test for infringement of Swiss-type second medical use claims. 

Applying the majority opinion of the Court, a generic product which does not identify in its packaging, labelling or patient instruction leaflet any potential uses which are subject to patent protection would, in most cases, not infringe a Swiss-type second medical use claim in the UK.  This could present a difficulty for enforcement of Swiss-type claims where the active agent is already approved and marketed for a non-infringing indication. 

In cases where a valid second medical use patent covers indications forming only part of the market for a medicine, it remains possible that a system could be set up to issue guidance requiring doctors to refer to an originator’s branded medicine in prescriptions for those indications.

Where there is no existing market for an active agent, for example because clinical trials for an earlier medical use failed, it should be easier to enforce a second medical use patent.  In 2017, the Supreme Court upheld Swiss-type claims as valid and infringed in Actavis UK Ltd v Eli Lilly [5].  

Conclusions

The Supreme Court decision in Warner-Lambert v Mylan and Actavis defines a role for plausibility in the requirement for sufficiency of disclosure of a second medical use patent.  The extent to which available experimental data make the claimed therapeutic use plausible should be considered in patent due diligence, and when drafting a patent application.  There is a lack of agreement over the correct test for infringement of Swiss-type claims in the UK, which is highlighted by the differing opinions of the Justices of the Supreme Court.  Much of the difficulty in the present case arose from the fact that pregabalin is marketed for its earlier medical uses.  It has been a priority to ensure that a patent for a second medical use would not deter a legitimate generic market in pregabalin for patent-expired uses.

Main points

  • Warner-Lambert’s second medical use patent for pregabalin for the treatment of pain was held to be invalid by the UK Supreme Court, and the opinion of the Court was that had the patent been valid, it would not have been infringed by Actavis.
  • The Supreme Court judgment defines a role for plausibility in the validity of a second medical use patent.  To be valid, the patent must disclose reasonable scientific grounds for expecting that the active agent will be effective in the claimed medical use.
  • The Supreme Court judgment may weaken existing second medical use patents, and due diligence should take plausibility into account.
  • The law on infringement of second medical use patents is not settled.  The Supreme Court favoured an approach in which the “outward presentation” of the generic product is of importance.  If the patient information leaflet and packaging of a generic product do not refer to the patented indication, it would likely not infringe a Swiss-type second medical use claim, but this may still depend on the overall context.

This article was first published in Pharmaceutical Licensing Group Business Development and Licensing Journal, Issue 28, June 2019.