Existing medicinal products are promising targets for development as therapeutic agents for new medical indications (so-called ‘drug repurposing’) because their safety as drugs will already have been validated in clinical trials. Thus, some of the risks associated with developing a new medicine may be avoided. Further, new uses of a medicinal substance sometimes become apparent during clinical trials – with Pfizer’s Viagra being perhaps the most notorious example.

It has been 30 years since the European Patent Office (EPO) endorsed the practice of claiming new medical uses of known agents in the ‘Swiss-type’ claim format – namely, the “use of substance X in the preparation of a medicament for treating indication Y”. However, until now, surprisingly little guidance on the scope and infringement of such claims has been forthcoming from the national courts in Europe. From a health policy perspective, it is important that second medical use inventions can receive enforceable patent protection in order to encourage their development. Yet there are competing budgetary demands on health services that favour the prescription and dispensing of generic drugs. These tensions have recently come to a head in the United Kingdom in ongoing litigation initiated by Warner-Lambert, in which the English courts issued multiple decisions on various aspects of infringement, available relief and validity in relation to Swiss-type patent claims.

Patented and non-patented markets for pregabalin

The disputes concern the drug pregabalin, which is marketed by Pfizer (the parent company of Warner-Lambert), under the trademark Lyrica. It is one of the Pfizer Group’s most successful products, with global sales in 2013 of approximately $4.6 billion and UK sales over the same period of approximately £310 million. Lyrica is marketed for three indications: epilepsy, generalised anxiety disorder (GAD) and neuropathic pain. Until 2015, Lyrica was the only pregabalin product on the market in the United Kingdom. However, the lapse of Warner-Lambert’s patent for the active compound per se in 2013 and expiry in 2014 of exclusivity in relation to the data used to obtain marketing authorisation for Lyrica paved the way for generic competition. Significantly, Warner-Lambert also holds a second medical use patent (EP0934061B) with Swiss-type claims directed to the “use of pregabalin and pharmaceutically acceptable salts thereof in the manufacture of a pharmaceutical composition for treating pain” (but without any equivalent claims covering the treatment of epilepsy or GAD). It is this second medical use patent (the pain patent) that Warner-Lambert has asserted in litigation against generic drug manufacturers, including Actavis and Sandoz.

Actavis obtained marketing approval for generic pregabalin for treating epilepsy and GAD (ie, the indications not covered by the pain patent). Actavis launched the generic product (under the trademark Lecaent) in February 2015 with a so-called ‘skinny label’ referring only to the non-infringing indications. Actavis also notified superintendent pharmacists that Lecaent was not licensed for the treatment of neuropathic pain.

The pain indication accounts for approximately 70% of the market for pregabalin. Understandably, Warner-Lambert feared that doctors would prescribe pregabalin for the treatment of neuropathic pain (ie, without specifying a brand), and that pharmacists would dispense Actavis’s generic Lecaent product without knowing that the pregabalin had been prescribed for the indication still subject to patent protection (ie, pain).

Other generic drug manufacturers have also launched skinny label generic pregabalin products, and Sandoz attempted to launch a full label generic pregabalin, in which the marketing authorisation and patient information leaflet refer to neuropathic pain in addition to the non-infringing indications.

Summary of UK litigation

Warner-Lambert initially sought an interim injunction against Actavis to impose conditions that would prevent Actavis from supplying the market that was covered by the pain patent. Justice Arnold in the High Court refused the interim injunction in a decision dated January 21 2015, finding that there was no serious issue to be tried in relation to direct infringement of the patent. His reasoning was based on a particular interpretation of the scope of a Swiss-type medical use claim. Nevertheless, on February 6 2015, Arnold decided to refuse Actavis’s application to strike out, or dismiss by summary judgment, Warner-Lambert’s claim for direct infringement. In a further development, on February 26 2015, Arnold granted to Pfizer an order compelling the UK healthcare authority National Health Service (NHS) England to issue central guidance to prescribers and pharmacists in relation to Warner-Lambert’s pregabalin product.

Warner-Lambert appealed the refusal of the interim injunction. In the event, the appeal was dismissed by the Court of Appeal on May 28 2015. Nevertheless, the appeal judges applied a different interpretation to the scope of a Swiss-type claim, which is more favourable to patent holders (stating that reasonable foreseeability was the relevant test for infringement, not the subjective intent of the manufacturer). This interpretation, which takes into account not only the activities of the manufacturer, but also the intentions of downstream parties, was considered and followed at full trial.

The full trial decision (the September judgment) was handed down by Arnold in the High Court on September 10 2015. On the facts, Arnold held that Actavis had not infringed the patent. In his view, the steps taken by Actavis to avoid Lecaent being dispensed for pain were sufficient to minimise the risk of this occurring. Although some instances of Lecaent being dispensed for pain had been cited in evidence, the judge found that it is proper to regard such exceptional cases as de minimis. Subsequent actions by Pfizer and NHS England guidance reduced this risk still further, such that subsequently manufactured batches of Lecaent also did not infringe.

The infringement action was combined with a revocation action initiated by Generics UK Ltd (trading as Mylan) and then Actavis in 2014, challenging the validity of the patent. The patent claims asserted against Actavis (Claims 1 and 3) were held to be invalid for insufficiency on the basis that the patent specification did not make it plausible that pregabalin could be used to treat all the types of pain covered by those claims. Other, narrower claims to specific types of peripheral neuropathic pain were considered valid.

In October 2015 Arnold gave Mylan, Actavis and Warner-Lambert leave to appeal his decision with respect to insufficiency; he also gave Warner-Lambert leave to appeal with respect to direct infringement. Foreseeing that its appeal against invalidity might be unsuccessful, Warner-Lambert applied to amend its patent by re-writing Claim 3, but this application was refused on November 25 2015 as an abuse of process on the basis that a conditional application to amend Claim 3 could and should have been made before trial. Nevertheless, the availability of appeal has a suspensive effect on the September judgment, and the finding of invalidity of the key claims might be reversed in due course.

In the separate dispute of Warner-Lambert v Sandoz, Arnold granted an interim injunction on November 4 2015 restraining Sandoz from further dealing in the full label generic pregabalin product that it had launched following the September judgment. In the same decision, Arnold also granted an interim injunction against the pharmacy group Lloyds, preventing the dispensing of the product, which Lloyds had purchased from Sandoz via a wholesaler. Warner-Lambert’s claim against Sandoz for patent infringement pertains to full label and skinny label pregabalin products. At the time of writing, it was expected to be heard at full trial in March 2016.

Interpretation of scope of Swiss-type claim

A key aspect of the court decisions has been the interpretation of the scope of Swiss-type claims. According to accepted jurisprudence, a claim to “use of substance X in the preparation of a medicament for treating indication Y” is regarded as a process claim, directed to the manufacturer of the medicament or pharmaceutical composition. In his decision of February 6 2015, Arnold found it persuasive that ‘preparation’ also includes acts of packaging and labelling.

In his decision of January 21 2015, Arnold held that the word ‘for’ in a Swiss-type claim means ‘suitable and intended for’ and that the relevant intention was that of Actavis, as the manufacturer of the medicine. On the evidence, Actavis had not intended Lecaent to be used to treat pain. This interpretation of ‘for’ places a burden on patent holders to prove subjective intent on the part of the manufacturer, and can also be seen as absolving downstream parties such as doctors and pharmacists from taking any steps to avoid the prescription and dispensing of a generic drug for a patented indication.

However, on appeal, the judges held that ‘for’ requires that the manufacturer knows, or it is reasonably foreseeable, that the drug will intentionally be used for the patented invention (in this case, pain). Crucially, this does not require the manufacturer to have any specific intention to use the invention itself; instead, it is the knowledge or reasonable foreseeability of the intentions of downstream parties that is decisive. The latter interpretation of Swiss-type claims was followed at full trial. Applying this interpretation to the infringement case, Arnold held that the downstream parties whose intentions are relevant are prescribing doctors and dispensing pharmacists, but not patients. It is apparent that there is a need for healthcare bodies to cooperate in avoiding the prescription and dispensing of a generic drug for a patented market, in order that the drug produced by the act of manufacture is not considered as infringing.

Protecting the patented market

The September judgment highlights actions taken by Actavis, Pfizer and various healthcare bodies to inform and facilitate the avoidance of mis-prescribing or mis-dispensing of generic pregabalin for the pain indication. Notably, in addition to writing to over 7,500 superintendent pharmacists, Actavis also wrote to every clinical commissioning group (CCG) in England and corresponding bodies in Wales, Scotland and Northern Ireland advising that Lecaent is not licensed for pain. In compliance with the court order, NHS England issued guidance to CCGs, advising that pregabalin should be prescribed for neuropathic pain under the brand name Lyrica and that when pregabalin is prescribed for neuropathic pain, Lyrica should be dispensed. Software packages used by general practitioners in the United Kingdom have now been updated to provide warnings of the existence of patent rights when pregabalin is prescribed for the treatment of pain.

In Warner-Lambert v Sandoz, Sandoz had argued that NHS England guidance would prevent the prescription of its full label product for pain, and that the availability of that product would cause Warner-Lambert no greater loss than that caused by the availability of generic skinny label pregabalin products. Arnold therefore had cause to consider the effectiveness of the NHS England guidance. He admitted that “the NHS Guidance is not yet fully effective in England so far as prescribing is concerned, and may not be so for some time to come”. This was in view of evidence cited by Warner-Lambert that the percentage of pregabalin prescriptions referring to Lyrica had not increased to levels approaching those expected, assuming that the patented indication accounts for 70% of the market. Arnold also noted that no equivalent of the NHS England guidance had been issued in Scotland. This evidence was relevant to the finding that there was significant risk that Warner-Lambert would suffer unquantifiable and irreparable harm if the injunction were not to be granted but Warner-Lambert was later successful at full trial. Arnold also considered that, if no injunction were granted, there was a risk of other full label generic pregabalin products coming onto the market, with consequent price depression for Pfizer’s Lyrica pregabalin. These factors, among others, favoured the grant of an interim injunction.

In his September judgment Arnold noted that one effect of the law of direct infringement is that if a batch of a drug was considered to infringe a Swiss-type claim, then downstream parties dealing with the drug – such as pharmacists – would also be liable for infringement. Such a warning provides an incentive to establish a robust system for protecting patented indications, to minimise the risk of unwitting patent infringement by healthcare bodies and professionals. Indeed, in his closing comments, Arnold called for a system for centralised and authoritative guidance to be issued to prescribers and other relevant stakeholders to separate the patented market for a drug from the non-patented market.

The subsequent granting of an interim injunction against Lloyds, preventing the dispensing of Sandoz’s full label pregabalin, illustrates the application of Arnold’s reasoning on the liability of downstream parties.

Interestingly, Arnold heard evidence from Lloyds’ quality and regulatory director explaining why Lloyds had declined to stock and dispense skinny label generic pregabalin products. He stated that there was a risk that the skinny label product could be dispensed to a patient for an unlicensed use (neuropathic pain), and that if the patient then suffered an adverse event, the dispensing pharmacist could face liability for having dispensed an unlicensed product where a licensed product existed. However, Arnold considered that skinny label generic pregabalin was not an unlicensed product according to regulatory guidance and that its supply for neuropathic pain would only be ‘off-label’ in the limited sense that the particular product is not licensed for the indication. However, pregabalin as such is authorised for that indication. Arnold concluded that there is no risk to a pharmacy of contravening any regulatory law or guidance if it dispenses a skinny label generic pregabalin product for neuropathic pain.

Until such time as prescription and dispensing practice is fully effective for safeguarding the patented market of a drug (if ever), the launch of a full label generic version appears to be a risky strategy.

Impact of decisions

The Court of Appeal decision in Warner Lambert v Actavis and its application in the full trial decision is potentially very significant for the pharma and biotech industries. To succeed in an infringement action, the patent holder must show that the manufacturer knew, or at least that it was reasonably foreseeable, that the generic medicine would be used for the patented indication. The full trial decision provides initial guidance on how this ‘reasonable foreseeability’ standard may be applied and the action that a generic manufacturer may need to take to safeguard against being held to infringe Swiss-type claims. It is worth noting that second medical use inventions must now be claimed at the EPO in the form of purpose-limited product claims (EPC2000 medical use claims). It remains to be seen whether the ‘reasonable foreseeability’ test is also applicable to the infringement of such claims, although this would seem likely.

In relation to the validity of Swiss claims (and, by extrapolation, EPC2000 medical use claims), the full trial decision also highlights the importance of including credible supporting data in the application as filed.

Arnold’s full trial decision is seen by some as controversial and, with appeals now pending, this story is far from over. Indeed, the prospect exists that an appeal might ultimately be heard by the Supreme Court.

Sheena Linehan

This article first appeared in IAM. For further information please visit www.iam-media.com.