The need for tailored and well-prepared strategies

The need for tailored and well-prepared strategies when enforcing second medical use claims across Europe

Sophie Rich, Jonathan Turnbull and Andrew Wells, Herbert Smith Freehills LLP

Recent European litigation concerning “skinny label” generic pregabalin has clearly illustrated the need for tailored enforcement strategies across Europe in light of the differing national approaches to infringement, procedural rules and market access regimes.

Background to the European pregabalin litigation

In Europe, the Pfizer Group markets medicinal products containing pregabalin as the sole active ingredient, approved for the treatment of a variety of indications, under the brand Lyrica. Following expiry of the relevant regulatory protections as well as the patent for pregabalin per se, Pfizer still had patent rights in force covering the use of pregabalin to treat pain (which was the most commercially valuable indication). Several generics companies wished to market generic pregabalin in Europe for non-patented indications and so obtained marketing authorisations (MAs) for their generic pregabalin products with “skinny labels” (ie, those generic products were authorised only for a sub-set of the indications set out in Lyrica’s MA, with the patented indications excluded as they had been “carved out”).

Establishing infringement

The key infringement issue is: is the fact that a generic drug is not authorised for use to treat patented indications (by virtue of its skinny label), on its own, sufficient from a legal and practical perspective to make the sale of these generic drugs non-infringing?
Although the form of second medical use claims is harmonised under the European Patent Convention, infringement is a matter of national law and the approach varies from country to country. 

In the pregabalin litigation across Europe, the relevant patent claims were in the “Swiss form” (the use of substance X for the preparation (or manufacture) of a medicament (or pharmaceutical composition) for treating disease Y). National courts across Europe had to consider both the direct and indirect infringement of Swiss-form claims where the generic product was manufactured outside of that country: there is a divergence of approach. In some jurisdictions, such as England and Wales, Swiss-form claims are treated as purpose-limited process claims; in others, they are treated for the purpose of infringement as being purpose-limited product claims. 

This is an important distinction that influences how national courts approach these claims. 

Direct infringement

If Swiss-form claims are treated as purpose-limited process claims, it is necessary to consider whether the generic product is a “product of an infringing process”. This requires a determination of whether the sales of the generic product were sales for use “for” the patented indication. Three broad approaches to this determination have arisen across Europe. 

First, an approach in which the intentions of the alleged infringer are not taken into account when determining whether a generic product is marketed/sold “for” the patented indication – all that are considered are the appearance and physical characteristics of the product as put on the market, from an objective perspective. 

The second and third approaches are related, as they both import a “mental element” to determining infringement. One approach considers the intention of the alleged infringer from an objective standpoint, while the other considers it from a subjective standpoint. 

Where Swiss-form claims are treated as purpose-limited process claims, the relevant intention (the mental element) is that of the generic manufacturer (even if it is not the party against whom patent infringement is being alleged). Where such claims are treated as purpose-limited product claims for the purpose of infringement, the relevant mental element is that of the alleged infringer (regardless of what acts they carry out in relation to the allegedly infringing product). When considering whether a mental element is relevant to the direct infringement of Swiss-form claims (and, if so, how it should be assessed), the national courts have diverged as to which of the three approaches they have adopted. The Netherlands has adopted a broad approach, which considers what the manufacturer could have foreseen was likely to happen with the product in question, assessed objectively. At the other extreme, the (non-binding) view of the majority of the UK Supreme Court in the pregabalin case was that a narrow approach should apply, taking into account only the physical characteristics of the generic product itself (including its packaging and labelling), assessed objectively. The approaches taken in other European countries (and in the dissenting minority of the UK Supreme Court) lie somewhere between these two extremes and take into account, to differing degrees, the subjective intent of the relevant party. 

Indirect infringement

When considering indirect infringement of Swiss-form claims, a narrow approach appears to have been taken by some jurisdictions, such as France and the UK. Under this approach, national law adopts a position that Swiss-form claims are purpose-limited process claims limited to the act of manufacture and, accordingly, indirect infringement can only be established by the supply of a “means essential” to that manufacturing process (or upstream from it). Conversely, any conduct downstream of manufacture (eg, steps undertaken by a pharmacist in dispensing the medicament or affixing a sticker to its packaging) will not be relevant to indirect infringement under this approach. 

Liability for indirect infringement, therefore, ends at the “manufacturer’s gate”, as the patented invention is the process completed by manufacture of the composition for the patent-protected use. Other countries, such as Denmark, Germany and Spain, have adopted a broader approach under which it is permissible to consider acts downstream of manufacture where the infringing use was deliberate or expected.

Litigation Strategy

In the absence of EU harmonisation, before settling any strategy it is critical to consider not only the impact of the above approaches to infringement, but also to understand the impact of a generic or biosimilar launch, and the national procedural laws and practices on interim relief. These factors will inform whether litigation is necessary and shape the steps taken. There are significant differences between different European countries, and even subtle differences are capable of having a marked impact on strategy. 

Impact of differing national approaches to infringement

The differing national approaches may necessitate the need to take action against (or include in any litigation) other entities involved in the sale of the generic product, such as pharmacies or the relevant national health service. This could be as a consequence of the relevant national law making it is easier to establish infringement against those entities or because more effective relief can be obtained if they are party to proceedings. 

For example, in the pregabalin litigation, proceedings were brought against pharmacies in Denmark; owing to the inclusion of the indication in Danish prescriptions, direct infringement by the pharmacies could be readily established. In the UK, the National Health Service Commissioning Board was joined to the proceedings and a court order obtained by Pfizer compelling the Board to issue guidance on the practices for prescribing pregabalin; the effect of which was to mitigate against the dispensing by pharmacists of the generic product for the carved-out patented indications. 

Market access factors influencing the likelihood of infringement

Market access regimes vary significantly across Europe and can also depend on the type of drug in question (eg, biologic or small molecule) and how it is sold (eg, retail or tender only). For example, for prescription-only retail drugs (such as pregabalin), it is critical to understand national prescribing practices in order to appreciate whether or not a skinny label has any real impact on the indications for which the generic drug is prescribed and used. 
Several factors will influence the extent and speed of sales of generic products in place of the corresponding prescription-only branded product (and, in particular, to what extent those generic products are sold and used for the patented indications). These factors include the following:

  • The ability of a physician to prescribe a medicinal product for a use outside of its approved indications (ie, “off-label”) is subject to national laws and practices. In several jurisdictions, such as the UK, there is a high degree of freedom for physicians to prescribe off-label, whereas, in other jurisdictions, such as France, a more restrictive approach is adopted. Clearly, a more permissive approach to off-label prescriptions increases the likelihood that the generic drug will be prescribed for the patented use, regardless of its skinny label. 
  • Whether prescriptions are written by physicians by reference to the brand name, or by reference to the relevant active ingredient (ie, generic prescribing), and whether physicians are made aware of relevant patents when prescribing. While generic prescribing is seen across Europe, the extent to which it is performed in practice again varies from country to country, as does the amount of information available to physicians on prescribing. If doctors tend (or are required) to prescribe generically regardless of indication, this will increase the likelihood of generic sales for patented indications; the converse will be true where doctors are required to prescribe by brand name. 
  • Whether the prescription states the relevant indication for which that patient is being treated. Although this is uncommon across Europe, the indication is stated on Danish prescriptions, for example. If prescriptions state the indication for which the drug is being prescribed, this may make it more likely that pharmacists will prescribe the branded drug where a patented indication is to be treated. 
  • The extent to which the patient or pharmacy will be reimbursed by either the state or their insurance policy for off-label prescriptions, and to what extent pharmacies are financially encouraged to prescribe generic products. Here, there is significant variation across Europe. Where off-label use is reimbursed and pharmacists are incentivised to dispense generic products, then there is likely to be rapid and significant uptake of the generic product for all indications (including those still covered by patents) in the absence of further measures specifically designed to prevent this. On the other hand, a restrictive approach to reimbursement of off-label prescriptions is more likely to significantly curtail the uptake of generic products for patented indications where these have been carved out from the generic product’s MA.

If, when working with the relevant regulatory and sales teams in each country, the impact of a likely generic launch is understood at an early stage, it may be possible to formulate a strategy for engagement with the relevant authorities and generic companies to mitigate the impact of generic launch on the patented indications.

Procedural factors influencing interim relief

The differing procedural laws and rules across Europe can impact the speed and availability of interim relief, as well as the potential liability arising from infringement or as a consequence of a wrongly granted interim injunction. In the UK, the decision of whether to grant an interim injunction includes consideration of whether damages are an adequate remedy, and an assessment of the relative balance of interests between the patentee and the alleged infringer. In contrast, in some other European countries (such as Denmark, France, the Netherlands and Switzerland), the assessment places a much greater emphasis on a substantive consideration of the infringement and validity of the underlying patent, and less (or no) weight on the relative balance of the parties’ interests. These different criteria also change the nature of the arguments and evidence required at an interim stage, which, in turn, can materially impact the speed at which proceedings can be commenced before, and subsequently determined by, each national court.

As a consequence of the above factors, it is essential to take a holistic approach to the enforcement of second medical use patents in Europe. Adopting a “one-size-fits-all” approach across Europe without regard to the differing legal frameworks and market access regimes is not going to yield optimal results, and may even be counterproductive. Successful enforcement by the patentee will require a proactive and close working relationship between its commercial, legal and regulatory teams at both national and Europe-wide levels. Early consideration of the issues and attempts to establish dialogue with the relevant national authorities may also help to avoid the need to go to court to resolve the issue and may even result in a more practical and effective solution. Even following the introduction of the Unified Patent Court, it will be necessary to consider carefully the national markets and regulatory systems when assessing how effective relief can be obtained Europe-wide; the relief sought and required in each European country will still need to be tailored to the specifics of the national market. Patent laws, regulation and practices will have to continue to evolve in a flexible fashion in order to strike the necessary fair balance in relation to the interests of all stakeholders regarding second medical use patents.

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