This article was first published on Lexis®PSL Corporate Crime on 22 February 2017. Click for a free trial of Lexis®PSL.

Introduction

The enforcement of second medical use patents is currently one of the hottest topics in European patent litigation. The dispute concerning Warner-Lambert’s patent for the use of pregabalin to treat pain has been very active in Europe and elsewhere since 2014 and has clarified a number of issues in relation to the construction, infringement and validity of second medical use patents. However, a number of issues remain unresolved.

Stepping back, the issue of the grant and enforcement of second medical use patents is part of a larger issue for wider society—namely how to encourage life sciences companies to devote the necessary resources to investigating potential new uses for existing medicines which are ultimately beneficial to patients and those entrusted with their care.

This article will consider briefly the pregabalin litigation and the lessons that can be learned from that saga. However, it will concentrate on the wider issue of how to encourage life sciences companies to expend the necessary resources to add new weapons to the physician’s armoury.

What is the goal?

If pharmaceutical products can keep individuals out of primary care and ideally in work (and thus paying taxes), this will invariably be less burdensome for society than having those individuals hospitalised or at home but unable to work. Of course it is also to the benefit and well-being of patients. To achieve this goal of finding new uses for existing drugs it is necessary to encourage pharmaceutical companies to invest in the research, development and bringing to market of new uses for existing medicines. This will almost inevitably mean providing the developer with a period of exclusivity for that use. However, it is equally important to ensure that this exclusivity does not restrict competition for other indications.

Success stories and missed opportunities

There are dozens of instances of existing medicines being developed for new uses. For instance, finasteride was first marketed for the treatment of prostate disorders but was found to be effective in the treatment of androgenetic alopecia. Thalidomide was first developed for respiratory infections, then notoriously to relieve morning sickness in pregnant women. It was later found to be useful in the treatment of leprosy and much later for cancer. Daclizumab was first used in transplant rejection but has been found to be effective in treating certain types of multiple sclerosis. However, the fact is that for every success story, there are many examples of missed opportunities.

Why are opportunities being missed?

It seems that one of the principal reasons why opportunities to develop new uses for existing medicines are not being taken up is a question of economics. It is generally understood that it costs on average approximately US$1bn to develop and market a new medicine from scratch. In return for this investment, the originator should expect to receive approximately 15 years of exclusivity in which time it can endeavour to make sufficient profit to invest in the research and development of the new generation of medicines and provide a return to its shareholders. On average, originator pharmaceutical companies re-invest around 20% of their turnover into research and development which, on any analysis, is a considerable proportion of the revenue of a business.

Developing and bringing to market a new use for a known medicine is inevitably less expensive than starting from scratch. However, it is still an expensive and time-consuming process. The Phase 3 clinical trials which will usually be required by the healthcare authorities to show that the medicine is safe and efficacious for the new use will likely cost hundreds of millions of dollars and take considerable time. The fact is that unless originators are given a period of exclusivity to make the outlay worthwhile, they are unlikely to expend the resource.

The law makers have long been aware of the need to encourage the development of existing drugs for new uses and have, either directly or by virtue of a legal/judicial fudge, given some sort of protection to new uses through second medical use patents. However the question remains whether second medical use patents are the right solution to this problem and, if they do not provide the complete answer, what other steps are necessary to provide sufficient incentives to originators?

Where are we now?

The patent systems of most major countries provide for some sort of patent protection for new uses for existing medicines.

In Europe, there is a prohibition on method of treatment claims which is now contained in Article 53(c) of the European Patent Convention (EPC) 2000. This exclusion was said to be necessary in order to preserve the freedom of medical practitioners to care for their patients. Bearing in mind this exclusion and also that, in general terms, novelty cannot be conferred on an existing product by ascribing a new use for that product, in 1984 the Enlarged Board of Appeal (EBA) of the European Patent Office (EPO) in the Eisai case decided to adopt the practice of the Swiss Patent Office in allowing claims in the form ‘Use of [drug X] in the manufacture of a medicament for the treating of [disease Y]’. This was considered to steer a course between the method of treatment prohibition and lack of novelty.

The construction of Swiss-type claims is tricky. Even at the highest level of generality, the courts of Europe are divided as to whether these claims should be treated as process claims or product claims. The English courts have consistently held that such claims are purpose-limited process claims whereas the German and Dutch courts have been prepared to construe the claims more purposively as purpose-limited product claims. This distinction matters because it will dictate which acts amount to infringement.

For over a decade now, generics companies have been able to carve out the patented indication from their label and thus seek approval for only the non-patented uses. However, in many countries including the UK, physicians are strongly encouraged to prescribe by reference to the generic or International Nonproprietary Name (INN name) for a drug only. Thus, in many circumstances, dispensing pharmacists will not know the condition for which the medicine is being dispensed and pharmacists are generally encouraged from a financial perspective to dispense a generic medicine where possible. There is therefore a real possibility that a carved out generic medicine will be dispensed and used for the patented indication. This is referred to as ‘cross-label’ use and is to be distinguished from true ‘off-label’ use where a drug is prescribed for an unauthorised indication. The latter involves medical judgment and may involve a degree of risk for the patient whereas the former is purely a legal issue.

For a long time, the question of whether a generics company needed to take additional steps beyond carving out was unsettled. However, although the comment was obiter, in the English Court of Appeal pregabalin decision in October 2016 (Warner-Lambert Company LLC v Generics (UK) Ltd (trading as Mylan) and others [2016] EWCA Civ 1006, [2016] All ER (D) 125 (Oct)), Floyd LJ opined that a generics company needed to take ‘all reasonable steps within its power’ to prevent use for the patented indication. Precisely what steps this will entail will no doubt become clear as time goes by. Courts of other Member States including France, the Netherlands and Germany seem to be heading in same direction as the English courts although homogeneity is not to be expected due to differences in the healthcare systems of each country.

It has been suggested that one way to try and ensure that a generic medicine is not dispensed for a patented indication is to fix a label to the product stating for example ‘NOT FOR USE IN [Y2]’. However it is questionable whether this is permissible in Europe for regulatory reasons and, in any event, it is likely that warnings of this nature would cause inappropriate alarm to patients. Also generally not permitted in the EU is to have a separate brand for the new indication.

One way to ensure that pharmacists are alerted to whether a branded medicine or a generic equivalent should be dispensed is to include the condition to be treated on the prescription. This is already done routinely in several countries but not in the UK. Another interesting development in the UK pregabalin case was that the NHS was ordered by the court to issue guidance to clinical commissioning groups and NHS pharmacy contractors that branded pregabalin (ie Lyrica®) should be prescribed for the patented pain indication whereas pregabalin should be prescribed for other indications. Although such guidance went against the mantra that prescriptions should be written with reference to the INN, the aim was to ensure that the second medical use patent was respected because, in the UK, if the brand name is written on the prescription then the branded medicine must be dispensed absent clinical contraindications. In a later judgment, Arnold J commented that:

‘I consider that it behoves patentees who want their second medical use patents enforced to provide NHS England with all the information and assistance it requires to enable it to issue appropriate guidance as and when required. I also consider that it behoves generic companies who want their interests in obtaining untroubled access to lawful markets protected to cooperate with NHS England as well.’

As well as linking up the physicians and the pharmacists, it is important that payors are also integrated. In the UK for example, it would be appropriate to create a system whereby the pharmacist was reimbursed at one level when dispensing a branded medicine in fulfilment of a prescription for the patented indication and at a lower level where a generic medicine is dispensed for a non-patented indication.

It’s not just about patents

But are second medical use patents enough to incentivise pharmaceutical companies to invest the necessary resources? In the authors’ view the answer is clearly no. The reason for this is that very often patents will not be available to developers of potential second medical uses for existing medicines. A common scenario could be where a physician treating a patient suffering from disease Y1 with X notices that a beneficial effect of treating condition Y2 is also unexpectedly occurring. If the physician publishes an account of this story, a later patent to the use of X to treat Y2 may be open to a validity challenge (although it could be argued that a one-off event would need to be proven in a cohort of patients for the medical community to be confident that X really could treat Y2). It seems that whether a patent is available or not, some other form of exclusivity ought to be given to the company which is prepared to invest in obtaining approval for the new use. The question is what sort of exclusivity and for how long should it last?

At the present time, an originator in Europe can be awarded an extra year of regulatory data protection (RDP) for a new indication. The period is three years in the US. Both periods seem inadequate to incentivise an investment of the proportions needed to bring a new use to market. In addition to patents, perhaps it would be appropriate to give longer periods of RDP or some form of market exclusivity? This could encourage originators to make the necessary investment even when the further use is unlikely to be patentable because of the prior art. Other types of incentive such as cash rewards and/or tax relief are a possibility.

Finally, as noted at the start of this article, clinical trials to prove that an existing medicine is safe and efficacious in a new disease can often be very time-consuming and expensive. Ways should be explored to reduce the time and cost of such trials while in no way jeopardising patient safety.

What are the obstacles?

The legal challenges surrounding, for example, the construction of second medical use patents and how to ensure that the branded medicine is used for the new indication while generic equivalents can be used for the old indications have been set out above. An arguably greater challenge lies in convincing the public that it is appropriate that the same medicine should cost say $1 if it is to be used to treat Y1 and $50 if it is to be used to treat Y2. The UK popular press is not alone in drawing attention to such matters and condemning ‘big pharma’ for the discrepancy. Explaining to the public that the medicine to treat Y2 costs more because of the work that went into showing that X was safe and efficacious for the treatment of Y2 cost hundreds of millions of dollars and that it is for the benefit to society as a whole that people with Y2 are treated with X rather than left untreated is a challenge.

How do we get there?

A first step must be to bring to the attention of those that create policy and make the law that this is a serious issue which demands their attention. A second step is to educate the public as to why it is appropriate that the same drug for a new use will cost more.

Thankfully, two of the world’s leading life sciences companies, Teva and Novartis have, together with University College, London, joined forces for the purpose of pushing this important issue higher up the political agenda. Conferences have already taken place in London and Seattle and now a new conference is in the planning phase, this time in the political heartland of the United States, Washington DC.