Personalised medicines and exclusive protection

Senior counsel Paul England provides in-depth analysis into the challenges and possible solutions of patenting personalised medicines in the United Kingdom and beyond.

Parallel developments in our understanding of molecular biology and in silico technologies have driven medical innovation far beyond the conventional field of small-molecule pharmaceuticals.

Combined with genetic information, computational techniques can be used to identify biological features - or 'biomarkers' - for diagnosis and treatment of the causes of disease at source, rather than merely symptoms. The ability to collect real-time data from individual patients also enables condition diagnosis and monitoring, just as digital imaging allows precise design and delivery of surgical treatments.

These sciences have enabled the creation of personalised medicine: the targeting of treatments for smaller populations within disease groups and individual patients themselves.

Where there is medical innovation, there is usually the need for patent protection. In fact, patent filing and dispute activity has diversified into the biotech and medical device sectors to equal that taking place in the pharma space. The basic patent laws in Europe, based largely on patent conventions that are now decades old, are keeping up well with new products and processes in these tech fields.

However, there are issues inherent to the nature of personalised treatments that are pushing the boundaries of the current patenting model in various ways.

Among other things, patenting requires that the subject matter being patented is novel. However, this notion is challenged when the innovation lies in finding a sub-population in a known disease group that particularly benefits from a known treatment.

This can happen, for example, when unwanted effects in a symptomatic population of people with no disease biomarker have masked the drug's true potential in those who do. Once those with the predictive biomarker to which the drug responds are identified, a drug that appears unpromising in the disease group as a whole - or even responsible for adverse events - can be demonstrated to have enhanced efficacy.

The challenge is to find novelty in a claim to the same drug and same therapeutic indication when it has already been used to treat the sub-population with the predictive biomarker inherently, by use in the whole group.

The answer to this question, according to EPO case law, is to require the claim to disclose the physiological or pathological characteristic that may be targeted to produce the improved treatment - it is not enough for the claims to merely provide information on the causal relationship that makes the treatment work. This distinction can be subtle; a number of national courts, including those in the United Kingdom, have yet to fully address the issue.

SPCs struggle to keep up

SPCs can provide up to five years of additional exclusivity protection for a small-molecule or biologic drug consisting of a novel active ingredient or combination of active ingredients that is covered by a patent and first-marketing authorisation.

That model worked for the medicine sector when the original SPC legislation was introduced in 1993, but has proved difficult to adapt to newer products.

This is acutely evident in the European Court of Justice's decision in Santen v Director of the French Patent Office (C-673/18). The court ruled that SPCs will not be permitted for second medical uses when the active ingredient has already been the subject of an earlier marketing authorisation. If second medical uses cannot be covered, then SPCs will be much less applicable to sub-population treatments.

Enforcing personalised medicine patents

If novelty can be established for personalised treatments, questions remain about their enforcement.

How can a sub-population patent prevent a generic version of the drug - which is sold for legitimate/off-patent purposes - from being used for the patented sub-population, either deliberately or accidentally?

Conversely, how does a generic/biosimilar company supply the drug for an unpatented purpose with the confidence that it will not be used for the patented sub-population?

The answer to this question is unresolved, at least in the United Kingdom. It may possibly lie in the tentative (because it was an obiter decision and not unanimous) test that the Supreme Court set in its judgment dealing with pregabalin second medical use claims (Warner-Lambert v Generics (2018) UKSC): the outward presentation test. This states that a finding of infringement depends on whether the product's outward appearance indicates that it is being marketed under the patented use. For example, dosage sizes and regimes that differ to those required for the sub-population is evidence that a product is not being sold for its patented purpose.

There is, however, no regulatory carve out available for sub-populations in the product packaging - so-called 'skinny labels' - in the same way that there is for indications, such as in pregabalin. Even if this were possible, it may not be helpful to carve out pathological features when even the patient and their doctor may not know they exist.

The long-term solution would seem to be a regulatory change in prescribing practice: to require doctors to diagnose and prescribe certain drugs according to patent protection. However, that could be resisted by the medical profession.

Even assuming that this issue is resolved, how does a court selectively injunct infringing use while allowing sales for legitimate uses? For this, courts may have to revisit the approaches taken by the lower courts in Warner-Lambert to decide whether it would be appropriate for those at risk of infringement to take somewhat onerous steps (eg, letters to doctors and pharmacies to warn them off the prescription and dispensing of third-party drugs for patented uses).

Resolving this issue is likely to require the courts to be flexible and creative in future. In the meantime, the above precautions should be considered.

The reality of final injunctions for life-saving products

English courts have consistently said that while final injunctions are discretionary, they remain cautious before declining to injunct. This is because an order of damages alone is tantamount to a compulsory licence - which should only be obtained under the appropriate statutory provisions.

There may be circumstances in which public interest is in tension with the issuing of a final injunction, such as treatments for serious medical conditions, or perhaps only for life-saving treatments.

It is not enough to invoke public interest that reasonable doctors would choose the defendant's drug or device in preference to the patentee's product. It is not even enough that reasonable doctors believe that the differences between life-saving products mean that for some patients, the patentee's product is not an adequate treatment but the rival product is. Instead, objective evidence is needed.

This does not have to mean that the public interest can only be invoked for treating clinical emergencies. It may include treatments such as mitral valve devices, because these are designed for relatively small groups of patients with very particular conditions for which other devices are unsuitable or unavailable. The same principle applies to a life-saving biologic treatment for which there is no suitable alternative for a particular patient group, but such cases are rare.

However, as treatments designed for particular conditions develop, more cases may be expected to fall within this bracket. Patent holders must consider that they may be unable to exclude competitors from the market, at least for a period, but can instead choose between a court award of damages or a negotiated settlement.

Patentability of treatment methods by surgery or therapy and diagnostic methods

These exclusions, which are found in Article 53(c) of the European Patent Convention (EPC), are a matter of policy: they protect clinicians and veterinarians from the threat of enforcement when going about their practice.

The EPO Boards interpret these exclusions narrowly. For example, to determine whether a claim is directed to a diagnostic method, the method must have been performed on a human or animal body (Diagnostic methods G 1/04).

This means that with appropriate drafting of the patent claims, the exclusion may be avoided. For example, products (eg, substances or compositions for use in a diagnostic method) may be patented, as may companion diagnostic apparatus.

Similar considerations apply to the drafting of patent claims to avoid exclusion for treatment methods practised on the body. This is particularly important for therapies performed on individuals, such as CAR T cell treatments.

The EPO Boards do not define 'treatment by surgery', and its meaning may be expected to change with time and convention. However, while some level of medical expertise and health risk should be involved, it is not limited to only therapeutic surgery or invasive methods.

Methods that do not themselves cover surgical steps but imply that such steps must take place have fallen on either side of the line defined by the exclusion. Devices functionally defined only in relation to the body of a patient are permissible. Consequently, the exclusion can be avoided by disclaiming embodiments where there is a direct intervention with the body.

The impact of orphan drug legislation

The standalone regime of market exclusivity provided in the Orphan Medicinal Products Regulation (141/2000) and its UK counterpart is designed to encourage companies to develop new drugs and to carry out research on existing drugs to treat rare diseases. In this context, rare diseases are those affecting no more than five in 10,000 people in the population, for which the likely revenues available do not justify the research required.

The key incentive for orphan drug development in this legislation is a 10-year period of market exclusivity for the indication in question, In addition, if an application for a marketing authorisation includes the study results conducted in accordance with an agreed paediatric investigation plan, the 10-year period is extendable to 12 years.

This market exclusivity may run in parallel with the drug marketing exclusivity, but is separate and distinct from it.

For a drug to qualify for orphan status, there is a quasi-novelty requirement:

• there must be either no satisfactory method of diagnosis, prevention or treatment of the condition concerned
• if there is such a method, the new medicine must be of significant benefit to those affected by the condition.

This is much broader than under the patent regime. In particular, 'significant benefit' may be based on the assumption of a more efficient formulation and means of administration than an authorised medicinal product with the same active substance and intended to treat the same condition. For example, 'particular benefits for a sub-sample of the population' can provide a significant benefit.

Enforcement of an orphan drug's 10-year exclusivity period is effectively achieved because, subject to narrow exceptions, no similar medicinal product to that drug can be authorised for placing on the market for the same therapeutic indication unless it is itself 'clinically superior'. Orphan drug protection is therefore a powerful right, designed specifically for personalised medicines.

The limitation on this form of protection is that it protects drugs and not devices or methods of diagnosis or treatment.

The road ahead

The diversification of the life sciences into previously unthought of areas does pose challenges for the patent system, which has been the mainstay of exclusivity protection for medical innovations for many decades. Will it cope?

The answer is that the patent system and the patent offices and courts that apply it - have proved remarkably adaptable over the years. That flexibility looks set to continue with personalised medicines, and issues ranging from novelty to enforcement should be resolved given time.

There are, however, areas in which new statutory rights have a role to play in supplementing patent protection, particularly when incentivising research into areas that would otherwise serve too few in the population to be economically viable. While the orphan drug legislation demonstrates how this can be done, SPC legislation does not and needs to be re-thought.

First published in the IAM Specialist Report.