Part 1 of a series of articles

When you go to the doctor you expect to be asked a lot of questions about your symptoms and your lifestyle, as the doctor builds up a clinical picture. That picture allows the doctor to diagnose your condition and to choose the most appropriate treatment. However, despite this approach forming the foundation of successful modern medicine, the information gathering exercise merely scratches the surface of accessible data, which could be used in providing a better diagnosis and better treatment regimes.

This is, at least in part, because the standard approach currently used concentrates on symptoms to allow the medical practitioner to infer a diagnosis of a condition. However, in reality the same symptoms can be, and very often are, caused by different underlying causes (i.e. different diseases) in different individuals (or even within the same individual on different occasions). We are familiar with the idea that a symptom like a headache can be caused by a number of different underlying pathologies or conditions (ranging from the relatively harmless such as mild dehydration or stress, or a cold, to the more serious such as stroke or brain tumour), and we therefore don’t think of headache as an illness in itself. However, most of us are much less familiar with the same principle applying to a wide range of other conditions, for example autism. Autism, like many other conditions (e.g. hypertension or schizophrenia) is no more a single illness than headache is, but rather is a heterogeneous grouping of neuro-developmental disorders with different causes in different individuals.

The growing practice of personalised medicine seeks to delve more deeply into the information held in our bodies, in order to get to the cause of the observed symptoms, and therefore to differentiate between different illnesses potentially causing the same symptoms. Instead of a traditional diagnosis (and consequent treatment) of, for example, autism, personalised medicine seeks to diagnose and distinguish autism caused by a mutation in gene X, and autism caused by a mutation in gene Y in the patient under investigation (even where the observable symptoms caused by these mutations are identical).

The potential benefit of the personalised medicine approach is huge. More accurate diagnosis of the cause of disease can allow for stratification of treatment options and enhanced prognostic information. Inappropriate treatments (which can be costly and have side effects) can be avoided and the most appropriate treatment can be provided more rapidly. Many personalised medicine approaches can reveal a predisposition to one or more conditions, even before those conditions arise, leading to the possibility of lifestyle planning to lower risk. Drugs which have been withdrawn because of adverse effects might be reinstated where companion diagnostic tests are able to reveal a population for whom those adverse effects are not a risk.

The data which can be used in the personalised medicine approach comes from an analysis of the individual’s DNA sequence, or the proteins or other biomarkers found in various body fluids. Such markers are usually easy to access and relatively easy to measure and analyse. The main technical challenge for the personalised medicine industry lies in the discovering the links between DNA sequences and other biomarkers, and observed symptoms and responses to treatment. Also important is the development of new rapid methods for the generation of large amounts of data about an individual’s genomic or proteomic make up, and the comparison of that data with known standards.

The enormous cost of the R&D required to meet these technical challenges needs to be driven by the promise of exclusivity granted in the form of intellectual property rights. However, as is often the way with emerging disruptive technologies, IP law is struggling to keep up and to accommodate this new technology, whilst at the same time maintaining intact long held boundaries designed to safeguard the public. The patent system must find a balance between adequately rewarding and encouraging innovation whilst protecting public interest, and this is particularly difficult in technologies like personalised medicine where complex ethical and moral considerations can arise.

In this series of articles we will look at some examples of where developers and innovators in the field of personalised medicine might legitimately expect to be rewarded with patent protection for their contribution, but where the current state of IP law can made adequate protection difficult to achieve.

In this, the first article, we look at the fundamental issue of gene patents. A significant activity of the diagnostics industry in recent times has been the discovery of genetic causes of known diseases. Traditional, laborious and difficult genetic linkage studies are now giving way to more sophisticated techniques such as comparative genomic hybridisation and mass SNP analysis, resulting in a rapid rise in the discovery of new genetic associations with diseases, and predispositions to diseases.

In the not-so-distant past, investigators discovering a genetic cause for a disease would have expected to be able to claim patent protection for the gene that they had found. Patent offices in the major jurisdictions could be persuaded to grant product claims to the gene (and variants defined according to a well used formula to prevent easy work-around). Gene claims were considered to relate to inventions rather than discoveries by virtue of the isolation of the gene from its natural environment (in much the same way as, for example, penicillin, might be thought of as an invention, if discovered and isolated now).

Because of this history, there are now many thousands of patents still in force both in Europe and the USA with gene claims. Some commentators have suggested that a very large percentage, if not all of the human genome is now covered by patents with product claims (although there is much debate on this issue, see for example [1] and [2]). On the face of it, these patents cover diagnostic genetic tests such as those discussed above, i.e. those tests forming a key part of a personalised medicine strategy.

Gene patents have come under fire from multiple attacks in Europe and the USA, and both the judiciary and the statute makers have been forced to act in the face of public pressure. In Europe, traditionally, that pressure was driven largely by moral considerations, the objection being that genes should not be patentable, since, to the objectors, ownership of any aspect or form of life is repugnant. In the USA, by contrast, a major thrust of the objections to gene patents emerges from the need to control the diagnostics industry’s grip on the provision of genetic testing. In a country where the healthcare payment system is at risk of disenfranchising a large indigent population, that grip is, in theory at least, all too easy to exploit or mismanage, and the fear is that potentially life saving therapy is being denied to those who cannot pay for the best genetic testing. Of course, there are elements of the moral arguments in the USA, and elements of the socio-economic arguments in Europe, and often the most successful campaigners employ a mixture of both attacks.

The law makers’ responses have differed in the two jurisdictions. In Europe the European Union (EU) has attempted, through the introduction of the Directive on the Legal Protection of Biotechnological Inventions (the Biotech Directive) [3], to strike a fair balance between protecting innovation and satisfying the morality based objectors (who object to a wide range of biotechnology related patents, not just gene patents). However, the Biotech Directive, whilst limiting the patentability of a number of biotechnology related activities, has had only a very limited impact on the validity of gene claims. It seems that the European Commission was satisfied that the combined requirement of novelty and inventive step (which will inevitably make new gene claims almost impossible to obtain in a post-genomic era in any event) is an adequate barrier to continued problems. In this way the EU has washed its hands of the problem in relation to patents already in force, leaving it to the domestic judiciary to hear individual cases as and when they arise.

One interesting twist in this European story, however, has played out in the case of Monsanto v Cefetra [4], heard by the European Court of Justice (CJEU). Monsanto had a patent covering a gene whose function was to render plants containing that gene resistant to its proprietary herbicide, Roundup (RTM). Monsanto took action to try and prevent Cefetra from importing soy meal into Europe, claiming it to be an infringement of the patent, since the soy from which the meal was generated included the gene (and as a consequence, the meal included the gene). Since the claims of the patent were to the gene itself, Monsanto argued that the soy meal, or the gene within it, infringed those claims.

The CJEU, however, took a different view, deciding that Article 9 of the Biotech Directive limited the scope of protection of the claims to materials in which the product is incorporated and in which the genetic information is contained and performs its function. The genetic material in the soy meal was incapable of performing its function (conferring resistance to Roundup), because soy meal is dead material. As a consequence, the patent claims did not extend to the gene in that context.

A moment’s thought about the use of a gene in an in vitro diagnostic assay, however, raises the spectre that the same logic would apply. Much depends upon the interpretation of the expression “performs its function” in relation to a gene used in a diagnostic test, but a strict interpretation (that the function is the gene’s normal, in vivo natural function) could be devastating for the diagnostic industry. It isn’t yet clear whether the CJEU has inadvertently (or perhaps deliberately) emasculated gene claims for the diagnostic industry in Europe. Only time, and a commercially important test case, will show.

In the USA, the problems associated with gene claims have been left to the courts to sort out, most prominently in the very well publicised Association for Molecular Pathology (AMP) v Myriad [5] case. The Supreme Court of the USA (SCOTUS) has recently heard oral arguments on the patentability of gene claims (i.e. whether or not such claims should be held invalid for being nothing more than a law or product of nature – and therefore patent ineligible). A decision is expected in late June 2013. Many commentators believe that Myriad will not have been successful in safeguarding gene claims from such an attack. If that is correct, the decision of SCOTUS will be the second of two devastating judgments for the diagnostics industry to emerge in just over a year. In March 2012 SCOTUS severely limited the possibility of securing diagnostic method claims in the US in its landmark decision in Prometheus v Mayo [6].

In summary, notwithstanding that new associations of genes and diseases are being made every day, the traditional product protection that used to be available is almost certainly a thing of the past. In Europe that is largely the result of a strict approach to considering the prior art effect of the published sequence of the human genome. In the USA there is the potential additional hurdle of patent ineligibility that could result from AMP v Myriad. Even for patents already granted, AMP v Myriad may have a devastating effect in the USA, whereas in Europe, although granted cases may be valid, their effective coverage of in vitro diagnostic kits must be in some doubt following Monsanto v Cefetra.