Clinical trials and stratified medicine—maximising patent exclusivity

It is important to understand the likelihood of obtaining the required degree of exclusivity, whether through strong patent protection, data exclusivity or orphan designation. Richard Korn and Stephanie Pilkington look at how patent exclusivity can be enhanced as development progresses.

Since patent applications are often filed at an early stage in the development of a drug, long before clinical trials are contemplated, there is a danger that the clinical and regulatory teams dealing with the trials may take the patent situation for granted.

Conversely, patent attorneys are typically handed responsibility for obtaining valid patents, assessing third-party rights and clearing the way to market, but have no professional role in the clinical trials. This separation of patent and clinical/regulatory teams can easily lead to potentially patentable and highly valuable new inventions being overlooked.

It may be possible to strengthen the patent position for a drug by paying careful attention to clinical trials. A significant quantity of data arises from clinical trials, some of which may give rise to patentable new inventions for aspects including new dosage regimes, formulations, combinations, medical indications, and biomarkers of success or failure.

Since the trials may be conducted many years after the initial patent filing, this may prolong the period of exclusivity significantly past the normal or extended patent term. It also provides an opportunity to obtain a broader territorial scope of patent protection and may even allow a patent position to be secured for a project that previously relied solely on protection arising from data exclusivity or orphan drug marketing exclusivity.

Detailed and timely communication between patent attorneys and the clinical/regulatory experts conducting clinical trials is important if such opportunities are to be identified and exploited.

New dosage regimes

The patentability of a novel and inventive dosage regime for a drug that was previously known for treating that medical indication has been confirmed at the European Patent Office, and in European countries such as Germany and the UK, although not in France.

Phase I and II trials routinely include dose escalation studies to identify appropriate doses of a drug for therapeutic use. These studies have the potential to result in patentable inventions, for example, if they show that the drug is therapeutically effective at a dose that was not expected to be active and would not otherwise have been used.

New formulations

It is standard practice in the pharmaceutical industry to identify improved formulations of successful drugs and to attempt to patent the new formulations to extend the duration of patent protection. Supporters of this practice consider it to be legitimate lifecycle management; its detractors, however, condemn this ‘evergreening’ as an abuse of the system that delays the introduction of generic medications and negatively affects public health.

What is sometimes overlooked is that the new formulation must meet the same requirements as any other invention in order for a patent to be granted. In order to be non-obvious, it will usually be necessary to show that the new formulation has a surprising or unexpected property.

The standards required to demonstrate patentability of new formulations are typically quite high, but vary from country to country. India, for example, has introduced a requirement into its patent law that a new form of a known substance will not be patentable unless it results in enhancement of the known efficacy of that substance. So, new formulations may not be patentable in India without data from a clinical trial.

New indications

In phase III trials, the efficacy of a drug is tested on relatively large patient groups, often in comparison to current treatments. Patients enrolled in these trials undergo a thorough medical examination prior to, during and at the conclusion of the trial in order to assess efficacy in relation to predetermined medical endpoints and to identify adverse events.

"Separation of patent and clinical/regulatory teams can easily lead to potentially patentable and highly valuable new inventions being overlooked."

Since a large amount of medical information is collected relating to the biological effects of the drug, it is at this stage that potential new indications might be uncovered. It is, of course, rare for a patentable new indication to be identified as a result of a clinical trial, primarily because other effects of the drug may not be revealed in the population being tested, and also because any newly identified indication may not itself be patentable. Nevertheless, it does occur.

Viagra® is a classic example of unexpected innovation. It is well known that the use of sildenafil citrate (Viagra®) for treating erectile dysfunction was identified as an unexpected side-effect in men being administered this drug during a trial for angina.

A further example of a new medical indication that was identified during a clinical trial is the use of a GLP-1 analogue to treat obesity. While assessing whether the drug was useful for normalising blood sugar levels in diabetics, it was discovered that the treatment also led to weight loss in patients in the trial. This new indication was then patented, providing a potentially valuable further line of protection.

New biomarkers and stratified medicine

The most promising route for identifying patentable inventions during clinical trials arises from studies to assess how sequence variation in the human genome, and variation in gene expression levels and other phenotypic variations, affect the clinical response to drugs.

Such information is increasingly collected and evaluated in clinical trials, but the recent draft guidance on clinical pharmacogenomics from the US Food and Drug Administration (FDA) seeks to place this on a more formal footing. The UK Technology Strategy Board’s Stratified Medicines Innovation Platform also aims to promote activity in this field.

Historically, heterogeneity in response to a drug has been a source of concern, but increasingly this may be viewed more as an opportunity. Stratification of a patient population may offer the promise of finding the patients that are really helped by a therapy, and potentially of being able to secure a patent position that reflects that selection and treatment approach.

Incorporating pharmacogenomics into clinical studies might be expected to identify populations who should receive different doses of a drug because of metabolic differences that may be identified by polymorphism in genes encoding metabolic enzymes, especially the cytochrome P450s. It may also identify responder populations, and populations at an increased risk of adverse events, based on their genetic characteristics. Each of these can potentially lead to patentable subject matter.

An example of genomic information affecting drug usage is the boxed warning on the product label for abacavir (Ziagen®). Patients who carry the HLA-B*5701 allele are at high risk of experiencing a serious and potentially fatal hypersensitivity reaction to abacavir. Screening for HLA-B*5701 status is recommended prior to the start of treatment, and treatment with abacavir should only be considered for HLA-B*5701-positive patients under exceptional circumstances.

Further examples include clopidogrel (Plavix®), whose metabolism is affected by genetic polymorphism in the CYP2C19 gene. A boxed warning on the Plavix® product label suggests genotyping to identify poor metabolisers, with an indication that those patients should consider alternative treatment. Responsiveness to warfarin is affected by polymorphism in the VKORC1 and CYP2C9 genes, and different starting doses are recommended depending upon a patient’s VKORC1 and CYP2C9 genotype.

At least in the context of relabelling drugs, the FDA currently expects that if a diagnostic test is essential for the safe and effective use of a therapeutic product, there is a cleared/ approved diagnostic test available concurrent with the drug label change. This may well also be the case for newly approved products.

Therefore, pharmacogenomics information obtained during a clinical trial has the potential to result in patent opportunities for obligatory companion diagnostic assays and kits, whether they are exploited in-house or out-licensed to a third party. Moreover, it may be possible to obtain patents for new methods of treatment, including a patient screening step, and medical uses based upon a newly defined population of patients to be treated.

Such patents are potentially of great value in providing effective market exclusivity, particularly if the drug is only approved for use in the specified populations. It is also possible that the stratification observations may lead to new compound screening methods and, potentially, identification of new chemical entities.

In the examples of abacavir, clopidogrel and warfarin, the pharmacogenomic information was only discovered post-marketing. With the growing facility for gathering and analysing ever greater volumes of data, it is more likely that correlations of this type will be picked up earlier in the clinical trials process, potentially increasing benefit to patients and the possibility of seeking patent protection.

Clearly, there are still potential concerns. The situation in the US is still evolving as to whether diagnostic methods constitute patentable subject matter. So far, it appears that it should be possible to find an acceptable claim format by careful consideration of the various strands of testing and treatment that make up a stratified or personalised medicine approach.

Accidental discoveries have always played an important role in the search for new drugs. Yet we subscribe to the maxim of Louis Pasteur that “in the field of observation, chance only favours the prepared mind”. Therefore, we recommend that a patent attorney is included as part of the team assessing clinical trial data to aid in determining whether a potentially patentable invention has been made. In the competitive world of the bio-pharma industry, patents provide a vital edge.

Being prepared to seize every advantage provided by information arising from clinical trials is more important than ever.

Dr Richard Korn is a senior associate at Potter Clarkson LLP. He can be contacted at: richard.korn@potterclarkson.com

Dr Stephanie Pilkington is a partner at Potter Clarkson LLP. She can be contacted at: stephanie.pilkington@potterclarkson.com