Date Posted: 16 August 2012
A research team, based at the University of Valladolid in Spain, has proposed using gene expression levels of an ocular surface protein as a diagnostic marker for the diagnosis of dry eye syndrome (DES). The research, published in the journal of Investigative Ophthalmology & Visual Science (Vol. 52, No.11, pp8363-8369) reports on a retrospective study, conducted between 2000-2009, on almost 70 patients with dry eye syndrome. Expression levels of several "mucins" -high molecular weight proteins found on the ocular surface- showed significantly lower levels of activity in patients with DES compare to age and sex-matched control subjects. However, as such observations may be viewed as reflecting "laws of nature", it is uncertain whether or not such discoveries can secure patent protection critical to delivering such a product to market.
DES has recently being re-defined as "a multi-factorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. Dry eye is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface". This new definition, issued in a report from the Definition and Classification Subcommittee of the International Dry Eye WorkShop, reflects current understanding of the disease and its multiple causes. In addition, the new definition introduces a scheme based on the severity of the dry eye disorder, providing practical clinical guidance in the application of treatments. As DES occurs in approximately 7-25% of the population it is therefore of significant economic importance and consequently of significant relevance to companies in the business of developing diagnostics and biomarkers.
The recent research, partly supported by Allergan and led by Drs. Rosa Corrales and Professor Margarita Calonge at the Institute of Applied OphthalmoloBiology (IOBA), University of Valladolid, employed conjunctival impression cytology on sixty-eight (68) patients with DES and fifty-nine (59) healthy subjects. The non-invasive method allows researchers to obtain epithelial cells from the ocular surface which may then be analysed for messenger RNA (mRNA) expression levels of the mucin genes. Of the eighteen (18) known human mucin genes, nine (9) are expressed on the ocular surface including MUC1, MUC2, MUC4, MUC5A, MUC7, MUC13, MUC15, MUC16 and MUC17. Mucin proteins are understood to keep the ocular surface wet and protected from a variety of environmental conditions and previous studies have suggested that ocular mucins are altered in patients with DES. The MUC1 gene in particular, demonstrated the greatest sensitivity (83.3%) and specificity (87.5%) among all of the mucins tested. As such, the finding may be used to develop a valuable clinical tool for both diagnosis and clinical trial endpoints.
The study by the Spanish research team, performed on superior bulbar conjunctival cell samples obtained from moderate to severe tear-deficient DES patients, showed significantly reduced levels of MUC1 in addition to lower expression levels of MUC2, MUC4 and MUC5AC (P<0.0001). MUC1 in particular plays a critical role in lubrication, apical surface protection and osmo-sensing and therefore a reduced expression pattern might explain the loss of surface integrity seen in DES patients. The authors of the study conclude that the use of MUC1 as a diagnostic marker for DES, "will not only increase the accuracy of classifying patients correctly, but also significantly aid in clinical trials for the development of therapeutic agents for this prevalent ocular disease".
However, while the science appears convincing, the path to exploiting such knowledge is less certain, especially in light of a recent US Supreme Court decision, (Mayo Collaborative Services, et al. [Mayo] v. Prometheus Laboratories, Inc. [Prometheus]), the practical impact of which may discourage investment in diagnostic and biomarker technologies. In a 9-0 unanimous decision delivered by Justice Steven Breyer, the Supreme Court ruled that intellectual property of the plaintiff (Prometheus) was invalid. The Mayo vs. Prometheus case involved a method for determining the optimal dosage of drugs to treat autoimmune disorders, on foot of which Prometheus (San Diego, California) took a patent infringement case against the Mayo Clinic (Rochester, Minnesota). The infringement case arose from the Mayo Clinic's use of an in-house diagnostic test rather than sending out samples to Prometheus for testing. The Mayo Clinic focused its defence on the argument that dosage adjustment was an abstract idea well established in medical practice and pre-dated any patented test. The Supreme Court agreed and declared that the intellectual property of Prometheus describing specific diagnostic tests was invalid. In outlining the ruling, Justice Bryers stated that "this Court has repeatedly emphasized a concern that patent law not inhibit future discovery by improperly tying up the use of laws of nature and the like." However, the fall-out goes well beyond Mayo & Prometheus as the ruling brings into question intellectual property which uses "laws of nature" or natural processes, of which biomarkers such as MUC1 for detecting risk of dry eye syndrome, are but one example.
The challenge now for those who discover biomarkers such as MUC1 is to understand how such discoveries can be adequately protected in order to attract the required capital to bring a product to market? As significant time, expense and regulatory approval are required to commercialise diagnostic products, investors are generally reluctant to support a costly development programme unless they can obtain some certainty they will enjoy a degree of market protection to recoup the investment. In the absence of clear guidelines or court rulings such certainty is eroded for inventors, patent attorneys and investors. Unfortunately, a significant ruling such as that delivered by the Supreme Court has the immediate practical impact of potentially stalling product development and investment in this space. Whatever happens next we can be sure that sorting out the new landscape will take time and time is often an asset that small companies lack, as do Universities who often have limited resources to protect the discoveries of the scientists. Universities, companies and investors making decisions today will now have to make such calls with yet another unknown thrown into the mix of the perilous path from bench to bedside. Clearly not an occupation for the faint-hearted.
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