Although Rosetta Genomics will not enjoy the exclusivity it used to have, its future has never looked brighter. First and foremost, in order to associate miRNAs with diseases, one must first know how to find and isolate them. It is important to remember that miRNAs were only recently discovered because nobody speculated they existed, let alone knew how to locate them. Rosetta's predictive algorithms enabled it to pick these tiny genes from the huge reservoir of the genome very efficiently compared to traditional methods. In parallel to discovering miRNAs, the company was using its sophisticated algorithms for identifying miRNAs that may serve as potential therapeutic and diagnostic candidates. This task requires a great deal of experience and analytical capabilities, which will be a very important differentiator going forward. Moreover, the company currently has the largest pipeline in the industry, with over 50 diagnostic markers in development, and it has also developed proprietary techniques for extracting and isolating miRNA from patients' tissues and body fluids. This is another crucial issue because even if there are miRNAs that can serve as targets, their presence and levels must be easily measured in patients. For example, biopsy samples may be very small and contain modest quantities of miRNAs, so any diagnostic test based on miRNA must enable researchers to obtain sufficient quantities of miRNA from every sample in a cost-efficient manner.

Having a head start over competition is always nice, but this technological gap is doomed to diminish with time, as companies with far greater resources than those of Rosetta can catch up by allocating the right amount of money and personnel. What makes Rosetta so promising is its extensive patent portfolio, consisting more than 60 patents, most of which are still pending. The company brilliantly filed patents for the miRNAs' sequences it discovered as well as for their potential uses and applications as markers or drug targets, very early in the discovery process. By doing so, it locked the majority of known (and probably unknown) miRNAs in the human genome. To date, the company was granted 2 miRNA patents and received a notice of allowance for two additional patents (which means the patent application is found to have met the requirements for patentability). It is important to note that every patent covers multiple miRNA sequences and a never-ending list of potential uses, as can be seen in the first ever granted patent for human miRNA. Just to put things in perspective, this patent was filed in November of 2002, only one year after miRNA was recognized as a widely occurring phenomenon. Assuming a similar waiting period from application to granting for additional miRNA patents, it is reasonable to expect a steady uptick in the amount of patent granting going forward. The company stated it has more than ten additional patents in advanced examination, and is constantly patenting more sequences and potential uses.

It is therefore of Rosetta's experience and expertise coupled with its strong intellectual property that turns it into such an attractive investment. Rosetta is involved in the development of diagnostic products as well as miRNA-based therapies. Naturally, diagnostics have a shorter time-to-market and better chances to reach the finish line, which implies that in the foreseeable future, the diagnostics market will be the major source of revenue for the company. Even though the company expects to file its first IND already next year, Rosetta should be regarded and evaluated as a diagnostics company. Hopefully, the activity in the diagnostics market will finance the long and costly clinical development of its therapeutic candidates, without the need to raise the typical amount of funds associated with clinical development. Nonetheless, this is the place to point out that despite the "buzz" around miRNAs, there is no way to predict future success in this field, and to date, there has not been a single IND filed for a miRNA-related therapeutic agent. On the diagnostics front things look more encouraging, as last week Rosetta Genomics submitted the first miRNA-based diagnostic product for regulatory approval.

 Rosetta Genomics' Activity In The Diagnostics Market 

So what makes miRNAs such promising diagnostic markers for cancer ?

First, there is a large body of evidence that the majority of human cancers are associated with a change in miRNA expression, so these changes may be used as reliable markers. Second, because miRNAs are genetic "master switches", turning on and off the production of tens or even hundreds of other genes, looking only at miRNAs may provide a simpler but a more "holistic" means for diagnosing the disease. Third, miRNAs can be amplified by standard procedures as opposed to proteins. This difference makes miRNA more sensitive markers than traditional protein diagnostics, as even one molecule of miRNA can be identified using amplification. Fourth, due to their small size, miRNAs are very stable and long lived inside the patient's body as well as in samples taken from patients. This is in bright contrast to messenger RNA (mRNA), which undergoes fast degradation. miRNAs have been found to remain stable for up to eleven years in "paraffin blocks", the standard practice of preserving tissues taken from patients. Therefore, it is possible to go back and analyze patients' miRNA profile, retrospectively, since the course of the disease is already known. This allows large-scale analyses to be conducted rapidly and efficiently, without the need of awaiting the actual course of disease to occur. Fifth, miRNA expression levels represent more closely the functional level of the gene, because they do not have to be translated into proteins in order to have a biological effect. In contrast, a change in the expression of mRNAs does not necessarily result in a change in the expression of the proteins they encode for. 

The company is active in multiple areas, but most of its efforts revolve around oncology, where good diagnostics are sometimes more important than good drugs. Most cancers are characterized by a primary tumor that, with time, invades nearby tissues and later sends metastases to distant organs. At their advanced stages, most cancers are incurable, even by the most efficient therapies, but in early stages, a tumor can be surgically removed and the patient can be cured.

There are two general types of diagnostic products in cancer: Early detection assays and classification assays. Although there are some early diagnosis tests such as PSA test for prostate cancer or colonoscopy for colon cancer, these tests suffer from serious drawbacks such as a high false alarm rate and patient inconvenience. The holy grail in cancer diagnostics is thus a simple and reliable test that does not involve patient  inconvenience. miRNA diagnostics are hoped to get the industry closer to achieving this goal, first with respect to reliability and later on with respect to patient convenience.

The classification assay field is attracting a lot of attention these days, as part of the personalized therapy trend, especially in the case of targeted therapies. It is now clearer than ever that there are subgroups of patients that respond differently to a given treatment. Consequently, there is a need for predicting factors such as response to treatment and risk of recurrence, so that an optimal treatment is tailored for each patient on an individual basis. For example, Herceptin^® and Tykerb^® are effective only in one out of three breast cancer patients, therefore, identifying the right patients is crucial. Rosetta expects to submit three classification assays for regulatory approval already this year.

The first of these assays was already submitted for regulatoryapprovalby Rosetta and its partner, The Columbia University Medical Center (CUMC). This assay is designed to differentiate between two subtypes of non-small cell lung cancer (NSCLC): squamous and non-squamous NSCLC. Until recently, both subtypes were treated the same way, but the introduction of Avastin^® and other antiangiogenic agents made the distinction between the two a necessity. Squamous patients who receive Avastin have a high risk (31%) of developing serious life-threatening bleeding from the lung. As a result, Avastin is used only in patients with non-squamous lung cancer. In the majority of cases the distinction between the two subtypes is easily done by a pathologist, based on morphological differences and known protein markers, but there are cases where the distinction is challenging either because the tumor is not fully differentiated or because there is a mix of both subtypes. In these cases, which are estimated to represent 5%-15% of cases, there is a true need for an objective and "digital" marker that can identify squamous tumors unequivocally.