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Published online on October 16, 21012

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http://www.sciclips.com/sciclips/blogArticle.do?id=1023&blog=Metabolon%20vs.%20Stemina %20-%20Are%20Biomarkers%20Patents%20can%20be%20Considered%20as

Metabolon vs. Stemina Are Biomarker Patents can be Considered as True Inventions?
The term patent usually refers to the exclusive right granted by a government to an inventor to manufacture, use, or sell an invention for a certain number of years (1). The definition of invention can be according to U.S. Patent Law .a new, useful process, machine, improvement, etc., that did not exist previously and that is recognized as the product of some unique intuition or genius, as distinguished from ordinary mechanical skill or craftsmanship.(2). According to legal precedents, laws of nature, natural phenomena and abstract ideas are not eligible for patenting (3). Based on the above mentioned definitions, it is tempting to speculate that numerous biomarker patents that have been granted may not be considered as true inventions. Biomarkers are biological molecules (protein, nucleic acid or metabolites) used as an indicator of a biological state, often used in reference to a disease. In other words, presence of biomarkers in patients are the consequences of manifestation of diseases, which may affect anatomical, physiological or genetic changes in patients, and these changes may stimulate differential expression of certain biomolecules. Now, the foremost philosophical and ethical question is whether the biomarkers are owned by patients or by the inventors/assignees. If patients do not develop a disease, biomarkers associated with a disease might not have been existed in a patient. Certainly, some kind of biomarker/s can be linked to the onset or progression of diseases and the occurrences of these biomarkers in patients are scientifically anticipated, except the fact that disease specific biomarkers need to be identified and characterized using existing or new technologies. Extensive pre-clinical and clinical validations are required to confirm the diagnostic accuracy and commercial viability of biomarkers. Intentionally or unintentionally, most of the biomarker patents do not address these critical factors, especially the relevance and validation of biomarkers with respect to clinical applications. Moreover, a single disease can have multiple biomarkers depends upon patients genetic, physiological and environmental factors (4), an indication that probably incidence of biomarkers may be related to individual patient or a group of patients, similar to the concept of personalized medicine. Indeed, most of the inventions described in biomarker patents did not consider these variables that can have significant impact on developing clinically useful biomarkers. Possibly, some disease specific biomarkers in claimed inventions might not even be associated with a disease; especially a panel of disease-related biomarkers that were identified using genomics or proteomics technologies (please read our blog (please read our blogStrategies for Rational and Personalized Cancer Biomarker Discovery to learn more about this argument). The incidence and relevance of biomarkers may be challenging and complex than we ever thought and the current patent process does not address these factors, which may be very specific to certain scientific 1|Page
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inventions such as biomarkers. For instance, a specific protein or gene mutation, can be called as biomarker A for the diagnosis of breast cancer, which is localized to a specific geographical location or ethnic group or gender or incidence of infectious diseases. There is a possibility that the biomarker A alone may not be sufficient to diagnose breast cancer in a different set of patients from a different geographical location or ethnic background etc. Instead, a combination of biomarker A and biomarker B or additional biomarkers may be required for accurate diagnosis of breast cancer in these patients. Therefore, biomarker A may not be broadly claimed as a biomarker of breast cancer, as we perceive in current biomarker patents. At the same time, the scientific utility and validity of claims based on a list of genes or proteins and the use of one or more genes from this list of genes/proteins for the diagnosis of diseases need to be critically evaluated (e.g. US patent #8,071,286). Similarly, patent claims on the use of specific peak shifts in mass spectrometry for the diagnosis of diseases (e.g. US patent #8,198,019) might be a highly speculative and non-scientific approach. The obvious reason is that these peak shifts were not well-defined and characterized; though it may be possible that these peak shits might have occurred due to the presence of disease specific biomarkers (e.g. proteins) in patients tested. However, similar peak shifts can also occur due to pos-translational modifications or mutations in a different biomarker associated with the same or a different disease. One of our major concerns is with broader patent claims that are based without any scientific evidence or scientific rational, more often experimental design and results may not be related to claimed inventions. Furthermore, there are several patents that are not true inventions; rather these patents may be based on known scientific principles or concepts. Metabolons US patent on the application of metabolite profiling for disease detection or diagnosis (US patent#7,550,258) could be a potential example for this. According to the claims of this patent, disease specific metabolites can be identified by comparing the metabolite profiling of sample derived from patients with a standard small molecular profiling (controls). Interestingly, there could be several earlier scientific reports that might be directly or indirectly demonstrated the applications of metabolic profiling for the detection or diagnosis of diseases. Some of these reports include metabolite profiling of rat liver during ischaemia (Brosnan et al (1970)), toxicology screening by profiling of unknown drugs and metabolites in urine and serum from patients with acute drug poisoning (Lai et al (1997)), organic acids profiling in urine and plasma from patients with high anion gap metabolic acidosis (HAGMA) (Pitt and Hauser (1998)), organic acid profiling using urine samples from patients with metabolic diseases (Garcia et al (1998)), automated metabolic profiling for the detection of organic acidemias (Yamaguchi et al (1999)), metabolic profiling for detecting selfpoisoning episodes with acetaminophen (Bales et al (1988)), tryptophan metabolite profiling in urine during typhoid fever (Powanda et al(1975)), urinary steroid metabolite profiling in patients with adrenocortical tumors (Minowada et al (1975)), metabolic profiling of catecholamine by-products in patients with pheochromocytoma ( Krstulovic et al (1980)), profiling of amino acids and acylcarnitines from blood spots for the diagnosis of inborn errors of metabolism (Rashed et al (1997)), metabolite screening test for the diagnosis of inherited metabolic diseases (Pang(1996)), identification of urinary metabolites for the diagnosis of organic acidemias (Kimura et al (1999)) etc. Based on the above published information, wouldnt it be possible for an ordinary researcher to think that metabolic profiling can be used for the diagnosis of human or animal or plant diseases (controls are always a default factor in 2|Page
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any scientific experiments)?. This may be also true with Metabolons patent on metabolic profiling of cells treated with biomolecules (proteins, peptides, nucleic acids etc.) (US patent#7,910,301). Some earlier reports such as endogenous metabolism stimulation by chemical or physical treatments in fungal spores ( Mandels and Magurie (1972)), hypothetical mechanisms proposed for metabolic stimulation by compounds (Web (1963) cross reference 22 in Mandels and Magurie (1972)), analysis of metabolites in spent culture media (Brooks (1977)) etc. might be potentially similar to the invention described in this patent. Interestingly, claimed inventions in this patent were also different from supporting experimental results or observations, such as the use of metabolite profiling in studying the effect of toxins and toxicology screening using cells were claimed without any experimental evidences (US patent#7,910,301). The described experimental observations on metabolite changes in ova-specific Tcells treated with stimulatory peptide antigen and antigen presenting cells could be possibly indirect evidence, which could be an assumption without considering some critical factors, such as cell types and cytotoxicity, optimal and minimal treatment dosage, compound structure and affinity etc, associated with developing an efficient and robust toxicity screening method using metabolite profiling. Most interestingly, experiments described in this patent (US patent#7,910,301) are almost identical to the experiments described in the patent related to the application of metabolite profiling for the diagnosis of diseases (US patent#7,550,258), even though these two patents had entirely different claimed inventions. The scientific merits of patent claims based on the observed results and the interpretation of data derived from these experiments need to be evaluated. Presumably, real experimental data supporting an invention might not be required for securing patents. If claimed inventions are proposed without adequate scientific research driven supporting evidences and reasonable interpretation of experimental results, as oppose to peer reviewed scientific publications, these patents may not have any scientific value or may not be scientifically acceptable. It is also true that assumptions or hypothesis can be generated from well-established scientific principles and observations; however, it wont be scientifically legitimate until and unless an assumption or hypothesis proven to be correct using reasonable and systematic experimental demonstration. In contrast, if scientific patent claims are merely based on assumptions, these claims can be scientifically mistaken and these patents may not only preclude innovation in biomarker discovery but also hinder the development of low-cost patient care diagnostics products. Unfortunately, current trends in biomarker patents neither facilitate scientific inventions nor commercial potential of biomarkers, rather these patents inversely affect advancement of innovative biomarker research that can deliver promising diagnostics products. Indeed, most of the biomarkers patents may not have commercial prospective, though patents are intend to protect the right to manufacture and sell invented products, due to the fact that these biomarkers were identified and characterized without following solid scientific principles and demonstrating clinical applications, which are indispensable for developing commercially viable products. This could be the reason why there are only very few clinical diagnostics products in the market, although thousands of biomarkers have been patented. Note: This scientific blog is a contribution from Sciclips Consultancy team.

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References References are hyperlinked to respective abstracts or full articles. Please click the reference numbers to the citation details Related blogs on biomarkers: Strategies for Rational and Personalized Cancer Biomarker Discovery Cancer Theranostics Potential Applications of Cancer Biomarker Database How to Identify Clinically Successful Biomarkers? Potential Use of Drug Response-Efficacy Biomarkers for Predicting Life-Threatening Disease Causing Side Effects of Therapeutic Drugs Related tools: Comprehensive cancer biomarker database with companion diagnostics pathway Bioprotocols database Disclaimer: This blog, by any means, should not be considered as legal analysis of Metabolon Inc., v. Stemina Biomarker Discovery Inc. case. In this blog, we analyzed the potential scientific limitations and pitfalls of biomarker patents, primarily based on the information extracted from abstracts or full articles of scientific publications, without considering legal aspects of patents or patent laws whatsoever.

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