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Posts Tagged ‘Personalized medicine

The impact of gene patents on fostering innovation is a highly debated topic. Several compelling arguments have been put forward to support the notion that gene patents will promote innovation and banning gene patents will hamper current and future investments that may affect the development of future patient care products ((1). Further, the long-term effects of gene patents in innovation and research have been considered as myths (2). On the contrary, we believe granting patent rights to any naturally occurring biomolecules, such as genes, proteins or metabolites or nucleic acids (like miRNA), that are relevant to biomedical applications may hamper future innovations in developing cost-effective patient care products and services.

Gene patents are discoveries, not inventions – patenting discoveries may hamper scientific innovations

It is a well known fact that genes, proteins and other biomolecules present in humans or any other living organisms are naturally occurring and cannot be patented. The question is, whether naturally occurring genes or recombinant genes isolated from natural environment can be considered as a patentable invention? Several scientific aspects, excluding legal interpretations that will not be discussed in this blog, need to be considered to answer this question. The foremost argument is isolation and functional characterization of a gene is a discovery, it is not an invention. If discoveries are considered as patentable inventions, not only scientific discoveries are at stake but also it will hamper scientific knowledge based innovations that may lead to the development of innovative and low-cost patient care products, which are certainly required for reducing health care costs. Moreover, discovery based patents are vulnerable to costly legal battles that will slow down R&D innovations and deeply destroy entrepreneurial initiatives by start-ups, which are the core thriving force behind transforming scientific discoveries into patient care innovations.

Genes can be isolated and cloned using well-known technologies and such genes cannot be considered as inventions. However, a new method developed for isolating or cloning a gene may be considered as an invention. Likewise, identification of the function of a gene or a gene mutation associated with the incidence of a disease is a discovery, it cannot be considered as an invention. The obvious reason is the function of an isolated gene or the association of gene mutation/s with a particular disease is a natural occurring phenomenon that was not invented by researchers, rather it was discovered using known or inventive methods or technologies. Furthermore, isolating and cloning a natural gene in a vector or other formats do not mean that the inventor will automatically get all the rights on the use of a gene that is naturally present in humans or other living organisms. In other words, if a scientist has used inventive methods to isolate or clone a naturally occurring gene, the patent privileges should be limited to the process or the recombinant product, not extended to naturally occurring gene that is not patentable. Likewise, discovery of a compound present in a plant species is not an invention, however, development of a novel process for isolating this compound or a method of using this isolated compound for treating human or animal diseases can be an invention since it is not a naturally known phenomenon. Often, such examples have been cited to justify the validity of gene patents.

It is also important to note that isolated genes are of no use unless the clinical or diagnostic or therapeutic associations or roles of these genes have been discovered. The association of genes, gene mutations and biomarkers with diseases can be dependent on several factors such as ethnicity, geographical location, environmental factors, food habits etc. Granting patent rights to an inventor who has discovered a disease specific mutation in a gene for all possible known and undiscovered mutations in that gene cannot be scientifically justified. Such practices may result in hampering future discoveries since incentives from these discoveries are automatically transferred to a third party through their broad patent claims. Gene patents should not be granted for claims with broader applications without scientifically validated experimental evidences, which are very critical for any scientific inventions. Besides, patents do not follow basic scientific principles and this offer ample opportunities for inventors to claim any hypothetical or impracticable applications of patented genes, without even considering the scientific merits of their discoveries or inventions. Consequently, this may lead to unrealistic patent claims on clinical and commercial potentials of scientific discoveries that may not have any direct impact on improving patient care. If we continue with the practice of patenting discoveries, it will not only delay or prevent genuine applications of basic scientific discoveries but also challenge the fundamental ethical principles and values of scientific research.

genepatents

Fig.1: Possible impact of patentable and non-patentable discoveries in patient care innovations

Gene patents may hamper innovations in drug discovery and clinical diagnostics

Over expression or down regulation of genes can be associated with diseases and these genes can be used as therapeutic drug targets for the prevention or treatment of diseases. Likewise, over expression or down regulation of genes can be used as biomarkers for the diagnosis of diseases. Association of genes with a disease is a natural phenomenon and identification of such association is a discovery rather than an invention. The real use of disease specific genes will be the discovery of new drugs targeting genes or gene products that may lead to the development of novel drugs or new treatment methods. If a disease specific gene patent has a claim like “diseases can be treated by inhibiting the gene or gene products using drugs molecules such as, but not limited to, small molecules, proteins, oligonucleotides, antisense nucleic acids, miRNAs, antibodies, aptamers, peptides”, that could lead to a real problem. Such claims may block or decelerate promising research and development (R&D) activities related to a patented gene and destroy creativity in entrepreneurial scientist cum innovators, who could transform current limitations in clinical patient care into high potential enterprises that deliver innovative patient care products through creating large number of innovation driven jobs. In gene patents, genes and gene sequences as well as further downstream applications of genes can be patented without providing any supporting scientific experimental evidences. This is one of the most scientifically disputable aspects of gene patents, which may contain dubious and impracticable claims on the utility of genes. Gene patents can also slow-down or cripple innovations in promising next generation patient care strategies such as personalized medicine. Therefore, gene patents can be a real road block to innovations in drug discovery research, which may have long-term positive impact on inventing new therapeutic drugs or treatment methods, faster bench to clinics timeline, reducing mortality and morbidity from diseases, reducing health care costs and creating high growth entrepreneurial startups (Fig.1).

In clinical diagnostics arena, gene or similar biomarker patents may have different consequences. Identification of genes or biomolecules associated with diseases is only a primary step towards the development of clinical diagnostics assays. The most critical aspect is to develop and optimize highly sensitive, robust, reliable and cost-effective assays or methods for the detection of specific genes or biomolecules in patients for the accurate diagnosis of diseases. Undoubtedly, innovations are essential for the development of reliable and robust diagnostics assays, which are very critical for developing efficient clinical diagnostics products. Disease specific genes or biomarkers offer incredible opportunities for innovations through the development of 1) new diagnostic or companion diagnostic tools and methods, 2) methods for the prevention of diseases though early detection methods (diagnostic imaging, nanoparticle based diagnosis etc.), 3) new biomedical and analytical devices and instruments, 4) diagnostic assays to identify patient’s response to a particular drug, 5) methods for optimizing personalized drug treatment regimen (drug dose, drug treatment schedule etc), 6) methods for monitoring the efficacy of treatment (disease stage, tumor progression, tumor recurrence etc), 7) methods for predicting life-threatening side effects of therapeutic drugs and 8) novel theranostics (diagnostics therapy) approaches. The above-mentioned patentable high-value innovations can attract investments that can create sustainable entrepreneurial establishments and scientific jobs, which may be significantly higher that gene patents alone can offer. Conversely, granting patent rights to naturally occurring genes or biomarkers may obstruct health care related technological, scientific and clinical innovations that are very critical for developing life-saving patient care products.

Recombinant genes may not have any direct clinical or commercial value in patient care

Genes can be isolated and cloned using standard recombinant DNA methods, and these recombinant gene and gene products (proteins) can be used for studying structure-function analysis, which can be utilized for identifying drugs and developing diagnostic assays using known or inventive methods. The cloned gene may be considered as non-natural and may be patentable. However, recombinant genes may not have any direct clinical or commercial value whatsoever in patient care (exceptions are gene based innovations such as use of recombinant gene in gene therapy or recombinant gene based vaccines and biopharmaceuticals or cell therapy using cells expressing recombinant gene or similar specialized therapeutic/diagnostics technologies). The reasons are 1) any drugs that are invented will be targeted towards the natural gene present in humans, not the cloned gene, and 2) disease specific mutation/s in cloned gene has no value in diagnosing a disease, instead diagnosis must be performed through the detection of specific mutation/s in patients or patient derived samples using known or inventive methods. Granting patent rights to all possible use and applications of natural genes or gene variants based on the fact that recombinant gene is non-natural is not scientifically and ethically justifiable.

The general conception that banning gene patents will prevent innovations or investments may not be true, rather it will encourage innovations in critical areas where clinical health care inventions are required. These inventions may lead to the development of innovative cost-effective therapeutic drugs and clinical diagnostic tools that will reduce patient care costs. Granting patent rights to naturally occurring biomolecules such as genes, proteins or metabolites may hold back these innovations. It is unfortunate that if gene patents are treated as an easy source of return of investment (ROI) with less effort, without even taking into consideration the scientific, social and moral responsibilities of discoveries, which are more often publicly funded. It may be true that isolated genes may be unknown to us earlier; therefore, can it be considered as an invention? The answer will be no, because genes were already been present in humans and we could not isolate these genes due to the lack of suitable methods or technologies. Evidently, scientific and technological innovations in molecular cloning, sequencing, PCR, bioinformatics, biochemical methods etc., have created innovative ways to identify genes and assign functions, without these inventions genes would have been a still unknown factor. Thus, gene patents are not true inventions; rather these are discoveries made possible through other technological and scientific inventions. Most importantly, unprecedented innovations are warranted to establish the usefulness of genes for the invention of novel therapeutic drugs and clinical diagnostic assays that may provide clinical and economical benefits to patients. Unfortunately, gene patents and the complex legal interpretations of simple scientific principles surrounding gene patents may slow down or hamper future innovations in patient care, specifically the development of cost-effective novel diagnostic and therapeutic products that enable physicians to provide best possible care for their patients. Moreover, gene patents may lead to innovation bottlenecks that favor fewer inventions, restricted entrepreneurial initiatives, limited job growth, and non-competitive monopoly (Fig. 1).

Link to the original blog: Sciclips Blog .

Note: This scientific blog is a contribution from Sciclips Consultancy team.

References
References are hyperlinked to respective abstracts or full articles. Please click the reference numbers to the citation details

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This scientific blog critically analyzes potential complexities associated with current biomarker discovery approaches. According to the scientific arguments that have been put forward in this blog, thousands of biomarkers that are currently being reported may not be true biomarkers of the target disease, rather it may be a complex mixture of biomarkers, which may include target disease specific biomarker as well as biomarkers or biomolecules associated with other diseases, infections, gender, race/ethnic backgrounds, geographic-environmental factors, psychiatric condition/diseases and nutritional factors. Based on our analysis, we believe that an ideal biomarker discovery platform, which can lead to the development of reliable and robust diagnostics assays, should be developed by integrating comprehensive understanding of patients’ phenotypic, genetic and socio-environmental characteristics along with biological and functional relevance of all biomolecules that may be potentially identified and called as biomarkers. Several innovative strategies for developing rational and personalized biomarker discovery platforms have been suggested in this blog. These strategies include 1) Comprehensive genome-scale analysis based rational genetic biomarker discovery 2) Cell or tissue or organ specific function based rational or targeted biomarker discovery 3) Use of validated tissue/organ specific biomarkers or therapeutic drug targets for identifying non-invasive biomarkers, 4) Epidemiology-driven biomarker discovery for developing personalized diagnostic tools and 5) Integrated bioinformatics approaches for rational biomarker discovery. The relevance of disease prevalence and predictive value in biomarker discovery for personalized medicine, utility of rational or personalized biomarkers in clinical trials and applications of rationally identified biomarkers for diagnostics imaging or theranostics have also been discussed. Read the full blog (click on this title): Strategies for Rational and Personalized Cancer Biomarker Discovery

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Availability of a comprehensive cancer biomarker database may opens up scientific and technical opportunities in developing innovative oncologic theranostics (Rx/Dx), a diagnostic therapy process that leads to the development of successful personalized medicine strategies in cancer treatment.

With the growing trend towards the advancement of personalized medicine concept, there is a need to develop strategies and tools that can be used for individualized diagnosis and treatment. Theranostics based tools, a combination of diagnostics and therapeutics approach, offer promising agents that can be used for the improved diagnosis and treatment of various diseases. In oncologic theranostics, developing innovative personalized cancer treatment rely on the identification of novel cancer biomarkers and diagnostic assays to identify patient’s response to a particular drug, for optimizing personalized drug treatment regimen (drug dose, drug treatment schedule etc) and for monitoring the efficacy of treatment (disease stage, tumor progression, tumor recurrence etc). A best example for this will be the approval of Genentech’s Herceptin® with DakoCytomation’s HercepTest® for breast cancer theranostics. Future development of cancer theranostic tools depends on the discovery and validation of existing or novel cancer biomarkers. A database that contains comprehensive information on discovery phase or clinically validated biomarkers, along with therapeutic drug target information, can be a powerful tool in developing novel theranostic assays as well as for the discovery of new drug targets based on theranostics (Fig.1). A combination of therapeutic drug target and biomarker pathway analysis, in particular companion diagnostics pathways, can pave the path towards developing innovative strategies in cancer theranostics.

Fig. 1: Theranostics and cancer biomarker database in personalized medicine


Biomarkers that have potential applications in cancer theranostics can be broadly classified into:

1. Imaging biomarkers: Drug molecules labeled with imaging tags (e.g. NRI, MRI etc.) and antigen-directed imaging drugs (e.g. radiolabeled antibody drugs) are the very good examples. In this case, a single molecule can be used as a diagnostic and therapeutic agent, EGFR, VEGF and TAG-72 are very good examples where antibodies against these drug targets tagged with imaging markers can be used in theranostics. Imaging biomarkers can also be very useful in targeted surgical treatment of cancer. Labeled antibody based detection of phosphorylated or dephosphorylated will be an attractive theranostics tool in phosphorylation-dependent targeted cancer therapy and diagnosis. Epigenetic biomarkers are another attractive target for developing cancer theranostics. Applications of additional tools such as nanoparticles and gold particles have been demonstrated in theranostics.

2. Diagnostic/prognostic protein biomarkers: Immunohisotchemistry and immunoassays (e.g. ELISA) can be used in theranostic applications. Identification of diagnostic biomarkers that can be used as therapeutic drug targets will have significant impact in theranostics. Development of protein biomarker-directed antibodies (labeled) or small molecules or aptamers can be a potential theranostics tool.

3. Molecular diagnostic markers (genes/SNPs/miRNA/epigenetic): PCR, qPCR, DNA sequencing (including next generation sequencing), and microarray based technologies can be used as theranostics tools. Single step diagnostic therapy, like labeled antibody drug based theraostics, may be a challenging task with molecular diagnostic biomarkers, possible exceptions are siRNA or miRNA based cancer therapies.

4. Cell based biomarkers: Cancer stem cells, circulating tumor cells (CTCs) and tumor-infiltrating immune cells (CD68-positive macrophages/T-cells etc.) can be used in cancer theranostics. The diagnostic and therapeutic significance of these cell based biomarkers have been demonstrated in several published studies.

5. Drug efficacy/response/predictive biomarkers: Biomarkers include proteins, gene, miRNA, SNPs, metabolites etc., which can be successfully used for the development of companion diagnostic assays. These biomarkers can also become a therapeutic drug target for further discovery of theranostics based therapeutic drug targets.

6. Combination therapy response biomarkers: Combination therapy approaches have been demonstrated as an efficient treatment method for various cancers. However, the availability of companion therapy response biomarkers are limited (some of these biomarkers are included in our cancer biomarker database). Wide adoption of combination therapy as a method for cancer treatment may warrants a need for the discovery and validation of new biomarkers associated with combination therapy.

Identification of new biomarkers and availability of large number biomarkers may result in the development of theranostics for most of the cancer types. A cancer biomarker database that contains comprehensive and cumulative information on experimental and clinically validated biomarkers, especially companion diagnostic biomarkers and therapeutically relevant biomarkers, may opens up scientific and technical opportunities in developing innovative oncologic theranostics (Rx/Dx) tools.

Sciclips cancer biomarker database contains more than 8700 cancer biomarkers, which are classified into 1) diagnostic biomarkers 2) disease predictive/risk assessment biomarkers 3) drug efficacy/response biomarkers 4) prognostic biomarkers and 5) cancer companion diagnostics biomarker pathway. The biological and molecular functions, biological process associated, chromosomal location, SNPs and protein-protein interaction networks of each biomarker are listed in this database. This comprehensive information will be useful for the validation of existing biomarkers and for the identification and validation of new biomarkers for cancer theranostics. Please follow the link to see the details of cancer biomarker database: http://www.sciclips.com/sciclips/diagnostic-prognostic-cancer-biomarker-main.do

Related tools:

1. Biomarker protocols
2. Bioprotocols
3. Biomarker News
4. LinkedIn® Theranostics group

Related blogs:

1. Strategies for Rational and Personalized Cancer Biomarker Discovery

2. Cell based reporter assays: misleading approach in drug discovery?
3. Are stem cells ready as a next generation drug discovery tool?
4. Cell Based Reporter Assays vs. Animal Studies in Drug Discovery- Potential Limitations, Risks and Liabilities

In this new era of personalized medicine, there is a growing trend for custom synthesis of drugs for each and every patient depending on his/her genetic profile and biomarker discovery has come to the forefront of drug discovery research. The rapid growth of biomarker discovery will empower researcher to understand the spectrum of various diseases with applications in analytic epidemiology, clinical trials and disease prevention, diagnosis, and disease management. Biomarkers will be used as tools for target discovery, noninvasive early stage diagnosis of diseases, for evaluation of mode of action of a drug, dose determination and prediction of the drug effect. It will accelerate not only development of non-toxic and effective drugs but also help in monitoring patient health and response towards drug treatments.

With the growing trend of personalized healthcare concept and advancement in biomarker research, there is a need for a biomarker database. Sciclips has launched a unique biomarker database that has listed more than 29,000 biomarkers (for more than 1800 human diseases), extracted from U.S. patent, world intellectual property organization (WO) patent cooperation treaty (PCT) publications, and PubMed abstracts.

The database contains a diverse array of biomarkers, including:

• Protein/peptide/antibody biomarkers (7279 unique biomarkers)
• Metabolomic biomarkers (811 unique biomarkers)
• MicroRNA (miRNA) biomarkers (935 unique biomarkers)
• Cell-based biomarkers (27 unique biomarkers)
• Genotoxic/carcinogenic biomarkers (47 unique biomarkers)
• Disease risk assessment and predictive biomarkers (10,375 unique biomarkers)
• Epigenetic biomarkers based mainly on DNA methylation changes and histone modifications (700 unique biomarkers)
• Molecular diagnostic biomarkers, including gene/gene expression biomarkers, polymporphisms/SNP biomarkers (including linkage disequilibrium biomarkers) (7206 unique biomarkers)
• Drug efficacy/response biomarkers (7708 unique biomarkers), which are for monitoring the efficacy of the therapy, response of a biomarker for a drug treatment or determining the severity or monitoring the progression of a disease

Each biomarker is linked to various databases, such as PubMed (articles), Google Scholar (articles), GeneBank (nucleotide sequences), UniProt (protein sequences), USPTO (full text patents/patent applications), WO(PCT) (full text international patent applications) and Google patents (full text U.S. patents).

Sciclips has been a pioneer in developing databases in the field of drug targets from patent publications. All biomarkers listed in our database are cited and linked to respective patent publications. More than 80% of the information in patents and patent applications are not published in journals or elsewhere. Patent publications and data are more open access than journal articles, which often require subscription to see the full text. Unlike journal articles, the representation of scientific information in patents is very complex and specialized skills are needed to extract this information. For these reasons, researchers often do not refer to patent publications. Therefore, the availability of a biomarker database to provide early access to biomarker information from patent publications will have significant impact on on-going and future biomarker research. We believe our database will foster innovation in biomarker discovery by aiding researchers to find integrated scientific information.

Please follow this link to access our database:
http://www.sciclips.com/sciclips/diagnostic-biomarker-prognostic-biomarker-db.do

Related blog

1. Strategies for Rational and Personalized Cancer Biomarker Discovery


Comprehensive Cancer Bomarker Database

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