Articles de revues : « Genes – Patents »

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Dworkin, Gerald. « Should there be property rights in genes ? » Philosophical Transactions of the Royal Society of London. Series B : Biological Sciences 352, n^o 1357 (29 août 1997) : 1077–86. http://dx.doi.org/10.1098/rstb.1997.0088.

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This paper deals with the following questions. Are there property rights in the human body or its parts? What legal control is, or should be, available in respect of genetic material? Can, or should, patents be granted for genes or for products incorporating human genetic material? How extensive are patent rights over genetic material? Should ethical matters be a critical part of the patent granting process?

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Sampat, Bhaven, et Heidi L. Williams. « How Do Patents Affect Follow-On Innovation ? Evidence from the Human Genome ». American Economic Review 109, n^o 1 (1 janvier 2019) : 203–36. http://dx.doi.org/10.1257/aer.20151398.

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We investigate whether patents on human genes have affected follow-on scientific research and product development. Using administrative data on successful and unsuccessful patent applications submitted to the US Patent and Trademark Office, we link the exact gene sequences claimed in each application with data measuring follow-on scientific research and commercial investments. Using these data, we document novel evidence of selection into patenting: patented genes appear more valuable—prior to being patented— than non-patented genes. This evidence of selection motivates two quasi-experimental approaches, both of which suggest that on average gene patents have had no quantitatively important effect on follow-on innovation. (JEL I10, O31, O34)

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Aston, David J. « Genes, patents and insurance ». Nature 379, n^o 6567 (février 1996) : 672. http://dx.doi.org/10.1038/379672a0.

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Stevenson, Peter. « Genes, patents and insurance ». Nature 379, n^o 6567 (février 1996) : 672. http://dx.doi.org/10.1038/379672b0.

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Shaw, Giles. « Genes, patents and insurance ». Nature 379, n^o 6567 (février 1996) : 672. http://dx.doi.org/10.1038/379672c0.

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Cook-Deegan, Robert, et Subhashini Chandrasekharan. « Patents and Genome-Wide DNA Sequence Analysis : Is it Safe to Go into the Human Genome ? » Journal of Law, Medicine & ; Ethics 42, S1 (2014) : 42–50. http://dx.doi.org/10.1111/jlme.12161.

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Whether, and to what degree, do patents granted on human genes cast a shadow of uncertainty over genomics and its applications? Will owners of patents on individual genes or clusters of genes sue those performing whole-genome analyses on human samples for patent infringement? These are related questions that have haunted molecular diagnostics companies and services, coloring scientific, clinical, and business decisions. Can the profusion of whole-genome analysis methods proceed without fear of patent infringement liability?Whole-genome sequencing (WGS) is proceeding apace. Academic centers have been performing whole-genome and -exome sequencing (WES) in research for at least five years, and academic clinical laboratories with national reach have been doing sequencing for clinical applications for almost as long. Companies have also been offering WGS and WES as a clinical service for a few years now. So far as we know, no one has been sued for infringement of “gene patents” for performing WGS.

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Byrne, Noel. « Patents for plants and genes under the European Patent Convention ». Proceedings of the Royal Society of Edinburgh. Section B. Biological Sciences 99, n^o 3-4 (1992) : 141–52. http://dx.doi.org/10.1017/s026972700000556x.

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SynopsisThe cost of patenting an invention should be incurred only where the patent is likely to give the inventor an economic or a tactical advantage. Where it is practicable, secrecy may be preferable to patenting. If an advantage from patenting can be envisaged, then in Western Europe the inventor can apply either for a European patent under the European Patent Convention or for a national patent. The inventor in plant biotechnology faces a ban on patenting certain inventions, including plant varieties and essentially biological processes for the production of plants. But since this ban is interpreted strictly, there are opportunities for patenting what at first glance might seem not patentable. A patent application must give a written description of the invention that is complete enough for a skilled person to reproduce it. The inventor may be required to supplement the description in a patent specification for a biotechnological invention, by depositing a sample of relevant biological materials. A European patent is treated as a national patent in the country for which it was granted. Since a patent may be invalidated in enforcement proceedings, patenting may turn out to have been a costly mistake.

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Eisenberg, R. « Genes, patents, and product development ». Science 257, n^o 5072 (14 août 1992) : 903–8. http://dx.doi.org/10.1126/science.1502556.

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Moore, James N. « Plant Patenting : A Public Fruit Breeder's Assessment ». HortTechnology 3, n^o 3 (juillet 1993) : 262–66. http://dx.doi.org/10.21273/horttech.3.3.262.

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The strategy of plant patenting as a means to generate research funds is gaining increasing interest in fruit breeding programs in public institutions. Patenting can be a positive force in maintaining fruit breeding programs if applied to superior cultivars and supported by well-designed licensing and distribution procedures. To qualify for a plant patent, a cultivar must be distinct, new, and asexually propagated, and cannot be in public use or on sale more than 1 year prior to the application for patent. Plant patents provide protection only for the whole plant as described. In contrast, utility patents can be obtained to provide proprietary rights to individual plant genes, plant characteristics, and plant products. The possible impact of utility patents on future fruit breeding programs is discussed.

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Paulus, Aneel, Mayank Sharma, Shumail M. Paulus, Richa Menghani, Elisa M. Rodriguez, Ryan D. Frank, George Cooper et al. « Genomic Variability in Multiple Myeloma (MM) Patients By Race : An Analysis of the Publically Available Mmrf Commpass Study Database ». Blood 128, n^o 22 (2 décembre 2016) : 4432. http://dx.doi.org/10.1182/blood.v128.22.4432.4432.

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Abstract Background: Outcomes in multiple myeloma (MM) have improved significantly over the years but disparities in outcomes exist among MM patients (pts) belonging to different racial subgroups. Previous studies have explored healthcare access and utilization disparities for pts of different races as potential causes, but genomic differences, which could alter disease biology and clinical behavior, have not been studied. We utilized the MMRF CoMMpass database, which prospectively captures clinical and molecular characteristics of MM patients to explore race-based differences at the genomic level. Methods: The publically available CoMMpass trial database (data release version IA8) was utilized. Pts with race category of White (total n=698) and non-White (total n=223, comprising 129 Blacks, 19 Asians and 45 others) were analyzed for genomics including cytogenetics (fluorescent in situ hybridization; FISH), tumor diploidy (conventional karyotyping), gene expression profiling (GEP), gene copy number variations (CNV), gene single nucleotide variations (SNV) and genomic translocations analysis focused on genes from the FoundationOne Heme panel¨ (402 genes). GEP was considered significantly different between categories for more than or equal to a 2-fold change for a given gene (p<0.05). Categorical variables for FISH probes and diploidy status were compared by Chi-square or Fischer exact test, wherever applicable. Results: GEP clustering analysis uncovered 67 genes differentially expressed between Whites vs. non-Whites (Fig 1A). Baseline cytogenetics aberrations between both race cohorts showed statistically insignificant differences. Multiple cytogenetic abnormalities were seen most commonly in both race groups (~31%) with the distribution of others (in descending order) as such: Del13 > No abnormalities > t(11;14) > 1q amplification > Del17p or p53 > t(4;14) > Del1p > t(14;16) > t(14;20). Aneuploidy status showed insignificant differences between race groups with ~34% of patients from both groups having no aneuploidy. SNV data was present for 90% of Whites and 57% of non-Whites. Overall, 84% of genes had>1 SNV (84%), 2% translocations only and 14% had neither SNVs or translocations. SNVs were classified as Non-specific Non-Synonymous coding (NNSCs), Splice-site (SS) or Tier 1 (T1, codon deletion, insertion, frame-shift, etc.). A total of 880 NNSCs SNVs were observed: 670 in Whites across 227 genes, 210 in non-Whites across 120 genes. In whites, 57% of NNSC SNVs consisted of transition-type mutations and 43% as transversions. In non-Whites, transition mutations comprised 64% of all NNSC SNVs and transversions in the remaining 36%. A total of 38 SS SNVs were observed, 30 in Whites and 8 in non-Whites observed in 25 and 6 genes, respectively. In Whites, 57% of SS SNVs were transition type and remaining 43% were transversion. In non-Whites, an equal % of SS transition and transversion mutations were noted. A total of 240 T1 SNVs were noted; 182 in Whites seen in 82 genes; 58 in non-Whites seen 6 genes. In both Whites and non-Whites, frameshifts (41% in Whites, 47% in non-Whites) and stop-gained (46% in Whites, 45% in non-Whites) SNVs were most common. A total of 17 genes with>10 distinct SNVs were identified in Whites; 5 genes in non-Whites and 4 genes commonly seen in both cohorts (Fig 1B). In Whites, 17 genes were found to have translocations (intrachromosomal TRAF3 and PIK3R2 most common); in non-Whites, 5 genes had translocations (intrachromosomal CIC and EMSY most common). CNV analysis demonstrated 21 genes that were significantly altered with either copy number gain or loss between Whites vs. non-Whites (Fig 1C). Conclusions: We present the first race-based comprehensive genomic analysis utilizing the public interface of the CoMMpass trial. We discovered genomic differences between Whites and non-Whites at several levels including GEP, SNV and CNV, but not at the level of cytogenetics, which are in fact the most commonly performed clinical genomic analysis. Correlation of these variations with MM pt outcomes would be invaluable in understanding disease biology and hopefully mitigating some of the outcome disparities by pt race. As the database grows and becomes more enriched, separate analyses for Blacks, Asians and Hispanics would be attempted. Acknowledgments: We would like to thank the MMRF, Ms. Mary Derome and Dr. Jonathan Keats for providing scientific overview and technical support. Disclosures Fonseca: Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy; BMS: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Bayer: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Sanofi: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms. Ailawadhi:Takeda Oncology: Consultancy; Amgen Inc: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy.

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De Martino, Marco, Alfredo Fusco et Francesco Esposito. « HMGA and Cancer : A Review on Patent Literatures ». Recent Patents on Anti-Cancer Drug Discovery 14, n^o 3 (21 novembre 2019) : 258–67. http://dx.doi.org/10.2174/1574892814666190919152001.

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Background: The high mobility group A proteins modulate the transcription of numerous genes by interacting with transcription factors and/or altering the structure of chromatin. These proteins are involved in both benign and malignant neoplasias as a result of several pathways. A large amount of benign human mesenchymal tumors has rearrangements of HMGA genes. On the contrary, malignant tumors show unarranged HMGA overexpression that is frequently and causally related to neoplastic cell transformation. Here, we review the function of the HMGA proteins in human neoplastic disorders, the pathways by which they contribute to carcinogenesis and the new patents focused on targeting HMGA proteins. Objective: Current review was conducted to check the involvement of HMGA as a druggable target in cancer treatment. Methods: We reviewed the most recent patents focused on targeting HMGA in cancer treatment analyzing patent literature published during the last years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. Results: HMGA proteins are intriguing targets for cancer therapy and are objects of different patents based on the use of DNA aptamers, inhibitors, oncolytic viruses, antisense molecules able to block their oncogenic functions. Conclusion: Powerful strategies able to selectively interfere with HMGA expression and function could represent a helpful approach in the development of new anti-cancer therapies.

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Crespi, R. Stephen. « Patents on genes : clarifying the issues ». Nature Biotechnology 18, n^o 6 (juin 2000) : 683–84. http://dx.doi.org/10.1038/76548.

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Scott, David W., George W. Wright, Mickey Williams, Jason Lih, Elaine S. Jaffe, Andreas Rosenwald, Elias Campo et al. « Accurate Diagnosis of Aggressive B Cell Non-Hodgkin Lymphomas Using Gene Expression Profiling of Formalin-Fixed, Paraffin-Embedded Tissues ». Blood 124, n^o 21 (6 décembre 2014) : 3016. http://dx.doi.org/10.1182/blood.v124.21.3016.3016.

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Abstract Background: Currently, diagnosis of aggressive B cell non-Hodgkin lymphomas (agg-B-NHL) uses a varying combination of morphology, immunophenotyping, cytogenetics, and/or other molecular techniques resulting in a fragmented, confusing diagnostic system. We sought to develop a multi-analyte gene expression signature assay that could consolidate the diagnostic process into a single platform to improve standardization and accuracy. Methods: We used formalin-fixed, paraffin-embedded tissue biopsies, qualified by an expert Hematopathology review panel, tumor content of ≥60%, and confirmed B cell immunophenotype. Diagnostic categories included diffuse large B cell lymphoma (DLBCL) including the activated B cell-like (ABC), germinal center B cell-like (GCB) subtypes, unclassifiable (UNC) DLBCL, primary mediastinal B cell lymphoma (PMBCL), Burkitt lymphoma (BL), and mantle cell lymphoma (MCL). Using our previous GEP data, diagnostic signatures, nCounter system (Nanostring, Seattle, WA), and employing published procedures (Scott et al, Blood 2014); we designed probes to 800 genes with utility in distinguishing between these pathological entities. The training cohort comprised 107 unique cases, whose FFPET biopsies were independently assayed at the Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research (Frederick, MD) and the Centre for Lymphoid Cancer, BC Cancer Agency (Vancouver, BC). The resulting algorithm was locked down and applied to an independent cohort of 199 cases. The nucleic acids from FFPET biopsies from these cases were extracted and run across the two independent laboratories with 83 cases run at both laboratories to assess inter-laboratory performance. The gold standard by which the Nanostring classification was compared was based on Affymetrix gene expression profiling of matched frozen biopsies in the cases of ABC, GCB, and UNC DLBCL (Lenz et al. NEJM 2008) and on the pathological diagnosis by the Hematopathology review panel in the cases of BL, MCL, and PMBCL. The use of human tissues and clinical data for this study was approved by the University of Arizona Institutional Review Board in accordance with the Declaration of Helsinki. Results: The final locked algorithm consisted of 297 gene probes including 47 housekeeping genes. Thirty-six cases from the training cohort were run again on the new lot of Nanostring code set to allow for cross code set calibration of the assay. The laboratory procedure and algorithm, together termed the "Lymph5Cx" test, consists of a hierarchical series of pair-wise comparisons. In the independent validation set, 257/282 assays (91.1%) yielded gene expression data of sufficient quality (total of 185 of the 199 cases). A classification summary is given in the Table below. In this cohort, 136 cases (82%) were correctly assigned while 11 cases (6.6%) were assigned incorrect diagnoses as follows: 6 BL assigned to GCB, 1 GCB labeled a PMBCL, and 4 PMBCL assigned to DLBCL subtypes. The Lymph5Cx test included categories of indeterminate results between two diagnostic entities and were declared borderline, as indicated in the Table. The agreement between the 2 laboratory sites was 71/72 (99%) of cases that yielded adequate gene expression data at both sites. Conclusions: The Lymph5Cx test was robust and able to discriminate the often clinically difficult diagnostic categories of agg-B-NHL using a single methodology for cases with histologic and immunophenotypic features of an agg-B-NHL. Misclassification errors were low, suggesting that this test would be useful adjunct to current diagnostic methods. In addition, targetable pathways, as well as genes associated with known prognostic signatures in DLBCL (stromal) and MCL (proliferation) were quantified. Investigation into these latter aspects is on-going. Gene expression signature assays have become a useful clinical and research tool in the on-going area of precision therapeutics based on highly-defined molecular entities. Table # cases % accurate % borderline % error ABC 26 76.9% 23.1% 0.0% GCB 27 88.9% 7.4% 3.7% BL 48 68.8% 19.8% 11.5% PMBL 30 80.0% 6.7% 13.3% MCL 34 100.0% 0.0% 0.0% Disclosures Scott: Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Wright:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Williams:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Lih:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Jaffe:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Rosenwald:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Campo:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Chan:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Connors:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Smeland:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Braziel:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Ott:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Delabie:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Weisenburger:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Cook:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Greiner:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Fu:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Walsh:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Gascoyne:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Staudt:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Rimsza:Nanostring: Research Funding, The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties.

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Braggio, Esteban, Victoria X. Wang, Santiago Garcia, Laura Ann Bruins, Connie Lesnick, Jacqueline C. Barrientos, Susan M. O'Brien et al. « Novel Associations Between Mutations, Prognostic and Clinical Parameters in Untreated Progressive CLL : Data from E1912, a Randomized Phase III Study of the ECOG-ACRIN Cancer Research Group ». Blood 128, n^o 22 (2 décembre 2016) : 4373. http://dx.doi.org/10.1182/blood.v128.22.4373.4373.

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Abstract Sequencing studies have significantly improved our understanding of the CLL genetic landscape and allowed the identification of the first associations between specific mutations and clinical outcome. Hence, mutations in TP53, NOTCH1, SF3B1, BIRC3 and MYD88 are known to be associated with differential prognosis and have been incorporated in CLL risk stratification models. Despite the work performed on these 5 genes, several additional putative tumor-driver genes are recurrently mutated in CLL, but their clinical impact remains unclear. In order to gain further understanding, we performed targeted sequencing in baseline samples of 308 CLL patients (pts) participating in the North American Intergroup study (NAIG) designated as E1912 and led by ECOG. This trial is a randomized Phase III of Ibrutinib (Ibr) and Rituximab (R) vs FCR in previously untreated CLL. Besides the 5 genes aforementioned, we screened another 19 genes recurrently mutated in CLL, and 2 genes (BTK and PLCy2) recently associated with Ibr resistance. The CD5+/CD19+ B lymphocyte population of these pts was flow-sorted. All coding regions were amplified using customized oligos. Libraries were templated and enriched using IonOneTouch2 and IonOneTouch ES systems, respectively. Samples were run on an IonTorrent sequencer using 318TM chips. Variants were called using IonTorrent Somatic VariantCaller. VCF files were annotated using BioR, which provides annotation from NCBI/Ensembl, UCSC, dbSNP, HapMap, 1000Genomes, COSMIC, SIFT, and PolyPhen-2. Somatic variants with a Mapping Quality <20 or read depth <5X were removed. Variants of interest were inspected using Integrative Genomics Viewer. The mutational status of genes and pathways was analyzed for association with chromosomal abnormalities detected by FISH, expression of CD38, CD49d and ZAP70, Rai stage, age and gender. We were not able to evaluate associations to clinical responses for the different arms as this trial is still underway and remains blinded for clinical outcome. We found 511 SNVs (442 missense, 45 nonsense and 24 splice sites) and 115 indels. An average coverage of 770X depth was obtained, allowing the detection of minor subclonal mutations (<10% of reads) in almost 35% (218/626 mutations). Overall, 215 pts (70%) carried at least one mutated gene, 102 (33%) carried 2 or more and 32 (10%) 3 or more mutated genes. The most commonly mutated gene was SF3B1 (22%), followed by NOTCH1 (19%), ATM (12%), XPO1 (11%), BIRC3 (9%), KRAS (7%), BRAF, DDX3X, EGR2, POT1 and TP53 (6% each). No BTK or PLCy2 mutations were found in progressive but untreated CLLs. In contrast to a recent report (Nature 2015;526:525-30), we found BRAF mutations located in the canonical hotspot p.V600E (25% of total mutations). Another 13% were located in amino acid K601 (p.K601E/N) and the remaining in the kinase domain (p.G469A, p.D594G, p.F595L, p.G596R, p.L597Q).Nearly 27% of cases with activating mutations in the RAS pathway (BRAF, KRAS, NRAS), showed >1 mutation affecting one or more genes of the pathway. Similar observations were found in mutational hotspots of BIRC3 (30% of mutated cases showed >1 mutation), MED12 (18%), SF3B1 (7%), XPO1 (6%), and NOTCH1 (5%), suggesting the existence of genetic subclones showing convergent evolution in a substantial number of CLL. We found multiple associations between mutations and known prognostic and clinical parameters. These included mutations in NOTCH1 associated with +12 (p=0.005), and expression of ZAP70 (p=0.01), CD38 (p=0.001) and CD49d (p=0.004). Mutant BIRC3 was associated with +12 (p<0.001) and CD38 expression (p=0.01). Mutations in RAS pathway, with +12 (<0.001), and expression of CD38 (p=0.002) and CD49d (p=0.05). ATM (p=0.007) and EGR2 (p=0.002) with -11q; POT1 with CD49d expression (p=0.01), and MYD88 with -13q (p=0.04) and lack of CD38 (p=0.01) and CD49d (p=0.01) expression. This study, performed on a large cohort of untreated but progressive CLLs, provides novel data about the mutation status of driver genes and their associations with clinical and prognostic parameters. Our data indicate that convergent evolution is a common event in CLL, affecting several driver genes. Furthermore, it reinforces that BTK and PLCy2 mutations are not found in Ibr-naive pts. Finally, this study provides the genetic groundwork for subsequent prospective comparative analyses of the clinical outcome for CLL cohorts treated with Ibr-R vs FCR in this phase 3 NAIG trial. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Fonseca:Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Novartis: Consultancy; Janssen: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; AMGEN: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Sanofi: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Bayer: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms. Shanafelt:Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Cephalon: Research Funding; Hospira: Research Funding.

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Foster, Laura A. « Patents, Biopolitics, and Feminisms : Locating Patent Law Struggles over Breast Cancer Genes and the Hoodia Plant ». International Journal of Cultural Property 19, n^o 3 (août 2012) : 371–400. http://dx.doi.org/10.1017/s0940739112000215.

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AbstractThis article suggests three critical inquiries for formulating a feminist analysis of patent law. The first questions how patent law functions as a strategy within neoliberal, biopolitics. The second examines how patent law is structured through biopolitical techniques of governance by examining two conceptions of the public domain I call open public domain and protective public domain. The third inquiry, drawing upon feminist science studies, asks how women's reproductive and intellectual labor are valued and devalued in various different ways through new patent law technologies. In addition, two recent patent law are struggles are examined. These include an American Civil Liberties Union case against the patenting of breast cancer gene sequences and Southern African San struggles against patents related to the Hoodia gordonii plant. In conclusion, I argue that patent law functions within gendered and ethno-racialized forms of neoliberal, biopolitics involving the patenting of women's reproductive and intellectual labor within new bioeconomics.

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TRIBBLE, JACK L. « Gene Patents—A Pharmaceutical Perspective ». Cambridge Quarterly of Healthcare Ethics 7, n^o 4 (octobre 1998) : 429–32. http://dx.doi.org/10.1017/s0963180198004150.

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The decade-long debate over ownership of living human materials has recently intensified with the ability of biomedical research to isolate, purify, and use human genes and gene products as therapeutics, factories for the production of therapeutics, and targets for the identification of therapeutic pharmaceuticals. Indeed, advances in genomic research have resulted in the identification of hundreds of thousands of DNA fragments and hundreds of genes. Many within the scientific and business communities believe genes and gene fragments have commercial value and have filed patent applications on the nucleic acid sequences. This commercialization has amplified the discussion surrounding the ethics of patenting genes and the ownership of the human genome.

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Derry, Jason, et Yijan Chang. « Recent Patents Relating to Tumor Suppressor Genes ». Recent Patents on DNA & ; Gene Sequences 1, n^o 1 (1 février 2007) : 35–41. http://dx.doi.org/10.2174/187221507779814407.

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Offit, Kenneth, Angela Bradbury, Courtney Storm, Jon F. Merz, Kevin E. Noonan et Rebecca Spence. « Gene Patents and Personalized Cancer Care : Impact of theMyriadCase on Clinical Oncology ». Journal of Clinical Oncology 31, n^o 21 (20 juillet 2013) : 2743–48. http://dx.doi.org/10.1200/jco.2013.49.7388.

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Genomic discoveries have transformed the practice of oncology and cancer prevention. Diagnostic and therapeutic advances based on cancer genomics developed during a time when it was possible to patent genes. A case before the Supreme Court, Association for Molecular Pathology v Myriad Genetics, Inc seeks to overturn patents on isolated genes. Although the outcomes are uncertain, it is suggested here that the Supreme Court decision will have few immediate effects on oncology practice or research but may have more significant long-term impact. The Federal Circuit court has already rejected Myriad's broad diagnostic methods claims, and this is not affected by the Supreme Court decision. Isolated DNA patents were already becoming obsolete on scientific grounds, in an era when human DNA sequence is public knowledge and because modern methods of next-generation sequencing need not involve isolated DNA. The Association for Molecular Pathology v Myriad Supreme Court decision will have limited impact on new drug development, as new drug patents usually involve cellular methods. A nuanced Supreme Court decision acknowledging the scientific distinction between synthetic cDNA and genomic DNA will further mitigate any adverse impact. A Supreme Court decision to include or exclude all types of DNA from patent eligibility could impact future incentives for genomic discovery as well as the future delivery of medical care. Whatever the outcome of this important case, it is important that judicial and legislative actions in this area maximize genomic discovery while also ensuring patients' access to personalized cancer care.

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BYRNE, N. « Patents for genes, other biological materials and animals ». Trends in Biotechnology 11, n^o 10 (octobre 1993) : 409–11. http://dx.doi.org/10.1016/0167-7799(93)90002-q.

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Marshall, E. « Supreme Court Rules Out Patents on 'Natural' Genes ». Science 340, n^o 6139 (20 juin 2013) : 1387–88. http://dx.doi.org/10.1126/science.340.6139.1387.

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Poland, Susan Cartier. « Genes, Patents, and Bioethics--Will History Repeat Itself ? » Kennedy Institute of Ethics Journal 10, n^o 3 (2000) : 265–81. http://dx.doi.org/10.1353/ken.2000.0022.

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Levenson, Deborah. « Department of justice opposes patents on isolated genes ». American Journal of Medical Genetics Part A 155, n^o 2 (26 janvier 2011) : fm vii—fm viii. http://dx.doi.org/10.1002/ajmg.a.33919.

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Noel Byrne, Dr. « Patents for human genes, ownership of biological materials and other issues in patent law ». World Patent Information 15, n^o 4 (décembre 1993) : 199–202. http://dx.doi.org/10.1016/0172-2190(93)90225-l.

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Ann, Christoph. « Patents on Human Gene Sequences in Germany : On Bad Lawmaking and Ways to Deal With It ». German Law Journal 7, n^o 3 (1 mars 2006) : 279–91. http://dx.doi.org/10.1017/s2071832200004661.

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Whether patents should be granted on human genes or gene sequences is highly controversial, both ethically and politically; not only in Germany but throughout Europe and in most parts of the world. Proof of this has been the attention created by US biotechnology company Myriad Genetics, which, in 2001, obtained European patents for human gene sequences indicating an increased risk of certain types of cancer. In Germany the Bundestag has recently addressed the issue: the core of a newly introduced provision of the German Patent Statute (PatG) is Paragraph 1a Sec. 4 PatG, which limits the scope of patent protection available for human gene sequences or parts thereof. If the subject of an invention is a human gene sequence, Paragraph 1a Sec. 4 PatG requires disclosure of not only the sequence but also at least one application. Without such disclosure a human gene sequence is not patentable under German Patent Law. This is remarkable, because under the Directive of the European Parliament and the Council on the Legal Protection of Biotechnological Inventions, the so-called Biotechnology Directive of 1998, a piece of European Union legislation, the situation is different.

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Hermawan, Adam, et Herwandhani Putri. « Data mining analysis of miR-638 and key genes interaction in cisplatin resistant triple-negative breast cancer ». Indonesian Journal of Biotechnology 24, n^o 2 (4 décembre 2019) : 65. http://dx.doi.org/10.22146/ijbiotech.48732.

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Cisplatn is one of the chemotherapy for the treatment of triple‐negatve breast cancer (TNBC), but its eﬀectveness is limited because of the phenomenon of chemoresistance. miR‐638 was shown to regulate chemoresistance; however, it has never been validated in the cisplatn‐resistant tumor from patents. This present study aimed to identfy the key gene regulatory networks of miR‐638 and evaluate the potental role of the miR‐638 and its targets as potental prognosis biomarkers for cisplatn‐resistance triple‐negatve breast cancer patents. The miR‐638 target was obtained from the miRecords database while the mRNA of chemoresistance biomarker candidate was obtained from the GSE18864 of GEO database, which is mRNA of cisplatn‐resistance TNBC patents. CCND1 and FZD7 are potental candidates for cisplatn chemoresistance biomarkers in patents with TNBC. Moreover, a Kaplan‐Meier survival plot showed that breast cancer patents with low mRNA levels of FZD7 had signifcantly worse overall survival than those in higher mRNA expression group. Taken together, miR‐638 plays a role in cisplatn resistance mechanism through a mechanism involving its target gene CCND1 and FZD7. Overall, miR‐638, CCND1, and FZD7 are candidates for cisplatn biomarker resistance in TNBC.

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Saini, Mohini, Dhanjit Das, Animesh Dhara et Praveen Gupta. « Recent Developments in Patents Targeting Toll-Like Receptor Genes ». Recent Patents on DNA & ; Gene Sequences 1, n^o 3 (1 novembre 2007) : 227–39. http://dx.doi.org/10.2174/187221507782360263.

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Upperton, Ruth. « Should the New Zealand Parliament Allow the Intellectual Property Office of New Zealand to Continue to Grant Patents for Isolated Human Genes ? » Victoria University of Wellington Law Review 44, n^o 1 (1 mai 2013) : 91. http://dx.doi.org/10.26686/vuwlr.v44i1.5008.

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It is time for New Zealanders to decide whether we want to allow patents over isolated human genes. In making this decision, we should take heed of the pitfalls other jurisdictions have encountered in this area. In this article, I determine the approach New Zealand intellectual property law should take to the patenting of isolated human genes, with reference to the arguments and issues raised by the Myriad Genetics litigation in the United States of America. I conclude that a nuanced approach should be adopted. Isolated human genes are not patentable subject-matter from a legal perspective; however, patents in the field of gene therapeutics should be allowed on policy grounds.

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Zhou, Wuyuan, et Deng Chen. « Emerging Patent Landscape for Gene Therapy as a Potential Cure for COVID-19 ». Mathematical Problems in Engineering 2021 (8 janvier 2021) : 1–6. http://dx.doi.org/10.1155/2021/6630419.

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There is still a lack of effective therapies for treating SARS-CoV-2-infected patients, as doubts remain whether antibodies provide sufficient immunity for COVID-19, and the safety of vaccines under development needs further study. The treatment of coronavirus from the perspective of RNA interference-based gene therapy offers a more direct approach to combating viral genes in addition to traditional drugs and vaccines and is likely to have a promising future. In this paper, an analysis of the emerging patent landscape was given on gene therapies for coronavirus under development, highlighting patent applications' basic status, geographical distribution, time-series analysis of new inventors, and ranking of patent applicants. Relevant patents were also reviewed and summarized to provide ideas for the control of the current COVID-19 pandemic.

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Zhou, Wuyuan, et Deng Chen. « Emerging Patent Landscape for Gene Therapy as a Potential Cure for COVID-19 ». Mathematical Problems in Engineering 2021 (8 janvier 2021) : 1–6. http://dx.doi.org/10.1155/2021/6630419.

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There is still a lack of effective therapies for treating SARS-CoV-2-infected patients, as doubts remain whether antibodies provide sufficient immunity for COVID-19, and the safety of vaccines under development needs further study. The treatment of coronavirus from the perspective of RNA interference-based gene therapy offers a more direct approach to combating viral genes in addition to traditional drugs and vaccines and is likely to have a promising future. In this paper, an analysis of the emerging patent landscape was given on gene therapies for coronavirus under development, highlighting patent applications' basic status, geographical distribution, time-series analysis of new inventors, and ranking of patent applicants. Relevant patents were also reviewed and summarized to provide ideas for the control of the current COVID-19 pandemic.

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Kutovaya, Olga, Stacy Hung, Elena Viganò, Adele Telenius, Bruce W. Woolcock, Barbara Meissner, Shane Colborne et al. « UBR5 Mutations in Mantle Cell Lymphoma Lead to Increased Proliferation through a Cyclin D1-Dependent Mechanism ». Blood 132, Supplement 1 (29 novembre 2018) : 2849. http://dx.doi.org/10.1182/blood-2018-99-118524.

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Abstract Mantle cell lymphoma (MCL) is an aggressive type of non-Hodgkin lymphoma, with patient outcomes inferior to most other lymphoma subtypes. Recent progress in describing recurrent somatic gene mutations has led to a better understanding of MCL pathogenesis. However, the functional and clinical implications of many alterations remain to be elucidated. Here, to uncover the role of recurrent UBR5 gene mutations in lymphomagenesis, we studied a cohort of 248 MCL patients by targeted sequencing and performed genome editing of MCL-derived cell lines to investigate UBR5-mutation associated phenotypes in vitro. We identified deleterious UBR5 exon 58 hotspot mutations in 8% of MCL patients, all of which were mutually exclusive with CCND1 mutations. Proteomics analysis of Granta-519 and Jeko-1 cell lines with engineered UBR5 exon 58 indel mutations showed differential expression of genes involved in cell cycle and ubiquitination, and led to the discovery of decreased phosphorylation of CCND1 in the UBR5-mutated lines. Accordingly, in vitro studies of engineered genome-edited Granta-519, Jeko-1 and Mino cells revealed accumulation of cells in the S phase of the cell cycle, increased phosphorylation of retinoblastoma protein (Rb), and increased lymphoma cell proliferation. Our results demonstrate that UBR5 mutations, in addition to the hallmark t(11;14) translocation drive proliferation of MCL cells, potentially rendering mutation-carrying cells more sensitive to targeted therapies. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Roche: Research Funding; Celgene: Consultancy, Honoraria; Janssen: Research Funding. Steidl:Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Tioma: Research Funding.

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Roman-Rodriguez, Francisco J., Laura Ugalde, Lara A. Alvarez, Begoña Díez-Cabezas, Jordi Surrallés, Maria Jose Ramirez, Massimo Bogliolo et al. « NHEJ-Mediated Gene Editing, a Versatile Approach to Correct a Variety of Fanconi Anemia Genes in HSCs ». Blood 134, Supplement_1 (13 novembre 2019) : 4639. http://dx.doi.org/10.1182/blood-2019-129946.

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Allogeneic hematopoietic stem cell (HSC) transplantation is currently the only curative treatment for the bone marrow failure in Fanconi anemia (FA) patients. However, recent advances in lentiviral-mediated gene therapy have shown that corrected FA HSCs develop an in vivo proliferation advantage, facilitating the engraftment of corrected HSCs in non-conditioned FA patients. Based on these observations, we proposed that gene editing might constitute a promising alternative to correct patients' hematopoietic stem and progenitor cells (HSPCs) in this disorder. Since non-homologous end joining (NHEJ) is the most frequent repair pathway in HSCs, particularly in FA-HSCs, we aimed at exploiting this DNA repair mechanism to remove/compensate specific mutations in different FANC genes by the use of CRISPR/Cas9 system, thus mimicking spontaneous genetic reversions observed in FA mosaic patients. Our results in lymphoblastic cell lines from five different complementation groups (FANCA, FANCB, FANCC, FANCD2 and FANCD1/BRCA2) demonstrated the efficiency of this approach to generate potentially corrective events in all the different complementation groups studied. Importantly, corrected cells showed a marked proliferative advantage after in vitro culture and the analysis by next generation sequencing confirmed the expansion of cells harboring therapeutic events. Functional studies showing the reversion of mitomycin C sensitivity, FANCD2 foci formation and chromosomal instability supported the phenotypic correction of different mutations by NHEJ-mediated gene editing. Moving towards the clinical application of NHEJ-mediated repair we focused on improving the gene editing efficiency in HSCs. To this aim, chemically modified small guide RNAs (MS-sgRNAs) enabled us to increase the editing efficacy 8-fold compared to efficacies obtained with in vitro transcribed sgRNAs, reaching up to 89% indels in healthy donor hematopoietic stem/progenitor cells. Moreover, the CRISPR/Cas9 system demonstrated high editing capacity in the primitive HSCs capable of engrafting immunodeficient NSG mice, confirming the efficacy of NHEJ-editing to correct the phenotype of long-term repopulating HSCs. Finally, studies conducted in mobilized peripheral blood and bone marrow CD34+ cells from FA patients demonstrated the feasibility to correct FA HSCs by NHEJ-mediated gene editing and confirmed the proliferative advantage of NHEJ-mediated corrected cells both in vitro and in vivo. Our results suggest that NHEJ-mediated gene editing should constitute a versatile and simple therapeutic approach to efficiently correct specific mutations in FA and other monogenic disorders of the hematopoietic system. Disclosures Sevilla: Rocket Pharmaceuticals, Inc.: Honoraria, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rocket: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Honoraria. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding. Rio:Rocket Pharmaceuticals, Inc.: Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding.

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Leverve, F. « Patents on genes, usefulness, and the requirement of industrial application ». Journal of Intellectual Property Law & ; Practice 4, n^o 4 (1 avril 2009) : 289–95. http://dx.doi.org/10.1093/jiplp/jpp003.

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Tvedt, Morten Walløe. « Patent law and bioprospecting in Antarctica ». Polar Record 47, n^o 1 (11 juin 2010) : 46–55. http://dx.doi.org/10.1017/s0032247410000045.

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ABSTRACTThe number of patents and patent applications related to inventions based on biological material from the Antarctic is increasing. Bioprospecting in the Antarctic is happening with no explicit regulation of property rights or benefit sharing requirements. This leaves patent law as the only legal system to establish exclusive rights to genes, bacteria, and other biological material found in the Antarctic. Patent law is general in form and is applied to all areas of invention with very few adaptations to single fields of innovation. Therefore, it is interesting to identify the issues in patent law in cases in which the biological material from the Antarctic is likely to create challenges or loopholes. The aim of this article is to couple the understanding of this particular legal regime and of biological circumstances in the Antarctic with knowledge of the international patent system for the purpose of contributing to the work of the Antarctic Treaty Consultative Meetings (ATCMs) regarding bioprospecting in the Antarctic.

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Sheffer, Michal, Yiguo Hu, Ophir Shalem, Neville Sanjana, Eugen Dhimolea, Subhashis Sarkar, Megan A. Bariteau et al. « Genome-Scale Crispr-Cas9 Knockout Studies Reveal Mutifactorial and Functionally Overlapping Mechanisms of Myeloma Cell Resistance to Proteasome Inhibition ». Blood 124, n^o 21 (6 décembre 2014) : 273. http://dx.doi.org/10.1182/blood.v124.21.273.273.

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Abstract Acquired or de novo resistance to established and investigational therapies represents a major clinical challenge for multiple myeloma (MM) and other neoplasias. Despite extensive efforts, clinically-validated molecular markers that predict for proteasome inhibitor (PSI) resistance in most MM patients remain elusive. This challenge is partly due to limited availability so far of molecular data on MM patients before the start of PSI treatment vs. immediately after resistance to it develops; this challenge may also reflect the heterogeneity of the complex molecular mechanisms regulating MM cell response to PSIs. We hypothesized that resistance to PSIs can be mediated by disruption of several functionally overlapping genes, and that the prevalence of any of these lesions may be too low to detect in datasets available thus far. To examine this latter hypothesis, we performed a genome-wide screen for genes whose loss confers to MM cells resistance against bortezomib, through the use of the CRISPR (clustered regularly interspaced short palindromic repeats)–associated nuclease Cas9 system. Specifically RPMI-8226 MM cells were transduced with lentiviral construct for Cas9 nuclease, followed by lentiviral delivery of a genome-scale pooled library of 123,411 single-guide RNAs (sgRNAs), which selectively align to target sequences at the 5′ constitutive exons of 18,080 genes and direct the Cas9 nuclease to cause double-stranded cleavage and loss of function of the respective gene. From the pool of MM cells transduced with the sgRNA library and treated with bortezomib, treatment-resistant cells were processed for deep sequencing, to identify enriched sgRNAs and their corresponding genes. We identified that loss-of-function of 33 candidate genes is associated with bortezomib resistance. We observed a high level of consistency between independent sgRNAs targeting the same gene, as well as a high rate of hit confirmation across different biological replicates. Notably, this set of candidate bortezomib-resistance genes was distinct from the "hits" we identified through a parallel CRISPR screen on the same cell line for resistance to a different targeted therapy (namely the bromodomain inhibitor JQ1), supporting the ability of this approach to identify treatment-specific resistance genes. These candidate bortezomib-resistance genes have documented or presumed roles in the regulation of extrinsic and intrinsic apoptotic cascades, autophagy, Toll-like receptor and NF-kappaB signaling, aggresome function, heat shock protein expression, chromatin remodeling, nutrient sensing, and tumor suppressor gene networks. Importantly, information from several publically available molecular profiling datasets converge to support the putative clinical relevance of these genes. For instance, gene expression data from tumor cells of bortezomib-naive patients with advanced MM revealed several transcriptional signatures of these candidate genes (defined by low transcript levels for any of the genes in the signature) which correlated with shorter time to disease progression after treatment with bortezomib (p<0.01, log-rank test), but not dexamethasone (p>0.426). Congruent with these findings, the highly bortezomib-responsive clinical setting of newly-diagnosed MM is associated with low cumulative frequency of mutations of these bortezomib-resistance genes (e.g. cumulative mutation rate of 3.9%, 95% confidence interval [CI] 1.25-6.55%). Notably, in other malignancies that are typically PSI-resistant, a higher cumulative frequency of such lesions is observed (average of ~28%, range 0-76%, 95% CI 22.46-32.70%; 57 datasets from 20+ neoplasias examined). In summary, this first application of the CRISPR/Cas9-based technology in MM illustrates its power to interrogate gene function on a genome-wide scale. This approach identifies bortezomib-resistance genes that are associated with pathways linked with the regulation of proteasome inhibitor response. Results from molecularly-annotated clinical samples converge to support a possible role for these genes in bortezomib resistance. This experience supports the value of CRISPR/Cas9-based studies to dissect the molecular mechanisms of treatment resistance in MM and other hematologic neoplasias (* equal contribution of M.S. and Y.H.). Disclosures Shalem: Broad Institute: Patent application for CRISPR technology Patents & Royalties. Sanjana:Broad Institute: Patent application for CRISPR technology Patents & Royalties. Zhang:Broad Institute: Patent application for CRISPR technology Patents & Royalties. Mitsiades:Johnson & Johnson: Research Funding; Amgen: Research Funding; Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals: Consultancy, Honoraria.

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Carreño-Venegas, Andrea, Julián Mora-Oberlaender et Alejandro Chaparro-Giraldo. « Identification and freedom to operate analysis of potential genes for drought tolerance in maize ». Agronomía Colombiana 35, n^o 2 (1 mai 2017) : 150–57. http://dx.doi.org/10.15446/agron.colomb.v35n2.60706.

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Drought tolerance is an important character for agricultural crops, particularly corn. Genes confering this feature can be patented, thus hindering their use. From a thorough analysis, three genes (DREB, ZAT10 and CspB) were identified and their sequences were captured in the NCBI database. From these sequences and using free software tools, expression cassettes -including regulatory regions (promoters E35S + Pleader, Ubi-1, rab17; terminators Trub, Tnos)- were designed. Patent searches were conducted in international databases (The Lens and PATENTSCOPE). Four patents and an application were found. In the Colombian national database of the Superintendence of Industry and Commerce (SIC), only the application made through PCT was identified. The claims and nucleotide sequences contained in the application were analyzed and it was found that they do not affect the expression cassettes designed. There is freedom to operate for these constructs and it is possible to continue developing drought-tolerant GM maize lines for the domestic market.

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Wang, Tianjiao, Hua Sun, Daniel Cui Zhou, Ruiyang Liu, Lijun Yao, Mark A. Fiala, Daniel R. Kohnen et al. « Single-Cell Pathway Enrichment and Regulatory Profiling of Multiple Myeloma across Disease Stages ». Blood 134, Supplement_1 (13 novembre 2019) : 364. http://dx.doi.org/10.1182/blood-2019-131361.

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Multiple myeloma (MM) is a hematological malignancy, defined by aberrant monoclonal proliferation of plasma cells in the bone marrow, that to date remains an incurable disease despite advances in treatment. Key genetic and epigenetic alterations that drive MM pathogenesis have been identified, but a comprehensive profile of affected cellular pathways has yet to be fully characterized. In this study, we integrate whole-genome and whole-exome sequencing data with single-cell RNA sequencing (scRNA-seq) data from 13 patients across multiple treatment stages to 1) assess differential pathway enrichment between tumor subpopulations, 2) trace the clonal evolution of dominant disease mechanisms, and 3) investigate signaling interactions between surrounding cell types. We also analyzed bulk genomic and transcriptomic data from 662 additional Multiple Myeloma Research Foundation (MMRF) tumor samples as a large reference cohort for highly prevalent pathway disturbances. To assess whether tumor subpopulations rely on different oncogenic programs for proliferation, we analyzed the differential expression of key genes (FDR-adjusted p-value <0.05) in 12 canonical oncogenic pathways. Cell cycle, Hippo, RTK/RAS, and NFkB pathways contain the highest numbers of differentially expressed genes, with certain subclusters upregulating as many as 25% of annotated cell cycle genes and over 90% of annotated Hippo genes, whereas p53, Notch, Nrf2, and DNA repair genes tend to be uniformly expressed across subpopulations. Next, we evaluated changes in pathway enrichment across different disease timepoints, with the goal of capturing the reorganization of functional profiles through successive treatment and relapse cycles. We assessed statistical enrichment of pathways containing differentially expressed genes (DEGs) unique to Smoldering Multiple Myeloma (SMM), primary, and relapse stages using the KEGG pathway database (n = 2, 17, and 7 pathways, respectively; FDR-adjusted p-value of enrichment < 0.05). SMM is the only stage where hematopoietic differentiation and the PI3K-Akt pathways are variably expressed between plasma cell subpopulations, suggesting that these pathways may play a role in initiating events. Only primary tumor samples show significant intra-tumor variability of p53 regulation, which is lost in the relapsed tumor and may reflect selection due to treatment. Relative to SMM, primary and relapse samples are enriched for changes in the MAPK, NFkB, RAP1, and cell cycle pathways, indicating potential sources of tumor resistance. We then analyzed pathway enrichment within the tumor microenvironment to enhance our understanding of tumor development in the context of surrounding tissues. We see frequent changes in many immune cell types in TLR signaling as the disease progresses, driven by differential expression of NFkB1A, JUN, and FOS, all of which are key upstream regulators of the AP-1 pathway and responders to the MAPK and PI3K signaling cascades. These microenvironment changes may be complementary to the PI3K and MAPK dysregulation observed in tumor plasma cells. Proteasome and ubiquitin genes, which affect secretion, autophagy, and apoptosis pathways that may be relevant to MM pathogenesis are also frequently differentially expressed in immune cells between disease stages. Finally, we integrate bulk whole-exome and whole-genome sequencing analysis (from both the 13-patient cohort and MMRF) to obtain a more complete understanding of how pathways become dysregulated in MM. Our findings advance the understanding of how MM tumor subpopulations differentially regulate cellular pathways and interact within the tumor microenvironment. Disclosures O'Neal: Wugen: Patents & Royalties: Patent Pending; WashU: Patents & Royalties: Patent Pending. Rettig:WashU: Patents & Royalties: Patent Application 16/401,950. Oh:Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding. DiPersio:Amphivena Therapeutics: Consultancy, Research Funding; Magenta Therapeutics: Equity Ownership; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees.

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Klein, Roger D., et Maurice J. Mahoney. « LabCorp v. Metabolite Laboratories : The Supreme Court Listens, but Declines to Speak ». Journal of Law, Medicine & ; Ethics 36, n^o 1 (2008) : 141–49. http://dx.doi.org/10.1111/j.1748-720x.2008.00243.x.

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Molecular genetic testing has increasingly been incorporated into clinical medicine, and this trend is likely to accelerate in the future. The introduction of genetic testing into medical practice is beginning to collide head on with patents that claim ownership of correlations between human genetic variants and predisposition to disease, response to therapeutic drugs, and susceptibility to pharmacologic side effects. Patent holders or licensees of genes, genetic variants, and their genotype-phenotype correlations are already using the threat of litigation to monopolize genetic tests for important well-known syndromes like Duchenne Muscular Dystrophy and inherited breast and ovarian cancer, in addition to a host of less commonly discussed conditions.

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Pottage, Alain. « The Inscription of Life in Law : Genes, Patents, and Bio-politics ». Modern Law Review 61, n^o 5 (septembre 1998) : 740–65. http://dx.doi.org/10.1111/1468-2230.00177.

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Dyer, C. « US judge rules that patents on breast cancer genes are unlawful ». BMJ 340, apr01 1 (1 avril 2010) : c1870. http://dx.doi.org/10.1136/bmj.c1870.

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Krainer, Adrian. « Spliceosome : Physiology and Disease Pathogenesis ». Blood 128, n^o 22 (2 décembre 2016) : SCI—17—SCI—17. http://dx.doi.org/10.1182/blood.v128.22.sci-17.sci-17.

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Abstract Pre-mRNA splicing is an essential step for the expression of intron-containing genes, i.e., the majority of genes. Splicing is a high-fidelity process, as required for the correct expression of proteins. However, there is flexibility in the selection of competing splice sites, which gives rise to alternative splicing, a regulated process that greatly increases the diversity of the proteome. Splicing is catalyzed in a stepwise manner by the spliceosome, a macromolecular machine that consists of 5 small RNAs and more than 100 proteins. Key insights about the structure and dynamics of spliceosomal complexes have recently been obtained through cryo-electron microscopy studies. Dysregulated splicing can arise from mutations in the splice sites or regulatory elements of individual genes, from alterations in the levels of regulatory splicing factors (activators and repressors), or from mutations in splicing-factor genes. All of these scenarios can give rise to various cancers, depending on the affected gene and the cellular context. Interestingly, recurrent somatic heterozygous mutations in particular splicing factors involved in branchpoint-sequence and 3'-splice-site recognition have emerged as key drivers of certain myeloid neoplasias. This presentation will review relevant features of the spliceosome machinery, the functional implications for normal and pathological conditions, and the potential for novel therapies. Disclosures Krainer: Ionis Pharmaceuticals: Consultancy, Honoraria, Patents & Royalties, Research Funding; Stoke Therapeutics: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Co-founder, Patents & Royalties; Cold Spring Harbor Laboratory: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; H3 Biomedicine: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Paradise, J. « INTELLECTUAL PROPERTY : Patents on Human Genes : An Analysis of Scope and Claims ». Science 307, n^o 5715 (11 mars 2005) : 1566–67. http://dx.doi.org/10.1126/science.1105162.

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Lenzer, J. « Patents on breast cancer genes are illegal and stymie research, say scientists ». BMJ 339, n^o 17 3 (17 novembre 2009) : b4899. http://dx.doi.org/10.1136/bmj.b4899.

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Rogers, Douglas L. « CODING FOR LIFE - SHOULD ANY ENTITY HAVE THE EXCLUSIVE RIGHT TO USE AND SELL ISOLATED DNA ? » Pittsburgh Journal of Technology Law and Policy 12 (13 avril 2012) : 85–152. http://dx.doi.org/10.5195/tlp.2012.93.

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Myriad Genetics, Inc. ("Myriad") obtained patents in the 1990s on two "isolated" human breast and ovarian cancer susceptibility genes ("BRCA"). Myriad did not list all the isolated sequences it claims to have a right to monopolize, but instead claims a patent on the physical phenomena itself -- all DNA segments that code for the BRCA1 polypeptide, even the sequences Myriad has not identified and even those someone else in the future creates or isolates the sequences of through a method or methods not contemplated by Myriad. An impressive array of non-profit medical societies, doctors and patients sued to have the Myriad patents declared invalid. In 2010, the District Court for the Southern District of New York held in Association for Molecular Pathology v. United States Patent and Trademark Office that the claimed product patents for isolated DNA segments constituted unpatentable subject matter under 35 U.S.C. §101. On July 29, 2011, a divided panel of the Federal Circuit reversed the District Court and held that the isolated DNA segments constituted patentable subject matter. Of the three member panel, Judge Lourie concluded that the isolated DNA was markedly different than the native DNA, so constituted patentable subject matter. Although Judge Moore agreed that certain DNA segments constituted patentable subject matter, she believed that the longer isolated DNA segments probably did not constitute patentable subject matter. However, primarily in light of the fact that the US Patent and Trademark Office has been granting patents for isolated DNA for years, Judge Moore concurred in the judgment of Judge Lourie. Judge Bryson concurred on one of the product claims (for synthetic cDNA) but dissented on claims pertaining to the isolated DNA segments on the grounds that isolated DNA did not differ markedly from the native DNA and that the function of the isolated DNA was identical to the function of the native DNA.The Supreme Court stated that "Congress may not authorize the issuance of patents whose effects are to remove existent knowledge from the public domain, or to restrict free access to materials already available." This article argues that the Federal Circuit - not Congress - has done just that and has given Myriad a wall to restrict free access to materials that have literally been in humans for centuries. The isolated DNA segments of claim 1 do exactly the same coding as do the native segments--nothing more; nothing less. The segments of claim 1 do not act as primers or probes, so they do not have markedly different characteristics or utility than native DNA, which the Supreme Court has ruled courts must consider. Moreover, the functioning of the sequence of the nucleotide bases is a physical phenomenon that Myriad has not created but has captured in its claim. Judges Lourie and Moore disregarded Supreme Court precedent and the fundamental principle that physical phenomena are not patentable subject matter.

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CAPLAN, ARTHUR L. « What's So Special about the Human Genome ? » Cambridge Quarterly of Healthcare Ethics 7, n^o 4 (octobre 1998) : 422–24. http://dx.doi.org/10.1017/s0963180198004137.

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Glenn McGee argues that the time is now for debating the morality of patenting human genes. In one sense he is surely right. While thousands of patents have been issued or are pending on many gene sequences, public policy with respect to ownership of the human genome is still far from settled. So a debate about the ethics of patenting genes is, if nothing else, timely. In another sense however, Professor McGee is wrong.

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Maneva, Veselina. « Legal Protection of Genetic Research ». Yearbook of the Law Department 9, n^o 10 (12 février 2022) : 180–97. http://dx.doi.org/10.33919/yldnbu.20.9.6.

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The article discusses the patentability of the results of genetic research, in particular the sequence of genes in the molecular structure of deoxyribonucleic acid. The main approaches established in the American, European and national legal system regarding the protection of genetic inventions are presented. The main points in a decision of the Court of Justice of the EU are analysed. Both the criteria for patentability of an element of the human body and the hypotheses referring to the exceptions to patentability corresponding to the provisions of Directive 98/44/EC on the legal protection of biotechnological inventions, the Convention on Human Rights and Biomedicine of Oviedo, the European Patent Convention and the TRIPS Agreement. The connection between the importance of genetic research and the development of the innovative economy based on the patents for these inventions is substantiated.

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Jiang, Yiming, Xiaoning Hu et Haiying Huang. « Recent Patents on Biosafety Strategies of Selectable Marker Genes in Genetically Modified Crops ». Recent Patents on Food, Nutrition & ; Agriculture 6, n^o 1 (10 décembre 2014) : 3–15. http://dx.doi.org/10.2174/2212798406666141024104637.

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Huys, Isabelle, Gert Matthijs et Geertrui Van Overwalle. « The fate and future of patents on human genes and genetic diagnostic methods ». Nature Reviews Genetics 13, n^o 6 (18 mai 2012) : 441–48. http://dx.doi.org/10.1038/nrg3255.

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Alyileili, Salem Rashed, Khaled El-Tarabily, Wissam Hachem Ibrahim, Mohsin Sulaiman et Ahmed Soliman Hussein. « Effect of Trichoderma reesei Degraded Date Pits Supplementation on Growth Performance, Immunoglobulin Levels, and Intestinal Barrier Functions of Broiler Chickens ». Recent Patents on Food, Nutrition & ; Agriculture 11, n^o 2 (18 septembre 2020) : 168–81. http://dx.doi.org/10.2174/2212798410666190716163009.

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Background: Date palm (Phoenix dactylifera L.) is a dominant fruit crop in most Arabian countries. Date pits, as a major byproduct which remained after consumption of date flesh, proved to be a valuable source of energy. Objectives: The impact of degraded date pits (DDP) on growth performance, intestinal bacterial population, and expression profiles of intestinal genes in broilers was determined. Recent patents have been established on DDP from the European patent office (EP2586318B1), Hong Kong patent registry office (HK1184642) and by the United States patent and trademark office (US8968729B2 and US10265368B2). Methods: Solid-state degradation system (SSD) was used for the preparation of DDP using Trichoderma reesei. One-day-old Brazilian broiler chicks “Cobb 500” were randomly divided into six treatments with six replicates, which consisted of a normal diet containing only corn-soy (control), diet containing corn-soy + (20%, 50g/100Kg oxytetracycline), diet containing corn-soy + 10% (DDP), diet containing corn-soy + 0.2% mannan oligosaccharides (MOS), diet containing corn-soy + 0.1% mannose, and diet containing corn-soy + 0.2% mannose. Results: There were no significant differences in body weight, feed intake, and feed conversion ratio (FCR) in broilers among the treatments. The bacterial count was significantly decreased in 10% DDP diet-fed broilers, 0.2% MOS and antibiotic diet-fed broilers. Immunoglobulin levels in serum and intestinal contents and expression pattern of genes in jejunum were upregulated in 10% DDP and 0.2% MOS diet-fed broilers. Conclusion: DDP can be used as an energy source for replacing part of corn, mannan oligosaccharide and also recommended as a potential alternative to antimicrobials in broilers diet.

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Degnin, Michelle, Cristina E. Tognon, Christopher A. Eide, Beth Wilmot, Shannon K. McWeeney, Daniel Bottomly, Rebecca Smith et Brian J. Druker. « High-Throughput Validation of Mutations Identified in Primary Leukemia Cells ». Blood 128, n^o 22 (2 décembre 2016) : 4725. http://dx.doi.org/10.1182/blood.v128.22.4725.4725.

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Abstract Next generation sequencing has enabled the cataloguing of mutations found in many different cancers. The mutational burden for any given leukemia patient can range from 2 to hundreds of non-somatic mutations and it can therefore be challenging to separate drivers from the passengers. In performing deep sequencing on 139 primary leukemia samples using a custom capture library of ~1,800 genes including all kinases, phosphatases, and a variety of growth factors, cytokine receptors, and adapter proteins, we identified 3,390 non-somatic unique SNV and indel mutations in 1,286 genes. Many of the changes identified were non-recurrent or low frequency mutations found a single patient or a small numbers of patients. To determine the functional consequences, each mutation must be created and tested in vitro. We sought to develop a high throughput method to: 1) prioritize mutations for validation, 2) create mutations for testing, and 3) assess the transformative capacity of each mutation using a BaF3 growth factor independence assay. Using the following heuristic we ranked and prioritized mutations for further validation: i) include only high quality sequence variant cells; ii) exclude mutations found in >50% of samples iii) include mutations not found in dbSNP or 1000 genomes, or in 1000 genomes with a global mutant allele frequency less than or equal to 0.1; and iv) include mutations found dbSNP but not in 100 genomes with a cohort frequency equal to or less than <5%. Variants were ranked using HitWalker (Bottomly et al. 2013 PubMed ID: 23303510). HitWalker uses random walks with restarts algorithm to rank mutations based on proximity to known functionally important targets. These functionally important targets were identified using data from small molecule inhibitor screens performed on freshly isolated leukemia cells from each patient sample. We then prioritized 784 mutations for creation based on a HiWalker rank of 1-20. After mutations were ranked and prioritized, an R-based program, PrimeR, was used to automate mutagenesis primer design. Primers were batch ordered and arranged in 96-well plates based on primer Tm to enable the use of gradient PCR. Mutagenesis was performed on cDNA Entry clones purchased from commercial sources. Greater than 50% of the initial mutagenesis reactions were successful in producing mutagenized plasmids with no non-specific mutations. Confirmed mutations and their wild type counter parts were transferred into retroviral vector destination clones using Gateway LR Clonase II (ThermoFisher Scientific). Following LR Clonase reactions, we repeated sequencing and found no non-specific mutations and opted to identify successful constructs solely by restriction digestion/DNA gel analysis in future runs. IL-3 withdrawl assays were performed using round bottom 96-well plates, enabling removal of IL-3 from the cell media. Cells were split equally into 5 flat bottomed 96-well tissue culture plates, and covered with breathable seals and incubated at 37°C. Every 4 days MTS was added to a single plate according to the manufacturers specification and a cell viability assay was performed. Wells possessing an absorbance of 0.100 or higher compared to the blanks were considered to contain mutations of interest, and were subsequently repeated using traditional growth factor independence assays in 25mL flasks. Using this method we have screened 86 mutations along with their wildtype controls and identified 10 mutations with transformative capacity in 7 genes. All transforming mutations had a HitWalker rank of 1-3 supporting the use of HitWalker in prioritizing mutations for further validation. Disclosures Druker: Dana-Farber Cancer Institute: Patents & Royalties: Millipore royalties via Dana-Farber Cancer Institute; Array: Patents & Royalties; Curis: Patents & Royalties; Pfizer: Patents & Royalties; CTI: Consultancy, Equity Ownership; Cylene: Consultancy, Equity Ownership; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Agios: Honoraria; Ambit BioSciences: Consultancy; AstraZeneca: Consultancy; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses; Roche: Consultancy; ARIAD: Patents & Royalties: inventor royalties paid by Oregon Health & Science University for licenses, Research Funding; BMS: Research Funding; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Dana-Farber Cancer Institute: Patents & Royalties: Millipore royalties via Dana-Farber Cancer Institute; Array: Patents & Royalties; Curis: Patents & Royalties; Pfizer: Patents & Royalties.

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Nobles, Christopher L., John K. Everett, Shantan Reddy, Joseph A. Fraietta, David L. Porter, Noelle V. Frey, Stephan A. Grupp et al. « Vector Integration and Efficacy of CD19-Directed CAR T Cell Therapy in Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL) ». Blood 132, Supplement 1 (29 novembre 2018) : 4548. http://dx.doi.org/10.1182/blood-2018-99-117034.

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Abstract CD19-specific Chimeric Antigen Receptor (CTL019)-engineered T-cells provide a breakthrough for personalized cancer therapy. An anti-CD19 CAR gene with 41BB costimulatory domain is delivered into patient T-cells ex vivo using a lentiviral vector, expanded in culture and then reinfused into patients. While dramatically successful for some treatment-refractory cancers, a significant proportion of patients do not experience therapeutic levels of CAR T cell expansion - thus it is important to investigate factors driving successful expansion in responders in more detail. Here we have analyzed sites of lentiviral vector integration in CAR T cells from trials to ALL and CLL, comparing successful and unsuccessful therapy in longitudinal data sets for 40 subjects. The location of each integrated vector marks a cell lineage uniquely allowing the fate mapping of individual CAR-engineered T cells in the infusion product and after adoptive transfer. We found that 81.4% of integrations had occurred in annotated transcription units which is consistent with previous reports for lentiviral vector integration sites. Relatively larger and more diverse populations of CAR-modified T-cells were associated with improved outcome (Chao1 index, p=0.043). Population sizes were also significantly more diverse in the infusion product compared with day 28 post-infusion, and more diverse at this time point when comparing responders with non-responders, or even partial responders with non-responders (p<0.05). Thus, the population size measured in the infusion product and one month after infusion forecasts the patient's response to CTL019. Vector integration can also modify activity of nearby genes, as we recently reported for an integration event in the DNA methylcytosine dioxygenase gene TET2, where clonal CTL019 expansion was associated with successful therapy (Fraietta et. al., Nature, 2018). Insertional mutagenesis was evaluated here over five criteria, including i) clonal expansion after infusion, ii) increasing frequency of unique integration sites per gene after infusion, iii) development of orientation bias, iv) long-term persistence, and v) accumulation of integration site clusters. Our analysis disclosed genes and cell pathways, including apoptosis and epigenetics, associated with superior cell proliferation and persistence. These data thus provide multiple approaches for improvement of the anti-leukemia activity of CAR T cells. Disclosures Fraietta: Novartis: Patents & Royalties: WO/2015/157252, WO/2016/164580, WO/2017/049166. Porter:Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board; Genentech: Other: Spouse employment. Frey:Servier Consultancy: Consultancy; Novartis: Consultancy. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy. Siegel:Novartis: Research Funding. Lacey:Novartis Pharmaceuticals Corporation: Patents & Royalties; Tmunity: Research Funding; Parker Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. June:Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees. Melenhorst:Shanghai UNICAR Therapy, Inc: Consultancy; novartis: Patents & Royalties, Research Funding; Casi Pharmaceuticals: Consultancy; Incyte: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding.

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Articles de revues sur le sujet « Genes – Patents »

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