• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    This invention relates to new methods for measuring the performance of treatments to inactivate pathogens and target cells, such as light, photochemical, chemical or radiation-based treatments in blood, blood products and cosmetics. to be used as quality control. These new methods include, but are not limited to comparing antioxidant potency with the cut-off value for antioxidant potency that has been defined as specific for a given sample and considered to be processed correctly or by comparing antioxidant potency before and after processing. , because their difference attests to the execution of said processing.
    公开号:CH713411B1
    申请号:CH00859/18
    申请日:2015-12-18
    公开日:2021-03-31
    发明作者:Abonnenc Mélanie；Tacchini Philippe；Crettaz David；Senego Giona；Prudent Michel；Lion Niels
    申请人:Service Regional Vaudois De Transfusion Sanguine；
    IPC主号:
    专利说明:

    Scope of the invention
    The present invention refers to new methods for measuring the execution of treatments to inactivate pathogens or targeted cells such as light treatments, photo-chemical, chemical or based on irradiations on the blood, derived products blood and cosmetic products, and in particular, new methods to measure the performance of treatments to inactivate pathogens and target cells in blood and blood products as a quality control test.
    Information about the invention
    [0002] Inactivation treatments for pathogens or targeted cells are used in several fields, including the fields of the health, food, beverage and cosmetic industries in order to guarantee the products against the presence of pathogens, viruses. , bacterial contaminations or unwanted contaminants. These treatments include, but are not limited to exposure to different wavelengths or isotopic radiation or in combination with one or more photosensitive chemical compounds or the addition of one or more chemical compounds responsible for the generation of free radicals or molecules with excited states.
    [0003] In the food, beverage and cosmetic industries, gamma irradiation is often used to control pathogens, which can be destroyed, see their growth slowed down or become incapable of reproducing, depending on the dose used (1). When product pallets are exposed to a radiation source, built-in dosimeters are used to determine what dose was achieved (2), but despite a strict regulatory framework, including labeling of irradiated products (3) , the result of the treatment is not evaluated.
    Pathogen and target cell inactivation technologies are widely used in blood banks to reduce the risk of bacterial contamination and to deal with the emergence of new pathogens in blood components. Several types of blood products can be processed to inactivate pathogens and target cells such as platelet concentrates, plasma, red blood cells or whole blood.
    [0005] The technologies for inactivating pathogens or cells targeted for treating platelet concentrates are based on photochemical treatments or treatments based on irradiation. Photochemical treatments use photoactive compounds in combination with exposure to ultraviolet rays. For example, the “Intercept Blood system” from Cerus, Concord USA uses a psoralen derivative with exposure to ultraviolet A to inactivate pathogens in platelet concentrates and plasma. Psoralen intercalates into the double strands of DNA or RNA and covalently links them ("cross linked") following UVA exposure, which at the same time blocks DNA or RNA replication. pathogens. Since platelets lack genomic DNA, they are not functionally affected by this treatment. However, it has been shown that the DNA, RNA or microRNA of mitochondria could be altered, apparently, without adverse consequences. Another example is the Mirasol technology (Terumo BCT, Lakehood, USA) which relies on the addition of a riboflavin in combination with UVA and UVB exposure. This treatment generates oxidative lesions on the DNA of the pathogen. A third technology, known as Theraflex (Macopharma, France), uses ultraviolet C as the sole treatment to treat platelet concentrates. The first two technologies have been shown to be effective in reducing pathogens and are used in several blood banks around the world, while the third is still in a clinical evaluation phase.
    [0006] The inactivation of pathogens relates to other products derived from blood, such as plasma which can be treated with the Intercept Blood System according to the description above or also with methylene blue (Macopharma, France). Methylene blue is a phenothiazine compound which is activated by visible light and known to generate reactive oxygen species which are responsible for its pathogen inactivating properties.
    [0007] The inactivation of pathogens in whole blood also shows growing interest in its application in countries with limited resources. Currently, two technologies are under evaluation. The first is a Mirasol photochemical treatment as described above (Terumo BCT) and the second is a chemical activation developed by Cerus.
    [0008] In specific cases, the erythrocyte concentrates or the platelet concentrates can be irradiated to prevent the presence of diseases associated with the problems of graft versus host reactions. The goal is to inactivate lymphocytes while preserving the functionality of blood cells. For this purpose, the erythrocyte concentrates can be subjected to a gamma irradiation dose of between 25 and 50 Gray. In the past, platelet concentrates were treated with UVB irradiation, but this is less common because photochemical treatments used to inactivate pathogens also inactivate residual lymphocytes present in platelet concentrates.
    Another application of photochemical treatments in hematology is extracorporeal photopheresis which comprises the ex-vivo exposure of peripheral blood mononuclear cells, including pathogenic or autoreactive T lymphocytes, to a photoreactive compound and exposure ultraviolet A, followed by re-infusion of peripheral blood mononuclear cells into the patient.
    Extracorporeal photopheresis has been applied to the treatment of skin T cell lymphomas, alloimmune disorders linked to immune cells and autoimmune diseases (4).
    [0011] The European Council recommends that quality control tests be introduced to verify the effectiveness of inactivation of pathogens in blood components (5, 6). Commonly, an indicator attached to the illuminated container provides visual evidence that the package has received partial or complete processing in the illuminator, and should not be re-illuminated. Optionally, the illuminator can be connected to the blood bank management system to block an unilluminated or twice illuminated bag. An indicator of UVA exposure, which changes color from light blue to dark blue depending on its exposure was tested by Isola et al. (4). This indicator provides visual quality assurance for monitoring INTERCEPT therapy, but this system is not commonly used in blood banks. These checkpoints are necessary during the preparation steps of the blood components to avoid errors, but are not a check of the product itself. During the preclinical and clinical evaluation phase of INTERCEPT, the effectiveness of the system was evaluated by measuring the photo-degradation of amotosalen by high performance liquid chromatography or based on the assumption that complex formation is occurring. proportion with the UVA dose applied (7, 8, 9).
    Bruchmüller et al. developed a polymerase chain reaction (PCR) -based inhibition assay to document the process of inactivation of platelet concentrates with the INTERCEPT system (10, 11, 12). Statistically, an amotosalen-DNA complex is formed approximately every 268 base pairs on mitochondrial DNA (mtDNA) (13). Large amplicons are therefore more likely to contain amotosalen complexes than small amplicons used as an internal control. Bakkour et al. worked on the same concept, using PCR as a quality control for pathogen reduction with riboflavin and UVB light (Mirasol, Terumo BCT, Lakewood, CO, USA) (14). Although the PCR inhibition test has the advantage of documenting DNA damage, i.e. the target of the pathogen inactivation treatment, mitochondrial DNA extraction and PCR reaction take time consuming and require instrumentation that is not always available in blood banks. Therefore, there is a need for quick and straightforward quality control testing. This test should ensure that the product has been treated with the photochemical reagent and has been exposed to the appropriate dose of ultraviolet light.
    The invention
    An aim of the present invention is to meet the needs mentioned above in relation to prior knowledge. The invention fulfills this object by providing a method for determining the performance of a treatment for inactivating pathogens or target cells on blood, its derivative products and cosmetic products, provided that these products show a measurable antioxidant potency. before the treatment, the method comprises: a) A sample of said product, which has been subjected to a light, photo-chemical, chemical or irradiation-based treatment to inactivate pathogens or targeted cells; b) measuring the antioxidant power of said sample; c) compare the value of the antioxidant power obtained in phase (b) with the value of the antioxidant power obtained by measuring another sample of said product, this other sample of said product not having been the subject of a treatment of inactivation of pathogens or target cells and / or compare the value of the antioxidant power obtained during phase (b) with a limit value of the predetermined antioxidant power, below which said product is considered to be treated with success.
    The measurement of the antioxidant power, in accordance with the chemical definition of an antioxidant, corresponds to the capacity of the sample measured to donate one or more electrons, so that they can neutralize the radical species. Several synonyms for "antioxidant power" known to experts in the field are "total antioxidant capacity", "antioxidant level" or "antioxidant activity" or "reducing capacity". Antioxidant power is defined by the ability to prevent oxidation in accordance with the definition of redox reactions, integrating the oxidation and simultaneous reduction of two reactive compounds, one being oxidized, the other being reduced. These measures include, but are not limited to the use of electrochemical methods (15), including the technology developed by Edel-for-life with the use of devices and the Edel methodology (16, 17), methods based on spectro- and photo-chemistry, included, but not limited to ORAC (18), DPPH (19), TRAP, TEAC and FRAP (20) and antioxidant scavenging (22) methods, methods based on liquid chromatography (23), mass spectrometry (24) and / or any other method designed and available to measure antioxidant potency.
    According to a preferred implementation of the invention, the method is used for blood and products derived from blood. Using the comparison of the antioxidant potency of a product derived from treated or untreated blood or using the comparison of the antioxidant potency of blood or a blood derivative with a predetermined limit value, as a control quality provides a new and inventive solution to perform these tests.
    Brief Description of Figures
    Figure 1 shows the quality control test as measured by the antioxidant potency of a product treated with a pathogen or target cell inactivation treatment. Figure 2 shows the determination of the limit value of the antioxidant power which distinguishes the treated sample from the untreated one measured by A) the ROC curve. In this particular example, the product is a double dose of platelet concentrate treated with a photochemical treatment (Intercept Blood System, Cerus) (B) The EDEL limit value is the point of intersection between the sensitivity and specificity curves. The likelihood ratio of the greatest positive probability and D) the smallest negative probability are associated with the optimal cutoff value. Figure 3 shows A) the significant decrease (P <0.0001) of the antioxidant power in double doses of platelet concentrates treated with a photochemical treatment (Intercept Blood System, Cerus). A limit value of 74.5 EDEL has been preset for this blood derivative. Below this value, the double dose of platelet concentrates is considered to be processed correctly. B) The histogram distribution shows two distinct populations for those samples from double dose of untreated and treated platelet concentrates. Figure 4 shows the significant decrease (P <0.0001) in the antioxidant potency of plasma units treated with photochemical treatment (Intercept Blood System, Cerus). A limit value of 130 EDEL has been preset for this blood derivative. Below this value, the plasma sample is considered to be processed correctly. Figure 5 shows the significant decrease in the antioxidant power of a cosmetic cream treated with ultraviolet exposure (280 nm, d = 5 cm) for 15, 20 and 30 minutes.
    Detailed description of the invention
    This invention relates to novel methods for measuring the performance of treatments to inactivate pathogens or targeted cells, such as light, photo-chemical, chemical or radiation-based treatments of blood, blood-derived products and cosmetic products. In particular, the method can be used as a quality control to verify the performance of inactivation treatments of pathogens or target cells of blood and blood products. Quality control testing may be mandatory to release a product or a random test to measure the stability and efficiency of the production procedure.
    According to a preferred implementation, the present invention provides a method for determining the execution of treatments to inactivate pathogens or targeted cells such as light, photochemical, chemical or radiation treatments based on blood and blood. blood products, the method comprises the following sequential steps: a) According to a blood product or a blood product which has been treated with photochemical treatment and / or in combination with the addition of one or more photo compounds -sensitive, chemical or based on irradiation; b) measuring a sample of said blood product or of the product derived from blood; c) measuring the antioxidant power of said blood sample or of the product derived from the treated blood; d) compare the antioxidant potency measured between the treated and untreated samples and / or with a value of the limit antioxidant potency which must be defined for each blood product or product derived from blood and below which the product is considered to be correctly treaty.
    In a preferred embodiment, the limit value of the antioxidant power between the untreated samples and the treated samples is determined for each type of blood product in each blood bank before using the test routinely. In fact, the antioxidant power depends on the characteristics of the blood product, in particular its plasma content which can be influenced by technical blood preparations which are different from one blood bank to another.
    [0020] In a preferred embodiment, the antioxidant power is measured only in the blood sample or the sample of the product derived from the blood and compared to the predefined limit value. In this case, it is not necessary to analyze the blood sample or the sample of blood-derived product before and after the treatment.
    In a preferred embodiment, the antioxidant power is measured with EDEL technology. Measuring with EDEL technology consists of an electrochemical analysis by pseudo-titration (17, 18). The sample to be analyzed is deposited on an electrochemical sensor, exposed to an increasing oxidation potential, while the oxidation current is measured and pseudo-titrated against an ideal antioxidant. The result obtained is expressed in EDEL, an arbitrary unit which corresponds to the equivalent antioxidant power of a 1micromolar solution of vitamin C. In more details, the EDEL method consists of the following sequential steps:Collect a sample of blood or blood-derived product before and after light, photo-chemical or radiation-based treatmentA few microliters of the blood sample or blood derivative is placed in the EDEL sensor to measure its antioxidant power. The antioxidant power is expressed in EDEL and 1 EDEL corresponds to the equivalent antioxidant power of a solution of one micromolar of vitamin C.A limit value is defined for each blood product or blood-derived product below which, the blood product or the blood-derived product is considered to be correctly processed.Once the cut-off value is determined for a type of product, for example, blood or a blood-derived product, only the antioxidant potency of the processed product is measured.
    Examples
    The following examples serve to illustrate certain applications of the present invention and are not considered to limit its scope.
    [0023] Figure 1shows the diagram of the quality control to verify the execution of the oxidative treatment measured by the antioxidant potency in a blood product, a product derived from blood or a cosmetic product. In this particular example, the antioxidant power is measured by pseudo-titration with EDEL technology (EDEL For Life, Lausanne, Switzerland). A few microliters of the treated product are placed on the EDEL microsensor to measure its antoxidant power expressed in EDEL (1 EDEL is equivalent to 1 micromolar of vitamin C). Processing is considered incomplete when the measured EDEL value remains above the limit value and complete when the EDEL value is below the limit value. This quality control test takes only a few minutes from sample collection to result. The EDEL limit value must be previously determined once for each type of product before applying this routine quality control test.
    Products derived from blood, such as platelet concentrates and plasma can be treated to inactivate pathogens with photchemical treatments (Figures 2, 3 and 4). In the present example, the INTERCEPT system (Cerus, Concord, USA) was used to inactivate pathogens and consists of the following sequential steps:Add a photoactive compound, amotosalen to the bag of platelet concentrate or plasma;Treat the platelet concentrate or the plasma bag with exposure to ultraviolet A with a dose of 3.9 J / cm <2>;Remove the remains of the photoactive product using an absorbent product;Store platelet concentrates or plasma bags under blood bank storage conditions prior to delivery.
    Platelet concentrates can be collected by apheresis during which the donor's blood is passed through an apparatus which separates by centrifugation a particular component, in this case the platelets and returns the other components to the donor. Depending on the characteristics of the donor, his platelet concentration, several types of blood products can be obtained, for example, a single, double or triple dose of platelet concentrates by apheresis. In this example, double doses of platelet apheresis concentrates collected in 39% plasma and 61% additive solution and showing an average of 5.2-10 <11> platelets are analyzed.
    Figure 2 shows the determination of the limit value of the antioxidant power which distinguishes the untreated samples from the treated samples. The limit value of the antioxidant potency for a double dose of platelet concentrate of aphera treated with the INTERCEPT system (Cerus) was determined using the ROC curve (Figure 2A). This limit value was determined from 27 untreated samples and 42 processed samples. The area under the ROC curve was 0.9802 with a P value <0.0001, indicating very good sensitivity and specificity of the test.
    The cutoff value is the point of intersection between the sensitivity and specificity curves (Figure 2B) and is 74.5 EDEL in this particular product. The greatest positive probability and the smallest negative probability are associated with the optimal cut-off value.
    The validity of the present invention is also demonstrated by the following results obtained on a double dose of platelet apheresis concentrate treated with the INTERCEPT system (Cerus) (Figure 3). The treated platelet concentrate shows a significantly lower value (53 ± 17 EDEL) compared to the same untreated sample (97 ± 15 EDEL, p <0.0001). The EDEL limit value of 74.5 EDEL has been defined for this product (Figure 2). Below this limit value, it can be considered that the photochemical treatment was completely carried out. In this particular example, the risk of false positives is 1%, that of false negatives is 4%. This is due to the variability between donors in terms of their difference in the antioxidant potency of the plasma. As an example, the average antioxidant potency of a double dose of untreated aphera platelet concentrate is 97 EDEL with a minimum value of 71 EDEL and a maximum value of 131 EDEL.
    The present invention can also be applied to other products derived from blood, comprising for example, but not limited to plasma treated with the INTERCEPT system (Cerus) (Figure 4). Plasma bags (n = 6 and n = 12 for untreated and treated plasma, respectively) were analyzed to measure their antioxidant potency with EDEL technology. The antioxidant potency of untreated plasma was 175 ± 13 EDEL. After INTERCEPT treatment, the EDEL value is drastically reduced and falls from 175 ± 13 EDEL to 90 ± 7 EDEL (p <0.0001). No false positives or false negatives were detected in this case.
    [0030] Exposure to ultraviolet is also a common procedure for killing potential contaminants in a variety of products, including cosmetics. Figure 5 shows that 15 minutes of exposure to ultraviolet (280 nm, d = 5 cm) reduces the antioxidant power of a cosmetic formulation by half and 30 minutes is sufficient to reduce it to 0.
    The present invention, including, but not limited to the use of EDEL technology to measure antioxidant potency can be used to confirm the performance of inactivation treatments of pathogens or targeted cells in the blood, blood-derived products and cosmetic products according to this description. In particular, the use of the EDEL test to measure antioxidant potency can be used to confirm the execution of pathogen or target cell inactivation treatments in blood and blood products.
    References
    [0032] 1. anon., Gamma Irradiators for Radiation Processing, IAEA, Vienna, 2005 2. http://www.sterigenics.com/services/food_safetylfood_irradiation_questions_a nswers.pdf 3. GENERAL STANDARD FOR THE LABELLING OF PREPACKAGED FOODS, CODEX STAN 1-1985 4. Transfusion medicine and hemostasis, CD Hillyer, BH Shaz, JC Zimring, TC Abshire, Elsevier ISBN 978-0-12-374432 5. Council of Europe EDftQoMH, European Committee on Blood Transfusion. Guide to the repair, use and quality assurance of blood components, 18th edition (CD-P-TS), p. 102.2015; Bakkour S, Chafets DM, Wen L, et al. 6. Development of a mitochondrial DNA real-time polymerase chain reaction assay for quality control of pathogen reduction with riboflavin and ultraviolet light. Vox Blood. 2014. 7. Monitoring photochemical pathogen inactivation treatment using amotosalen and ultraviolet-A light: evaluation of an indicator label. Isola H, Brandner D, Cazenave JP, et al. Vox Blood. 2010; 99 (4): 402. 8. Pathogen Inactivation of Platelet and Plasma Blood Components for Transfusion Using the INTERCEPT Blood System. Irsch J, Lin L. Transfus Med Hemother. 2011; 38 (1): 19-31. 9. Effect of the psoralen-based photochemical pathogen inactivation on mitochondrial DNA in platelets. Platelets. ; Bruchmuller I, Losel R, Bugert P, et al. 2005; 16 (8): 441-5; 10. Targeting DNA and RNA in Pathogens: Mode of Action of Amotosalen HCI. Transfusion Medicine and Hemotherapy. Wollowitz S 2004: 11-6. 11. Effect of the psoralen-based photochemical pathogen inactivation on mitochondrial DNA in platelets. Platelets. Bruchmuller I, Losel R, Bugert P, et al. 2005; 16 (8): 441-5. 12. Polymerase chain reaction inhibition assay documenting the amotosalen-based photochemical pathogen inactivation process of platelet concentrates. Transfusion. Bruchmuller I, Janetzko K, Bugert P, et al. 2005; 45 (9): 1464-72. 13. Effect of the psoralen-based photochemical pathogen inactivation on mitochondrial DNA in platelet. Bruchmuller I, Losel R, Bugert P, et al Platelets. 2005; 16 (8): 441. 14. Development of a mitochondrial DNA real-time polymerase chain reaction assay for quality control of pathogen reduction with riboflavin and ultraviolet light. Bakkour S, Chafets DM, Wen L, et al. Vox Blood. 2014. 15. Potentiometric study of antioxidant activity: development and prospects. Crit Rev Anal Chem. Ivanova AV1, Gerasimova EL, Brainina KhZ. 2015; 45 (4): 311-22. 16. Electrochemical Pseudo-Titration of Water-Soluble Antioxidants. Philippe Tacchini, Andreas Lesch, Alice Neequaye, Gregoire Lagger, Jifeng Liu, Fernando Cort.s-Salazar, Hubert H Girault, Electroanalysis, vol. 25 (4), p. 922-930, 2013. 18. WO 2006094529 A1 19. Role of alkoxyl radicals on the fluorescein-based ORAC (Oxygen Radical Absorbance Capacity) assay. Dorta E, Atala E, Aspee A, Speisky H, Lissi E, Lopez-Alarcon C. Free Radic Biol Med. 2014 Oct; 75 Suppl 1: S38. 20. Use and Abuse of the DPPH (·) Radical. Foti MC. J Agric Food Chem. 2015 Oct 14; 63 (40): 8765-76. 21 Assessing and comparing the total antioxidant capacity of commercial beverages: application to beers, wines, waters and soft drinks using TRAP, TEAC and FRAP methods. Queirós RB1, Tafulo PA, Sales MG, Comb Chem High Throughput Screen. 2013 Jan; 16 (1): 22-31. 22. A Continuous Visible Light Spectrophotometric Approach To Accurately Determine the Reactivity of Radical-Trapping Antioxidants. Haidasz EA, Van Kessel AT, Pratt DA. J Org Chem. 2015 Nov 13. 23. Determination of polyphenolic compounds in Cirsium palustre (L.) extracts by high performance liquid chromatography with chemiluminescence detection. Nalewajko-Sieliwoniuk E, Malejko J, Mozolewska M, Wolyniec E, Nazaruk J. Talanta. 2015 Feb; 133: 38-44. talanta.2014 24. Identification and semi-quantitative determination of anti-oxidants in lubricants employing thin-layer chromatography-spray mass spectrometry.Kreisberger G, Himmelsbach M, Buchberger W, Klampfl CW. J Chromatogr A. 2015 Feb 27; 1383: 169-74.
    权利要求:
    Claims (7)
    [1]
    1.method for determining whether treatments applied to inactivate pathogens or target cells in blood, blood-derived products and cosmetic products, have been performed completely, said products being products that exhibit measurable antioxidant activity before their treatment, this method comprising;a) make available a sample of a product which has been exposed to a light, photo-chemical, chemical or radiation-based treatment to inactivate the pathogens or the targeted cells;b) Measure the antioxidant power of said sample;c) i) compare the value of the antioxidant power obtained in phase b) with the value of the antioxidant power obtained by measuring another sample of said product, this other sample of said product not having been the subject of the treatment applied to inactivate pathogens or targeted cells,ii) compare the values of the antioxidant power obtained in phase b) with a value of the predetermined antioxidant power and considered as a limit value, below which the said product is considered to be successfully treated,and oriii) compare the value of the antioxidant power obtained in phase b) with the value of the antioxidant power of the same product not treated to inactivate the pathogens or the target cells, so as to calculate the reduction in the antioxidant power by subtracting the value of the antioxidant power of the treated product with the value of the antioxidant power of the untreated product, and comparing said reduction in antioxidant power to a predefined value, said predefined value corresponding to the expected reduction.
    [2]
    2. Method according to claim 1, in which the limit value of the antioxidant power is determined before phase c) by using the measurements of the antioxidant power of said treated and untreated sample.
    [3]
    3. Method according to claim 1 or 2, wherein said product is a cosmetic product selected from a group of formulations for the treatment of the skin, nails, lips, hair and eyes.
    [4]
    4. The method of claim 1 or 2, wherein the products derived from blood are selected from a group of products which include platelet concentrates, plasma and erythrocyte concentrates.
    [5]
    5. Method according to any one of the preceding claims, in which the antioxidant power is measured by electrochemistry, spectrophotometry or by liquid chromatography and / or mass spectrometry.
    [6]
    6. Method according to any one of the preceding claims, in which the antioxidant power is measured by electrochemical pseudo-titration.
    [7]
    7. Method according to any one of the preceding claims, in which the predetermined limit value of the antioxidant power of the product is established before step c) by measuring the antioxidant power of the product in a statistically relevant number of samples, as well before only after treatment.
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    同族专利:
    公开号 | 公开日
    WO2017103661A1|2017-06-22|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2002082093A2|2001-04-02|2002-10-17|Tufts University|Methods to measure lipid antioxidant activity|
    CA2601247A1|2005-03-11|2006-09-14|Edel Therapeutics S.A.|Method and device for the electrochemical pseudo-titration of antioxidant substances|
    RU2015126762A|2012-12-18|2017-01-25|Караг Аг|DEVICE AND METHOD FOR PASTERIZATION OF BREAST MILK|CA3108065A1|2018-07-31|2020-02-06|Loxo Oncology, Inc.|Spray-dried dispersions and formulations of -5-amino-3-methyl)phenyl)-1--1h-pyrazole-4-carboxamide|
    法律状态:
    2019-09-13| PCAR| Change of the address of the representative|Free format text: NEW ADDRESS: C/O OMNIS-IP SA AVENUE DE RIOND-BOSSON 3, 1110 MORGES (CH) |
    2019-09-30| PUE| Assignment|Owner name: SERVICE REGIONAL VAUDOIS DE TRANSFUSION SANGUI, CH Free format text: FORMER OWNER: EDEL-FOR-LIFE S.A., CH |
    2019-12-30| AZW| Rejection (application)|
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/IB2015/059781|WO2017103661A1|2015-12-18|2015-12-18|Quality control assay to monitor the completeness of pathogen or targeted cell inactivation treatments in biological, foodstuff, drinks and cosmetics products|
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