JP2018532771A5 - - Google Patents
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- JP2018532771A5 JP2018532771A5 JP2018533996A JP2018533996A JP2018532771A5 JP 2018532771 A5 JP2018532771 A5 JP 2018532771A5 JP 2018533996 A JP2018533996 A JP 2018533996A JP 2018533996 A JP2018533996 A JP 2018533996A JP 2018532771 A5 JP2018532771 A5 JP 2018532771A5
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- Prior art keywords
- compound
- pharmaceutical composition
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- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims 45
- 239000008194 pharmaceutical composition Substances 0.000 claims 23
- 229910052739 hydrogen Inorganic materials 0.000 claims 9
- 239000001257 hydrogen Substances 0.000 claims 9
- 125000000217 alkyl group Chemical group 0.000 claims 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 7
- 201000010099 disease Diseases 0.000 claims 7
- 239000002552 dosage form Substances 0.000 claims 6
- 239000003937 drug carrier Substances 0.000 claims 4
- 208000001573 Cataplexy Diseases 0.000 claims 3
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 206010041349 Somnolence Diseases 0.000 claims 3
- 201000003631 narcolepsy Diseases 0.000 claims 3
- 150000003839 salts Chemical class 0.000 claims 3
- 239000000243 solution Substances 0.000 claims 3
- 208000001640 Fibromyalgia Diseases 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 206010043118 Tardive Dyskinesia Diseases 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
- 230000003111 delayed effect Effects 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 239000000839 emulsion Substances 0.000 claims 2
- 206010016256 fatigue Diseases 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims 2
- 239000008297 liquid dosage form Substances 0.000 claims 2
- 239000002002 slurry Substances 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 239000000725 suspension Substances 0.000 claims 2
- 239000012730 sustained-release form Substances 0.000 claims 2
- 239000006188 syrup Substances 0.000 claims 2
- 235000020357 syrup Nutrition 0.000 claims 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims 1
- 229920001817 Agar Polymers 0.000 claims 1
- 102000009027 Albumins Human genes 0.000 claims 1
- 108010088751 Albumins Proteins 0.000 claims 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 208000032841 Bulimia Diseases 0.000 claims 1
- 206010006550 Bulimia nervosa Diseases 0.000 claims 1
- 229920002101 Chitin Polymers 0.000 claims 1
- 229920001661 Chitosan Polymers 0.000 claims 1
- 102000008186 Collagen Human genes 0.000 claims 1
- 108010035532 Collagen Proteins 0.000 claims 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- 229920002307 Dextran Polymers 0.000 claims 1
- 108010010803 Gelatin Proteins 0.000 claims 1
- 229920000084 Gum arabic Polymers 0.000 claims 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims 1
- 229930195725 Mannitol Natural products 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims 1
- 241000720974 Protium Species 0.000 claims 1
- 241000978776 Senegalia senegal Species 0.000 claims 1
- 229920002472 Starch Polymers 0.000 claims 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims 1
- 229930006000 Sucrose Natural products 0.000 claims 1
- 229920001615 Tragacanth Polymers 0.000 claims 1
- 235000010489 acacia gum Nutrition 0.000 claims 1
- 239000000205 acacia gum Substances 0.000 claims 1
- 239000008272 agar Substances 0.000 claims 1
- 235000010419 agar Nutrition 0.000 claims 1
- 229940072056 alginate Drugs 0.000 claims 1
- 235000010443 alginic acid Nutrition 0.000 claims 1
- 229920000615 alginic acid Polymers 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims 1
- 239000000305 astragalus gummifer gum Substances 0.000 claims 1
- 230000031018 biological processes and functions Effects 0.000 claims 1
- 239000007894 caplet Substances 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- 239000005018 casein Substances 0.000 claims 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 claims 1
- 235000021240 caseins Nutrition 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 229920001436 collagen Polymers 0.000 claims 1
- 229910052805 deuterium Inorganic materials 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- -1 elixir Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000000796 flavoring agent Substances 0.000 claims 1
- 235000013355 food flavoring agent Nutrition 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 239000008273 gelatin Substances 0.000 claims 1
- 229920000159 gelatin Polymers 0.000 claims 1
- 235000019322 gelatine Nutrition 0.000 claims 1
- 235000011852 gelatine desserts Nutrition 0.000 claims 1
- 239000007897 gelcap Substances 0.000 claims 1
- 125000005456 glyceride group Chemical group 0.000 claims 1
- 239000008187 granular material Substances 0.000 claims 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims 1
- 239000008101 lactose Substances 0.000 claims 1
- 239000007937 lozenge Substances 0.000 claims 1
- 239000001630 malic acid Substances 0.000 claims 1
- 235000011090 malic acid Nutrition 0.000 claims 1
- 239000000845 maltitol Substances 0.000 claims 1
- 235000010449 maltitol Nutrition 0.000 claims 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims 1
- 229940035436 maltitol Drugs 0.000 claims 1
- 239000000594 mannitol Substances 0.000 claims 1
- 235000010355 mannitol Nutrition 0.000 claims 1
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 235000010981 methylcellulose Nutrition 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 230000004770 neurodegeneration Effects 0.000 claims 1
- 208000015122 neurodegenerative disease Diseases 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000001814 pectin Substances 0.000 claims 1
- 235000010987 pectin Nutrition 0.000 claims 1
- 229920001277 pectin Polymers 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000006187 pill Substances 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 239000000600 sorbitol Substances 0.000 claims 1
- 235000010356 sorbitol Nutrition 0.000 claims 1
- 239000008107 starch Substances 0.000 claims 1
- 235000019698 starch Nutrition 0.000 claims 1
- 239000005720 sucrose Substances 0.000 claims 1
- 235000000346 sugar Nutrition 0.000 claims 1
- 238000013268 sustained release Methods 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 229920001059 synthetic polymer Polymers 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNPCT/CN2015/090326 | 2015-09-23 | ||
| PCT/CN2015/090326 WO2017049470A1 (en) | 2015-09-23 | 2015-09-23 | Prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof |
| CN201610782104.1 | 2016-08-31 | ||
| CN201610782104 | 2016-08-31 | ||
| PCT/CN2016/099763 WO2017050259A1 (en) | 2015-09-23 | 2016-09-22 | Prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2021003292A Division JP2021073214A (ja) | 2015-09-23 | 2021-01-13 | γ−ヒドロキシ酪酸(GHB)のプロドラッグ、その組成物および使用 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| JP2018532771A JP2018532771A (ja) | 2018-11-08 |
| JP2018532771A5 true JP2018532771A5 (enExample) | 2019-11-07 |
| JP6830671B2 JP6830671B2 (ja) | 2021-02-17 |
| JP6830671B6 JP6830671B6 (ja) | 2021-03-10 |
Family
ID=58385660
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018533996A Active JP6830671B6 (ja) | 2015-09-23 | 2016-09-22 | γ−ヒドロキシ酪酸(GHB)のプロドラッグ、その組成物および使用 |
| JP2021003292A Pending JP2021073214A (ja) | 2015-09-23 | 2021-01-13 | γ−ヒドロキシ酪酸(GHB)のプロドラッグ、その組成物および使用 |
| JP2022167283A Pending JP2023011677A (ja) | 2015-09-23 | 2022-10-19 | γ-ヒドロキシ酪酸(GHB)のプロドラッグ、その組成物および使用 |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2021003292A Pending JP2021073214A (ja) | 2015-09-23 | 2021-01-13 | γ−ヒドロキシ酪酸(GHB)のプロドラッグ、その組成物および使用 |
| JP2022167283A Pending JP2023011677A (ja) | 2015-09-23 | 2022-10-19 | γ-ヒドロキシ酪酸(GHB)のプロドラッグ、その組成物および使用 |
Country Status (10)
| Country | Link |
|---|---|
| US (7) | US10457627B2 (enExample) |
| EP (2) | EP4119539A1 (enExample) |
| JP (3) | JP6830671B6 (enExample) |
| KR (1) | KR102279993B1 (enExample) |
| CN (2) | CN108283000B (enExample) |
| AU (1) | AU2016328150B2 (enExample) |
| CA (2) | CA3207643A1 (enExample) |
| ES (1) | ES2930848T3 (enExample) |
| TW (1) | TWI716458B (enExample) |
| WO (1) | WO2017050259A1 (enExample) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA3207643A1 (en) | 2015-09-23 | 2017-03-30 | XWPharma Ltd. | Prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof |
| UY37341A (es) | 2016-07-22 | 2017-11-30 | Flamel Ireland Ltd | Formulaciones de gamma-hidroxibutirato de liberación modificada con farmacocinética mejorada |
| US12478604B1 (en) | 2016-07-22 | 2025-11-25 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US11504347B1 (en) | 2016-07-22 | 2022-11-22 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US11986451B1 (en) | 2016-07-22 | 2024-05-21 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US11602512B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US11602513B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US11000498B2 (en) | 2016-07-22 | 2021-05-11 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US12186296B1 (en) | 2016-07-22 | 2025-01-07 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| KR102378845B1 (ko) | 2017-03-30 | 2022-03-24 | 엑스더블유파마 리미티드 | 이환형 헤테로아릴 유도체 및 이의 제조 및 용도 |
| US20200114015A1 (en) * | 2017-04-11 | 2020-04-16 | John K. Thottathil | Novel Alpha-Hydroxy Carboxylic Acid And Derivatives And Other GRAS- Based Prodrugs Of Gamma-Hydroxybutyrate (GHB) And Uses Thereof |
| CN112004802B (zh) | 2018-09-30 | 2021-12-28 | 凯瑞康宁生物工程(武汉)有限公司 | 作为神经元组胺受体-3拮抗剂的化合物及其用途 |
| AU2020231916B2 (en) | 2019-03-01 | 2025-08-28 | Flamel Ireland Limited | Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state |
| CN115244028A (zh) * | 2019-12-20 | 2022-10-25 | 凯瑞康宁生物工程有限公司 | 4-缬氨酰氧基丁酸的合成方法 |
| AU2021292406B2 (en) * | 2020-06-18 | 2024-03-14 | XWPharma Ltd. | Controlled release granulations of water-soluble active pharmaceutical ingredients |
| AU2021293941B2 (en) * | 2020-06-18 | 2024-03-28 | XWPharma Ltd. | Pharmaceutical granulations of water-soluble active pharmaceutical ingredients |
| CN116261451A (zh) * | 2020-07-24 | 2023-06-13 | 凯瑞康宁生物工程有限公司 | γ-羟基丁酸衍生物的药物组合物和药物动力学 |
| CN115666527B (zh) | 2020-10-05 | 2025-03-07 | 凯瑞康宁生物工程有限公司 | γ-羟基丁酸衍生物的修饰释放组合物 |
| TW202300139A (zh) * | 2021-03-19 | 2023-01-01 | 凱瑞康寧生技股份有限公司 | γ-羟基丁酸衍生物的聯合釋放製劑的藥代動力學 |
| US20230110028A1 (en) * | 2021-08-11 | 2023-04-13 | Tris Pharma, Inc. | Oxybate polyethylene glycol prodrugs |
| US11779557B1 (en) | 2022-02-07 | 2023-10-10 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
| US11583510B1 (en) | 2022-02-07 | 2023-02-21 | Flamel Ireland Limited | Methods of administering gamma hydroxybutyrate formulations after a high-fat meal |
| AU2023257266A1 (en) * | 2022-04-21 | 2024-08-22 | Zevra Therapeutics, Inc. | Gamma-hydroxybutyrate delivering compounds and processes for making and using them |
| US20240092727A1 (en) | 2022-09-06 | 2024-03-21 | XWPharma Ltd. | Crystalline 4-((l-valyl)oxy)butanoic acid |
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-
2016
- 2016-09-22 CA CA3207643A patent/CA3207643A1/en active Pending
- 2016-09-22 EP EP22193274.2A patent/EP4119539A1/en not_active Withdrawn
- 2016-09-22 EP EP16848140.6A patent/EP3353145B1/en active Active
- 2016-09-22 CN CN201680055377.4A patent/CN108283000B/zh active Active
- 2016-09-22 US US15/762,559 patent/US10457627B2/en active Active
- 2016-09-22 ES ES16848140T patent/ES2930848T3/es active Active
- 2016-09-22 CN CN202110325330.8A patent/CN113061089A/zh active Pending
- 2016-09-22 WO PCT/CN2016/099763 patent/WO2017050259A1/en not_active Ceased
- 2016-09-22 AU AU2016328150A patent/AU2016328150B2/en active Active
- 2016-09-22 KR KR1020187010448A patent/KR102279993B1/ko active Active
- 2016-09-22 JP JP2018533996A patent/JP6830671B6/ja active Active
- 2016-09-22 CA CA2999367A patent/CA2999367C/en active Active
- 2016-09-23 TW TW105130864A patent/TWI716458B/zh active
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2019
- 2019-02-13 US US16/275,165 patent/US10501401B2/en active Active
- 2019-10-15 US US16/601,908 patent/US10640451B2/en active Active
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2020
- 2020-03-26 US US16/831,086 patent/US10774031B2/en active Active
- 2020-08-07 US US16/988,027 patent/US10941107B2/en active Active
- 2020-08-07 US US16/988,200 patent/US20200369599A1/en not_active Abandoned
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- 2021-01-13 JP JP2021003292A patent/JP2021073214A/ja active Pending
- 2021-01-14 US US17/149,170 patent/US20210130281A1/en not_active Abandoned
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2022
- 2022-10-19 JP JP2022167283A patent/JP2023011677A/ja active Pending
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