JP2020530282A5 - - Google Patents
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- Publication number
- JP2020530282A5 JP2020530282A5 JP2020500057A JP2020500057A JP2020530282A5 JP 2020530282 A5 JP2020530282 A5 JP 2020530282A5 JP 2020500057 A JP2020500057 A JP 2020500057A JP 2020500057 A JP2020500057 A JP 2020500057A JP 2020530282 A5 JP2020530282 A5 JP 2020530282A5
- Authority
- JP
- Japan
- Prior art keywords
- uricase
- replaced
- utilis
- recombinant
- recombinant variant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108010092464 Urate Oxidase Proteins 0.000 claims description 79
- 241000735249 Madhuca utilis Species 0.000 claims description 24
- 241000235646 Cyberlindnera jadinii Species 0.000 claims description 21
- 235000004279 alanine Nutrition 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 19
- 230000035772 mutation Effects 0.000 claims description 19
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 16
- 238000006467 substitution reaction Methods 0.000 claims description 14
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 13
- 102220357239 c.151G>A Human genes 0.000 claims description 13
- 235000013922 glutamic acid Nutrition 0.000 claims description 13
- 239000004220 glutamic acid Substances 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 9
- 235000003704 aspartic acid Nutrition 0.000 claims description 9
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 9
- 239000013604 expression vector Substances 0.000 claims description 9
- 239000004471 Glycine Substances 0.000 claims description 8
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 8
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 8
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 8
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 8
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 8
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 8
- 229960000310 isoleucine Drugs 0.000 claims description 8
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 8
- 239000004474 valine Substances 0.000 claims description 8
- 239000004472 Lysine Substances 0.000 claims description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 7
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 7
- 239000004473 Threonine Substances 0.000 claims description 7
- 201000005569 Gout Diseases 0.000 claims description 6
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 6
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 239000003064 xanthine oxidase inhibitor Substances 0.000 claims description 6
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 5
- 108010019160 Pancreatin Proteins 0.000 claims description 5
- 229940116731 Uricosuric agent Drugs 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 150000007523 nucleic acids Chemical group 0.000 claims description 5
- 229940055695 pancreatin Drugs 0.000 claims description 5
- 239000003383 uricosuric agent Substances 0.000 claims description 5
- 239000004475 Arginine Substances 0.000 claims description 4
- 241000588724 Escherichia coli Species 0.000 claims description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims description 4
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007903 gelatin capsule Substances 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 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 description 4
- 239000006186 oral dosage form Substances 0.000 claims description 4
- 239000006201 parenteral dosage form Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 229940116269 uric acid Drugs 0.000 claims description 4
- 102220518628 Baculoviral IAP repeat-containing protein 6_T47E_mutation Human genes 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000006207 intravenous dosage form Substances 0.000 claims description 2
- 239000008185 minitablet Substances 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 229920003169 water-soluble polymer Polymers 0.000 claims description 2
- 102200038952 rs3762568 Human genes 0.000 claims 9
- 239000000203 mixture Substances 0.000 claims 7
- 150000001413 amino acids Chemical group 0.000 claims 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N Alanine Chemical compound CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 102000039446 nucleic acids Human genes 0.000 claims 1
- 108020004707 nucleic acids Proteins 0.000 claims 1
- 239000002773 nucleotide Substances 0.000 claims 1
- 125000003729 nucleotide group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 description 21
- 201000001431 Hyperuricemia Diseases 0.000 description 8
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- -1 (d) at position 51 Chemical compound 0.000 description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 description 2
- 229960003459 allopurinol Drugs 0.000 description 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical group OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 2
- 229960002529 benzbromarone Drugs 0.000 description 2
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 2
- 229960005101 febuxostat Drugs 0.000 description 2
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 2
- 229960004773 losartan Drugs 0.000 description 2
- 229960003081 probenecid Drugs 0.000 description 2
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical group CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 230000003424 uricosuric effect Effects 0.000 description 1
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2023109386A JP2023126877A (ja) | 2017-07-07 | 2023-07-03 | 組換えウリカーゼ酵素 |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762529726P | 2017-07-07 | 2017-07-07 | |
| US62/529,726 | 2017-07-07 | ||
| US201862678511P | 2018-05-31 | 2018-05-31 | |
| US62/678,511 | 2018-05-31 | ||
| PCT/US2018/041015 WO2019010369A1 (en) | 2017-07-07 | 2018-07-06 | RECOMBINANT ENZYME URICASE |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2023109386A Division JP2023126877A (ja) | 2017-07-07 | 2023-07-03 | 組換えウリカーゼ酵素 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2020530282A JP2020530282A (ja) | 2020-10-22 |
| JP2020530282A5 true JP2020530282A5 (enExample) | 2021-08-12 |
Family
ID=64951239
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020500057A Pending JP2020530282A (ja) | 2017-07-07 | 2018-07-06 | 組換えウリカーゼ酵素 |
| JP2023109386A Pending JP2023126877A (ja) | 2017-07-07 | 2023-07-03 | 組換えウリカーゼ酵素 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2023109386A Pending JP2023126877A (ja) | 2017-07-07 | 2023-07-03 | 組換えウリカーゼ酵素 |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US20200308534A1 (enExample) |
| EP (1) | EP3655527A4 (enExample) |
| JP (2) | JP2020530282A (enExample) |
| CN (1) | CN111373034A (enExample) |
| AU (1) | AU2018297309A1 (enExample) |
| CA (1) | CA3069197A1 (enExample) |
| IL (1) | IL271813A (enExample) |
| WO (1) | WO2019010369A1 (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112646790A (zh) * | 2019-10-11 | 2021-04-13 | 上海君实生物医药科技股份有限公司 | 改进的尿酸酶及其用于治疗高尿酸血症的方法 |
| EP4110283A4 (en) * | 2020-02-25 | 2024-02-28 | Synlogic Operating Company, Inc. | Recombinant bacteria engineered to treat diseases associated with uric acid and methods of use thereof |
| KR20230110281A (ko) | 2020-11-03 | 2023-07-21 | 프로탈릭스 리미티드 | 변형된 유리카제(uricase) 및 이의 용도 |
| CN114480320B (zh) * | 2022-02-28 | 2024-01-16 | 复旦大学 | 重组夜猴尿酸酶及其应用 |
| CN118497162B (zh) * | 2024-05-24 | 2025-05-16 | 广东少和生物科技有限公司 | 黑酵母菌尿酸氧化酶及其突变体和应用 |
| CN119876071B (zh) * | 2025-03-12 | 2025-10-21 | 开平牵牛生化制药有限公司 | 低免疫原性的高活性人源尿酸氧化酶突变体 |
| CN119876069B (zh) * | 2025-03-12 | 2025-10-21 | 开平牵牛生化制药有限公司 | 具有高活性且免疫原性弱化的人源尿酸氧化酶突变体 |
Family Cites Families (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3462313B2 (ja) * | 1995-08-24 | 2003-11-05 | キッコーマン株式会社 | 変異型ウリカーゼ、変異型ウリカーゼ遺伝子、新規な組み換え体ｄｎａ及び変異型ウリカーゼの製造法 |
| US6783965B1 (en) | 2000-02-10 | 2004-08-31 | Mountain View Pharmaceuticals, Inc. | Aggregate-free urate oxidase for preparation of non-immunogenic polymer conjugates |
| PT1588716E (pt) | 1998-08-06 | 2011-05-25 | Mountain View Pharmaceuticals | Conjugados de peg-urato oxidase e sua utiliza??o |
| US6913915B2 (en) | 2001-08-02 | 2005-07-05 | Phoenix Pharmacologics, Inc. | PEG-modified uricase |
| US20050049166A1 (en) * | 2003-08-29 | 2005-03-03 | Huang Tsao-Chin Clare | Enzyme-based cleaning composition and method of use |
| GB0326676D0 (en) * | 2003-11-15 | 2003-12-17 | Astrazeneca Ab | Protein |
| CN1980687B (zh) * | 2004-02-09 | 2015-05-13 | 人类基因科学公司 | 清蛋白融合蛋白 |
| JP2008506785A (ja) | 2004-07-21 | 2008-03-06 | フロリダ大学 リサーチファウンデーション インコーポレイティッド | インスリン抵抗性の治療及び予防のための組成物及び方法 |
| JP5033177B2 (ja) | 2006-04-12 | 2012-09-26 | サビエント ファーマセウティカルズ インク． | 陽イオン界面活性剤によるタンパク質の精製 |
| WO2009120707A1 (en) * | 2008-03-24 | 2009-10-01 | Altus Pharmaceuticals Inc. | Uricase compositions and methods of use |
| CN101390969A (zh) * | 2008-11-03 | 2009-03-25 | 中国人民解放军军事医学科学院生物工程研究所 | 降低血液中尿酸浓度的药物 |
| CN101875922B (zh) * | 2009-04-30 | 2012-02-22 | 重庆医科大学 | 一种重组苛求芽孢杆菌胞内尿酸酶及其聚乙二醇修饰与应用 |
| PL398781A1 (pl) | 2009-06-25 | 2012-11-19 | Savient Pharmaceuticals, Inc. | Sposoby i zestawy do prognozowania ryzyka wystapienia reakcji na wlew oraz zaniku odpowiedzi której posrednicza przeciwciala poprzez monitorowanie kwasu moczowego w surowicy podczas terapii z zastosowaniem pegylowanej urykazy |
| CN109706217B (zh) * | 2010-02-05 | 2022-12-09 | 新英格兰生物实验室公司 | 高保真性限制性内切核酸酶 |
| CN102586315A (zh) * | 2012-02-21 | 2012-07-18 | 章泽人 | 一种低尿酸分泌量益生菌及其制备方法 |
| EP2986720B1 (en) * | 2013-04-17 | 2017-09-06 | Council of Scientific & Industrial Research | Uricase mutants |
| CN104342415A (zh) * | 2014-07-08 | 2015-02-11 | 吉林省金梓源生物科技有限公司 | 一种重组尿酸酶的制备方法 |
| TW201618773A (zh) * | 2014-08-11 | 2016-06-01 | 艾森塔製藥公司 | Ｂｔｋ抑制劑、ｐｉ３ｋ抑制劑、ｊａｋ－２抑制劑、及／或ｃｄｋ４／６抑制劑的治療組合物 |
| CN106554948B (zh) | 2015-09-29 | 2019-06-25 | 上海生物制品研究所有限责任公司 | 突变型尿酸酶、peg修饰的突变型尿酸酶及其应用 |
| EP4445955A3 (en) | 2016-03-11 | 2025-01-08 | Cartesian Therapeutics, Inc. | Formulations and doses of pegylated uricase |
| EP3538135A4 (en) | 2016-11-11 | 2020-07-29 | Horizon Pharma Rheumatology LLC | POLYTHERAPIES OF PREDNISONE AND URICASE MOLECULES AND THEIR USES |
| CN110612122A (zh) | 2017-03-11 | 2019-12-24 | 西莱克塔生物科技公司 | 与用抗炎剂和包含免疫抑制剂之合成纳米载体进行的组合治疗相关的方法和组合物 |
| CN107308452A (zh) * | 2017-05-29 | 2017-11-03 | 钟术光 | 一种稳定生物活性材料的组合物的制备方法 |
| GB201713732D0 (en) * | 2017-08-25 | 2017-10-11 | Alta Innovations Ltd | Tat expression system |
| CN109223707B (zh) | 2018-09-13 | 2020-12-08 | 中国药科大学 | 一种尿酸酶外用凝胶制剂、其制备方法及用途 |
| CN109846909B (zh) * | 2019-01-31 | 2022-03-22 | 武汉康复得生物科技股份有限公司 | 可在肠道中催化尿酸降解的组合物及其制备方法和应用 |
| CA3139550A1 (en) * | 2019-05-10 | 2020-11-19 | Peg-Bio Biopharm Co., Ltd. (Chongqing) | Polyethylene glycol-modified urate oxidase |
-
2018
- 2018-07-06 CA CA3069197A patent/CA3069197A1/en active Pending
- 2018-07-06 AU AU2018297309A patent/AU2018297309A1/en not_active Abandoned
- 2018-07-06 US US16/628,743 patent/US20200308534A1/en not_active Abandoned
- 2018-07-06 CN CN201880054605.5A patent/CN111373034A/zh active Pending
- 2018-07-06 JP JP2020500057A patent/JP2020530282A/ja active Pending
- 2018-07-06 WO PCT/US2018/041015 patent/WO2019010369A1/en not_active Ceased
- 2018-07-06 EP EP18827590.3A patent/EP3655527A4/en not_active Withdrawn
-
2019
- 2019-11-05 US US16/674,325 patent/US10815461B2/en active Active
-
2020
- 2020-01-02 IL IL271813A patent/IL271813A/en unknown
-
2023
- 2023-07-03 JP JP2023109386A patent/JP2023126877A/ja active Pending
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