JP2016520586A5 - - Google Patents
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- JP2016520586A5 JP2016520586A5 JP2016513093A JP2016513093A JP2016520586A5 JP 2016520586 A5 JP2016520586 A5 JP 2016520586A5 JP 2016513093 A JP2016513093 A JP 2016513093A JP 2016513093 A JP2016513093 A JP 2016513093A JP 2016520586 A5 JP2016520586 A5 JP 2016520586A5
- Authority
- JP
- Japan
- Prior art keywords
- construct
- her3
- polypeptide construct
- her2
- amino acid
- 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.)
- Withdrawn
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- 229920001184 polypeptide Polymers 0.000 claims description 115
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 115
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 115
- 239000000427 antigen Substances 0.000 claims description 108
- 102000036639 antigens Human genes 0.000 claims description 108
- 108091007433 antigens Proteins 0.000 claims description 108
- 210000004027 cell Anatomy 0.000 claims description 68
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 54
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 54
- 101001010819 Homo sapiens Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 claims description 50
- 206010028980 Neoplasm Diseases 0.000 claims description 49
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims description 48
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 claims description 48
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 34
- 206010006187 Breast cancer Diseases 0.000 claims description 26
- 208000026310 Breast neoplasm Diseases 0.000 claims description 26
- 229960000575 trastuzumab Drugs 0.000 claims description 26
- 102000040430 polynucleotide Human genes 0.000 claims description 25
- 108091033319 polynucleotide Proteins 0.000 claims description 25
- 239000002157 polynucleotide Substances 0.000 claims description 25
- 201000011510 cancer Diseases 0.000 claims description 22
- 241000124008 Mammalia Species 0.000 claims description 17
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 claims description 15
- 239000013598 vector Substances 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 230000011664 signaling Effects 0.000 claims description 8
- 102400000058 Neuregulin-1 Human genes 0.000 claims description 6
- 108090000556 Neuregulin-1 Proteins 0.000 claims description 6
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 6
- 230000005907 cancer growth Effects 0.000 claims description 6
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 6
- 230000035755 proliferation Effects 0.000 claims description 5
- 239000003053 toxin Substances 0.000 claims description 5
- 231100000765 toxin Toxicity 0.000 claims description 5
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 4
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229940127089 cytotoxic agent Drugs 0.000 claims description 4
- 238000006471 dimerization reaction Methods 0.000 claims description 4
- 229960001433 erlotinib Drugs 0.000 claims description 4
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 239000000833 heterodimer Substances 0.000 claims description 4
- 229960004891 lapatinib Drugs 0.000 claims description 4
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 4
- 229960002087 pertuzumab Drugs 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 229960001612 trastuzumab emtansine Drugs 0.000 claims description 4
- 210000004881 tumor cell Anatomy 0.000 claims description 4
- 229930126263 Maytansine Natural products 0.000 claims description 3
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 claims description 3
- 230000002018 overexpression Effects 0.000 claims description 3
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 2
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 claims description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 claims description 2
- 241000699802 Cricetulus griseus Species 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 2
- 208000035327 Oestrogen receptor positive breast cancer Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 108010044540 auristatin Proteins 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims description 2
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 claims description 2
- 229930195731 calicheamicin Natural products 0.000 claims description 2
- 229960004117 capecitabine Drugs 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 229960005395 cetuximab Drugs 0.000 claims description 2
- 239000002738 chelating agent Substances 0.000 claims description 2
- 238000002512 chemotherapy Methods 0.000 claims description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- 238000012258 culturing Methods 0.000 claims description 2
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 2
- 239000000539 dimer Substances 0.000 claims description 2
- 238000010494 dissociation reaction Methods 0.000 claims description 2
- 230000005593 dissociations Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000328 estrogen antagonist Substances 0.000 claims description 2
- 102000015694 estrogen receptors Human genes 0.000 claims description 2
- 108010038795 estrogen receptors Proteins 0.000 claims description 2
- 201000007281 estrogen-receptor positive breast cancer Diseases 0.000 claims description 2
- 201000006585 gastric adenocarcinoma Diseases 0.000 claims description 2
- 229960002584 gefitinib Drugs 0.000 claims description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 2
- 230000014509 gene expression Effects 0.000 claims description 2
- 239000003102 growth factor Substances 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 210000004408 hybridoma Anatomy 0.000 claims description 2
- 238000003364 immunohistochemistry Methods 0.000 claims description 2
- 239000002955 immunomodulating agent Substances 0.000 claims description 2
- 229940121354 immunomodulator Drugs 0.000 claims description 2
- 230000002584 immunomodulator Effects 0.000 claims description 2
- 230000001939 inductive effect Effects 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 229940043355 kinase inhibitor Drugs 0.000 claims description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims description 2
- 229960003881 letrozole Drugs 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000026535 luminal A breast carcinoma Diseases 0.000 claims description 2
- 208000026534 luminal B breast carcinoma Diseases 0.000 claims description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 229940124302 mTOR inhibitor Drugs 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 238000012986 modification Methods 0.000 claims description 2
- 230000004048 modification Effects 0.000 claims description 2
- 230000035772 mutation Effects 0.000 claims description 2
- 230000002611 ovarian Effects 0.000 claims description 2
- 210000001672 ovary Anatomy 0.000 claims description 2
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 2
- 201000005825 prostate adenocarcinoma Diseases 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 230000002285 radioactive effect Effects 0.000 claims description 2
- 150000003384 small molecules Chemical class 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 238000000338 in vitro Methods 0.000 claims 3
- 208000037841 lung tumor Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 241001465754 Metazoa Species 0.000 description 4
- 229960005558 mertansine Drugs 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 231100000682 maximum tolerated dose Toxicity 0.000 description 2
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 description 1
- 101000652736 Homo sapiens Transgelin Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 102100031013 Transgelin Human genes 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361821197P | 2013-05-08 | 2013-05-08 | |
| US61/821,197 | 2013-05-08 | ||
| PCT/US2014/037401 WO2014182970A1 (en) | 2013-05-08 | 2014-05-08 | Bispecific her2 and her3 antigen binding constructs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2016520586A JP2016520586A (ja) | 2016-07-14 |
| JP2016520586A5 true JP2016520586A5 (enExample) | 2017-06-15 |
Family
ID=51867759
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016513093A Withdrawn JP2016520586A (ja) | 2013-05-08 | 2014-05-08 | 二重特異性ｈｅｒ２およびｈｅｒ３抗原結合性構築物 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US10239951B2 (enExample) |
| EP (1) | EP2994164B1 (enExample) |
| JP (1) | JP2016520586A (enExample) |
| AU (1) | AU2014262566A1 (enExample) |
| CA (1) | CA2910945A1 (enExample) |
| WO (1) | WO2014182970A1 (enExample) |
Families Citing this family (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2604490C2 (ru) | 2010-11-05 | 2016-12-10 | Займворкс Инк. | ДИЗАЙН УСТОЙЧИВОГО ГЕТЕРОДИМЕРНОГО АНТИТЕЛА С МУТАЦИЯМИ В Fc ДОМЕНЕ |
| AU2012222833B2 (en) | 2011-03-03 | 2017-03-16 | Zymeworks Inc. | Multivalent heteromultimer scaffold design and constructs |
| KR102052774B1 (ko) | 2011-11-04 | 2019-12-04 | 자임워크스 인코포레이티드 | Ｆｃ 도메인 내의 돌연변이를 갖는 안정한 이종이합체 항체 설계 |
| SG11201405468QA (en) | 2012-03-14 | 2014-10-30 | Regeneron Pharma | Multispecific antigen-binding molecules and uses thereof |
| US9499634B2 (en) | 2012-06-25 | 2016-11-22 | Zymeworks Inc. | Process and methods for efficient manufacturing of highly pure asymmetric antibodies in mammalian cells |
| IN2015DN01115A (enExample) | 2012-07-13 | 2015-06-26 | Zymeworks Inc | |
| KR102545617B1 (ko) | 2012-11-28 | 2023-06-20 | 자임워크스 비씨 인코포레이티드 | 가공된 면역글로불린 중쇄-경쇄 쌍 및 이들의 용도 |
| US9914785B2 (en) | 2012-11-28 | 2018-03-13 | Zymeworks Inc. | Engineered immunoglobulin heavy chain-light chain pairs and uses thereof |
| SI3110849T1 (sl) | 2014-02-28 | 2021-01-29 | Merus N.V. | Protitelo, ki veže ERBB-2 in ERBB-3 |
| EA201692476A1 (ru) | 2014-05-28 | 2017-07-31 | Займворкс Инк. | Модифицированные антигенсвязывающие полипептидные конструкции и их применение |
| US11566082B2 (en) | 2014-11-17 | 2023-01-31 | Cytiva Bioprocess R&D Ab | Mutated immunoglobulin-binding polypeptides |
| CA2968258A1 (en) | 2014-11-27 | 2016-06-02 | Zymeworks Inc. | Methods of using bispecific antigen-binding constructs targeting her2 |
| KR20180025865A (ko) | 2015-07-06 | 2018-03-09 | 리제너론 파마슈티칼스 인코포레이티드 | 다중특이적 항원 결합 분자 및 이의 용도 |
| EP3322735A4 (en) | 2015-07-15 | 2019-03-13 | Zymeworks Inc. | ACTIVE CONJUGATED BIS-SPECIFIC ANTIGEN-BONDING CONSTRUCTS |
| CA3000869A1 (en) * | 2015-10-08 | 2017-04-13 | Zymeworks Inc. | Antigen-binding polypeptide constructs comprising kappa and lambda light chains and uses thereof |
| BR112018008068A2 (en) | 2015-10-23 | 2018-11-13 | Merus N.V. | binding molecules that inhibit cancer growth |
| MA43416A (fr) | 2015-12-11 | 2018-10-17 | Regeneron Pharma | Méthodes pour ralentir ou empêcher la croissance de tumeurs résistantes au blocage de l'egfr et/ou d'erbb3 |
| WO2017102789A1 (en) * | 2015-12-17 | 2017-06-22 | F. Hoffmann-La Roche Ag | Combination therapy of anti-her3 antibodies and anti-her2 antibodies |
| US11352446B2 (en) | 2016-04-28 | 2022-06-07 | Regeneron Pharmaceuticals, Inc. | Methods of making multispecific antigen-binding molecules |
| US10889615B2 (en) | 2016-05-11 | 2021-01-12 | Cytiva Bioprocess R&D Ab | Mutated immunoglobulin-binding polypeptides |
| US10730908B2 (en) | 2016-05-11 | 2020-08-04 | Ge Healthcare Bioprocess R&D Ab | Separation method |
| US11708390B2 (en) | 2016-05-11 | 2023-07-25 | Cytiva Bioprocess R&D Ab | Method of storing a separation matrix |
| US10703774B2 (en) | 2016-09-30 | 2020-07-07 | Ge Healthcare Bioprocess R&D Ab | Separation method |
| JP7031934B2 (ja) | 2016-05-11 | 2022-03-08 | サイティバ・バイオプロセス・アールアンドディ・アクチボラグ | 分離マトリックス |
| ES2909833T3 (es) | 2016-05-11 | 2022-05-10 | Cytiva Bioprocess R & D Ab | Método de limpieza y/o desinfección de una matriz de separación |
| EP3455243B1 (en) | 2016-05-11 | 2021-03-24 | Cytiva BioProcess R&D AB | Separation matrix |
| US10654887B2 (en) | 2016-05-11 | 2020-05-19 | Ge Healthcare Bio-Process R&D Ab | Separation matrix |
| US12448411B2 (en) | 2016-09-30 | 2025-10-21 | Cytiva Bioprocess R&D Ab | Separation method |
| CA3058343A1 (en) | 2017-03-31 | 2018-10-04 | Merus N.V. | Erbb-2 and erbb-3 binding bispecific antibodies for use in the treatment of cells that have an nrg1 fusion gene |
| US12195551B2 (en) | 2017-05-17 | 2025-01-14 | Merus N.V. | Combination of an ErbB-2/ErbB-3 bispecific antibody with endocrine therapy for breast cancer |
| CN110809583A (zh) | 2017-06-07 | 2020-02-18 | 瑞泽恩制药公司 | 用于内化酶的组合物和方法 |
| HUE071182T2 (hu) | 2017-08-09 | 2025-08-28 | Merus Nv | EGFR és CMET kötõ antitestek |
| IL277049B2 (en) | 2018-03-13 | 2024-02-01 | Zymeworks Bc Inc | Conjugates of biparatopic anti-HER2 antibody and drug and methods of use |
| JP7328990B2 (ja) * | 2018-04-30 | 2023-08-17 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | Ｈｅｒ２及び／またはａｐｌｐ２に結合する抗体及び二重特異性抗原結合分子、ならびにそれらのコンジュゲート及び使用 |
| MX2020012350A (es) | 2018-05-17 | 2021-01-29 | Regeneron Pharma | Anticuerpos anti-cd63, conjugados y usos de estos. |
| GB201913079D0 (en) * | 2019-09-11 | 2019-10-23 | Hummingbird Bioscience Holdings Pte Ltd | Treatment and prevention of cancer using her3 antigen-binding molecules |
| TW202304994A (zh) | 2021-04-02 | 2023-02-01 | 美商泰尼歐生物公司 | 促效性抗ｉｌ－２ｒ抗體及使用方法 |
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2014
- 2014-05-08 WO PCT/US2014/037401 patent/WO2014182970A1/en not_active Ceased
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- 2014-05-08 CA CA2910945A patent/CA2910945A1/en not_active Abandoned
- 2014-05-08 US US14/888,580 patent/US10239951B2/en not_active Expired - Fee Related
- 2014-05-08 AU AU2014262566A patent/AU2014262566A1/en not_active Abandoned
- 2014-05-08 JP JP2016513093A patent/JP2016520586A/ja not_active Withdrawn
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