US20130245089A1 - Method for administration - Google Patents

Method for administration Download PDF

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Publication number
US20130245089A1
US20130245089A1 US13/759,647 US201313759647A US2013245089A1 US 20130245089 A1 US20130245089 A1 US 20130245089A1 US 201313759647 A US201313759647 A US 201313759647A US 2013245089 A1 US2013245089 A1 US 2013245089A1
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United States
Prior art keywords
day
compound
days
cancer
treatment
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Abandoned
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US13/759,647
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Inventor
Kelli Glenn
Brian Higgins
Gwen Nichols
Kathryn Packman
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Hoffmann La Roche Inc
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Hoffmann La Roche Inc
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Priority to US13/759,647 priority Critical patent/US20130245089A1/en
Assigned to HOFFMANN-LA ROCHE INC. reassignment HOFFMANN-LA ROCHE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GLENN, Kelli, HIGGINS, BRIAN, NICHOLS, Gwen, PACKMAN, KATHRYN
Publication of US20130245089A1 publication Critical patent/US20130245089A1/en
Priority to US14/217,929 priority patent/US20140200255A1/en
Priority to US14/596,747 priority patent/US20150126575A1/en
Priority to US14/673,153 priority patent/US20150202182A1/en
Priority to US16/510,256 priority patent/US20190328708A1/en
Priority to US16/519,516 priority patent/US11382892B2/en
Priority to US16/951,153 priority patent/US11738003B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention is related to improved methods of administration of 4- ⁇ [(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino ⁇ -3-methoxy-benzoic acid (referred to herein as Compound A) in the treatment of cancer.
  • the invention relates to improved methods of administration of Compound A that provide desirable antineoplastic effects with a tolerable level of toxicity.
  • the methods of the invention are characterized by administering less frequent doses comprising relatively high concentrations of Compound A. This protocol is expected to be safer and at least as effective as, possibly more effective than, administering more frequent doses at lower concentrations or larger doses at intermittent periods.
  • Compound A is an orally administered pyrrolidine that inhibits the binding of MDM2 to p53 and is thus useful in the treatment of cancer. It has the following chemical structure:
  • Compound A is especially effective, and best tolerated, in cancer therapy when administered in the specific doses and pursuant to the specific protocols herein described.
  • the present invention relates to a method of treating a patient suffering with cancer, in particular colon, breast, prostate, lung or kidney cancer or osteosarcoma, comprising administering to the patient Compound A in an amount of from about 800 to about 3000 mg/day, or from about 1000 to about 2500 mg/day, or from about 1250 to about 1800 mg/day, for an administration period of up to about 7 days, preferably up to about 5 days, on days 1-7, or preferably days 1-5, of a 28 day treatment cycle, followed by a rest period of from about 21 to about 23 days, preferably up to about 23 days.
  • FIG. 1 illustrates the antitumor activity, as demonstrated by the change in mean tumor volume over time, of Compound A monotherapy for a number of different dosing schedules, including a continuous 5 day dosing schedule.
  • FIG. 2 shows the increased lifespan of mice treated with Compound A for the different dosing schedules also reflected in FIG. 1 .
  • Tumor control means that the perpendicular diameters of measurable lesions have not increased by 25% or more from the last measurement. See, e.g., World Health Organization (“WHO”) Handbook for Reporting Results of Cancer Treatment, Geneva (1979).
  • WHO World Health Organization
  • the determination of tumor control or shrinkage is made by known methods. For example, by evaluation of patient symptoms, physical examination, X-ray, MRI or CAT scan or other commonly accepted evaluation modalities.
  • the present invention relates to a method of treating a patient suffering with cancer, in particular colon, breast, prostate or kidney cancer as well as osteo or tissue sarcoma, comprising administering to the patient Compound A in an amount of from about 800 to about 3000 mg/day, or from about 1000 to about 2500 mg/day, or from about 1250 to about 1800 mg/day, for an administration period of up to about 7 days, preferably up to about 5 days, on days 1-7, or preferably days 1-5, of a 28 day treatment cycle, followed by a rest period of from about 21 to about 23 days, preferably up to about 23 days.
  • the course of a preferred cycle is about 28 days, though cycles anywhere between about 14 and about 28 days are contemplated. This treatment cycle is repeated for as long as the tumor remains under control and the regimen is clinically tolerated.
  • Dosages of Compound A can be applied either as a body surface area (“BSA”) adapted dose (mg/m 2 /day) or following flat dosing (mg/day).
  • BSA body surface area
  • Compound A may be administered as a single dose daily or divided into multiple daily doses.
  • a patient's body measurement in square meters (“m 2 ”) typically ranges from about 1.4 m 2 to about 2.2 m 2 .
  • the total amount of Compound A to be delivered in a treatment cycle (mg) using a BSA adapted dose would be calculated as follows:
  • Compound A is administered daily for about 5 days, on days 1-5 of a treatment cycle, followed by a rest period of 23 days (“5+/23 ⁇ ”).
  • the 5+/23 ⁇ treatment schedule is expected to be superior to interim schedules or to longer schedules as currently on-going Phase I studies indicate that in solid tumors, maximal apoptosis occurs only after about 48 hours of continuous exposure and longer schedules seem to present occurrence of delayed thrombocytopenia (“TCP”).
  • TCP delayed thrombocytopenia
  • a 3-5 daily treatment schedule is expected to provide the best benefit ratio taking into consideration efficacy and toxicity
  • Compound A is administered daily, either once or twice (bid) daily, preferably once daily.
  • the compound is administered to the patient in an oral unit dosage form, most preferably in tablet form.
  • the 5 day treatment schedule is repeated every twenty-eight days, or as soon as permitted by recovery from toxicity, for so long as the tumor is under control or regressing and the patient tolerates the regimen.
  • these treatment cycles are repeated for a total of up to about 12 cycles.
  • Compound A is administered daily in an amount from about 800 to about 3000 mg/day for up to about 5 days on days 1-5 of a 28 day cycle.
  • Compound A is administered daily in an amount from about 1000 to about 2500 mg/day for up to about 5 days on days 1-5 of a 28 day cycle.
  • Compound A is administered daily in an amount from about 1250 to about 1800 mg/day for up to about 5 days on days 1-5 of a 28 day cycle.
  • the present invention may be exemplified by controlled preclinical animal studies as shown in the Examples below, which illustrates the invention without limitation.
  • weight loss was graphically represented as percent change in mean group body weight, using the formula: ((W ⁇ W 0 )/W 0 ) ⁇ 100, where ‘W’ represents mean body weight of the treated group at a particular day, and ‘W 0 ’ represents mean body weight of the same treated group at initiation of treatment.
  • Maximum weight loss was also represented using the above formula, and indicated the maximum percent body weight loss that was observed at any time during the entire experiment for a particular group. Toxicity is defined as ⁇ 20% of mice in a given group demonstrating ⁇ 20% body weight loss and/or death.
  • TGI Tumor Growth Inhibition
  • ILS Assessment of Survival/Increase in Life Span
  • Efficacy data was graphically represented as the mean tumor volume ⁇ standard error of the mean (SEM).
  • tumor volumes of treated groups were presented as percentages of tumor volumes of the control groups (% T/C), using the formula: 100 ⁇ ((T ⁇ T 0 )/(C ⁇ C 0 )), where T represented mean tumor volume of a treated group on a specific day during the experiment, T 0 represented mean tumor volume of the same treated group on the first day of treatment; C represented mean tumor volume of a control group on the specific day during the experiment, and C 0 represented mean tumor volume of the same treated group on the first day of treatment.
  • Tumor volume (in cubic millimeters) was calculated using the ellipsoid formula: (D ⁇ (d 2 ))/2, where “D” represents the large diameter of the tumor and “d” represents the small diameter.
  • tumor regression and/or percent change in tumor volume was calculated using the formula: ((T ⁇ T 0 )/T 0 ) ⁇ 100, where ‘T’ represents mean tumor volume of the treated group at a particular day, and ‘T 0 ’ represents mean tumor volume of the same treated group at initiation of treatment.
  • the percent of increased life space was calculated as: 100 ⁇ [(median survival day of treated group ⁇ median survival day of control group)/median survival day of control group].
  • Median survival was determined utilizing Kaplan Meier survival analysis. Survival in treated groups was statistically compared with the vehicle group and survival comparisons were done between groups using the log-rank test (Graph Pad Prism, La Jolla, Calif., USA). Differences between groups were considered significant when the probability value (p) was ⁇ 0.05.
  • Compound A was formulated as an amorphous solid dispersion micro-bulk precipitate (MBP) powder containing 30% drug substance and 70% HPMC-AS polymer was reconstituted immediately before administration as a suspension in Klucel/Tween, and remaining suspension was discarded after dosing. All dose levels are reported as the actual dosage of Compound A rather than including drug plus polymer.
  • MBP amorphous solid dispersion micro-bulk precipitate
  • mice Female athymic Crl:NU-Foxn1nu mice (10/group), obtained from Charles River Laboratories (Wilmington, Del.) were utilized when they were approximately 10-12 weeks of age and weighed 23-25 g. The health of the mice was assessed daily by gross observation and analyses of blood samples taken from sentinel animals housed on shared shelf racks. All animals were allowed to acclimate and recover from any shipping-related stress for a minimum of 72 hours prior to experimental use. Autoclaved water and irradiated food (5058-ms Pico Lab mouse chow, Purina Mills, Richmond, Ind.) were provided ad libitum, and the animals were maintained on a 12 hour light and dark cycle. Cages, bedding and water bottles were autoclaved before use and changed weekly. All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals, local regulations, and protocols approved by the Roche Animal Care and Use Committee in an AAALAC accredited facility.
  • SJSA cells (ATCC) were maintained in RPMI 1640+10% (v/v) heat-inactivated FBS+1% (v/v) 200 nM L-glutamine. Each mouse received 5 ⁇ 10 6 cells in a 1:1 mixture of phosphate buffered saline and Matrigel in a total volume of 0.2 ml. Cells were implanted subcutaneously in the right flank using a 1 cc syringe and a 26 gauge needle.
  • Compound A was administered orally (po) using a 1 cc syringe and 18-gauge gavage needle (0.2 ml/animal). Treatment duration was 2-4 weeks. Dates of tumor implant, treatment initiation (study start date), and termination of treatment (study end date) can be found in Table 6 below. The starting tumor volume for this study was about 220 mm 3 . Tumor volumes and animal body weights were measured three times per week and animals were monitored for clinical signs daily.
  • FIGS. 1 and 2 The results of this experiment are summarized Tables 1-3 below and FIGS. 1 and 2 . As can be seen, the 5 day treatment schedule yielded the greatest percent increase in life span (% ILS) as well as high percent tumor growth inhibition (% TGI) with reasonable toxicity. FIG. 1 also shows good growth inhibitory activity of the 5 day on/23 day off treatment schedule.
  • the 5 days on and 23 days off (5+/23 ⁇ ) schedule is predicted to reduce MDM2 inhibitor-induced thrombocytopenia in humans undergoing treatment for solid tumors, while still maintaining antitumor efficacy, as compared to other regimens considered.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
US13/759,647 2012-03-19 2013-02-05 Method for administration Abandoned US20130245089A1 (en)

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Application Number Priority Date Filing Date Title
US13/759,647 US20130245089A1 (en) 2012-03-19 2013-02-05 Method for administration
US14/217,929 US20140200255A1 (en) 2012-03-19 2014-03-18 Method for administration
US14/596,747 US20150126575A1 (en) 2012-03-19 2015-01-14 Method for administration
US14/673,153 US20150202182A1 (en) 2012-03-19 2015-03-30 Method for administration
US16/510,256 US20190328708A1 (en) 2012-03-19 2019-07-12 Method for administration
US16/519,516 US11382892B2 (en) 2012-03-19 2019-07-23 Method for administration
US16/951,153 US11738003B2 (en) 2012-03-19 2020-11-18 Method for administration

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US13/759,647 US20130245089A1 (en) 2012-03-19 2013-02-05 Method for administration

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015198266A1 (en) 2014-06-26 2015-12-30 Novartis Ag Intermittent dosing of mdm2 inhibitor
US20170227544A1 (en) * 2014-10-10 2017-08-10 Hoffmann-La Roche Inc. Methods for personalizing patient cancer therapy with an mdm2 antagonist
WO2018092020A1 (en) 2016-11-15 2018-05-24 Novartis Ag Dose and regimen for hdm2-p53 interaction inhibitors
WO2018178925A1 (en) 2017-03-31 2018-10-04 Novartis Ag Dose and regimen for an hdm2-p53 interaction inhibitor in hematological tumors
EP3459933A3 (en) * 2014-04-15 2019-05-29 F. Hoffmann-La Roche AG Solid forms of a pharmaceutically active compound
WO2019180576A1 (en) 2018-03-20 2019-09-26 Novartis Ag Pharmaceutical combinations
WO2020128894A1 (en) 2018-12-20 2020-06-25 Novartis Ag Combinations of a hdm2-p53 interaction inhibitor and a bcl2 inhibitor and their use for treating cancer
US11192898B2 (en) 2016-04-06 2021-12-07 The Regents Of The University Of Michigan MDM2 protein degraders

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY192032A (en) * 2013-01-22 2022-07-24 Hoffmann La Roche Pharmaceutical composition with improved bioavailability
SG11201908659RA (en) 2017-03-27 2019-10-30 Noile Immune Biotech Inc Chimeric antigen receptor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100152190A1 (en) * 2008-09-18 2010-06-17 David Joseph Bartkovitz Substituted Pyrrolidine-2-Carboxamides

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7884107B2 (en) * 2006-06-30 2011-02-08 Merck Substituted piperidines that increase P53 activity and the uses thereof
TR201900306T4 (tr) * 2006-12-14 2019-02-21 Exelixis Inc Mek inhibitörlerini kullanma yöntemleri.
US20120010235A1 (en) * 2010-07-12 2012-01-12 Xin-Jie Chu N-substituted pyrrolidines
US9216170B2 (en) 2012-03-19 2015-12-22 Hoffmann-La Roche Inc. Combination therapy for proliferative disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100152190A1 (en) * 2008-09-18 2010-06-17 David Joseph Bartkovitz Substituted Pyrrolidine-2-Carboxamides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Kline et al. Solid Tumors in Children. Journal of Pediatric Nursing, (2003) vol. 18, 96-102. *
Penel et al. Weekly paclitaxel in metastatic angiosarcoma. A FNCLCC French Sarcoma Group (GSF-GETO) phase II trial. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol. 25, No 18S (June 20 Supplement), 2007: 10002. *
Zalupski et al. Adjuvant Therapy of Osteosarcoma-A Phase II Trial. Cancer (2004) vol. 100, pp.818-825. *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3459933A3 (en) * 2014-04-15 2019-05-29 F. Hoffmann-La Roche AG Solid forms of a pharmaceutically active compound
EP3160463B1 (en) 2014-06-26 2020-10-21 Novartis AG Intermittent dosing of mdm2 inhibitor
US11419870B2 (en) 2014-06-26 2022-08-23 Novartis Ag Intermittent dosing of MDM2 inhibitor
WO2015198266A1 (en) 2014-06-26 2015-12-30 Novartis Ag Intermittent dosing of mdm2 inhibitor
US20170227544A1 (en) * 2014-10-10 2017-08-10 Hoffmann-La Roche Inc. Methods for personalizing patient cancer therapy with an mdm2 antagonist
US11192898B2 (en) 2016-04-06 2021-12-07 The Regents Of The University Of Michigan MDM2 protein degraders
EP3541387B1 (en) 2016-11-15 2021-04-21 Novartis AG Dose and regimen for hdm2-p53 interaction inhibitors
CN109982702A (zh) * 2016-11-15 2019-07-05 诺华股份有限公司 HDM2-p53相互作用抑制剂的剂量及方案
AU2017362040B2 (en) * 2016-11-15 2020-04-30 Novartis Ag Dose and regimen for HDM2-p53 interaction inhibitors
WO2018092020A1 (en) 2016-11-15 2018-05-24 Novartis Ag Dose and regimen for hdm2-p53 interaction inhibitors
RU2762573C2 (ru) * 2016-11-15 2021-12-21 Новартис Аг Доза и режим введения для ингибиторов взаимодействия hdm2 с p53
AU2017362040C1 (en) * 2016-11-15 2020-09-10 Novartis Ag Dose and regimen for HDM2-p53 interaction inhibitors
US20190298719A1 (en) * 2016-11-15 2019-10-03 Novartis Ag Dose and regimen for hdm2-p53 interaction inhibitors
US10966978B2 (en) 2016-11-15 2021-04-06 Novartis Ag Dose and regimen for HDM2-p53 interaction inhibitors
WO2018178925A1 (en) 2017-03-31 2018-10-04 Novartis Ag Dose and regimen for an hdm2-p53 interaction inhibitor in hematological tumors
WO2019180576A1 (en) 2018-03-20 2019-09-26 Novartis Ag Pharmaceutical combinations
WO2020128898A1 (en) 2018-12-20 2020-06-25 Novartis Ag Pharmaceutical combinations
WO2020128892A1 (en) 2018-12-20 2020-06-25 Novartis Ag Extended low dose regimens for mdm2 inhibitors
WO2020128894A1 (en) 2018-12-20 2020-06-25 Novartis Ag Combinations of a hdm2-p53 interaction inhibitor and a bcl2 inhibitor and their use for treating cancer
EP4249513A2 (en) 2018-12-20 2023-09-27 Novartis AG Combinations of a hdm2-p53 interaction inhibitor and a bcl2 inhibitor and their use for treating cancer

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MX356948B (es) 2018-06-20
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US20210069149A1 (en) 2021-03-11
US20190328708A1 (en) 2019-10-31
DK2827858T3 (en) 2016-08-22
RU2014141365A (ru) 2016-05-10
HK1204934A1 (en) 2015-12-11
MX2014010586A (es) 2014-09-18
JP2015510906A (ja) 2015-04-13
KR20160089549A (ko) 2016-07-27
BR112014018135A8 (pt) 2021-10-19
HRP20161295T1 (hr) 2016-11-18
RS55250B1 (sr) 2017-02-28
CN110013478A (zh) 2019-07-16
CY1118070T1 (el) 2017-06-28
PL2827858T3 (pl) 2017-01-31
RU2638795C2 (ru) 2017-12-15
ES2593066T3 (es) 2016-12-05
CN104203232A (zh) 2014-12-10
US11738003B2 (en) 2023-08-29
CA2859940A1 (en) 2013-09-26
EP2827858A1 (en) 2015-01-28
KR20190035957A (ko) 2019-04-03
PT2827858T (pt) 2016-09-23
JP6224690B2 (ja) 2017-11-01
SI2827858T1 (sl) 2016-11-30
EP2827858B1 (en) 2016-07-20
BR112014018135A2 (enrdf_load_stackoverflow) 2017-06-20
JP2017061461A (ja) 2017-03-30
CA2859940C (en) 2020-03-24
HUE029933T2 (en) 2017-04-28
WO2013139687A1 (en) 2013-09-26
KR20210016073A (ko) 2021-02-10
KR102438597B1 (ko) 2022-08-31
KR20140133583A (ko) 2014-11-19

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