BR112018003634B1 - Forma cristalina de sesqui-hidrato de um inibidor parp, método de preparação da dita forma cristalina e composição farmacêutica compreendendo a dita forma - Google Patents

Forma cristalina de sesqui-hidrato de um inibidor parp, método de preparação da dita forma cristalina e composição farmacêutica compreendendo a dita forma Download PDF

Info

Publication number
BR112018003634B1
BR112018003634B1 BR112018003634-0A BR112018003634A BR112018003634B1 BR 112018003634 B1 BR112018003634 B1 BR 112018003634B1 BR 112018003634 A BR112018003634 A BR 112018003634A BR 112018003634 B1 BR112018003634 B1 BR 112018003634B1
Authority
BR
Brazil
Prior art keywords
compound
crystalline form
solvent
crystalline
hydrate
Prior art date
Application number
BR112018003634-0A
Other languages
English (en)
Portuguese (pt)
Other versions
BR112018003634A2 (en
BR112018003634A8 (pt
Inventor
Wang Hexiang
Changyou Zhou
Bo Ren
Xianzhao Kuang
Original Assignee
Beigene Switzerland Gmbh
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=58099633&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=BR112018003634(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Beigene Switzerland Gmbh filed Critical Beigene Switzerland Gmbh
Publication of BR112018003634A2 publication Critical patent/BR112018003634A2/en
Publication of BR112018003634A8 publication Critical patent/BR112018003634A8/pt
Publication of BR112018003634B1 publication Critical patent/BR112018003634B1/pt

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/55131,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/55171,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Saccharide Compounds (AREA)
BR112018003634-0A 2015-08-25 2016-08-22 Forma cristalina de sesqui-hidrato de um inibidor parp, método de preparação da dita forma cristalina e composição farmacêutica compreendendo a dita forma BR112018003634B1 (pt)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN2015088003 2015-08-25
CN2015/088003 2015-08-25
CNCN2015/088003 2015-08-25
PCT/CN2016/096200 WO2017032289A1 (en) 2015-08-25 2016-08-22 Process for preparing parp inhibitor, crystalline forms, and uses thereof

Publications (3)

Publication Number Publication Date
BR112018003634A2 BR112018003634A2 (en) 2018-11-21
BR112018003634A8 BR112018003634A8 (pt) 2023-01-17
BR112018003634B1 true BR112018003634B1 (pt) 2023-11-21

Family

ID=58099633

Family Applications (1)

Application Number Title Priority Date Filing Date
BR112018003634-0A BR112018003634B1 (pt) 2015-08-25 2016-08-22 Forma cristalina de sesqui-hidrato de um inibidor parp, método de preparação da dita forma cristalina e composição farmacêutica compreendendo a dita forma

Country Status (15)

Country Link
US (1) US10457680B2 (https=)
EP (1) EP3341375B1 (https=)
JP (1) JP6940039B2 (https=)
KR (1) KR20180041748A (https=)
CN (2) CN107922425B (https=)
AU (1) AU2016312011B2 (https=)
BR (1) BR112018003634B1 (https=)
CA (1) CA2994895A1 (https=)
EA (1) EA037366B1 (https=)
IL (2) IL296835A (https=)
MX (1) MX385450B (https=)
NZ (1) NZ739876A (https=)
TW (1) TWI736550B (https=)
WO (1) WO2017032289A1 (https=)
ZA (1) ZA201800765B (https=)

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2014DN06169A (https=) 2011-12-31 2015-08-21 Beigene Ltd
EP3341375B1 (en) 2015-08-25 2022-04-13 BeiGene, Ltd. Process for preparing parp inhibitor, crystalline forms, and uses thereof
CN110087730B (zh) * 2016-09-27 2023-03-28 百济神州(苏州)生物科技有限公司 使用包含parp抑制剂的组合产品治疗癌症
TW201840564A (zh) 2017-02-28 2018-11-16 英屬開曼群島商百濟神州有限公司 稠合的四環或五環二氫二氮呯幷哢唑酮的鹽的結晶形式及其用途
US12121518B2 (en) 2017-03-09 2024-10-22 The Board Of Supervisors Of Louisiana State Universi And Agricultural And Mechanical College PARP-1 and methods of use thereof
WO2018165615A1 (en) 2017-03-09 2018-09-13 The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Parp-1 and methods of use thereof
US20200155567A1 (en) * 2017-07-17 2020-05-21 Beigene, Ltd. Treatment of cancers using a combination comprising parp inhibitors, temozolomide and/or radiation therapy
JP7407740B2 (ja) 2018-05-18 2024-01-04 ノバルティス アーゲー Tlr7/tlr8阻害剤の結晶形態
WO2019228499A1 (en) * 2018-06-01 2019-12-05 Beigene, Ltd. Maintenance therapy of a parp inhibitor in treating gastric cancer
USD926356S1 (en) * 2019-03-14 2021-07-27 Tuanfang Liu Battery for electronic cigarette
CN111171031B (zh) * 2019-05-10 2021-04-09 百济神州(苏州)生物科技有限公司 一种含parp抑制剂倍半水合物产物的制备方法
CN111171002B (zh) * 2019-05-16 2021-04-06 百济神州(苏州)生物科技有限公司 一种parp抑制剂中间体的制备方法
CN111171001B (zh) * 2019-05-16 2022-04-29 百济神州(苏州)生物科技有限公司 一种parp抑制剂中间体的结晶方法
CN112007011B (zh) * 2019-05-31 2024-07-23 百济神州(苏州)生物科技有限公司 一种parp抑制剂微丸胶囊及其制备工艺
KR20220016028A (ko) * 2019-05-31 2022-02-08 베이진 엘티디 Parp 억제제 펠릿 제조 및 이의 제조방법
WO2021046014A1 (en) 2019-09-03 2021-03-11 Teva Czech Industries S.R.O Solid state forms of pamiparib and process for preparation thereof
AU2024265078A1 (en) 2023-05-04 2025-12-11 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
IL326136A (en) 2023-08-07 2026-03-01 Revolution Medicines Inc RMC-6291 for use in the treatment of a disease or disorder associated with the RAS protein
US20250154171A1 (en) 2023-10-12 2025-05-15 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025217307A1 (en) 2024-04-09 2025-10-16 Revolution Medicines, Inc. Methods for predicting response to a ras(on) inhibitor and combination therapies
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
US20250375445A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026006747A1 (en) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Ras inhibitors
WO2026015796A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015790A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015825A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Use of ras inhibitor for treating pancreatic cancer
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026050446A1 (en) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Ras inhibitors
WO2026072904A2 (en) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions and methods for treating lung cancer

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
OA11749A (en) 1999-01-11 2005-07-19 Agouron Pharma Tricyclic inhibitors of poly(adp-ribose)polymerases.
MXPA03004832A (es) 2000-12-01 2004-05-04 Guilford Pharm Inc Compuestos y sus usos.
CA2512683C (en) * 2003-01-09 2010-03-16 Pfizer Inc. Tricyclic compounds protein kinase inhibitors for enhancing the efficacy of anti-neoplastic agents and radiation therapy
ES2625817T3 (es) 2008-08-06 2017-07-20 Medivation Technologies, Inc. Inhibidores de tipo Dihidropiridoftalazinona de poli(ADP-ribosa)polimerasa (PARP)
IN2014DN06169A (https=) * 2011-12-31 2015-08-21 Beigene Ltd
EA034666B1 (ru) 2013-09-13 2020-03-04 Бейджин Свитзерланд Гмбх Антитело против pd-1 и его применение для лечения рака или вирусной инфекции и фрагмент антитела
TWI726608B (zh) 2014-07-03 2021-05-01 英屬開曼群島商百濟神州有限公司 抗pd-l1抗體及其作為治療及診斷之用途
US9637488B2 (en) 2015-01-29 2017-05-02 Fuqiang Ruan Heterocyclic compounds as inhibitors of class I PI3KS
EP3341375B1 (en) 2015-08-25 2022-04-13 BeiGene, Ltd. Process for preparing parp inhibitor, crystalline forms, and uses thereof
CN110087730B (zh) * 2016-09-27 2023-03-28 百济神州(苏州)生物科技有限公司 使用包含parp抑制剂的组合产品治疗癌症
TW201840564A (zh) 2017-02-28 2018-11-16 英屬開曼群島商百濟神州有限公司 稠合的四環或五環二氫二氮呯幷哢唑酮的鹽的結晶形式及其用途
US20200155567A1 (en) 2017-07-17 2020-05-21 Beigene, Ltd. Treatment of cancers using a combination comprising parp inhibitors, temozolomide and/or radiation therapy
CN111171031B (zh) * 2019-05-10 2021-04-09 百济神州(苏州)生物科技有限公司 一种含parp抑制剂倍半水合物产物的制备方法

Also Published As

Publication number Publication date
JP2018528199A (ja) 2018-09-27
IL257442A (en) 2018-04-30
IL257442B (en) 2022-11-01
EA037366B1 (ru) 2021-03-18
TWI736550B (zh) 2021-08-21
MX2018002322A (es) 2018-04-11
JP6940039B2 (ja) 2021-09-22
EP3341375A4 (en) 2019-01-16
BR112018003634A2 (en) 2018-11-21
KR20180041748A (ko) 2018-04-24
US10457680B2 (en) 2019-10-29
WO2017032289A1 (en) 2017-03-02
CA2994895A1 (en) 2017-03-02
CN107922425B (zh) 2021-06-01
TW201718586A (zh) 2017-06-01
CN112521390A (zh) 2021-03-19
EA201890547A1 (ru) 2018-07-31
EP3341375A1 (en) 2018-07-04
MX385450B (es) 2025-03-18
AU2016312011A1 (en) 2018-03-08
US20190177325A1 (en) 2019-06-13
EP3341375B1 (en) 2022-04-13
IL257442B2 (en) 2023-03-01
AU2016312011B2 (en) 2021-02-04
BR112018003634A8 (pt) 2023-01-17
NZ739876A (en) 2022-09-30
CN107922425A (zh) 2018-04-17
IL296835A (en) 2022-11-01
ZA201800765B (en) 2019-10-30

Similar Documents

Publication Publication Date Title
BR112018003634B1 (pt) Forma cristalina de sesqui-hidrato de um inibidor parp, método de preparação da dita forma cristalina e composição farmacêutica compreendendo a dita forma
US8741911B2 (en) Raf inhibitor compounds
EP2066673B1 (en) Tricyclic compounds and its use as tyrosine kinase modulators
EA035680B1 (ru) Малеатные соли ингибитора braf киназы, кристаллические формы, способы их получения и применения
ES3028360T3 (en) Deuterated n-benzenesulfonylbenzamide compound for inhibiting bcl-2 protein and composition and use thereof
BR112015017963A2 (pt) composto de fenil amino pirimidina deuterado, método para preparar a composição farmacêutica, composição farmacêutica e uso do composto
JPWO2018143403A1 (ja) 複素環化合物
WO2023036156A1 (zh) Dna-pk选择性抑制剂及其制备方法和用途
KR20250088625A (ko) 헤테로고리계 유도체 억제제의 염, 결정형 및 이의 제조 방법과 응용
CN116535359A (zh) 一种含吲唑基的羟肟酸衍生物及其应用
ES2784325T3 (es) Formas cristalinas de sales farmacéuticamente aceptables de N-(4-((3-(2-amino-4-pirimidinil)-2-piridinil)oxi)fenil)-4-(4-metil-2-tienil)-1-ftalazinamina y usos de las mismas
TW202102507A (zh) 含吲唑基的三并環類衍生物的鹽及其晶型
CN117956996A (zh) 用于yap/tead调节的化合物和方法及其适应证
BR112021009381A2 (pt) compostos espiro heterocíclicos como inibidores de receptor de am2
HK40040143A (en) Process for preparing parp inhibitor, crystalline forms, and uses thereof
TWI867817B (zh) 一種二噁烷並喹啉類化合物的鹽、其晶型以及它們的製備方法及用途
TW202519531A (zh) 含丙烯酮類生物抑制劑的晶型及其製備方法和應用
WO2018099451A1 (zh) 化合物的晶型
HK40114858A (zh) Prmt5-mta抑制剂
HK40042846B (zh) Fgfr4抑制剂及其应用

Legal Events

Date Code Title Description
B07D Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]

Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS.

B350 Update of information on the portal [chapter 15.35 patent gazette]
B07G Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]

Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021

B06U Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]
B25A Requested transfer of rights approved

Owner name: BEIGENE SWITZERLAND GMBH (CH)

B07A Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]
B09A Decision: intention to grant [chapter 9.1 patent gazette]
B16A Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]

Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 22/08/2016, OBSERVADAS AS CONDICOES LEGAIS

B21F Lapse acc. art. 78, item iv - on non-payment of the annual fees in time

Free format text: REFERENTE A 9A ANUIDADE.

B24J Lapse because of non-payment of annual fees (definitively: art 78 iv lpi, resolution 113/2013 art. 12)

Free format text: EM VIRTUDE DA EXTINCAO PUBLICADA NA RPI 2844 DE 08-07-2025 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDA A EXTINCAO DA PATENTE E SEUS CERTIFICADOS, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013.