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Extract from the Register of European Patents

EP About this file: EP2563906

EP2563906 - PROCESS FOR CULTIVATION OF CHO CELLS [Right-click to bookmark this link]
Former [2013/10]IMPROVED CELL CULTIVATION PROCESS
[2017/20]
StatusPatent revoked
Status updated on  28.10.2024
Database last updated on 03.04.2025
FormerThe patent has been granted
Status updated on  06.10.2017
FormerGrant of patent is intended
Status updated on  30.05.2017
FormerExamination is in progress
Status updated on  23.11.2016
Most recent event   Tooltip01.11.2024Revocation of patentpublished on 04.12.2024  [2024/49]
Applicant(s)For all designated states
Novartis AG
Lichtstrasse 35
4056 Basel / CH
[2017/45]
Former [2013/10]For all designated states
Novartis AG
Lichtstrasse 35
4056 Basel / CH
Inventor(s)01 / JOOSTEN, Christoph E.
Novartis Pharma AG
Postfach
4002 Basel / CH
02 / LEIST, Christian
Novartis Pharma AG
Postfach 4002
4002 Basel / CH
03 / SCHMIDT, Jörg
Novartis Pharma AG
Postfach
4002 Basel / CH
 [2013/10]
Representative(s)Breuer, Markus, et al
Sendlinger Straße 29
80331 München / DE
[N/P]
Former [2017/45]Lehmeier, Thomas Jürgen
Novartis Pharma AG
Patent Department
4002 Basel / CH
Former [2013/45]Preißinger, Franziska
Novartis Pharma AG
Patent Department
4002 Basel / CH
Former [2013/10]Henkel, Breuer & Partner
Patentanwälte
Erika-Mann Strasse 23
80636 München / DE
Application number, filing date11715933.525.04.2011
[2017/45]
WO2011EP56507
Priority number, dateUS20100327846P26.04.2010         Original published format: US 327846 P
[2013/10]
Filing languageEN
Procedural languageEN
PublicationType: A2 Application without search report
No.:WO2011134919
Date:03.11.2011
Language:EN
[2011/44]
Type: A2 Application without search report 
No.:EP2563906
Date:06.03.2013
Language:EN
The application published by WIPO in one of the EPO official languages on 03.11.2011 takes the place of the publication of the European patent application.
[2013/10]
Type: B1 Patent specification 
No.:EP2563906
Date:08.11.2017
Language:EN
[2017/45]
Search report(s)International search report - published on:EP24.01.2013
ClassificationIPC:C12N5/02
[2013/10]
CPC:
C07K16/00 (EP,CN,US); C12P21/00 (KR); C12P21/005 (EP,CN,US);
C12N5/00 (EP,KR,US); C07K2317/14 (EP,CN,US); C12N2500/60 (EP,US);
C12N2510/02 (EP,US); C12N2523/00 (EP,US) (-)
Designated contracting statesAL,   AT,   BE,   BG,   CH,   CY,   CZ,   DE,   DK,   EE,   ES,   FI,   FR,   GB,   GR,   HR,   HU,   IE,   IS,   IT,   LI,   LT,   LU,   LV,   MC,   MK,   MT,   NL,   NO,   PL,   PT,   RO,   RS,   SE,   SI,   SK,   SM,   TR [2017/45]
Former [2013/10]AL,  AT,  BE,  BG,  CH,  CY,  CZ,  DE,  DK,  EE,  ES,  FI,  FR,  GB,  GR,  HR,  HU,  IE,  IS,  IT,  LI,  LT,  LU,  LV,  MC,  MK,  MT,  NL,  NO,  PL,  PT,  RO,  RS,  SE,  SI,  SK,  SM,  TR 
Extension statesBANot yet paid
MENot yet paid
TitleGerman:VERFAHREN ZUR KULTIVIERUNG VON CHO ZELLEN[2017/20]
English:PROCESS FOR CULTIVATION OF CHO CELLS[2017/45]
French:METHODE DE CULTURE CELLULAIRE DE CHO[2017/20]
Former [2013/10]VERBESSERTES ZELLKULTIVIERUNGSVERFAHREN
Former [2013/10]IMPROVED CELL CULTIVATION PROCESS
Former [2013/10]PROCÉDÉ AMÉLIORÉ DE CULTURE CELLULAIRE
Entry into regional phase26.11.2012National basic fee paid 
Examination procedure24.07.2013Examination requested  [2013/36]
05.09.2013Observations by third parties
10.09.2013Observations by third parties
21.05.2014Despatch of a communication from the examining division (Time limit: M04)
25.07.2014Reply to a communication from the examining division
22.04.2015Despatch of a communication from the examining division (Time limit: M06)
29.10.2015Reply to a communication from the examining division
12.07.2016Despatch of a communication from the examining division (Time limit: M04)
22.11.2016Reply to a communication from the examining division
31.05.2017Communication of intention to grant the patent
25.09.2017Fee for grant paid
25.09.2017Fee for publishing/printing paid
25.09.2017Receipt of the translation of the claim(s)
Divisional application(s)EP17199357.9  / EP3330370
EP21158392.7  / EP3862423
The date of the Examining Division's first communication in respect of the earliest application for which a communication has been issued is  21.05.2014
Opposition(s)Opponent(s)01  03.08.2018  08.08.2018  ADMISSIBLE
Dehns Ltd
10 Salisbury Square
London EC4Y 8JD / GB
Opponent's representative
Dehns
10 Old Bailey
London EC4M 7NG / GB
 02  07.08.2018  13.08.2018  ADMISSIBLE
Strawman Limited
Orchard Lea
Horns Lane
Combe, Witney
Oxfordshire OX29 8NH / GB
Opponent's representative
D Young & Co LLP
3 Noble Street
London EC2V 7BQ / GB
 03  07.08.2018  13.08.2018  ADMISSIBLE
Graf von Stosch, Andreas
Prinzregentenstrasse 22
80538 München / DE
Opponent's representative
Graf von Stosch, Andreas
Graf von Stosch
Patentanwaltsgesellschaft mbH
Prinzregentenstraße 22
80538 München / DE
 04  08.08.2018  13.08.2018  ADMISSIBLE
Weinzierl, Gerhard
Schiweck Weinzierl Koch
Patentanwälte Partnerschaft mbB
Ganghoferstraße 68B
80339 München / DE
Opponent's representative
Schiweck Weinzierl Koch Patentanwälte Partnerschaft mbB
Ganghoferstraße 68 B
80339 München / DE
 05  08.08.2018  13.08.2018  ADMISSIBLE
Neuefeind, Regina
Maiwald GmbH
Elisenhof
Elisenstraße 3
80335 München / DE
Opponent's representative
Maiwald GmbH
Elisenhof
Elisenstraße 3
80335 München / DE
 06  08.08.2018  13.08.2018  ADMISSIBLE
Maiwald GmbH
Elisenhof, Elisenstrasse 3
80335 München / DE
 07  08.08.2018  13.08.2018  ADMISSIBLE
F. Hoffmann-La Roche AG
Grenzacherstr. 124
4070 Basel / CH
Opponent's representative
Vossius & Partner Patentanwälte Rechtsanwälte mbB
Siebertstrasse 3
81675 München / DE
 [N/P]
Former [2021/16]
Opponent(s)01  03.08.2018  08.08.2018  ADMISSIBLE
Dehns Ltd
10 Salisbury Square
London EC4Y 8JD / GB
Opponent's representative
Dehns
St. Bride's House
10 Salisbury Square
London EC4Y 8JD / GB
 02  07.08.2018  13.08.2018  ADMISSIBLE
Strawman Limited
Orchard Lea
Horns Lane
Combe, Witney
Oxfordshire OX29 8NH / GB
Opponent's representative
D Young & Co LLP
120 Holborn
London EC1N 2DY / GB
 03  07.08.2018  13.08.2018  ADMISSIBLE
Graf von Stosch, Andreas
Prinzregentenstrasse 22
80538 München / DE
Opponent's representative
Graf von Stosch, Andreas
Graf von Stosch
Patentanwaltsgesellschaft mbH
Prinzregentenstraße 22
80538 München / DE
 04  08.08.2018  13.08.2018  ADMISSIBLE
Weinzierl, Gerhard
Schiweck Weinzierl Koch
Patentanwälte Partnerschaft mbB
Ganghoferstraße 68B
80339 München / DE
Opponent's representative
Schiweck Weinzierl Koch Patentanwälte Partnerschaft mbB
Ganghoferstraße 68 B
80339 München / DE
 05  08.08.2018  13.08.2018  ADMISSIBLE
Neuefeind, Regina
Maiwald Patentanwalts - und
Rechtsanwaltsgesellschaft mbH
Elisenhof
Elisenstraße 3
80335 München / DE
Opponent's representative
Maiwald Patent- und Rechtsanwaltsgesellschaft mbH
Elisenhof
Elisenstraße 3
80335 München / DE
 06  08.08.2018  13.08.2018  ADMISSIBLE
Maiwald Patent- und Rechtsanwaltsgesellschaft mbH
Elisenhof, Elisenstrasse 3
80335 München / DE
 07  08.08.2018  13.08.2018  ADMISSIBLE
F. Hoffmann-La Roche AG
Grenzacherstr. 124
4070 Basel / CH
Opponent's representative
Vossius & Partner Patentanwälte Rechtsanwälte mbB
Siebertstrasse 3
81675 München / DE
Former [2018/37]
Opponent(s)01  03.08.2018  08.08.2018  ADMISSIBLE
Dehns Ltd
10 Salisbury Square
London EC4Y 8JD / GB
Opponent's representative
Dehns
St. Brides House
10 Salisbury Square
London EC4Y 8JD / GB
 02  07.08.2018    ADMISSIBLE
Strawman Limited
Orchard Lea
Horns Lane
Combe, Witney
Oxfordshire OX29 8NH / GB
Opponent's representative
D Young & Co LLP
120 Holborn
London EC1N 2DY / GB
 03  07.08.2018    ADMISSIBLE
Graf von Stosch, Andreas
Prinzregentenstrasse 22
80538 München / DE
Opponent's representative
Graf von Stosch, Andreas
Graf von Stosch
Patentanwaltsgesellschaft mbH
Prinzregentenstraße 22
80538 München / DE
 04  08.08.2018    ADMISSIBLE
Weinzierl, Gerhard
Schiweck Weinzierl Koch
Patentanwälte Partnerschaft mbB
Ganghoferstraße 68B
DE-80339 München / DE
Opponent's representative
Schiweck Weinzierl Koch Patentanwälte Partnerschaft mbB
Ganghoferstraße 68 B
80339 München / DE
 05  08.08.2018    ADMISSIBLE
Neuefeind, Regina
Maiwald Patentanwalts - und
Rechtsanwaltsgesellschaft mbH
Elisenhof
Elisenstraße 3
80335 München / DE
Opponent's representative
Maiwald Patent- und Rechtsanwaltsgesellschaft mbH
Elisenhof
Elisenstraße 3
80335 München / DE
 06  08.08.2018    ADMISSIBLE
Maiwald Patent- und Rechtsanwaltsgesellschaft mbH
Elisenhof
Elisenstrasse 3
80335 München / DE
 07  08.08.2018    ADMISSIBLE
F. Hoffmann-La Roche AG
Grenzacherstr. 124
4070 Basel / CH
Opponent's representative
Vossius & Partner Patentanwälte Rechtsanwälte mbB
Siebertstrasse 3
81675 München / DE
23.08.2018Invitation to proprietor to file observations on the notice of opposition
01.03.2019Reply of patent proprietor to notice(s) of opposition
12.02.2020Date of oral proceedings
20.03.2020Despatch of interlocutory decision in opposition
20.03.2020Despatch of minutes of oral proceedings
16.10.2024Legal effect of revocation of patent [2024/49]
16.10.2024Despatch of communication that the patent will be revoked
Appeal following opposition27.05.2020Appeal received No.  T1153/20
30.07.2020Statement of grounds filed
08.10.2024Result of appeal procedure: revocation of the patent
16.10.2024Despatch of the decision of the Board of Appeal
29.05.2020Appeal received No.  T1153/20
29.07.2020Statement of grounds filed
08.10.2024Result of appeal procedure: revocation of the patent
16.10.2024Despatch of the decision of the Board of Appeal
29.05.2020Appeal received No.  T1153/20
28.07.2020Statement of grounds filed
08.10.2024Result of appeal procedure: revocation of the patent
16.10.2024Despatch of the decision of the Board of Appeal
08.05.2020Appeal received No.  T1153/20
28.07.2020Statement of grounds filed
08.10.2024Result of appeal procedure: revocation of the patent
16.10.2024Despatch of the decision of the Board of Appeal
Fees paidRenewal fee
12.04.2013Renewal fee patent year 03
25.03.2014Renewal fee patent year 04
10.04.2015Renewal fee patent year 05
11.04.2016Renewal fee patent year 06
10.04.2017Renewal fee patent year 07
Opt-out from the exclusive  Tooltip
competence of the Unified
Patent Court		 See the Register of the Unified Patent Court for opt-out data
Responsibility for the accuracy, completeness or quality of the data displayed under the link provided lies entirely with the Unified Patent Court.
Lapses during opposition  TooltipHU25.04.2011
AL08.11.2017
CY08.11.2017
CZ08.11.2017
FI08.11.2017
HR08.11.2017
MC08.11.2017
MK08.11.2017
RO08.11.2017
RS08.11.2017
SI08.11.2017
SK08.11.2017
SM08.11.2017
BG08.02.2018
NO08.02.2018
IS08.03.2018
LU25.04.2018
MT25.04.2018
[2020/33]
Former [2020/31]HU25.04.2011
CY08.11.2017
CZ08.11.2017
FI08.11.2017
HR08.11.2017
MC08.11.2017
MK08.11.2017
RO08.11.2017
RS08.11.2017
SI08.11.2017
SK08.11.2017
SM08.11.2017
BG08.02.2018
NO08.02.2018
IS08.03.2018
LU25.04.2018
MT25.04.2018
Former [2020/28]HU25.04.2011
CY08.11.2017
CZ08.11.2017
FI08.11.2017
HR08.11.2017
MC08.11.2017
RO08.11.2017
RS08.11.2017
SI08.11.2017
SK08.11.2017
SM08.11.2017
BG08.02.2018
NO08.02.2018
IS08.03.2018
LU25.04.2018
MT25.04.2018
Former [2020/08]CY08.11.2017
CZ08.11.2017
FI08.11.2017
HR08.11.2017
MC08.11.2017
RO08.11.2017
RS08.11.2017
SI08.11.2017
SK08.11.2017
SM08.11.2017
BG08.02.2018
NO08.02.2018
IS08.03.2018
LU25.04.2018
MT25.04.2018
Former [2019/08]CY08.11.2017
CZ08.11.2017
FI08.11.2017
HR08.11.2017
MC08.11.2017
RO08.11.2017
RS08.11.2017
SI08.11.2017
SK08.11.2017
SM08.11.2017
BG08.02.2018
NO08.02.2018
IS08.03.2018
LU25.04.2018
Former [2018/52]CY08.11.2017
CZ08.11.2017
FI08.11.2017
HR08.11.2017
MC08.11.2017
RO08.11.2017
RS08.11.2017
SI08.11.2017
SK08.11.2017
SM08.11.2017
BG08.02.2018
NO08.02.2018
IS08.03.2018
Former [2018/40]CY08.11.2017
CZ08.11.2017
FI08.11.2017
HR08.11.2017
RO08.11.2017
RS08.11.2017
SK08.11.2017
SM08.11.2017
BG08.02.2018
NO08.02.2018
IS08.03.2018
Former [2018/37]CY08.11.2017
CZ08.11.2017
FI08.11.2017
HR08.11.2017
RS08.11.2017
SK08.11.2017
SM08.11.2017
BG08.02.2018
NO08.02.2018
IS08.03.2018
Former [2018/24]FI08.11.2017
HR08.11.2017
RS08.11.2017
BG08.02.2018
NO08.02.2018
IS08.03.2018
Former [2018/22]FI08.11.2017
NO08.02.2018
Cited inInternational search[A]US2005019859  (SCHILLING BERNHARD M [US], et al) [A] 1-18 * Examples and claims *;
 [A]EP1757700  (GENENTECH INC [US]) [A] 1-18* Examples and claims *;
 [A]  - SATOSHI OGUCHI ET AL, "pH Condition in temperature shift cultivation enhances cell longevity and specific hMab productivity in CHO culture", CYTOTECHNOLOGY, KLUWER ACADEMIC PUBLISHERS, DO, (20070308), vol. 52, no. 3, doi:DOI:10.1007/S10616-007-9059-2, ISSN 1573-0778, pages 199 - 207, XP019499827 [A] 1-18 * Page 200, Materil and methods: Cell culture. Pages 201-22, Results: effect of the pH..., Fig. 1 and Discussion. *

DOI:   http://dx.doi.org/10.1007/s10616-007-9059-2
 [AP]  - GOMEZ NATALIA ET AL, "Effect of Temperature, pH, Dissolved Oxygen, and Hydrolysate on the Formation of Triple Light Chain Antibodies in Cell Culture", BIOTECHNOLOGY PROGRESS, (201009), vol. 26, no. 5, ISSN 8756-7938(print), pages 1438 - 1445, XP002638898 [AP] 1-18

DOI:   http://dx.doi.org/10.1002/btpr.465
Examination   - EVELYN TRUMMER ET AL, "Process parameter shifting: Part II. Biphasic cultivation - A tool for enhancing the volumetric productivity of batch processes using Epo-Fc expressing CHO cells", BIOTECHNOLOGY AND BIOENGINEERING, WILEY & SONS, HOBOKEN, NJ, US, vol. 94, no. 6, doi:10.1002/BIT.20958, ISSN 0006-3592, (20060820), pages 1045 - 1052, (20060530), XP002651719

DOI:   http://dx.doi.org/10.1002/BIT.20958
    - YOON S K ET AL, "Biphasic culture strategy for enhancing volumetric erythropoietin productivity of Chinese hamster ovary cells", ENZYME AND MICROBIAL TECHNOLOGY, STONEHAM, MA, US, vol. 39, no. 3, ISSN 0141-0229, (20060703), pages 362 - 365, (20060703), XP027948954
by applicantEP0764719
 US5856179
 WO0036092
 WO02101019
 US2003190710
 EP1373547
 US2004214289
 US2005019859
 EP1575998
 WO2006026445
 EP1757700
 EP1789571
 US2008081356
    - SAUER, BIOTECHNOLOGY AND BIOENGINEERING, (2000), vol. 67, pages 586 - 597
    - YOON ET AL., BIOTECHNOLOGY AND BIOENGINEERING, (2004), vol. 89, pages 346 - 358
    - KUWAE ET AL., JOURNAL OF BIOSCIENCE AND BIOENGINEERING, (2005), vol. 100, pages 502 - 510
    - CHEN ET AL., J BIOSCI BIOENG., (2004), vol. 97, no. 4, pages 239 - 43
    - WEIDEMANN ET AL., CYTOTECHNOLOGY, (1994), vol. 15, no. 1-3, pages 111 - 6
    - KAO, GENETICS, (1967), vol. 55, pages 513 - 524
    - KAO, PNAS, (1968), vol. 60, pages 1275 - 1281
    - PUCK, J. EXP. MED., (1958), vol. 108, pages 945 - 959
other   - TRUMMER E. ET AL, "Process parameter shifting: Part II. Biphasic cultivation - A tool for enhancingthe volumetric productivity of batch processes using Epo-Fc expressing CHO cells", BIOTECHNOLOGY AND BIOENGINEERING, (20060820), vol. 94, no. 6, pages 1045 - 1052, XP002641719
    - YOON S.K. ET AL, "Biphasic culture strategy for enhancing volumetric erythropoietin productivity of Chinese hamster ovary cells", ENZYME AND MICROBIAL TECHNOLOGY, (20060703), vol. 39, no. 3, pages 362 - 365, XP005459366

DOI:   http://dx.doi.org/10.1016/j.enzmictec.2005.11.029
OppositionWO2006026445
 WO2008121616
 US5122469
 US5672502
 US6924124
 US2008081356
 US2008182297
 WO2008141207
 WO2011134919
 WO9845411
 EP1757700
 WO9512664
 WO2008131374
 WO8700195
 US5871999
 US2005019859
 WO2006026408
 US2006148074
 US2007184529
 WO2008013809
 US2008070280
 WO2008055260
 US2008108553
 US2008269132
 US2009123975
 WO2006026447
    - TRUMMER et al., "Process parameter shifting: Part II. Biphasic cultivation - A tool for enhancing the volumetric productivity of batch processes using Epo-Fc expressing CHO cells", Biotechnol. Bioeng., (20060530), vol. 94, no. 6, pages 1045 - 1052, XP002651719

DOI:   http://dx.doi.org/10.1002/BIT.20958
    - Kuwae; Ohda S; Tamashima T; Miki H; Kobayashi H; K, "Development of a fed-batch culture process for enhanced production of recombinant human antithrombin by Chinese hamster ovary cells", Journal of Bioscience and Bioengineering, (20051101), vol. 100, no. 5, pages 502 - 510, XP005226103

DOI:   http://dx.doi.org/10.1263/jbb.100.502
    - Sung Hyun Kim; Gyun Min Lee, "Differences in Optimal pH and Temperature for Cell Growth and Antibody Production Between Two Chinese Hamster Ovary Clones Derived from the Same Parental Clone", J. Microbiol. Biotechnol,, (20070000), vol. 17, no. 5, pages 712 - 720, XP055414758
    - Yoon; Kim S K; Song S H; Lee J Y; G M, "Biphasic culture strategy for enhancing volumetric erythropoietin productivity of Chinese hamster ovary cells", Enzyme and Microbial Technology, (20060000), vol. 39, pages 362 - 365, XP005459366

DOI:   http://dx.doi.org/10.1016/j.enzmictec.2005.11.029
    - Yoon S K; Kim S H; Song J Y; Lee G M, "Biphasic culture strategy for enhancing volumetric erythropoietin productivity of Chinese hamster ovary cells", Enzyme and Microbial Technology, (20060703), vol. 39, pages 362 - 365, XP025095192

DOI:   http://dx.doi.org/10.1016/j.enzmictec.2005.11.029
    - Michael C. Borys, Nimish G. Dalal, Nicholas R. Abu-Absi, Sarwat F. Khattak, Ying Jing, Zizhuo Xing, Zheng Jian Li, "Effects of Culture Conditions on N-Glycolylneuraminic Acid (Neu5Gc) Content of a Recombinant Fusion Protein Produced in CHO Cells", Biotechnology and Bioengineering, vol. 105, no. 6, (20100415), pages 1048 - 1057, (20091228), XP055333158

DOI:   http://dx.doi.org/10.1002/bit.22644
    - TRUMMER et al., "Process parameter shifting: Part II. Biphasic cultivation - A tool for enhancing the volumetric productivity of batch processes using Epo-Fc expressing CHO cells", Biotechnology and Bioengineering, (20060530), vol. 94, no. 6, pages 1045 - 1052, XP002651719

DOI:   http://dx.doi.org/10.1002/BIT.20958
    - TRUMMER et al., "Process parameter shifting: Part I. Effect of DOT, pH, and temperature on the performance of Epo-Fc expressing CHO cells cultivated in controlled batch bioreactors", Biotechnology and Bioengineering, (20060530), vol. 94, no. 6, pages 1033 - 1044, XP002486305

DOI:   http://dx.doi.org/10.1002/bit.21013
    - TRUMMER, E. et al., "Process parameter shifting: Part II. Biphasic cultivation - A tool for enhancing the volumetric productivity of batch processes using Epo-Fc expressing CHO cells", Biotechnology and Bioengineering,, (20060530), vol. 94, no. 6, pages 1045 - 1052, XP002651719

DOI:   http://dx.doi.org/10.1002/BIT.20958
    - Yoon S K; Kim S H; Song J Y; Lee G M, "Biphasic culture strategy for enhancing volumetric erythropoietin productivity of Chinese hamster ovary cells", ENZYME AND MICROBIAL TECHNOLOGY,, (20060703), vol. 39, no. 3, pages 362 - 365, XP025095192

DOI:   http://dx.doi.org/10.1016/j.enzmictec.2005.11.029
    - HAMILTON W G; HAM R G, "CLONAL GROWTH OF CHINES HAMSTER CELL LINES IN PROTEIN-FREE MEDIA", In Vitro, (19770000), vol. 13, no. 9, pages 537 - 547, XP001042206
    - Martin Schröder; Kathrin Matischak; Peter Friedl, "Serum- and protein-free media formulations for the Chinese hamster ovary cell line DUKXB11", Journal of biotechnology, (20040301), vol. 108, no. 3, pages 279 - 292, XP055073796

DOI:   http://dx.doi.org/10.1016/j.jbiotec.2003.12.005
    - Birch; Racher J R; A J, "Antibody production", Advanced Drug Delivery Reviews,, (20060807), vol. 58, no. 5-6, pages 671 - 685, XP005611421

DOI:   http://dx.doi.org/10.1016/j.addr.2005.12.006
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