Extract from the Register of European Patents

About this file: EP2215124

EP2215124 - ANTIGEN BINDING PROTEINS TO PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 (PCSK9) [Right-click to bookmark this link]
StatusThe patent has been granted
Status updated on  22.01.2016
Database last updated on 14.12.2019
Most recent event   Tooltip05.08.2019Change: Date of oral proceedings 
05.08.2019Deletion: Despatch of minutes of oral proceedings 
Applicant(s)For all designated states
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799 / US
[2010/32]
Inventor(s)01 / JACKSON, Simon, Mark
2071 Birch Avenue
San Carlos, CA 94070 / US
02 / WALKER, Nigel Pelham, Clinton
20 Howland Hill Lane
Burlingame, CA 94010-6033 / US
03 / PIPER, Derek, Evan
675 Giannini Drive
Santa Clara, CA 95051 / US
04 / SHAN, Bei
349 Quay Lane
Redwood City, CA 94065 / US
05 / SHEN, Wenyan
60 Pugh Road
Wayne, PA 19087 / US
06 / CHAN, Joyce Chi, Yee
314 College Avenue
San Francisco, CA 94112 / US
07 / KING, Chadwick, Terence
1325 Moody Avenue
North Vancouver
British Columbia V7L 3T5 / CA
08 / KETCHEM, Randal, Robert
6332 152nd St. Se
Snohomish, WA 98296 / US
09 / MEHLIN, Christopher
2806 Northwest 61st Street
Seattle, WA 98107 / US
10 / CARABEO, Teresa, Arazas
1 Christopher Street, Apt. 8A
New York, NY 10014 / US
11 / CAO, Qiong
582 King Drive, Apt. 6
Dalt City, CA 94015 / US
 [2016/08]
Former [2010/32]01 / JACKSON, Simon, Mark
2071 Birch Avenue
San Carlos, CA 94070 / US
02 / WALKER, Nigel Pelham, Clinton
20 Howland Hill Lane
Burlingame, CA 94010-6033 / US
03 / PIPER, Derek, Evan
675 Giannini Drive
Santa Clara, CA 95051 / US
04 / SHAN, Bei
349 Quay Lane
Redwood City, CA 94065 / US
05 / SHEN, Wenyan
60 Pugh Road
Wayne, PA 19087 / US
06 / CHAN, Joyce Chi, Yee
314 College Avenue
San Francisco, CA 94112 / US
07 / KING, Chadwick, Terence
1325 Moody Avenue North Vancouver
British Columbia V7L 3T5 / CA
08 / KETCHEM, Randal, Robert
6332 152nd St. Se
Snohomish, WA 98296 / US
09 / MEHLIN, Christopher
2806 Northwest 61st Street
Seattle, WA 98107 / US
10 / CARABEO, Teresa, Arazas
1 Christopher Street, Apt. 8A
New York, NY 10014 / US
11 / CAO, Qiong
582 King Drive, Apt. 6
Dalt City, CA 94015 / US
Representative(s)Dörries, Hans Ulrich
df-mp Dörries Frank-Molnia & Pohlman
Patentanwälte Rechtsanwälte PartG mbB
Theatinerstrasse 16
80333 München / DE
[2016/08]
Former [2010/32]Dörries, Hans Ulrich
df-mp Fünf Höfe Theatinerstrasse 16
80333 München / DE
Former [2010/32]Dörries, Hans Ulrich
Df-mp Fünf Höfe Theatinerstraße 16
80333 München / DE
Application number, filing date08798550.322.08.2008
[2010/32]
WO2008US74097
Priority number, dateUS20080010630P09.01.2008         Original published format: US 10630 P
US20080086133P04.08.2008         Original published format: US 86133 P
US20070957668P23.08.2007         Original published format: US 957668 P
US20070008965P21.12.2007         Original published format: US 8965 P
[2010/32]
Filing languageEN
Procedural languageEN
PublicationType: A1  Application with search report
No.:WO2009026558
Date:26.02.2009
Language:EN
[2009/09]
Type: A1 Application with search report 
No.:EP2215124
Date:11.08.2010
Language:EN
The application has been published by WIPO in one of the EPO official languages on 26.02.2009
[2010/32]
Type: B1 Patent specification 
No.:EP2215124
Date:24.02.2016
Language:EN
[2016/08]
Search report(s)International search report - published on:EP26.02.2009
ClassificationInternational:C07K16/40, A61P3/06, A61K39/395, A61K45/06, A61K31/22, A61K31/366, A61K31/40, A61K31/405, A61K31/44, A61K31/47, A61K31/505, A61K31/66, A61K39/00, C12N15/113
[2016/02]
Former International [2013/47]C07K16/40, A61P3/06, A61K39/395, A61K45/06, A61K31/22, A61K31/366, A61K31/40, A61K31/405, A61K31/44, A61K31/47, A61K31/505, A61K31/66
Former International [2010/32]C07K16/40, A61P3/06, A61K39/395
Designated contracting statesAT,   BE,   BG,   CH,   CY,   CZ,   DE,   DK,   EE,   ES,   FI,   FR,   GB,   GR,   HR,   HU,   IE,   IS,   IT,   LI,   LT,   LU,   LV,   MC,   MT,   NL,   NO,   PL,   PT,   RO,   SE,   SI,   SK,   TR [2016/08]
Former [2010/32]AT,  BE,  BG,  CH,  CY,  CZ,  DE,  DK,  EE,  ES,  FI,  FR,  GB,  GR,  HR,  HU,  IE,  IS,  IT,  LI,  LT,  LU,  LV,  MC,  MT,  NL,  NO,  PL,  PT,  RO,  SE,  SI,  SK,  TR 
Extension statesAL18.03.2010
BA18.03.2010
MK18.03.2010
RS18.03.2010
TitleGerman:ANTIGENBINDENDE PROTEINE GEGEN PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYP 9 (PCSK9)[2010/32]
English:ANTIGEN BINDING PROTEINS TO PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 (PCSK9)[2010/32]
French:PROTÉINES DE LIAISON À UN ANTIGÈNE POUR LA PROPROTÉINE CONVERTASE SUBTILISINE KEXINE DE TYPE 9 (PCSK9)[2016/02]
Former [2010/32]PROTÉINES DE LIAISON À UN ANTIGÈNE POUR PROPROTÉINE CONVERTASE SUBTILISINE KEXINE DE TYPE 9 (PCSK9)
Entry into regional phase18.03.2010National basic fee paid 
18.03.2010Designation fee(s) paid 
18.03.2010Examination fee paid 
Examination procedure18.03.2010Examination requested  [2010/32]
13.04.2010Amendment by applicant (claims and/or description)
05.01.2011Despatch of a communication from the examining division (Time limit: M06)
15.07.2011Reply to a communication from the examining division
15.06.2012Despatch of a communication from the examining division (Time limit: M06)
21.12.2012Reply to a communication from the examining division
22.12.2012Observations by third parties
02.01.2013Observations by third parties
03.01.2013Observations by third parties
21.06.2013Despatch of a communication from the examining division (Time limit: M04)
28.06.2013Reply to a communication from the examining division
05.02.2014Despatch of a communication from the examining division (Time limit: M04)
05.06.2014Reply to a communication from the examining division
27.06.2014Observations by third parties
24.07.2014Despatch of a communication from the examining division (Time limit: M04)
28.11.2014Reply to a communication from the examining division
14.01.2015Despatch of a communication from the examining division (Time limit: M04)
24.02.2015Reply to a communication from the examining division
28.09.2015Observations by third parties
01.10.2015Observations by third parties
09.10.2015Cancellation of oral proceeding that was planned for 27.11.2015
19.10.2015Observations by third parties
01.11.2015Observations by third parties
27.11.2015Date of oral proceedings
27.11.2015Date of oral proceedings (cancelled)
09.12.2015Fee for grant paid
09.12.2015Fee for publishing/printing paid
10.12.2015Minutes of oral proceedings despatched
15.12.2015Communication of intention to grant the patent
16.12.2015Receipt of the translation of the claim(s)
Divisional application(s)EP13151343.4  / EP2615113
EP13151352.5  / EP2641917
EP13151375.6  / EP2615114
EP13151377.2   Application deemed to be withdrawn  : 16.02.2013
EP13151381.4  / EP2641918
EP15202482.4   Application refused  : 12.06.2016
EP16157015.5   Application refused  : 08.10.2016
EP16164634.4   Application refused  : 10.09.2016
EP16178361.8   Application refused  : 16.02.2017
EP16189650.1   Application refused  : 05.02.2017
EP16204336.8  / EP3202791
EP19207796.4
The date of the Examining Division's first communication in respect of the earliest application for which a communication has been issued is  05.01.2011
Opposition(s)Opponent(s)01  24.02.2016  01.12.2016  ADMISSIBLE
Sanofi
54 Rue La Boétie
75008 Paris / FR
Opponent's representative
Zwicker, Jörk
ZSP Patentanwälte PartG mbB
Hansastraße 32
80686 München / DE
 02  22.11.2016  04.06.2018  WITHDRAWN
Strawman Limited
Orchard Lea
Horns Lane
Combe, Witney
Oxfordshire OX29 8NH / GB
Opponent's representative
Mewburn Ellis LLP, et al
City Tower
40 Basinghall Street
London EC2V 5DE / GB
 03  24.11.2016  02.12.2016  ADMISSIBLE
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, IN 46285 / US
Opponent's representative
Ingham, Stephen Howard
Eli Lilly and Company Ltd
European Patent Operations
Lilly Research Centre
Erl Wood Manor, Sunninghill Road
Windlesham, Surrey, GU20 6PH / GB
 04  24.11.2016  02.12.2016  ADMISSIBLE
Sanofi-Aventis Deutschland GmbH/Sanofi-Aventis Groupe S.A./Sanofi Winthrop Industries S.A.
Brüningstr. 50/54 rue de la Boétie/
20 Avenue Raymond Aron
65926 Frankfurt am Main/75008 Paris/92160 Antony / DE
Opponent's representative
Zwicker, Jörk, et al
ZSP Patentanwälte PartG mbB
Hansastraße 32
80686 München / DE
 05  24.11.2016  02.12.2016  ADMISSIBLE
Regeneron Pharmaceuticals, Inc.
777 Old Saw Mill River Road
Tarrytown NY 10591 / US
Opponent's representative
Goodfellow, Hugh Robin
Carpmaels & Ransford LLP
One Southampton Row
London WC1B 5HA / GB
 [2019/04]
Former [2018/28]
Opponent(s)01  24.02.2016  01.12.2016  ADMISSIBLE
Sanofi
54 Rue La Boétie
75008 Paris / FR
Opponent's representative
Zwicker, Jörk
ZSP Patentanwälte PartG mbB
Hansastraße 32
80686 München / DE
 02  22.11.2016  04.06.2018  WITHDRAWN
Strawman Limited
Orchard Lea
Horns Lane
Combe, Witney
Oxfordshire OX29 8NH / GB
Opponent's representative
Walton, Seán Malcolm, et al
Mewburn Ellis LLP
City Tower
40 Basinghall Street
London EC2V 5DE / GB
 03  24.11.2016  02.12.2016  ADMISSIBLE
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, IN 46285 / US
Opponent's representative
Ingham, Stephen Howard
Eli Lilly and Company Ltd
European Patent Operations
Lilly Research Centre
Erl Wood Manor, Sunninghill Road
Windlesham, Surrey, GU20 6PH / GB
 04  24.11.2016  02.12.2016  ADMISSIBLE
Sanofi-Aventis Deutschland GmbH/Sanofi-Aventis Groupe S.A./Sanofi Winthrop Industries S.A.
Brüningstr. 50/54 rue de la Boétie/
20 Avenue Raymond Aron
65926 Frankfurt am Main/75008 Paris/92160 Antony / DE
Opponent's representative
Zwicker, Jörk, et al
ZSP Patentanwälte PartG mbB
Hansastraße 32
80686 München / DE
 05  24.11.2016  02.12.2016  ADMISSIBLE
Regeneron Pharmaceuticals, Inc.
777 Old Saw Mill River Road
Tarrytown NY 10591 / US
Opponent's representative
Goodfellow, Hugh Robin
Carpmaels & Ransford LLP
One Southampton Row
London WC1B 5HA / GB
Former [2017/01]
Opponent(s)01  24.02.2016  01.12.2016  ADMISSIBLE
Sanofi
54 Rue La Boétie
75008 Paris / FR
Opponent's representative
Zwicker, Jörk
ZSP Patentanwälte PartG mbB
Radlkoferstrasse 2
81373 München / DE
 02  22.11.2016   
Strawman Limited
Orchard Lea
Horns Lane
Combe, Witney
Oxfordshire OX29 8NH / GB
Opponent's representative
Walton, Seán Malcolm, et al
Mewburn Ellis LLP
City Tower
40 Basinghall Street
London EC2V 5DE / GB
 03  24.11.2016   
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, IN 46285 / US
Opponent's representative
Ingham, Stephen H.
Eli Lilly and Company Ltd
European Patent Operations
Lilly Research Centre
Erl Wood Manor, Sunninghill Road
Windlesham, Surrey, GU20 6PH / GB
 04  24.11.2016   
Sanofi-Aventis Deutschland GmbH/Sanofi-Aventis Groupe S.A./Sanofi Winthrop Industries S.A.
Brüningstr. 50/54 rue de la Boétie/
20 Avenue Raymond Aron
65926 Frankfurt am Main/75008 Paris/92160 Antony / DE
Opponent's representative
Zwicker, Jörk, et al
ZSP Patentanwälte PartG mbB
Radlkoferstrasse 2
81373 München / DE
 05  24.11.2016   
Regeneron Pharmaceuticals, Inc.
777 Old Saw Mill River Road
Tarrytown NY 10591 / US
Opponent's representative
Goodfellow, Hugh Robin
Carpmaels & Ransford LLP
One Southampton Row
London WC1B 5HA / GB
Former [2016/52]
Opponent(s)01  24.02.2016   
Sanofi
54 Rue La Boétie
75008 Paris / FR
Opponent's representative
Zwicker, Jörk
ZSP Patentanwälte PartG mbB
Radlkoferstrasse 2
81373 München / DE
 02  22.11.2016   
Strawman Limited
Orchard Lea
Horns Lane
Combe, Witney
Oxfordshire OX29 8NH / GB
Opponent's representative
Walton, Seán Malcolm, et al
Mewburn Ellis LLP
City Tower
40 Basinghall Street
London EC2V 5DE / GB
 03  24.11.2016   
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, IN 46285 / US
Opponent's representative
Ingham, Stephen H.
Eli Lilly and Company Ltd
European Patent Operations
Lilly Research Centre
Erl Wood Manor, Sunninghill Road
Windlesham, Surrey, GU20 6PH / GB
Former [2016/13]
Opponent(s)01  24.02.2016   
Sanofi
54 Rue La Boétie
75008 Paris / FR
Opponent's representative
Zwicker, Jörk
ZSP Patentanwälte PartG mbB
Radlkoferstrasse 2
81373 München / DE
10.01.2017Invitation to proprietor to file observations on the notice of opposition
02.05.2017Reply of patent proprietor to notice(s) of opposition
28.11.2018Date of oral proceedings
08.03.2019Despatch of interlocutory decision in opposition
08.03.2019Despatch of minutes of oral proceedings
Appeal following opposition08.05.2019Appeal received No.  T0845/19
18.07.2019Statement of grounds filed
30.11.2018Appeal received No.  T0845/19
18.07.2019Statement of grounds filed
30.11.2018Appeal received No.  T0845/19
08.07.2019Statement of grounds filed
24.03.2020Date of oral proceedings
Fees paidRenewal fee
17.08.2010Renewal fee patent year 03
11.08.2011Renewal fee patent year 04
10.08.2012Renewal fee patent year 05
19.08.2013Renewal fee patent year 06
13.08.2014Renewal fee patent year 07
10.08.2015Renewal fee patent year 08
Cited inInternational search[PX]WO2008063382  (MERCK & CO INC [US], et al) [PX] 1-38 * figure 4; example 6; table 3 *;
 [PX]WO2008057458  (MERCK & CO INC [US], et al) [PX] 1-38 * figure 4; example 6; table 3 *;
 [E]WO2008133647  (MERCK & CO INC [US], et al) [E] 1-38 * figure 4; example 6; table 3 *;
 [PX]WO2008057457  (MERCK & CO INC [US], et al) [PX] 1-38 * figure 4; example 6; table 3 *;
 [E]WO2008125623  (NOVARTIS AG [CH], et al) [E] 1-38 * page 72; examples 5,6 *;
 [PX]WO2008057459  (MERCK & CO INC [US], et al) [PX] 1-38 * figure 4; example 6; table 3 *
 [X]  - GROZDANOV PETAR N ET AL, "Expression and localization of PCSK9 in rat hepatic cells", BIOCHEMISTRY AND CELL BIOLOGY. BIOCHIMIE ET BIOLOGIE CELLULAIRE, XX, XX, (20060201), vol. 84, no. 1, ISSN 0829-8211, pages 80 - 92, XP008095646 [X] 1-28,30,31 * see "antibodies" page 81 *

DOI:   http://dx.doi.org/10.1139/O05-155
 [X]  - MAXWELL KARA N ET AL, "Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE, WASHINGTON, DC.; US, (20040504), vol. 101, no. 18, ISSN 0027-8424, pages 7100 - 7105, XP002493244 [X] 1-28,30,31 * see "Materials" on pages 7100 and 7101 *

DOI:   http://dx.doi.org/10.1073/pnas.0402133101
 [X]  - RASHID S ET AL, "Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE, WASHINGTON, DC.; US, (20050412), vol. 102, no. 15, ISSN 0027-8424, pages 5374 - 5379, XP002478031 [X] 1-28,30,31 * See "Antibodies and immunoblot analysis", page 5375 *

DOI:   http://dx.doi.org/10.1073/pnas.0501652102
 [X]  - BENJANNET SUZANNE ET AL, The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications., THE JOURNAL OF BIOLOGICAL CHEMISTRY 13 OCT 2006, VOL. 281, NR. 41, PAGE(S) 30561 - 30572, (20061013), ISSN 0021-9258, XP002506016 [X] 1-28,30,31 * see "experimental procedures - anti PCSK9 antibodies" page 30562 *

DOI:   http://dx.doi.org/10.1074/jbc.m606495200
 [X]  - LAGACE THOMAS A ET AL, "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice", JOURNAL OF CLINICAL INVESTIGATION, AMERICAN SOCIETY FOR CLINICAL INVESTIGATION, US, (20061101), vol. 116, no. 11, ISSN 0021-9738, pages 2995 - 3005, XP002493243 [X] 1-28,30,31 * see "methods - antibodies" page 3003 *

DOI:   http://dx.doi.org/10.1172/JCI29383
ExaminationEP2615114
    - LAGACE THOMAS A ET AL, "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice", JOURNAL OF CLINICAL INVESTIGATION, AMERICAN SOCIETY FOR CLINICAL INVESTIGATION, US, (20061101), vol. 116, no. 11, doi:10.1172/JCI29383, ISSN 0021-9738, pages 2995 - 3005, XP002493243

DOI:   http://dx.doi.org/10.1172/JCI29383
    - HYOCK JOO KWON ET AL, "Molecular basis for LDL receptor recognition by PCSK9", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, US, (20080212), vol. 105, no. 6, doi:10.1073 PNAS.0712064105, ISSN 0027-8424, pages 1820 - 1825, XP007912351

DOI:   http://dx.doi.org/10.1073/pnas.0712064105
    - DA-WEI ZHANG ET AL, "Binding of Proprotein Convertase Subtilisin/Kexin Type 9 to Epidermal Growth Factor-like Repeat A of Low Density Lipoprotein Receptor Decreases Receptor Recycling and Increases Degradation*", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, US, vol. 282, no. 25, doi:10.1074/JBC.M702027200, ISSN 0021-9258, (20070622), pages 18602 - 18612, (20070423), XP007912352

DOI:   http://dx.doi.org/10.1074/jbc.M702027200
    - NI YAN G ET AL, "A proprotein convertase subtilisin-like/kexin type 9 (PCSK9) C-terminal domain antibody antigen-binding fragment inhibits PCSK9 internalization and restores low density lipoprotein uptake", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, INC, BETHESDA, MD, USA, vol. 285, no. 17, doi:10.1074/JBC.M110.113035, ISSN 1083-351X, (20100423), pages 12882 - 12891, (20100219), XP002619048

DOI:   http://dx.doi.org/10.1074/JBC.M110.113035
    - Third Report of tho National Choiesterol Education Progiam (NCEP) Ecpert Panelon Detection. Evaluation, and Treatment cf High Blood Cholesterol in Mults (AdultTreatment Panel IH) Final Report, (20020901), pages 3161 - 3167
    - Saurabh Saha ET AL, "Solution Structure of the LDL Receptor EGF-AB Pair", STRUCTURE, US, (20010601), vol. 9, no. 6, doi:10.1016/S0969-2126(01)00606-2, ISSN 0969-2126, pages 451 - 456, XP055229481

DOI:   http://dx.doi.org/10.1016/S0969-2126(01)00606-2
    - Steven Malby ET AL, "The First Epidermal Growth Factor-like Domain of the Low-Density Lipoprotein Receptor Contains a Noncanonical Calcium Binding Site +", Biochemistry, US, (20010201), vol. 40, no. 8, doi:10.1021/bi002322l, ISSN 0006-2960, pages 2555 - 2563, XP055229482

DOI:   http://dx.doi.org/10.1021/bi002322l
otherEP2615114
 WO2008125623
 EP2615114
    - LAGACE T. ET AL, "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in ivers of parabiotic mice", JOURNAL OF CLINICAL INVESTIGATION, (20061101), vol. 116, no. 11, pages 2995 - 3005, XP002493243

DOI:   http://dx.doi.org/10.1172/JCI29383
    - KWON H.J. ET AL, "Molecular basis for LDL receptor recognition by PCSK9", PNAS, (20080212), vol. 105, no. 6, pages 1820 - 1825, XP007912351

DOI:   http://dx.doi.org/10.1073/pnas.0712064105
    - ZHANG D.W. ET AL, "Binding of Proprotein Convertase Subtilisin/Kexin Type 9 to Epidermal Growth Factor-like Repeat A of Low Density Lipoprotein Receptor Decreases Receptor Recycling and Increases Degradation", JOURNAL OF BIOLOGICAL CHEMISTRY, (20070622), vol. 282, no. 25, pages 18602 - 18612, XP007912352

DOI:   http://dx.doi.org/10.1074/jbc.M702027200
    - J.M. PÉREZ DE LA LASTRA, "EPITOPE MAPPING OF 10 MONOCLONAL ANTIBODIES AGAINST THE PIG ANALOGUE OF HUMAN MEMBRANE COFACTOR PROTEIN (MCP)", IMMUNOLOGY, (1999), vol. 96, pages 663 - 670, XP055217740

DOI:   http://dx.doi.org/10.1046/j.1365-2567.1999.00732.x
OppositionWO2009026558
 WO2008125623
 WO2009100297
 WO2008057457
 WO2006081171
 EP2215124
    - SEIDAH, N.G. et al., "the secretory proprotein convertase neutral apoptosis-regulated convertase 1 (narc-1): liver regeneration and nenronal differentiation", PNAS, (20030000), vol. 100, no. 3, pages 928 - 933, XP002495458

DOI:   http://dx.doi.org/10.1073/pnas.0335507100
    - ABIFADEL M. et al., "mutations in pcsk9 cause autosomal dominant hypercholesterolemia", Nat. Genet., (20030000), vol. 34, no. 2, page 154, XP002253513

DOI:   http://dx.doi.org/10.1038/ng1161
    - BENJANNET, S. et al., "narc-1/pcsk9 and its natural mutants", JBC, (20040000), vol. 279, no. 47, pages 48865 - 48875, XP002495460

DOI:   http://dx.doi.org/10.1074/jbc.M409699200
    - TIMMS K.M. et al., "a mutation in pck9 causing autosomal-dominant hypercholesterolemia in utah pedigree", Hum. Genet., (20040000), vol. 114, no. 4, pages 349 - 353, XP055264602

DOI:   http://dx.doi.org/10.1007/s00439-003-1071-9
    - MAXWELL K.N et al., "adenoviral mediated expression of pck9 in mice results in a low density lipoprotein receptor knockout phenotype", PNAS, (20040000), vol. 101, no. 18, pages 7100 - 7105, XP002493244

DOI:   http://dx.doi.org/10.1073/pnas.0402133101
    - QIAN Y.-W. et al., "secreted pck9 downregulates low density lipoprotein receptor throuth receptor mediated endocytosis", J . Lipid Res., (20070000), vol. 48, no. 7, pages 1488 - 1498, XP055265230

DOI:   http://dx.doi.org/10.1194/jlr.M700071-JLR200
    - COHEN J. et al., "low ldl cholesterol in individuals of african descent resulting from frequent nonsense mutations in pcsk9", Nat. Genet., (20050000), vol. 37, no. 2, pages 161 - 165, XP008102949

DOI:   http://dx.doi.org/10.1038/ng1509
    - ZHAO Z. et al., "molecular characterization of loss of function mutations in pcsk9 and identification of a compound heterozygote", Am. J. Hum. Genet., (20060000), vol. 79, pages 514 - 523, XP055265231

DOI:   http://dx.doi.org/10.1086/507488
    - LAGACE T.A. et al., "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice", J. Clin. Invest., (20060000), vol. 116, no. 11, pages 2995 - 3005, XP002493243

DOI:   http://dx.doi.org/10.1172/JCI29383
    - FISHER T.S. et al., "Effects of pH and Low Density Lipoprotein (LDL) on PCSK9-dependent LDL Receptor Regulation", J. Biol. Chem., (20070510), vol. 282, no. 28, pages 20502 - 20512, XP055265234

DOI:   http://dx.doi.org/10.1074/jbc.M701634200
    - ZHANG D.-W. et al., "Binding of Proprotein Convertase Subtilisin/Kexin Type 9 to Epidermal Growth Factor-like Repeat A of Low Density Lipoprotein Receptor Decreases Receptor Recycling and Increases Degradation*", J. Biol. Chem., (20070000), vol. 282, no. 25, pages 18602 - 18612, XP007912352

DOI:   http://dx.doi.org/10.1074/jbc.M702027200
    - CUNNINGHAM D. et al., "Structural and biophysical studies of PCSK9 and its mutants linked to familialhypercholesterolemia", Nat. Struct. Mol. Biol., vol. 14, no. 5, pages 413 - 419, XP002507497

DOI:   http://dx.doi.org/10.1038/NSMB1235
    - NI, Y.G. et al., "A PCSK9-binding antibody that structurally mimics theEGF(A) domain of LDL-receptor reduces LDL cholesterolin vivo 1", J. Lipid Res., (20110000), vol. 52, pages 78 - 86, XP002686538

DOI:   http://dx.doi.org/10.1194/jlr.m011445
    - KWON, H.J. et al., "Molecular basis for LDL receptor recognition by PCSK9", PNAS, vol. 105, no. 6, page 1820, XP007912351

DOI:   http://dx.doi.org/10.1073/pnas.0712064105
    - davis et al, "Antibody Engineering, Methods and Protocols", Methods in Molecular Biology, Totowa, New Jersey, U.S., (20040000), vol. 248, XP055265232

DOI:   http://dx.doi.org/10.1385/1-59259-666-5:191
    - HOOGENBOOM, H.R., TIBTECH, (19970000), vol. 15, page 62, XP004034115

DOI:   http://dx.doi.org/10.1016/S0167-7799(97)84205-9
    - YANG W.P. et al., J. Mol. Biol., (19950000), vol. 254, page 392, XP000199739

DOI:   http://dx.doi.org/10.1006/jmbi.1995.0626
    - HARLOW, E. et al., Antibodies, A Laboratory Manual, New York, (19880000), XP055288200
    - RASHID, S. et al., "Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9", PNAS, (20050000), vol. 102, no. 15, page 5374, XP002478031

DOI:   http://dx.doi.org/10.1073/pnas.0501652102
    - PEREZ DE LA LASTRA et al., Immunology, (19990000), vol. 96, pages 663 - 670, XP055217740

DOI:   http://dx.doi.org/10.1046/j.1365-2567.1999.00732.x
    - SEIDAH, N.G. et al., "the secretory proprotein convertase neural apoptosis regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation", PNAS, (20030000), vol. 100, no. 3, page 928, XP002495458

DOI:   http://dx.doi.org/10.1073/pnas.0335507100
    - ABIFADEL M. et al., "mutations in PCKSK9 cause autosomal dominant hypercholesterolemia", Nat. Genet., (20030000), vol. 34, no. 2, page 154, XP002253513

DOI:   http://dx.doi.org/10.1038/ng1161
    - BENJANNET, S. et al., "NARC-1/PCSK9 and its natural mutants", JBC, (20040000), vol. 279, no. 47, page 48875, XP002495460

DOI:   http://dx.doi.org/10.1074/jbc.M409699200
    - TIMMS K.M. et al., "a mutation in PCK9 causing autosomal dominant hypercholesterolemia in a Utah pedigree", Hum. Genet., (20040000), vol. 114, no. 4, page 349, XP055264602

DOI:   http://dx.doi.org/10.1007/s00439-003-1071-9
    - MAXWELL K.N et al., "adenoviral mediated expression of PCSK9 in mice results in a low density lipoprotein receptor knockout phenotype", PNAS, (20040000), vol. 101, no. 18, page 7100, XP002493244

DOI:   http://dx.doi.org/10.1073/pnas.0402133101
    - QIAN Y.-W. et al., "secreted PCSK9 downregulated low density lipoprotein receptor through receptor mediated endocytosis", J. Lipid Res., (20070000), vol. 48, no. 7, page 1488, XP055265230

DOI:   http://dx.doi.org/10.1194/jlr.M700071-JLR200
    - COHEN J. et al., "low LDL cholesterol in individuals of African descent resulting fro frequent nonsense mutations in PCSK9", Nat. Genet., (20050000), vol. 37, no. 2, pages 161 - 65, XP008102949

DOI:   http://dx.doi.org/10.1038/ng1509
    - ZHAO Z. et al., "molecular characterization of loss of function mutations in PCSK9 and identification of a compound heterozygote", Am. J. Hum. Genet., (20060000), vol. 79, pages 514 - 23, XP055265231

DOI:   http://dx.doi.org/10.1086/507488
    - LAGACE T.A. et al., "secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in the livers of parabiotic mice", J. Clin. Invest., (20060000), vol. 116, no. 11, page 2995, XP002493243

DOI:   http://dx.doi.org/10.1172/JCI29383
    - FISHER T.S. et al., "effects of PH and LDL on PCSK9 dependent LDL receptor regulation", J. Biol. Chem., (20070510), vol. 282, no. 28, page 20502, XP055265234

DOI:   http://dx.doi.org/10.1074/jbc.M701634200
    - ZHANG D.-W. et al., "Binding of Proprotein Convertase Subtilisin/Kexin Type 9 to Epidermal Growth Factor-like Repeat A of Low Density Lipoprotein Receptor Decreases Receptor Recycling and Increases Degradation*", J. Biol. Chem., vol. 282, no. 25, page 18602, XP007912352

DOI:   http://dx.doi.org/10.1074/jbc.M702027200
    - CUNNINGHAM D. et al., "Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia", Nat. Struct. Mol. Biol., (20070415), vol. 14, no. 5, page 413, XP002507497

DOI:   http://dx.doi.org/10.1038/NSMB1235
    - Analysis of the features of claim 1
    - Enlarged version of Fig. 1 depicting the non-linear epitope comprising amino acids 187- 202 , 231-246 , and 368-383 of PCSK9 bound by preferred PCSK9-specific antibodies disclosed in Novartis (D14
    - Enlarged version of Fig. 2 depicting the overlap between the amino acid residues that are bound by preferred PCSK9-specific antibodies disclosed in Novartis (D14
    - Enlarged version of Fig. 3 depicting the overlap between the amino acid residues that are bound by antibodies disclosed in Novartis (D14) and the residues positioned within 8 Angstroms of 31H4
    - Enlarged version of Fig. 4 depicting the amino acid residues taught in PB to be bound by the EGFa domain of the LDL Receptor
    - Enlarged version of Fig. 5 depicting the overlap between the amino acid residues that are bound by preferred PCSK9-specific antibodies disclosed in Novartis (D14
    - Calculation of IC50 of the antibodies of D14 to PCSK9
    - NI, Y.G. et al., "a PCSK9 binding antibody that structurally mimics the EGF domain of LDL receptor reduces LDL cholesterol in vivo", J. Lipid Res., (20110000), vol. 52, page 78, XP002686538

DOI:   http://dx.doi.org/10.1194/jlr.m011445
    - Atomic coordinates and structure factors deposited with the Protein Data Bank under the accession code: ''2xtj'' and amino acid sequences of the proteins in fasta format
    - KWON, H.J. et al., "molecular basis of LDL receptor recognition by PCSK9", PNAS, (20080204), vol. 105, no. 6, page 1820, XP007912351

DOI:   http://dx.doi.org/10.1073/pnas.0712064105
    - "Antibody Engineering, Methods and Protocols", Methods in Molecular Biology, Totowa, New Jersey, U.S., (20040000), vol. 248, XP055265232

DOI:   http://dx.doi.org/10.1385/1-59259-666-5:191
    - HOOGENBOOM, H.R., "designing and optimizing library selection strategies for generating high affinity antibodies", TIBTECH, (19970000), vol. 15, page 62, XP004034115

DOI:   http://dx.doi.org/10.1016/S0167-7799(97)84205-9
    - YANG W.P. et al., "CDR walking mutagenesis for the affinity maturation of a potent human anti HIV1 antibody into the picomolar range", J. Mol. Biol., (19950000), vol. 254, page 392, XP000199739

DOI:   http://dx.doi.org/10.1006/jmbi.1995.0626
    - Antibodies, A Laboratory Manual, (19880000), XP055265233
    - RASHID, S. et al., "decreased plasma cholesterol and hypersensitivity tot statins in mice lacking PCSK9", PNAS, (20050000), vol. 102, no. 15, page 5374, XP002478031

DOI:   http://dx.doi.org/10.1073/pnas.0501652102
    - PEREZ DE LA LASTRA et al., "epitope mapping of 10 monoclonal antibodies against the pig analogue of human membrane cofactor protein (MCP)", Immunology, (19990000), vol. 96, pages 663 - 670, XP055217740

DOI:   http://dx.doi.org/10.1046/j.1365-2567.1999.00732.x
    - SEIDAH, N.G. et al., "the secretory proprotein convertase neural apoptosis regulated convertase 1", PNAS, (20030000), vol. 100, no. 3, page 928, XP002495458

DOI:   http://dx.doi.org/10.1073/pnas.0335507100
    - ABIFADEL M. et al., "mutations in PCSK9 cause autosomal dominant hypercholesterolemia", Nat. Genet., (20030000), vol. 34, no. 2, page 154, XP002253513

DOI:   http://dx.doi.org/10.1038/ng1161
    - BENJANNET, S. et al., "narc PCSK9 and its natural mutants", JBC, (20040000), vol. 279, no. 47, page 48875, XP002495460

DOI:   http://dx.doi.org/10.1074/jbc.M409699200
    - TIMMS K.M. et al., "a mutation in PCSK9 causing autosomal dominant hypercholesterolemia in a Utah pedigree", Hum. Genet., (20040000), vol. 114, no. 4, page 349, XP055264602

DOI:   http://dx.doi.org/10.1007/s00439-003-1071-9
    - QIAN Y.-W. et al., "secreted PCSK9 downregulates low density lipoprotein receptor through receptor mediated endocytosis", J. Lipid Res., (20070000), vol. 48, no. 7, page 1488, XP055265230

DOI:   http://dx.doi.org/10.1194/jlr.M700071-JLR200
    - COHEN J. et al., "low LDL cholesterol in individuals of African descent resulting fro frequent nonsense mutations", Nat. Genet., (20050000), vol. 37, no. 2, pages 161 - 65, XP008102949

DOI:   http://dx.doi.org/10.1038/ng1509
    - ZHAO Z. et al., "molecular characterization of loss of function mutations in PCSK9 and identifcation", Am. J. Hum. Genet., (20060000), vol. 79, pages 514 - 23, XP055265231

DOI:   http://dx.doi.org/10.1086/507488
    - LAGACE T.A. et al., "secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice", J. Clin. Invest., (20060000), vol. 116, no. 11, page 2995, XP002493243

DOI:   http://dx.doi.org/10.1172/JCI29383
    - FISHER T.S. et al., "effects of PH and low density lipoprotein on PCSK9 dependent LDL receptor regulation", J. Biol. Chem., (20070510), vol. 282, no. 28, page 20502, XP055265234

DOI:   http://dx.doi.org/10.1074/jbc.M701634200
    - ZHANG D.-W. et al., "binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor like repeat", J. Biol. Chem., vol. 282, no. 25, page 18602, XP007912352

DOI:   http://dx.doi.org/10.1074/jbc.M702027200
    - CUNNINGHAM D. et al., "structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia", Nat. Struct. Mol. Biol., (20070415), vol. 14, no. 5, page 413, XP002507497

DOI:   http://dx.doi.org/10.1038/NSMB1235
    - Enlarged version of Fig. 1 depicting the non-linear epitope comprising amino acids, pages 187 - 202, 231-246 , and 368-383
    - NI, Y.G. et al., "A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo", J. Lipid Res., (20110000), vol. 52, page 78, XP002686538

DOI:   http://dx.doi.org/10.1194/jlr.m011445
    - Atomic coordinates and structure factors deposited with the Protein Data Bank under the accession code ''2xtj'' and amino acid sequences of the proteins in fasta format
    - KWON, H.J. et al., "molecular basis for LDL receptor recognition by PCSK9", PNAS, vol. 105, no. 6, page 1820, XP007912351

DOI:   http://dx.doi.org/10.1073/pnas.0712064105
    - Antibody Engineering, Methods and Protocols, Methods in Molecular Biology, Totowa, New Jersey, U.S., (20040000), vol. 248
    - YANG W.P. et al., "CDR WALKING MUTAGENESIS FOR THE AFFINITY MATURATION OF A POTENT HUMAN ANTI-HIV-1 ANTIBODY INTO THE PICOMOLAR RANGE", J. Mol. Biol., (19950000), vol. 254, page 392, XP000199739

DOI:   http://dx.doi.org/10.1006/jmbi.1995.0626
    - PEREZ DE LA LASTRA et al., "Epitope mapping of 10 monoclonal antibodies against the pig analogue of human membrane cofactor protein (MCP)", Immunology, (19990000), vol. 96, pages 663 - 670, XP055217740

DOI:   http://dx.doi.org/10.1046/j.1365-2567.1999.00732.x
    - NI, Y.G. et al., "A proprotein convertase subtilisin-like/kexin type 9 (PCSK9) C-terminal domain antibody antigen-binding fragment inhibits PCSK9 internalization and restores low density lipoprotein uptak", J. Biol. Chem., (20100423), vol. 285, no. 17, pages 12882 - 12891, XP002619048

DOI:   http://dx.doi.org/10.1074/JBC.M110.113035
    - Declaration of Dr Darren Kamikura and CV
    - Declaration of Dr Malgorzata Gonciarz and CV
    - Illustration of 31H4 binding to hPCSK9