Extract from the Register of European Patents

About this file: EP3524676

EP3524676 - OPSIN POLYPEPTIDES AND METHODS OF USE THEREOF [Right-click to bookmark this link]
StatusRequest for examination was made
Status updated on  14.02.2020
Database last updated on 21.02.2020
FormerThe application has been published
Status updated on  12.07.2019
Most recent event   Tooltip14.02.2020The date on which the examining division becomes responsible, has been established 
14.02.2020Request for examination filedpublished on 18.03.2020 [2020/12]
14.02.2020Change - designated statespublished on 18.03.2020 [2020/12]
Applicant(s)For all designated states
The Board of Trustees of the Leland Stanford Junior University
Office of the General Counsel
Building 170, Third Floor, Main Quad
P.O. Box 20386
Stanford, CA 94305-2038 / US
[2019/38]
Former [2019/33]For all designated states
The Board of Trustees of The Leland Stanford Junior University
Office of The General Counsel
Building 170, 3rd Floor, Main Quad
P.O. Box 20386
Stanford, CA 94305-2038 / US
Inventor(s)01 / DEISSEROTH, Karl
720 Alvarado Row
Stanford, CA 94305 / US
02 / ZHANG, Feng
P.O. Box
91 Sidney Street, No. 801
Cambridge, MA 02139 / US
 [2019/33]
Representative(s)Mewburn Ellis LLP
City Tower
40 Basinghall Street
London EC2V 5DE / GB
[2019/33]
Application number, filing date19153835.412.12.2012
[2019/33]
Priority number, dateUS201161576858P16.12.2011         Original published format: US 201161576858 P
[2019/33]
Filing languageEN
Procedural languageEN
PublicationType: A1 Application with search report 
No.:EP3524676
Date:14.08.2019
Language:EN
[2019/33]
Search report(s)(Supplementary) European search report - dispatched on:EP07.05.2019
ClassificationInternational:C12N15/00, C07K1/00, C07K14/00
[2019/33]
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 [2020/12]
Former [2019/33]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 
TitleGerman:OPSIN-POLYPEPTIDE UND VERFAHREN ZU IHRER VERWENDUNG[2019/33]
English:OPSIN POLYPEPTIDES AND METHODS OF USE THEREOF[2019/33]
French:POLYPEPTIDES OPSINES ET LEURS PROCÉDÉS D'UTILISATION[2019/33]
Examination procedure07.02.2020Amendment by applicant (claims and/or description)
07.02.2020Examination requested  [2020/12]
07.02.2020Date on which the examining division has become responsible
Parent application(s)   TooltipEP12858055.2  / EP2791333
Fees paidRenewal fee
25.01.2019Renewal fee patent year 03
25.01.2019Renewal fee patent year 04
25.01.2019Renewal fee patent year 05
25.01.2019Renewal fee patent year 06
25.01.2019Renewal fee patent year 07
13.12.2019Renewal fee patent year 08
Documents cited:Search[Y]WO2011116238  (UNIV LELAND STANFORD JUNIOR [US], et al) [Y] 1-15 * abstract *;
 [XY]US2011165681  (BOYDEN EDWARD S [US], et al) [X] 1,3-15 * abstract * * paragraph [0047] * * paragraph [0074] * * paragraph [0089] * * paragraph [0110] * [Y] 2;
 [XP]WO2012027358  (HARVARD COLLEGE [US], et al) [XP] 1-15 * abstract * * paragraph [0199] - paragraph [0200]; claims 1-22; tables 3,5; sequences 86,17,18,20 *
 [Y]  - SHARMA ADRIAN K ET AL, "Evolution of rhodopsin ion pumps in haloarchaea", BMC EVOLUTIONARY BIOLOGY, BIOMED CENTRAL LTD., LONDON, GB, (20070518), vol. 7, no. 1, doi:10.1186/1471-2148-7-79, ISSN 1471-2148, page 79, XP021027855 [Y] 1-15 * abstract *

DOI:   http://dx.doi.org/10.1186/1471-2148-7-79
 [Y]  - "SubName: Full=Bacteriorhodopsin {ECO:0000313|EMBL:ABT17417.1};", UniProt, (20100810), Database accession no. A7U0Y6, URL: EBI, XP002739968 [Y] 1-15 * sequence . *
 [Y]  - XUE HAN ET AL, "A High-Light Sensitivity Optical Neural Silencer: Development and Application to Optogenetic Control of Non-Human Primate Cortex", FRONTIERS IN SYSTEMS NEUROSCIENCE, (20110413), vol. 5, doi:10.3389/fnsys.2011.00018, XP055265835 [Y] 1-15 * abstract *

DOI:   http://dx.doi.org/10.3389/fnsys.2011.00018
 [Y]  - ZHANG F ET AL, "Optogenetic interrogation of neural circuits: Technology for probing mammalian brain structures", NATURE PROTOCOLS, NATURE PUBLISHING GROUP, GB, vol. 5, no. 3, doi:10.1038/NPROT.2009.226, ISSN 1750-2799, (20100301), pages 439 - 456, (20100218), XP009172355 [Y] 1-15 * abstract * * page 439, column r, paragraph 2 - page 440, column l, paragraph 1; figure 1; table 1 *

DOI:   http://dx.doi.org/10.1038/nprot.2009.226
by applicantUS2004131637
 WO9617951
 WO9412649
 WO9303769
 WO9319191
 WO9428938
 WO9511984
 WO9500655
 WO9309239
 US6566118
 US6989264
 US6995006
 WO9911764
 WO9118088
 US4797368
 US6596535
 US5139941
 EP0488528
 US6649811
 US5387742
 US7632679
 US6447784
 US6066476
 US6020192
 US5985577
 US5976796
 US5968750
 US5968738
 US5958713
 US5919445
 US5874304
    - J. Biol. Chem., (19690000), vol. 243, pages 3552 - 59
    - ALTSCHUL et al., J. Mol. Biol., (19900000), vol. 215, pages 403 - 10
    - PULKKINEN; MILLER, J. Bacteriol., (19910000), vol. 173, no. 1, pages 86 - 93
    - ALPUCHE-ARANDA et al., PNAS, (19920000), vol. 89, no. 21, pages 10079 - 83
    - HARBORNE et al., Mol. Micro., (19920000), vol. 6, pages 2805 - 2813
    - DUNSTAN et al., Infect. Immun., (19990000), vol. 67, pages 5133 - 5141
    - MCKELVIE et al., Vaccine, (20040000), vol. 22, pages 3243 - 3255
    - CHATFIELD et al., Biotechnol, (19920000), vol. 10, pages 888 - 892
    - "GenBank", Database accession no. AX798980
    - "GenBank", Database accession no. AX798961
    - "GenBank", Database accession no. AX798183
    - SHETRON-RAMA et al., Infect. Immun., (20020000), vol. 70, pages 1087 - 1096
    - VALDIVIA; FALKOW, Mol. Microbiol., (19960000), vol. 22, page 367
    - HILLEN,W.; WISSMANN,A., Topics in Molecular and Structural Biology, Protein-Nucleic Acid Interaction, Macmillan, (19890000), vol. 10, pages 143 - 162
    - MELTON et al., Nucl. Acids Res., (19840000), vol. 12, page 7035
    - DEBOER et al., Proc. Natl. Acad. Sci. U.S.A., (19830000), vol. 80, pages 21 - 25
    - LI et al., Invest Opthalmol Vis Sci, (19940000), vol. 35, page 2543 2549
    - BORRAS et al., Gene Ther, (19990000), vol. 6, page 515 524
    - LI; DAVIDSON, PNAS, (19950000), vol. 92, page 7700 7704
    - SAKAMOTO et al., H Gene Ther, (19990000), vol. 5, page 1088 1097
    - ALI et al., Hum Gene Ther, (19980000), vol. 9, page 81 86
    - FLANNERY et al., PNAS, (19970000), vol. 94, page 6916 6921
    - BENNETT et al., Invest Opthalmol Vis Sci, (19970000), vol. 38, page 2857 2863
    - JOMARY et al., Gene Ther, (19970000), vol. 4, page 683 690
    - ROLLING et al., Hum Gene Ther, (19990000), vol. 10, page 641 648
    - ALI et al., Hum Mol Genet, (19960000), vol. 5, page 591 594
    - SAMULSKI et al., J. Vir., (19890000), vol. 63, pages 3822 - 3828
    - MENDELSON et al., Virol, (19880000), vol. 166, pages 154 - 165
    - FLOTTE et al., PNAS, (19930000), vol. 90, pages 10613 - 10617
    - MIYOSHI et al., PNAS, (19970000), vol. 94, page 10319 23
    - TAKAHASHI et al., J Virol, (19990000), vol. 73, page 7812 7816
    - BLACKLOW, Parvoviruses and Human Disease, (19880000), pages 165 - 174
    - ROSE, Comprehensive Virology, (19740000), vol. 3, page 1
    - "The Evolution of Parvovirus Taxonomy", P. TATTERSALL, Parvoviruses, Hudder Arnold, (20060000), pages 5 - 14
    - DE BOWLES; JE RABINOWITZ; RJ SAMULSKI, The Genus Dependovirus, Hudder Arnold, (20060000), pages 15 - 23
    - "GenBank", Database accession no. L04147
    - "GenBank", Database accession no. M55301
    - CHEN et al., Cell, (19870000), vol. 51, pages 7 - 19
    - LLEWELLYN et al., Nat. Med., (20100000), vol. 16, page 1161
    - "GenBank", Database accession no. S62283
    - Nucl. Acids. Res., (19870000), vol. 15, pages 2363 - 2384
    - Neuron, (19910000), vol. 6, pages 583 - 594
    - RADOVICK et al., Proc. Natl. Acad. Sci. USA, (19910000), vol. 88, pages 3402 - 3406
    - OBERDICK et al., Science, (19900000), vol. 248, pages 223 - 226
    - BARTGE et al., Proc. Natl. Acad. Sci. USA, (19880000), vol. 85, pages 3648 - 3652
    - COMB et al., EMBO J., (19880000), vol. 17, pages 3793 - 3805
    - LIU et al., Gene Therapy, (20040000), vol. 11, pages 52 - 60
    - LEE et al., Development, (20040000), vol. 131, pages 3295 - 3306
    - MAYFORD et al., Proc. Natl. Acad. Sci. USA, (19960000), vol. 93, page 13250
    - CARRIER et al., J. Immunol., (19920000), vol. 148, pages 1176 - 1181
    - SIZEMORE et al., Science, (19950000), vol. 270, pages 299 - 302
    - MATZ et al., Nature Biotechnol., (19990000), vol. 17, pages 969 - 973
    - GRADINARU et al., J. Neurosci., (20070000), vol. 27, no. 52, pages 14231 - 14238
    - ZHANG et al., Nature, (20070000), vol. 446, pages 633 - 639
    - ZHANG et al., Nature Reviews Neuroscience, (20070000), vol. 8, pages 577 - 581
    - MAYBERG HS et al., "Deep Brain Stimulation for Treatment-Resistant Depression", Neuron, (20050303), vol. 45, pages 651 - 660
    - SCHLAEPFER et al., "Deep Brain stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depression", Neuropsychopharmacology, (20070000), pages 1 - 10
    - DEISSEROTH, K., "Optogenetics", Nat Methods, (20110000), vol. 8, pages 26 - 29
    - DEISSEROTH, K., "Controlling the brain with light", Sci Am, (20100000), vol. 303, pages 48 - 55
    - FENNO, L.; YIZHAR, O.; DEISSEROTH, K., "The development and application of optogenetics", Annu Rev Neurosci, (20110000), vol. 34, doi:doi:10.1146/annurev-neuro-061010-113817, pages 389 - 412, XP055135085

DOI:   http://dx.doi.org/10.1146/annurev-neuro-061010-113817
    - YIZHAR, O.; FENNO, L.E.; DAVIDSON, T.J.; MOGRI, M.; DEISSEROTH, K., "Optogenetics in neural systems", Neuron, (20110000), vol. 71, doi:doi:10.1016/j.neuron.2011.06.004, pages 9 - 34, XP028379910

DOI:   http://dx.doi.org/10.1016/j.neuron.2011.06.004
    - WANG, C.; KANE, M.A.; NAPOLI, J.L., "Multiple retinol and retinal dehydrogenases catalyze all-trans-retinoic acid biosynthesis in astrocytes", J Biol Chem, (20110000), vol. 286, pages 6542 - 6553
    - BOYDEN, E.S.; ZHANG, F.; BAMBERG, E.; NAGEL, G.; DEISSEROTH, K., "Millisecond-timescale, genetically targeted optical control of neural activity", Nat Neurosci, (20050000), vol. 8, doi:doi:10.1038/nn1525, pages 1263 - 1268, XP055012811

DOI:   http://dx.doi.org/10.1038/nn1525
    - LI, X. et al., "Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin", Proc Natl Acad Sci U S A, (20050000), vol. 102, doi:doi:10.1073/pnas.0509030102, pages 17816 - 17821, XP009159155

DOI:   http://dx.doi.org/10.1073/pnas.0509030102
    - BI, A. et al., "Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration", Neuron, (20060000), vol. 50, doi:doi:10.1016/j.neuron.2006.02.026, pages 23 - 33, XP002406402

DOI:   http://dx.doi.org/10.1016/j.neuron.2006.02.026
    - ISHIZUKA, T.; KAKUDA, M.; ARAKI, R.; YAWO, H., "Kinetic evaluation of photosensitivity in genetically engineered neurons expressing green algae light-gated channels", Neurosci Res, (20060000), vol. 54, doi:doi:10.1016/j.neures.2005.10.009, pages 85 - 94, XP024955895

DOI:   http://dx.doi.org/10.1016/j.neures.2005.10.009
    - NAGEL, G. et al., "Light activation of channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses", Curr Biol, (20050000), vol. 15, doi:doi:10.1016/j.cub.2005.11.032, pages 2279 - 2284, XP027513347

DOI:   http://dx.doi.org/10.1016/j.cub.2005.11.032
    - GRADINARU, V. et al., "Targeting and readout strategies for fast optical neural control in vitro and in vivo", J Neurosci, (20070000), vol. 27, doi:doi:10.1523/JNEUROSCI.3578-07.2007, pages 14231 - 14238, XP055401440

DOI:   http://dx.doi.org/10.1523/JNEUROSCI.3578-07.2007
    - GUNAYDIN, L.A. et al., "Ultrafast optogenetic control", Nat Neurosci, (20100000), vol. 13, doi:doi:10.1038/nn.2495, pages 387 - 392, XP055135011

DOI:   http://dx.doi.org/10.1038/nn.2495
    - BERNDT, A.; YIZHAR, O.; GUNAYDIN, L.A.; HEGEMANN, P.; DEISSEROTH, K., "Bistable neural state switches", Nat Neurosci, (20090000), vol. 12, doi:doi:10.1038/nn.2247, pages 229 - 234, XP055106451

DOI:   http://dx.doi.org/10.1038/nn.2247
    - KLEINLOGEL, S. et al., "Ultra light-sensitive and fast neuronal activation with the Ca(2+)-permeable channelrhodopsin CatCh", Nat Neurosci, (20110000), vol. 14, doi:doi:10.1038/nn.2776, pages 513 - 518, XP055009508

DOI:   http://dx.doi.org/10.1038/nn.2776
    - ZHANG, F. et al., "Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri", Nat Neurosci, (20080000), vol. 11, doi:doi:10.1038/nn.2120, pages 631 - 633, XP002487916

DOI:   http://dx.doi.org/10.1038/nn.2120
    - GOVORUNOVA, E.G.; SPUDICH, E.N.; LANE, C.E.; SINESHCHEKOV, O.A.; SPUDICH, J.L., "New channelrhodopsin with a red-shifted spectrum and rapid kinetics from Mesostigma viride", MBio, (20110000), vol. 2, pages eOO 115 - 00111
    - LIN, J.Y.; LIN, M.Z.; STEINBACH, P.; TSIEN, R.Y., "Characterization of engineered channelrhodopsin variants with improved properties and kinetics", Biophys J, (20090000), vol. 96, doi:doi:10.1016/j.bpj.2008.11.034, pages 1803 - 1814, XP008151895

DOI:   http://dx.doi.org/10.1016/j.bpj.2008.11.034
    - WANG, H. et al., "Molecular determinants differentiating photocurrent properties of two channelrhodopsins from chlamydomonas", J Biol Chem, (20090000), vol. 284, doi:doi:10.1074/jbc.M807632200, pages 5685 - 5696, XP008151880

DOI:   http://dx.doi.org/10.1074/jbc.M807632200
    - WEN, L. et al., "Opto-current-clamp actuation of cortical neurons using a strategically designed channelrhodopsin", PLoS One, (20100000), vol. 5, page e12893
    - STEHFEST, K.; HEGEMANN, P., "Evolution of the channelrhodopsin photocycle model", Chemphyschem, vol. 11, doi:doi:10.1002/cphc.200900980, pages 1120 - 1126, XP055136138

DOI:   http://dx.doi.org/10.1002/cphc.200900980
    - BAMANN, C.; KIRSCH, T.; NAGEL, G.; BAMBERG, E., "Spectral characteristics of the photocycle of channelrhodopsin-2 and its implication for channel function", J Mol Biol, (20080000), vol. 375, doi:doi:10.1016/j.jmb.2007.10.072, pages 686 - 694, XP022400110

DOI:   http://dx.doi.org/10.1016/j.jmb.2007.10.072
    - SUGIYAMA, Y. et al., "Photocurrent attenuation by a single polar-to-nonpolar point mutation of channelrhodopsin-2", Photochem Photobiol Sci, (20090000), vol. 8, pages 328 - 336
    - HEDRICK, T.; WATERS, T.H., "Spiking patterns of neocortical L5 pyramidal neurons in vitro change with temperature", Front Cell Neurosci, (20110000), vol. 5, page 1
    - CARDIN, J.A. et al., "Driving fast-spiking cells induces gamma rhythm and controls sensory responses", Nature, (20090000), vol. 459, pages 663 - 667
    - SOHAL, V.S.; ZHANG, F.; YIZHAR, O.; DEISSEROTH, K., "Parvalbumin neurons and gamma rhythms enhance cortical circuit performance", Nature, (20090000), vol. 459, doi:doi:10.1038/nature07991, pages 698 - 702, XP055135667

DOI:   http://dx.doi.org/10.1038/nature07991
    - TSAI, H.C. et al., "Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning", Science, (20090000), vol. 324, doi:doi:10.1126/science.1168878, pages 1080 - 1084, XP055107925

DOI:   http://dx.doi.org/10.1126/science.1168878
    - ATASOY, D.; APONTE, Y.; SU, H.H.; STERNSON, S.M., "A FLEX switch targets Channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping", J Neurosci, (20080000), vol. 28, doi:doi:10.1523/JNEUROSCI.1954-08.2008, pages 7025 - 7030, XP055482038

DOI:   http://dx.doi.org/10.1523/JNEUROSCI.1954-08.2008
    - CHATER, T.E.; HENLEY, J.M.; BROWN, J.T.; RANDALL, A.D., "Voltage- and temperature-dependent gating of heterologously expressed channelrhodopsin-2", J Neurosci Methods, (20100000), vol. 193, pages 7 - 13
    - ZHANG, F. et al., "Multimodal fast optical interrogation of neural circuitry", Nature, (20070000), vol. 446, doi:doi:10.1038/nature05744, pages 633 - 639, XP002487911

DOI:   http://dx.doi.org/10.1038/nature05744
    - GRADINARU, V. et al., "Molecular and cellular approaches for diversifying and extending optogenetics", Cell, (20100000), vol. 141, doi:doi:10.1016/J.CELL.2010.02.037, pages 154 - 165, XP002704864

DOI:   http://dx.doi.org/10.1016/J.CELL.2010.02.037
    - HAN, X.; BOYDEN, E.S., "Multiple-color optical activation, silencing, and desynchronization of neural activity, with single-spike temporal resolution", PLoS One, (20070000), vol. 2, page e299
    - WITTEN, I.B. et al., "Cholinergic interneurons control local circuit activity and cocaine conditioning", Science, (20100000), vol. 330, doi:doi:10.1126/science.1193771, pages 1677 - 1681, XP055135834

DOI:   http://dx.doi.org/10.1126/science.1193771
    - STUBER, G.D. et al., "Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking", Nature, (20110000), vol. 475, pages 377 - 380
    - TYE, K.M. et al., "Amygdala circuitry mediating reversible and bidirectional control of anxiety", Nature, (20110000), vol. 471, doi:doi:10.1038/nature09820, pages 358 - 362, XP055287700

DOI:   http://dx.doi.org/10.1038/nature09820
    - GRADINARU, V.; THOMPSON, K.R.; DEISSEROTH, K., "eNpHR: a Natronomonas halorhodopsin enhanced for optogenetic applications", Brain Cell Biol, (20080000), vol. 36, doi:doi:10.1007/s11068-008-9027-6, pages 129 - 139, XP002557433

DOI:   http://dx.doi.org/10.1007/s11068-008-9027-6
    - CHOW, B.Y. et al., "High-performance genetically targetable optical neural silencing by light-driven proton pumps", Nature, (20100000), vol. 463, doi:doi:10.1038/nature08652, pages 98 - 102, XP055248714

DOI:   http://dx.doi.org/10.1038/nature08652
    - HAN, X. et al., "A high-light sensitivity optical neural silencer: development and application to optogenetic control of non-human primate cortex", Front. Syst. Neurosci., (20110000), vol. 5, doi:doi:10.3389/fnsys.2011.00018, XP055265835

DOI:   http://dx.doi.org/10.3389/fnsys.2011.00018
    - ZIMMERMANN, D. et al., "Effects on capacitance by overexpression of membrane proteins", Biochem Biophys Res Commun, (20080000), vol. 369, doi:doi:10.1016/j.bbrc.2008.02.153, pages 1022 - 1026, XP022575456

DOI:   http://dx.doi.org/10.1016/j.bbrc.2008.02.153
    - ZHAO, Y. et al., "An expanded palette of genetically encoded Ca(2) indicators", Science, (20110000), vol. 333, pages 1888 - 1891
    - GOTO, Y.; O'DONNELL, P., "Network synchrony in the nucleus accumbens in vivo", J Neurosci, (20010000), vol. 21, pages 4498 - 4504
    - SANCHEZ-VIVES, M.V.; MCCORMICK, D.A., "Cellular and network mechanisms of rhythmic recurrent activity in neocortex", Nat Neurosci, (20000000), vol. 3, pages 1027 - 1034
    - NAGEL, G. et al., "Channelrhodopsin-2, a directly light-gated cation-selective membrane channel", Proc Natl Acad Sci USA, (20030000), vol. 100, doi:doi:10.1073/pnas.1936192100, pages 13940 - 13945, XP002406405

DOI:   http://dx.doi.org/10.1073/pnas.1936192100
    - GOOLD, C.P.; NICOLL, R.A., "Single-cell optogenetic excitation drives homeostatic synaptic depression", Neuron, (20100000), vol. 68, pages 512 - 528
    - LINDSAY, T.H.; THIELE, T.R.; LOCKERY, S.R., "Optogenetic analysis of synaptic transmission in the central nervous system of the nematode Caenorhabditis elegans", Nat Commun, (20110000), vol. 2, page 306
    - TAYLOR, C.P.; DUDEK, F.E., "Synchronous neural afterdischarges in rat hippocampal slices without active chemical synapses", Science, (19820000), vol. 218, pages 810 - 812
    - REN, J. et al., "Habenula ''cholinergic'' neurons co-release glutamate and acetylcholine and activate postsynaptic neurons via distinct transmission modes", Neuron, (20110000), vol. 69, pages 445 - 452
 WO2005US27091