111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008399514B2
`
`(12) United States Patent
`Lukashev et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,399,514 B2
`Mar. 19,2013
`
`(54) TREATMENT FOR MULTIPLE SCLEROSIS
`
`(75)
`
`Inventors: Matvey E. Lukashev, Tewksbury, MA
`(US); Gilmore O'Neill, Medford, MA
`(US)
`
`(73) Assignee: Biogen Idee MA Inc., Cambridge, MA
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.c. 154(b) by 0 days.
`
`(21) Appl. No.: 13/372,426
`
`(22) Filed:
`
`Feb. 13,2012
`
`(65)
`
`Prior Publication Data
`
`US 2012/0196931 Al
`
`Aug. 2, 2012
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 12/526,296, filed as
`application No. PCTIUS2008/001602 on Feb. 7, 2008,
`now abandoned.
`
`(60) Provisional application No. 60/888,921, filed on Feb.
`8,2007.
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31122
`(52) U.S. Cl. ....................................................... 514/549
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,515,974 A
`511985 Zecher et al.
`511988 Sato et al.
`4,746,668 A
`711989 Speiser et al.
`4,851,439 A
`911990 Speiser et al.
`4,959,389 A
`911992 Speiser et al.
`5,149,695 A
`5,214,196 A
`511993 Blank
`5,242,905 A
`911993 Blank
`1011994 Blank
`5,359,128 A
`611995 Speiser et al.
`5,424,332 A
`5,451,667 A
`911995 Speiser et al.
`711996 Chiesi et al.
`5,538,968 A
`5,548,059 A
`811996 Bayley et al.
`1011999 Clikeman et al.
`5,972,363 A
`6,277,882 Bl
`8/2001 Joshi et al.
`6,355,676 Bl
`3/2002 Joshi et al.
`6,359,003 Bl
`3/2002 Joshi et al.
`6,436,992 Bl
`8/2002 Joshi et al.
`6,509,376 Bl
`112003 Joshi et al.
`6,812,248 B2
`1112004 Zhang et al.
`6,858,7 50 B2
`212005 Joshi et al.
`7,056,950 B2
`6/2006 Rath
`112007 Joshi et al.
`7,157,423 B2
`7,279,331 B2
`1012007 Black et al.
`7,320,999 B2
`112008 Joshi et al.
`7,364,900 B2
`4/2008 Black et al.
`7,417,045 B2
`8/2008 Anilkumar et al.
`7,432,240 B2
`10/2008 Joshi et al.
`1112009 Joshi et al.
`7,612,110 B2
`7,619,001 B2
`1112009 Joshi et al.
`12/2009 Johnson et al.
`7,638,119 B2
`7,790,916 B2
`9/2010 Joshi et al.
`
`7,803,840 B2
`7,871,977 B2
`7,906,659 B2
`7,915,310 B2
`8,067,467 B2
`2003/0176365 Al
`2004/0054001 Al
`2005/0245612 Al
`2007/0027076 Al
`2008/0089861 Al
`2008/0233185 Al
`201010130607 Al
`201110112196 Al
`201110124615 Al
`201110293711 Al
`201210165404 Al
`
`912010 Joshi et al.
`112011 Rischer et al.
`3/2011 Joshi et al.
`3/2011 Joshi et al.
`1112011 Joshi et al.
`912003 Blass
`3/2004 Joshi et al.
`1112005 Blass
`212007 Joshi et al.
`4/2008 Went et al.
`912008 Joshi et al.
`512010 Gold
`5/2011 Lukashev
`5/2011 Joshi et al.
`1212011 Joshi et al.
`6/2012 Lukashev
`
`CA
`CN
`DE
`DE
`DE
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`GB
`JP
`JP
`JP
`JP
`RU
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`2248955 Al
`511997
`1125141 A
`6/1996
`2530372 Al
`111977
`2621214 Al
`1111977
`2840498 Bl
`8/1979
`3834794 Al
`4/1990
`19721099 Al
`1111998
`0188749 A2
`7/1986
`0312697 A2
`4/1989
`0518388 A2
`12/1992
`0793966 Al
`9/1997
`0852233 Al
`7/1998
`2291422 A
`111996
`54-80439 A
`6/1979
`6-345644 A
`12/1994
`8-99906 A
`4/1996
`9-221428 A
`8/1997
`2 189813 Cl
`912002
`WO 89/01930 Al
`3/1989
`WO 94/28883 Al
`12/1994
`WO 95/25102 Al
`9/1995
`WO 96/01122 Al
`111996
`WO 96/08970 Al
`3/1996
`WO 97/09984 Al
`3/1997
`WO 97/13504 Al
`4/1997
`(Continued)
`
`OTHER PUBLICATIONS
`
`Thomson Innovation Patent Record, DWPI Accession No. 1979-
`58797B, English Abs.language Abstract of Japanese Patent Publica(cid:173)
`tion No. 54-80439 A, (1979).
`
`(Continued)
`
`John Ulm
`Primary Examiner -
`(74) Attorney, Agent, or Firm - Sterne, Kessler, Goldstein
`& Fox P.L.L.c.
`
`(57)
`
`ABSTRACT
`
`Provided are certain methods of screening, identifYing, and
`evaluating neuroprotective compounds useful for treatment
`of neurological diseases, such as, e.g., multiple sclerosis
`(MS). The compounds described upregulate the cellular cyto(cid:173)
`protective pathway regulated by Nrf2. Also provided are cer(cid:173)
`tain methods of utilizing such compounds in therapy for
`neurological disease, particularly, for slowing or reducing
`demyelination, axonal loss, or neuronal and oligodendrocyte
`death.
`
`20 Claims, 4 Drawing Sheets
`
`Page 1 of 30
`
`

`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008399514B2
`
`(12) United States Patent
`Lukashev et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,399,514 B2
`Mar. 19,2013
`
`(54) TREATMENT FOR MULTIPLE SCLEROSIS
`
`(75)
`
`Inventors: Matvey E. Lukashev, Tewksbury, MA
`(US); Gilmore O'Neill, Medford, MA
`(US)
`
`(73) Assignee: Biogen Idee MA Inc., Cambridge, MA
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.c. 154(b) by 0 days.
`
`(21) Appl. No.: 13/372,426
`
`(22) Filed:
`
`Feb. 13,2012
`
`(65)
`
`Prior Publication Data
`
`US 2012/0196931 Al
`
`Aug. 2, 2012
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 12/526,296, filed as
`application No. PCTIUS2008/001602 on Feb. 7, 2008,
`now abandoned.
`
`(60) Provisional application No. 60/888,921, filed on Feb.
`8,2007.
`
`(51)
`
`Int. Cl.
`(2006.01)
`A61K 31122
`(52) U.S. Cl. ....................................................... 514/549
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,515,974 A
`511985 Zecher et al.
`511988 Sato et al.
`4,746,668 A
`711989 Speiser et al.
`4,851,439 A
`911990 Speiser et al.
`4,959,389 A
`911992 Speiser et al.
`5,149,695 A
`5,214,196 A
`511993 Blank
`5,242,905 A
`911993 Blank
`1011994 Blank
`5,359,128 A
`611995 Speiser et al.
`5,424,332 A
`5,451,667 A
`911995 Speiser et al.
`711996 Chiesi et al.
`5,538,968 A
`5,548,059 A
`811996 Bayley et al.
`1011999 Clikeman et al.
`5,972,363 A
`6,277,882 Bl
`8/2001 Joshi et al.
`6,355,676 Bl
`3/2002 Joshi et al.
`6,359,003 Bl
`3/2002 Joshi et al.
`6,436,992 Bl
`8/2002 Joshi et al.
`6,509,376 Bl
`112003 Joshi et al.
`6,812,248 B2
`1112004 Zhang et al.
`6,858,7 50 B2
`212005 Joshi et al.
`7,056,950 B2
`6/2006 Rath
`112007 Joshi et al.
`7,157,423 B2
`7,279,331 B2
`1012007 Black et al.
`7,320,999 B2
`112008 Joshi et al.
`7,364,900 B2
`4/2008 Black et al.
`7,417,045 B2
`8/2008 Anilkumar et al.
`7,432,240 B2
`10/2008 Joshi et al.
`1112009 Joshi et al.
`7,612,110 B2
`7,619,001 B2
`1112009 Joshi et al.
`12/2009 Johnson et al.
`7,638,119 B2
`7,790,916 B2
`9/2010 Joshi et al.
`
`7,803,840 B2
`7,871,977 B2
`7,906,659 B2
`7,915,310 B2
`8,067,467 B2
`2003/0176365 Al
`2004/0054001 Al
`2005/0245612 Al
`2007/0027076 Al
`2008/0089861 Al
`2008/0233185 Al
`201010130607 Al
`201110112196 Al
`201110124615 Al
`201110293711 Al
`201210165404 Al
`
`912010 Joshi et al.
`112011 Rischer et al.
`3/2011 Joshi et al.
`3/2011 Joshi et al.
`1112011 Joshi et al.
`912003 Blass
`3/2004 Joshi et al.
`1112005 Blass
`212007 Joshi et al.
`4/2008 Went et al.
`912008 Joshi et al.
`512010 Gold
`5/2011 Lukashev
`5/2011 Joshi et al.
`1212011 Joshi et al.
`6/2012 Lukashev
`
`CA
`CN
`DE
`DE
`DE
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`GB
`JP
`JP
`JP
`JP
`RU
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`2248955 Al
`511997
`1125141 A
`6/1996
`2530372 Al
`111977
`2621214 Al
`1111977
`2840498 Bl
`8/1979
`3834794 Al
`4/1990
`19721099 Al
`1111998
`0188749 A2
`7/1986
`0312697 A2
`4/1989
`0518388 A2
`12/1992
`0793966 Al
`9/1997
`0852233 Al
`7/1998
`2291422 A
`111996
`54-80439 A
`6/1979
`6-345644 A
`12/1994
`8-99906 A
`4/1996
`9-221428 A
`8/1997
`2 189813 Cl
`912002
`WO 89/01930 Al
`3/1989
`WO 94/28883 Al
`12/1994
`WO 95/25102 Al
`9/1995
`WO 96/01122 Al
`111996
`WO 96/08970 Al
`3/1996
`WO 97/09984 Al
`3/1997
`WO 97/13504 Al
`4/1997
`(Continued)
`
`OTHER PUBLICATIONS
`
`Thomson Innovation Patent Record, DWPI Accession No. 1979-
`58797B, English Abs.language Abstract of Japanese Patent Publica(cid:173)
`tion No. 54-80439 A, (1979).
`
`(Continued)
`
`John Ulm
`Primary Examiner -
`(74) Attorney, Agent, or Firm - Sterne, Kessler, Goldstein
`& Fox P.L.L.c.
`
`(57)
`
`ABSTRACT
`
`Provided are certain methods of screening, identifYing, and
`evaluating neuroprotective compounds useful for treatment
`of neurological diseases, such as, e.g., multiple sclerosis
`(MS). The compounds described upregulate the cellular cyto(cid:173)
`protective pathway regulated by Nrf2. Also provided are cer(cid:173)
`tain methods of utilizing such compounds in therapy for
`neurological disease, particularly, for slowing or reducing
`demyelination, axonal loss, or neuronal and oligodendrocyte
`death.
`
`20 Claims, 4 Drawing Sheets
`
`Page 2 of 30
`
`

`
`US 8,399,514 B2
`Page 2
`
`WO
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`FOREIGN PATENT DOCUMENTS
`WO 97/44054 A2
`1111997
`WO 97/48405 Al
`12/1997
`WO 98/04290 A2
`2/1998
`WO 98127970 A2
`7/1998
`WO 99121565 Al
`1111998
`8/2001
`WO 01159072 Al
`WO 02102190 A2
`112002
`WO 02/38142 A2
`5/2002
`WO 021064129 A2
`8/2002
`WO 03/020908 A2
`3/2003
`WO 03/032969 A2
`4/2003
`WO 2005/023241 Al
`3/2005
`WO 2005/027899 Al
`3/2005
`WO 2006/037342 A2
`4/2006
`WO 2006/050730 Al
`5/2006
`WO 2006/055871 A2
`5/2006
`WO 2006/088836 A2
`8/2006
`WO 2006/088837 A2
`8/2006
`WO 2006/088840 Al
`8/2006
`WO 2006/088919 A2
`8/2006
`WO 2006/088920 Al
`8/2006
`WO 2006/088921 A2
`8/2006
`WO 2006/091428 A2
`8/2006
`WO 2007/005879 A2
`112007
`WO 2007/006307 A2
`112007
`WO 2007/042034 Al
`4/2007
`4/2007
`WO 2007/042035 A2
`WO 2008/096271 A2
`8/2008
`8/2008
`WO 2008/097596 A2
`8/2011
`WO 20111100589 Al
`
`OTHER PUBLICATIONS
`
`English language Abstract of German Patent Publication No. DE 38
`34794 AI, European Patent Office, Espacenet database-Worldwide
`(2001).
`English language Abstract of Japanese Patent Publication No. JP
`6-345644 A, European Patent Office, Espacenet database-World(cid:173)
`wide (2001).
`English language Abstract of Japanese Patent Publication No. JP
`8-99906 A, European Patent Office, Espacenet database-World(cid:173)
`wide (2001).
`English language Abstract of Japanese Patent Publication No. JP
`9-221428 A, European Patent Office, Espacenet database-World(cid:173)
`wide (2001).
`English language Abstract of WIPO Patent Publication No. WO
`97/48405 AI, European Patent Office, Espacenet database-World(cid:173)
`wide (2001).
`English language Abstract of Russian Patent Publication No. RU 2
`189 813 Cl, European Patent Office, Espacenet database-World(cid:173)
`wide (2002).
`English language Abstract of WIPO Patent Publication No. WO
`2005/027899 AI, European Patent Office, Espacenet database(cid:173)
`Worldwide (2005).
`Altmeyer, P.J., et ai., "Antipsoriatic effect of fumaric acid derivatives
`Results of a multicenter double-blind study in 100 patients," Journal
`of the American Academy of Dermatology 30( 6): 977 -981, American
`Academy of Dermatology, Inc., United States (1994).
`Andersson, M., et ai., "Cytokine profile in interferon-j3 treated mul(cid:173)
`tiple sclerosis patients: reduction of interleukin-l0 mRNA express(cid:173)
`ing cells in peripheral blood," Eur. J Neurol. 4:567-571, Rapid Sci(cid:173)
`ence Publishers, England (1997).
`Bacharach-Buhles, M., et ai., "Fumaric Acid Esters (FAEs) Suppress
`CD 15- and ODP 4-positive Cells in Psoriasis," Acta. Derm. Venereol.
`Suppl. (Stockh) 186:79-82, Scandinavian University Press, Norway
`(1994).
`Balashov, K.E., et al., "Defective regulation ofIFNy and IL-12 by
`endogenous IL-I0 in progressive MS," Neurology 55: 192-198, AAN
`Enterprises, Inc., United States (2000).
`Becanovic, K., et al., "Paradoxical effects of arthritis-regulating
`chromosome 4 regions on myelin oligodendrocyte glycoprotein-in(cid:173)
`duced encephalomyelitis in congenic rats," Eur. J
`Immunol.
`33: 1907-1916, Wiley-VCH Verlag GmbH & Co. KGaA, Germany
`(2003).
`
`Bettelli, E. and Nicholson, L.B., "The Role ofCytokines in Experi(cid:173)
`mental Autoimmune Encephalomyelitis," Arch. Immun. Ther. Exp.
`48:389-398, Warszawa, Panstwowy Zaklad Wydawn Lekarskich,
`Switzerland (2000).
`Brown, T.R. and Kraft, G.H., "Multiple Sclerosis: A Paradigm Shift,"
`Phys. Med Rehabil. Clin. N. Am. 16:xvii-xx, Elsevier Inc., United
`States (2005)
`Cannella, B., et al., "IL-1O Fails to Abrogate Experimental Autoim(cid:173)
`mune Encephalomyelitis," J Neuroscience Research 45:735-746,
`Wiley-Liss, Inc., United States (1996).
`Correale, J., et ai., "Sulfasalazine aggravates experimental autoim(cid:173)
`mune encephalomyelitis and causes an increase in the number of
`autoreactive T cells," J Neuroimmunol. 34:109-120, Elsevier Sci(cid:173)
`ence Publishers B.Y., Netherlands (1991).
`Dahlman, I., et ai., "Quantitative trait loci disposing for both experi(cid:173)
`mental arthritis and encephalomyelitis in the DA rat; impact on
`severity of myelin oligodendrocyte glycoprotein-induced experi(cid:173)
`mental autoimmune encephalomyelitis and antibody isotype pat(cid:173)
`tern," Eur. J Immunol. 28:2188-2196, Wiley-VCH Verlag GmbH,
`Germany (1998).
`Dal Canto, R.A., et al., "Local Delivery of TNF by Retrovirus(cid:173)
`Transduced T Lymphocytes Exacerbates Experimental Autoimmune
`Encephalomyelitis," Clinical Immunol. 90(1):10-14, Academic
`Press, United States (1999).
`De Graaf, K.L., et ai., "MHC Class II Isotype- and Allele-Specific
`Attenuation of Experimental Autoimmune Encephalomyelitis," J
`Immunol. 173:2792-2802, The American Association of Immunolo(cid:173)
`gists, Inc., United States (2004).
`De Haan, P., "The Risk ofSensibilization and Contact Uritcaria upon
`Topical Application of Fumaric Acid Derivatives," Dermatology
`188: 126-130, Karger AG, Switzerland (1994).
`De Jong, R., et ai., "Selective stimulation of T helper 2 cytokine
`responses by the anti -psoriasis agent monomethylfumarate," Eur. J
`Immunol. 26:2067-2074, Verlag Chemie GmbH, Germany (1996).
`Del Prete, G., "The Concept of Type-l and Type-2 Helper T Cells and
`Their Cyotkines in Humans," Intern. Rev. Immunol. 16:427-455,
`OPA (Overseas Publishers Association) Amsterdam B.Y., England
`(1998).
`Dethlefsen, L.A., "Toxic Effects of Acute Glutathione Depletion by
`Buthionine Sulfoximine and Dimethylfumarate on Murine Mam(cid:173)
`mary Carcinoma Cells," Radiation Res. 114:215-224, Academic
`Press, Inc., United States (1988).
`Di Marco, R., et ai., "Curative effects of recombinant human
`Interleukin -6 in DA rats with protracted relapsing experimental aller(cid:173)
`gic encephalomyelitis," J Neuroimmunol. 116:168-177, Elsevier
`Science B.Y., Netherlands (2001).
`Di Rosa, E, et ai., "LackofTh2 cytokine increase during spontaneous
`remission of experimental allergic encephalomyelitis," Eur. J
`Immunol. 28:3893-3903, Wiley-VCH Verlag GmbH, Germany
`(1998).
`Djerbi, M., et ai., "Expression of the Long Form of Human FLIP by
`Retroviral Gene Transfer of Hemopoietic Stem Cells Exacerbates
`Immunol.
`Experimental Autoimmune Encephalomyelitis," J
`170:2064-2073, The American Association of Immunologists, Inc.,
`United States (2003).
`Ducker, P. and Pfeiff, B., "Zwei Faile von Nebenwirkungen einer
`H+G
`Zeitschriji
`fur
`Fumarsaureester-Lokaltharapie,"
`Hautkrankheiten 65:734-736, Grosse Verlag Berlin, Germany (1990)
`(Abstract Only in English).
`Ferber, LA., et ai., "Mice with a Disrupted IFN-y Gene Are Suscep(cid:173)
`of Experimental Autoimmune
`tible
`to
`the
`Induction
`Encephalomyelitis (EAE)," J Immunol. 156:5-7, The American
`Association ofImmunologists, United States (1996).
`Ferrante, P., et ai., "Cytokine Production and Surface Marker Expres(cid:173)
`sion in Acute and Stable Multiple Sclerosis: Altered IL-12 Produc(cid:173)
`tion and Augmented Signaling. Lymphocytic Activation Molecule
`(SLAM)-Expressing Lymphocytes in Acute Multiple Sclerosis," J
`Immunol. 160: 1514-1521, The American Association ofImmunolo(cid:173)
`gists, United States (1998).
`Fliegner, L. and Spiegel, P., "Osteomalazie als offenbar seltene
`Nebenwirkung der oralen Fumarsauretherapie," Hautarzt 43:554-
`560, Springer-Verlag, Germany (1992) (Abstract Only in English).
`
`Page 3 of 30
`
`

`
`US 8,399,514 B2
`Page 3
`
`Furlan, R., et al., "Interferon-i3 treatment in multiple sclerosis
`patients decreases the number of circulating T cells producing inter(cid:173)
`feron-y and interleukin-4," J Neuroimmunol. 111 :86-92, Elsevier
`Science B.Y., Netherlands (2000).
`Galli, G., et ai., "Macrophage-derived chemokine production by
`activated human T cells in vitro and in vivo: preferential association
`with the production of type 2 cytokines," Eur. J Immunol. 30:204-
`210, Wiley-VCH Verlag GmbH, Germany (2000).
`Gasser, M., et al., "Host Vs Graft and Graft Vs Host Reactions After
`Allogeneic Heterotopic Small Bowel Transplantation in the Rat,"
`Transplant. Proc. 24(3):1128-1129, Appleton & Lange, United
`States (1992).
`Genain, c.P., et ai., "Late Complications of Immune Deviation
`Therapy in a Nonhuman Primate," Science 274:2054-2057, Ameri(cid:173)
`can Association for the Advancement of Science, United States
`(1996).
`Ghoreschi, K. and Riicken, M., "Immune Deviation Strategies in the
`Therapy of Psoriasis," Current Drug Targets-Inflammation &
`Allergy 3:193-198, Bentham Science Publishers Ltd., Netherlands
`(2004).
`Ghoreschi, K., et ai., "Fumarates induce a DC2 phenotype in
`dendritic cells that establishes protective Th2 responses," Arch.
`Dermatol. Forschung 296:420, Springer Verlag, Germany (2005)
`(Abstract Only).
`Ghoreschi, K., et ai., "Fumaric acid ester an antipsoriatic drug abol(cid:173)
`ishes the capacity of T cells to induce Thl-mediated autoimmune
`disease," Arch. Dermatol. Res. 294:28, Springer Verlag, Germany
`(2002) (Abstract Only).
`Gielen, A.W., et ai., "Expression of T cell immunoglobulin- and
`mucin-domain-containing molecules-l and -3 (TIM-l and -3) in the
`rat nervous and immune systems," J Neuroimmunol. 164:93-104,
`Elsevier B.Y., Netherlands (2005).
`Gijbels, K., et al., "Administration of Neutralizing Antibodies to
`Interleukin-6
`(IL-6) Reduces Experimental Autoimmune
`Encephalomyelitis and is Associated with Elevated Levels of IL-6
`Bioactivity in Central Nervous System and Circulation," Mol. Med
`1(7):795-805, Molecular Medicine, United States (1995).
`Giovannoni, G. and Miller, D.H., "Multiple sclerosis and its treat(cid:173)
`ment," JR. Coli. Physicians Lond 33(4):315-322, Royal College of
`Physicians, England (1999).
`Guggenmos, J., et al., "Antibody Cross-Reactivity between Myelin
`Oligodendrocyte Glycoprotein and the Milk Protein Butyrophilin in
`Multiple Sclerosis," J Immunol. 172:661-668, The American Asso(cid:173)
`ciation ofImmunologists, Inc., United States (2004).
`Hemmer, B., et ai, "Cytokine Phenotype of Human Autoreactive T
`Cell Clones Specific for the Immunodominant Myelin Basic Protein
`Peptide (83-99)," J Neurosci. Res. 45:852-862, Wiley-Liss, Inc.,
`United States (1996).
`Hintzen, R.Q. and Polman, C.H., "Th-cell modulation in multiple
`sclerosis," Immunol. Today 18(10):507-508, ElsevierlNorth-Holland
`Biomedical Press, England (1997).
`Hohenegger, M., et ai., "Nephrotoxicity of Fumaric Acid
`Monoethylester (FA ME)," Advances in Experimental Medicine and
`Biology 252:265-272, Kluwer Academic, United States (1989).
`Hultgren, B., et al., "Genetic Absence of y-Interferon Delays but
`Does Not Prevent Diabetes in NOD Mice," Diabetes 45:812-817,
`American Diabetes Association, United States (1996).
`English language excerpt from Hunziker, T and Schmidli, J., "Is
`Psoriasis an.Autoimmune Disease?" Therapeutische Umschau
`50: 110-113, Determatologische Klinik der Universitdt Bern, Swit(cid:173)
`zerland (1993).
`Hunziker, T
`"Psoriasis, eine Autoim(cid:173)
`J.,
`and Schmidli,
`Umschau
`50: 110-113,
`Therapeutische
`munkrankheit?"
`Determatologische Klinik der Universitiit Bern, Switzerland (1993).
`Issazadeh, S., et ai., "Cytokine production in the central nervous
`rats with
`experimental
`autoimmune
`system of Lewis
`encephalomyelitis: dynamics of mRNA expression for interleukin-
`10, interleukin-12, cytolysin, tumor necrosis factor ex and tumor
`necrosis factor 13," J Neuroimmunol. 61:205-212, Elsevier Science
`B.V, Netherlands (1995).
`Issazadeh, S., et ai., "Interferon y, Interleukin 4 and Transforming
`Growth Factor i3in Experimental Autoimmune Encephalomyelitis in
`Lewis Rats: Dynamics of Cellular mRNA Expression in the Central
`
`Nervous System and Lymphoid Cells," J Neurosci. Res. 40:579-590,
`Wiley-Liss, Inc., United States (1995).
`Issazadeh, S., et ai., "Cytokines in relapsing experimental autoim(cid:173)
`mune encephalomyelitis in DA rats: persistent mRNA expression of
`proinflanunatory cytokines and absent expression of interleukin-lO
`and transforming growth factor-i3," J Neuroimmunol. 69:103-115,
`Elsevier Science B.V Netherlands (1996).
`Issazadeh, S., et ai., "Major histocompatibility complex-controlled
`on
`experimental
`autoimmune
`protective
`influences
`encephalomyelitis are peptide specific," Eur. J Immunol. 27:1584-
`1587, VCH Verlagsgeseelschaft mbH, Germany (1997).
`Kappos, L., et ai., "Efficacy and safety of oral fumarate in patients
`with
`relapsing-remitting multiple
`sclerosis:
`a multicentre,
`randomised, double-blind, placebo-controlled phase IIb study," Lan(cid:173)
`cet 372: 1463-1472, Lancet Publishing Group., England (2008).
`Khademi, M., et al., "Induction of systemic TNFex in Natalizumab(cid:173)
`treated multiple sclerosis," Eur. J Neurol. 15:309-312, European
`Federation of Neurological Sciences, England (2008).
`Khademi, M., et ai., "Reduction of both pro- and anti-inflanunatory
`cytokines after 6 months of interferon beta-la treatment of multiple
`sclerosis," J Neuroimmunol. 103:202-210, Elsevier Science B.Y.,
`Netherlands (2000).
`Khademi , M., et ai., "T Cell Ig- and Mucin-Domain-Containing
`Molecule-3 (TIM-3) and TIM-l Molecules Are Differentially
`Expressed on Human Thl and Th2 Cells and in Cerebrospinal Fluid(cid:173)
`Derived Mononuclear Cells in Multiple Sclerosis," J Immunol.
`172:7169-7176, The American Association ofImmunologists, Inc.,
`United States (2004).
`Kiehl, R. and Ionescu, G., "A Defective Purine Nucleotide Synthesis
`Pathway in Psoriatic Patients," Acta Derm. Venereol. (Stockh)
`72:253-255, Society for
`the Publication of Acta Dermato(cid:173)
`Venerologica, Sweden (1992).
`Kjellen, P., et ai., "Genetic influence on disease course and cytokine
`response in relapsing experimental allergic encephalomyelitis," Int.
`Immunol. 10:333-340, Oxford University Press, England (1998).
`Kolbach, D.N. and Nieboer, C., "Fumaric acid therapy in psoriasis:
`Results and side effects of 2 years of treatment," JAm. Acad. Derm.
`27(5):769-771, Mosby, United States (1992).
`Krakauer, M., et ai., "Dynamic T-Iymphocyte Chemokine Receptor
`Expression Induced by Interferon-beta Therapy in Multiple Sclero(cid:173)
`sis," Scand. J Immunol. 64:155-163, Blackwell Publishing Ltd.,
`England (2006).
`Krakowski, M. and Owens, T, "Interferon-y confers resistance to
`experimental allergic encephalomyelitis," Eur. J Immunol. 26: 1641-
`1646, VCH Verlagsgesellschaft mbH, Germany (1996).
`Kuroda, K., et ai., "Fumaric Acid Enhances DNA Synthesis of Rat
`Hepatocytes by Counteracting the Toxicities of Mitomycin C and
`Aflatoxin B 1 ," Jpn. J Cancer Res. (Gann) 77:750-758, Japanese
`Cancer Association, Japan (1986).
`LaFaille, J.J., et ai., "Myelin Basic Protein-specific T Helper 2 (Th2)
`Cells Cause Experimental Autoimmune Encephalomyelitis in
`Immunodeficient Hosts Rather than Protect Them from the Disease,"
`J Exp. Med. 186(2):307-312, The Rockefeller University Press,
`United States (1997).
`LaFaille, J.J., "The Role of Helper T Cell Subsets in Autoimmune
`Diseases," Cytokine & Growth Factor Rev. 9(2): 139-151, Elsevier
`Science Ltd., England (1998).
`Lahti, A. and Maibach, H.I., "Contact urticaria from diethyl
`fumarate," Contact Dermatitis 12:139-140, Munksgaard, Denmark
`(1985).
`Laman, J.D., et ai., "Balancing the ThllTh2 concept in multiple
`sclerosis," Immunol. Today 19(11):489-490, ElsevierlNorth-Holland
`Biomedical Press, England (1998).
`Lehnert, S., et ai., "Radiation Response of Drug-Resistant Variants of
`a Human Breast Cancer Cell Line: The Effect of Glutathione Deple(cid:173)
`tion," Radiation Res. 124:208-215, Academic Press, Inc., United
`States (1990).
`Liedtke, W., et ai., "Effective Treatment of Models of Multiple Scle(cid:173)
`rosis by Matrix Metalloproteinase Inhibitors," Ann. Neurol.
`44( 1 ):35-46, The American Neurological Association, United States
`(1998).
`Link, J., et ai., "Organ-specific autoantigens induce interferon-y and
`interleukin-4 mRNA expression in mononuclear cells in multiple
`
`Page 4 of 30
`
`

`
`US 8,399,514 B2
`Page 4
`
`sclerosis and myasthenia gravis," Neurology 44:728-734, The Ameri(cid:173)
`can Academy of Neurology, United States (1994).
`Link, J., et ai., "Organ-specific Autoantigens Induce Transforming
`Growth Factor-i3 mRNA Expression in Mononuclear Cells in Mul(cid:173)
`tiple Sclerosis and Myasthenia Gravis," Annals Neurol. 35: 197-203,
`The American Neurological Association, United States (1994).
`Link, J., et ai., "Optic neuritis is associated with myelin basic protein
`and proteolipid protein reactive cells producing interferon-y,
`interleukin-4 and transforming growth factor-i3," J Neuroimmunol.
`49:9-18, Elsevier Science B.V, Netherlands (1994).
`Link, J., et ai., "Increased Transforming Growth Factor-i3,
`Interleukin-4, and Interferon-y in Multiple Sclerosis," Ann. Neurol.
`36(3):379-386, The American Neurological Association, United
`States (1994).
`Link, H., "The cytokine storm in multiple sclerosis," Mult. Scler.
`4:12-15, Stockton Press, England (1998).
`Linker, R.A., et ai., "Fumarates for the treatment of multiple sclero(cid:173)
`sis: potential mechanisms of action and clinical studies," Expert Rev.
`Neurother. 8(11): 1683-1690, Expert Reviews Ltd., England (2008).
`Lobell, A., et ai., "Suppressive DNA Vaccination in Myelin
`Oligodendrocyte Glycoprotein Peptide-Induced Experimental
`Autoimmune Encephalomyelitis Involves a Tl-Biased Immune
`Response," J Immunol. 170:1806-1813, The American Association
`ofImmunologists, Inc., United States (2003).
`Lobell, A., et al., "Vaccination with DNA Encoding an
`Immunodominant Myelin Basic Protein Peptide Targeted to Fe of
`Immunoglobulin G Suppresses Experimental Autoimmune
`Encephalomyelitis," J Exp. Med.
`187(9):1543-1548, The
`Rockefeller University Press, United States (1998).
`Lopez, E., et al., "Interferon y, IL2, IL4, ILI0 and TNFa Secretions
`in Multiple Sclerosis Patients Treated with an Anti-CD4 Monoclonal
`Antibody," Autoimmunity 29:87-92, OPA (Overseas Publishers
`Association) N.V, England (1999).
`Lorentzen, J.c., et ai., "Genetic analysis of inflanunation, cytokine
`mRNA expression and disease course of relapsing experimental
`autoimmune encephalomyelitis in DA rats," J Neuroimmunol.
`80:31-37, Elsevier Science N.V, Netherlands (1997).
`Lorentzen, J.c., et al., "Protracted, relapsing and demyelinating
`experimental autoimmune encephalomyelitis in DA rats immunized
`with syngeneic spinal cord and incomplete Freund's adjuvant," J
`Neuroimmunol. 63:193-205, Elsevier Science B.V, Netherlands
`(1995).
`Lyons, J.-A., et al., "Pathogenesis of acute passive murine
`encephalomyelitis II. Thl phenotype of the inducing population is
`not sufficient to cause disease," J Neuroimmunol. 93:26-36, Elsevier
`Science B.V, Netherlands (1999).
`Miiiittii, J.A., et ai., "Neutrophils secreting tumor necrosis factor
`alpha infiltrate the central nervous systems of BALB/c mice with
`experimental autoimmune encephalomyelitis," J Neuroimmunol.
`90: 162-175, Elsevier Science B.V, Netherlands (1998).
`Martin, R., et ai., "T helper cell differentiation in multiple sclerosis
`and autoimmunity," Immunol. Today 19(11):495-498, Elsevier Sci(cid:173)
`ence, England (1998).
`Mattner, E, et ai., "Inhibition of Thl development and treatment of
`chronic-relapsing experimental allergic encephalomyelitis by a non(cid:173)
`hypercalcemic analogue of 1,25-dihydroxyvitamin D3 ," Eur. J
`Immunol. 30:498-508, Wiley-VCH Verlag GmbH, Germany (2000).
`Matusevicius, D., et ai., "Auto antigen-induced IL-13 mRNA expres(cid:173)
`sion is increased in blood mononuclear cells in myasthenia gracis and
`multiple sclerosis," Eur. J Neurol. 4:468-475, Rapid Science Pub(cid:173)
`lisher, England (1997).
`Asadullah, K., et ai., "Influence of monomethylfumarate on
`monocytic cytokine formation---explanation for adverse and thera(cid:173)
`peutic effects in psoriasis?" Arch. Dermatol. Res. 289:623-630,
`Springer-Verlag, Germany (1997).
`Bacharach-Buhles, M., et al., "The Effect of Fumaric Acid Esters and
`Dithranol on Acanthosis and Hyperproliferation in Psoriasis
`vulgaris," Acta Derm. Venereol. (Stockh)76:190-193, Scandinavian
`University Press, Sweden (1996).
`Balashov, K.E., et ai., "Increased interleukin 12 production in pro(cid:173)
`gressive multiple sclerosis: Induction by activated CD4+ T cells via
`
`CD40 ligand," Proc. Natl. Acad. Sci. USA 94:599-603, The National
`Academy of Sciences of the United States of America, United States
`(1997).
`Barcia, c., et al., "Parkinson's Disease and Inflanunatory Changes,"
`Neurotox. Res. 5(6):411-418, FP Graham Publishing Co., United
`States (2003).
`Breuer, K., et al., "Therapy of noninfectious granulomatous skin
`diseases with fumaric acid esters," Br. J Dermatol. 152: 1290-1295,
`British Association of Dermatologists, England (2005).
`Eberlein-Konig, B., et ai., "Disseminated Granuloma Annulare(cid:173)
`Treatment with Fumaric Acid Esters," Dermatology 210:223-226, S.
`Karger AG, Switzerland (2005).
`Link, H., et ai., "Virus-reactive and autoreactive T cells are accumu(cid:173)
`lated in cerebrospinal fluid in multiple sclerosis," J Neuroimmunol.
`38:63-74, Elsevier Science Publishers B.V, Netherlands (1992)
`Litjens, N.H.R., et al., "Monomethylfarnarate affects polarization of
`monocyte-derived dendritic cells resulting in down-regulated Thl
`lymphocyte responses," Eur. J Immunol. 34:565-575, Wiley-VCH
`Verlag GmbH & Co. KGaA, Germany (2004).
`Litjens, N.H.R., et ai., "Pharmacokinetics of oral fumarates in
`healthy subjects," Br. J Clin. Pharmacol. 58(4):429-432, Blackwell
`Publishing Ltd, England (2004).
`Lobell, A., et ai., "Presence of CpG DNA and the Local Cytokine
`Milieu Determine the Efficacy of Suppressive DNA Vaccination in
`Immunol.
`Experimental Autoimmune Encephalomyelitis," J
`163:4754-4762, The American Association of Immunologists,
`United States (1999).
`Loewe, R., et al., "Dimethyl fumarate Inhibits TNF-Induced Nuclear
`Entry of NF-KKb/p65 in Human Endothelial Cells," J Immunol.
`168:4781-4787, The American Association of Immunologists,
`United States (2002).
`Luft, R., "The development of mitochondrial medicine," Proc. Natl.
`Acad. Sci. USA 91:8731-8738, National Academy of Sciences,
`United States (1994).
`Mayne, M., et ai., "Antisense Oligodeoxynucleotide Inhibition of
`Tumor Necrosis Factor-a Expression is Neuroprotective After
`Intracerebral Hemorrhage," Stroke 32:240-248, American Heart
`Association, Inc., United States (2001).
`McGeer, P.L., et ai., "Expression of the histocompatibility
`glycoprotein HLA-DR in neurological disease," Acta Neuropathol.
`76:550-557, Springer-Verlag, Germany (1988).
`Muhallab, S., et ai., "Intra-CNS activation by antigen-specific T
`lymphocytes in experimental autoimmune encephalomyelitis," J
`Neuroimmunol. 113:202-211, Elsevier Science B.V, Netherlands
`(2001).
`Musiek, E.S., et ai., "Cyclopentenone isoprostanes are novel bioac(cid:173)
`tive products oflipid oxidation which enhance neurodegeneration," J
`Neurochem.
`97: 130 1-1313,
`International
`Society
`for
`Neurochemistry, England (2006).
`Mustafa, M.l., et al., "T cell immunity and interferon-y secretion
`during experimental allergic encephalomyelitis in Lewis rats," J
`Neuroimmunol. 31: 165 -177, Elsevier Science Publishers B. V, N eth(cid:173)
`erlands (1991).
`Mustafa, M., et ai., "Immunopharmacologic Modulation of Experi(cid:173)
`mental Allergic Encephalomyelitis: Low-Dose Cyclosporin-A
`Treatment Causes Disease Relapse and Increased Systemic T and B
`Cell-Mediated Myelin-Directed Autoimmunity," Scand. J Immunol.
`38:499-507, Blackwell Scientific Publications, England (1993).
`Mustafa, M., et ai., "The major histocompatibility complex influ(cid:173)
`ences myelin basic protein 63-88-induced T cell cytokine profile and
`experimental autoimmune encephalomyelitis," Eur. J Immunol.
`23:3089-3095, VCH Verlagsgesellschaft mbH, Germany (1993).
`Mustafa, M., et ai., "Protective Influences on Experimental Autoim(cid:173)
`mune Encephalomyelitis by MHC Class I and Class II Alleles," J
`Immunol. 153:3337-3344, The American Association of Immunolo(cid:173)
`gists, United States (