`
`(12) Ulllted States Patent
`Lukashev et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,399,514 B2
`Mar. 19, 2013
`
`US008399514B2
`
`(54) TREATMENT FOR MULTIPLE SCLEROSIS
`
`(75) Inventors: Matvey E. Lukashev, TeWksbury, MA
`Us _G.l
`(),N .n M df d MA
`(
`)’
`1 more
`‘*1 a
`e or ’
`(Us)
`
`(73) Assignee: Biogen Idec MA Inc., Cambridge, MA
`(Us)
`
`.
`( * ) Not1ce:
`
`.
`.
`.
`.
`Subject' to any d1scla1mer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(1)) by 0 days.
`
`(21) Appl~ p10‘Z 13/372,426
`
`22 F1 d
`(
`)
`1e '
`
`F b 13 2012
`e '
`’
`
`PI‘iOI‘
`US 2012/0196931A1
`
`Data
`Aug. 2, 2012
`
`.
`
`.
`
`Related U.S. Appllcatlml Data (63) Continuation of application No. 12/526,296, ?led as
`
`.
`.
`appl1cat1onNo.
`noW abandoned.
`.
`.
`.
`.
`(60) Prov1s1onal appl1cat1on No. 60/888,921, ?led on Feb.
`8, 2007.
`
`O11
`
`7,
`
`(51) [UL CL
`
`(200601)
`A61K 31/22
`(52) US. Cl. ..................................................... .. 514/549
`(58) Field of Classi?cation Search ...................... .. None
`See application ?le for complete search history.
`
`(56)
`
`.
`References Clted
`
`9/2010 Joshi etal.
`7,803,840 B2
`1/2011 Rischer et al.
`7,871,977 B2
`3/2011 108196491
`7,906,659 B2
`3/2011 Joshlet al.
`7,915,310 B2
`8,067,467 B2 11/2011 Joshi et al.
`2003/0176365 A1
`9/2003 Blass
`2004/0054001 A1
`3/2004 Joshi et al.
`2005/0245612 A1 11/2005 B1888
`2007/0027076 A1
`2/2007 Joshi et al.
`2008/0089861 A1
`4/2008 Went et al.
`2008/0233185 A1
`9/2008 Joshi et al.
`2010/0l30607 A1
`50010 Gold
`2011/0112196 A1
`5/2011 Lukashev
`2011/0124615 A1
`5/2011 Joshi et al.
`2011/0293711 A1 12/2011 Joshi et al.
`2012/0165404 A1
`6/2012 Lukashev
`
`CA
`CN
`
`DE
`DE
`DE
`DE
`
`EP
`EP
`EP
`EP
`GB
`JP
`JP
`JP
`JP
`RU
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`FOREIGN PATENT DOCUMENTS
`2248955 A1
`5/1997
`1125141 A
`6/1996
`
`26 21214 A1 11/1977
`28 40 498 B1
`8/1979
`38 34 794 A1
`4/1990
`197 21099 A1 11/1998
`
`4/1989
`0 0 312 697 A2
`
`0 518 388 A2 12/1992
`0 793 966 Al
`9/1997
`0 852 233 A1
`7/1998
`2 291422 A
`1/1996
`54_80439 A
`6/1979
`6-345644 A 12/1994
`8-99906 A
`4/1996
`9221428 A
`8/1997
`2189 813 C1
`9/2002
`WO 89/01930 A1
`3/1989
`WO 94/28883 A1 12/1994
`WO 95/25102 Al
`9/1995
`WO 96/01122 A1
`1/1996
`WO 96/08970 A1
`3/1996
`WO 97/09984 A1
`3/1997
`WO 97/13504 A1
`4/1997
`
`(Commued)
`
`OTHER PUBLICATIONS
`Thomson Innovation Patent Record, DWPI Accession No. 1979
`58797B, English Abs. language Abstract ofJapanese Patent Publica
`tion No. 54-80439 A, (1979).
`
`_
`(Continued)
`
`_
`_
`Prlmary Exammer * John Ulm
`(74) Attorney, Agent, or Firm * Sterne, Kessler, Goldstein
`& FOX RL'L'C
`
`(57)
`
`ABSTRACT
`
`.
`
`.
`
`Provided are certain methods of screening, identifying, and
`evaluat1ng neuroprotectlve compounds useful ‘for treatment
`of neurolog1cal d1seases, such as, e.g., multiple sclerosis
`(MS). The compounds descr1bed upregulate the cellular cyto
`protective pathWay regulated by Nr12. Also provided are cer
`tain methods of utiliZing such compounds in therapy for
`1
`.
`1 d.
`rt.
`1
`1
`f
`1
`.
`d .
`neuro og1ca 1sease, pa 1cu ar y, or s oW1ng or re uc1ng
`demyel1nat1on, axonal loss, or neuronal and ol1godendrocyte
`death.
`
`20 Claims, 4 Drawing Sheets
`
`U.S. PATENT DOCUMENTS
`4,515,974 A
`5/1985 Zecher et al.
`4,746,668 A
`5/1988 S2110 et al.
`2
`25:12:; 2:
`531493695 A
`9/1992 Speiser et a1:
`5,214,196 A
`5/1993 Blank
`5,242,905 A
`9/1993 Blank
`5,359,128 A 10/1994 Blank
`5,424,332 A
`6/1995 Speiser et a1.
`5,451,667 A
`9/1995 Speiser et a1.
`5,538,968 A
`7/ 1996 Chiesi et al.
`5,548,059 A
`8/1996 Bayley et a1~
`5,972,363 A 10/1999 Clikeman et al.
`6,277,882 B1
`8/2001 Joshi et al.
`6,355,676 B1
`3/2002 Joshi et al.
`6,359,003 B1
`3/2002 Joshi et al.
`6,436,992 B1
`8/2002 Joshi et al.
`1i;
`gilshl et
`200% Joshi et a1‘
`6,858,750 B2
`6/2006 Rath
`7,056,950 B2
`l/2007 Joshi et a1,
`7 ,157 ,423 B2
`7,279,331 B2 10/2007 Black et al
`7’320’999 B2
`1/ 2008 Josh‘ et al'
`7,364,900 B2
`4/2008 Black et al.
`7,417,045 B2
`800% Anilkumar et a1‘
`7,432,240 B2 10/200g Joshi et a1‘
`7,612,110 B2 11/2009 Joshi et al.
`7,619,001 B2 11/2009 Joshi et al.
`7,638,119 B2 12/2009 Johnson et al.
`7,790,916 B2
`9/2010 Joshi et al.
`
`,
`
`,
`
`ang e
`
`.
`
`Sawai (IPR2019-00789), Ex. 1001, p. 001
`
`
`
`US 8,399,514 B2
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`WO 97/44054 A2 11/1997
`W0
`WO 97/48405 A1
`12/1997
`W0
`WO 98/04290 A2
`2/1998
`W0
`WO 98/27970 A2
`7/1998
`W0
`WO 99/21565 A1
`11/1998
`W0
`WO 01/59072 A1
`8/2001
`W0
`WO 02/02190 A2
`1/2002
`W0
`WO 02/38142 A2
`5/2002
`W0
`W0 02/064129 A2
`8/2002
`W0
`W0 03/020908 A2
`3/2003
`W0
`W0 03/032969 A2
`4/2003
`W0
`W0 WO 2005/023241 A1
`3/2005
`W0 WO 2005/027899 A1
`3/2005
`W0 WO 2006/037342 A2
`4/2006
`W0 WO 2006/050730 A1
`5/2006
`W0 WO 2006/055871 A2
`5/2006
`W0 WO 2006/088836 A2
`8/2006
`W0 WO 2006/088837 A2
`8/2006
`W0 WO 2006/088840 A1
`8/2006
`W0 WO 2006/088919 A2
`8/2006
`W0 WO 2006/088920 A1
`8/2006
`W0 WO 2006/088921 A2
`8/2006
`W0 WO 2006/091428 A2
`8/2006
`W0 WO 2007/005879 A2
`1/2007
`W0 WO 2007/006307 A2
`1/2007
`W0 WO 2007/042034 A1
`4/2007
`W0 WO 2007/042035 A2
`4/2007
`W0 WO 2008/096271 A2
`8/2008
`W0 WO 2008/097596 A2
`8/2008
`W0 WO 2011/100589 A1
`8/2011
`
`OTHER PUBLICATIONS
`
`English language Abstract of German Patent Publication No. DE 38
`34 794 A1, European Patent Of?ce, Espacenet databaseiWorldwide
`(2001).
`English language Abstract of Japanese Patent Publication No. JP
`6-345644 A, European Patent Of?ce, Espacenet databaseiWorld
`wide (2001).
`English language Abstract of Japanese Patent Publication No. JP
`8-99906 A, European Patent Of?ce, Espacenet databaseiWorld
`wide (2001).
`English language Abstract of Japanese Patent Publication No. JP
`9-221428 A, European Patent Of?ce, Espacenet databaseiWorld
`wide (2001).
`English language Abstract of WIPO Patent Publication No. WO
`97/48405 A1, European Patent Of?ce, Espacenet databaseiWorld
`wide (2001).
`English language Abstract of Russian Patent Publication No. RU 2
`189 813 C1, European Patent Of?ce, Espacenet databaseiWorld
`wide (2002).
`English language Abstract of WIPO Patent Publication No. WO
`2005/027899 A1, European Patent Of?ce, Espacenet databasei
`Worldwide (2005).
`Altmeyer, PJ., et al., “Antipsoriatic effect of fumaric acid derivatives
`Results of a multicenter double-blind study in 100 patients,” Journal
`oftheAmerican Academy ofDermatology 30(6)1977-981, American
`Academy of Dermatology, Inc., United States (1994).
`Andersson, M., et al., “Cytokine pro?le in interferon-[5 treated mul
`tiple sclerosis patients: reduction of interleukin-10 mRNA express
`ing cells in peripheral blood,” Eur. .1. Neurol. 41567-571, Rapid Sci
`ence Publishers, England (1997).
`Bacharach-Buhles, M., et al., “Fumaric Acid Esters (FAEs) Suppress
`CD 15- and ODP 4-positive Cells in Psoriasis,”Acta. Derm. Venereol.
`Suppl. (Stockh) 186179-82, Scandinavian University Press, Norway
`(1994).
`Balashov, K.E., et al., “Defective regulation of IFNy and IL-12 by
`endogenous IL-10 in progressive MS,” Neurology 551192-198, AAN
`Enterprises, Inc., United States (2000).
`Becanovic, K., et al., “Paradoxical effects of arthritis-regulating
`chromosome 4 regions on myelin oligodendrocyte glycoprotein-in
`duced encephalomyelitis in congenic rats,” Eur. .1. Immunol.
`3311907-1916, Wiley-VCH Verlag GmbH & Co. KGaA, Germany
`(2003).
`
`Bettelli, E. and Nicholson, L.B., “The Role of Cytokines in Experi
`mental Autoimmune Encephalomyelitis,” Arch. Immun. T her. Exp.
`481389-398, WarsZawa, Panstwowy Zaklad Wydawn Lekarskich,
`Switzerland (2000).
`Brown, TR. and Kraft, G.H., “Multiple Sclerosis: A Paradigm Shift,”
`Phys. Med Rehabil. Clin. N. Am. 161xvii-xx, Elsevier Inc., United
`States (2005)
`Cannella, B., et al., “IL-10 Fails to Abrogate Experimental Autoim
`mune Encephalomyelitis,” .1. Neuroscience Research 451735-746,
`Wiley-Liss, Inc., United States (1996).
`Correale, J ., et al., “SulfasalaZine aggravates experimental autoim
`mune encephalomyelitis and causes an increase in the number of
`autoreactive T cells,” .1. Neuroimmunol. 341109-120, Elsevier Sci
`ence Publishers B.V., Netherlands (1991).
`Dahlman, I., et al., “Quantitative trait loci disposing for both experi
`mental arthritis and encephalomyelitis in the DA rat; impact on
`severity of myelin oligodendrocyte glycoprotein-induced experi
`mental autoimmune encephalomyelitis and antibody isotype pat
`tern,” Eur. .1. Immunol. 2812188-2196, Wiley-VCH Verlag GmbH,
`Germany (1998).
`Dal Canto, RA, et al., “Local Delivery of TNF by Retrovirus
`Transduced T Lymphocytes Exacerbates Experimental Autoimmune
`Encephalomyelitis,” Clinical Immunol. 90(1): 10- 14, Academic
`Press, United States (1999).
`De Graaf, K.L., et al., “MHC Class II Isotype- and Allele-Speci?c
`Attenuation of Experimental Autoimmune Encephalomyelitis,” .1.
`Immunol. 1 7312792-2802, The American Association of Immunolo
`gists, Inc., United States (2004).
`De Haan, P., “The Risk of SensibiliZation and Contact Uritcaria upon
`Topical Application of Fumaric Acid Derivatives,” Dermatology
`1881126-130, Karger AG, Switzerland (1994).
`De Jong, R., et al., “Selective stimulation of T helper 2 cytokine
`responses by the anti-psoriasis agent monomethylfumarate,” Eur. .1.
`Immunol. 2612067-2074, Verlag Chemie GmbH, Germany (1996).
`Del Prete, G., “The Concept of Type-1 and Type-2 Helper T Cells and
`Their Cyotkines in Humans,” Intern. Rev. Immunol. 161427-455,
`OPA (Overseas Publishers Association) Amsterdam B.V., England
`(1998).
`Dethlefsen, L.A., “Toxic Effects of Acute Glutathione Depletion by
`Buthionine Sulfoximine and Dimethylfumarate on Murine Mam
`mary Carcinoma Cells,” Radiation Res. 1141215-224, Academic
`Press, Inc., United States (1988).
`Di Marco, R., et al., “Curative effects of recombinant human
`Interleukin-6 in DA rats with protracted relapsing experimental aller
`gic encephalomyelitis,” .1. Neuroimmunol. 1161168-177, Elsevier
`Science B.V., Netherlands (2001).
`Di Rosa, F., et al., “Lack of Th2 cytokine increase during spontaneous
`remission of experimental allergic encephalomyelitis,” Eur .1.
`Immunol. 2813893-3903, Wiley-VCH Verlag GmbH, Germany
`(1998).
`Djerbi, M., et al., “Expression of the Long Form of Human FLIP by
`Retroviral Gene Transfer of Hemopoietic Stem Cells Exacerbates
`Experimental Autoimmune Encephalomyelitis,” .1. Immunol.
`17012064-2073, The American Association of Immunologists, Inc.,
`United States (2003).
`Ducker, P. and Pfeiff, B., “Zwei Falle von Nebenwirkungen einer
`FumarsaureesteriLokaltharapie,”
`H+G Zeitschrift
`fur
`Hautkrankheiten 651734-736, Grosse Verlag Berlin, Germany ( 1990)
`(Abstract Only in English).
`Ferber, I.A., et al., “Mice with a Disrupted IFN-y Gene Are Suscep
`tible
`to
`the
`Induction
`of Experimental Autoimmune
`Encephalomyelitis (EAE),” .1. Immunol. 15615-7, The American
`Association of Immunologists, United States (1996).
`Ferrante, P, et al., “Cytokine Production and Surface Marker Expres
`sion in Acute and Stable Multiple Sclerosis: Altered IL-12 Produc
`tion and Augmented SignalingLymphocytic Activation Molecule
`(SLAM)-Expressing Lymphocytes in Acute Multiple Sclerosis,” .1.
`Immunol. 16011514-1521, The American Association of Immunolo
`gists, United States (1998).
`Fliegner, L. and Spiegel, P, “OsteomalaZie als offenbar seltene
`Nebenwirkung der oralen Fumarsauretherapie,” Hautarzt 43 1554
`560, Springer-Verlag, Germany (1992) (Abstract Only in English).
`
`Sawai (IPR2019-00789), Ex. 1001, p. 002
`
`
`
`US 8,399,514 B2
`Page 3
`
`Furlan, R., et al., “Interferon-[5 treatment in multiple sclerosis
`patients decreases the number of circulating T cells producing inter
`feron-y and interleukin-4,” .1. Neuroimmunol. 111186-92, Elsevier
`Science B.V., Netherlands (2000).
`Galli, G., et al., “Macrophage-derived chemokine production by
`activated human T cells in vitro and in vivo: preferential association
`with the production of type 2 cytokines,” Eur .1. Immunol. 301204
`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 Ra ,”
`Transplant. Proc. 24(3)11128-1129, Appleton & Lange, United
`States (1992).
`Genain, C.P., et al., “Late Complications of Immune Deviation
`Therapy in a Nonhuman Primate,” Science 27412054-2057, Ameri
`can Association for the Advancement of Science, United States
`(1996).
`Ghoreschi, K. and Rocken, M., “Immune Deviation Strategies in the
`Therapy of Psoriasis,” Current Drug Targetsiln?ammation &
`Allergy 31193-198, Bentham Science Publishers Ltd., Netherlands
`(2004).
`Ghoreschi, K., et al., “Fumarates induce a DC2 phenotype in
`dendritic cells that establishes protective Th2 responses,” Arch.
`Dermatol. Forschung 2961420, Springer Verlag, Germany (2005)
`(Abstract Only).
`Ghoreschi, K., et al., “Fumaric acid ester an antipsoriatic drug abol
`ishes the capacity of T cells to induce Thl-mediated autoimmune
`disease,” Arch. Dermatol. Res. 294128, Springer Verlag, Germany
`(2002) (Abstract Only).
`Gielen, A.W., et al., “Expression of T cell immunoglobulin- and
`mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the
`rat nervous and immune systems,” .1. Neuroimmunol. 164193-104,
`Elsevier B.V., 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)1795-805, Molecular Medicine, United States (1995).
`Giovannoni, G. and Miller, D.H., “Multiple sclerosis and its treat
`ment,”.1. R. Coll. Physicians Lond 33(4)1315-322, 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,” .1. Immunol. 1 721661-668, The American Asso
`ciation of Immunologists, Inc., United States (2004).
`Hemmer, B., et al, “Cytokine Phenotype of Human Autoreactive T
`Cell Clones Speci?c for the Immunodominant Myelin Basic Protein
`Peptide (83-99),” .1. Neurosci. Res. 451852-862, Wiley-Liss, Inc.,
`United States (1996).
`HintZen, R.Q. and Polman, C.H., “Th-cell modulation in multiple
`sclerosis,”1mmunol. Today 18(10)1507-508, Elsevier/North-Holland
`Biomedical Press, England (1997).
`Hohenegger, M., et al., “Nephrotoxicity of Fumaric Acid
`Monoethylester (FA ME),” Advances in Experimental Medicine and
`Biology 2521265-272, Kluwer Academic, United States (1989).
`Hultgren, B., et al., “Genetic Absence of y-Interferon Delays but
`Does Not Prevent Diabetes in NOD Mice,” Diabetes 451812-817,
`American Diabetes Association, United States (1996).
`English language excerpt from HunZiker, T. and Schmidli, J ., “Is
`Psoriasis an.Autoimmune Disease?” T herapeutische Umschau
`501110-113, Determatologische Klinik der Universitdt Bern, Swit
`Zerland (1993).
`“Psoriasis, eine Autoim
`HunZiker, T. and Schmidli, J .,
`Umschau
`501110-113,
`munkrankheit?”
`T herapeutische
`Determatologische Klinik der Universitat Bern, Switzerland (1993).
`IssaZadeh, S., et al., “Cytokine production in the central nervous
`system of Lewis rats
`with
`experimental autoimmune
`encephalomyelitis: dynamics of mRNA expression for interleukin
`10, interleukin-12, cytolysin, tumor necrosis factor 01 and tumor
`necrosis factor [5,” .1. Neuroimmunol. 611205-212, Elsevier Science
`B.V, Netherlands (1995).
`IssaZadeh, S., et al., “Interferon y, Interleukin 4 and Transforming
`Growth Factor Bin Experimental Autoimmune Encephalomyelitis in
`Lewis Rats: Dynamics of Cellular mRNA Expression in the Central
`
`Nervous System and Lymphoid Cells,”.1. Neurosci. Res. 401579-590,
`Wiley-Liss, Inc., United States (1995).
`IssaZadeh, S., et al., “Cytokines in relapsing experimental autoim
`mune encephalomyelitis in DA rats1 persistent mRNA expression of
`proin?ammatory cytokines and absent expression of interleukin-10
`and transforming growth factor-[5,” .1. Neuroimmunol. 691103-115,
`Elsevier Science B.V Netherlands (1996).
`IssaZadeh, S., et al., “Major histocompatibility complex-controlled
`protective
`in?uences
`on
`experimental
`autoimmune
`encephalomyelitis are peptide speci?c,” Eur .1. Immunol. 2711584
`1587, VCH Verlagsgeseelschaft mbH, Germany (1997).
`Kappos, L., et al., “Ef?cacy and safety of oral fumarate in patients
`with relapsing-remitting multiple sclerosis: a multicentre,
`randomised, double-blind, placebo-controlled phase IIb study,” Lan
`cet 37211463-1472, Lancet Publishing Group., England (2008).
`Khademi , M., et al., “Induction of systemic TNFOL in NataliZumab
`treated multiple sclerosis,” Eur .1. Neurol. 151309-312, European
`Federation of Neurological Sciences, England (2008).
`Khademi, M., et al., “Reduction of both pro- and anti-in?ammatory
`cytokines after 6 months of interferon beta-1a treatment of multiple
`sclerosis,” .1. Neuroimmunol. 1031202-210, Elsevier Science B.V.,
`Netherlands (2000).
`Khademi , M., et al., “T Cell Ig- and Mucin-Domain-Containing
`Molecule-3 (TIM-3) and TIM-1 Molecules Are Differentially
`Expressed on Human Th1 and Th2 Cells and in Cerebrospinal Fluid
`Derived Mononuclear Cells in Multiple Sclerosis,” .1. Immunol.
`17217169-7176, The American Association of Immunologists, Inc.,
`United States (2004).
`Kiehl, R. and Ionescu, G., “A Defective Purine Nucleotide Synthesis
`Pathway in Psoriatic Patients,” Acta Derm. Venereol. (Stockh)
`721253-255, Society for the Publication of Acta Dermato
`Venerologica, Sweden (1992).
`Kjellén, P., et al., “Genetic in?uence on disease course and cytokine
`response in relapsing experimental allergic encephalomyelitis,” Int.
`Immunol. 101333-340, 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,” .1. Am. Acad Derm.
`27(5)1769-771, Mosby, United States (1992).
`Krakauer, M., et al., “Dynamic T-lymphocyte Chemokine Receptor
`Expression Induced by Interferon-beta Therapy in Multiple Sclero
`sis,” Scand. .1. Immunol. 641155-163, Blackwell Publishing Ltd.,
`England (2006).
`Krakowski, M. and Owens, T., “Interferon-y confers resistance to
`experimental allergic encephalomyelitis,” Eur .1. Immunol. 2611641
`1646, VCH Verlagsgesellschaft mbH, Germany (1996).
`Kuroda, K., et al., “Fumaric Acid Enhances DNA Synthesis of Rat
`Hepatocytes by Counteracting the Toxicities of Mitomycin C and
`A?atoxin Bl,” .1pn. .1. Cancer Res. (Gann) 771750-758, Japanese
`Cancer Association, Japan (1986).
`LaFaille, J.J., et al., “Myelin Basic Protein-speci?c T Helper 2 (Th2)
`Cells Cause Experimental Autoimmune Encephalomyelitis in
`Immunode?cient Hosts Rather than Protect Them from the Disease,”
`.1. Exp. Med. 186(2)1307-312, The Rockefeller University Press,
`United States (1997).
`LaFaille, J .J ., “The Role of Helper T Cell Subsets in Autoimmune
`Diseases,” Cytola'ne & Growth Factor Rev. 9(2)1139-151, Elsevier
`Science Ltd., England (1998).
`Lahti, A. and Maibach, H.I., “Contact urticaria from diethyl
`fumarate,” Contact Dermatitis 121139-140, Munksgaard, Denmark
`(1985).
`Laman, J.D., et al., “Balancing the Th1/Th2 concept in multiple
`sclerosis,” Immunol. Today 19(11)1489-490, Elsevier/North-Holland
`Biomedical Press, England (1998).
`Lehnert, S., et al., “Radiation Response of Drug-Resistant Variants of
`a Human Breast Cancer Cell Line: The Effect of Glutathione Deple
`tion,” Radiation Res. 1241208-215, Academic Press, Inc., United
`States (1990).
`Liedtke, W., et al., “Effective Treatment of Models of Multiple Scle
`rosis by Matrix Metalloproteinase Inhibitors,” Ann. Neurol.
`44(1)135-46, The American Neurological Association, United States
`(1998).
`Link, J ., et al., “Organ-speci?c autoantigens induce interferon-y and
`interleukin-4 mRNA expression in mononuclear cells in multiple
`
`Sawai (IPR2019-00789), Ex. 1001, p. 003
`
`
`
`US 8,399,514 B2
`Page 4
`
`sclerosis and myasthenia gravis,” Neurology 44 :728-734, The Ameri
`can Academy of Neurology, United States (1994).
`Link, J ., et al., “Organ-speci?c Autoantigens Induce Transforming
`Growth Factor-[5 mRNA Expression in Mononuclear Cells in Mul
`tiple Sclerosis and Myasthenia Gravis,” Annals Neurol. 35: 197-203,
`The American Neurological Association, United States (1994).
`Link, J ., et al., “Optic neuritis is associated with myelin basic protein
`and proteolipid protein reactive cells producing interferon-y,
`interleukin-4 and transforming growth factor-[5,” .1. Neuroimmunol.
`49:9-18, Elsevier Science B.V., Netherlands (1994).
`Link, J .,
`et al., “Increased Transforming Growth Factor-[5,
`Interleukin-4, and Interferon-y in Multiple Sclerosis,” Ann. Neurol.
`3 6(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, RA, et al., “Fumarates for the treatment of multiple sclero
`sis: potential mechanisms of action and clinical studies,” Expert Rev.
`Neurother. 8(1 1): 1683-1690, Expert Reviews Ltd., England (2008).
`Lobell, A., et al., “Suppressive DNA Vaccination in Myelin
`Oligodendrocyte Glycoprotein Peptide-Induced Experimental
`Autoimmune Encephalomyelitis Involves a Tl-Biased Immune
`Response,” .1. Immunol. 1 70:1806-1813, The American Association
`of Immunologists, Inc., United States (2003).
`Lobell, A., et al., “Vaccination with DNA Encoding an
`Immunodominant Myelin Basic Protein Peptide Targeted to Fc of
`Immunoglobulin G Suppresses Experimental Autoimmune
`Encephalomyelitis,” .1.
`Exp. Med. 187(9):1543-1548, The
`Rockefeller University Press, United States (1998).
`Lopez, E., et al., “Interferon y, IL2, IL4, IL10 and TNFOL 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 al., “Genetic analysis of in?ammation, cytokine
`mRNA expression and disease course of relapsing experimental
`autoimmune encephalomyelitis in DA rats,” .1. 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,” .1.
`Neuroimmunol. 63: 193 -205, Elsevier Science B.V., Netherlands
`(1995).
`Lyons, J .-A., et al., “Pathogenesis of acute passive murine
`encephalomyelitis II. Th1 phenotype of the inducing population is
`not suf?cient to cause disease,”.1. Neuroimmunol. 93:26-36, Elsevier
`Science B.V., Netherlands (1999).
`Maatta, J .A., et al., “Neutrophils secreting tumor necrosis factor
`alpha in?ltrate the central nervous systems of BALB/c mice with
`experimental autoimmune encephalomyelitis,” .1. Neuroimmunol.
`90: 162-175, Elsevier Science B.V., Netherlands (1998).
`Martin, R., et al., “T helper cell differentiation in multiple sclerosis
`and autoimmunity,” Immunol. Today 19(11):495-498, Elsevier Sci
`ence, England (1998).
`Mattner, E, et al., “Inhibition of Th1 development and treatment of
`chronic -relapsing experimental allergic encephalomyelitis by a non
`hypercalcemic analogue of 1,25-dihydroxyvitamin D3,” Eur .1.
`Immunol. 3 0:498-508, Wiley-VCH Verlag GmbH, Germany (2000).
`Matusevicius, D., et al., “Autoantigen-induced IL-13 mRNA expres
`sion is increased in blood mononuclear cells in myasthenia gracis and
`multiple sclerosis,” Eur .1. Neurol. 4:468-475, Rapid Science Pub
`lisher, England (1997).
`Asadullah, K., et al., “In?uence of monomethylfumarate on
`monocytic cytokine formation4explanation for adverse and thera
`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 al., “Increased interleukin 12 production in pro
`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 In?ammatory 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 .1. Dermatol. 152: 1290-1295,
`British Association of Dermatologists, England (2005).
`Eberlein-Konig, B., et al., “Disseminated Granuloma Annularei
`Treatment with Fumaric Acid Esters,” Dermatology 210:223-226, S.
`Karger AG, Switzerland (2005).
`Link, H., et al., “Virus-reactive and autoreactive T cells are accumu
`lated in cerebrospinal ?uid in multiple sclerosis,” .1. Neuroimmunol.
`38:63-74, Elsevier Science Publishers B.V., Netherlands (1992)
`Litjens, N.H.R., et al., “Monomethylfamarate affects polarization of
`monocyte-derived dendritic cells resulting in down-regulated Th1
`lymphocyte responses,” Eur. .11mmunol. 34:565-575, Wiley-VCH
`Verlag GmbH & Co. KGaA, Germany (2004).
`Litjens, N.H.R., et al., “Pharmacokinetics of oral fumarates in
`healthy subjects,”Br .1. Clin. Pharmacol. 58(4):429-432, Blackwell
`Publishing Ltd, England (2004).
`Lobell, A., et al., “Presence of CpG DNA and the Local Cytokine
`Milieu Determine the Ef?cacy of Suppressive DNA Vaccination in
`Experimental Autoimmune Encephalomyelitis,” .1. Immunol.
`163:4754-4762, The American Association of Immunologists,
`United States (1999).
`Loewe, R., et al., “Dimethylfumarate Inhibits TNF-Induced Nuclear
`Entry of NF-KKb/p65 in Human Endothelial Cells,” .1. 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 al., “Antisense Oligodeoxynucleotide Inhibition of
`Tumor Necrosis Factor-0t Expression is Neuroprotective After
`Intracerebral Hemorrhage,” Stroke 32:240-248, American Heart
`Association, Inc., United States (2001).
`McGeer, P.L., et al., “Expression of the histocompatibility
`glycoprotein HLA-DR in neurological disease,” Acta Neuropathol.
`76:550-557, Springer-Verlag, Germany (1988).
`Muhallab, S., et al., “Intra-CNS activation by antigen-speci?c T
`lymphocytes in experimental autoimmune encephalomyelitis,” .1.
`Neuroimmunol. 113:202-211, Elsevier Science B.V., Netherlands
`(2001).
`Musiek, E.S., et al., “Cyclopentenone isoprostanes are novel bioac
`tive products of lipid oxidation which enhance neurodegeneration,” .1.
`Neurochem.
`97: 1301-13 13,
`International
`Society
`for
`Neurochemistry, England (2006).
`Mustafa, M.I., et al., “T cell immunity and interferon-y secretion
`during experimental allergic encephalomyelitis in Lewis rats,” .1.
`Neuroimmunol. 31: 165-177, Elsevier Science Publishers B.V., Neth
`erlands (1991).
`Mustafa, M., et al., “Immunopharmacologic Modulation of Experi
`mental Allergic Encephalomyelitis: Low-Dose CyclosporiniA
`Treatment Causes Disease Relapse and Increased Systemic T and B
`Cell-Mediated Myelin-Directed Autoimmunity,” Scand. .1. Immunol.
`38:499-507, Blackwell Scienti?c Publications, England (1993).
`Mustafa, M., et al., “The major histocompatibility complex in?u
`ences myelin basic protein 63-88-induced T cell cytokine pro?le and
`experimental autoimmune encephalomyelitis,” Eur .1. Immunol.
`23:3089-3095, VCH Verlagsgesellschaft mbH, Germany (1993).
`Mustafa, M., et al., “Protective In?uences on Experimental Autoim
`mune Encephalomyelitis by MHC Class I and Class II Alleles,” .1.
`Immunol. 153:3337-3344, The American Association of Immunolo
`gists, United States (1994).
`Navikas, V., et al., “Increased mRNA Expression of IL-10 in
`Mononuclear Cells in Multiple Sclerosis and Optic Neuritis,” Scand.
`.1. Immunol. 41: 171-178, Blackwell Scienti?c Publications, England
`(1995).
`
`Sawai (IPR2019-00789), Ex. 1001, p. 004
`
`
`
`US 8,399,514 B2
`Page 5
`
`Navikas, V., et al., “Augmented expression of tumour necrosis fac
`[OI-0t and lymphotoxin in mononuclear cells in multiple sclerosis and
`optic neuritis,” Brain 1191213-223, Oxford University Press,
`England (1996).
`Nibbering, P.H., et al., “Effects of Monomethylfumarate on Human
`Granulocytes,”.1. Invest. Dermatol. 101 137-42, The Society for Inves
`tigative Dermatology, Inc., United States (1993).
`Nibbering, P.H., et al., “Intracellular signalling by binding sites for
`the antipsoriatic agent monomethylfumarate on human granulo
`cytes,”Br .1. Dermatol. 13 7:65-75, British Association of Dermatolo
`gists, England (1997).
`Nieboer, C., et al., “Systemic therapy with fumaric acid derivates:
`New possibilities in the treatment of psoriasis,” .1. Am. Acad.
`Dermatol. 201601-608, Mosby, United States (1989).
`Ockenfels, H.M., et al., “The antipsoriatic agent dimethylfumarate
`immunomodulates T-cell cytokine secretion and inhibits cytokines of
`the psoriatic cytokine network,” Br. .1. Dermatol. 1391390-395, Brit
`ish Association of Dermatologists, England (1998).
`Olsson, T., et al., “Autoreactive T Lymphocytes in Multiple Sclerosis
`Determined by Antigen-induced Secretion of Interferon-y,” .1. Clin.
`Invest. 861981-985, The American Society for Clinical Investigation,
`Inc., United States (1990).
`Olsson, T., “Cytokines in neuroin?ammatory disease: role of myelin
`autoreactive T cell production of interferon-gamma,” .1. Neuroim
`munol. 401211-218, Elsevier Science Publishers B.V., Netherlands
`(1992).
`Olsson, T., et al., “Increased numbers of T cells recognizing multiple
`myelin basic protein epitopes in multiple sclerosis,” Eur .1. Immunol.
`2211083-1087, VCH Verlagsgesellschaft mbH, Germany (1992).
`Olsson, T., “Cerebrospinal Fluid,” Ann. Neurol. 361S100-S102,
`American Neurological Association, United States (1994).
`Olsson, T., “Role of cytokines in multiple sclerosis and experimental
`autoimmune encephalomyelitis,” Eur. .1. Neurol. 117-19, Rapid Com
`munications of Oxford Ltd., England (1994).
`Olsson, T., “Cytokine-producing cells in experimental autoimmune
`encephalomyelitis and multiple sclerosis,” Neurology 45(Suppl
`6)1S11-S15, Lipincott Williams & Wilkins, United States (1995).
`Olsson, T., et al., “Genetics of rat neuroin?ammation,” .1. Neuroim
`munol. 1071191-200, Elsevier Science B.V., Netherlands (2000).
`Olsson, T., et al., “Depletion ofV[55.2/5.3 T cells with a humanized
`antibody in patients with multiple sclerosis,” Eur .1. Neurol. 9:153
`164, European Federation of Neurological Societies, England
`(2002).
`Olsson, T., et al., “Harm or healidivergent effects of autoimmune
`neuroin?ammation?” TRENDS in Immunol. 24(1)15-6, Elsevier Sci
`ence Ltd., England (2003).
`Panitch, H.S., et al., “Exacerbations of Multiple Sclerosis in Patients
`Treated With Gamma Interferon,” Lancet 3291893-895, Lancet Pub
`lishing Group, England (1987).
`Pereira, M.A., et al., “Use of azoxyrnethane-induced foci of aberrant
`crypts in rat colon to identify potential cancer chemopreventive
`agents,” Carcinogenesis 15(5): 1049-1054, Oxford University Press,
`England (1994).
`Pette, M., et al., “Differential effects of phosphodiesterase type
`4-speci?c inhibition on human autoreactive myelin-speci?c T cell
`clones,” .1. Neuroimmunol 981147-156, Elsevier Science B.V., Neth
`erlands (1999).
`Prochaska, H.J., et al., “Elevation of Glutathione Levels by Phase II
`Enzyme Inducers: Lack of Inhibition of Human Immunode?ciency
`Virus Type 1 Replication in Chronically Infected Monocytoid Cells,”
`Mol. Pharmacol. 451916-92 1, The American Society for Pharmacol
`ogy and Experimental Therapeutics, United States (1994).
`Rao, C.V., et al., “Chemoprevention of Azoxymethane-Induced
`Colon
`Cancer
`by
`Ascorbylpalmitate,
`Carbenoxolone,
`Dimethylfumarate and p-Methoxyphenol in Male F344 Rats,” Anti
`cancer Res. 1511199-1204, Anticancer Research, Greece (1995).
`Rao, KS. and Mishra, S.H., “Antihepatotoxic activity of
`monomethyl fumarate isolated from F umaria indica,” .1.
`Ethnopharmacol. 601207-213, Elsevier Science Ireland Ltd., Ireland
`(1998).
`Ristori, G., et al., “T cell response to myelin basic protein before and
`after treatment with interferon beta in multiple sclerosis,” .1. Neuroim
`munol. 99:91-96, Elsevier Science B.V., Netherlands (1999).
`
`Robinson, W.H., et al., “Protein microarrays guide tolerizing DNA
`vaccine treatment of autoimmune encephalomyelitis,” Nat.
`Biotechnol. 21(9): 1033-1039, Nature Publishing Group, United
`States (2003).
`Rohowsky-Kochan, C., et al., “Impaired interleukin-12 prod