PCT PCT
`
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION WORLD INTELLECTUAL PROPERTY ORGANIZATION
`
`International Bureau International Bureau
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`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`WO 98/05357 WO 98/05357
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`
`
`(11) International Publication Number: (cid:9)(11) International Publication Number: (cid:9)
`
`
`(51) International Patent Classification 6 : (51) International Patent Classification 6 :
`
`A61K 39/395, 31/505 // (A61K 39/395, A61K 39/395, 31/505 // (A61K 39/395,
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`31:505) 31:505)
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`
`
`Al Al
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`(43) International Publication Date: (cid:9)(43) International Publication Date: (cid:9)
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`
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`12 February 1998 (12.02.98) 12 February 1998 (12.02.98)
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`
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`(21) International Application Number: (cid:9)(21) International Application Number: (cid:9)
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`
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`PCTIGB97/02058 PCTIGB97/02058
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`
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`(22) International Filing Date: (cid:9)(22) International Filing Date: (cid:9)
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`
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`1 August 1997 (01.08.97) 1 August 1997 (01.08.97)
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`
`(30) Priority Data: (30) Priority Data:
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`08/690,775 (cid:9)08/690,775 (cid:9)
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`
`
`I August 1996 (01.08.96) (cid:9)I August 1996 (01.08.96) (cid:9)
`
`
`
`US US
`
`
`(71) Applicant (for all designated States except US): THE (71) Applicant (for all designated States except US): THE
`
`KENNEDY INSTITUTE OF RHEUMATOLOGY KENNEDY INSTITUTE OF RHEUMATOLOGY
`
`[GB/GB]; 1 Aspenlea Road, Hammersmith, London W6 [GB/GB]; 1 Aspenlea Road, Hammersmith, London W6
`
`81.H (GB). 81.H (GB).
`
`
`(72) Inventors; and (72) Inventors; and
`
`(75) Inventors/Applicants (for US only): FELDMANN, Marc (75) Inventors/Applicants (for US only): FELDMANN, Marc
`
`[AU/GB]; 2 Church Street, Highgate, London N6 4QT [AU/GB]; 2 Church Street, Highgate, London N6 4QT
`
`(GB). MAINI, Ravinder, Nath [GB/GB]; 151 Castelnau, (GB). MAINI, Ravinder, Nath [GB/GB]; 151 Castelnau,
`
`Barnes, London SW I3 9EW (GB). Barnes, London SW I3 9EW (GB).
`
`
`(74) Agents: HARVEY, David, Gareth et al.; Graham Watt & Co., (74) Agents: HARVEY, David, Gareth et al.; Graham Watt & Co.,
`
`Riverhead, Sevenoaks, Kent TN I3 2BN (GB). Riverhead, Sevenoaks, Kent TN I3 2BN (GB).
`
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR, (81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, F1, GB, GE, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, F1, GB, GE,
`
`GH, HU, IL, IS, JP, KE, KG, KP, KR, KZ, I.C, LK, LR, GH, HU, IL, IS, JP, KE, KG, KP, KR, KZ, I.C, LK, LR,
`
`LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ,
`
`PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, Ti, TM, TR, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, Ti, TM, TR,
`
`TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO patent (GH, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO patent (GH,
`
`KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ, KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ,
`
`BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
`
`CH, DE, DK, ES, FI, FR, GB, GR, 1E, IT, LU, MC, NL, CH, DE, DK, ES, FI, FR, GB, GR, 1E, IT, LU, MC, NL,
`
`PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`
`ML, MR NE, SN, TD, TG). ML, MR NE, SN, TD, TG).
`
`
`Published Published
`
`With international search report. With international search report.
`
`Before the expiration of the time limit for amending the Before the expiration of the time limit for amending the
`
`claims and to be republished in the event of the receipt of claims and to be republished in the event of the receipt of
`
`amendments. amendments.
`
`
`
`(54) Title: ANTI-TNF ANTIBODIES AND METHOTREXATE IN THE TREATMENT OF AUTOIMMUNE DISEASE (54) Title: ANTI-TNF ANTIBODIES AND METHOTREXATE IN THE TREATMENT OF AUTOIMMUNE DISEASE
`
`
`
`(57) Abstract (57) Abstract
`
`
`Methods for treating and/or preventing a TNF-mediated disease in an individual are disclosed. Also disclosed is a composition Methods for treating and/or preventing a TNF-mediated disease in an individual are disclosed. Also disclosed is a composition
`
`comprising methotrexate and an anti-tumor necrosis factor antibody. TNE-mediated diseases include rheumatoid arthritis, Crohn's disease, comprising methotrexate and an anti-tumor necrosis factor antibody. TNE-mediated diseases include rheumatoid arthritis, Crohn's disease,
`
`and acute and chronic immune diseases associated with transplantation. and acute and chronic immune diseases associated with transplantation.
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`Ex. 1009 - Page 1
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`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AL
`AM
`AM
`AT
`AT
`AU
`AU
`AZ
`AZ
`BA
`BA
`BB
`BB
`
`BE BE
`BF
`BF
`BG
`BG
`BJ
`BJ
`
`BR BR
`BY
`BY
`CA
`CA
`CF
`CF
`CG
`CG
`
`CH CH
`
`CI CI
`
`CM CM
`
`CN CN
`CU
`CU
`CZ
`CZ
`DE
`DE
`DK
`DK
`
`EE EE
`
`Albania
`Albania
`Armenia
`Armenia
`Austria
`Austria
`Australia
`Australia
`Azerbaijan
`Azerbaijan
`Bosnia and Herzegovina
`Bosnia and Herzegovina
`Barbados
`Barbados
`Belgium
`Belgium
`Burkina Faso
`Burkina Faso
`Bulgaria
`Bulgaria
`Benin
`Benin
`Brazil
`Brazil
`Belarus
`Belarus
`Canada
`Canada
`Central African Republic
`Central African Republic
`Congo
`Congo
`Switzerland
`Switzerland
`Cote d'Jvoire
`Cate d'Jvoire
`Cameroon
`Cameroon
`China
`China
`Cuba
`Cuba
`Czech Republic
`Czech Republic
`Germany
`Germany
`Denmark
`Denmark
`Estonia
`Estonia
`
`ES
`ES
`Fl
`Fl
`FR
`FR
`GA
`GA
`
`GB GB
`GE
`GE
`GII
`GII
`
`GN GN
`GR
`GR
`HU
`HU
`IE
`IE
`IL
`IL
`IS
`IS
`
`IT IT
`JP
`JP
`KE
`KE
`
`KG KG
`KP
`KP
`
`
`KR KR
`KZ
`KZ
`LC
`LC
`
`LI LI
`LK
`LK
`
`LR LR
`
`Spain
`Spain
`Finland
`Finland
`France
`France
`Gabon
`Gabon
`United Kingdom
`United Kingdom
`Georgia
`Georgia
`Ghana
`Ghana
`Guinea
`Guinea
`Greece
`Greece
`I lungary
`I lungary
`Ireland
`Ireland
`Israel
`Israel
`Iceland
`Iceland
`Italy
`Italy
`Japan
`Japan
`Kenya
`Kenya
`Kyrgyzstan
`Kyrgyzstan
`Democratic People's
`Democratic People's
`Republic of Korea
`Republic of Korea
`Republic of Korea
`Republic of Korea
`Kazakstan
`Kazakstan
`Saint Lucia
`Saint Lucia
`Liechtenstein
`Liechtenstein
`Sri Lanka
`Sri Lanka
`Liberia
`Liberia
`
`LS
`LS
`LT
`LT
`LU
`LU
`1,1/
`LV
`MC
`MC
`MD
`MD
`MG
`MG
`MK
`MK
`
`ML
`ML
`MN
`MN
`
`MR MR
`
`MW MW
`
`MX MX
`NE
`NE
`NI.
`Ni
`
`NO NO
`NZ
`NZ
`PL
`PL
`
`PT PT
`RO
`RO
`RU
`RU
`
`SD SD
`SE
`SE
`SG
`SG
`
`Lesotho
`Lesotho
`Lithuania
`Lithuania
`Luxembourg
`Luxembourg
`Latvia
`Latvia
`Monaco
`Monaco
`Republic of Moldova
`Republic of Moldova
`Madagascar
`Madagascar
`The former Yugoslav
`The former Yugoslav
`Republic of Macedonia
`Republic of Macedonia
`Mali
`Mali
`Mongolia
`Mongolia
`Mauritania
`Mauritania
`Malawi
`Malawi
`Mexico
`Mexico
`Niger
`Niger
`Netherlands
`Netherlands
`Norway
`Norway
`New Zealand
`New Zealand
`Poland
`Poland
`Portugal
`Portugal
`Romania
`Romania
`Russian Federation
`Russian Federation
`Sudan
`Sudan
`Sweden
`Sweden
`Singapore
`Singapore
`
`SI
`SI
`SK
`SK
`SN
`SN
`SZ
`SZ
`TD
`TD
`TG
`TG
`TJ
`TJ
`TM
`TM
`TR
`TR
`TT
`TT
`UA
`UA
`UG
`UG
`US
`US
`UZ
`UZ
`VN
`VN
`YU
`YU
`'LW
`ZW
`
`Slovenia
`Slovenia
`Slovakia
`Slovakia
`Senegal
`Senegal
`Swaziland
`Swaziland
`Chad
`Chad
`Togo
`Togo
`Tajikistan
`Tajikistan
`Turkmenistan
`Turkmenistan
`Turkey
`Turkey
`Trinidad and Tobago
`Trinidad and Tobago
`Ukraine
`Ukraine
`Uganda
`Uganda
`United States of America
`United States of America
`Uzbekistan
`Uzbekistan
`Viet Nam
`Viet Nam
`Yugoslavia
`Yugoslavia
`Zimbabwe
`Zimbabwe
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`Ex. 1009 - Page 2
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`

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`
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`WO 98/05357 (cid:9)WO 98/05357 (cid:9)
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`
`
`PCT/GB97/02058 PCT/GB97/02058
`
`
`ANTI-TNF ANTIBODIES AND METHOTREXATE ANTI-TNF ANTIBODIES AND METHOTREXATE
`
`IN THE TREATMENT OF AUTOIMMUNE DISEASE IN THE TREATMENT OF AUTOIMMUNE DISEASE
`
`
`
`Descriution Descriution
`
`
`gackarcund of the Invention gackarcund of the Invention
`
`Monocytes and macrophages secrete cytokines known as Monocytes and macrophages secrete cytokines known as
`
`tumor necrosis factor alpha (TNFa) and tumor necrosis tumor necrosis factor alpha (TNFa) and tumor necrosis
`
`factor beta (TNFg) in response to endotoxin or other factor beta (TNFg) in response to endotoxin or other
`
`stimuli. TNFa is a soluble homotrimer of 17 kD protein stimuli. TNFa is a soluble homotrimer of 17 kD protein
`
`subunits (Smith et al., J. Biol. Chem. 262:6951- 6954 subunits (Smith et al., J. Biol. Chem. 262:6951- 6954
`
`(1987)). A membrane-bound 26 kD precursor form of TNF also (1987)). A membrane-bound 26 kD precursor form of TNF also
`
`exists (Kriegler et al., Cell 53:45-53 (1988)). For exists (Kriegler et al., Cell 53:45-53 (1988)). For
`
`reviews of TNF, see Beutler et al., Nature 320:584 (1986); reviews of TNF, see Beutler et al., Nature 320:584 (1986);
`
`Old, Science 230:630 (1986); and Le et a/., Lab. Invest. Old, Science 230:630 (1986); and Le et a/., Lab. Invest.
`
`56:234 (1987). 56:234 (1987).
`
`Cells other than monocytes or macrophages also produce Cells other than monocytes or macrophages also produce
`
`TNFc. For example, human non-monocytic tumor cell lines TNFc. For example, human non-monocytic tumor cell lines
`
`produce tumor necrosis factor (TNF) (Rubin et al., J. Exp. produce tumor necrosis factor (TNF) (Rubin et al., J. Exp.
`
`Med. 164:1350 (1986); Spriggs et al., Proc. Natl. Acad. Med. 164:1350 (1986); Spriggs et al., Proc. Natl. Acad.
`
`Sci. USA 84:6563 (1987)). CD4+ and CD8+ peripheral blood T Sci. USA 84:6563 (1987)). CD4+ and CD8+ peripheral blood T
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`
`
`SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26)
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`Ex. 1009 - Page 3
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`
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`WO 98/05357 (cid:9)WO 98/05357 (cid:9)
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`
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`PCT/GB97102058 PCT/GB97102058
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`
`
`-2- -2-
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`
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`5 (cid:9)5 (cid:9)
`
`
`lymphocytes and some cultured T and B cell lines (Cuturi et lymphocytes and some cultured T and B cell lines (Cuturi et
`
`al., J. Exp. Med. 165:1581 (1987); Sung et al., J. Exp. al., J. Exp. Med. 165:1581 (1987); Sung et al., J. Exp.
`
`Med. 268:1539 (1988); Turner et al., Eur. J. Immunol. Med. 268:1539 (1988); Turner et al., Eur. J. Immunol.
`
`17:1807-1814 (1987)) also produce TNFa. 17:1807-1814 (1987)) also produce TNFa.
`
`TNF causes pro-inflammatory actions which result in TNF causes pro-inflammatory actions which result in
`
`tissue injury, such as degradation of cartilage and bone, tissue injury, such as degradation of cartilage and bone,
`
`induction of adhesion molecules, inducing procoagulant induction of adhesion molecules, inducing procoagulant
`
`activity on vascular endothelial cells (Pober et al., J. activity on vascular endothelial cells (Pober et al., J.
`
`Immunol. /36:1680 (1986)), increasing the adherence of Immunol. /36:1680 (1986)), increasing the adherence of
`
`10 neutrophils and lymphocytes (Pober et al., J. Immunol. 10 neutrophils and lymphocytes (Pober et al., J. Immunol.
`
`138:3319 (1987)), and stimulating the release of platelet 138:3319 (1987)), and stimulating the release of platelet
`
`activating factor from macrophages, neutrophils and activating factor from macrophages, neutrophils and
`
`vascular endothelial cells (Camussi et al., J. Exp. Med. vascular endothelial cells (Camussi et al., J. Exp. Med.
`
`166:1390 (1987)). 166:1390 (1987)).
`
`Recent evidence associates TNF with infections (Cerami Recent evidence associates TNF with infections (Cerami
`
`et al., Immunol. Today 9:28 (1988)), immune disorders, et al., Immunol. Today 9:28 (1988)), immune disorders,
`
`neoplastic pathologies (Oliff et al., Cell 50:555 (1987)), neoplastic pathologies (Oliff et al., Cell 50:555 (1987)),
`
`autcimmune pathologies and graft-versus-host pathologies autcimmune pathologies and graft-versus-host pathologies
`
`(Piguet et al., J. Exp. Med. 166:1280 (1987)). The (Piguet et al., J. Exp. Med. 166:1280 (1987)). The
`
`20 association of TNF with cancer and infectious pathologies 20 association of TNF with cancer and infectious pathologies
`
`is often related to the host's catabolic state. Cancer is often related to the host's catabolic state. Cancer
`
`patients suffer from weight loss, usually associated with patients suffer from weight loss, usually associated with
`
`anorexia. anorexia.
`
`The extensive wasting which is associated with cancer, The extensive wasting which is associated with cancer,
`
`25 and other diseases, is known as "cachexia" (Kern et al., J. 25 and other diseases, is known as "cachexia" (Kern et al., J.
`
`Parent. Enter. Nutr. 12:286-298 (1988)). Cachexia includes Parent. Enter. Nutr. 12:286-298 (1988)). Cachexia includes
`
`progressive weight loss, anorexia, and persistent erosion progressive weight loss, anorexia, and persistent erosion
`
`of body mass in response to a malignant growth. The of body mass in response to a malignant growth. The
`
`fundamental physiological derangement can relate to a fundamental physiological derangement can relate to a
`
`30 decline in food intake relative to energy expenditure. The 30 decline in food intake relative to energy expenditure. The
`
`cachectic state causes most cancer morbidity and mortality. cachectic state causes most cancer morbidity and mortality.
`
`TNF can mediate cachexia in cancer, infectious pathology, TNF can mediate cachexia in cancer, infectious pathology,
`
`and other catabolic states. and other catabolic states.
`
`TNF also plays a central role in gram-negative sepsis TNF also plays a central role in gram-negative sepsis
`
`35 and endotoxic shock (Michie et al., Br. J. Surg. 76:670-671 35 and endotoxic shock (Michie et al., Br. J. Surg. 76:670-671
`
`
`
`15 (cid:9)15 (cid:9)
`
`
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`SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26)
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`Ex. 1009 - Page 4
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`

`
`
`WO 98/05357 (cid:9)WO 98/05357 (cid:9)
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`
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`PCT/GB97/02058 PCT/GB97/02058
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`
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`-3- -3-
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`(1989); Debets et al., Second Vienna Shock Forum, p.463-466 (1989); Debets et al., Second Vienna Shock Forum, p.463-466
`
`(1989); Simpson et al., Crit. Care Clin. 5:27-47 (1989)), (1989); Simpson et al., Crit. Care Clin. 5:27-47 (1989)),
`
`including fever, malaise, anorexia, and cachexia. including fever, malaise, anorexia, and cachexia.
`
`Endotoxin strongly activates monocyte/macrophage production Endotoxin strongly activates monocyte/macrophage production
`
`and secretion of TNF and other cytokines (Kornbluth et al., and secretion of TNF and other cytokines (Kornbluth et al.,
`
`J. Immunol. 137:2585-2591 (1986)). TNF and other J. Immunol. 137:2585-2591 (1986)). TNF and other
`
`monocyte-derived cytokines mediate the metabolic and monocyte-derived cytokines mediate the metabolic and
`
`neurohormonal responses to endotoxin (Michie et al., New neurohormonal responses to endotoxin (Michie et al., New
`
`Engl. J. Med. 318:1481-1486 (1988)). Endotoxin Engl. J. Med. 318:1481-1486 (1988)). Endotoxin
`
`10 administration to human volunteers produces acute illness 10 administration to human volunteers produces acute illness
`
`20 (cid:9)20 (cid:9)
`
`
`
`
`with flu-like symptoms including fever, tachycardia, with flu-like symptoms including fever, tachycardia,
`
`increased metabolic rate and stress hormone release increased metabolic rate and stress hormone release
`
`(Revhaug et al., Arch. Surg. 123:162-170 (1988)). (Revhaug et al., Arch. Surg. 123:162-170 (1988)).
`
`Circulating TNF increases in patients suffering from Circulating TNF increases in patients suffering from
`
`15 Gram-negative sepsis (Waage et al., Lancet 1:355-357 15 Gram-negative sepsis (Waage et al., Lancet 1:355-357
`
`(1987); Hammerle et al., Second Vienna Shock Forum (1987); Hammerle et al., Second Vienna Shock Forum
`
`p. 715-718 (1989); Debets et al., Crit. Care Med. p. 715-718 (1989); Debets et al., Crit. Care Med.
`
`/7:489-497 (1989); Calandra et al., J. Infect. Dis. /7:489-497 (1989); Calandra et al., J. Infect. Dis.
`
`161:982-987 (1990)). 161:982-987 (1990)).
`
`Thus, TNFa has been implicated in inflammatory Thus, TNFa has been implicated in inflammatory
`
`diseases, autoimmune diseases, viral, bacterial and diseases, autoimmune diseases, viral, bacterial and
`
`parasitic infections, malignancies, and/or neurogenerative parasitic infections, malignancies, and/or neurogenerative
`
`diseases and is a useful target for specific biological diseases and is a useful target for specific biological
`
`therapy in diseases, such as rheumatoid arthritis and therapy in diseases, such as rheumatoid arthritis and
`
`25 Crohn's disease. Beneficial effects in open-label trials 25 Crohn's disease. Beneficial effects in open-label trials
`
`with a chimeric monoclonal antibody to TNFa (cA2) have been with a chimeric monoclonal antibody to TNFa (cA2) have been
`
`reported with suppression of inflammation (Elliott et al., reported with suppression of inflammation (Elliott et al.,
`
`Arthritis Rheum. 36:1681-1690 (1993); Elliott et al., Arthritis Rheum. 36:1681-1690 (1993); Elliott et al.,
`
`Lancet 344:1125-1127 (1994)). See also, Van Dullemen et Lancet 344:1125-1127 (1994)). See also, Van Dullemen et
`
`30 al., Gastroenterology 109:129-135 (1995). Beneficial 30 al., Gastroenterology 109:129-135 (1995). Beneficial
`
`results in a randomized, double-blind, placebo-controlled results in a randomized, double-blind, placebo-controlled
`
`trial with cA2 have also been reported with suppression of trial with cA2 have also been reported with suppression of
`
`inflammation (Elliott et al., Lancet 344:1105-1110 (1994)). inflammation (Elliott et al., Lancet 344:1105-1110 (1994)).
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`
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`SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26)
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`Ex. 1009 - Page 5
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`WO 98/05357 (cid:9)WO 98/05357 (cid:9)
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`
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`PCT/GB97/02058 PCT/GB97/02058
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`
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`-4- -4-
`
`
`Summary of the Invention Summary of the Invention
`
`The present invention is based on the discovery that The present invention is based on the discovery that
`
`treatment of patients suffering from a TNF-mediated disease treatment of patients suffering from a TNF-mediated disease
`
`with a tumor necrosis factor antagonist, such as an anti- with a tumor necrosis factor antagonist, such as an anti-
`
`5 tumor necrosis factor antibody, as adjunctive and/or 5 tumor necrosis factor antibody, as adjunctive and/or
`
`concomitant therapy to methotrexate therapy produces a concomitant therapy to methotrexate therapy produces a
`
`rapid and sustained reduction in the clinical signs and rapid and sustained reduction in the clinical signs and
`
`symptoms of the disease. The present invention is also symptoms of the disease. The present invention is also
`
`based on the unexpected and dramatic discovery that a based on the unexpected and dramatic discovery that a
`
`10 multiple dose regimen of a tumor necrosis factor 10 multiple dose regimen of a tumor necrosis factor
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`antaaonist, such as an anti-tumor necrosis factor antibody, antaaonist, such as an anti-tumor necrosis factor antibody,
`
`when administered adjunctively with methotrexate to an when administered adjunctively with methotrexate to an
`
`individual suffering from a TNF-mediated disease produces a individual suffering from a TNF-mediated disease produces a
`
`highly beneficial or synergistic clinical response for a highly beneficial or synergistic clinical response for a
`
`15 significantly longer duration compared to that obtained 15 significantly longer duration compared to that obtained
`
`with a single or multiple dose regimen of the antagonist with a single or multiple dose regimen of the antagonist
`
`administered alone or that obtained with methotrexate administered alone or that obtained with methotrexate
`
`administered alone. As a result of Applicants' invention, administered alone. As a result of Applicants' invention,
`
`a method is provided herein for treating and/or preventing a method is provided herein for treating and/or preventing
`
`20 a TNF-mediated disease in an individual comprising co-20 a TNF-mediated disease in an individual comprising co-
`
`administering an anti-TNF antibody or a fragment thereof administering an anti-TNF antibody or a fragment thereof
`
`and methotrexate to the individual in therapeutically and methotrexate to the individual in therapeutically
`
`effective amounts. In a particular embodiment, effective amounts. In a particular embodiment,
`
`methotrexate is administered in the form of a series cf low methotrexate is administered in the form of a series cf low
`
`25 doses separated by intervals of days or weeks. 25 doses separated by intervals of days or weeks.
`
`A method is also provided herein for treating and/or A method is also provided herein for treating and/or
`
`preventing recurrence of a TNF-mediated disease in an preventing recurrence of a TNF-mediated disease in an
`
`individual comprising co-administering an anti-TNF antibody individual comprising co-administering an anti-TNF antibody
`
`or a fragment thereof and methotrexate to the individual in or a fragment thereof and methotrexate to the individual in
`
`30 therapeutically effective amounts. TNF-mediated diseases 30 therapeutically effective amounts. TNF-mediated diseases
`
`include rheumatoid arthritis, Crohn's disease, and acute include rheumatoid arthritis, Crohn's disease, and acute
`
`and chronic immune diseases associated with an ailogenic and chronic immune diseases associated with an ailogenic
`
`transplantation (e.g., renal, cardiac, bone marrow, liver, transplantation (e.g., renal, cardiac, bone marrow, liver,
`
`pancreatic, small intestine, skin or lung transplantation). pancreatic, small intestine, skin or lung transplantation).
`
`
`
`SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1009 - Page 6
`
`

`

`WO 98/05357 (cid:9)
`WO 98/05357 (cid:9)
`
`PCT/G1397/02058
`PCT/GB97/02058
`
`-5-
`-5-
`
`Therefore, in one embodiment, the invention relates to
`Therefore, in one embodiment, the invention relates to
`
`a method of treating and/or preventing rheumatoid arthritis a method of treating and/or preventing rheumatoid arthritis
`in an individual comprising co-administering an anti-TNF
`in an individual comprising co-administering an anti-TNF
`antibody or a fragment thereof and methotrexate to the
`antibody or a fragment thereof and methotrexate to the
`
`individual in therapeutically effective amounts. In a individual in therapeutically effective amounts. In a
`second embodiment, the invention relates to a method of
`second embodiment, the invention relates to a method of
`treating and/or preventing Crohn's disease in an individual
`treating and/or preventing Crohn's disease in an individual
`comprising co-administering an anti-TNF antibody or a
`comprising co-administering an anti-TNF antibody or a
`fragment thereof and methotrexate to the individual in
`fragment thereof and methotrexate to the individual in
`10 therapeutically effective amounts. In a third embodiment,
`10 therapeutically effective amounts. In a third embodiment,
`the invention relates to a method of treating and/or
`the invention relates to a method of treating and/or
`
`preventing other autoimmune diseases and/or acute or preventing other autoimmune diseases and/or acute or
`chronic immune disease associated with a transplantation in
`chronic immune disease associated with a transplantation in
`an individual, comprising co-administering an anti-TNF
`an individual, comprising co-administering an anti-TNF
`15 antibody or a fragment thereof and methotrexate to the
`15 antibody or a fragment thereof and methotrexate to the
`individual in therapeutically effective amounts.
`individual in therapeutically effective amounts.
`A further embodiment of the invention relates to
`A further embodiment of the invention relates to
`comnositions comprising an anti-TNF antibody or a fragment
`compositions comprising an anti-TNF antibody or a fragment
`thereof and methotrexate.
`thereof and methotrexate.
`In addition to anti-TNF antibodies, TNF antagonists
`In addition to anti-TNF antibodies, TNF antagonists
`include anti-TNF antibodies and receptor molecules which
`include anti-TNF antibodies and receptor molecules which
`bind specifically to TNF; compounds which prevent and/or
`bind specifically to TNF; compounds which prevent and/or
`inhibit TNF synthesis, TNF release or its action on target
`inhibit TNF synthesis, TNF release or its action on target
`cells, such as thalidomide, tenidap, phosphodiesterase
`cells, such as thalidomide, tenidap, phosphodiesterase
`
`inhibitors (e.g, pentoxifylline and rolipram), A2b 25 inhibitors (e.g, pentoxifylline and rolipram), A2b
`adenosine receptor agonists and A2b adenosine receptor
`adenosine receptor agonists and A2b adenosine receptor
`enhancers; and compounds which prevent and/or inhibit TNF
`enhancers; and compounds which prevent and/or inhibit TNF
`receptor signalling.
`receptor signalling.
`
`20 (cid:9)
`20 (cid:9)
`
`30 (cid:9)
`30 (cid:9)
`
`Brief Description of the Drawings
`Brief Description of the Drawings
`Figures 1A-1C are a set of three graphs showing the
`Figures 1A-1C are a set of three graphs showing the
`results over time for swollen joint count in rheumatoid
`results over time for swollen joint count in rheumatoid
`arthritis (RA) patients receiving cA2 treatment (1 mg/kg,
`arthritis (RA) patients receiving cA2 treatment (1 mg/kg,
`3 mg/kg or 10 mg/kg) with or without methotrexate. Results
`3 ma/kg or 10 ma/kg) with or without methotrexate. Results
`for :he placebo group (methotrexate alone) are shown with
`for :he placebo group (methotrexate alone) are shown with
`
`SUBSTITUTE SHEET (RULE 26)
`SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1009 - Page 7
`
`

`

`WO 98/05357 (cid:9)
`WO 98/05357 (cid:9)
`
`PCT/6B97/02058
`PCT/GB97/02058
`
`-6-
`-6-
`
`5 (cid:9)
`5 (cid:9)
`
`the 1 mg/kg group. The number of patients with data at
`the 1 mg/kg group. The number of patients with data at
`
`each evaluation visit is shown at the bottom of each graph. each evaluation visit is shown at the bottom of each graph.
`
`White circle = - methotrexate (MTX-); black circle = White circle = - methotrexate (MTX-); black circle =
`+ methotrexate (MTX+); square = placebo.
`+ methotrexate (MTX+); square = placebo.
`
`Figures 2A-2C are a set of three graphs showing the Figures 2A-2C are a set of three graphs showing the
`
`results over time for tender joint count in RA patients results over time for tender joint count in RA patients
`
`receiving cA2 treatment (1 mg/kg, 3 mg/kg or 10 mg/ka) with receiving cA2 treatment (1 mg/kg, 3 mg/kg or 10 mg/ka) with
`or without methotrexate. Results for the placebo group
`or without methotrexate. Results for the placebo group
`
`(methotrexate alone) are shown with the 1 mg/kg group. The (methotrexate alone) are shown with the 1 mg/kg group. The
`
`10 number of patients with data at each evaluation visit is 10 number of patients with data at each evaluation visit is
`
`shown at the bottom of each graph. White circle = shown at the bottom of each graph. White circle =
`
`- methotrexate; black circle = + methotrexate; sauare = - methotrexate; black circle = + methotrexate; sauare =
`
`placebo. placebo.
`
`Figures 3A-3C are a set of three graphs showing the Figures 3A-3C are a set of three graphs showing the
`15 results over time for the Physician's Global Disease
`15 results over time for the Physician's Global Disease
`
`Assessment in RA patients receiving cA2 treatment (1 mg/kg, Assessment in RA patients receiving cA2 treatment (1 mg/kg,
`
`3 mg/kg or 10 mg/kg) with or without methotrexate. Results 3 mg/kg or 10 mg/kg) with or without methotrexate. Results
`
`for the placebo group (methotrexate alone) are shown with for the placebo group (methotrexate alone) are shown with
`the 1 mg/kg group. The number of patients with data at
`the 1 mg/kg group. The number of patients with data at
`
`20 each evaluation visit is shown at the bottom of each graph. 20 each evaluation visit is shown at the bottom of each graph.
`White circle = - methotrexate; black circle =
`White circle = - methotrexate; black circle =
`+ methotrexate; sauare = placebo.
`+ methotrexate; sauare = placebo.
`
`Figures 4A-4C are a set of three graphs showing the Figures 4A-4C are a set of three graphs showing the
`
`results over time for the Patient Disease Assessment in RA results over time for the Patient Disease Assessment in RA
`25 patients receiving cA2 treatment (1 mg/kg, 3 mg/kg or
`25 patients receiving cA2 treatment (1 mg/kg, 3 mg/kg or
`
`10 mg/kg) with or without methotrexate. Results for the 10 mg/kg) with or without methotrexate. Results for the
`
`placebo group (methotrexate alone) are shown with the placebo group (methotrexate alone) are shown with the
`
`1 mg/kg group. The number of patients with data at each 1 ma/kg group. The number of patients with data at each
`
`evaluation visit is shown at the bottom of each graph. evaluation visit is shown at the bottom of each graph.
`30 White circle = - methotrexate; black circle =
`30 White circle = - methotrexate; black circle =
`
`+ methotrexate; square . placebo. + methotrexate; square = placebo.
`Figures 5A-5C are a set of three graphs showing the
`Figures 5A-5C are a set of three graphs showing the
`
`results over time for C-reactive protein (CRP) results over time for C-reactive protein (CRP)
`
`concentration in RA patients receiving cA2 treatment concentration in RA patients receiving cA2 treatment
`
`35 (1 mg/kg, 3 mg/kg or 10 mg/kg) with or without (1 mg/kg, 3 mg/kg or 10 mg/kg) with or without
`35 (cid:9)
`
`SUBSTITUTE SHEET (RULE 26)
`SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1009 - Page 8
`
`

`

`
`
`WO 98/05357 (cid:9)WO 98/05357 (cid:9)
`
`
`
`PCT/GB97/02058 PCT/GB97/02058
`
`
`
`-7- -7-
`
`
`methotrexate. Results for the placebo group (methotrexate methotrexate. Results for the placebo group (methotrexate
`
`alone) are shown with the 1 mg/kg group. The number of alone) are shown with the 1 mg/kg group. The number of
`
`patients with data at each evaluation visit is shown at the patients with data at each evaluation visit is shown at the
`
`bottom of each graph. White circle = - methotrexate; black bottom of each graph. White circle = - methotrexate; black
`
`5 circle = + methotrexate; square = placebo. 5 circle = + methotrexate; square = placebo.
`
`Figures 6A-6C are a set of three graphs showing the Figures 6A-6C are a set of three graphs showing the
`
`results over time for the Health Assessment Questionnaire results over time for the Health Assessment Questionnaire
`
`(HAQ) in RA patients receiving cA2 treatment (1 mg/kg, (HAQ) in RA patients receiving cA2 treatment (1 mg/kg,
`
`3 mg/kg or 10 mg/kg) with or without methotrexate. Results 3 mg/kg or 10 mg/kg) with or without methotrexate. Results
`
`10 for the placebo group (methotrexate alone) are shown with 10 for the placebo group (methotrexate alone) are shown with
`
`the 1 mg/kg croup. The number of patients with data at the 1 mg/kg croup. The number of patients with data at
`
`each evaluation visit is shown at the bottom of each graph. each evaluation visit is shown at the bottom of each graph.
`
`White circle = - methotrexate; black circle = White circle = - methotrexate; black circle =
`
`+ methotrexate; square = placebo. + methotrexate; square = placebo.
`
`Figures 7A-7F are a set of six graphs showing the Figures 7A-7F are a set of six graphs showing the
`
`serum cA2 concentration in each RA patient receiving cA2 serum cA2 concentration in each RA patient receiving cA2
`
`treatment (1 mg/kg, 3 mg/kg or 10 mg/kg) with or without treatment (1 mg/kg, 3 mg/kg or 10 mg/kg) with or without
`
`methotrexate, plotted over time. Data plotted are the methotrexate, plotted over time. Data plotted are the
`
`serum cA2 concentrations obtained just before the serum cA2 concentrations obtained just before the
`
`20 administration of cA2 at weeks 2, 6, 10 and 14 and then at 20 administration of cA2 at weeks 2, 6, 10 and 14 and then at
`
`weeks 18 and 26. The scales for the serum cA2 weeks 18 and 26. The scales for the serum cA2
`
`concentration are condensed with higher doses of cA2. concentration are condensed with higher doses of cA2.
`
`Figures 8A and 8B are a set of two graphs showing the Figures 8A and 8B are a set of two graphs showing the
`
`median serum cA2 concentration over time in RA patients median serum cA2 concentration over time in RA patients
`
`25 receiving 3 mg/kg cA2 (top panel) or 10 mg/kg cA2 (bottom 25 receiving 3 mg/kg cA2 (top panel) or 10 mg/kg cA2 (bottom
`
`panel) with or without methotrexate. Square = panel) with or without methotrexate. Square =
`
`+ methotrexate; circle or triangle = - methotrexate. + methotrexate; circle or triangle = - methotrexate.
`
`
`
`15 (cid:9)15 (cid:9)
`
`
`Detailed Description of the Invention Detailed Description of the Invention
`
`The present invention relates to the discovery that The present invention relates to the discovery that
`
`30 tumor necrosis factor antagonists can be administered to 30 tumor necrosis factor anta