`
`(12) United States Patent
`Fischkoff et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,073,987 B2
`*Jul. 7, 2015
`
`METHODS OF ADMINISTERING ANTI-TNFa
`ANTIBODIES
`
`Applicant: AbbVie Biotechnology Ltd., Hamilton
`(BM)
`
`Inventors: Steven A. Fischkoff, Short Hills, NJ
`(US); Joachim Kempeni, Neustadt
`(DE); Roberta Weiss, Wynnewood, PA
`(US)
`
`Assignee: AbbVie Biotechnology Ltd., Hamilton
`(BM)
`
`Notice: (cid:9)
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 14/292,759
`
`(22) Filed: (cid:9)
`
`May 30, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2015/0017175 Al (cid:9)
`
`Jan. 15, 2015
`
`Related U.S. Application Data
`
`Continuation of application No. 10/163,657, filed on
`Jun. 5, 2002. now Pat. No. 8,889,135.
`
`Provisional application No. 60/296,961, filed on Jun.
`8, 2001.
`
`Int. Cl.
`A61K 39/395
`CO7K 16/24
`A61K 9/00
`A61K 39/00
`(52) U.S. Cl.
`CPC (cid:9)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`CO7K 16/241 (2013.01); A61K 39/3955
`(2013.01); A61K 2039/505 (2013.01); A61K
`2039/54 (2013.01); A61K 2039/545 (2013.01);
`A61K 2300/00 (2013.01); C07K 2317/21
`(2013.01); CO7K 2317/76 (2013.01); A61K
`9/0019 (2013.01); C07K 2317/565 (2013.01);
`C07K 2317/52 (2013.01); C07K 2317/56
`(2013.01)
`
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,231,024 A
`5,336,181 A
`5,654,407 A
`5,698,195 A
`5,705,389 A
`5,795,967 A
`5,859,205 A
`5,877,293 A
`5,929,212 A
`
`7/1993 Moeller et al.
`8/1994 Nakao et al.
`8/1997 Boyle et al.
`12/1997 Le
`1/1998 Braham et al.
`8/1998 Aggarwal et al.
`1/1999 Adair et al.
`3/1999 Adair et al,
`7/1999 Jolliffe et al.
`
`8/1999 Sarno
`5,945,098 A
`11/1999 Adair et al.
`5,994,510 A
`1/2000 Tobinick
`6,015,557 A
`2/2000 Corbo et al.
`6,024,938 A
`7/2000 Salfeld
`6,090,382 A
`1/2001 Lam et al.
`6,171,586 B1
`4/2001 McClure et al.
`6,214,870 B1
`5/2001 Stenzel et al.
`6,235,281 B1
`7/2001 Salfeld et al.
`6,258,562 B1
`8/2001 Feldman et al.
`6,270,766 B1
`7/2002 Tobinick
`6,423,321 B2
`1/2003 Salfeld et al.
`6,509,015 B1
`3/2003 Tobinick
`6,537,549 B2
`5/2003 Hjertman et al.
`6,562,006 B1
`12/2006 van de Winkel et al,
`7,153,507 B2
`5/2007 Salfeld et al.
`7,223,394 B2
`7/2007 Heavner et al.
`7,250,165 B2
`1/2011 Wan et al.
`7,863,426 B2
`4/2011 Maksymowych et al.
`7,919,264 B2
`8,889,135 B2 * 11/2014 Fischkoff et al.
`2001/0004456 Al
`6/2001 Tobinick
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`CA
`CA
`
`2243459 (cid:9)
`8/1997
`2261630 (cid:9)
`2/1998
`(Continued)
`OTHER PUBLICATIONS
`
` 424/145.1
`
`Wolfe et al. (J Rheumatol. Jun. 2001;28(6):1423-30 which was pre-
`sented in Chicago, Illinois, USA, Feb. 17-18. 2000 as part of the
`Symposium Proceedings: Changing Goals for Rheumatoid Arthritis
`Treatment: Evidence and Insight).*
`Chey 2001, "Infliximab for Patients With Refractory Ulcerative
`Colitis," Inflamm Bowel Dis. 7(Supp.1 ): S30- S33.
`Haynes et al., 1998, "A comparison of the disease-modifying and
`cytokine-regulating activities of tenidap, piroxicam and
`cyclosporin-A using the adjuvant-induced model of arthritis in rats,"
`Inflarnrnopharmacology 6(3):193-202.
`Lichtenstein 2001, "Commentary. Is infliximab effective for induc-
`tion of remission in patients with ulcerative colitis?"Inflamm Bowel
`Dis. 7(2): 89 -93 .
`Prupas et al., 1996, "Tenidap in patients with Rheumatoid arthritis: A
`4-week, placebo-controlled study," Scant J Rheumatology
`25(6):345-351.
`Sands et al., 2001, "Infliximab in the treatment of severe, steroid-
`refractory ulcerative colitis: A pilot study," Inflamm Bowel Dis.
`7(2):83-88.
`
`(Continued)
`
`Primary Examiner — Zachary Skelding
`(74) Attorney, Agent, or Firm — Dechert LLP
`
`ABSTRACT
`(57) (cid:9)
`Methods of treating disorders in which INFa activity is
`detrimental via biweekly, subcutaneous administration of
`human antibodies, preferably recombinant human antibod-
`ies, that specifically bind to human tumor necrosis factor a
`(hTNFa) are disclosed. The antibody may be administered
`with or without methotrexate. These antibodies have high
`affinity for hTNFa (e.g., Ic=10-8 M or less). a slow off rate
`for hTNFa dissociation (e.g., Ici=10-3 sec-1 or less) and
`neutralize hTNFa activity in vitro and in vivo. An antibody of
`the invention can be a full-length antibody or an antigen-
`binding portion thereof. Kits containing a pharmaceutical
`composition and instructions for dosing, and preloaded
`syringes containing pharmaceutical compositions are also
`encompassed by the invention.
`
`2 Claims, 6 Drawing Sheets
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`
`
`US 9,073,987 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`8/2001 Tobinick
`2001/0016195 Al (cid:9)
`10/2001 Tobinick
`2001/0026801 Al (cid:9)
`1/2003 Teoh et al.
`2003/0012786 Al (cid:9)
`3/2003 Heavner
`2003/0049725 Al (cid:9)
`5/2003 Salfeld et al.
`2003/0092059 Al (cid:9)
`8/2003 Abdelghany et al.
`2003/0161828 Al (cid:9)
`11/2003 Salfeld et al.
`2003/0219438 Al (cid:9)
`12/2003 Fischkoff et al.
`2003/0235585 Al (cid:9)
`1/2004 Fischkoff et al.
`2004/0009172 Al (cid:9)
`2/2004 Krause et al.
`2004/0033228 Al (cid:9)
`6/2004 Knight et al.
`2004/0120952 Al (cid:9)
`7/2004 Banerjee et al.
`2004/0126372 Al (cid:9)
`7/2004 Banerjee et al.
`2004/0131614 Al (cid:9)
`7/2004 Banerjee et al.
`2004/0136989 Al (cid:9)
`7/2004 Banerjee et al.
`2004/0136990 Al (cid:9)
`7/2004 Banerjee et al.
`2004/0136991 Al (cid:9)
`8/2004 Banerjee et al.
`2004/0151722 Al (cid:9)
`8/2004 Kaymakcalan et al.
`2004/0166111 Al (cid:9)
`11/2004 Banerjee et al.
`2004/0219142 Al (cid:9)
`6/2005 Heavner et al.
`2005/0123541 Al (cid:9)
`11/2005 Le et al.
`2005/0249735 Al (cid:9)
`1/2006 Hoffman et al.
`2006/0009385 Al (cid:9)
`1/2006 Le et al.
`2006/0018907 Al (cid:9)
`2/2006 Salfeld et al.
`2006/0024293 Al (cid:9)
`4/2006 Hoffman et al.
`2006/0083741 Al (cid:9)
`7/2006 Krause et al.
`2006/0153846 Al (cid:9)
`11/2006 Knight et al.
`2006/0246073 Al (cid:9)
`1/2007 Heavner et al.
`2007/0003548 Al (cid:9)
`2/2007 Hoffman et al.
`2007/0041905 Al (cid:9)
`3/2007 Hoffman et al.
`2007/0071747 Al (cid:9)
`4/2007 Hoffman et al.
`2007/0081996 Al (cid:9)
`7/2007 Maksymowych et al.
`2007/0172897 Al (cid:9)
`8/2007 Le et al.
`2007/0196373 Al (cid:9)
`8/2007 Banerjee et al.
`2007/0202104 Al (cid:9)
`10/2007 Salfeld et al.
`2007/0249813 Al (cid:9)
`2007/0292442 Al 12/2007 Wan et al.
`2007/0298040 Al (cid:9)
`12/2007 Le et al.
`2008/0025976 Al (cid:9)
`1/2008 Le et al.
`2009/0148513 Al (cid:9)
`6/2009 Fraunhofer et al.
`2009/0280065 Al (cid:9)
`11/2009 Willian et al.
`2010/0034823 Al (cid:9)
`2/2010 Borhani et al.
`2010/0040604 Al (cid:9)
`2/2010 Salfeld et al.
`2010/0160894 Al (cid:9)
`6/2010 Julian et al.
`2010/0278822 Al (cid:9)
`11/2010 Fraunhofer et al.
`2011/0002935 Al (cid:9)
`1/2011 Wan et al.
`2011/0054414 Al (cid:9)
`3/2011 Shang et al.
`2011/0171227 Al (cid:9)
`7/2011 Okun et al.
`2011/0300151 Al (cid:9)
`12/2011 Okun et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`EP (cid:9)
`GB (cid:9)
`HU (cid:9)
`HU (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`WO (cid:9)
`
`1/1990
`351789 A2 (cid:9)
`5/1990
`366043 Al (cid:9)
`7/1992
`492448 Al (cid:9)
`8/1992
`186833 B2 (cid:9)
`11/1994
`212489 B1 (cid:9)
`12/1994
`101681 B1 (cid:9)
`6/1995
`659766 Al (cid:9)
`8/2001
`614984 B1 (cid:9)
`1/2002
`1174148 (cid:9)
`8/2002
`1232753 Al (cid:9)
`11/2002
`1254666 Al (cid:9)
`1/2013
`1406656 B1 (cid:9)
`12/1994
`2279077 A (cid:9)
`12/1995
`211626 (cid:9)
`11/1998
`215242 (cid:9)
`2/1991
`WO 91/02078 Al (cid:9)
`4/1991
`WO 91/04054 Al (cid:9)
`7/1991
`WO 91/09967 Al (cid:9)
`7/1992
`WO 92/11383 Al (cid:9)
`WO 92/16553 Al 10/1992
`WO 93/06213 Al (cid:9)
`4/1993
`WO 93/11793 Al (cid:9)
`6/1993
`WO 94/29347 Al 12/1994
`
`9/1995
`WO 95/23813 Al (cid:9)
`WO (cid:9)
`2/1997
`WO 97/04801 Al (cid:9)
`WO (cid:9)
`WO 9729131 Al * 8/1997
`WO (cid:9)
`WO 98/04281 Al (cid:9)
`2/1998
`WO (cid:9)
`WO 98/05357 Al (cid:9)
`2/1998
`WO (cid:9)
`WO 98/56418 Al 12/1998
`WO (cid:9)
`WO 00/51637 Al (cid:9)
`9/2000
`WO (cid:9)
`WO 01/00229 Al (cid:9)
`1/2001
`WO (cid:9)
`WO 01/37874 A2 (cid:9)
`5/2001
`WO (cid:9)
`WO 01/47554 Al (cid:9)
`7/2001
`WO (cid:9)
`WO 01/94585 Al 12/2001
`WO (cid:9)
`WO 02/12502 A2 (cid:9)
`2/2002
`WO (cid:9)
`WO 02/096461 Al 12/2002
`WO (cid:9)
`WO 02/100330 A3 12/2002
`WO (cid:9)
`WO 03/080672 Al 10/2003
`WO (cid:9)
`WO (cid:9) WO 2006/041970 A2 4/2006
`
`OTHER PUBLICATIONS
`Chandry 2000, "D2E7," Current Opinion in Anti-Inflammatory &
`Immunomodulatory Investigational Drugs 2(1):31 -34 .
`Rutgeerts 1999, "Review article: efficacy of infliximab in Chron's
`disease—induction and maintenance of remission," Ailment
`Pharmacol Ther 13(Supp1 4):9-15.
`Targan, et al., 1997 "A Short-Term Study of Chimeric Monoclonal
`Antibody cA2 to Tumor Necrosis Factor a for Crohn's Disease," N
`Engl J. Med. 337(15):1029-1035.
`Felson, et al., 1998, "Should Improvement in Rheumatoid Arthritis
`Clinical Trials be Defined as Fifty Percent or Seventh Percent
`Improvement in Core Set Measures, Rather than Twenty Percent?,"
`Arthritis & Rheumatism 41(9): 1564 -1570.
`Rowland & Unadkat, 1981, Acceptable Sampling Times at Plateau
`for Drug Analysis, Br. J. Clin. Pharmac. 12:687-689.
`Abraham et al., 1995, "Efficacy and Safety of Monoclonal Antibody
`to Human Tumor Necrosis Factor a in Patients with Sepsis Syn-
`drome," JAMA 273(12): 934-941.
`Abraham, 1998, "Cytokine modifiers: pipe dream or reality?" Chest
`Mar. 1998 LNKD-PubMed:9515897 113(3) Suppl 224S-227S.
`Arthur et al., 1999, "Safety of self-injection of gold and methotrex-
`ate," J Rheumatol 26(2):302-305.
`Aulton, 2001, Pharmaceutics: The Science of Dosage Form Design,
`2"d Ed., pp. 275-288.
`Barbuto et al., 1993, "Production of Neutralizing Antibodies to
`Tumor Necrosis Factor by Human Tumor-Infiltrating B Lympho-
`cytes," Proc Am Assoc Cancer Res 34:487 (abstract 2904).
`Barrera et al., 1999, "Effect of a Fully Human Anti-TNFa
`Monoclonal Antibody on the Local and Systemic Expression of
`INFa and IL-18,"Arthritis Rheum 42(Supp1 9):S75.
`Barrera et al., 2001. "Effects of Treatment with a Fully Human
`Anti-Tumor Necrosis Factor a Monoclonal Antibody on the Local
`and Systemic Homeostasis of Interleukin 1 and TNFa in Patients
`with Rheumatoid Arthritis," Ann Rheum Dis 60(7):660-669.
`Barrera et al., 2002,"Drug survival, efficacy and toxicity of
`monotherapy with a fully human anti-tumour necrosis with a fully
`human anti-tumour necrosis factor-a antibody compared with
`methotrexate in long-standing rheumatoid arthritis," Rheurnatologv
`41:430-439.
`BASF. Pharma Letter, 1999, "Positive data with CAT, BASF arthritis
`drug".
`BASF. Pharma Letter, 2000, "BASF moves into phase III with
`D2E7".
`BASF. Pharma Letter, 2000, "BASF sees D2E7 filing next year;
`potential against Enbrel".
`Bendtzen et al., 1990, "Auto-Antibodies to IL-la and INFa in
`Normal Individuals and in Infectious and Immunoinflammatory Dis-
`orders," The Physiological and Pathological Effects of Cytokines,
`Wiley-Liss, Inc., pp. 447-452.
`Bodansky & Lather (eds.), 1973, Advances in Clinical Chemistry,
`Academic Press, vol. 16, p. 63.
`Boekstegers et al., 1994, "Repeated administration of a F(ab')2 frag-
`ment of an anti-tumor necrosis factor a monoclonal antibody in
`patients with severe sepsis: effects on the cardiovascular system and
`cytokine levels," Shock 1(4):237-245.
`
`(cid:9)
`
`
`US 9,073,987 B2
`Page 3
`
`(56) (cid:9)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Bombardier et al.. 2002, "Pattern of DMARD use in a North Ameri-
`can Cohort of Patients with Early Rheumatoid Arthritis (RA)
`(SONORA)." Arthritis Rheum 46(Suppl 9):S344.
`Borigini et al., 1995, "Innovative Treatment Approaches for Rheu-
`matoid Arthritis: Combination Therapy," Bailliere's Clinical
`Rheumatology 9(4): 689-710.
`Boyle et al., 1993, "A Novel Monoclonal Human IgIM Autoantibody
`which Binds Recombinant Human and Mouse Tumor Necrosis Fac-
`tor-a" Cell Immunol 152:556-568.
`Boyle et al., 1993, "The B5 Monoclonal Human Autoantibody Binds
`to Cell Surface TNFa on Human Lymphoid Cells and Cell Lines and
`Appears to Recognize a Novel Epitope" Cell Immunol 152:569-581.
`Breedveld et al., 2001, "The Fully Human Anti-TNF Antibody
`Adalimumab (D2E7) in Combination with Methotrexate (MIX) in
`the Treatment of Active Rheumatoid Arthritis: Results of a 2-Year
`Study," Presented at: The Annual Meeting of the European League
`Against Rheumatism (EULAR), Prague, Czech Republic, Jun. 2001.
`Breedveld et al., 2002, "The Long-term Efficacy and Safety of
`Adalimumab (D2E7), the Fully Human Anti-TNF Monoclonal Anti-
`body, in Combination with Methotrexate in the Treatment of Rheu-
`matoid Arthritis: Results of a 2-Year Study," J Clin Rheumatol
`8(Suppl 3): S46.
`Breedveld et al., 2006, "A Multicenter, Randomized, Double-Blind
`Clinical Trial of Combination Therapy With Adalimumab Plus
`Methotrexate Versus Methotrexate Alone or Adalimumab Alone in
`Patients With Early, Aggressive Rheumatoid Arthritis Who Had Not
`Had Previous Methotrexate Treatment," Arthritis Rheum 54(1):26-
`37,
`Bresnihan et al., 2001, "The safety and efficacy of interleukin-1
`receptor antagonist in the treatment of rheumatoid arthritis," Semin
`Arthritis Rheum 30(5) (Suppl 2):17-20.
`Burmester et al,, 2002, "Long-Term Efficiacy and Safety of
`Adalimumab (D2E7) Monotherapy in Patients With DMARD-Re-
`fractory Rheumatoid Arthritis-Results From a 2-Year Study,"
`Arthritis Rheum 46(Suppl 9):S537.
`Burmester et al., 2013, "Efficacy, Pharmacokinetics, and Safety of
`Different Doses of Methotrexate in Combination With Adalimumab:
`Results from the CONCERTO Trial,"Ann Rheum Dis 72(Suppl 3):72
`(abstract OP0067).
`Cambridge Antibody Technology Group, PLLC, 1998, "Impressive
`clinical data with CAT/BASF human antibody in rheumatoid arthri-
`tis," Press Release.
`Case, 2001, "Old and New Drugs Used in Rheumatoid Arthritis: A
`Historical Perspective," Am J Ther 8:163-179.
`Center for Drug Evaluation and Research and Center for Biologics
`Evaluation and Research, Application No. 125057.0, Statistical
`review(s) for Abbott Lab's adalimumab in the treatment of rheuma-
`toid arthritis, Nov. 12, 2002, pp. 1-27.
`Chikanza & Sakkas, 2000, "Advances in the Therapy of Rheumatoid
`Arthritis with Biological Agents" Emerging Drugs 5(4):367-384.
`Chow et al., 1994, "Effect of monoclonal antibody on human tumor
`necrosis factor (TNF MAb) on INFo,, IL-1p, and IL-6 levels in
`patients with sepsis syndrome," Clinical Research 42(2):299A.
`Cleland et al., 2001, "A specific molar ratio of stabilizer to protein is
`required for storage stability of a lyophilized monoclonal antibody,"
`J Pharm Sci 90(3):310-321.
`Coe et al,, 2011, "Population differences in proinflammatory biol-
`ogy: Japanese have healthier profiles than Americans," Brain Behav
`Immun 25(3):494-502.
`Cohen et al., 1996, "Intercept: An international, multicenter, placebo-
`controlled trial of monoclonal anitbody to human tumor necrosis
`factor-a in patients with sepsis," Crit Care Med 24(9):1431-1440.
`Concerto clinical trial information, excerpt from https://www.
`clinicaltrialregister.eu on study NCT01185301 (as submitted to EPO
`on Oct. 9. 2013).
`Cox et al. 1994,"A directory of human germ-line VKsegments reveals
`a strong bias in their usage," Eur J Irnrnunol 24(2):827-836.
`
`Davis et al. 1995. "Preclinical pharmacokinetic evaluation of the
`respiratory syncytial virus-specific reshaped human monoclonal
`antibody RSHZ 19," Drug Metab Dispos 23(10).1028-1036.
`den Broeder et al., 1998, "The Effect of D2E7, a New Human Anti-
`TNFa Monoclonal Antibody, on the Oxidative Burst of PMN in
`Patients with RA," Arthritis Rheum 41(9):S57 No. 150.
`den Broeder et al., 2002, "A Single Dose, Placebo Controlled Study
`of the Fully Human Anti-Tumor Necrosis Factor-a Antibody
`Adalimumab (D2E7) in Patients with Rheumatoid Arthritis," J
`Rheumatol 29(11).2288-2298.
`den Broeder et al.. 2002, "Long term anti-tumour necrosis factor a
`monotherapy in rheumatoid arthritis: effect on radiological course
`and prognostic value of markers of cartilage turnover and endothelial
`activation," Ann Rheum Dis 61:311-318.
`Department of Surgery, University of Toronto, Annual Report ( 1998-
`1999).
`Detournay et al., 1998, "Prefilled disposable syringes vs. conven-
`tional injection systems. European Medico economic analysis," Eur
`J Hosp Pharm 4(4):109-113.
`Duna et al.. 1992, "Pharmaceutical Dosage Forms: Parenteral Medi-
`cations," Marcel Dekker, Inc., vol. 1., ra Ed., pp. 21-26.
`Egan et al., 1998, "A Randomized, Single-Blind, Pharmacokinetic
`and Dose Response Study of Subcutaneous Methotrexate, 15 and 25
`mg/wk, for Refractory Ulcerative Colitis and Crohn' s Disease," Gas-
`troenterology 114(Supp11):A970-A971 (abstract G3978).
`Eissner et al., 2000, "Naive Monocytes Can Trigger Transendothelial
`Migration of Peripheral Blood Cells Through the Induction of
`Endothelial Tumor Necrosis Factor-a," Scand J Immunol 51:251-
`261.
`Elliott et al., 1993, "Treatment of rheumatoid arthritis with chimeric
`monoclonal antibodies to tumor necrosis factor a," Arthritis Rheum
`36(12): 1681-90 .
`Elliott et al., 1995, "TNFa Blockade in Rheumatoid Arthritis: Ratio-
`nale, Clinical Outcomes and Mechanisms of Action," Intl J
`Immunopharmac 17(2 ): 141 -145 .
`European Medicines Agency, 2004, "Scientific Discussion," Pre-
`scribing Info for HUMIRA®.
`European Medicines Agency, "Summary of Product Characteristics,"
`HUMIRA®, accessed on Aug. 13, 2013.
`Emery et al., 1999, "Targeted therapies in rheumatoid arthritis: the
`need for action," Rheumatology (Oxford) 38(10):911-912.
`Emery et al., 2001, "Changes in PRO-MMP-1 in Relation to Standard
`Measures of Disease Activity Over a 6 Month Treatment Period with
`Adalimumab (D2E7) in Rheumatoid Arthritis," Arthritis Rheum
`44(9):S215.
`Fautrel et al., 2000, "Interest of anti-TNF-a treatment in inflamma-
`tory and infectious diseases," Rev Med Interne 21:872-888.
`FDA Prescription info for HUMIRA® (Revised Sep. 2012).
`FDA Prescription info for HUMIRA® (Revised May 2013).
`FDA summary of product characteristics of HUMIRA®
`(adalimumab) (2002) pp. 1-16.
`Feldmann et al., 2001, "Anti-TNFa Therapy of Rheumatoid Arthri-
`tis: What Have We Learned," Annu Rev Immunol 19:163-196.
`Figini et al., 1994, "In Vitro Assembly of Repertoires of Antibody
`Chains on the Surface of Phage by Renaturation,"J Mol Biol 239:68-
`78,
`Fomsguaard et al., 1989, "Auto-antibodies to Tumor Necrosis Factor
`a in Healthy Humans and Patients with Inflammatory Diseases and
`Gram-Negative Bacterial Infections." Scand J Immunol 30:219-223.
`Foote & Winter, 1992, "Antibody Framework Residues Affecting the
`Conformation of the Hypervariable Loops." J Mol Biol 224(2):487-
`499,
`Furst et al, 2002, "Safety and Efficacy of Adalimumab (D2E7), a
`Fully Human Anti-TNF-a Monoclonal Antibody, Given in Combi-
`nation with Standard Antirheumatic Therapy: Safety Trial of
`Adalimumab in Rheumatoid Arthritis," Arthritis Rheum 46(Suppl
`9): S572.
`Furst et al., 2002, "Safety and Efficacy of Adalimumab (D2E7), a
`Fully Human Anti-TNF-a Monoclonal Antibody, Given in Combi-
`nation with Standard Antirheumatic Therapy: Safety Trial of
`Adalimumab in Rheumatoid Arthritis (STAR)," Ann Rheum Dis
`61(Suppl 1): S572.
`
`
`
`US 9,073,987 B2
`Page 4
`
`(56) (cid:9)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Furst et al., 2001, "TNF Blockade by the Fully Human Monoclonal
`Antibody Adalimumab (D2E7), in the Armada Trial Results in
`Decreases in Serum Matrix Metalloproteinase (MMP) Levels Along
`with Impressive Clinical Improvement in Refractory RA Patients,"
`Arthritis Rheum 44(Suppl 9):S215.
`Gallagher et al., 2001, "A multicenter, open-label, prospective, ran-
`domized, dose-ranging pharmacokinetic study of the anti-TNF-a
`antibody afelimomab in patients with sepsis syndrome," Intensive
`Care Med 27(7): 1169 -78.
`Giuliani et al.. 2001, "Serum interleukin-6, soluble interleukin-6
`receptor and soluble gp130 exhibit different patterns of age- and
`menopause-related changes,"
`Experimental Gerontology
`36:547-557.
`Goto & Sumida, 2002 "[Adalimumab]," English abstract MEDLINE
`abstract NEM12510366.
`Goto & Sumida, 2002, "[Adalimumab]," Nihon Rinsho 60(12):2384-
`2389 (in Japanese).
`Griffiths et al., 1993,"Human anti-self antibodies with high specific-
`ity from phage display libraries," The EMBO J12(2):725-734.
`Grubb, 1994, "Human immunoglobulin allotypes and Mendelian
`polymorphism of the human immunoglobulin genes," in Oss C.J.,
`Regenmortel M.H.V. (eds): Immunochemistry, New York, Dekker,
`pp. 47-68, see pp. 47-55.
`Hawkins et al., 1992, "Selection of Phage Antibodies by Binding
`Affinity Mimicking Affinity Maturation," J Mol Biol 226:889-896.
`Hillgren et al., 2002, "Protection mechanism of Tween 80 during
`freeze-thawing of a model protein, LDH," Intl J Pharmaceutics 237
`(1-2) 57-69.
`Holler et al., 1995, "Modulation of Acute Graft-Versus-Host Disease
`After Allogeneic Bone Marrow Transplantation by Tumor Necrosis
`Factor a (TNFa) Release in the Course of Pretransplant Condition-
`ing: Role of Conditioning Regimens and Prophylactic Application of
`a Monoclonal Antibody Neutralizing Human TNFa (MAK 195E),"
`Blood 86(3):890-899.
`Holliger et al., 2005, "Engineered antibody fragments and the rise of
`single domains," Nat Biotechnol 23(9):1126-36.
`Holt et al., 2003, "Domain Antibodies: Proteins for Therapy," Trends
`in Biotech 21(11): 484-490.
`Hoogenboom et al., 1996, "Converting rodent into human antibodies
`by guided selection," Antibody Engineering, Oxford University
`Press, Ch. 8. pp. 169-185.
`Huse et al., 1989, "Generation of a large combinatorial library of the
`immunoglobulin repertoire in phage lambda," Science 246:1275-81.
`Ikezu & Gendelman, 2008, "Autoimmune Diseases," Springer,
`Neuroimmune Pharmacology. p. 283.
`Janeway et al., 1997, "The protein products of MHC class I and class
`II genes are highly polymorphic," Immunobiology, 3'd Ed., pp. 4:24-
`4:30.
`Janeway et al., 2001, Immunobiology, 56 Ed., Garland Science, pp.
`94-105.
`Jespers et al., 1994, "Guiding the Selection of Human Antibodies
`from Phage Display Repertoires to a Single Epitope of an Antigen,"
`Bio/Technology 12:899-903.
`Jones, 2013, Declaration in opposition proceedings to EP 1 406 656.
`Jorgensen et al., 1998, "Interleukin-4 and Interleukin-10 are
`Chondroprotective and Decreases Mononuclear Cell Recruitment in
`Human Rheumatoid Synovium in vivo," Immunol 93(4):518-523.
`Kanakoudi-Tsakalidou et al., 2001, "Influenza vaccination in chil-
`dren with chronic rheumatic diseases and long-term immunosuppres-
`sive therapy," Clin Exp Rheumatol 19:589-594.
`Kavanaugh, 1998. "Anti-Tumor Necrosis Factor-a Monoclonal Anti-
`body Therapy for Rheumatoid Arthritis," Emerging Therapeutics
`24(3):593-614.
`Kavanaugh et al., 2002, "The Armada Trial: 12-Month Efficacy and
`Safety of Combination Therapy with Adalimumab (D2E7), the First
`Fully Human Anti-TNF Monoclonal Antibody, and Methotrexate
`(MTX) in Patients with Active Rheumatoid Arthritis," Ann Rheum
`Dis 61(Suppl I):S168.
`
`Kavanaugh et al., 2002, "Treatment with Adalimumab (D2E7) does
`not Affect Normal Immune Responsiveness," Arthritis Rheum
`46(Suppl 9):S132.
`Kaymakcalan et al., 2002, "Comparison of Adalimumab (D2E7),
`Infliximab, and Etanercept in the Prevention of Polyarthritis in the
`Transgene Murine Model of Rheumatoid Arthritis," Arthritis Rheum
`46(Suppl 9):S304.
`Kempeni, 1999, "Preliminary Results of Early Clinical Trials with
`the Fully Human Anti-TNFa Antibody D2E7," Ann Rheum Dis
`58(Suppl I): 170-172.
`Kempeni, 2000, "Update on D2E7: a Fully Human Anti-Tumor
`Necrosis Factor a Monoclonal Antibody," Ann Rheum Dis 59(Suppl
`I):144-145.
`Keystone et al., 2001, "The ARMADA Trial: A Double-Blind Pla-
`cebo Controlled Trial of the Fully Human Anti-TNF Monoclonal
`Antibody Adalimumab (D2E7) in Patients with Active RA on
`Methotrexate (MTX)," Arthritis Rheum 44(Suppl 9): 5213 (abstract
`965).
`Keystone et al., 2001, "The Fully Human Anti-TNF Monoclonal
`Antibody Adalimumab (D2E7), dose ranging study: the 24-week
`Clinical Results in Patients with Active RA on Methotrexate Therapy
`(the ARMADA trial)." Presented at European League Against Rheu-
`matism—Annual Congress (abstract OP0086).
`Keystone et al., 2002, "Efficacy and safety of adalimumab (D2E7),
`the fully human anti-tnf monoclonal antibody, in MTX partial
`responders: Results of the 24-week ARMADA trial," J Clin
`Rheumatol 9(Suppl 3):569.
`Keystone et al., 2003, "Subgroup Analysis of Radiographic Progres-
`sion in RA Patients Treated with Adalimumab," Ann Rheum Dis
`62(Suppl I): 169 (Poster THU0198).
`Kobelt et al., 2003, "The Cost-Effectiveness of Infliximab
`(Remicade) in the Treatment of Rheumatoid Arthritis in Sweden and
`the United Kingdom based on the ATTRACT Study," Rheumatol
`42(2)326-335.
`Kremer et al., 2001 "Rational Use of New and Existing Disease-
`Modifying Agents in Rheumatoid Arthritis," Ann Intern Med
`134:695-706,
`Kupper, 2008, declaration during examination of EP 1 406 656.
`Lerner et al., 1992, "Antibodies without immunization," Science
`258:1313-1314.
`The Lenercept Multiple Sclerosis Study Group and The University of
`British Columbia MS/MRI Analysis Group, 1999, "TNF neutraliza-
`tion in MS: Results of a randomized, placebo-controlled multicenter
`study," Neurology 53(3):457-465.
`Leusch et al., 1991, "Failure to demonstrate TNFa-specific
`autoantibodies in human sera by ELISA and Western blot," J
`Immunol Methods 139:145-147.
`Levine, 2000 "Pharmacology: Drug Actions and Reactions,"
`Parthenon, 6th Ed. pp. 99-102.
`Lewis et al., 1994, "Use of alanine scanning mutagenesis to improve
`the affinity of an anti„120 (HIV) antibody,"J Cell Biochem 18D:215.
`Linder et al., 1997, "Peripheral Blood Mononuclear Cells Invade
`Programmed Cell Death in Human Endothelial Cells and May Pre-
`vent Repairs: Role of Cytokines," Blood 89(6):1931-1938.
`Lipsky et al., 2000,"Infliximab and Methotrexate in the Treatment of
`Rheumatoid Arthritis," NEligl J Med 343:1594-1602.
`Lorenz, 2002, "Technology Evaluation: Adalimumab. Abbott Labo-
`ratories," Curr Op Mol Ther 4(2):185-190.
`Low, 1996, thesis extract, Cambridge University.
`Low et al., 1996, "Mimicking Somatic Hypermutation: Affinity
`Maturation of Antibodies Displayed on Bacteriophage Using a Bac-
`terial Mutator Strain," J Mot Biol 260:359-368.
`Mailer et al., 1990,"Monoclonal antibodies to human tumor necrosis
`factor a: in vitro and vivo application," Cytokine 2(3):162-69.
`Maini et al., 1998, "Therapeutic efficacy of multiple intravenous
`infusions of anti-tumor necrosis factor a monoclonal antibody com-
`bined with low-dose weekly methotrexate in rheumatoid arthritis,"
`Arthritis Rheum 41(9):1552-1563.
`Maini et al.. 1999, "Infliximab (chimeric anti-tumour necrosis factor
`a monoclonal antibody) versus placebo in rheumatoid arthritis
`patients receiving concomitant methotrexate: a randomized phase III
`trial," Lancet 354:1932-1939.
`"The Major Components of Blood" Website (May 12, 2001, pp. 1-2).
`
`
`
`US 9,073,987 B2
`Page 5
`
`(56) (cid:9)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Marks et al., 1991, "By-passing immunization: Human antibodies
`from V-gene libraries displayed on phage," J Mol Biol 222:581-97.
`Massarotti et al., 2002, "Treatment Patterns in Early-Onset Rheuma-
`toid Arthritis (RA): Results from the Sonora Study," Ann Rheum Dis
`61(Suppl I) : S93 .
`Medynski, 1994, "Phage Display: All Dressed UP and Ready to
`Role," Bio/Technology 12:1134-1136.
`Multidose Pharmacokinetics Website Calculator, p. 1-7 (http://home.
`fuse.net/clymer/graphs/pkplot.html, accessed on May 30, 2013).
`Munro & Capell, 1997, "Prevalence of Low Body Mass in Rheuma-
`toid Arthritis: Association with the Acute Phase Response," Ann
`Rheum Dis 56(5):326-329.
`Mutschler, 1981, "Arzneimittelwirkungen." Wissenschaftliche
`Verlagsgesellschaft mbH, 4th Ed. Chapter 2.6.5 p. 40-41.
`Nancey et al., 2008, "Serum interleukin-6. Soluble interleukin-6
`receptor and Crohn's disease activity," Dig Dis Sci 53:242-247.
`National Institutes of Health definition of the term "dose" (nlm.nih.
`gov/medlineplus/mplusdictionary.html, accessed on Nov. 23, 2009).
`Nesbitt et al.. 2007, "Mechanism of action of certolizumab pegol
`(CDP870): In vitro comparison with other anti-tumor necrosis factor
`cc agents," Inflamm Bowel Dis 13(11):1323-1332.
`Nilsson, 1995, "Antibody engineering," Current Opinion in Struc-
`tural Biology 5:450-456.
`Office Action cited during prosecution of U.S. Appl. No. 10/622,932,
`dated Apr. 16, 2010 (Inventor: Subhashis Bonerjee).
`Office Action cited during prosecution of U.S. Appl. No. 11/435,844,
`dated Sep. 20, 2010 (Inventor: Rebecca S. Hoffman).
`Office Action cited during prosecution of U.S. Appl. No. 10/422,287,
`dated Sep. 8, 2011, (Inventor: Steven Fischkoff).
`Ogilvie et al., 2001, "Treatment of psoriatic arthritis with antitumour
`necrosis factor-a antibody clears skin lesions of psoriasis resistant to
`treatment with meth otrexate," British Journal of Dermatology 144:
`587-589.
`Opposition of Amgen Inc. to EP 1 406 656 (Aug. 29, 2013).
`Opposition of Pfizer Inc. to EP 1 406 656 (Sep. 26, 2013).
`Opposition of AET BioTechnologie GmbH to EP 1 406 656 (Oct. 3,
`2013).
`Opposition of Kilburn & Strode LLP to EP 1 406 656 (Oct. 7, 2013).
`Opposition of Gedeon Richter Pharma GmbH to EP 1 406 656 (Oct.
`7, 2013).
`Opposition of Strawman Limited to EP 1 406 656 (Oct. 7, 2013).
`Opposition of Generics [UK] Limited (trading as Mylan) to EP 1 406
`656 (Oct. 7, 2013).
`Opposition of Teva Pharmaceutical Industries Ltd. To EP 1 406 656
`(Oct. 8, 2013).
`Opposition of George Schlich to EP 1 406 656 (Oct. 8, 2013).
`Opposition of Zwicker, Schnappauf & Partner to EP 1 406 656 (Oct.
`8, 2013).
`Opposition of Wolfgang Weiss to EP 1 406 656 (Oct. 8, 2013).
`Opposition of Markus Breuer to EP 1 406 656 (Oct. 8, 2013).
`Opposition of Christian Apelt to EP 1 406 656 (Oct. 9, 2013).
`Opposition of William E. Bird to EP 1 406 656 (Oct. 9, 2013).
`Opposition of Hoffman-Eitle to EP 1 406 656 (Oct. 9, 2013).
`Osborn et al.. 2005, "From rodent reagents to human therapeutics
`using antibody guided selection," Methods 36:61-68.
`Paulus et al., 2000, "Relative Contributions of the Components of the
`American College of Rheumatology 20% Criteria for Improvement
`to Responder Status in Patients with Early Seropositive Rheumatoid
`Arthritis," Arthritis Rheum 43(12): 2743 -5270.
`Pincus at al., 1999, "Combination Therapy with Multiple Disease-
`Modifying Antirheumatic Drugs in Rheumatoid Arthritis: A Preven-
`tive Strategy" Ann Intern Med 131:768-774.
`PK Solutions 2.0 Website, pp. 1-12 (http://www.summitpk.corff
`pksolutions/pksolutions.htm, accessed on Dec. 12, 2000).
`PR Newswire, 2001, `Abbott Laboratories' D2E7-the next genera-
`tion anti-INF-shows promise in rheumatoid arthritis patients,"
`Abbott Press Release.
`
`PR Newswire-FirstCall "Abbott Laboratories' HUMIRA®
`Adalimumab Marks Successful First Year Treating Patients with
`Rheumatoid Arthritis," Dec. 30, 2003, pp. 1-4.
`Prescribing Information for Humira (adalimumab) Injection, Solu-
`tion for Subcutaneous use Initial U.S. Approval: 2002 (Updated Mar.
`2009).
`Prescribing information for REMICADErm (infiliximab),
`Centocor, Inc. 2000, Malvern, PA, USA, Revised Dec. 1, 2000, pp.
`14-31.
`Present et al., 1999. "Infliximab for the treatment of fistulas in
`patients with Crohn's disease," NEngl JMed 340:1398-1405.
`Queen et al., 1989, "A humanized antibody that binds to the
`interleukin 2 receptor," Proc Nati Acad Sc USA 86:10029-10033.
`Rajpal et al., 2005, "A General Method for Greatly Improving the
`Affinity of Antibodies by Using Combinatorial Libraries," Proc Natl
`Acad Sc USA 102(24): 8466 -8471.
`Rau et al., 1998, "Long-term Efficacy and Tolerability of Multiple
`I.V. Doses of the Fully Human Anti-TNF-Antibody D2E7 in Patients
`with Arthritis," Arthritis Rheum 41(Suppl 9):555 (abstract 1371.
`Rau et al., 1999, "Effective Combination of the Fully Human Anti-
`TNF Antibody D2E7 and Methotrexate in Active Rheumatoid Arthri-
`tis," Ann Rheum Dis 58(Suppl):217 (abstract 907).
`Rau et al., 1999, "Erfahrungen mit D2E7" [Experiments with D2E7],
`Z Rheumatol 58(Suppl 1):I21 (abstract S51).
`Rau et al., 1999, "Kombinationstherapie mit dem humanen Anti-
`TNF-Antikorper D2E7 and Merhotrexat bei aktiver chronischer
`Polyarthritis," Z Rheumatol 58(1):i35 (abstrac