US008497277B2
`
`(12) United States Patent
`Honigberg et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8.497.277 B2
`*Jul. 30, 2013
`
`(54) INHIBITORS OF BRUTON'S TYROSINE
`KNASE
`
`(75) Inventors: Lee Honigberg, San Francisco, CA
`(US); Erik Verner, Belmont, CA (US);
`Zhengying Pan, Austin, TX (US)
`
`(73) Assignee: Pharmacyclics, Inc., Sunnyvale, CA
`(US)
`
`(*) Notice:
`
`-
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is Subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 13/312,606
`
`(22) Filed:
`
`Dec. 6, 2011
`
`(65)
`
`Prior Publication Data
`US 2012/OO95O26A1
`Apr. 19, 2012
`
`Related U.S. Application Data
`(60) Continuation of application No. 13/249,066, filed on
`Sep. 29, 2011, which is a continuation of application
`No. 12/356,498, filed on Jan. 20, 2009, now Pat. No.
`8,088,781, which is a division of application No.
`1 1/617,645, filed on Dec. 28, 2006, now Pat. No.
`7,514,444.
`(60) Provisional application No. 60/826,720, filed on Sep.
`22, 2006, provisional application No. 60/828,590,
`filed on Oct. 6, 2006.
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. C.
`AOIN 43/90
`A 6LX3/59
`CO7D 487/00
`U.S. C.
`USPC ........................................ 514/262.1; 54.4/262
`Field of Classification Search
`None
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,397,787 A
`3, 1995 Buzzetti
`6, 160,010 A 12/2000 Uckun et al.
`6,221,900 B1
`4/2001 Uckun et al.
`6,326,469 B1
`12/2001 Ullrich et al.
`6,506,769 B2
`1/2003 Snow et al.
`6,660,744 B1
`12/2003 Hirst et al.
`6,753,348 B2
`6, 2004 Uckun et al.
`6,770,639 B2
`8, 2004 Snow et al.
`6,921,763 B2
`7/2005 Hirst et al.
`7,138,420 B2 11/2006 Bentzien et al.
`7,332,497 B2
`2/2008 Hirst et al.
`7,514,444 B2
`4/2009 Honigberg et al.
`7,718,662 B1
`5, 2010 Chen
`7,732,454 B2
`6, 2010 Verner
`7,741,330 B1
`6, 2010 Chen
`7,825,118 B2 11/2010 Honigberg et al.
`7,960,396 B2
`6/2011 Honigberg et al.
`
`8/2011 Honigberg et al.
`8,008,309 B2
`1/2012 Honigberg et al.
`8,088,781 B2
`4/2012 Honigberg et al.
`8, 158,786 B2
`7/2012 Honigberg et al.
`8,232,280 B2
`8/2012 Honigberg et al.
`8,236,812 B2
`2/2002 Snow et al.
`2002/001646.0 A1
`2002fO155505 A1 10, 2002 Wells et al.
`2003, OO13125 A1
`1/2003 Braisted et al.
`2003/0040461 A1
`2/2003 Mcatee
`2003/O125235 A1
`T/2003 Foxwell
`2004/OOO6083 A1
`1/2004 Hirst et al.
`2005/0008640 A1
`1/2005 Waegell et al.
`2005, OO84905 A1
`4, 2005 PreScott et al.
`2005/0090499 A1
`4, 2005 Currie et al.
`2005/0101604 A1
`5/2005 Currie et al.
`2005, 0196851 A1
`9, 2005 Uckun
`2005/0209255 A1
`9, 2005 Jimenez et al.
`2006, 00794.94 A1
`4, 2006 Santi et al.
`2006.0167090 A1
`7/2006 Uckun et al.
`2007/0281907 A1 12/2007 Watkins
`2008/0076921 A1
`3/2008 Honigberg et al.
`2008. O108.636 A1
`5/2008 Honigberg et al.
`2008, 02145O1 A1
`9, 2008 Pan
`2009/O105209 A1
`4/2009 Dewdney et al.
`2009/O181987 A1
`T/2009 Honigberg
`2010, 0004270 A1
`1/2010 Honigberg
`2010.0022561 A1
`1/2010 Honigberg et al.
`2010.0041677 A1
`2/2010 Honigberg et al.
`2010/0254905 A1 10/2010 Honigberg et al.
`2010/0324050 Al 12/2010 Honigberg et al.
`2011 OO39868 A1
`2/2011 Honigberg et al.
`Continued
`(Continued)
`FOREIGN PATENT DOCUMENTS
`1473O39
`11, 2004
`WO-97-2816.1
`8, 1997
`(Continued)
`OTHER PUBLICATIONS
`Apsel et al. “Targeted Polypharmacology: Discovery of Dual Inhibi
`tors of Tyrosine and Phosphoinositide Kinases.” Nature Chem. Bio.
`2008, 4(11):691-699.
`Arnold, L.D. et al., “Pyrrolo[2,3-dipyrimidines Containing an
`Extended 5-Substituent as Potent and Selective Inhibitors of lok 1.”
`Bioorg. Med. Chem. Lirs. 10:2167-2170 (2000).
`Browning, J.L., “B cells move to centre stage: novel opportunities for
`autoimmune disease treatment”. Nature Reviews/Drug Discovery
`vol. 5, Jul. 2006, pp. 564-576.
`(Continued)
`Primary Examiner — Jeffrey Murray
`(74) Attorney, Agent, or Firm — Wilson, Sonsini, Goodrich
`& Rosati
`
`EP
`WO
`
`(57)
`ABSTRACT
`Disclosed herein are compounds that form covalent bonds
`with Bruton's tyrosine kinase (Btk). Also described are irre
`versible inhibitors of Btk. Methods for the preparation of the
`compounds are disclosed. Also disclosed are pharmaceutical
`compositions that include the compounds. Methods of using
`the Btkinhibitors are disclosed, alone or in combination with
`other therapeutic agents, for the treatment of autoimmune
`diseases or conditions, heteroimmune diseases or conditions,
`cancer, including lymphoma, and inflammatory diseases or
`conditions.
`
`18 Claims, 8 Drawing Sheets
`
`SAN EX 1019, Page 1
`
`

`

`US 8,497.277 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
`2011 OO86866 A1
`4, 2011 Chen
`2011/O177011 A1
`7, 2011 Currie et al.
`2011/0224235 A1
`9/2011 Honigberg et al.
`2011/0281322 A1 1 1/2011 Honigberg et al.
`2012,00652O1 A1
`3/2012 Honigberg et al.
`2012,007 1497 A1
`3/2012 Buggy et al.
`2012fOO87915 A1
`4/2012 Buggy et al.
`2012,0088912 A1
`4/2012 Honigberg et al.
`2012/009.5026 A1
`4/2012 Honigberg et al.
`2012/010O138 A1
`4/2012 Buggy et al.
`2012/0101113 A1
`4/2012 Honigberg et al.
`2012/0101114 A1
`4/2012 Honigberg et al.
`2012/0108612 A1
`5/2012 Honigberg et al.
`333.9.
`A.
`38: E. et al
`onigberg et al.
`2012/01298.21 A1
`5/2012 Honigberg et al.
`2012/0129873 A1
`5/2012 Honigberg et al.
`2012/0135944 A1
`5/2012 Honigberg et al.
`2012fO165328 A1
`6/2012 Honigberg et al.
`2012/0178753 A1
`7/2012 Honigberg et al.
`2012/0183535 A1
`7/2012 Buggy et al.
`2012fO184013 A1
`7/2012 Honigberg et al.
`2012/0184567 A1
`7/2012 Honigberg et al.
`2012/0202264 A1
`8/2012 Honigberg et al.
`2012fO214826 A1
`8/2012 Honigberg et al.
`2012/0252821 A1 10/2012 Honigberg et al.
`2012/0252822 A1 10/2012 Honigberg et al.
`2012/0277225 A1 1 1/2012 Honigberg et al.
`2012,0277254 Al 11/2012 Honigberg et al.
`2012,0277255 A1 11/2012 Honigberg et al.
`2012/0283276 A1 1 1/2012 Honigberg et al.
`2012/0283277 A1 1 1/2012 Honigberg et al.
`2012/0296089 A1 1 1/2012 Honigberg et al.
`2012/03291.30 Al 12/2012 Honigberg et al.
`2013,0005745 A1
`1/2013 Honigberg et al.
`2013,0005746 A1
`1/2013 Honigberg et al.
`2013, OO12525 A1
`1/2013 Honigberg et al.
`2013, OO18060 A1
`1/2013 Honigberg et al.
`2013.0035334 A1
`2/2013 Honigberg et al.
`
`FOREIGN PATENT DOCUMENTS
`WO-99-54286
`10, 1999
`WO
`WO-00-00823
`1, 2000
`WO
`WO-00-56737 A2
`9, 2000
`WO
`WO-01-19829 A2
`3, 2001
`WO
`WO-01-19829 A3
`3, 2001
`WO
`WO-01-25238 A2
`4/2001
`WO
`WO-01-41754
`6, 2001
`WO
`WO-01-44258 A1
`6, 2001
`WO
`WE75; A2 g38
`W.
`WO-02-076986 A1 10, 2002
`WO
`WO-02-080926
`10, 2002
`WO
`WO-03-000187
`1, 2003
`WO
`WO-03-013540
`2, 2003
`WO
`WO-03-0462OO
`6, 2003
`WO
`WO-03-097645
`11, 2003
`WO
`WO WO-2004-074290
`9, 2004
`WO WO-2004-096.253
`11, 2004
`WO WO-2004-100868 A2 11/2004
`WO WO 2004-100868 A2 11/2004
`WO WO-2004-100868 A3 11, 2004
`WO WO-2005-OOO197
`1, 2005
`WO WO-2005-005429
`1, 2005
`WO WO-2005-O 14599
`2, 2005
`WO WO-2005-037843
`4/2005
`WO WO-2005-060956
`7/2005
`WO WO-2005-074603
`8, 2005
`WO WO-2006-036527
`4/2006
`WO WO-2006-050946
`5, 2006
`WO WO-2006-053121
`5, 2006
`WO WO-2006-0990.75
`9, 2006
`WO WO-2006-124462
`11, 2006
`WO WO-2007-0O2325
`1, 2007
`WO WO-2007-058832
`5/2007
`WO WO-2007-087068
`8, 2007
`WO WO-2007-136790
`11, 2007
`
`WO WO-2008-03921.8
`WO WO-2008-054827 A2
`WO WO-2008-121742
`WO WO-2009-051822
`WO WO-2009-1585.71
`WO WO-2010-009342 A2
`WO WO-2010-009342 A3
`WO WO-2010-126960
`WO WO-2011-034907
`WO WO-2011-153514
`WO WO-2011-1625.15
`WO WO-2012-021444
`
`4/2008
`5, 2008
`10, 2008
`4/2009
`12/2009
`1, 2010
`1, 2010
`11, 2010
`3, 2011
`12/2011
`12/2011
`2, 2012
`
`OTHER PUBLICATIONS
`Chang et al. “The Bruton tyrosine kinase inhibitor PCI-32765 ame
`s
`liorates autoimmune arthritis by inhibition of multiple effector cells.
`Arthritis Research & Therapy 2011, 13:R115.
`Cohen, M.S. et al., “Structural Bioinformatics-Based Design of
`Selective, Irreversible Kinase Inhibitors.” Science, vol.308, May 27,
`2005, pp. 1318-1321.
`Desiderio, S., “Role of Btk in B cell development and signaling.”
`Curr: Op. in I
`log 1997, 9:534-540
`ur: p. in immunology 1991, 9:54-54u.
`F. W.1 -
`.
`Dorwald, F. A. Side Reactions in Organic Synthesis, Wiley:VCH,
`Weinheimp. IX. of Preface, Wiley-VCH Verlag GmbH & Co. KGaA
`(2005).
`Fruman, D.A., "Xid-like Phenotypes: A B Cell Signalosome Takes
`Shape.” Immunity 13: 1-3 (Jul. 2000).
`Gold, Michael R. “To make antibodies or not signaling by the B-cell
`antigen receptor.” Trends in Pharmacological Sciences, 23(7):316
`324 (Jul. 2002)
`is Required f
`H
`d Ni i J. et al., “Bruton's T in Ki
`orwood, Nicole J. et al. Bruton's lyrosin Minase is Kequired Ior
`Lipopolysaccharide induced Tumor Necrosis Factor O. Produc
`tion.” J. Exp. Med. 197(12):1603-1611 (Jun. 2003).
`Iwaki, Shokiet al., “Btk Plays a Crucial Role in the Amplification of
`FceRI-mediated Mast Cell Activation by Kit,” J. Biol. Chem.
`280(48):40261-40270 (Dec. 2, 2005).
`Jefferies, Caroline A. et al., “Bruton's Tyrosine Kinase is a Toll?
`Interleukin-1 Receptor Domain-binding Protein That Participates in
`Nuclear Factor KBActivation by Toll-like Receptor 4.”.J. Biol. Chem.
`278:26258-26264 (2003).
`Kawakami, Yuko et al., “Terreic acid, a quinone epoxide inhibitor of
`Bruton's tyrosine kinase.” PNAS USA96:2227-2232 (1999)
`& 8
`---
`Kuppers, R., “Mechanisms of B-cell lymphoma pathogenesis,
`Nature Reviews/Cancer, vol. 5, Apr. 2005, pp. 251-262.
`Kurosaki, Tomohiro, “Functional dissection of BCR signaling path
`ways.” Curr: Op. Imm. 12:276-281 (2000).
`Lui, Yi et al. "Structural Basis for selective inhibition of Src family
`R ity and Biology, 1999, No. 6, pp. 671-678, in
`particulariable pe.
`Mahajan, S. et al., “Rational Design and Synthesis of a Novel Anti
`leukemic Agent Targeting Bruton's Tyrosine Kinase (BTK), LFM
`A13 O-Cyano-B-Methyl-N-(2,5-Dibromophenyl)Propenamide).”J.
`of Biol. Chem., vol. 274, No. 14, Apr. 2, 1999, pp. 9587-9599.
`Mangla, Anita et al., “Pleiotropic consequences of Bruton tyrosin
`kinase deficiency in myeloid lineages lead to poor inflammatory
`Blood
`responses, Blo 104(4): 1191-1197 (2004).
`Niiro, Hiroaki and Clark, Edward A., “Regulation of B-Cell Fate by
`Antigen-Receptor Signals.” Nature Reviews 2:945-956 (2002).
`Nisitani, S. et al., “In situ detection of activated Bruton's tyrosine
`kinase in the Ig signaling complex by phosphopeptide-specific
`monoclonal antibodies.” PNAS USA96:2221-2226 (1999).
`Oligino, Thomas J. and Dalrymple, Stacie A., “Targeting B cells for
`the treactment of rheumatoid arthritis.” Arthiritus Res Ther 5(Suppl.
`Y .
`4):S7-S11 (2002).
`Pan, Z. et al., “Discovery of Selectable Irreversible Inhibitors for
`s
`Bruton's Tyrosine Kinase.” ChemMedChem 2006, 1, 1-5.
`& Sw
`Pan, Zhengying et al., Discovery of Selective Irreversible Inhibitors
`for Bruton's Tyrosine Kinase.” ChemMedChem 2007, 2:58-61, com
`pound 1 et al. table 1.
`Quek, L.S. et al., “A role for Bruton's tyrosine kinase (Btk) in platelet
`activation by collagen.” Curr: Biol. 8(20): 1137-1140 (1998).
`
`SAN EX 1019, Page 2
`
`

`

`US 8,497.277 B2
`Page 3
`
`Sada, Kiyonao and Yamamura, Hirohei. “Protein-Tyrosine Kinases
`and Adaptor Proteins in FceRI-Mediated Signaling in Mast Cells.”
`Curr: Mol. Med. 3(1):85-94 (2003).
`Schaeffer, Edward M. and Schwartzberg, Pamela L., “Tec family
`kinases in lymphocyte signaling and function. Curr: Op. Imm.
`12:282-288 (2000).
`Shaffer, A.L.. et al., Lymphoid malignancies: the dark side of B-cell
`differentiation, Nature Reviews/Immunology, vol. 2, Dec. 2002, pp.
`920-932.
`15.
`“Tyrosine Kinase Inhibitors.
`al.,
`et
`Smaill, J.B.
`and
`4-(Phenylamino)quinazoline
`4-(Phenylamino)pridodipyrimidine Acrylamides as Irresversible
`Inhibitors of the ATP Binding Site of the Epidermal Growth Factor
`Receptor.” J. Med. Chem.42(10): 1803-1815 (1999).
`Smith, C.I. Edvard et al., “The Tec family of cytoplasmic tyrosine
`kinases: mammalian Btk, Bmx. Itk, Tec, Txk and homologs in other
`species.” BioEssays 23:436446 (2001).
`Smolen, Josef S. and Steiner, Gunter, “Therapeutic Strategies for
`Rheumatoid Arthritis.” Nature Reviews 2:473-488 (2003).
`Traxler et al. “Use of a Pharmacophore Model for the Design of
`EGF-R Tyrosine Kinase Inhibitors: 4-(Phenylamino)pyrazolo 3,4-
`dipyrimidines.” J. Med Chem 1997, 40(22):3601-3616.
`Uckun, Fatih M. et al., “The Anti-leukemic Bruton's Tyrosin Kinase
`Inhibitor
`O-cyano-B-hydroxy-3-mehyl-N-(2,5-
`dibromophenyl)Propenamide
`(LFM-A13)Prevents
`Fatal
`Thromboembolism.” Leuk. Lymphoma 44(9): 1569-1577 (2003).
`Uckun, Fatih M. et al., “In Vivo Pharmacokinetic Features, Toxicity
`Profile, and Chemosensitizing Activity of C-Cyano-B-hydroxy-3-
`methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a Novel
`Antileukemic Agent Targeting Bruton's Tyrosine Kinase.” Clin. Can
`cer Res. 8:1224-1233 (2002).
`Uckun, F.M., “Bruton's Tyrosin Kinase (BTK) as a Dual-Function
`Regulator of Apoptosis.” Biochem. Pharmacology, vol. 56, pp. 683
`691, 1998.
`Uckun, Fatih M. et al., “BTK as a Mediator of Radiation-Induced
`Apoptosis in DT-40 Lymphoma B Cells.” Science vol. 273 No. 5278,
`pp. 1096-1 100 (1996).
`Ucken et al. “Bruton's tyrosine kinase as a molecular target in treat
`ment of leukemias and lymphomas as well as inflammatory disorders
`and autoimmunity.” Expert Opinion Ther: Patents 2010, 20011):1-14.
`Vassilev, A.O. and Uckun, F.M., “Therapeutic Potential of Inhibiting
`Bruton's Tyrosine Kinase, (BTK). Current Pharmaceutical Design,
`2004, 10, 1757-1766.
`Vassilev, Alexei et al., “Bruton's Tyrosine Kinase as an Inhibitor of
`the Fas/CD95 Death-inducing Signaling Complex.” J. Biol. Chem.
`274(3):1646-1656 (1999).
`Vippagunta et al., “Crystalline Solids.” Advanced Drug Delivery
`Reviews 48:3-26 (2001).
`Yamamoto, Noriyuki et al., “The Orally Available Spleen Tyrosine
`Kinase
`Inhibitor
`247-(3,4-Dimethoxyphenyl)-imidazo[1,2-
`cpyrimidin-5-ylamino-nicotinamide Dihydrochloride (BAY61
`3606) Blocks Antigen-Induced Airway Inflammation in Rodents.”J.
`Pharma. and Exp. Therapeutics 306(3): 1174-1181 (2003).
`EP06850.039 Supplemental Search Report dated Feb. 9, 2010.
`EP06850386.1 Search Report and Written Opinion dated Sep. 10,
`2010.
`http://www.uspto.gov/web/offices/pac/dapplpecha.htm#7.
`accessed Feb. 16, 2011.
`U.S. Appl. No. 13/011,258 mailed Nov. 22, 2011.
`EP 10155834.4 Search Report dated May 19, 2010.
`EP08744513 Supplementary Search Report dated Mar. 11, 2010.
`EP10823966 Supplementary European Search Report mailed Oct.
`17, 2011.
`U.S. Appl. No. 13/654,173, filed Oct. 17, 2012, Honigberg et al.
`U.S. Appl. No. 13/736,812, filed Jan. 8, 2013, Buggy et al.
`Advanietal. “The BTK inhibitor PCI-32765 is highly active and well
`tolerated in patients (PTS) with relapsed/refractory B cell malignan
`cies: final results from a phase 1 study. Ann. Oncol., 22(Suppl 4):
`abstract 153 (2011).
`Banker et al. “Modern Pharmaceutics.” p. 596 (1996).
`Brown et at. "Phase Ib trial of AVL-292, a covalent inhibitor of
`Bruton's tyrosine kinase (Btk), in chronic lymphocytic leukemia
`(CLL) and B-non-Hodgkin lymphoma (B-NHL)'. J. Clin. Oncol.
`
`last
`
`30(suppl):abstract 8032 (2012); online retrieved on Oct. 4, 2012
`Retrieved from the Internet: <http://www.asco.org/ASCOv2/Meet
`ings/Abstracts?&vmview=abst detail view&conflD=114
`&abstractID=98841>.
`Burger, J.A., “Targeting the microenvironment in chronic
`lymphocytic leukemia is changing the therapeutic landscape'. Curr.
`Opin. Oncol. (Epub Sep 6, 2012), 24(6):643-649 (Nov. 2012).
`Carmi et al. “Clinical perspectives for irreversible tyrosine kinase
`inhibitors in cancer.” Biochem. Pharmacol. (Epub Aug. 4, 2012),
`84(11): 1388-1399 (Dec. 2012).
`Czuczman etal. "Rituximab in combination with fludarabine chemo
`therapy in low-grade or follicular lymphoma'. J. Clin. Oncol.
`23(4):694-704 (Feb. 1, 2005).
`Davids et al. “Targeting the B Cell Receptor Pathway in Chronic
`Lymphocytic Leukemia', Leuk. Lymphoma (Epub May 23, 2012),
`53(12):2362-2370 (Dec. 2012).
`EA200901313 Notification of Office Action mailed Oct. 31, 2011.
`Edwards, C.M.. “BTK inhibition in myeloma: targeting the seed and
`the soil”. Blood 120(9): 1757-1759 (Aug. 2012).
`EP 06850039.6 Search Report and Written Opinion dated Feb. 15,
`2010.
`EP 087445 13.6 Search Report and Written Opinion dated Mar. 18,
`2010.
`EP 09798770.5 Search Report and Written Opinion dated Oct. 28,
`2011.
`EP 10155834.4 Search Report and Written Opinion dated May 27,
`2010.
`EP 10823966.6 Written Opinion dated Dec. 6, 2011.
`EP 12151943.3 Search Report and Written Opinion dated Mar. 13,
`2012.
`EP 12166295.1 Search Report and Written Opinion dated Nov. 6,
`2012.
`EP 12166296.9 Search Report and Written Opinion dated Nov. 8,
`2012.
`EP 12166298.5 Search Report and Written Opinion dated Nov. 7,
`2012.
`EP 12166300.9 Search Report and Written Opinion dated Oct. 31,
`2012.
`EP 12166301.7 Search Report and Written Opinion dated Nov. 6,
`2012.
`EP 12166302.5 Search Report and Written Opinion dated Nov. 6,
`2012.
`EP 12166305.8 Search Report and Written Opinion dated Nov. 6,
`2012.
`EP 12166306.6 Search Report and Written Opinion dated Nov. 8,
`2012.
`EP 12172840.6 Search Report and Written Opinion dated Dec. 12,
`2012.
`EP 12172841.4 Search Report and Written Opinion dated Jan. 2,
`2013.
`Fisher et al. "Prolonged disease-free survival in Hodgkin's disease
`with MOPP reinduction after first relapse'. Ann. Intern. Med.,
`90(5):761-763 (1979).
`Fowler et al. “The Bruton's tyrosine kinase inhibitor ibrutinib (PCI
`32765) is active and tolerated in relapsed follicular lymphoma'. 54th
`American Society of Hematology Annual Meeting and Exposition,
`Atlanta, GA, Abstract 156 (Dec. 8-11, 2012).
`Giuliani, N., “Multiple myeloma bone disease: pathophysiology of
`osteoblast inhibition.” Blood (Epub Aug. 17, 2006), 108(13)-3992
`3996 (2006).
`Hantschel et al. “The Btk Tyrosine Kinase is a Major Target of the
`Bcr-Ab1 Inhibitor Dasatinib', PNAS 104(33): 13283-13288 (2007).
`Hata et al. “Bruton's tyrosine kinase-mediated Interleukin-2 gene
`activation in mast cells,” J. Biol. Chem. 273(18): 10979-10987
`(1998).
`Herman et al. “Bruton tyrosine kinase represents a promising thera
`peutic target for treatment of chronic lymphocytic leukemia and is
`effectively targeted by PCI-32765”. Blood (Epub Mar. 21, 2011),
`117(23):6287-6296 (Jun. 2011).
`
`SAN EX 1019, Page 3
`
`

`

`US 8,497.277 B2
`Page 4
`
`Hiddeman et al. “Frontline therapy with rituximab added to the
`combination of cyclophosphamide, doxorubicin, Vincristine, and
`prednisone (CHOP) significantly improves the outcome for patients
`with advanced-stage follicular lymphoma compared with therapy
`with CHOP alone: results of a prospective randomized study of the
`German Low-Grade Lymphoma Study Group”. Blood (Epub Aug.
`25, 2005), 106(12):3725-3732 (Dec. 2005).
`Korade-Mirnics et al. “Src kinase-mediated signaling in leukocytes.”
`J. Leukoc. Bio., 68(5):603-613 (Nov. 2000).
`Kozaki et al. “Development of a Bruton's tyrosine kinase (Btk)
`inhibitor-ONO-WG-307, a potential treatment for B-cell malignan
`cies'. 53rd American Society of Hematology Annual Meeting and
`Exposition, San Diego, CA. Poster #857 (Dec. 10-13, 2011).
`Mallis et al. “Structural characterization of a proline-driven
`conformational Switch within the ItkSH2 domain.” Nat. Struct. Biol.,
`9(12):900-905 (2002).
`Middendorp et al. “Tumor Suppressor Function of Bruton Tyrosine
`Kinase is Independent of its catalytic activity”. Blood 105(0:259-261
`(2005).
`Mukoyama et al., “Preparation of imidazol 1.5-alpyrazine deriva
`tives, pharmaceutical compositions containing them, and their uses
`for prevention or treatment of protein tyrosine kinase-related dis
`eases,” retrieved from STN Database Accession No. 2005:2994.62,
`Patent No.JP2005089352, Apr. 7, 2005, *abstract.
`Pagel et al. “Induction of apoptosis using inhibitors of
`lysophosphatidic acid acyltransferase-beta and anti-CD20
`monoclonal antibodies for treatment of human non-Hodgkin's
`lymphomas'. Clin. Cancer Res. (Epub Jul. 6, 2005), 11(13):4857
`4866 (2005).
`PCT/US09/50897 IPER and Written Opinion dated Jan. 27, 2011.
`PCT/US09/50897 Search Report dated Mar. 15, 2010.
`Peterson et al. "Prolonged single-agent versus combination chemo
`therapy in indolent follicular lymphomas: a study of the cancer and
`leukemia group'. Br. J. Clin. Oncol., 21(1):5-15 (Jan. 1, 2003).
`Ponader et al. “The Bruton tyrosine kinase inhibitor PCI-32765
`thwarts chronic lymphocytic leukemia cell Survival and tissue hom
`ing in vitro and in vivo”. Blood (Epub Dec. 16, 2011), 119(5): 1182
`1189 (Feb. 2012).
`Powers et al. "Irreversible Inhibitors of Serine, Cysteine, and
`Threonine Proteases.” Chem. Rev., 102(12):4639-4750 (2002).
`Prakash et al. “Chicken Sarcoma to human cancers: a lesson in
`molecular therapeutics.” The Ochsner Journal, 7(2):61-64 (Jan. 1,
`2007).
`Robak et al. "A Targeted Therapy for Protein and Lipid Kinases in
`Chronic Lymphocytic Leukemia'. Curr. Med. Chem. (Epub Jul. 24.
`2012), 19(31):5294-5318 (2012).
`Robak et al. “Tyrosine kinase inhibitors as potential drugs for B-cell
`lymphoid malignancies and autoimmune disorders'. Expert Opin.
`Investig. Drugs (Epub May 22, 2012), 21(7):921-947 (Jul. 2012).
`Rushworth et al. “BTK inhibitor ibrutinib is cytotoxic to myeloma
`and potently enhances bortezomib and lenalidomide activities
`through NF-kB”. Cell Signal (Epub Sep. 11, 2012), 25(1):106-112
`(Jan. 2013).
`Schwamb et al. "B-cell receptor triggers drug sensitivity of primary
`CLL cells by controlling glucosylation of ceramides'. Blood (Epub
`Aug. 27, 2012), 120(19):3978-3985 (Nov. 2012).
`.S. Appl. No. 1 1/617,645 Final Office Action mailed Oct. 16, 2008.
`.S. Appl. No. 1 1/617,645. Notice of Allowance mailed Feb. 9, 2009.
`.S. Appl. No. 1 1/617,645 Office Action mailed Jan. 24, 2008.
`.S. Appl. No. 1 1/617,645 Office Action mailed May 13, 2008.
`.S. Appl. No. 1 1/692,870 Final Office Action mailed Aug. 19, 2009.
`.S. Appl. No. 1 1/692,870 Office Action mailed Jan. 26, 2009.
`.S. Appl. No. 12/356,498 Final Office Action mailed Jul. 8, 2011.
`.S. Appl. No. 12/356,498 Office Action mailed Apr. 14, 2011.
`.S. Appl. No. 12/499,002 Final Office Action mailed Dec. 14, 2012.
`.S. Appl. No. 12/499,002 Final Office Action mailed Oct. 25, 2011.
`.S. Appl. No. 12/499,002 Office Action mailed Jun. 5, 2012.
`.S. Appl. No. 12/499,008 Office Action mailed Jul 19, 2011.
`.S. Appl. No. 12/594,805 Office Action mailed Oct. 15, 2012.
`.S. Serial No. 12/727,703 Final Office Action mailed Jul. 19, 2011.
`.S. Appl. No. 12/887,428 Office Action mailed Apr. 20, 2011.
`.S. Appl. No. 13/162,449 Office Action mailed Feb. 9, 2012.
`.S. Appl. No. 13/249,066 Office Action mailed Nov. 27, 2012.
`
`U.S. Appl. No. 13/312,606 Office Action mailed Sep. 19, 2012.
`U.S. Appl. No. 13/328,718 Final Office Action mailed Dec. 27, 2012.
`U.S. Appl. No. 13/328,718 Office Action mailed Jul. 3, 2012.
`U.S. Appl. No. 13/340,276 Office Action mailed Sep. 26, 2012.
`U.S. Appl. No. 13/361,733 Notice of Allowance mailed Nov. 14.
`2012.
`U.S. Appl. No. 13/361,733 Office Action mailed Jul. 6, 2012.
`U.S. Appl. No. 13/404,422 Office Action mailed Sep. 28, 2012.
`U.S. Appl. No. 13/410,110 Office Action mailed Sep. 28, 2012.
`U.S. Appl. No. 13/439,775 Office Action mailed Dec. 10, 2012.
`U.S. Appl. No. 13/526,161 Office Action mailed Nov. 27, 2012.
`U.S. Appl. No. 13/526,163 Office Action mailed Nov. 28, 2012.
`U.S. Appl. No. 13/607.036 Office Action mailed Nov. 14, 2012.
`Vose, J.M., “Mantle cell lymphoma: 2012 update on diagnosis, risk
`stratification, and clinical management'. Am. J. Hematol. 87(6):604
`609 (Jun. 2012).
`Wilkinson et al. “Selective tyrosine kinase inhibitors.” Expert Opin.
`Emerging Drugs 5(3):287-297 (2000).
`Witzens-Harig et al. “Current treatment of mantle cell lymphoma:
`results of a national Survey and consensus meeting”. Ann Hematol.
`(Epub Aug. 29, 2012), 91 (11):1765-1772 (Nov. 2012).
`Witzig et al. “Lenalidomide oral monotherapy produces durable
`responses in relapsed or refractory indolent non-Hodgkin's
`lymphoma, J. Clin. Oncol. (Epub Oct. 5, 2009), 27:5404-5409
`(2009).
`Wolff, M.E., "Burger's Medicinal Chemistry and Drug Discovery.”
`5th Ed. Part 1, pp.975-977 (1995).
`Yasuhiro et al. “ONO-WG-307, a Novel, Potent and Selective Inhibi
`tor of Bruton's Tyrosine Kinase, in Sustained inhibition of the Erk,
`Akt and PKD signaling pathways', 53rd American Society of Hema
`tology Annual Meeting and Exposition, San Diego, CA. Poster #2021
`(Dec. 10-13, 2011).
`Zhu et al. "Calpain Inhibitor II Induces Caspase-dependent
`Apoptosis in Human Acute Lymphoblastic Leukemia and Non
`Hodgkin's Lymphoma Cells as well as Some Solid Tumor Cells'.
`Clin. Cancer Res.6:2456-2463 (2000).
`EP 087445 13.6 Examination Report dated Jan. 16, 2013.
`EP 12151943.3 Examination Report dated Feb. 5, 2013.
`EP 12172842.2 Partial Search Report dated Jan. 24, 2013.
`EP 12172843.0 Search Report and Written Opinion dated Jan. 18.
`2013.
`U.S. Appl. No. 13/341,695 Office Action mailed Feb. 1, 2013.
`U.S. Appl. No. 13/747,322, filed Jan. 22, 2013, Buggy et al.
`U.S. Appl. No. 13/747,319, filed Jan. 22, 2013, Buggy et al.
`Tinmouth et al. “Fludarabine in alkylator-resistant follicular non
`Hodgkin's lymphoma'. Leuk. Lymphoma, 41(1-2): 137-145 (2001).
`U.S. Appl. No. 13/340,409, filed Dec. 29, 2011, Honigberg et al.
`U.S. Appl. No. 13/606,949, filed Sep. 7, 2012, Honigberg et al.
`U.S. Appl. No. 13/612,143, filed Sep. 12, 2012, Honigberg et al.
`Advanietal. “The BTK inhibitor PCI-32765 is highly active and well
`tolerated in patients (PTS) with relapsed/refractory B cell malignan
`cies: final results from a phase I study. Ann. Oncol., 22(Suppl 4):
`abstract 153 (2011).
`Apsel et al. “Targeted Polypharmacology: Discovery of Dual Inhibi
`tors of Tyrosine and Phosphoinositide Kinases.” Nature Chem. Bio.
`4(11):691-699 (2008).
`Arnold et al. “Pyrrolo[2,3-dipyrimidines Containing an Extended
`5-Substituent as Potent and Selective Inhibitors of lck 1.” Bioorg.
`Med. Chem. Ltrs. 10:2167-2170 (2000).
`Brown et al. "Phase Ib trial of AVL-292, a covalent inhibitor of
`Bruton's tyrosine kinase (Btk), in chronic lymphocytic leukemia
`(CLL) and B-non-Hodgkin lymphoma (B-NHL)'. J. Clin. Oncol.
`30(suppl):abstract 8032 (2012); online retrieved on Oct. 4, 2012
`Retrieved from the Internet: <http://www.asco.org/ASCOv2/Meet
`ings/Abstracts?&vmview=abst detail view&conflD=114
`&abstractID=98841>.
`Browning, J.L., “B cells move to centre stage: novel opportunities for
`autoimmune disease treatment'. Nature Reviews/Drug Discovery,
`5:564-576 (Jul 2006).
`Burchat et al., “Pyrazolo 3,4-dipyrimidines Containing an Extended
`3-Substituent as Potent Inhibitors of Lck—a Selectivity Insight.”
`Bioorg. Med. Chem. Ltrs. 12:1687-1690 (2002).
`
`SAN EX 1019, Page 4
`
`

`

`US 8,497.277 B2
`Page 5
`
`Carmi et al. “Clinical perspectives for irreversible tyrosine kinase
`inhibitors in cancer.” Biochem. Pharmacol. (Epub Aug 4, 2012),
`84(11): 1388-1399 (Dec. 2012).
`Chang et al. “The Bruton tyrosine kinase inhibitor PCI-32765 ame
`liorates autoimmunearthritis by inhibition of multiple effector cells.”
`Arthritis Research & Therapy, 13:R115 (2011).
`Cohen et al. "Structural Bioinformatics-Based Design of Selective,
`Irreversible Kinase Inhibitors.” Science, 308: 1318-1321 (May 27,
`2005).
`Desiderio, S., “Role of Btk in B cell development and signaling.”
`Curr. Opin. Imm. 9:534-540 (1997).
`Dorwald, F.Z., Side Reactions in Organic Synthesis, Wiley:VCH,
`Weinheimp. IX of Preface, Wiley-VCH Verlag GmbH & Co. KGaA
`(2005).
`EA201000599 Search Report dated Nov. 15, 2010.
`Edwards, C.M.. “BTK inhibition in myeloma: targeting the seed and
`the soil”. Blood 120(9): 17574759 (Aug. 2012).
`EP 06850386.1 Search Report and Written Opinion dated Sep. 10,
`2010.
`EP 087445 13.6 Search Report and Written Opinion dated. Mar. 18,
`2010.
`EP 10823966.6 Search Report dated Oct. 17, 2011.
`EP 1215943.3 Search Report and Written Opinion dated Mar. 13,
`2012.
`EP 12166295.1 Search Report and Written Opinion dated. Nov. 6,
`2012.
`Fabian et al. "A Small molecule-kinase interaction map for clinical
`kinase inhibitors.” Nature Biotechnology, 2005, 23(3): 329-336.
`Fruman, D.A., "Xid-like Phenotypes: A B Cell Signalosome Takes
`Shape'. Immunity, 13: 1-3 (Jul. 2000).
`Giuliani, N., “Multiple myeloma bone disease: pathophysiology of
`osteoblast inhibition.” Blood (Epub Aug. 17, 2006), 108(13):3992
`3996 (2006).
`Gold, M.R., “To make antibodies or not:signaling by the B-cell
`antigen receptor.” Trends in Pharmacological Sciences, 23(7):316
`324 (Jul. 2002).
`Hantschel et al. “The Btk Tyrosine Kinase is a Major Target of the
`Bcr-Abl Inhibitor Dasatinib', PNAS 104(33): 13283-13288 (2007).
`Hiddeman et al. “Frontline therapy with rituximab added to the
`combination of cyclophosphamide, doxorubicin, Vincristine, and
`prednisone (CHOP) significantly improves the outcome for patients
`with advanced-stage follicular lymphoma compared with therapy
`with CHOP alone: results of a prospective randomized study of the
`German Low-Grade. Lymphoma Study Group”. Blood (Epub Aug.
`25, 2005), 106(12):3725-3732 (Dec. 2005).
`Horwood et al. “Bruton's Tyrosin Kinase Is Required for
`Lipopolysaccharide—induced Tumor Necrosis Factor O. Produc
`tion.” J. Exp. Med., 197(12):1603-1611 (Jun. 2003).
`http://www.uspto.gov/web/offices/pac/dapplpecha.htm#7.
`accessed Feb. 16, 2011.
`Iwaki et al. “Btk Plays a Crucial Role in the Amplification of FceRI
`mediated Mast Cell Activation by Kit,” J. Biol. Chem.
`280(48):40261-46270 (Dec. 2, 2005).
`Jefferies et al. “Bruton's Tyrosine Kinase is a Toll/Interleukin-1
`Receptor Domain-binding Protein That Participates in Nuclear Fac
`tor KB Activation by Toll-like Receptor 4.” J. Biol. Chem.
`278:26258-26264 (2003).
`Kawakami et al. “Terreic acid, a quinone epoxide inhibitor of
`Bruton's tyrosine kinase.” PNAS USA, 96:2227-2232 (1999).
`Korade-Mirnics et al. “Src kinase-mediated signaling in leukocytes.”
`J. Leukoc. Bio., 68(5):603-613 (Nov. 2000).
`Kuppers, R., “Mechanisms of B-cell lymphoma pathogenesis.”
`Nature Reviews/Cancer, 5:251-262 (Apr. 2005).
`Kurosaki, T. "Functional dissection of BCR signaling pathways.”
`Curr, Op. Imm. 12:276-281 (2000).
`Liu et al. “Structural Basis for selective inhibition of Src family
`kinases by PPI.” Chemistry and Biology, 1999, No. 6, pp. 671-678, in
`particular table 1, p. 671.
`Luskova, P. and Draber, P. “Modulation of the Fce Receptor I Sig
`naling by Tyrosin Kinase Inhibitors: Search for Therapeutic Targets
`of Inflammatory and Allergy Diseases. Curr. Pharmaceutical Design
`10:1727-1737 (2004).
`
`last
`
`Mahajan et al. “Rational Design and Synthesis of a Novel Anti
`leukemic Agent Targeting Bruton's Tyrosine Kinase (BTK), LFM
`A13 O-Cyano-B-Methyl-N-(2,5-Dibromophenyl)Propenamide).” J.
`Biol. Chem., 274(14):9587-9599 (Apr. 2, 1999).
`Mangla et al. "Pleiotropic consequences of Bruton tyrosin kinase
`deficiency in myeloid lineages lead to poor inflammatory responses.”
`Blood, 104(4): 1191-1197 (2004).
`Merged Markush Service Search, Jun. 27, 2005.
`Middendorp et al. “Tumor Suppressor Function of Bruton Tyrosine
`Kinase is Independent of its catalytic activity”. Blood 105(1):259
`261 (2005).
`Mukoyama et al., “Preparation of imidazol 1.5-alpyrazine deriva
`tives, pharmaceutical compositions containing them, and their uses
`for prevention or treatment of protein tyrosine kinase-related dis
`eases,” retrieved from STN Database Accession No. 2005:2994.62
`abstract.
`Niiro, H. and Clark, E.A., “Regulation of B-Cell Fate by Antigen
`Receptor Signals.” Nature Reviews, 2:945-956 (2002).
`Nisitani et al. “In situ detection of activated Bruton's tyrosine kinase
`in the Ig signaling complex by phosphopeptide-specific monoclonal
`antibodies.” PNAS USA, 96:2221-2226 (1999).
`Oligino, T.J. and Dalrymple, S.A., “Targeting B cells for the treat
`ment of rheumatoid arthritis.” Arthirits Res. Ther. 5(Suppl4):S7
`S11 (2002).
`Panet al. “Discovery of Selective Irreversible Inhibitors for Bruton's
`Tyrosine Kinase.” ChemMedChem, 2:58-61 (2007).
`PCT/US06/49626 Search Report dated Apr. 9, 2008.
`PCT/US08/0.58528 Search Report and Written Opinion dated Sep.
`30, 2008.
`PCT/US 10/52377 Search Report and Written Opinion mailed Jun.
`29, 2011.
`Quek et al. “A role for Bruton's tyrosine kinase (Btk) in platelet
`activation by collagen.” Curr. Biol. 8(20): 1137-1140 (1998).
`Sada, K. and Yamamura, H., “Protein-Tyrosine Kinases and Adaptor
`Proteins in FceRI-Mediated Signaling in Mast Cells.” Curr. Mol.
`Med., 3(1): 85-94 (2003).
`Schaeffer, E.M. and Schwartzberg, P.L., “Tec family kinases in lym
`phocyte signaling and function.” Curr. Opin. Imm., 12:282-288
`(2000).
`Science IP CAS Search, Mar. 16, 2006.
`Science IP CAS Search, Sep. 5, 2006.
`Shaffer et al. "Lymphoid malignancies: the dark side of B-cell differ
`entiation.” Nat