`US010272083B2
`
`(12) United States Patent
`Hamdy et al.
`
`US 10,272,083 B2
`(IO) Patent No.:
`(45) Date of Patent:
`Apr. 30, 2019
`
`(54) METHODS OF TREATING CHRONIC
`LYMPHOCYTIC LEUKEMIA AND SMALL
`LYMPHOCYTIC LEUKEMIA USING A BTK
`INHIBITOR
`
`(71) Applicant: Acerta Pharma B.V., Oss (NL)
`
`(72)
`
`Inventors: Ahmed Hamdy, Santa Cruz, CA (US);
`Wayne Rothbaum, New York, NY
`(US); Raquel Izumi, San Carlos, CA
`(US); Brian Lannutti, Solana Beach,
`CA (US); Todd Covey, San Carlos, CA
`(US); Roger Ulrich, Sammamish, WA
`(US); Dave Johnson, Aptos, CA (US);
`Tjeerd Barf, Ravenstein (NL); Allard
`Kaptein, Zaltbommel (NL)
`
`(73) Assignee: ACERTA PHARMA B.V., Oss (NL)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.:
`
`15/112,968
`
`(22) PCT Filed:
`
`Jan.21, 2015
`
`(86) PCT No.:
`
`PCT /IB2015/000645
`
`§ 371 (c)(l),
`(2) Date:
`
`Jul. 20, 2016
`
`(87) PCT Pub. No.: WO2015/110923
`
`PCT Pub. Date: Jul. 30, 2015
`
`(65)
`
`Prior Publication Data
`
`US 2017/0095471 Al
`
`Apr. 6, 2017
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`Related U.S. Application Data
`
`Provisional application No. 62/035,777, filed on Aug.
`11, 2014, provisional application No. 61/929,742,
`filed on Jan. 21, 2014, provisional application No.
`61/974,665, filed on Apr. 3, 2014.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 3114985
`A61K 39/395
`A61K 45106
`C07K 16128
`U.S. Cl.
`CPC .... A61K 3114985 (2013.01); A61K 39/39558
`(2013.01); A61K 45106 (2013.01); C07K
`1612887 (2013.01); C07K 2317/24 (2013.01);
`C07K 2317/732 (2013.01)
`Field of Classification Search
`CPC .............. A61K 31/4985; A61K 31/498; A61K
`31/4995; A61K 31/50; A61K 39/395558;
`A61K 45/06
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`12/2008 Dong et al.
`7,459,554 B2
`11/2010 Honigberg et al.
`7,825,118 B2
`6/2011 Honigberg et al.
`7,960,396 B2
`2/2013 Chen et al.
`8,377,946 Bl
`2/2014 deMan et al.
`8,658,794 B2
`3/2016 Barf et al.
`9,290,504 B2
`4/2006 Beck et al.
`2006/0084654 Al
`3/2008 Honigberg et al.
`2008/0076921 Al
`10/2011 Honigberg et al.
`2011/0257203 Al
`2012/0053189 Al
`3/2012 Loury
`4/2012 Honigberg et al.
`2012/0095026 Al
`5/2012 Honigberg et al.
`2012/0129821 Al
`5/2012 Honigberg et al.
`2012/0135944 Al
`6/2012 Honigberg et al.
`2012/0165328 Al
`2013/0018032 Al
`1/2013 Chen et al.
`3/2013 Yamamoto et al.
`2013/0079327 Al
`2013/0338172 Al * 12/2013 Smyth.
`
`2014/0073593 Al
`3/2014 Conklin et al.
`2014/0179673 Al * 6/2014 Evarts .
`
`2014/0206681 Al
`
`7/2014 Kim et al.
`(Continued)
`
`C07D 487/04
`514/262.1
`
`C07D 471/08
`514/210.21
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`WO
`
`1/2013
`2548877
`3/2001
`2001019828
`6/2001
`2007064993
`(Continued)
`
`OTHER PUBLICATIONS
`
`Calquence Prescribing Information dated Oct. 2017.
`(Continued)
`
`Primary Examiner - Micah Paul Young
`(74) Attorney, Agent, or Firm - Morgan, Lewis &
`Bockius LLP
`
`(57)
`
`ABSTRACT
`
`Therapeutic methods of treating chronic lymphocytic leu(cid:173)
`kemia (CLL) and small lymphocytic leukemia (SLL) are
`described. In certain embodiments, the invention includes
`therapeutic methods of treating CLL and SLL using a BTK
`inhibitor. In certain embodiments, the invention includes
`therapeutic methods of treating subtypes of CLL and SLL
`using a BTK inhibitor, including subtypes of CLL in patients
`sensitive to thrombosis and subtypes of CLL that increase
`monocytes and NK cells in peripheral blood after treatment
`with a BTK inhibitor. In certain embodiments, the invention
`includes therapeutic methods of treating CLL and SLL using
`a combination of a BTK inhibitor and an anti-CD20 anti(cid:173)
`body.
`
`20 Claims, 25 Drawing Sheets
`
`Specification includes a Sequence Listing.
`
`SANDOZ INC.
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`US 10,272,083 B2
`Page 2
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`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2014/0212425 Al
`
`7/2014 Chang et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`2002080926
`2003065995
`2005037836
`2005097800
`2007061737
`20070648
`2007106503
`2008121742
`2009076170
`2010126960
`2011095556
`2011119663
`2011152351
`2011153514
`2012158843
`2013003629
`2013010380
`2013010868
`2013010869
`WO 2013010868 Al *
`WO-2013010868 Al *
`2013059738
`2015057992 Al
`2014130856 A2
`2014143807
`2014159745
`2014159745
`2015083008 Al
`
`10/2002
`8/2003
`4/2005
`10/2005
`5/2007
`6/2007
`9/2007
`10/2008
`6/2009
`11/2010
`8/2011
`9/2011
`12/2011
`12/2011
`11/2012
`1/2013
`1/2013
`1/2013
`1/2013
`1/2013
`1/2013
`4/2013
`4/2014
`8/2014
`9/2014
`10/2014
`2/2015
`6/2015
`
`C07D 487/04
`C07D 487/04
`
`OTHER PUBLICATIONS
`
`Imbruvica Prescribing Information dated Nov. 2013.
`Imbruvica Prescribing Information dated Feb. 2014.
`Byrd et al. (2016) N. Engl. J. Med. 374, 323-332.
`Berge et al. "Pharmaceutical salts" 66(1) J. Pharm. Sci. 1-19 (1977).
`Bingham et al., "Over one hundred solvates ofsulfathlazole" Chem.
`Commun. 603-04 (2001).
`Caira et al., "Preparation and Crystal Characterization of a Polymorph,
`a Monohydrate, and an Ethyl Acetate Solvate of the Antifungal
`Fluconazole," 93(3) J. Pharma. Sci. 601-11 (2004).
`Davis et al., "Chronic active B-cell-receptor signaling in diffuse
`large B-cell lymphoma," 463 Nature 88-92 (2010).
`Dhar et al., "Synthesis and SAR of p38a MAP kinase inhibitors
`based on heterobicyclic scaffolds," 17 Bioorg. & Med. Chem. Lett.
`5019-24 (2007).
`Gaudet et al., "A Homogeneous Fluorescence Polarization Assay
`Adaptable for a Range of Protein Serine/Threonine and Tyrosine
`Kinases," 8(2) J. Biomol. Screening 164-75 (2003).
`Gennaro (ed.), Remington: The Science and Practice of Pharmacy
`20th edition (2000).
`Gilfillan et al., "The tyrosine kinase network regulating mast cell
`activation," 288 Immun. Rev. 149-69 (2009).
`Gould "Salt selection for basic drugs" 33 Intl J. Pharmaceutics
`201-217 (1986).
`Greene & Wuts, Protective Groups in Organic Synthesis, 2d Edition
`(1991).
`
`Harder et al., "Gain- and Loss-of-Function Lyn Mutant Mice Define
`a Critical Inhibitory Role for Lyn in the Myeloid Lineage" 15
`immunity 603-15 (2001).
`Hartz et al., "Synthesis and Evaluation of imidazo[l,5-a]pyrazines
`as Corticotrophin Releasing Hormone Receptor Ligands," 12 Bioorg.
`& Med. Chem. Lett. 291-94 (2002).
`Higuchi et al. (eds.), Pro-drugs as Novel Delivery Systems. 14
`A.C.S. Symposium Series (1975).
`Ji et al., ""A novel, potent, and selective insulin-like growth factor-I
`receptor kinase inhibitor blocks insulin-like growth factor-I receptor
`signaling in vitro and inhibits insulin-like growth factor-Ireceptor(cid:173)
`dependent tumor growth in vivo,"" 6(8) Mo!. Cancer Ther. 2158-67
`(2007).
`King et al., "Nucleofugallty effects in the pyridine promoted for(cid:173)
`mation of esters from 2-substituted ethanesulfonyl chlorides," 66
`Can. J. Chem. 1109-16 ( 1988).
`Klinghoffer et al., "Src family kinases are required for integrin but
`not PDGFR signal transduction," 18(9) EMBO J. 2459-71 (1999).
`Lim et al., "Anti-CD20 monoclonal antibodies: historical and future
`perspectives," 95(1) Hematological 135-43 (2010).
`Lowell et al., "Deficiency of the Hck and Src Tyrosine Kinases
`Results in Extreme Levels of Extramedullary Hematopoiesis,"
`87(5) Blood 1780-92 (1996).
`Mitchell et al., Synthesis of C-nucleoside isosteres of 9-(2-
`hydroxyethoxymethyl)guanine (acyclovir), 21 (3) J. Heterocyclic
`Chem. 697-99 (1984).
`Mukalyama et al., "Synthesis and c-Src inhibitory activity of
`imidazo[l,5-a]pyrazine derivatives as an agent for treatment of
`acute ischemic stroke," 15 Bloom. & Med. Chem. 868-85 (2007).
`Mulvihill et al.," 1,3-Disubstituted-imidazo[ 1,5-a ]pyrazines as insulin(cid:173)
`like growth-factor-I receptor (IGF-IR) inhibitors", 17 Bioorg. &
`Med. Chem. Lett. 1091-97 (2007).
`Mulvihill et al., "Novel 2-phenylquinolin-7-yl-derived imidazo[ 1,5-
`a ]pyrazines as potent insulin-growth factor-I receptor (IGF-IR)
`inhibitors", 16 Bioorg. & Med. Chem. 1359-75 (2008).
`Odom et al., "Negative Regulation of immunoglobulin E-dependent
`Allergic Responses by Lyn Kinase," 199(11) J. Exp. Med. 1491-
`1502 (2004).
`Pan et al., "Discovery of Selective Irreversible Inhibitors for Bruton's
`Tyrosine Kinase," 2 ChemMedChem 58-61 (2007).
`Roby et al., "Alterations in Reproductive Function in Src Tyrosine
`Kinase Knockout Mice", 26 Endocrine 169-76 (2005).
`Roche (ed.), Bioreversible Carriers in Drug Design, Pergamon Press
`(1987).
`Shinohara et al., "Tyrosine Kinases Btk and Tee Regulate Osteoclast
`Differentiation by Linking RANK and ITAM Signals" 132 Cell
`794-806 (2008).
`Van Tonder et al., "Preparation and Physicochemical Characteriza(cid:173)
`tion of 5 Niclosamide Solvates and 1 Hemisolvate", 5(1) AAPS
`PharmScITech Article 12 (2004).
`Written Opinion dated Aug. 10, 2016 relating to PCT/IB2016/
`053988.
`International Search Report dated Aug. 10, 2016 relating to PCT/
`IB2016/053988.
`Byrd et al., "Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic
`Leukemia", N Engl J Med, vol. 374, No. 5, pp. 323-332 (2016).
`International Search Report for PCT/IB2015/000645, dated Aug.
`31, 2015.
`Written Opinion for PCT/IB2015/000645.
`International Search Report for PCT/IB2015/002140, dated Feb. 28,
`2016.
`Written Opinion for PCT/IB2015/002140.
`
`* cited by examiner
`
`SANDOZ INC.
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`Ex. 1001, p. 2 of 78
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 1 of 25
`
`US 10,272,083 B2
`
`CD86
`
`CD69
`
`1
`
`.........
`tu)
`
`-Ji
`E 0.5 -0
`
`&.ci
`
`0 w
`
`0
`
`0.91
`
`0.45
`
`Expression in B Cells (3h)
`11 BTK inhibitor
`□ ibrutinib
`
`FIG. l
`
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`Sheet 2 of 25
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`US 10,272,083 B2
`
`FIG. 2
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`Sheet 3 of 25
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`US 10,272,083 B2
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`FIG. 3
`
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`Apr. 30, 2019
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`Sheet 4 of 25
`
`US 10,272,083 B2
`
`_,_ lbrutinib
`-.. Formula (II)
`
`lbrutinib
`
`~ - 90
`
`"o'
`
`'ii
`.::::
`....
`::,.
`:::,
`00
`w, ... LL
`w,
`' C:
`0 ·;;
`m w, ...
`0 ....
`a..
`
`0)
`
`110
`
`Formula (H)
`
`100
`
`so
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`FIG. 4
`
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`Sheet 5 of 25
`
`US 10,272,083 B2
`
`-
`-
`
`Formula (I!)
`lbrutinib
`
`Days
`
`FIG. 5
`
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`Ex. 1001, p. 7 of 78
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`Sheet 6 of 25
`
`US 10,272,083 B2
`
`Formula (I!}
`
`-.. lbrutinib (N = 28)
`Formula (II) (N = 18)
`-
`
`ibrutinib
`
`110
`
`100
`
`80
`
`- 90
`~ Q -iij
`
`>
`i::
`:::,
`r.n
`
`Q.>
`Q.>
`
`L. u.
`'
`C
`.2
`
`El')
`El')
`Q.>
`L.
`
`a, e
`a.
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0 ~~#$#~,,,,,,,,#~#,
`
`Days
`
`FIG. 6
`
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`Ex. 1001, p. 8 of 78
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`Sheet 7 of 25
`
`US 10,272,083 B2
`
`30
`
`Formula (II) (N = 18}
`!brutinib (N = 28)
`
`Formula(!!)
`0-------------------------------------
`• ~ # $ #~ ## # # # $ #$#~ # #
`Days
`
`FIG. 7
`
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`Ex. 1001, p. 9 of 78
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`Sheet 8 of 25
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`US 10,272,083 B2
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`FIG. 8
`
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`Apr. 30, 2019
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`Sheet 9 of 25
`
`US 10,272,083 B2
`
`Co!'lort
`O 100rng 81D R!F~
`□ 200mg OD Naiv,i
`+ 400:np OD RJ:::~
`X Combo
`
`300
`
`0
`02-009
`
`250
`
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`□
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`0
`o
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`~
`
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`
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`0
`+
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`+ ---:r a o
`
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`
`□
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`□
`01-032
`b
`01-041
`
`. tr
`03-011
`
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`
`+
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`
`0
`03-015
`
`+
`□ 01-017
`
`0
`
`50
`
`X
`01-202
`
`FIG.9
`
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`Ex. 1001, p. 11 of 78
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`
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 10 of 25
`
`US 10,272,083 B2
`
`Cohort
`0 :oom:;1 B!D Plf<
`□ LUGmg OD t,-Jc/{vs~
`+ 4G0mci GD f-"liR
`X Co(nbG
`
`0
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`
`250
`
`0
`
`08
`
`0
`
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`
`□ 02-010
`
`-:(cid:173)
`·-:
`C1 ~;o
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`
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`
`+
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`+
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`
`□
`01-038
`
`-30
`
`-40
`
`40
`
`60
`
`BO
`
`FIG. 10
`
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`Ex. 1001, p. 12 of 78
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`Sheet 11 of 25
`
`US 10,272,083 B2
`
`fl()()
`
`400
`
`Cohort
`o rno,-,,9 B:D Htr<.
`□ 200;::g 00 !'<c1ivc1
`+ 400mgiJDWE
`X Cornbo
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`V')
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`-~::
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`+.
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`.
`a
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`
`+
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`X
`.
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`
`0
`
`01-202X
`
`FIG. 11
`
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`Ex. 1001, p. 13 of 78
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 12 of 25
`
`US 10,272,083 B2
`
`Cohort
`0 100mg SiD R!R
`□ ~:oorr.g OD 1",i:3hlE:
`+ 400n--:f; QD R/R
`x c:o:-nbo
`
`0
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`
`0
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`
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`□ □
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`
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`
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`
`E.
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`
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`
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`
`-40
`
`60
`
`FIG. 12
`
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`Ex. 1001, p. 14 of 78
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`
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`Apr. 30, 2019
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`Sheet 13 of 25
`
`US 10,272,083 B2
`
`□ ·:•:;:·:,·,.:.-. ::-;:---~: :.---::,..;'
`+~: .. ~:~,"-!· :{/:;-:t: ~ .. ::::"::::)
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`
`FIG. 13
`
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`Ex. 1001, p. 15 of 78
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`Sheet 14 of 25
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`US 10,272,083 B2
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`:-5;•,:;•:N?.X❖:•:-;!.~
`0 '.::;,'.·.:t:-~ ·~ • <.~::: :: R: • '.·_:})::,.·: · ·::-.,::.::,·,::-:·:::•:•: :·\~:::~;:..·.,:. f
`o•:s .. ;;:,,;-,-:,,,,,,;,·, .. ·,,;,,,,,
`+ ·,: .. ::·.bt· ::::i -:,3! :'-,::-:::::--;i
`X ·:::::·~K
`* .. ., ·v. ·.· ... _,: .. : r .. ,. :·
`◊ ,,,,,,,:,.;-:- :'(".\'-')•,
`1:,. :::;.;,;;.;-:- :'(:lk:·,
`
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`~'.
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`
`FIG. 14
`
`SANDOZ INC.
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`Ex. 1001, p. 16 of 78
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`
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 15 of 25
`
`US 10,272,083 B2
`
`6,000
`
`-..
`<7-l
`E
`1
`._, 4,000···
`(cy e
`<
`
`2,.000
`
`oJ"·
`0
`
`150
`
`200
`
`100
`Time (sec)
`
`FIG. 15
`
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`Ex. 1001, p. 17 of 78
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`Sheet 16 of 25
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`US 10,272,083 B2
`
`GPVI Induced aggregation
`
`....,... Formula II
`,.. !brntinib
`
`60
`
`40
`
`20
`
`•
`
`o-· - - - - - - - - - - - - - - - -
`to
`t5
`OJJ
`-1.5
`log {Drug]
`
`FIG. 16
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 18 of 78
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 17 of 25
`
`US 10,272,083 B2
`
`GPVI Induced aggregation
`
`.... Formula II
`...... ibrutinib
`
`oL==::::::::::::::::::=:::::,•
`
`0
`
`1500
`1000
`500
`Compound [nM]
`
`2000
`
`FIG. 17
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 19 of 78
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`Apr. 30, 2019
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`Sheet 18 of 25
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`US 10,272,083 B2
`
`Induced IFN-y release
`
`ft{Jt)
`
`150
`
`6(10
`
`45tl
`
`3ml
`
`15-0
`
`::r
`e
`I
`·-·
`
`~
`~
`~
`
`NK
`HER1i
`Allti-HE~ mM
`!&utin!b{l,Mj
`Fomiula!l(µM)
`
`O•,...........,
`+++..--t+
`t + + + f
`•
`+ + + +
`.1 1
`,
`•
`•
`'1
`
`•
`
`•·
`
`60-0
`
`4$0
`
`:l
`
`i ·--
`
`~
`~ 3M
`
`1$1.}
`
`ftK
`llHL-4
`AA!l-Ctl2tl mAb
`lbr:tmnib ~]1:~.M)
`formn!a ll{~M}
`
`f+t++ ♦
`t + t
`t
`•
`t-
`- + + + +
`•
`? 1 1
`...
`...
`".
`...
`...
`•
`•
`•
`" 1
`
`FIG. 18
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 20 of 78
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 19 of 25
`
`US 10,272,083 B2
`
`CD107a+ expression
`(NK activation rnarker)
`
`40
`
`10
`
`l}
`
`NK
`0Hl4
`Atttl~t):4!is mM:>
`li;.r!i!ijf:i!:b faMt
`fomm!a II: (µMl
`
`++~ ♦♦ ·+
`.~+ - 4 4 - . ; . ,
`•
`•
`•
`-+
`-+
`,t.
`.1 1 •
`, 1
`
`NK
`Hl~1i
`Aittl.f.!ER2 mA.b
`*b:rtl:t!nlb {?M)
`Formllla 1:1 {!<iii.JI)
`
`~♦➔...+++
`
`N
`
`,;;,
`
`•
`
`+·
`,
`
`,;.,
`
`. . . ♦
`
`.. + ♦
`,1 1
`
`FIG. 19
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 21 of 78
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 20 of 25
`
`US 10,272,083 B2
`
`• • • w
`
`¼
`
`··♦···
`
`~
`
`.•·
`
`""(JS-~.
`
`'"'
`
`-
`
`·-:--
`
`· - • . •
`
`.'-
`
`·._ • .,._.-::- _ , . y
`
`Autoto-gous CLL, CGl-1746 {1 uM}
`Atdoh.){'.l0U$ CLL ibrutinib O ur.tl
`..
`..
`Autoiogous GLL, BTK inh.A (1 uM}
`AutOfM.OUS (>LL BTK inhB ii uM'l
`+
`AutoiorJous CLL,
`l
`Formula (JI)
`
`... (.
`
`i +·
`
`/~--,-+--~ -t?"
`
`o 0.1
`
`1
`Rltuximab Concentration (ugt:ml)
`25:1 E:T Ratio
`
`,:·········· ::
`
`to
`
`FIG. 20
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 22 of 78
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 21 of 25
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`US 10,272,083 B2
`
`FIG. 21
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 23 of 78
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 22 of 25
`
`US 10,272,083 B2
`
`···Ill·· NK:RaJt CG!~ 1746 fl uM)
`v.£r NK:RaJi,, lbrutin\b {1 ufS)
`---•--- NK:R.aj( BTK !nhA fh.if.dJ
`100·i
`' ·"'"-" NK:Rafi, BTK in!18 fluM}
`··+·· NK:RaJL Formula (ff) {1 uM)
`
`).
`
`•• v:•••~••,:••••••=•••:•.••••••:•C•A=••,••••••••·
`
`.J .
`
`. ··::::.~:--~--:•·~~-·~~-(cid:173)
`
`J ..
`
`+.
`~~~
`:i:
`
`: .~-------·- -r ··········· ...
`
`·.
`
`i
`
`:'
`
`1
`0 0,1
`:FUtu:dmab Com:entration {ug.fml}
`25:·1 E:T Ratio
`
`10
`
`FIG. 22
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 24 of 78
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 23 of 25
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`US 10,272,083 B2
`
`* p::::OA~til
`**P"o,o,o-OS
`
`Oonor2
`
`FIG. 23
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 25 of 78
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`Apr. 30, 2019
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`Sheet 24 of 25
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`US 10,272,083 B2
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`FIG. 24
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 26 of 78
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`Apr. 30, 2019
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`Sheet 25 of 25
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`US 10,272,083 B2
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`FIG. 25
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1001, p. 27 of 78
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`US 10,272,083 B2
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`1
`METHODS OF TREATING CHRONIC
`LYMPHOCYTIC LEUKEMIA AND SMALL
`LYMPHOCYTIC LEUKEMIA USING A BTK
`INHIBITOR
`
`FIELD OF THE INVENTION
`
`2
`may not eradicate residual malignent B cell populations in
`the microenvironment of the bone marrow and lymph nodes,
`where protective stromal cells prevent apoptosis. There is
`thus an urgent need for treatments that reduce or overcome
`the protective effect of the microenvironment on CLL cells
`to enable superior clinical responses in patients.
`
`5
`
`Therapeutic methods of treating chronic lymphocytic
`leukemia using a Bruton's tyrosine kinase (BTK) inhibitor
`are disclosed herein.
`
`BACKGROUND OF THE INVENTION
`
`Bruton's Tyrosine Kinase (BTK or Btk) is a TEC family
`non-receptor protein kinase expressed in B cells and
`myeloid cells. The function of BTK in signaling pathways
`activated by the engagement of the B cell receptor (BCR)
`and FCERl on mast cells is well established. Functional
`mutations in BTK in humans result in a primary immuno(cid:173)
`deficiency disease characterized by a defect in B cell devel(cid:173)
`opment with a block between pro- and pre-B cell stages. The
`result is an almost complete absence of B lymphocytes,
`causing a pronounced reduction of serum immunoglobulin
`of all classes. These findings support a key role for BTK in
`the regulation of the production of auto-antibodies in auto(cid:173)
`immune diseases.
`Other diseases with an important role for dysfunctional B
`cells are B cell malignancies. The reported role for BTK in
`the regulation of proliferation and apoptosis of B cells
`indicates the potential for BTK inhibitors in the treatment of
`B cell lymphomas. BTK inhibitors have thus been devel(cid:173)
`oped as potential therapies, as described in 0. J. D'Cruz and
`F. M. Uckun, OncoTargets and Therapy 2013, 6, 161-176.
`B cell chronic lymphocytic leukemia (CLL) is one of the
`most prevalent B cell malignancies in adults. CLL is char(cid:173)
`acterized by an expansion of monoclonal mature B cells.
`CLL patients who relapsed after standard treatments gener(cid:173)
`ally experience poor outcomes. Although survival has been
`improved by the addition of immunotherapies such as ritux(cid:173)
`imab to standard chemotherapies such as fludarabine and
`cyclophosphamide, as described in M. Hallek, et al., Lancet,
`2010, 76, 1164-74, many standard treatments are associated
`with toxicities and immunosuppression. There is therefore a
`significant need to identify less toxic and highly efficacious
`treatments for CLL. Small lymphocytic leukemia (SLL) is
`closely related to CLL, and differs only in that a lower level
`of monoclonal lymphocytes is observed in blood than in
`CLL, along with an enlarged spleen or lymph nodes. There
`is also a significant need to identify less toxic and highly
`efficacious treatments for SLL.
`CLL (and SLL) cells rapidly accumulate and are resistant
`to apoptosis in vivo, but are known to die rapidly in vitro. M.
`Buchner, et al., Blood 2010, 115, 4497-506. One cause of
`this effect is from nonmalignant accessory cells in the tumor
`microenvironment, such as stromal cell contact mediated
`cell survival. Strama! cells in the bone marrow and lymph
`nodes are known to have an antiapoptotic and protective
`effect on CLL cells, protecting them from both chemothera(cid:173)
`peutic and spontaneous apoptosis. R. E. Mudry, et al., Blood
`2000, 96, 1926-32. The chemokine SDFla (CXCL12)
`directs homing of CLL cells towards protective niches. M.
`Burger, et al., Blood 2005, 106, 1824-30. Existing drugs that
`target the BCR pathway in B cell malignancies can lead to
`some lymphocytosis, i.e. lymphocyte egress from nodal
`compartments, through disruption of CXCR4-SDF1a sig(cid:173)
`naling and other adhesion factors in bone marrow and the
`resulting mobilization of cells. However, existing therapies
`
`SUMMARY OF THE INVENTION
`
`10
`
`In an embodiment, the invention includes a method of
`treating CLL and/or SLL, comprising the step of orally
`administering, to a human in need thereof, a Bruton's
`tyrosine kinase (BTK) inhibitor, wherein the BTK inhibitor
`is
`(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imi-
`15 dazo[l ,5-a ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a
`pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
`or prodrug thereof.
`In an embodiment, the invention includes a method of
`treating CLL and/or SLL, comprising the step of orally
`20 administering, to a human in need thereof, a Bruton's
`tyrosine kinase (BTK) inhibitor, wherein the BTK inhibitor
`is
`(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imi(cid:173)
`dazo[l ,5-a ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a
`pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
`25 or prodrug thereof, wherein the BTK inhibitor is adminis(cid:173)
`tered once daily at a dose selected from the group consisting
`of 100 mg, 175 mg, 250 mg, and 400 mg.
`In an embodiment, the invention includes a method of
`treating CLL and/or SLL, comprising the step of orally
`30 administering, to a human in need thereof, a Bruton's
`tyrosine kinase (BTK) inhibitor, wherein the BTK inhibitor
`is
`(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imi(cid:173)
`dazo[l ,5-a ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a
`pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
`35 or prodrug thereof, wherein the BTK inhibitor is adminis(cid:173)
`tered twice daily at a dose of 100 mg.
`In an embodiment, the invention includes a method of
`treating CLL and/or SLL, comprising the step of orally
`administering, to a human in need thereof, a Bruton's
`40 tyrosine kinase (BTK) inhibitor, wherein the BTK inhibitor
`is
`(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imi(cid:173)
`dazo[l ,5-a ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a
`pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
`or prodrug thereof, wherein the CLL increases monocytes
`45 and NK cells in peripheral blood after treatment with
`Formula (II) for a period selected from the group consisting
`of about 14 days, about 28 days, or about 56 days.
`In an embodiment, the invention includes a method of
`treating CLL and/or SLL, comprising the step of orally
`50 administering, to a human in need thereof, a Bruton's
`tyrosine kinase (BTK) inhibitor, wherein the BTK inhibitor
`is
`(S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imi(cid:173)
`dazo[l ,5-a ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a
`pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
`55 or prodrug thereof, wherein the CLL is selected from the
`group consisting of IgVH mutation negative CLL, ZAP-70
`positive CLL, ZAP-70 methylated at CpG3 CLL, CD38
`positive CLL, CLL with a 17p13.1 (17p) deletion, CLL with
`a llq22.3 (liq) deletion, CLL in a human sensitive to
`60 platelet-mediated thrombosis, CLL in a human presently
`suffering from platelet-mediated thrombosis, CLL in a
`human previously suffering from platelet-mediated throm(cid:173)
`bosis, or combinations thereof.
`In an embodiment, the invention includes a method of
`65 treating CLL and/or SLL, comprising the step of orally
`administering, to a human in need thereof, a Bruton's
`tyrosine kinase (BTK) inhibitor, wherein the BTK inhibitor
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1001, p. 28 of 78
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`US 10,272,083 B2
`
`3
`(S )-4-(8-amino-3-(1-(but-2-ynoyl )pyrrolidin-2-yl )imi(cid:173)
`is
`dazo [ 1,5-a ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a
`pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
`or prodrug thereof, further comprising the step of adminis(cid:173)
`tering a therapeutically effective dose of an anti-CD20 5
`antibody selected from the group consisting of rituximab,
`obinutuzumab, ofatumumab, veltuzumab,
`tositumomab,
`ibritumomab, and fragments, derivatives, conjugates, vari(cid:173)
`ants,
`radioisotope-labeled complexes, and biosimilars
`thereof.
`In an embodiment, the invention includes a method of
`treating CLL and/or SLL, comprising the step of orally
`administering, to a human in need thereof, a Bruton's
`tyrosine kinase (BTK) inhibitor, wherein the BTK inhibitor
`is
`(S )-4-(8-amino-3-(1-(but-2-ynoyl )pyrrolidin-2-yl )imi(cid:173)
`dazo [ 1,5-a ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a
`pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
`or prodrug thereof, further comprising the step of adminis(cid:173)
`tering a therapeutically effective dose of an anticoagulant or
`antiplatelet active pharmaceutical ingredient.
`In an embodiment, the invention includes a method of
`treating CLL and/or SLL, comprising the step of orally
`administering, to a human in need thereof, a Bruton's
`tyrosine kinase (BTK) inhibitor, wherein the BTK inhibitor
`is
`(S )-4-(8-amino-3-(1-(but-2-ynoyl )pyrrolidin-2-yl )imi(cid:173)
`dazo [ 1,5-a ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a
`pharmaceutically acceptable salt, solvate, hydrate, cocrystal,
`or prodrug thereof, further comprising the step of adminis(cid:173)
`tering a therapeutically effective dose of an anticoagulant or
`antiplatelet active pharmaceutical ingredient, wherein the
`anticoagulant or antiplatelet active pharmaceutical ingredi(cid:173)
`ent is selected from the group consisting of acenocoumarol,
`anagrelide, anagrelide hydrochloride, abciximab, aloxiprin,
`antithrombin, apixaban, argatroban, aspirin, aspirin with
`extended-release dipyridamole, beraprost, betrixaban, biva(cid:173)
`lirudin, carbasalate calcium, cilostazol, clopidogrel, clopi(cid:173)
`dogrel bisulfate, cloricromen, dabigatran etexilate, darexa(cid:173)
`ban, dalteparin, dalteparin sodium, defibrotide, dicumarol,
`diphenadione, dipyridamole, ditazole, desirudin, edoxaban,
`enoxaparin, enoxaparin sodium, eptifibatide, fondaparinux,
`fondaparinux sodium, heparin, heparin sodium, heparin cal(cid:173)
`cium, idraparinux, idraparinux sodium, iloprost, indobufen,
`lepirudin,
`low molecular weight heparin, melagatran,
`nadroparin, otamixaban, pamaparin, phenindione, phen(cid:173)
`procoumon, prasugrel, picotamide, prostacyclin, rama(cid:173)
`troban, reviparin, rivaroxaban, sulodexide, terutroban, ter(cid:173)
`utroban
`sodium,
`ticagrelor,
`ticlopidine,
`ticlopidine
`hydrochloride, tinzaparin, tinzaparin sodium, tirofiban, tiro(cid:173)
`fiban hydrochloride, treprostinil, treprostinil sodium, tri(cid:173)
`flusal, vorapaxar, warfarin, warfarin sodium, ximelagatran,
`salts thereof, solvates thereof, hydrates thereof, and combi(cid:173)
`nations thereof.
`In an embodiment, the invention includes a method of
`treating a hematological malignancy in a human comprising
`the step of administering a therapeutically effective dose of
`a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-
`amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l ,5-a]
`pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceuti(cid:173)
`cally acceptable salt, solvate, hydrate, cocrystal, or prodrug
`thereof, and wherein the hematological malignancy is
`selected from the group consisting of non-Hodgkin's lym(cid:173)
`phoma (NHL), diffuse large B cell lymphoma (DLBCL),
`follicular lymphoma (FL), mantle cell lymphoma (MCL),
`Hodgkin's lymphoma, B cell acute lymphoblastic leukemia
`(B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobu- 65
`linemia (WM), Burkitt's lymphoma, multiple myeloma, or
`myelofibrosis.
`
`4
`In an embodiment, the invention includes a method of
`treating a hematological malignancy in a human comprising
`the step of administering a therapeutically effective dose of
`a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-
`amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l ,5-a]
`pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceuti-
`cally acceptable salt, solvate, hydrate, cocrystal, or prodrug
`thereof, and wherein the hematological malignancy is
`selected from the group consisting of non-Hodgkin's lym-
`10 phoma (NHL), diffuse large B cell lymphoma (DLBCL),
`follicular lymphoma (FL), mantle cell lymphoma (MCL),
`Hodgkin's lymphoma, B cell acute lymphoblastic leukemia
`(B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobu(cid:173)
`linemia (WM), Burkitt's lymphoma, multiple myeloma, or
`15 myelofibrosis, wherein the BTK inhibitor is administered
`once daily at a dose selected from the group consisting of
`100 mg, 175 mg, 250 mg, and 400 mg.
`In an embodiment, the invention includes a method of
`treating a hematological malignancy in a human comprising
`20 the step of administering a therapeutically effective dose of
`a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-
`amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l ,5-a]
`pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceuti(cid:173)
`cally acceptable salt, solvate, hydrate, cocrystal, or prodrug
`25 thereof, and wherein the hematological malignancy is
`selected from the group consisting of non-Hodgkin's lym(cid:173)
`phoma (NHL), diffuse large B cell lymphoma (DLBCL),
`follicular lymphoma (FL), mantle cell lymphoma (MCL),
`Hodgkin's lymphoma, B cell acute lymphoblastic leukemia
`30 (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobu(cid:173)
`linemia (WM), Burkitt's lymphoma, multiple myeloma, or
`myelofibrosis, wherein the BTK inhibitor is administered
`twice daily at a dose of 100 mg.
`In an embodiment, the invention includes a method of
`35 treating a hematological malignancy in a human comprising
`the step of administering a therapeutically effective dose of
`a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-
`amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l ,5-a]
`pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceuti-
`40 cally acceptable salt, solvate, hydrate, cocrystal, or prodrug
`thereof, and wherein the hematological malignancy is
`selected from the group consisting of non-Hodgkin's lym(cid:173)
`phoma (NHL), diffuse large B cell lymphoma (DLBCL),
`follicular lymphoma (FL), mantle cell lymphoma (MCL),
`45 Hodgkin's lymphoma, B cell acute lymphoblastic leukemia
`(B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobu(cid:173)
`linemia (WM), Burkitt's lymphoma, multiple myeloma, or
`myelofibrosis, wherein
`the hematological malignancy
`increases monocytes and NK cells in peripheral blood after
`50 treatment with Formula (II) for a period selected from the
`group consisting of about 14 days, about 28 days, or about
`56 days.
`In an embodiment, the invention includes a method of
`treating a hematological malignancy in a human comprising
`55 the step of administering a therapeutically effective dose of
`a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-
`amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l ,5-a]
`pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceuti(cid:173)
`cally acceptable salt, solvate, hydrate, cocrystal, or prodrug
`60 thereof, and wherein the hematological malignancy is non(cid:173)
`Hodgkin's lymphoma (NHL), wherein the NHL is selected
`from the group consisting of indolent NHL and aggressive
`NHL.
`In an embodiment, the invention includes a method of
`treating a hematological malignancy in a human comprising
`the step of administering a therapeutically effective dose of
`a BTK inhibitor, wherein the BTK inhibitor is (S)-4-(8-
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1001, p. 29 of 78
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`US 10,272,083 B2
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`5
`amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[l ,5-a]
`pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceuti(cid:173)
`cally acceptable salt, solvate, hydrate, cocrystal, or prodrug
`thereof, and wherein the hematological malignancy is dif(cid:173)
`fuse large B cell lymphoma (DLBCL), wherein the DLBCL 5
`is selected from the group consisting of activated B-cell like
`diffuse large B-cell lymphoma (DLBCL-ABC) a