I 1111111111111111 1111111111 111111111111111 IIIII 1111111111111111 IIII IIII IIII
`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)
`
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`
`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
`
`(56)
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`
`SANDOZ INC.
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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`Sheet 2 of 25
`
`US 10,272,083 B2
`
`FIG. 2
`
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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`Sheet 3 of 25
`
`US 10,272,083 B2
`
`FIG. 3
`
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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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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`

`U.S. Patent
`
`Apr. 30, 2019
`
`Sheet 5 of 25
`
`US 10,272,083 B2
`
`-
`-
`
`Formula (I!)
`lbrutinib
`
`Days
`
`FIG. 5
`
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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`Sheet 8 of 25
`
`US 10,272,083 B2
`
`FIG. 8
`
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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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
`
`+·
`□
`03-008
`2(150 01-033
`0
`o
`02-008
`~
`
`((J
`
`{;
`c~)
`t.:1
`0
`+
`,f.)
`·-:~-
`
`~jG
`
`0
`(J
`+ ---:r a o
`
`(J
`
`□
`02-010 •
`□
`01-032
`b
`01-041
`
`. tr
`03-011
`
`-f.iO
`
`+
`03-007
`
`0
`03-015
`
`+
`□ 01-017
`
`0
`
`50
`
`X
`01-202
`
`FIG.9
`
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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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
`02-009
`
`250
`
`0
`
`08
`
`0
`
`□
`01-028
`
`□ 02-010
`
`-:(cid:173)
`·-:
`C1 ~;o
`( ) J:.
`
`0
`
`+
`03-008
`
`+
`03-007
`
`□
`01-038
`
`-30
`
`-40
`
`40
`
`60
`
`BO
`
`FIG. 10
`
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`

`U.S. Patent
`
`Apr. 30, 2019
`
`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
`
`V')
`
`>•.
`8
`§ :;on
`-~::
`w
`rn P. 25G
`SI.
`~ 20D
`u
`':(_ z
`
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`
`·JSG·
`
`1DO
`
`60
`
`0
`
`□ 01-028
`+.
`01~33 □ 01-032
`03-008
`.
`a
`
`0
`01-041
`
`+
`, a
`'03-01103-007
`X
`.
`01-203
`
`0
`
`01-202X
`
`FIG. 11
`
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`Ex. 1001, p. 13 of 78
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`

`U.S. Patent
`
`Apr. 30, 2019
`
`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
`02-009
`
`0
`02-008
`
`01-033 □ 01-028
`□ □
`01-032
`
`GOO
`
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`
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`
`E.
`£ .?:00
`
`160
`
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`
`50
`
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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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`U.S. Patent
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`Apr. 30, 2019
`
`Sheet 13 of 25
`
`US 10,272,083 B2
`
`□ ·:•:;:·:,·,.:.-. ::-;:---~: :.---::,..;'
`+~: .. ~:~,"-!· :{/:;-:t: ~ .. ::::"::::)
`X '.:•,:~~:;(
`
`f ~t~:)
`+:
`( ~:-:;.~:.
`
`FIG. 13
`
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`Ex. 1001, p. 15 of 78
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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 14 of 25
`
`US 10,272,083 B2
`
`:-5;•,:;•:N?.X❖:•:-;!.~
`0 '.::;,'.·.:t:-~ ·~ • <.~::: :: R: • '.·_:})::,.·: · ·::-.,::.::,·,::-:·:::•:•: :·\~:::~;:..·.,:. f
`o•:s .. ;;:,,;-,-:,,,,,,;,·, .. ·,,;,,,,,
`+ ·,: .. ::·.bt· ::::i -:,3! :'-,::-:::::--;i
`X ·:::::·~K
`* .. ., ·v. ·.· ... _,: .. : r .. ,. :·
`◊ ,,,,,,,:,.;-:- :'(".\'-')•,
`1:,. :::;.;,;;.;-:- :'(:lk:·,
`
`\-}::(}
`-:::
`~'.
`~:- :5:·{}
`
`FIG. 14
`
`SANDOZ INC.
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`Ex. 1001, p. 16 of 78
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`

`U.S. Patent
`
`Apr. 30, 2019
`
`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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`U.S. Patent
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`Apr. 30, 2019
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`Sheet 16 of 25
`
`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.
`
`IPR2023-00478
`
`Ex. 1001, p. 18 of 78
`
`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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.
`
`IPR2023-00478
`
`Ex. 1001, p. 19 of 78
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`

`U.S. Patent
`
`Apr. 30, 2019
`
`Sheet 18 of 25
`
`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.
`
`IPR2023-00478
`
`Ex. 1001, p. 20 of 78
`
`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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.
`
`IPR2023-00478
`
`Ex. 1001, p. 21 of 78
`
`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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.
`
`IPR2023-00478
`
`Ex. 1001, p. 22 of 78
`
`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`Sheet 21 of 25
`
`US 10,272,083 B2
`
`FIG. 21
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1001, p. 23 of 78
`
`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`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.
`
`IPR2023-00478
`
`Ex. 1001, p. 24 of 78
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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`Sheet 23 of 25
`
`US 10,272,083 B2
`
`* p::::OA~til
`**P"o,o,o-OS
`
`Oonor2
`
`FIG. 23
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1001, p. 25 of 78
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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`Sheet 24 of 25
`
`US 10,272,083 B2
`
`FIG. 24
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1001, p. 26 of 78
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`

`

`U.S. Patent
`
`Apr. 30, 2019
`
`Sheet 25 of 25
`
`US 10,272,083 B2
`
`FIG. 25
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1001, p. 27 of 78
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`US 10,272,083 B2
`
`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
`
`

`

`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
`
`

`

`US 10,272,083 B2
`
`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