-~
`
` WIPO
`
`WORLD
`INTELLECTUAL PROPERTY
`ORGANIZATION
`
`DOCUMENT MADE AVAILABLE UNDER THE
`PATENT COOPERATION TREATY (PCT)
`PCT /I B2015/000645
`International application number:
`
`International filing date:
`
`21 January 2015 (21.01.2015)
`
`Document type:
`
`Document details:
`
`Certified copy of priority document
`
`Country/Office:
`Number:
`Filing date:
`
`us
`62/035,777
`11 August 2014 (11.08.2014)
`
`Date of receipt at the International Bureau:
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`09 February 2015 (09.02.2015)
`
`Remark: Priority document submitted or transmitted to the International Bureau in compliance with Rule
`17.1(a),(b) or (b-bis)
`
`34, chemin des Colombettes
`1 2 I I Geneva 20, Switze1·1and
`
`www.wipo.int
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 1 of 196
`
`

`

`Patent 1111:d Tn1.dcm:1rk Offkc
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 2 of 196
`
`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 05/31/2015. 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
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`Provisional Application for Patent Cover Sheet
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`Ahmed
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`Inventor 2
`
`Hamdy
`
`Santa Cruz
`
`CA
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`City
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`State
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`Wayne
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`Inventor 3
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`Rothbaum
`
`New York
`
`NY
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`Middle Name
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`City
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`State
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`Raquel
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`Inventor 4
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`Izumi
`
`San Carlos
`
`CA
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`Brian
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`Lannutti
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`Solana Beach
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`Todd
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`Inventor 6
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`Covey
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`San Carlos
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`CA
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`State
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`Roger
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`Inventor 7
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`Ulrich
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`Sammamish
`
`WA
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`Dave
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`Inventor 8
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`Johnson
`
`Seattle
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`WA
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`City
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`Tjeerd
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`Barf
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`Raven stein
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`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 3 of 196
`
`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 05/31/2015. 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid 0MB control number
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`Inventor 9
`
`Given Name
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`Family Name
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`City
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`State
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`Allard
`
`Kaptein
`
`Zaltmommel
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`generated within this form by selecting the Add button.
`
`I
`
`Add
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`I
`
`Title of Invention
`
`Therapeutic Combination of a Pl3K Inhibitor and a BTK Inhibitor
`
`Attorney Docket Number (if applicable)
`
`055112-5002-02-PR
`
`Correspondence Address
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`Direct all correspondence to (select one):
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`Customer Number
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`28977
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`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
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`(!) No.
`0 Yes, the invention was made by an agency of the United States Government. The U.S. Government agency name is:
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`Government agency and Government contract number are:
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`EFS - Web 1.0.1
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`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 4 of 196
`
`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 05/31/2015. 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid 0MB control number
`
`Entity Status
`Applicant asserts small entity status under 37 CFR 1.27 or applicant certifies micro entity status under 37 CFR 1.29
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`0 Applicant asserts small entity status under 37 CFR 1.27
`0 Applicant certifies micro entity status under 37 CFR 1.29. Applicant must attach form PTO/SB/15A or B or equivalent.
`(!) No
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`Signature
`
`Please see 37 CFR 1.4(d) for the form of the signature.
`
`Signature
`
`/Frederick G. Vogt/
`
`Date (YYYY-MM-DD)
`
`2014-08-11
`
`First Name
`
`Frederick G.
`
`Last Name
`
`Vogt
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`Registration Number
`(If appropriate)
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`70115
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`EFS - Web 1.0.1
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 5 of 196
`
`

`

`Privacy Act Statement
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`enforcement agency, if the USPTO becomes aware of a violation or potential violation of law or regulation.
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 6 of 196
`
`

`

`120
`
`100
`
`C 80
`0
`.:; 60
`:0
`.c
`C
`
`40
`
`~ 0
`
`20
`
`0
`
`-20
`
`1/41
`
`~ Tested Btk inhibitor
`"'~'" Tested Pl3K inhibitor
`Btki + Pl3Ki (1 000nM)
`Btki + Pl3Ki (300nM)
`"&l" Btki + Pl3Ki (1 00nM)
`+ Btki + Pl3Ki (30nM)
`_.. Btki + Pl3Ki (1 0nM)
`"~" Btki + Pl3Ki (3nM)
`
`-10
`
`-8
`Log M compound
`
`-6
`
`FIG. 1
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 7 of 196
`
`

`

`2/41
`
`~ Tested Btk inhibitor
`"~"' Tested Pl3K inhibitor
`Btki + Pl3Ki (1 000OnM)
`Btki + Pl3Ki (3000nM)
`·'~" Btki + Pl3Ki (1 000nM)
`+ Btki + Pl3Ki (300nM)
`+ Btki + Pl3Ki (1 00nM)
`-~, Btki + Pl3Ki (30nM)
`
`-4
`
`.
`
`§...
`
`·~,t~~~~~~
`-8
`Log M lont"l>ound
`
`120
`
`100
`
`C: 80
`0
`+:. 60
`:0
`.c:
`C:
`
`40
`
`~ 0
`
`20
`
`0
`
`-20
`
`FIG. 2
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 8 of 196
`
`

`

`3/41
`
`~ ---~-,.C
`ro: ·~ >
`
`~
`
`[Tested Btk inhibitor]
`
`,,,-.~ Tested Pt3Ki
`
`"'"~'" (10 µM)Tested P!3Ki
`
`FIG. 3
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 9 of 196
`
`

`

`4/41
`4/41
`
`2.0-
`
`i}4i}——a
`
`•
`
`T
`
`T
`
`4l&.
`
`X9PuU]UOI9]yU|
`
`,t-t-f#.·
`.
`. ~
`•
`0~0"""'-----------~-
`~ " ~
`¼")
`~
`~ ~ .r:t
`*
`j
`j
`~
`
`Ct
`Cf
`~ ~
`
`f
`
`FIG. 4
`FIG. 4
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1013, p. 10 of 196
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 10 of 196
`
`

`

`5/41
`
`111111
`
`111111
`
`1111111
`
`.:;
`co 1.0
`C:
`.c
`E
`0
`(.)
`
`0.5
`
`....................... ~~~~ -~ - - - - - - - - - -
`~
`
`1111
`
`0 . 0 - - - - - - - - - - - - ~ ~ - - ~
`ED75 ED90
`ED25
`ED50
`
`FIG. 5
`
`1111111 Maver-1
`
`Jeko
`®
`• Sup-B15
`w CCRF
`
`Antagonistic
`
`Synergistic
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 11 of 196
`
`

`

`6/41
`
`Dose-effect curve
`
`0.50
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`I
`2
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 6
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 12 of 196
`
`

`

`7/41
`
`Dose-effect curve
`
`1.0
`
`0.8
`
`I
`2
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 7
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 13 of 196
`
`

`

`8/41
`
`Dose-effect
`
`curve
`
`0.80
`
`t5
`&
`LlJ
`
`I
`2
`
`I
`6
`
`4
`Dose
`
`I
`8
`
`I
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 8
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 14 of 196
`
`

`

`9/41
`
`Dose-effect curve
`
`0.40
`
`0.30
`
`+-'
`
`C) & 0.20
`w
`
`10
`
`1
`
`
`
`~
`
`4
`Dose
`
`b
`
`m
`
`~
`
`x lnh.1 +lnh.3
`·+ lnh.1
`o lnh.3
`
`FIG. 9
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 15 of 196
`
`

`

`1051
`
`11111
`
`®
`
`SU-DHL-4
`Jeko
`
`1111!
`
`Antagonistic
`
`Synergistic
`
`S
`'O
`C 1.5
`C
`0
`;;
`«s 1.0
`C ·-.0
`E o 0.5
`. ------.&i.----,-------~
`""
`00
`~
`ED50
`ED25
`ED75 ED90
`
`(.)
`
`1111!
`
`10/41
`
`11111
`
`FIG. 10
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 16 of 196
`
`

`

`11/41
`
`Dose-effect curve
`
`......
`0
`&
`UJ
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 11
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 17 of 196
`
`

`

`12/41
`
`Dose-effect curve
`
`1 0 ~-·-----=-=-==-'~®~,· ·=--···=····:::::·····.:::::·····=····=·····:::::.·····=····=·····:::::.····=·····=· ========i~
`
`0.8
`
`0.6
`
`0.4
`
`......
`0
`&
`UJ
`
`··:··
`
`0.21
`0 t
`
`I
`2
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 12
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 18 of 196
`
`

`

`13/41
`
`1:1
`
`1.5
`
`~
`
`~
`
`I
`
`~
`
`>< Cl)
`'C
`
`C: -C:
`
`w ~
`-----·--·--·--·--------------------------=A~---
`
`0
`.:;
`co 1.0
`·-.c
`C:
`E o 0.5
`
`(..)
`
`w·
`o.o ...... ----111-----...... - - -..... - - -
`ED25
`EDS0
`ED75 ED90
`
`FIG. 13
`
`®
`
`JVM-2
`~ SUP-B15
`II CCRF
`A Mino
`~ Ramos
`Antagonistic
`
`Synerglstlc
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 19 of 196
`
`

`

`14/41
`
`Dose-effect curve
`
`0.50
`
`0.40 .,.'7-~~-·~- _______ ____@
`i ::::r-@
`
`: ~~~·-+-
`
`--i--
`
`0.10
`
`2
`
`4
`Dose
`
`6
`
`8
`
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 14
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 20 of 196
`
`

`

`15/41
`
`Dose-effect curve
`
`0.40
`
`0.30
`
`...... u
`
`~ -w
`
`0
`X _________ --@----------------------~------------------~----
`
`2
`
`4
`Dose
`
`6
`
`8
`
`10
`
`x lnh.l+lnh.3
`-+ lnh.1
`o lnh.3
`
`FIG. 15
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 21 of 196
`
`

`

`16/41
`
`Dose-effect curve
`
`0.50
`
`0.40
`
`__, 0.30
`()
`&
`UJ 0.20
`
`0.10
`
`I
`2
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`x lnh.1 +lnh.3
`-+ lnh.1
`o lnh.3
`
`FIG. 16
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 22 of 196
`
`

`

`17/41
`
`Dose-effect curve
`
`0.50
`
`0.40
`
`•• +••+•
`
`t5 0.30 . ·:~::>-····)i--····--·""
`.f+
`~
`W 0.20
`
`~--------~-------------@
`
`I
`
`6
`
`I
`
`8
`
`I
`
`10
`
`2
`
`-- ~___,,--,- -
`
`o.10J
`Q L--0
`t-
`4
`Dose
`x lnh.l +lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 17
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 23 of 196
`
`

`

`51 : su-DHL-1
`
`10
`
`><
`Q)
`'g 1_5
`
`18/41
`
`~ Pfeiffer
`
`111 Raji
`
`Antagonistic
`
`Synergistic
`
`C:
`0
`;;
`co 1.0
`C:
`.0
`
`E o 0.5
`
`(.J
`
`w·
`'W'
`~-
`II
`Ill
`Ill
`0 . 0 - - - - - - - - - - - - - - - - -
`ED25
`ED50
`ED75 ED90
`
`11111
`
`FIG. 18
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 24 of 196
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`

`19/41
`
`Dose-effect curve
`
`0.20
`
`0.15
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`I
`2
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 19
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 25 of 196
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`

`20/41
`
`Dose-effect curve
`
`X
`
`0.30
`
`+-'
`()
`
`~ 4-w
`
`0.20
`
`0.10
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`x lnh.1 +lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 20
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 26 of 196
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`

`

`21/41
`
`Dose-effect curve
`
`1.0
`
`0.8
`
`a l
`
`I
`2
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 21
`
`SANDOZ INC.
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`Ex. 1013, p. 27 of 196
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`

`

`22/41
`
`~ DOHH2
`
`Ly1
`®
`w Ly19
`Ly?
`11
`❖ SU-DHL-2
`
`Antagonistic
`
`Synergistic
`
`11111
`
`II
`
`~ ~
`ED75 ED90
`
`•
`
`;::;
`ca 1.0
`C: ·-.c
`E o 0.5
`
`(.J
`
`II
`~
`o.o-----1"!!:---- ~
`ED25
`EDS0
`
`~
`
`FIG. 22
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 28 of 196
`
`

`

`0.20
`
`0.15
`
`t5 & 0.10
`
`UJ
`
`a 1
`
`I
`2
`
`x lnh.1 +lnh.3
`·+ lnh.1
`o lnh.3
`
`23/41
`
`Dose-effect curve
`
`--
`____________ __,_---------.><
`--
`~--
`--
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`FIG. 23
`
`SANDOZ INC.
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`Ex. 1013, p. 29 of 196
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`

`24/41
`
`Dose-effect curve
`
`0.25
`
`0.05
`
`2
`
`4
`
`Dose
`
`6
`
`8
`
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 24
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 30 of 196
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`

`

`25/41
`
`Dose-effect curve
`
`1.0
`
`0.8
`
`0.2
`
`Q !
`
`I
`2
`
`x lnh.1 +lnh.3
`+ lnh.1
`o lnh.3
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`FIG. 25
`
`SANDOZ INC.
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`Ex. 1013, p. 31 of 196
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`

`26/41
`
`Dose-effect curve
`
`0.25
`
`0.20
`
`X .
`
`6
`
`8
`
`10
`
`2
`4
`Dose
`x lnh.l+lnh.3
`+· lnh.1
`o lnh.3
`
`FIG. 26
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 32 of 196
`
`

`

`><Q) 1:1 : w K562
`
`U937
`SU-DHL-6
`
`11111 Daudi
`
`w ~
`
`'C
`c: 1.5
`C:
`0
`;;
`n:s 1.0
`C: ·-.c
`E o 0.5
`
`27/41
`
`FIG. 27
`
`Antagonistic
`
`Synergistlc
`
`(.)
`
`~
`
`~
`
`~-
`•
`•
`•
`• 11111
`~
`I
`'W
`0.0---------------____....,_ ____ _
`®
`ED75 ED90
`ED25
`ED50
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 33 of 196
`
`

`

`28/41
`
`Dose-effect curve
`
`0.50
`
`0.40
`
`..., 0.30
`0
`&
`UJ 0.20
`
`2
`
`4
`Dose
`
`6
`
`8
`
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 28
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 34 of 196
`
`

`

`29/41
`
`Dose-effect curve
`
`0.15
`
`0.10
`
`X .
`
`x lnh.l+lnh.3
`-+ lnh.1
`o lnh.3
`
`FIG. 29
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 35 of 196
`
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`

`30/41
`
`Dose-effect curve
`
`0.50
`
`0.40
`
`()
`
`...... 0.30
`&
`UJ 0.20
`
`0.10
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`x lnh.1 +lnh.3
`+- lnh.1
`o lnh.3
`
`FIG. 30
`
`SANDOZ INC.
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`Ex. 1013, p. 36 of 196
`
`

`

`31/41
`
`Dose-effect curve
`
`X .
`
`0.40
`
`0.30
`
`..... (.)
`© 0.20
`tt:: w
`
`Dose
`
`I
`8
`
`I
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 31
`
`SANDOZ INC.
`
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`Ex. 1013, p. 37 of 196
`
`

`

`32/41
`
`• Rec-1
`~ SU-DHL-6
`V HBL-1
`TMD-8
`
`11111
`
`Antagonistic
`
`Synergistic
`
`~ ca 1.0
`C: ·-.c
`E o 0.5
`
`(.)
`
`~
`
`~
`ii
`i
`0 . 0 - - - - - - - - -
`ED25
`EDS0
`
`~
`
`w·
`
`'
`
`ED75 ED90
`
`FIG. 32
`
`SANDOZ INC.
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`IPR2023-00478
`
`Ex. 1013, p. 38 of 196
`
`

`

`33/41
`33/41
`
`2.0
`2.0
`
`ROPuOHeUIqU[?
`
`C
`.o
`·+-' 1.0
`ro
`C: ,_
`.c
`E
`0 o 0.5 ..
`
`FIG. 33
`FIG. 33
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1013, p. 39 of 196
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 39 of 196
`
`

`

`34/41
`
`Dose-effect curve
`
`··•···•
`
`0.40
`
`0.30
`
`t5
`~ 0.20
`w
`
`0.10
`
`.. ··
`
`8
`
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 34
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 40 of 196
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`

`

`35/41
`
`Dose-effect curve
`
`1.0 o.s }c;;;. ······················. ·····
`
`······=-----=----=-----=---=---~-------=················ ····•
`
`····
`
`0
`
`f //
`
`-,-
`
`--~---
`---~----------------------------------
`
`- -
`0. ~ /
`/0
`
`0.
`
`t5
`
`©
`
`l:u
`
`2
`
`4
`Dose
`
`6
`
`8
`
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 35
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 41 of 196
`
`

`

`36/41
`
`Dose-effect curve
`
`0.40
`
`0.30
`
`+-'
`(.)
`~ 0.20
`......
`w
`
`T
`4
`Dose
`
`I
`6
`
`1 ···························t
`8
`10
`
`x lnh.l+lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 36
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 42 of 196
`
`

`

`37/41
`
`Dose-effect curve
`
`0
`
`0.40
`
`0.30
`
`t5
`2 '+--
`UJ
`
`I
`2
`
`I
`4
`Dose
`
`I
`6
`
`I
`8
`
`I
`10
`
`x lnh.1 +lnh.3
`+ lnh.1
`o lnh.3
`
`FIG. 37
`
`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 43 of 196
`
`

`

`38/41
`38/41
`
`pe0.008
`
`p~0.001
`
`p=0.05
`•
`
`6
`
`.,._,.
`N
`E
`E
`
`(mrn2}
`
`TumorVolumes
`
`00
`
`FIG. 38
`FIG. 38
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1013, p. 44 of 196
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 44 of 196
`
`

`

`39/41
`39/41
`
`60
`
` SILOALJO[ETON%ATISI08/
`deoIALATTOS
`
`FIG. 39
`FIG. 39
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1013, p. 45 of 196
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 45 of 196
`
`

`

`mcdAl,bd
`2101%9
`
`40/41
`40/41
`
` 25POO[RIOT}O
`
`FIG. 40
`FIG. 40
`
`SANDOZINC.
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`IPR2023-00478
`
`Ex. 1013, p. 46 of 196
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 46 of 196
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`

`

`EMS$9[EIO1%+E*94,9202.P09
`
`so
`
`geaag
`
`a)
`
`41/41
`41/41
`
`FIG, 41
`FIG. 41
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1013, p. 47 of 196
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1013, p. 47 of 196
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`
`
`

`

`Attorney Docket No.: 055112-5002-PR-02
`
`THERAPEUTIC COMBINATION OF A PI3K INHIBITOR AND A BTK INHIBITOR
`
`FIELD OF THE INVENTION
`
`[001]
`
`A therapeutic combination of a phosphoinositide 3-kinase (PI3K) inhibitor and a
`
`Bruton's Tyrosine Kinase (BTK) inhibitor and uses of the therapeutic combination are disclosed
`
`herein.
`
`BACKGROUND OF THE INVENTION
`
`[002]
`
`PI3K inhibitors are members of a unique and conserved family of intracellular lipid
`
`kinases that phosphorylate the 3'-OH group on phosphatidylinositols or phosphoinositides. PI3K
`
`inhibitors are key signaling enzymes that relay signals from cell surface receptors to downstream
`
`effectors. The PI3K family comprises 15 kinases with distinct substrate specificities, expression
`
`patterns, and modes ofregulation. The class I PI3K inhibitors (pl lOa, pl 10~, pl 108, and pl l0y)
`
`are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3,
`
`which engages downstream effectors such as those in the Akt/PDKI pathway, mTOR, the Tee
`
`family kinases, and the Rho family GTPases.
`
`[003]
`
`The PI3K signaling pathway is known to be one of the most highly mutated in human
`
`cancers. PI3K signaling is also a key factor in disease states including hematologic
`
`malignancies, non-Hodgkin lymphoma (such as diffuse large B-cell lymphoma), allergic contact
`
`dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive
`
`pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic
`
`complications, and inflammatory complications of the cardiovascular system such as acute
`
`coronary syndrome. The role of PI3K in cancer has been discussed, for example, in J. A.
`
`Engleman, Nat. Rev. Cancer 2009, 9, 550-562. The PBK-8 and PI3K-y isoforms are
`
`preferentially expressed in normal and malignant leukocytes.
`
`[004]
`
`The delta (8) isoform of class I PI3K (PBK-8) is involved in mammalian immune
`
`system functions such as T-cell function, B-cell activation, mast cell activation, dendritic cell
`
`function, and neutrophil activity. Due to its role in immune system function, PBK-8 is also
`
`involved in a number of diseases related to undesirable immune response such as allergic
`
`reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis,
`
`DBl/ 80293456.1
`
`1
`
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`IPR2023-00478
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`Ex. 1013, p. 48 of 196
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`Attorney Docket No.: 055112-5002-PR-02
`
`auto-immune diseases such as lupus, asthma, emphysema and other respiratory diseases. The
`
`gamma (y) isoform of class I PI3K (PI3K-y) is also involved in immune system functions and
`
`plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis,
`
`and autoimmune diseases such as lupus.
`
`[005]
`
`Downstream mediators of the PI3K signal transduction pathway include Akt and
`
`mammalian target of rapamycin (mTOR). One important function of Akt is to augment the
`
`activity of mTOR, through phosphorylation of TSC2 and other mechanisms. mTOR is a serine(cid:173)
`
`threonine kinase related to the lipid kinases of the PI3K family and has been implicated in a wide
`
`range of biological processes including cell growth, cell proliferation, cell motility and survival.
`
`Disregulation of the mTOR pathway has been reported in various types of cancer.
`
`[006]
`
`In view of the above, PI3K inhibitors are prime targets for drug development, as
`
`described in J.E. Kurt and I. Ray-Coquard, Anticancer Res. 2012, 32, 2463-70. Several PI3K
`
`inhibitors are known, including those those that are PBK-8 inhbitors, PI3K-y inhibitors and those
`
`that are PBK-8,y inhibitors.
`
`[007]
`
`Bruton's Tyrosine Kinase (BTK) is a Tee 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 immunodeficiency disease
`
`characterized by a defect in B cell development 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 autoimmune diseases.
`
`[008]
`
`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 ofB cells indicates the
`
`potential for BTK inhibitors in the treatment of B cell lymphomas. BTK inhibitors have thus
`
`been developed as potential therapies, as described in 0. Cruz et al., OncoTargets and Therapy
`
`2013, 6, 161-176.
`
`[009]
`
`In many solid tumors, the supportive microenvironment (which may make up the
`
`majority of the tumor mass) is a dynamic force that enables tumor survival. The tumor
`
`DBl/ 80293456.1
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`2
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`Ex. 1013, p. 49 of 196
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`Attorney Docket No.: 055112-5002-PR-02
`
`microenvironment is generally defined as a complex mixture of "cells, soluble factors, signaling
`
`molecules, extracellular matrices, and mechanical cues that promote neoplastic transformation,
`
`support tumor gmwth and invasion, protect the tumor from host immunity, forster therapeutic
`
`resistance, and provide niches for dominant metastases to thrive," as described in Swartz et al.,
`
`Cancer Res., 2012, 72, 2473. Although tumors express antigens that should be recognized by T
`
`cells, tumor clearance by the immune system is rare because of immune suppression by the
`
`microenvironment. Addressing the tumor cells themselves with e.g. chemotherapy has also
`
`proven to be insufficient to overcome the protective effects of the microenvironment. New
`
`approaches are thus urgently needed for more effective treatment of solid tumors that take into
`
`account the role of the microenvironment.
`
`[0010] The present invention includes the unexpected discovery that the combination of a
`
`PI3K inhibitor with a BTK inhibitor is effective in the treatment of any of several types of
`
`cancers such as leukemia, lymphoma and solid tumor cancers.
`
`SUMMARY OF THE INVENTION
`
`[0011]
`
`Tn an embodiment, the invention includes a method of treating leukemia, lymphoma or
`
`a solid tumor cancer in a subject, comprising co-administering to a mammal in need thereof a
`
`therapeutically effective amount of a PI3K inhibitor and a BTK inhibitor.
`
`[0012]
`
`In an embodiment, the invention includes a method of treating leukemia, lymphoma or
`
`a solid tumor cancer in a subject, comprising co-administering to a mammal in need thereof a
`
`therapeutically effective amount of a PI3K-y inhibitor and a BTK inhibitor.
`
`[0013]
`
`In an embodiment, the invention includes a method of treating leukemia, lymphoma or
`
`a solid tumor cancer in a subject, comprising co-administering to a mammal in need thereof a
`
`therapeutically effective amount of a PI3K-8 inhibitor and a BTK inhibitor.
`
`[0014]
`
`In an embodiment, the invention includes a method of treating leukemia, lymphoma or
`
`a solid tumor cancer in a subject, comprising co-administering to a mammal in need thereof a
`
`therapeutically effective amount of a PI3K-y,8 inhibitor and a BTK inhibitor.
`
`DBl/ 80293456.1
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`3
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 50 of 196
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`

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`Attorney Docket No.: 055112-5002-PR-02
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0015] The foregoing summary, as well as the following detailed description of the invention,
`
`will be better understood when read in conjunction with the appended drawings.
`
`[0016] FIG. 1 illustrates the sensitivity of the TMD8 diffuse large B cell lymphoma (DLBCL)
`
`cell line to individual treatment with the BTK inhibitor of Formula XVIII ("Tested Btk
`
`Inhibitor") and the PBK inhibitor of Formula IX ("Tested PBK Inhibitor") and combined
`treatment with Formula XVIII and Formula IX ("Btki + PI3Ki") at different concentrations. The
`
`concentration of the first agent in the combination (the BTK inhibitor) and the concentration of
`
`the individual agents is given on the x-axis, and the concentration of the added PBK inhibitor in
`
`combination with the BTK inhibitor is given in the legend.
`
`l 0017] FIG. 2 illustrates the sensitivity of the MINO mantle cell lymphoma cell to individual
`treatment with the BTK inhibitor of Formula XVIII ("Tested Btk Inhibitor") and the PBK
`
`inhibitor of Formula IX ("Tested PBK Inhibitor") and combined treatment with Formula XVIII
`and Formula IX ("Btki + PI3Ki") at different concentrations. The concentration of the first agent
`in the combination (the BTK inhibitor) and the concentration of the individual agents is given on
`
`the x-axis, and the concentration of the added PBK inhibitor in combination with the BTK
`
`inhibitor is given in the legend.
`
`[0018] FIG. 3 illustrates the proprofliferative activity in primary mantle cell lymphoma cells of
`
`Formula XVIII ("Tested Btki") and Formula IX ("Tested PI3Ki"). The percentage viability of
`
`cells("% viability", y-axis) is plotted versus the concentration of the Formula XVIII ("[Tested
`
`Btk Inhibitor]", x-axis). The concentration of the individual BTK and PT3K inhibitors (i.e. not in
`
`combination) arc also given on the x-axis.
`
`[0019] FIG. 4 illustrates the interaction index of the combination of the BTK inhibitor of
`
`Formula XVIII and the PBK inhibitor of Formula IX in primary mantle cell lymphoma cells.
`
`l0020J FlG. 5 illustrates the synergy observed in certain cell lines when the BTK inhibitor of
`
`Formula (XVIII) and the PBK-8 inhibitor of Formula (IX) are combined. The tested cell lines
`
`include Maver-I (B cell lymphoma, mantle), Jeko (B cell lymphoma, mantle), CCRF (B
`
`lymphoblast, acute lymphoblastic leukemia), and SUP-B15 (B lymphoblast, acute lymphoblastic
`
`DBl/ 80293456.1
`
`4
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1013, p. 51 of 196
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`

`

`Attorney Docket No.: 055112-5002-PR-02
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`leukemia). The dose-effect curves for these cell lines are given in FIG. 6, FIG. 7, FIG. 8, and
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`FIG. 9. ED25, ED50, ED75, and ED90 refer to the effective doses causing 25%, 50%, 75%, and
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`90% of the maximum biological effect (proliferation).
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`[0021] FIG. 6 illustrates the dose-effect curves obtained for the tested Maver-I cell line (B cell
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`lymphoma, mantle) using combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1 ")
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`and the PBK-8 inhibitor of Formula (IX) ("Inh.3"). The y-axis ("Effect") is given in units of Fa
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`(fraction affected) and the x-axis ("Dose") is given in linear units of µM.
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`[0022] FIG. 7 illustrates the dose-effect curves obtained for the tested Jeko cell line (B cell
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`lymphoma, mantle) using combined dosing of the BTK inhibitor of Formula (XVIII) ("Inh.1 ")
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`and the PBK-8 inhibitor of Formula (IX) ("Inh.3"). The y-axis ("Effect") is given in units of Fa
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`(fraction affected) and the x-axis ("Dose") is given in linear units of µM.
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`[0023] FIG. 8 illustrates the dose-effect curves obtained for the tested CCRF cell line (B
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`lymphoblast, acute lymphoblastic leukemia) using combined dosing of the BTK inhibitor of
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`Formula (XVIII) ("Inh.1") and the PBK-8 inhibitor of Formula (IX) ("Inh.3"). The y-axis
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`("Effect") is given in units of Fa (fraction affected) and the x-axis ("Dose") is given in linear
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`units of µM.
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`[0024] FIG. 9 illustrates the dose-effect curves obtained for the tested SUP-B15 cell line (B
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`lymphoblast, acute lymphoblastic leukemia) using combined dosing of the BTK inhibitor of
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`Formula (XVIII) ("Inh.1") and the PBK-8 inhibitor of Formula (I