( 12 ) United States Patent
`Sampath et al .
`
`( 10 ) Patent No .: US 10,993,942 B2
`( 45 ) Date of Patent :
`* May 4 , 2021
`
`US010993942B2
`
`( 72 )
`
`( 54 ) COMBINATION THERAPY OF A TYPE II
`ANTI - CD20 ANTIBODY WITH A SELECTIVE
`BCL - 2 INHIBITOR
`( 71 ) Applicants : GENENTECH , INC . , South San
`Francisco , CA ( US ) ; HOFFMANN - LA
`ROCHE INC . , Little Falls , NJ ( US ) ;
`ABBVIE INC . , North Chicago , IL ( US )
`Inventors : Deepak Sampath , South San Francisco ,
`CA ( US ) ; Christian Klein , Iffeldorf
`( DE ) ; Wayne John Fairbrother , South
`San Francisco , CA ( US ) ; Sari L.
`Heitner Enschede , River Forest , IL
`( US ) ; Rod A. Humerickhouse ,
`Highland Park , IL ( US ) ; Andrew W.
`Roberts , Melbourne ( AU ) ; John F.
`Seymour , Melbourne ( AU )
`( 73 ) Assignees : GENENTECH , INC . , South San
`Francisco , CA ( US ) ; HOFFMANN - LA
`ROCHE INC . , Little Falls , NJ ( US ) ;
`ABBVIE INC . , North Chicago , IL ( US )
`Subject to any disclaimer , the term of this
`patent is extended or adjusted under 35
`U.S.C. 154 ( b ) by 0 days .
`This patent is subject to a terminal dis
`claimer .
`( 21 ) Appl . No .: 16 / 827,650
`( 22 ) Filed :
`Mar. 23 , 2020
`( 65 )
`Prior Publication Data
`Aug. 13 , 2020
`US 2020/0253963 A1
`Related U.S. Application Data
`( 63 ) Continuation of application No. 15 / 365,595 , filed on
`Nov. 30 , 2016 , which is a continuation of application
`No. 14 / 020,761 , filed on Sep. 6 , 2013 , now Pat . No.
`9,539,251 .
`( 60 ) Provisional application No. 61 / 698,379 , filed on Sep.
`7 , 2012
`
`( * ) Notice :
`
`( 51 )
`
`( 52 )
`( 58 )
`
`( 56 )
`
`Int . Cl .
`( 2006.01 )
`A61K 31/496
`( 2006.01 )
`A61P 35/02
`A61P 35/00
`( 2006.01 )
`U.S. CI .
`A61K 31/496 ( 2013.01 )
`???
`Field of Classification Search
`A61K 31/496
`???
`424 / 133.1
`USPC
`See application file for complete search history .
`References Cited
`U.S. PATENT DOCUMENTS
`
`7,767,684 B2
`8,173,811 B2
`8,546,399 B2
`
`8/2010 Bruncko et al .
`5/2012 Bruncko et al .
`10/2013 Bruncko et al .
`
`11/2015 Bruncko et al .
`9,174,982 B2
`1/2017 Sampath et al .
`9,539,251 B2
`2005/0123546 Al
`6/2005 Umana et al .
`3/2008 Elmore et al .
`2008/0076779 Al
`4/2009 Friess et al .
`2009/0098118 A1
`2010/0305122 A1
`12/2010 Bruncko et al .
`2012/0028925 A1
`2/2012 Tao et al .
`4/2014 Bruncko et al .
`2014/0113910 Al
`FOREIGN PATENT DOCUMENTS
`WO 2005044859 A2
`5/2005
`12/2010
`WO 2010138588 A2
`
`WO
`WO
`
`OTHER PUBLICATIONS
`Obinutuzumab_GA101 - MeSH - NCBI ( Sep. 7 , 2009 ) . *
`Bottcher et al . , 2012 , “ Minimal residual disease quantification is an
`independent predictor of progression - free and overall survival in
`chronic lymphocytic leukemia : a multivariate analysis from the
`randomized GCLLSG CLL8 trial , ” J Clin Oncol . , 30 ( 9 ) : 980-988 .
`Busken et al . , 2003 , Digestive Disease Week Abstracts and Itinerary
`Planner , 2003 , abstract No. 850 .
`Czuczman et al . , 2010 , “ The future of CD20 monoclonal antibody
`therapy in B - cell malignancies ” , Leukemia & Lymphoma , 51 ( 6 ) : 983
`994 .
`Davids et al . , 2012 , “ Targeting the B - cell lymphoma / leukemia 2
`family in cancer , ” J Clin Oncol . , 30 ( 25 ) : 3127-3135 .
`Flinn et al . , 2014 , “ Preliminary Results of a Phase 1b Study
`( GP28331 ) Combining GDC - 0199 ( ABT - 199 ) and Obinutuzumab
`in Patients with Relapsed / Refractory or Previously Untreated Chronic
`Lymphocytic Leukemia , ” Blood , 124 ( 21 ) .
`Hallek et al . , 2008 , “ Guidelines for the diagnosis and treatment of
`chronic lymphocytic leukemia : a report from the International
`Workshop on Chronic Lymphocytic Leukemia updating the National
`Cancer Institute - Working Group 1996 guidelines , ” Blood , 111 ( 12 ) : 5446
`5456 and Errata , Blood , 2008 , 112 ( 13 ) : 5259 .
`Hallek et al . , 2010 , “ Addition of rituximab to fludarabine and
`cyclophosphamide in patients with chronic lymphocytic leukaemia :
`a randomised , open - label , phase 3 trial , ” Lancet , 376 ( 9747 ) : 1164
`1174 .
`Herting et al . , 2010 , “ Enhanced Activity of GA101 , a Novel Type
`II , Glycoengineered CD20 Antibody , In Combination with
`Bendamustine or Fludarabine , and with the Bcl - 2 Family Inhibitors
`ABT - 737 or ABT - 263 , ” Blood , 116 ( abstract # 3915 ) : 1-2 .
`Howard et al . , 2011 , “ The tumor lysis syndrome , " N Engl J Med . ,
`364 ( 19 ) : 1844-1854 .
`International Search Report for International Patent Application No.
`PCT / US2013 / 058557 completed on Oct. 24 , 2013 ( 4 pages ) .
`Kaiser , 2006 , “ Cancer . First pass at cancer genome reveals complex
`landscape " , Science , 313 ( 5792 ) : 1370 .
`Kaplan et al . , 1958 , “ Nonparametric Estimation from Incomplete
`Observations , ” Journal of the American Statistical Association ,
`53 ( 282 ) : 457-481 .
`
`( Continued )
`Primary Examiner Yan Xiao
`( 74 ) Attorney , Agent , or Firm — Jones Day
`( 57 )
`ABSTRACT
`The present invention is directed to a combination therapy
`involving a type II anti - CD20 antibody and a selective Bcl - 2
`inhibitor for the treatment of a patient suffering from cancer ,
`particularly , a CD20 - expressing cancer .
`30 Claims , 5 Drawing Sheets
`Specification includes a Sequence Listing .
`
`DRL EXHIBIT 1001 PAGE 1
`
`DRL EXHIBIT 1001 PAGE 1
`
`

`

`US 10,993,942 B2
`Page 2
`
`( 56 )
`
`References Cited
`
`OTHER PUBLICATIONS
`Laprevotie et al . , 2013 ,
`“ Recombinant human IL - 15 trans
`presentation by B leukemic cells from chronic lymphocytic leuke
`mia induces autologous NK cell proliferation leading to improved
`anti - CD20 immunotherapy , ” J Immunol . , 191 ( 7 ) : 3634-3640 with
`supplemental data .
`Macauley et al . , 2012 , “ American Association for Cancer Research
`( AACR ) , 103rd , Annual meeting Chicago , Illinois , ” ( Mar. 31 - Apr .
`4 , 2012 ) , Drugs of the Future 2012 Prous Science ESP , 37 : 6 : 451
`455 .
`Mossner et al . , 2010 , “ Increasing the efficacy of CD20 antibody
`therapy through the engineering of a new type II anti - CD20 anti
`body with enhanced direct and immune effector cell - mediated
`B - cell cytotoxicity ” , Blood , 115 ( 22 ) : 4393-4402 .
`Rawstron et al . , 2007 , “ International standardized approach for flow
`cytometric residual disease monitoring in chronic lymphocytic
`leukaemia , ” Leukemia , 21 ( 5 ) : 956-964 .
`Sampath et al . , 2013 ,
`“ Abstract A245 : Combination of the
`glycoengineered Type II CD20 antibody obinutuzumab ( GA101 ) ,
`and the novel Bcl - 2 selective inhibitor , ABT - 199 ( GDC - 0199 ) ,
`results in superior in vitro and in vivo anti - tumor activity in models
`of B - cell malignancies , ” Mol Cancer Ther , 12 ( 11 Suppl ) .
`Sampath et al . , 2013 , “ Combination of the glycoengineered Type II
`CD20 antibody obinutuzumab ( GA101 ) and the novel Bcl - 2 selec
`tive Inhibitor GDC - 0199 Results in superior In Vitro and In Vivo
`Anti - tumor activity in models of B - Cell Malignancies , ” Blood ,
`122 ( 21 ) .
`Souers et al . , 2013 ,
`“ ABT - 199 , a potent and selective BCL - 2
`inhibitor , achieves antitumor activity while sparing platelets , ” Nat
`Med . , 19 ( 2 ) : 202-208 .
`Taber's Cyclopedic Medical Dictionary , 1985 , F.A. Davis Com
`pany , Philadelphia , p . 274 .
`
`“ Models for Prevention and Treatment of
`Aggarwal et al . , 2009 ,
`Cancer : Problems vs Promises , ” Biochem Pharmacol . , vol . 78 , issue
`No. 9 , pp . 1083-1094 ( Author Manuscript version ) ( 27 pages ) .
`Davids et al . , 2013 ,
`“ ABT - 199 : Taking Dead Aim at BCL - 2 , "
`Cancer Cell , vol . 23 , pp . 139-141 .
`Troy , 2009 , “ The End of Medical Miracles ? ” The Wall Street
`Journal , updated Jun . 1 , 2009 , [ retrieved on Jun . 12 , 2016 ] . Retrieved
`from the Internet < URL : http://www.wsj.com/articles/
`SB124389153780873939 > ( 9 pages ) .
`Davids et al . , 2012 , “ The BCL - 2 - Specific BH3 - Mimetic ABT - 199
`( GDC - 0199 ) Is Active and Well - Tolerated in Patients with Relapsed
`Non - Hodgkin Lymphoma : Interim Results of a Phase I Study , ”
`Meeting Abstract , 54th ASH Annual Meeting , Nov. 16 , 2012 ,
`Blood , 120 ( 21 ) : Abstract 304 ( 3 pages ) .
`Elmore , 2012 ,
`“ AVT - 199 : A Potent and Selective Bel - 2 Inhibitor , "
`Presentation , Session “ New Drugs on the Horizon 2 , ” Apr. 1 , 2012 ,
`American Association for Cancer Research ( AACR ) 103rd Annual
`Meeting ( Chicago , IL ) ( 35 pages ) .
`Roberts et al . , 2012 ,
`" Selective Inhibition of BCL - 2 is Active
`Against Chronic Lymphocytic Leukemia ( CLL ) : First clinical Expe
`rience with the BH3 - Mimetic ABT - 199 , ” Meeting Abstract , 17th
`Congress of the European Hematology Association , Jun . 2012 ,
`Haematologica , 97 ( sl ) : Abstract 0546 on pp . 219-220 ( 5 pages ) .
`Roberts et al . , 2012 ,
`“ Selective Inhibition of BCL - 2 is Active
`Against Chronic Lymphocytic Leukemia ( CLL ) : First Clinical
`Experience with the BH3 - Mimetic ABT - 199 ( GDC - 0199 ) , ” Presen
`tation , Jun . 16 , 2012 , 17th Congress of the European Hematology
`Association ( Amsterdam , The Netherlands ) ( 30 pages ) .
`Seymour et al . , 2012 , “ The BCL - 2 - Specific BH3 - Mimetic ABT - 199
`( GDC - 0199 ) Is Active and Well - Tolerated in Patients with Relapsed /
`Refractory Chronic Lymphocytic Leukemia : Interim Results of a
`Phase I First - in - Human Study , ” Meeting Abstract , 54th ASH Annual
`Meeting , Nov. 16 , 2012 , Blood , 120 ( 21 ) : Abstract 3923 ( 3 pages ) .
`Prescribing Information for VENCLEXTA ( venetoclax ) tablets , for
`oral use , Apr. 2016 ( 25 pages ) .
`Prescribing Information for VENCLEXTA ( venetoclax ) tablets , for
`oral use , revised Jul . 2019 ( 49 pages ) .
`* cited by examiner
`
`DRL EXHIBIT 1001 PAGE 2
`
`DRL EXHIBIT 1001 PAGE 2
`
`

`

`U.S. Patent
`
`May4, 2021
`
`Sheet 1 of 5
`
`US 10,993,942 B2
`
`FIG1
`
`~@— AS Vihicie Saline} + Vehicle (80%Phasai}
`weee SY GAT, Imig/kg
`weg CP GDCHNSS, 1Obmas/kg
`ow OH GAT imos/kg + GDC-O199. 1o0mikg
`
`S886
`
`2S
`
`2RER
`
`yee b
`
`HRE
`
`
`
`(rom) a*
`
`
`FittedTamorVolume
`
`APP
`
`oe eoce ale
`Be ie adhe ec net ae ghee
`
`” ere
`
`BE
`
`Baarrattiahanintiaantiniaadiaantinntiantandaactiaadanctunadaundnadaatiuantanuiaaabaandaabaaianataadaandaashanshanstagad
`BSS
`48
`‘
`a3
`'
`38
`a
`a
`
`
`BEDI
`BOOS
`
`Day
`
`DRL EXHIBIT 1001 PAGE 3
`
`DRL EXHIBIT 1001 PAGE 3
`
`DRL EXHIBIT 1001 PAGE 3
`
`

`

`U.S. Patent
`
`May 4 , 2021
`
`Sheet 2 of 5
`
`US 10,993,942 B2
`
`FIG 2
`
`Schedule A Dosing Schema : GDC - 0199 Step - Up Dosing for
`Three Weeks Before Starting Obinutuzumab
`
`GDC - 0199
`
`Escalaton
`
`Obinutuzumab administration : W4 ( C1022 ) , W5 ( C2D1 ) , W6 ( C2D8 ) , W9 ( C3D1 ) , W13 ( C4D1 ) ,
`W17 ( C501 ) , W21 ( C6D1 ) and W25 ( 0701 )
`A GDC - 0199 50 mg dose ( starting dose ) : W1 ( C1D1 through C107 )
`O GDC - 0199 100 mg dose : W2 ( C1D8 through C1D15 )
`O GDC - 0199 300 mg dose ( ending dose ) : W3 ( C1D16 ) through W28 ( C7D28 )
`
`C - cycle ; D - day ; W - week .
`
`DRL EXHIBIT 1001 PAGE 4
`
`DRL EXHIBIT 1001 PAGE 4
`
`

`

`U.S. Patent
`
`May 4 , 2021
`
`Sheet 3 of 5
`
`US 10,993,942 B2
`
`FIG 3
`Schedule B Dosing Schema : Obinutuzumab Administered
`Before GDC - 0199 Dose - Escalation
`
`Cohort 1
`
`C2
`
`W13
`
`Escalation
`
`W202
`Obing zumab administration : W1 ( C1 , split dose on D1 and D2 ) , W2 ( C108 ) , W3 ( C1D15 ) , z
`W5 ( C2D1 ) , W9 ( C301 ) , W13 ( C401 ) , W17 ( C501 ) , and W21 ( C6D1 )
`A GDC - 0199 50 mg dose ( starting dose ) : W2 ( C1D9 through C1D14 )
`GDC - 0199 100 mg dose : W3 ( C1015 through C1021 )
`O GDC - 0199 300 mg dose ( ending dose ) : W4 ( C1D22 ) through W24 ( C6D28 )
`
`Cohort 2
`
`GDC - 0199
`
`CS
`
`Escalation
`W2D2
`Obinutuzumab administration : W1 ( C1 , split dose on D1 and 02 ) , W2 ( C108 ) , W3 ( C1D15 ) .
`W5 ( C2D1 ) , W9 ( C3D1 ) , W13 ( C4D1 ) , W17 ( C501 ) , and W21 ( C6D1 )
`GDC - 0199 100 mg dose ( starting dose ) : W2 ( C109 through C1D14 )
`GDC - 0199 300 mg dose ( ending dose ) : W3 ( C1015 ) through W24 ( C6D28 )
`Cohort 3
`
`W9
`
`W13
`
`GDC - 0199
`Dose
`Escalation
`W2D2
`Obinutuzumab administration : W1 ( C1 , split dose on D1 and D2 ) , W2 ( C1D8 ) , W3 ( C1D15 ) , W5 ( C201 ) ,
`W9 ( C3D1 ) , W13 ( C401 ) , W17 ( C5D1 ) , and W21 ( C6D1 )
`O GDC - 0199 300 mg dose : W2 ( C109 ) through W24 ( C6028 )
`
`W21
`
`C - cycle ; D - day ; W week .
`Schedule B includes approximately three dosing cohorts to be enrolled sequentially .
`
`DRL EXHIBIT 1001 PAGE 5
`
`DRL EXHIBIT 1001 PAGE 5
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`

`

`U.S. Patent
`
`May 4 , 2021
`
`Sheet 4 of 5
`
`US 10,993,942 B2
`
`36
`
`34
`
`32
`
`30
`
`28
`
`26
`
`24
`
`22
`
`20
`
`18
`
`16
`
`
`
`
`
`Tumor volume ; Median and Inter Quartile Range ; n = 9-10
`
`
`
`
`
`RO5072759 ; 1mg / kg .p .; Day 18 , 25 , 32 Rituximab ; 1mg / kg 1.p .; Day 18 , 25 , 32
`GDC - 0199 ; 100mg / kg p.o .; Day 18 - 34
`+ - GDC - 0199 ; 100mg / kg p.o .; Day 18 - 34
`
`RO5072759 ; 1mg / kg 1.p. , Day 18 , 25 , 32
`Rituximab ; 1mg / kg i.p .; Day 18 , 25 , 32
`GDC - 0199 ; 100mg / kg p.o .; Day 18 34
`
`
`
`Vehicle i.p.
`
`MO
`
`4500
`
`4000
`
`3500
`
`1500
`
`1000
`
`500
`
`3000
`) ( mm3
`
`2500
`2000
`
`TV
`
`
`FIG . 4
`
`
`
`
`
`Day after tumor cell inoculation
`
`
`
`
`
`DRL EXHIBIT 1001 PAGE 6
`
`DRL EXHIBIT 1001 PAGE 6
`
`

`

`U.S. Patent
`
`May 4 , 2021
`
`Sheet 5 of 5
`
`US 10,993,942 B2
`
`FIG 5
`
`4000 © Control
`GA - 101 1mg / kg , QWX3
`GDC - 0199 100mg / kg , QDX21
`GA101 + GDC - 0199 QDX21
`GA101 + GDC - 0199 QDX45
`
`3000
`
`
`
`
`
`Fitted Tumor Volume ( mm )
`
`2000
`
`1000
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`Day
`GA - 101 + GDC - 0199
`
`GA - 101 + GDC - 0199 > GDC - 0199 only
`
`DRL EXHIBIT 1001 PAGE 7
`
`DRL EXHIBIT 1001 PAGE 7
`
`

`

`US 10,993,942 B2
`
`1
`2
`ized B - Lyl antibodies , effectively initiate target cell death
`COMBINATION THERAPY OF A TYPE II
`via caspase - independent apoptosis with concomitant phos
`ANTI - CD20 ANTIBODY WITH A SELECTIVE
`phatidylserine exposure .
`BCL - 2 INHIBITOR
`The shared common features of type I and type II anti
`This application is a continuation of U.S. patent applica- 5 CD20 antibodies are summarized in Table 1 below .
`tion Ser . No. 15 / 365,595 , filed Nov. 30 , 2016 , which is a
`continuation of application Ser . No. 14 / 020,761 , filed Sep. 6 ,
`TABLE 1
`2013 , now U.S. Pat . No. 9,539,251 , which claims priority to
`Properties of type I and type II anti - CD20 antibodies
`U.S. Provisional No. 61 / 698,379 , filed Sep. 7 , 2012 , the
`content of which is incorporated herein by reference in its
`type I anti - CD20 antibodies
`entirety .
`type I CD20 epitope
`Incorporated herein by reference is the Sequence Listing
`Localize CD20 to lipid rafts
`Increased CDC ( if IgG1 isotype )
`being concurrently submitted via EFS - Web as an ASCII text
`ADCC activity ( if IgG1 isotype )
`file named “ 12655-152-999_SEQ_LISTING ” , created Mar.
`Full binding capacity
`23 , 2020 , and being 9,834 bytes in size .
`Homotypic aggregation
`Apoptosis induction upon
`TECHNICAL FIELD
`cross - linking
`
`type II anti - CD20 antibodies
`type II CD20 epitope
`Do not localize CD20 to lipid rafts
`Decreased CDC ( if IgG1 isotype )
`ADCC activity ( if IgG1 isotype )
`Reduced binding capacity
`Stronger homotypic aggregation
`Strong cell death induction without
`cross - linking
`
`10
`
`15
`
`The present invention is directed to a combination therapy 20
`involving a type II anti - CD20 antibody and a selective Bcl - 2
`inhibitor for the treatment of a patient suffering from cancer ,
`particularly a CD20 - expressing cancer .
`BACKGROUND
`
`The Bcl - 2 family of proteins regulates programmed cell
`death triggered by developmental cues and in response to
`multiple Stress signals ( Cory . S. , and Adams , J. M. , Nature
`Reviews Cancer 2 ( 2002 ) 647-656 ; Adams , Genes and
`Development 17 ( 2003 ) 2481-2495 ; Danial , N. N. , and
`25 Korsmeyer , S. J. , Cell 116 ( 2004 ) 205-219 ) . Whereas cell
`survival is promoted by Bcl - 2 itself and several close
`relatives ( Bcl - xL , Bel - W , Mcl - 1 and Al ) , which bear three or
`The CD20 molecule ( also called human B - lymphocyte-
`tour conserved Bcl - 2 homology ( BH ) regions , apoptosis is
`restricted differentiation antigen or Bp35 ) is a hydrophobic
`driven by two other sub - families . The initial signal for cell
`transmembrane protein with a molecular weight of approxi-
`mately 35 kD located on pre - B and mature B lymphocytes 30 death is conveyed by the diverse group of BH3 - only pro
`( Valentine , M. A. , et al . , J. Biol . Chem . 264 ( 19 ) ( 1989 )
`teins , including Bad , Bid , Bim , Puma and Noxa , which have
`11282-11287 ; and Einfield , D. A. , et al . EMBO J. 7 ( 3 )
`in common only the small BH3 interaction domain ( Huang
`ser , Cell 103 ( 2000 ) 839-842 ) . How er , Bax or
`and
`( 1988 ) 711-717 ) . CD20 is found on the surface of greater
`Bak , multi - domain proteins containing BH1 - BH3 , are
`than 90 % of B cells from peripheral blood or lymphoid
`organs and is expressed during early pre - B cell development 35 required for commitment to cell death ( Cheng , et al . ,
`Molecular Cell 8 ( 2001 ) 705-711 ; Wei , M. C. , et al . , Science
`and remains until plasma cell differentiation . CD20 is pres
`292 ( 2001 ) 727-730 ; Zong , W. X. , et al . , Genes and Devel
`ent on both normal B cells as well as malignant B cells . In
`opment 15 148 ( 2001 ) 1-1486 ) . When activated , they can
`particular , CD20 is expressed on greater than 90 % of B cell
`permeabilize the outer membrane of mitochondria and
`non - Hodgkin's lymphomas ( NHL ) ( Anderson , K. C. , et al . , 40 release pro - apoptogenic factors ( e.g. cytochrome C ) needed
`Blood 63 ( 6 ) ( 1984 ) 1424-1433 ) but is not found on hema
`to activate the caspases that dismantle the cell ( Wang , K. ,
`topoietic stem cells , pro - B cells , normal plasma cells , or
`Genes and Development 15 ( 2001 ) 2922-2933 ; ( Adams ,
`other normal tissues ( Tedder , T. F. , et al . , J , Immunol . 135 ( 2 )
`2003 supra ) ; Green , D. R. , and Kroemer , G. , Science 305
`( 1985 ) 973-979 ) .
`( 2004 ) 626-629 ) .
`The 85 amino acid carboxyl - terminal region of the CD20
`Interactions between members of these three factions of
`45
`protein is located within the cytoplasm . The length of this
`the Bcl - 2 family dictate whether a cell lives or dies . When
`region contrasts with that of other B cell - specific surface
`BH3 - only proteins have been activated , for example , in
`structures such as IgM , IgD , and IgG heavy chains or
`response to DNA damage , they can bind via their BH3
`histocompatibility antigens class II a or chains , which have
`domain to a groove on their pro - survival relatives ( Sattler , et
`relatively short intracytoplasmic regions of 3 , 3 , 28 , 15 , and 50 al . , Science 275 ( 1997 ) 983-986 ) . How the BH3 - only and
`16 amino acids , respectively ( Komaromy , M. , et al . , NAR 11
`Bcl - 2 - like proteins control the activation of Bax and Bak ,
`( 1983 ) 6775-6785 ) . Of the last 61 carboxyl - terminal amino
`however , remains poorly understood ( Adams , 2003 supra ) .
`acids , 21 are acidic residues , whereas only 2 are basic ,
`Most attention has focused on Bax . This soluble monomeric
`indicating that this region has a strong net negative charge .
`protein ( Hsu , Y. T. , et al . , Journal of Biological Chemistry
`The GenBank Accession No. is NP - 690605 . It is thought 55 272 ( 1997 ) 13289-13834 ; Wolter , K. G. , et al . , Journal of
`that CD20 might be involved in regulating an early step ( s )
`Cell Biology 139 ( 1997 ) 1281-92 ) normally has its mem
`in the activation and differentiation process of B cells
`brane targeting domain inserted into its groove , probably
`( Tedder . T. et al . , Eur . J. Immunol . 16 ( 1986 ) 881-887 ) and
`accounting for its cytosolic localization ( Nechushtan , A. , et
`could function as a calcium ion channel ( Tedder , T. F. , et al . ,
`al . , EMBO Journal 18 ( 1999 ) 2330-2341 ; Suzuki , et al . , Cell
`60 103 ( 2000 ) 645-654 ; Schinzel , A. , et al . , J Cell Biol 164
`J. Cell . Biochem . 14D ( 1990 ) 195 ) .
`There exist two different types of anti - CD20 antibodies
`( 2004 ) 1021-1032 ) . Several unrelated peptides / proteins
`which differ significantly in their mode of CD20 binding and
`have been proposed to modulate Bax activity , reviewed in
`biological activities ( Cragg , M. S. , et al . , Blood 103 ( 2004 )
`Lueken - Ardjomande , S. , and Martinou , J. C. , J Cell Sci 118
`2738-2743 ; and Cragg , M. S. , et al . , Blood 101 ( 2003 )
`( 2005 ) 473-483 , but their physiological relevance remains to
`1045-1052 ) . Type I antibodies , as e.g. rituximab , are potent 65 be established . Alternatively , Bax may be activated via
`in complement mediated cytotoxicity , whereas type II anti-
`direct engagement by certain BH3 - only proteins ( Lucken
`bodies , as e.g. Tositumoinab ( B1 ) , 11B8 , AT80 or human-
`Ardjomande , S. , and Martinou . J. C , 2005 supra ) , the best
`
`DRL EXHIBIT 1001 PAGE 8
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`DRL EXHIBIT 1001 PAGE 8
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`US 10,993,942 B2
`
`3
`4
`In an embodiment , the type II anti - CD20 antibody has
`documented being a truncated form of Bid , tBid ( Wei , M. C. ,
`increased antibody dependent cellular cytotoxicity ( ADCC ) .
`et al . , Genes und Development 14 ( 2000 ) 2060-2071 ;
`In an embodiment , at least 40 % of the oligosaccharides of
`Kuwana , T. , et al . , Cell 111 ( 2002 ) 331-342 ; Roucou , X. , et
`the Fc region of said type II anti - CD20 antibody are non
`al . , Biochemical Journal 368 ( 2002 ) 915-921 ; Callum , P. F. ,
`et al . , Mol Cell 16 ( 2004 ) 807-818 ) . As discussed elsewhere 5 fucosylated .
`( Adams 2003 supra ) , the oldest model , in which Bcl - 2
`In an embodiment , the selective Bcl - 2 inhibitor is GDC
`directly engages Bax ( Oltvai , Z. N. , et al . , Cell 74 ( 1993 )
`0199 ( also known as ABT - 199 ) , or a pharmaceutically
`609-619 ) , has become problematic because Bcl - 2 is mem acceptable salt thereof .
`In an embodiment , the cancer is a non - solid tumor .
`brane bound while Bax is cytosolic , and their interaction
`In certain embodiments , methods are provided for the
`seems highly dependent on the detergents used for cell lysis
`treatment of a cancer in a human in need thereof comprising
`( Hsu , Y. T. , and Youle , 1997 supra ) . Nevertheless , it is well
`administering to said human a GA101 antibody and / or
`established that the BH3 region of Bax can mediate asso
`GDC - 0199 in multiple dosing cycles . In an embodiment ,
`ciation with Bcl - 2 ( Zha , H. , and Reed , J. , Journal of Bio
`each dosing cycle of the multiple dosing cycle is for at least
`logical Chemistry 272 ( 1997 ) 31482-88 ; Wang , K. , et al . , 15 1 week . In an embodiment , each dosing cycle of the multiple
`Molecular and Cellular Biology 18 ( 1998 ) 6083-6089 ) and
`dosing cycle is for at 2 , for at least 3 , for at least 4 , for at least
`that Bcl - 2 prevents the oligomerization of Bax , even though
`5 , or for at least 6 weeks .
`no heterodimers can be detected ( Mikhailov , V. , et al . ,
`In an embodiment wherein the GA101 antibody and
`Journal of Biological Chemistry 276 ( 2001 ) 18361-18374 ) .
`GDC - 0199 are administered to the human in multiple dosing
`Thus , whether the pro - survival proteins restrain Bax activa- 20 cycles , GA101 antibody can , for example , be administered
`tion directly or indirectly remains uncertain .
`once per dosing cycle for one or more dosing cycles of the
`Although Bax and Bak seem in most circumstances to be
`multiple dosing cycles . The amount of GA101 administered
`functionally equivalent ( Lindsten . T. , et al . , Molecular Cell
`per dose can , for example , be between about 300 mg to
`6 ( 2000 ) 1389-1399 ; Wei . M. C. , et al . , 2001 supra ) , sub-
`about 3000 mg , or between about 500 mg to about 3000 mg ,
`stantial differences in their regulation would be expected 25 or about 500 mg to about 1200 mg .
`from their distinct localization in healthy cells . Unlike Bax ,
`In an embodiment wherein the GA101 antibody and
`which is largely cytosolic , Bak resides in complexes on the
`GDC - 0199 are administered to the human in multiple dosing
`outer membrane of mitochondria and on the endoplasmic
`cycles , GDC - 0199 can , for example , be administered each
`reticulum of healthy cells ( Wei , M. C. , et al . , 2000 supra ;
`day in a dosing cycle for one or more dosing cycles of the
`Zong , W. X. , et al . , Journal of Cell Biology 162 ( 2003 ) 30 multiple dosing cycles . In an embodiment , GDC - 0199 is
`59-69 ) . Nevertheless , on receipt of cytotoxic signals , both
`administered in fewer than all of the days of the initial
`Bax and Bak change conformation , and Bax translocates to
`dosing cycle , and is administered each day of the dosing
`the organellar membranes , where both Bax and Bak then
`cycles of the multiple dosing cycles that follow the initial
`form homo - oligomers that can associate , leading to mem-
`dosing cycle . The amount of GDC - 0199 administered per
`brane permeabilization ( Hsu , Y. T. , et al . , PNAS 94 ( 1997 ) 35 day can be between about 10 mg to about 1,000 mg , about
`3668-3672 ; Wolter , K. G. , et al . , 1997 supra ; Antonsson , B. ,
`20 mg to about 800 mg , about 20 mg to about 500 mg , or
`et al . , journal of Biological Chemistry 276 ( 2001 ) 11615-
`between about 50 mg to about 300 mg .
`11623 ; Nechushtan , A. , et al . , Journal of Cell Biology 153
`In an embodiment , both the GA101 antibody and GDC
`( 2001 ) 1265-1276 ; Wei , M. C. , et al . , 2001 supra ; Mikhailov ,
`0199 are administered to the patient in at least 2 , 3 , 4 , 5 , 6 ,
`V. , et al . , Journal of Biological Chemistry 278 ( 2003 ) 40 7 , 8 , or more than 8 , dosing cycles of the multiple dosing
`cycles .
`5 : 367-5376 ) .
`There exist various Bcl - 2 inhibitors , which all have the
`In certain embodiments of the methods provided for the
`same property of inhibiting prosurvival members of the
`treatment of a cancer in a human in need thereof comprising
`Bcl - 2 family of proteins and are therefore promising candi-
`administering to said human both a GA101 antibody and
`dates for the treatment of cancer . Such Bcl - 2 inhibitors are 45 GDC - 0199 in multiple dosing cycles , following the last
`e.g. Oblimersen , SPC - 2996 , RTA - 402 , Gossypol , AT - 101 ,
`dosing cycle of multiple dosing cycles , GDC - 0199 alone can
`Obatoclax mesylate , A - 371191 , A - 385358 , A - 438744 , ABT-
`be administered to the human in the absence of the GA101
`737 , ABT - 263 , AT - 101 , BL - 11 , BL - 193 , GX - 15-003 ,
`antibody , or the GA101 antibody alone can be administered
`2 - Methoxyantimyein A3 , HA - 14-1 , KF - 67544 , Purpurogal-
`to the patient in the absence of GDC - 0199 . For instance ,
`lin , TP - TW - 37 , YC - 137 and Z - 24 , and are described e.g. in 50 when GDC - 0199 is administered alone to the human ( e.g. ,
`Zhai , D. , et al . , Cell Death and Differentiation 13 ( 2006 )
`following the last cycle of multiple dosing cycles wherein
`both GDC - 0199 and the GA101 antibody are administered
`1419-1421 .
`Smith , M. R. , et al , Molecular Cancer Therapeutics 3 ( 12 )
`to the human ) , GDC - 0199 can be administered to the human
`( 2004 ) 1693-1699 and Ramanarayanan , J. et al . , British
`for at least 3 , 4 , 5 , 6 , 7 , 8 or 9 days , or for 10 or more days ,
`Journal of Haematology 127 ( 5 ) ( 2004 ) 519-530 , refer to a 55 for 20 or more days , or for 30 or more days .
`combination of a type I anti - CD20 antibody ( rituximab ) with
`In yet another embodiment of the methods provided
`antisense Bcl - 2 oligonucleotides ( Oblimersen ) .
`wherein a GA101 antibody and GDC - 0199 are administered
`to the patient in multiple dosing cycles , the multiple dosing
`cycles comprise an escalating dosing cycle in which GDC
`SUMMARY OF THE INVENTION
`60 0199 is administered to the patient in escalating daily dose
`amounts during the escalating dosing cycle .
`Provided herein are methods for the treatment of a patient
`suffering from cancer , comprising co - administering , to a
`patient in need of such treatment , a type II anti - CD20
`DESCRIPTION OF THE FIGURES
`antibody and a selective Bcl - 2 inhibitor . The co - administra
`tion may be simultaneous or sequential in either order .
`An example of the type II anti - CD20 antibody for use in
`the present invention is a GA101 antibody .
`
`FIG . 1. Antitumor activity of combined treatment of a
`type II anti - CD20 antibody ( GA101 antibody , in this case ,
`obinutuzumab ) with a Bcl - 2 inhibitor ( ABT - 199 , a.k.a.
`
`10
`
`65
`
`DRL EXHIBIT 1001 PAGE 9
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`DRL EXHIBIT 1001 PAGE 9
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`

`

`US 10,993,942 B2
`
`20
`
`5
`6
`pharmaceutically acceptable salt thereof for 1 , 2 , 3 , 4 , 5 , 6 ,
`GDC - 0199 ) . Arrows and line under the x - axis indicates the
`or 7 days , followed by co - administering an effective amount
`days of dosing of GA101 and GDC - 0199 , respectively .
`of said GA101 antibody antibody and 2- ( 1H - pyrrolo [ 2,3 - b ]
`FIG . 2. Exemplary dosing schedule for administering
`pyridin - 5 - yloxy ) -4- ( 4- ( 2- ( 4 - chlorophenyl ) -4,4 - dimethyl
`GDC - 199 with obinutuzumab .
`FIG . 3. Exemplary dosing schedule for administering 5 cyclohex - l - enyl ) methyppiperazin - 1 - yl ) -N- ( 3 - nitro - 4 - ( ( tet
`rahydro - 2H - pyran - 4 - yl ) methylamino ) phenylsulfonyl )
`GDC - 199 with obinutuzumab .
`FIG . 4. Antitumor activities of a type II anti - CD20
`benzamide or a pharmaceutically acceptable salt thereof for
`antibody ( obinutuzumab , a.k.a. RO5072759 ) used alone or
`one or more dosing periods .
`in combination with GDC - 0199 , and of a type I anti - CD20
`The present invention also relates to a method fir the
`antibody ( rituximab ) used alone or in combination with 10 treatment of a human in need thereof comprising adminis
`GDC - 0199 on human Z138 mantle cell lymphoma cells .
`tering an effective amount of said GA101 antibody once
`FIG . 5. Results from xenograft model of aggressive
`every dosing period for 1 , 2 , 3 , 4 , 5 or 6 cycles , followed by
`lymphoma demonstrating that single agent treatment with
`co - administering an effective amount of said GA101 anti
`GDC - 0199 following combination of GDC - 0199 with type
`body antibody once every dosing period and 2- ( 1H - pyrrolo
`II anti - CD20 antibody ( GA101 antibody , in this case , obinu- 15 [ 2,3 - b ] pyridin - 5 - yloxy ) -4- ( 4 - ( ( 2- ( 4 - chlorophenyl ) -4,4 - dim
`ethyleyclohex - l - enyl ) methyl ) piperazin - 1 - yl ) -N- ( 3 - nitro - 4
`tuzumab ) delays tumor regrowth .
`( ( tetrahydro - 2H - pyran - 4 - yl ) methylamino ) phenylsulfonyl )
`benzamide or a pharmaceutically acceptable salt thereof
`DETAILED DESCRIPTION OF THE
`one , two or three times a day for one or more dosing periods .
`INVENTION
`The present invention also relates to a method for the
`treatment of a human in need thereof comprising adminis
`The present invention relates to the method described
`tering an effective amount of 2- ( 1H - pyrrolo [ 2,3 - b ] pyridin
`above .
`The present invention also relates to a method for the
`5 - yloxy ) -4- ( 4- ( 2-4 - chlorophenyl ) -4,4 - dimethyleyclohex
`1 - enypmethyl ) piperazin - 1 - yl ) -N - 3 - nitro - 4 - ( ( tetrahydro
`treatment of a human in need thereof comprising adminis-
`tering to said human an effective amount of a GA101 25 2H - pyran - 4 - yl ) methylarnino ) phenylsulfortyl ) benzamide or
`antibody or 2- ( 1H - pyrrolo [ 2,3 - b ] pyridin - 5 - yloxy ) -4- ( 4 - ( ( 2-
`a pharmaceutically acceptable salt thereof one , two or three
`( 4 - chlorophenyl ) -4,4 - dimethylcyclohex - 1 - enyl ) methyl ) pip-
`times a day for 1 , 2 , 3 , 4.5 or 6 dosing periods , followed by
`erazin - 1 - yl ) -N- ( 3 - nitro - 4- ( tetrabydro - 2H - pyran - 4 - yl ) meth-
`co - administering an effective amount of said GA101 anti
`ylamino ) phenylsulfonypbenzamide or a pharmaceutically
`body once every dosing period and 2-1H - pyrrolo [ 2,3 - b ]
`acceptable salt thereof for one or more dosing periods , 30 pyridin - 5 - yloxy ) -4- ( 4 - ( ( 2- ( 4 - chlorophenyl ) -4,4 - dimethyl
`followed by co - administering an effective amount of said
`cyclohex - l - enyl ) methyppiperazin - 1 - yl ) -N- ( 3 - nitro - 4
`GA101 antibody and 2- ( 1H - pyrrolo [ 2,3 - b ] pyridin - 5 - yloxy )-
`( ( tetrahydro - 2H - pyran - 4 - yl ) methylamino ) phenylsulfonyl )
`4- ( 4- ( 2- ( 4 - chlorophenyl ) -4,4 - dimethylcyclohex - l - enyl )
`benzamide or a pharmaceutically acceptable salt thereof
`methyl ) piperazin - 1 - yl ) -N- ( 3 - nitro - 4 - ( ( tetrahydro - 2H - pyran-
`one , two or three times a day for one or more dosing periods .
`4 - yl ) methylamino ) phenylsulfonyl ) benzamide
`The present invention also relates to any one of the above
`a 35
`pharmaceutically acceptable salt thereof for one or more
`methods ,
`wherein the effective amount of said
`dosing periods .
`GA101 antibody is 500 , 600 , 700 , 800 , 900 , 1000 , 1100 ,
`The present invention also relates to a method for the
`1200 , 1300 , 1400 , 1500 , 1600 , 1700 , 1800 , 1900 , 2000 ,
`2100 , 2200 , 2300 , 2400 , 2500 , 2600 ,