UTILITY PATENT APPLICATION
`
`METHODS OF TREATING AND PREVENTING GRAFT VERSUS HOST DISEASE
`
`WSGR Docket No. 25922—885 .201
`
`Inventor(s):
`
`John C. BYRD
`
`Citizen of the United States of America, Residing at
`1950 Arlington Avenue
`Columbus, OH 43212
`
`Jason A. DUBOVSKY
`
`Citizen of the United States of America, Residing at
`2505 Avalon Place
`
`Columbus, OH 43219
`
`Nataraj an MUTHUSAMY
`Citizen of India, Residing at
`6129 Glenworth Court
`
`Galloway, OH 43119
`
`Amy J o JOHNSON
`Citizen of the United States of America, Residing at
`5396 Winters Run Road
`
`Dublin, OH 43016
`
`David MIKLOS
`
`Citizen of United States of America, Residing at
`875 Blake Wilbur Drive, MC 582
`
`Stanford, CA 94305
`
`Assignee:
`
`Pharmacyclics, Inc.
`
`995 East Arques Avenue
`
`Sunnyvale, CA 94085
`
`A Delaware corporation
`
`Entity:
`
`Large Business Concern
`
`\vfiR
`
`Wilson Sonsini Goodrich 5% Rosati
`PROHESSIONA i. fLflli‘P'JRA'I {ON
`
`650 Page Mill Road
`Palo Alto, CA 94304
`
`(650) 493—9300 (Main)
`
`(650) 493—6811 (Facsimile)
`
`Filed Electronically on: October 24, 2014
`
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`

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`WSGR Docket No. 25922—885201
`
`METHODS OF TREATING AND PREVENTING GRAFT VERSUS HOST DISEASE
`
`CROSS-REFERENCE
`
`[0001] This application claims the benefit of priority of US Provisional Application No.
`
`61/895,981, filed October 25, 2013; US Provisional Application No. 61/910,945, filed December 2,
`
`2013; US Provisional Application No. 61/973,173, filed March 31, 2014; and US Provisional
`
`Application No. 61/973,176 filed March 31, 2014, each of which is incorporated herein by reference.
`
`SEQUENCE LISTING
`
`[0001.1] The instant application contains a Sequence Listing which has been submitted in ASCII
`
`format via EFS —Web and is hereby incorporated by reference in its entirety. Said ASCII copy,
`
`created on October 20, 2014, is named 25922—885—20lSEQ.txt and is 633 bytes in size.
`
`BACKGROUND OF THE INVENTION
`
`[0002] Chronic graft versus host disease (cGVHD) is the most common long—term complication
`
`following allogeneic stem cell transplant (SCT), affecting 30—70% of patients who survive beyond
`
`the first 100 days. cGVHD and its associated immune deficiency have been identified as a leading
`
`cause of non—relapse mortality (NRM) in allogeneic SCT survivors. SCT survivors with cGVHD are
`
`4.7 times as likely to develop severe or life—threatening health conditions compared with healthy
`
`siblings, and patients with active cGVHD are more likely to report adverse general health, mental
`
`health, functional impairments, activity limitation, and pain than allo—SCT survivors with no history
`
`of cGVHD. Any organ system can be affected, and further morbidity is frequently caused by long—
`
`term exposure to the corticosteroids and calcineurin inhibitors required to treat the condition.
`
`SUMMARY OF THE INVENTION
`
`[0003] Disclosed herein, in some embodiments, are methods of preventing the occurrence of graft
`
`versus host disease (GVHD) or reducing the severity of GVHD occurrence in a patient requiring cell
`
`transplantation comprising administration of a therapeutically effective amount of an ACK inhibitor
`
`(e. g., an ITK or BTK inhibitor). In some embodiments, disclosed herein are methods of reducing the
`
`severity of GVHD occurrence in a patient requiring cell transplantation comprising administration of
`
`a therapeutically effective amount of an ACK inhibitor (e. g., an ITK or BTK inhibitor). In some
`
`embodiments the ACK inhibitor is a compound of Formula (A). In some embodiments, disclosed
`
`herein are methods of preventing the occurrence of graft versus host disease (GVHD) or reducing
`
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`WSGR Docket No. 25922—885201
`
`the severity of GVHD occurrence in a patient requiring cell transplantation, comprising
`
`administration of a therapeutically effective amount of a compound of Formula (A) having the
`
`structure:
`
`R3\ 32
`N
`
`R1
`
`N \m%A
`
`N
`
`N
`R4
`
`Formula (A);
`
`wherein:
`
`Ais N;
`
`R1 is phenyl—O—phenyl or phenyl—S—phenyl;
`
`R2 and R3 are independently H;
`
`R4 is L3-X-L4-G, wherein,
`
`L3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl,
`
`optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl,
`
`optionally substituted or unsubstituted alkynyl;
`
`X is optional, and when present is a bond, —O—, —C(=O)—, —S—, —S(=O)—, —S(=O)2—, —NH—, —NR9—,
`
`—NHC(O)—, —C(O)NH—, —NR9C(O)—, —C(O)NR9—, —S(=O)2NH—, —NHS(=O)2—, —S(=O)2NR9—, —
`
`NRgS(=O)2—, —OC(O)NH—, —NHC(O)O—, —OC(O)NR9—, —NR9C(O)O—, —CH=NO—, —ON=CH—, —
`
`NR10C(O)NR10—, heteroaryl—, aryl—, —NR10C(=NR11)NR10—, —NR10C(=NR11)—, —C(=NR11)NR10—, -
`
`OC(=NR11)—, or —C(=NR11)O-;
`
`L4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or
`
`unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
`
`substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
`
`heterocycle;
`
`or L3, X and L4 taken together form a nitrogen containing heterocyclic ring;
`
`q, ,0 R6
`0
`R6
`0
`/S /
`/
`EMR7 EMR LLL‘
`R8
`R8
`
`6 ,
`
`,
`
`R6
`E?
`/S\%\
`51‘
`R8
`
`R7
`
`R7
`
`,
`
`, or
`
`R6
`i 9
`_P%
`R26
`R8
`
`R7
`
`, wherein,
`
`G is
`
`-2-
`
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`WSGR Docket No. 25922—885201
`
`R6, R7 and R3 are independently selected from among H, halogen, CN, OH, substituted or
`
`unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted
`
`cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
`
`substituted or unsubstituted heteroaryl;
`
`each R9 is independently selected from among H, substituted or unsubstituted lower alkyl,
`
`and substituted or unsubstituted lower cycloalkyl;
`
`each R10 is independently H, substituted or unsubstituted lower alkyl, or substituted or
`
`unsubstituted lower cycloalkyl; or
`
`two R10 groups can together form a 5—, 6—, 7—, or 8—membered heterocyclic ring; or
`
`R10 and R11 can together form a 5—, 6—, 7—, or 8—membered heterocyclic ring; or each R11 is
`
`independently selected from H or substituted or unsubstituted alkyl; or a pharmaceutically
`
`acceptable salt thereof. In some embodiments, L3, X and L4 taken together form a nitrogen
`
`containing heterocyclic ring. In some embodiments, the nitrogen containing heterocyclic ring is a
`
`piperidine group. In some embodiments, G is
`
`EMR7 911%
`R8
`or
`
`R6. In some embodiments,
`
`the compound of Formula (A) is l—[(3R)—3—[4—amino—3—(4—phenoxyphenyl)pyrazolo[3,4—d]pyrimidin—
`
`l—yl]piperidin—l—yl]prop—2—en—l—one. In some embodiments, the patient has cancer. In some
`
`embodiments, the patient has a hematological malignancy. In some embodiments, the patient has a
`
`relapsed or refractory hematological malignancy. In some embodiments, the patient has a B—cell
`
`malignancy. In some embodiments, the patient has a T—cell malignancy. In some embodiments, the
`
`patient has a leukemia, a lymphoma, or a myeloma. In some embodiments, the B—cell malignancy is
`
`a non—Hodgkin’s lymphoma. In some embodiments, the B—cell malignancy is chronic lymphocytic
`
`leukemia (CLL). In some embodiments, the B—cell malignancy is a relapsed or refractory B—cell
`
`malignancy. In some embodiments, the B—cell malignancy is a relapsed or refractory non—Hodgkin’s
`
`lymphoma. In some embodiments, the B—cell malignancy is a relapsed or refractory CLL. In some
`
`embodiments, the patient has high risk CLL. In some embodiments, the patient has a l7p
`
`chromosomal deletion. In some embodiments, the patient has 10%, 20%, 30%, 40%, 50%, 60%,
`
`70%, 80%, 90%, or greater CLL as determined by bone marrow biopsy. In some embodiments, the
`
`patient has received one or more prior anticancer agents. In some embodiments, the anticancer agent
`
`is selected from among alemtuzumab, bendamustine, bortezomib, CAL—101, chlorambucil,
`
`-3-
`
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`WSGR Docket No. 25922—885201
`
`cyclophosphamide, dexamethasone, docetaxel, doxorubicin, endostatineverolimus, etoposide,
`
`fludarabine, fostamatinib, hydroxydaunorubicin, ibritumomab, ifosphamide, lenalidomide,
`
`mesalazine, ofatumumab, paclitaxel, pentostatin, prednisone, rituXimab, temsirolimus, thalidomide,
`
`tositumomab, vincristine, or a combination thereof. In some embodiments, the anticancer agent is
`
`rituXimab. In some embodiments, the anticancer agent is alemtuzumab. In some embodiments, the
`
`anticancer agent is fludarabine, cyclophosphamide, and rituXimab (FCR). In some embodiments, the
`
`anticancer agent is oxaliplatin, fludarabine, cytarabine, rituXimab (OFAR). In some embodiments,
`
`the amount of the ACK inhibitor compound (e. g., a compound of Formula (A)) prevents or reduces
`
`GVHD while maintaining a graft—versus—leukemia (GVL) reaction effective to reduce or eliminate
`
`the number of cancerous cells in the blood of the patient. In some embodiments, the cell
`
`transplantation is a hematopoietic cell transplantation. In some embodiments, the GVHD is acute
`
`GVHD. In some embodiments, the GVHD is chronic GVHD. In some embodiments, the GVHD is
`
`sclerodermatous GVHD. In some embodiments, the GVHD is steroid resistant GVHD. In some
`
`embodiments, the GVHD is cyclosporin—resistant GVHD. In some embodiments, the GVHD is
`
`refractory GVHD. In some embodiments, the GHVD is oral GVHD. In some embodiments, the oral
`
`GVHD is reticular oral GVHD. In some embodiments, the oral GVHD is erosive oral GVHD. In
`
`some embodiments, the oral GVHD is ulcerative oral GVHD. In some embodiments, the oral
`
`GVHD is GVHD of the oral cavity. In some embodiments, the oral GVHD is GVHD of the
`
`oropharyngeal region. In some embodiments, the oral GVHD is GVHD of the pharyngeal region. In
`
`some embodiments, the oral GVHD is GVHD of the esophageal region. In some embodiments, the
`
`oral GVHD is acute oral GVHD. In some embodiments, the oral GVHD is chronic oral GVHD. In
`
`some embodiments, the patient exhibits one or more symptoms of GVHD. In some embodiments,
`
`the patient has or will receive an allogeneic bone marrow or hematopoietic stem cell transplant. In
`
`some embodiments, the ACK inhibitor compound (e. g., a compound of Formula (A)) is administered
`
`concurrently with an allogeneic bone marrow or hematopoietic stem cell transplant. In some
`
`embodiments, the ACK inhibitor compound (e. g., a compound of Formula (A)) is administered prior
`
`to an allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the ACK
`
`inhibitor compound (e. g., a compound of Formula (A)) is administered subsequent to an allogeneic
`
`bone marrow or hematopoietic stem cell transplant. In some embodiments, the patient is a candidate
`
`for receiving HLA—mismatched hematopoietic stem cells. In some embodiments, the patient is a
`
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`

`

`WSGR Docket No. 25922—885201
`
`candidate for receiving unrelated donor hematopoietic stem cells, umbilical vein hematopoietic stem
`
`cells, or peripheral blood stem cells. In some embodiments, the ACK inhibitor compound (e. g., a
`
`compound of Formula (A)) is administered orally. In some embodiments, the ACK inhibitor
`
`compound (e. g., a compound of Formula (A)) is administered at a dosage of between about 0.1
`
`mg/kg per day to about 100 mg/kg per day. In some embodiments, the ACK inhibitor compound
`
`(e. g., a compound of Formula (A)) is administered at a dosage of about 40 mg/day, about 140
`
`mg/day, about 280 mg/day, about 420 mg/day, about 560 mg/day, or about 840 mg/day. In some
`
`embodiments, the ACK inhibitor compound (e. g., a compound of Formula (A)) is administered in
`
`combination with other prophylactic agents. In some embodiments, the ACK inhibitor compound
`
`(e. g., a compound of Formula (A)) is administered from day l to about day 120 following allogeneic
`
`bone marrow or hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor
`
`compound (e. g., a compound of Formula (A)) is administered from day l to about day 1000
`
`following allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the
`
`ACK inhibitor compound (e. g., a compound of Formula (A)) is administered in combination with
`
`one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is
`
`a corticosteroid. In some embodiments, the therapeutic agent is cyclosporine (CSA), mycophenolate
`
`mofetil (MMF) or a combination thereof. In some embodiments, the patient has or will receive a
`
`donor lymphocyte infusions (DLI).In some embodiments, the patient is administered one or more
`
`DLIs. In some embodiments, the patient is administered two or more DLIs. In some embodiments,
`
`the DLI comprises CD3+ lymphocytes. In some embodiments, the patient is administered one or
`
`more donor lymphocyte infusions (DLI) following an allogeneic bone marrow or hematopoietic stem
`
`cell transplant. In some embodiments, the ACK inhibitor compound (e. g., a compound of Formula
`
`(A)) is administered concurrently with a DLI following allogeneic bone marrow or hematopoietic
`
`stem cell transplant. In some embodiments, the ACK inhibitor compound (e. g., a compound of
`
`Formula (A)) is administered prior to a DLI following an allogeneic bone marrow or hematopoietic
`
`stem cell transplant. In some embodiments, the ACK inhibitor compound (e. g., a compound of
`
`Formula (A)) is administered following a DLI following an allogeneic bone marrow or
`
`hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound (e. g., a
`
`compound of Formula (A)) is ibrutinib.
`
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`WSGR Docket No. 25922—885201
`
`[0004] Disclosed herein, in some embodiments, are methods of treating a patient for alleviation of a
`
`bone marrow mediated disease, comprising administering to the patient allogeneic hematopoietic
`
`stem cells and/or allogeneic T—cells, and a therapeutically effective amount of an ACK inhibitor
`
`(e. g., an ITK or BTK inhibitor). In some embodiments, disclosed herein are methods of treating a
`
`patient for alleviation of a bone marrow mediated disease, with alleviation of consequently
`
`developed graft versus host disease (GVHD), comprising administering to the patient allogeneic
`
`hematopoietic stem cells and/or allogeneic T—cells, and a therapeutically effective amount of a
`
`compound of Formula (A):
`
`R3\ 32
`N
`
`R1
`
`N \m%A
`
`N
`
`N
`R4
`
`Formula (A);
`
`wherein:
`
`Ais N;
`
`R1 is phenyl—O—phenyl or phenyl—S—phenyl;
`
`R2 and R3 are independently H;
`
`R4 is L3-X-L4-G, wherein,
`
`L3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl,
`
`optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl,
`
`optionally substituted or unsubstituted alkynyl;
`
`X is optional, and when present is a bond, —O—, —C(=O)—, —S—, —S(=O)—, —S(=O)2—, —NH—, —NR9—,
`
`—NHC(O)—, —C(O)NH—, —NR9C(O)—, —C(O)NR9—, —S(=O)2NH—, —NHS(=O)2—, —S(=O)2NR9—, —
`
`NRgS(=O)2—, —OC(O)NH—, —NHC(O)O—, —OC(O)NR9—, —NR9C(O)O—, —CH=NO—, —ON=CH—, —
`
`NR10C(O)NR10—, heteroaryl—, aryl—, —NR10C(=NR11)NR10—, —NR10C(=NR11)—, —C(=NR11)NR10—, -
`
`OC(=NR11)—, or —C(=NR11)O-;
`
`L4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or
`
`unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
`
`substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
`
`heterocycle;
`
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`WSGR Docket No. 25922—885201
`
`or L3, X and L4 taken together form a nitrogen containing heterocyclic ring;
`
`0
`R6
`0
`/
`. a)? 7 HEMR6
`
`G is
`
`8
`
`,
`
`R
`
`Cos/’0 R6
`/ /
`IILL
`R
`
`8
`
`R
`
`7
`
`,
`
`,
`
`R6
`(IF?
`g
`R6
`(IS?
`/ % _ %\
`R20 R
`LLLL
`R
`7
`
`R
`
`I
`
`8
`
`, or
`
`8
`
`R
`
`7
`
`.
`
`, wherein,
`
`R6, R7 and R3 are independently selected from among H, halogen, CN, OH, substituted or
`
`unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted
`
`cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
`
`substituted or unsubstituted heteroaryl;
`
`each R9 is independently selected from among H, substituted or unsubstituted lower alkyl,
`
`and substituted or unsubstituted lower cycloalkyl;
`
`each R10 is independently H, substituted or unsubstituted lower alkyl, or substituted or
`
`unsubstituted lower cycloalkyl; or
`
`two R10 groups can together form a 5—, 6—, 7—, or 8—membered heterocyclic ring; or
`
`R10 and R11 can together form a 5—, 6—, 7—, or 8—membered heterocyclic ring; or
`
`each R11 is independently selected from H or substituted or unsubstituted alkyl; or a
`
`pharmaceutically acceptable salt thereof, is administered prior to, concurrently with, or following the
`
`allogeneic hematopoietic stem cells and/or allogeneic T—cells. In some embodiments, L3, X and L4
`
`taken together form a nitrogen containing heterocyclic ring. In some embodiments, the nitrogen
`
`containing heterocyclic ring is a piperidine group. In some embodiments, G is
`
`R8
`
`or
`
`571M
`
`R6. In some embodiments, the compound of Formula (A) is l—[(3R)—3—[4—amino—3—(4—
`
`phenoxyphenyl)pyrazolo [3 ,4—d] pyrimidin— l—yl] piperidin— l —yl] prop—2—en— 1 —one. In some
`
`embodiments, the patient has cancer. In some embodiments, the patient has a hematological
`
`malignancy. In some embodiments, the patient has a relapsed or refractory hematological
`
`malignancy. In some embodiments, the patient has a leukemia, a lymphoma, or a myeloma. In some
`
`embodiments, the patient has a B—cell malignancy. In some embodiments, the B—cell malignancy is a
`
`non—Hodgkin’s lymphoma. In some embodiments, the B—cell malignancy is chronic lymphocytic
`
`leukemia (CLL). In some embodiments, the B—cell malignancy is a relapsed or refractory B—cell
`
`malignancy. In some embodiments, the B—cell malignancy is a relapsed or refractory non—Hodgkin’s
`
`SAN EX 1029, Page 08
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`WSGR Docket No. 25922—885201
`
`lymphoma. In some embodiments, the B—cell malignancy is a relapsed or refractory CLL. In some
`
`embodiments, the patient has high risk CLL. In some embodiments, the patient has a l7p
`
`chromosomal deletion. In some embodiments, the patient has 10%, 20%, 30%, 40%, 50%, 60%,
`
`70%, 80%, 90%, or greater CLL as determined by bone marrow biopsy. In some embodiments, the
`
`patient has received one or more prior anticancer agents. In some embodiments, the anticancer agent
`
`is selected from among alemtuzumab, bendamustine, bortezomib, CAL—101, chlorambucil,
`
`cyclophosphamide, dexamethasone, docetaxel, doxorubicin, endostatineverolimus, etoposide,
`
`fludarabine, fostamatinib, hydroxydaunorubicin, ibritumomab, ifosphamide, lenalidomide,
`
`mesalazine, ofatumumab, paclitaxel, pentostatin, prednisone, rituXimab, temsirolimus, thalidomide,
`
`tositumomab, vincristine, or a combination thereof. In some embodiments, the anticancer agent is
`
`rituXimab. In some embodiments, the anticancer agent is alemtuzumab. In some embodiments, the
`
`anticancer agent is fludarabine, cyclophosphamide, and rituXimab (FCR). In some embodiments, the
`
`anticancer agent is oxaliplatin, fludarabine, cytarabine, rituXimab (OFAR). In some embodiments,
`
`the amount of the ACK inhibitor compound (e. g., a compound of Formula (A)) prevents or reduces
`
`GVHD while maintaining a graft—versus—leukemia (GVL) reaction effective to reduce or eliminate
`
`the number of cancerous cells in the blood of the patient. In some embodiments, the cell
`
`transplantation is a hematopoietic cell transplantation. In some embodiments, the GVHD is acute
`
`GVHD. In some embodiments, the GVHD is chronic GVHD. In some embodiments, the GVHD is
`
`sclerodermatous GVHD. In some embodiments, the GVHD is steroid resistant GVHD. In some
`
`embodiments, the GVHD is cyclosporin—resistant GVHD. In some embodiments, the GVHD is
`
`refractory GVHD. In some embodiments, the GHVD is oral GVHD. In some embodiments, the oral
`
`GVHD is reticular oral GVHD. In some embodiments, the oral GVHD is erosive oral GVHD. In
`
`some embodiments, the oral GVHD is ulcerative oral GVHD. In some embodiments, the oral
`
`GVHD is GVHD of the oral cavity. In some embodiments, the oral GVHD is GVHD of the
`
`oropharyngeal region. In some embodiments, the oral GVHD is GVHD of the pharyngeal region. In
`
`some embodiments, the oral GVHD is GVHD of the esophageal region. In some embodiments, the
`
`oral GVHD is acute oral GVHD. In some embodiments, the oral GVHD is chronic oral GVHD. In
`
`some embodiments, the patient exhibits one or more symptoms of GVHD. In some embodiments,
`
`the patient has or will receive an allogeneic bone marrow or hematopoietic stem cell transplant. In
`
`some embodiments, the ACK inhibitor compound (e. g., a compound of Formula (A)) is administered
`
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`WSGR Docket No. 25922—885201
`
`concurrently with an allogeneic bone marrow or hematopoietic stem cell transplant. In some
`
`embodiments, the ACK inhibitor compound (e. g., a compound of Formula (A)) is administered prior
`
`to an allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the ACK
`
`inhibitor compound (e. g., a compound of Formula (A)) is administered subsequent to an allogeneic
`
`bone marrow or hematopoietic stem cell transplant. In some embodiments, the patient is a candidate
`
`for receiving HLA—mismatched hematopoietic stem cells. In some embodiments, the patient is a
`
`candidate for receiving unrelated donor hematopoietic stem cells, umbilical vein hematopoietic stem
`
`cells, or peripheral blood stem cells. In some embodiments, the ACK inhibitor compound (e. g., a
`
`compound of Formula (A)) is administered at a dosage of between about 0.1 mg/kg per day to about
`
`100 mg/kg per day. In some embodiments, the ACK inhibitor compound (e. g., a compound of
`
`Formula (A)) is administered at a dosage of about 40 mg/day, about 140 mg/day, about 280 mg/day,
`
`about 420 mg/day, about 560 mg/day, or about 840 mg/day. In some embodiments, the ACK
`
`inhibitor compound (e. g., a compound of Formula (A)) is administered orally. In some
`
`embodiments, the ACK inhibitor compound (e. g., a compound of Formula (A)) is administered in
`
`combination with additional therapeutic agents. In some embodiments, the additional therapeutic
`
`agent is a corticosteroid. In some embodiments, the additional therapeutic agent is cyclosporine
`
`(CSA), mycophenolate mofetil (MMF) or a combination thereof. In some embodiments, the ACK
`
`inhibitor compound (e. g., a compound of Formula (A)) is administered from day l to about day 120
`
`following allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the
`
`ACK inhibitor compound (e. g., a compound of Formula (A)) is administered from day l to about
`
`day 1000 following allogeneic bone marrow or hematopoietic stem cell transplant. In some
`
`embodiments, the patient has or will receive a donor lymphocyte infusion (DLI). In some
`
`embodiments, the patient has or will receive two or more donor lymphocyte infusions (DLI). In
`
`some embodiments, the patient is administered one or more donor lymphocyte infusions (DLI). In
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`some embodiments, the DLI comprises CD3+ lymphocytes. In some embodiments, the patient is
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`administered one or more donor lymphocyte infusions (DLI) following an allogeneic bone marrow
`
`or hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound (e. g., a
`
`compound of Formula (A)) is administered concurrently with a DLI following allogeneic bone
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`marrow or hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound
`
`(e. g., a compound of Formula (A)) is administered prior to a DLI following an allogeneic bone
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`marrow or hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound
`
`(e. g., a compound of Formula (A)) is administered following a DLI following an allogeneic bone
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`marrow or hematopoietic stem cell transplant. In some embodiments, the ACK inhibitor compound
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`(e. g., a compound of Formula (A)) is ibrutinib.
`
`[0005] In some embodiments, disclosed herein are methods of reducing the severity of GVHD
`
`occurrence in a patient requiring cell transplantation comprising administration of a therapeutically
`
`effective amount of ibrutinib (l—[(3R)—3—[4—amino—3—(4—phenoxyphenyl)pyrazolo[3,4—d]pyrimidin—l—
`
`yl]piperidin—l—yl]prop—2—en—l—one). In some embodiments, the patient has cancer. In some
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`embodiments, the patient has a hematological malignancy. In some embodiments, the patient has a
`
`relapsed or refractory hematological malignancy. In some embodiments, the patient has a B—cell
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`malignancy. In some embodiments, the patient has a T—cell malignancy. In some embodiments, the
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`patient has a leukemia, a lymphoma, or a myeloma. In some embodiments, the B—cell malignancy is
`
`a non—Hodgkin’s lymphoma. In some embodiments, the B—cell malignancy is chronic lymphocytic
`
`leukemia (CLL). In some embodiments, the B—cell malignancy is a relapsed or refractory B—cell
`
`malignancy. In some embodiments, the B—cell malignancy is a relapsed or refractory non—Hodgkin’s
`
`lymphoma. In some embodiments, the B—cell malignancy is a relapsed or refractory CLL. In some
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`embodiments, the patient has high risk CLL. In some embodiments, the patient has a l7p
`
`chromosomal deletion. In some embodiments, the patient has 10%, 20%, 30%, 40%, 50%, 60%,
`
`70%, 80%, 90%, or greater CLL as determined by bone marrow biopsy. In some embodiments, the
`
`patient has received one or more prior anticancer agents. In some embodiments, the anticancer agent
`
`is selected from among alemtuzumab, bendamustine, bortezomib, CAL—101, chlorambucil,
`
`cyclophosphamide, dexamethasone, docetaxel, doxorubicin, endostatineverolimus, etoposide,
`
`fludarabine, fostamatinib, hydroxydaunorubicin, ibritumomab, ifosphamide, lenalidomide,
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`mesalazine, ofatumumab, paclitaxel, pentostatin, prednisone, rituXimab, temsirolimus, thalidomide,
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`tositumomab, vincristine, or a combination thereof. In some embodiments, the anticancer agent is
`
`rituXimab. In some embodiments, the anticancer agent is alemtuzumab. In some embodiments, the
`
`anticancer agent is fludarabine, cyclophosphamide, and rituXimab (FCR). In some embodiments, the
`
`anticancer agent is oxaliplatin, fludarabine, cytarabine, rituXimab (OFAR). In some embodiments,
`
`the amount of ibrutinib prevents or reduces GVHD while maintaining a graft—versus—leukemia
`
`(GVL) reaction effective to reduce or eliminate the number of cancerous cells in the blood of the
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`patient. In some embodiments, the cell transplantation is a hematopoietic cell transplantation. In
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`some embodiments, the GVHD is acute GVHD. In some embodiments, the GVHD is chronic
`
`GVHD. In some embodiments, the GVHD is sclerodermatous GVHD. In some embodiments, the
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`GVHD is steroid resistant GVHD. In some embodiments, the GVHD is cyclosporin—resistant
`
`GVHD. In some embodiments, the GVHD is refractory GVHD. In some embodiments, the GHVD
`
`is oral GVHD. In some embodiments, the oral GVHD is reticular oral GVHD. In some
`
`embodiments, the oral GVHD is erosive oral GVHD. In some embodiments, the oral GVHD is
`
`ulcerative oral GVHD. In some embodiments, the oral GVHD is GVHD of the oral cavity. In some
`
`embodiments, the oral GVHD is GVHD of the oropharyngeal region. In some embodiments, the oral
`
`GVHD is GVHD of the pharyngeal region. In some embodiments, the oral GVHD is GVHD of the
`
`esophageal region. In some embodiments, the oral GVHD is acute oral GVHD. In some
`
`embodiments, the oral GVHD is chronic oral GVHD. In some embodiments, the patient exhibits one
`
`or more symptoms of GVHD. In some embodiments, the patient has or will receive an allogeneic
`
`bone marrow or hematopoietic stem cell transplant. In some embodiments, the ibrutinib is
`
`administered concurrently with an allogeneic bone marrow or hematopoietic stem cell transplant. In
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`some embodiments, the ibrutinib is administered prior to an allogeneic bone marrow or
`
`hematopoietic stem cell transplant. In some embodiments, the ibrutinib is administered subsequent to
`
`an allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the patient
`
`is a candidate for receiving HLA—mismatched hematopoietic stem cells. In some embodiments, the
`
`patient is a candidate for receiving unrelated donor hematopoietic stem cells, umbilical vein
`
`hematopoietic stem cells, or peripheral blood stem cells. In some embodiments, the ibrutinib is
`
`administered orally. In some embodiments, the ibrutinib is administered at a dosage of between
`
`about 0.1 mg/kg per day to about 100 mg/kg per day. In some embodiments, the ibrutinib is
`
`administered at a dosage of about 40 mg/day, about 140 mg/day, about 280 mg/day, about 420
`
`mg/day, about 560 mg/day, or about 840 mg/day. In some embodiments, the ibrutinib is
`
`administered in combination with other prophylactic agents. In some embodiments, the ibrutinib is
`
`administered from day l to about day 120 following allogeneic bone marrow or hematopoietic stem
`
`cell transplant. In some embodiments, the ibrutinib is administered from day l to about day 1000
`
`following allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments, the
`
`ibrutinib is administered in combination with one or more additional therapeutic agents. In some
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`embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the
`
`therapeutic agent is cyclosporine (CSA), mycophenolate mofetil (MMF) or a combination thereof. In
`
`some embodiments, the patient has or will receive a donor lymphocyte infusions (DLI).In some
`
`embodiments, the patient is administered one or more DLIs. In some embodiments, the patient is
`
`administered two or more DLIs. In some embodiments, the DLI comprises CD3+ lymphocytes. In
`
`some embodiments, the patient is administered one or more donor lymphocyte infusions (DLI)
`
`following an allogeneic bone marrow or hematopoietic stem cell transplant. In some embodiments,
`
`the ibrutinib is administered concurrently with a DLI following allogeneic bone marrow or
`
`hematopoietic stem cell transplant. In some embodiments, the ibrutinib is administered prior to a
`
`DLI following an allogeneic bone marrow or hematopoietic stem cell transplant. In some
`
`embodiments, the ibrutinib is administered following a DLI following an allogeneic bone marrow or
`
`hematopoietic stem cell transplant.
`
`INCORPORATION BY REFERENCE
`
`[0006] All publications, patents, and patent applications mentioned in this specification are herein
`
`incorporated by reference to the same extent as if each individual publication, patent, or patent
`
`application was specifically and individually indicated to be incorporated by reference.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0007] The novel features of the invention are set forth with particularity in the appended claims. A
`
`better understanding of the features and advantages of the present invention will be obtained by
`
`reference to the following detailed description that sets forth illustrative embodiments, in which the
`
`principles of the invention are utilized, and the accompanying drawings of which:
`
`[0008] FIG. 1 exemplifies that ibrutinib ameliorates cGVHD symptomatology after allotransplant.
`
`C57BL/6 mice were engrafted with LP/J bone marrow after 850 cGy lethal irradiation. 25 days post—
`
`transplant mice were randomly assigned to ibrutinib, vehicle, or cyclosporine groups. Panel A shows
`
`images showing external signs of cGVHD including alopecia, scleroderma, and fibrotic lesions at
`
`day 36 post—transplant. Ibrutinib treatment group displayed few external signs of cGVHD
`
`progression as compared to vehicle or cyclosporine groups. Panel B shows an analysis of cGVHD
`
`mouse groups using a physical scoring system adapted from Cooke et al., which incorporates weight,
`
`posture, coat condition, skin condition, and mobility. Scoring was conducted on day 36 post—
`
`transplantation. Panel C shows the LP/J—>C57BL/6 cGVHD scoring. Each category: coat condition,
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`skin condition, weight, posture, mobility, and vitality are individually scored and summed to achieve
`
`an overall cGVHD condition score. Scores are taken by a consistent unbiased observer with no
`
`knowledge of treatment cohorts. Panel D provides images of cGVHD mouse groups at day 39 post—
`
`HSCT. Panel E provides images of H&E stained skin preparations of sclerodermatous skin lesions
`
`showing levels of dermal fibrosis, epidermal hyperplasia, serocellular crusting, erosion, and
`
`lymphohistiocytic infiltration, consistent with cGVHD.
`
`[0009] FIG. 2 exemplifies that Tregs are not inhibited by ibrutinib. Panel A provides a p