Claims for Patent: 9,694,071

Summary for Patent: 9,694,071

Title:	Combination of anti-CD20 antibody and PI3 kinase selective inhibitor
Abstract:	Highly effective combinations of a compound of formula A (a PI3K.delta. selective inhibitor) and anti-CD20 antibodies are provided herein for the treatment and amelioration of PI3K.delta. and/or CD20 mediated diseases and disorders. In particular, the combination can be used to treat cancers and autoimmune diseases. More particularly, the invention provided for a combination of a compound of formula A, or stereoisomers thereof, and ublituximab for the treatment and/or amerioration of hematological malignancies such as leukemia and lymphoma.
Inventor(s):	Weiss; Michael S. (New York, NY), Miskin; Hari P. (New York, NY), Sportelli; Peter (New York, NY), Vakkalanka; Swaroop K. V. S. (La Chaux de Fonds, CH)
Assignee:	TG Therapeutics, Inc. (New York, NY) Rhizen Pharmaceuticals NA (CH) Laboratoire Francais du Fractionnement et des Biotechnologies (FR)
Application Number:	14/440,139
Patent Claims:	1. A method of inhibiting proliferation of a CD20-positive, hematopoietic cell population comprising contacting the population with a combination comprising (i) the compound (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrim- idin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and (ii) an anti-CD20 antibody or antigen-binding fragment thereof, wherein said anti-CD20 antibody or fragment (a) is ublituximab or (b) binds to the same epitope as ublituximab. 2. The method of claim 1, wherein said antibody or fragment comprises the VH CDR1, CDR2 and CDR3 region of sequences SEQ ID NO:1, 2, and 3, and the VL CDR1, CDR2 and CDR3 region of sequences SEQ ID NO:6, 7, and 8. 3. The method of claim 2, wherein the anti-CD20 antibody or antigen-binding fragment thereof comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:9. 4. The method of claim 1, wherein said anti-CD20 antibody is ublituximab. 5. The method of claim 1, wherein said compound is (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrim- idin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and said anti-CD20 antibody is ublituximab. 6. The method of claim 1, wherein the population is contacted with (i) a first composition comprising (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrim- idin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and (ii) a second composition comprising the anti-CD20 antibody or fragment. 7. The method of claim 6, wherein the compound is (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrim- idin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and the anti-CD20 antibody is ublituximab. 8. The method of claim 1, wherein the population is in a human subject. 9. The method of claim 8, wherein the subject has a disease or disorder associated with excessive B-cell proliferation, cancer or an autoimmune disease or disorder. 10. The method of claim 9, wherein the cancer is a hematological malignancy. 11. The method of claim 10, wherein the hematological malignancy is lymphoma or leukemia. 12. The method of claim 10, wherein the hematological malignancy is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom's macroglobulinemia (WM), B-cell lymphoma and diffuse large B-cell lymphoma (DLBCL). 13. The method of claim 9, wherein the cancer overexpresses CD20. 14. The method claim 9, wherein the cancer is refractory to chemotherapy. 15. The method of claim 8, wherein the subject has previously been treated with chemotherapy, rituximab, or a combination thereof. 16. The method of claim 8, wherein said compound and said anti-CD20 antibody or fragment are administered to the subject sequentially or simultaneously. 17. The method of claim 16, wherein said compound and said anti-CD20 antibody or fragment are contained in the same pharmaceutical composition or in separate pharmaceutical compositions. 18. The method of claim 8, further comprising administering at least one additional therapeutic agent to the subject selected from the group consisting of a proteasome inhibitor, Bortezomib (Velcade.RTM.), Carfilzomib (PR-171), PR-047, disulfiram, lactacystin, PS-519, eponemycin, epoxomycin, aclacinomycin, CEP-1612, MG-132, CVT-63417, PS-341, vinyl sulfone tripeptide inhibitors, ritonavir, PI-083, (+/-)-7-methylomuralide, (-)-7-methylomuralide, lenalidomide, and combinations thereof. 19. The method of claim 8, further comprising administering at least two additional therapeutic agents to the subject, wherein the two additional therapeutic agents are selected from the group consisting of: a) CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); b) R-CHOP (rituximab-CHOP); c) hyperCV AD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); d) R-hyperCV AD (rituximab-hyperCV AD); e) FCM (fludarabine, cyclophosphamide, mitoxantrone); f) R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); g) bortezomib and rituximab; h) temsirolimus and rituximab; i) temsirolimus and Velcade.RTM.; j) Iodine-131 tositumomab (Bexxar.RTM.) and CHOP; k) CVP (cyclophosphamide, vincristine, prednisone); l) R-CVP (rituximab-CVP); m) ICE (iphosphamide, carboplatin, etoposide); n) R-ICE (rituximab-ICE); o) FCR (fludarabine, cyclophosphamide, rituximab); p) FR (fludarabine, rituximab); and q) D.T. PACE (Dexamethasone, Thalidomide, Cisplatin, Adriamycin, Cyclophosphamide, Etoposide). 20. A kit comprising (i) the compound (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrim- idin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and (ii) an anti-CD20 antibody or antigen-binding fragment thereof, wherein said anti-CD20 antibody or fragment (a) is ublituximab or (b) binds to the same epitope as ublituximab. 21. The kit of claim 20, wherein said compound is (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrim- idin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one and said anti-CD20 antibody is ublituximab. 22. The kit of claim 20, wherein said anti-CD20 antibody or fragment and said compound are contained within the same composition or are in separate compositions. 23. The kit of any one of claim 20, further comprising one or more additional active agents. 24. A pharmaceutical composition comprising (i) (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrim- idin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, and (ii) an anti-CD20 antibody or antigen-binding fragment thereof, wherein said anti-CD20 antibody or fragment (a) is ublituximab or (b) binds to the same epitope as ublituximab. 25. The pharmaceutical composition of claim 24, wherein said anti-CD20 antibody is ublituximab.

Details for Patent 9,694,071

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2032-11-02
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2032-11-02
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2032-11-02