Claims for Patent: 10,494,432

Summary for Patent: 10,494,432

Title:	Anti-CD79B antibodies and immunoconjugates and methods of use
Abstract:	The present invention is directed to compositions of matter useful for the treatment of hematopoietic tumor in mammals and to methods of using those compositions of matter for the same.
Inventor(s):	Chen; Yvonne (San Mateo, CA), Dennis; Mark (San Carlos, CA), Dornan; David (San Mateo, CA), Elkins; Kristi (San Francisco, CA), Junutula; Jagath Reddy (Fremont, CA), Polson; Andrew (San Francisco, CA), Zheng; Bing (Mountain View, CA)
Assignee:	Genentech, Inc. (South San Francisco, CA)
Application Number:	13/973,669
Patent Claims:	1. A method of treating a cancerous B cell proliferative disorder comprising administering to a human an effective amount of an immunoconjugate comprising an anti-CD79b antibody, wherein the antibody comprises (a) an HVR-L1 sequence of SEQ ID NO: 194; (b) an HVR-L2 sequence of SEQ ID NO: 195; (c) an HVR-L3 sequence of SEQ ID NO: 196; (d) an HVR-H1 sequence of SEQ ID NO: 202; (e) an HVR-H2 sequence of SEQ ID NO: 203; and (f) an HVR-H3 sequence of SEQ ID NO: 204; and, wherein said antibody is covalently attached to a cytotoxic agent. 2. The method of claim 1, wherein the cancerous B cell proliferative disorder is selected from the group consisting of lymphoma, myeloma, non-Hodgkins lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), aggressive NHL, indolent lymphoma, follicular lymphoma (FL), relapsed aggressive NHL, relapsed indolent NHL, relapsed NHL, refractory NHL, refractory indolent NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), and mantle cell lymphoma. 3. The method of claim 1, wherein the cytotoxic agent is selected from the group consisting of a toxin, a chemotherapeutic agent, a drug moiety, an antibiotic, a radioactive isotope, and a nucleolytic enzyme. 4. The method of claim 1, wherein the immunoconjugate comprises the formula Ab-(L-D).sub.p, wherein Ab is the anti-CD79b antibody, D is a drug moiety, L is a linker moiety, and p ranges from 1 to 20. 5. The method of claim 4, wherein L comprises the formula: -A.sub.a-W.sub.w-Y.sub.y- wherein: A is a Stretcher unit covalently attached to Ab; a is 0 or 1; each W is independently an Amino Acid unit; w is an integer ranging from 0 to 12; Y is a Spacer unit covalently attached to the drug moiety; and y is 0, 1 or 2. 6. The method of claim 5 wherein the immunoconjugate comprises the formula: ##STR00040## wherein PAB is para-aminobenzylcarbamoyl, and R.sup.17 is a divalent radical selected from the group consisting of (CH.sub.2).sub.r, C.sub.3-C.sub.8 carbocyclyl, O--(CH.sub.2).sub.r, arylene, (CH.sub.2).sub.rarylene, -arylene-(CH.sub.2).sub.r--, (CH.sub.2).sub.r--(C.sub.3C.sub.8 carbocyclyl), (C.sub.3C.sub.8 carbocyclyl)-(CH.sub.2).sub.r, C.sub.3-C.sub.8 heterocyclyl, (CH.sub.2).sub.r--(C.sub.3-C.sub.8 heterocyclyl), --C.sub.3-C.sub.8 heterocyclyl)-(CH.sub.2).sub.r, --(CH.sub.2).sub.r C(O)NR.sup.b(CH.sub.2).sub.r--, --(CH.sub.2CH.sub.2O).sub.r--, --(CH.sub.2CH.sub.2O).sub.r --CH.sub.2, --(CH.sub.2).sub.rC(O)NR.sup.b(CH.sub.2CH.sub.2O).sub.r--, --(CH.sub.2).sub.rC(O)NR.sup.b(CH.sub.2CH.sub.2O).sub.r--CH.sub.2--, --CH.sub.2CH.sub.2O).sub.rC(O)NR.sup.b(CH.sub.2CH.sub.2O).sub.r--, --(CH.sub.2CH.sub.2O).sub.r C(O)NR.sup.b(CH.sub.2CH.sub.2O).sub.r--CH.sub.2--, and --(CH.sub.2CH.sub.2O).sub.rC(O)NR.sup.b(CH.sub.2).sub.r--; wherein R.sup.b is H, C.sub.1-C.sub.6 alkyl, phenyl, or benzyl; and r is independently an integer ranging from 1 to 10. 7. The method of claim 6 wherein W.sub.w, is valine-citrulline. 8. The method of claim 7, wherein R.sup.17 is (CH.sub.2).sub.5 or (CH.sub.2).sub.2. 9. The method of claim 4, wherein the immunoconjugate comprises the formula: ##STR00041## 10. The method of claim 4, wherein L comprises 4-((2,5-dioxopyrrolidin-1-yl)methyl)cyclohexanecarboxylic acid (SMCC), 4-mercaptopentanoic acid (SPP), 4-mercaptobutanoic acid (SPDB), 6-maleimidocaproyl (MC), valine-citrulline (val-cit), p aminobenzyloxycarbonyl (PAB), 6-maleimidocaproyl-valine-citrulline-p aminobenzyloxycarbonyl (MC-val-cit-PAB) and/or Bis-Maleimido polyethylene glycol (BMPEO). 11. The method of claim 4, wherein D is auristatin. 12. The method of claim 11, wherein the auristatin is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). 13. The method of claim 12, wherein D is MMAE, having the structure: ##STR00042## wherein the wavy line indicates the attachment site to the linker L. 14. The method of claim 4, wherein D is maytansinoid. 15. The method of claim 14, wherein the maytansinoid is DM1 or DM4, having the structures: ##STR00043## wherein the wavy line indicates the attachment site to the linker L. 16. The method of claim 1, wherein the anti-CD79b antibody comprises the heavy chain variable domain sequence of SEQ ID NO: 208 and the light chain variable domain sequence of SEQ ID NO: 207. 17. The method of claim 1, wherein the anti-CD79b antibody comprises the heavy chain sequence of SEQ ID NO: 308 and the light chain sequence of SEQ ID NO: 307. 18. The method of claim 4, wherein the anti-CD79b antibody comprises the heavy chain variable domain sequence of SEQ ID NO: 208 and the light chain variable domain sequence of SEQ ID NO: 207. 19. The method of claim 4, wherein the anti-CD79b antibody comprises the heavy chain sequence of SEQ ID NO: 308 and the light chain sequence of SEQ ID NO: 307. 20. The method of claim 1, wherein the cancerous B cell proliferative disorder is non-Hodgkins lymphoma (NHL). 21. The method of claim 1, wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 22. The method of claim 1, wherein the cancerous B cell proliferative disorder is relapsed NHL or refractory NHL. 23. The method of claim 1, wherein the cancerous B cell proliferative disorder is follicular lymphoma (FL). 24. The method of claim 1, further comprising administering to the human an effective amount of another therapeutic agent. 25. The method of claim 24, wherein the therapeutic agent is selected from the group consisting of an antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressive agent, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, a cancer vaccine, and a growth-inhibitory agent. 26. The method of claim 24, wherein the therapeutic agent is selected from one or more of tamoxifen, letrozole, exemestane, anastrozole, irinotecan, cetuximab, fulvestrant, vinorelbine, erlotinib, bevacizumab, vincristine, imatinib mesylate, sorafenib, lapatinib, trastuzumab, cisplatin, gemcitabine, methotrexate, vinblastine, carboplatin, paclitaxel, 5-fluorouracil, doxorubicin, bortezomib, melphalan, prednisone, and docetaxel. 27. The method of claim 24, wherein the therapeutic agent is an anti-CD20 antibody. 28. The method of claim 24, wherein the therapeutic agent is an anti-CD20 antibody and wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 29. The method of claim 24, wherein the therapeutic agent is an anti-CD20 antibody and wherein the cancerous B cell proliferative disorder is follicular lymphoma (FL). 30. The method of claim 27, wherein the anti-CD20 antibody is rituximab. 31. The method of claim 24, wherein the therapeutic agent is a chemotherapeutic agent. 32. The method of claim 31, wherein the chemotherapeutic agent comprises one or more of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone. 33. The method of claim 31, wherein the chemotherapeutic agent comprises cyclophosphamide, doxorubicin, and prednisone. 34. The method of claim 27, further comprising administering to the human a chemotherapeutic agent. 35. The method of claim 34, wherein the chemotherapeutic agent comprises cyclophosphamide, doxorubicin, and prednisone. 36. The method of claim 35, wherein the cancerous B cell proliferative disorder is non-Hodgkin's lymphoma (NHL). 37. The method of claim 36, wherein the anti-CD20 antibody is rituximab. 38. The method of claim 35, wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 39. The method of claim 38, wherein the anti-CD20 antibody is rituximab. 40. A method of treating a cancerous B cell proliferative disorder comprising administering to a human an effective amount of an immunoconjugate comprising an anti-CD79b antibody (Ab), wherein Ab comprises (a) an HVR-L1 sequence of SEQ ID NO: 194; (b) an HVR-L2 sequence of SEQ ID NO: 195; (c) an HVR-L3 sequence of SEQ ID NO: 196; (d) an HVR H1 sequence of SEQ ID NO: 202; (e) an HVR-H2 sequence of SEQ ID NO: 203; and (f) an HVR-H3 sequence of SEQ ID NO: 204; and wherein the immunoconjugate comprises the formula: ##STR00044## wherein Val is valine; Cit is citrulline; and p ranges from 1 to 8. 41. The method of claim 40, wherein the cancerous B cell proliferative disorder is selected from the group consisting of lymphoma, myeloma, non-Hodgkins lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), aggressive NHL, indolent lymphoma, follicular lymphoma (FL), relapsed aggressive NHL, relapsed indolent NHL, relapsed NHL, refractory NHL, refractory indolent NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), and mantle cell lymphoma. 42. The method of claim 40, wherein the cancerous B cell proliferative disorder is non-Hodgkins lymphoma (NHL). 43. The method of claim 40, wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 44. The method of claim 40, wherein the cancerous B cell proliferative disorder is relapsed NHL or refractory NHL. 45. The method of claim 40, wherein the cancerous B cell proliferative disorder is follicular lymphoma (FL). 46. The method of claim 40, further comprising administering to the human an effective amount of another therapeutic agent. 47. The method of claim 46, wherein the therapeutic agent is selected from the group consisting of an antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressive agent, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, a cancer vaccine, and a growth-inhibitory agent. 48. The method of claim 46, wherein the therapeutic agent is selected from one or more of tamoxifen, letrozole, exemestane, anastrozole, irinotecan, cetuximab, fulvestrant, vinorelbine, erlotinib, bevacizumab, vincristine, imatinib mesylate, sorafenib, lapatinib, trastuzumab, cisplatin, gemcitabine, methotrexate, vinblastine, carboplatin, paclitaxel, 5-fluorouracil, doxorubicin, bortezomib, melphalan, prednisone, and docetaxel. 49. The method of claim 46, wherein the therapeutic agent is an anti-CD20 antibody. 50. The method of claim 46, wherein the therapeutic agent is an anti-CD20 antibody and wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 51. The method of claim 46, wherein the therapeutic agent is an anti-CD20 antibody and wherein the cancerous B cell proliferative disorder is follicular lymphoma (FL). 52. The method of claim 49, wherein the anti-CD20 antibody is rituximab. 53. The method of claim 46, wherein the therapeutic agent is a chemotherapeutic agent. 54. The method of claim 53, wherein the chemotherapeutic agent comprises one or more of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone. 55. The method of claim 53, wherein the chemotherapeutic agent comprises cyclophosphamide, doxorubicin, and prednisone. 56. The method of claim 49, further comprising administering to the human a chemotherapeutic agent. 57. The method of claim 56, wherein the chemotherapeutic agent comprises cyclophosphamide, doxorubicin, and prednisone. 58. The method of claim 57, wherein the cancerous B cell proliferative disorder is non-Hodgkin's lymphoma (NHL). 59. The method of claim 58, wherein the anti-CD20 antibody is rituximab. 60. The method of claim 57, wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 61. A method of treating a cancerous B cell proliferative disorder comprising administering to a human an effective amount of an immunoconjugate comprising an anti-CD79b antibody (Ab), wherein Ab comprises the heavy chain variable domain sequence of SEQ ID NO: 208; and the light chain variable domain sequence of SEQ ID NO: 207; and wherein the immunoconjugate comprises the formula: ##STR00045## wherein Val is valine; Cit is citrulline; and p ranges from 1 to 8. 62. The method of claim 61, wherein the cancerous B cell proliferative disorder is selected from the group consisting of lymphoma, myeloma, non-Hodgkins lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), aggressive NHL, indolent lymphoma, follicular lymphoma (FL), relapsed aggressive NHL, relapsed indolent NHL, relapsed NHL, refractory NHL, refractory indolent NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), and mantle cell lymphoma. 63. The method of claim 61, wherein the cancerous B cell proliferative disorder is non-Hodgkins lymphoma (NHL). 64. The method of claim 61, wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 65. The method of claim 61, wherein the cancerous B cell proliferative disorder is relapsed NHL or refractory NHL. 66. The method of claim 61, wherein the cancerous B cell proliferative disorder is follicular lymphoma (FL). 67. The method of claim 61, further comprising administering to the human an effective amount of another therapeutic agent. 68. The method of claim 67, wherein the therapeutic agent is selected from the group consisting of an antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressive agent, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, a cancer vaccine, and a growth-inhibitory agent. 69. The method of claim 67, wherein the therapeutic agent is selected from one or more of tamoxifen, letrozole, exemestane, anastrozole, irinotecan, cetuximab, fulvestrant, vinorelbine, erlotinib, bevacizumab, vincristine, imatinib mesylate, sorafenib, lapatinib, trastuzumab, cisplatin, gemcitabine, methotrexate, vinblastine, carboplatin, paclitaxel, 5-fluorouracil, doxorubicin, bortezomib, melphalan, prednisone, and docetaxel. 70. The method of claim 67, wherein the therapeutic agent is an anti-CD20 antibody. 71. The method of claim 67, wherein the therapeutic agent is an anti-CD20 antibody and wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 72. The method of claim 67, wherein the therapeutic agent is an anti-CD20 antibody and wherein the cancerous B cell proliferative disorder is follicular lymphoma (FL). 73. The method of claim 70, wherein the anti-CD20 antibody is rituximab. 74. The method of claim 67, wherein the therapeutic agent is a chemotherapeutic agent. 75. The method of claim 74, wherein the chemotherapeutic agent comprises one or more of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone. 76. The method of claim 74, wherein the chemotherapeutic agent comprises cyclophosphamide, doxorubicin, and prednisone. 77. The method of claim 70, further comprising administering to the human a chemotherapeutic agent. 78. The method of claim 77, wherein the chemotherapeutic agent comprises cyclophosphamide, doxorubicin, and prednisone. 79. The method of claim 78, wherein the cancerous B cell proliferative disorder is non-Hodgkin's lymphoma (NHL). 80. The method of claim 79, wherein the anti-CD20 antibody is rituximab. 81. The method of claim 78, wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 82. A method of treating a cancerous B cell proliferative disorder comprising administering to a human an effective amount of an immunoconjugate comprising an anti-CD79b antibody (Ab), wherein Ab comprises the heavy chain sequence of SEQ ID NO: 308 and the light chain sequence of SEQ ID NO: 307; and wherein the immunoconjugate comprises the formula: ##STR00046## wherein Val is valine; Cit is citrulline; and p ranges from 1 to 8. 83. The method of claim 82, wherein the cancerous B cell proliferative disorder is selected from the group consisting of lymphoma, myeloma, non-Hodgkins lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), aggressive NHL, indolent lymphoma, follicular lymphoma (FL), relapsed aggressive NHL, relapsed indolent NHL, relapsed NHL, refractory NHL, refractory indolent NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), and mantle cell lymphoma. 84. The method of claim 82, wherein the cancerous B cell proliferative disorder is non-Hodgkins lymphoma (NHL). 85. The method of claim 82, wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 86. The method of claim 82, wherein the cancerous B cell proliferative disorder is relapsed NHL or refractory NHL. 87. The method of claim 82, wherein the cancerous B cell proliferative disorder is follicular lymphoma (FL). 88. The method of claim 82, further comprising administering to the human an effective amount of another therapeutic agent. 89. The method of claim 88, wherein the therapeutic agent is selected from the group consisting of an antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressive agent, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, a cancer vaccine, and a growth-inhibitory agent. 90. The method of claim 88, wherein the therapeutic agent is selected from one or more of tamoxifen, letrozole, exemestane, anastrozole, irinotecan, cetuximab, fulvestrant, vinorelbine, erlotinib, bevacizumab, vincristine, imatinib mesylate, sorafenib, lapatinib, trastuzumab, cisplatin, gemcitabine, methotrexate, vinblastine, carboplatin, paclitaxel, 5-fluorouracil, doxorubicin, bortezomib, melphalan, prednisone, and docetaxel. 91. The method of claim 88, wherein the therapeutic agent is an anti-CD20 antibody. 92. The method of claim 88, wherein the therapeutic agent is an anti-CD20 antibody and wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 93. The method of claim 88, wherein the therapeutic agent is an anti-CD20 antibody and wherein the cancerous B cell proliferative disorder is follicular lymphoma (FL). 94. The method of claim 91, wherein the anti-CD20 antibody is rituximab. 95. The method of claim 90, wherein the therapeutic agent is a chemotherapeutic agent. 96. The method of claim 95, wherein the chemotherapeutic agent comprises one or more of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone. 97. The method of claim 95, wherein the chemotherapeutic agent comprises cyclophosphamide, doxorubicin, and prednisone. 98. The method of claim 91, further comprising administering to the human a chemotherapeutic agent. 99. The method of claim 98, wherein the chemotherapeutic agent comprises cyclophosphamide, doxorubicin, and prednisone. 100. The method of claim 99, wherein the cancerous B cell proliferative disorder is non-Hodgkin's lymphoma (NHL). 101. The method of claim 100, wherein the anti-CD20 antibody is rituximab. 102. The method of claim 9, wherein the cancerous B cell proliferative disorder is diffuse large B-cell lymphoma (DLBCL). 103. The method of claim 4, wherein p is from 2 to 5. 104. The method of claim 40, wherein p is from 2 to 5. 105. The method of claim 61, wherein p is from 2 to 5. 106. The method of claim 82, wherein p is from 2 to 5. 107. A method of treating a diffuse large B-cell lymphoma, comprising administering to a human an effective amount of an immunoconjugate comprising an anti-CD79b antibody (Ab), wherein Ab comprises (a) an HVR-L1 sequence of SEQ ID NO: 194; (b) an HVR-L2 sequence of SEQ ID NO: 195; (c) an HVR-L3 sequence of SEQ ID NO: 196; (d) an HVR-H1 sequence of SEQ ID NO: 202; (e) an HVR-H2 sequence of SEQ ID NO: 203; and (f) an HVR-H3 sequence of SEQ ID NO: 204; and wherein the immunoconjugate comprises the formula: ##STR00047## wherein Val is valine; Cit is citrulline; and p ranges from 1 to 8; the method further comprising administering to the human an effective amount of each of rituximab, cyclophosphamide, doxorubicin, and prednisone. 108. A method of treating a diffuse large B-cell lymphoma, comprising administering to a human an effective amount of an immunoconjugate comprising an anti-CD79b antibody (Ab), wherein Ab comprises the heavy chain variable domain sequence of SEQ ID NO: 208 and the light chain variable domain sequence of SEQ ID NO: 207; and wherein the immunoconjugate comprises the formula: ##STR00048## wherein Val is valine; Cit is citrulline; and p ranges from 1 to 8; the method further comprising administering to the human an effective amount of each of rituximab, cyclophosphamide, doxorubicin, and prednisone. 109. A method of treating a diffuse large B-cell lymphoma, comprising administering to a human an effective amount of an immunoconjugate comprising an anti-CD79b antibody (Ab), wherein Ab comprises the heavy chain sequence of SEQ ID NO: 308 and the light chain sequence of SEQ ID NO: 307; and wherein the immunoconjugate comprises the formula: ##STR00049## wherein Val is valine; Cit is citrulline; and p ranges from 1 to 8; the method further comprising administering to the human an effective amount of each of rituximab, cyclophosphamide, doxorubicin, and prednisone. 110. A method of treating a diffuse large B-cell lymphoma, comprising administering to a human an effective amount of an immunoconjugate comprising an anti-CD79b antibody (Ab), wherein Ab comprises the heavy chain variable domain sequence of SEQ ID NO: 208 and the light chain variable domain sequence of SEQ ID NO: 207; and wherein the immunoconjugate comprises the formula: ##STR00050## wherein Val is valine; Cit is citrulline; and p ranges from 1 to 8; the method further comprising administering to the human an effective amount of one or more chemotherapeutic agents. 111. A method of treating a diffuse large B-cell lymphoma, comprising administering to a human an effective amount of an immunoconjugate comprising an anti-CD79b antibody (Ab), wherein Ab comprises the heavy chain sequence of SEQ ID NO: 308; and the light chain sequence of SEQ ID NO: 307; and wherein the immunoconjugate comprises the formula: ##STR00051## wherein Val is valine; Cit is citrulline; and p ranges from 1 to 8; the method further comprising administering to the human an effective amount of one or more chemotherapeutic agents. 112. The method of claim 110, wherein the method further comprises administering to the human an effective amount of an anti-CD20 antibody. 113. The method of claim 111, wherein the method further comprises administering to the human an effective amount of an anti-CD20 antibody. 114. The method of claim 107, wherein p is from 3 to 4. 115. The method of claim 108, wherein p is from 3 to 4. 116. The method of claim 109, wherein p is from 3 to 4. 117. The method of claim 110, wherein p is from 3 to 4. 118. The method of claim 111, wherein p is from 3 to 4.

Details for Patent 10,494,432

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2027-07-16
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2027-07-16
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2027-07-16