	US 11,033,495 C1 (13,014th)
	Manufacturing of bupivacaine multivesicular liposomes
Jeffrey S. Hall, San Diego, CA (US); David J. Turnbull, San Diego, CA (US); John J. Grigsby, Jr., San Diego, CA (US); Soroush M. Ardekani, San Diego, CA (US); Paige N. Davis, San Diego, CA (US); Louie D. Garcia, San Diego, CA (US); Stephanie M. Kurz, San Diego, CA (US); and Kathleen D. A. Los, San Diego, CA (US)
Filed by Pacira Pharmaceuticals, Inc., San Diego, CA (US)
Assigned to Pacira Pharamaceuticals, Inc.
Reexamination Request No. 90/019,692, Oct. 3, 2024.
Reexamination Certificate for Patent 11,033,495, issued Jun. 15, 2021, Appl. No. 17/156,400, Jan. 22, 2021.
Ex Parte Reexamination Certificate issued on Aug. 19, 2025.
Int. Cl. A61K 9/12 (2006.01); A61K 9/1277 (2025.01); A61K 31/451 (2006.01); B01D 15/16 (2006.01); B01D 61/14 (2006.01); B01F 3/22 (2006.01)

CPC A61K 9/1277 (2013.01) [A61K 31/451 (2013.01); B01D 2315/10 (2013.01); B01D 2315/16 (2013.01); B01F 2215/044 (2013.01); B01F 2215/0477 (2013.01); B01F 2215/0481 (2013.01)]

Attention is directed to the decision of Pacira Pharm. Inc. v. eVenus Pharm. Labs. Inc. 2:21-cv-19829 D.N.J. Aug. 27, 2024. This reexamination may not have resolved all questions raised by this decision. See 37 CFR 1.552(c) for ex parte reexamination and 37 CFR 1.906(c) for inter partes reexamination.

AS A RESULT OF REEXAMINATION, IT HAS BEEN DETERMINED THAT:

Claim 1 is cancelled.

Claim 8 is determined to be patentable as amended.

New claims 23-110 are added and determined to be patentable.

Claims 2-7 and 9-22 were not reexamined.

8. The composition of claim 7, wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. . for six months.

[ 23. The composition of claim 7, wherein the erucic acid concentration in the composition is from about 22 μg/mL to about 23 μg/mL after the composition is stored at 25° C. for one month.]

[ 24. The composition of claim 7, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for erucic acid concentration of no more than about 3.3 after being stored at 25° C. for each of 1 month, 3 months, and 6 months.]

[ 25. The composition of claim 1, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for erucic acid concentration of no more than about 2.5 after being stored at 25° C. for one month.]

[ 26. The composition of claim 1, wherein the erucic acid concentration in the composition is no more than about 38 μg/mL after the composition is stored at 25° C. for two months; and

wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for erucic acid concentration of no more than about 3.1 after being stored at 25° C. for two months.]

[ 27. The composition of claim 1, wherein the erucic acid concentration in the composition is no more than about 54 μg/mL after the composition is stored at 25° C. for three months; and

[ 28. The composition of claim 7, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for erucic acid concentration of no more than about 0.6 after being stored at 25° C. for six months.]

[ 29. The composition of claim 7, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for supernatant pH of no more than about 0.8 after being stored at 25° C. for each of 1 month, 3 months, and 6 months.]

[ 30. The composition of claim 1, wherein the composition has a supernatant pH of about 7.4.]

[ 31. The composition of claim 1, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for supernatant pH of no more than about 0.8 after being stored at 25° C. for 1 month.]

[ 32. The composition of claim 7, wherein the bupivacaine encapsulated MVLs have an internal pH of about 5.5.]

[ 33. The composition of claim 7, wherein the DEPC and the DPPG are present in the bupivacaine encapsulated MVLs in a mass ratio of DEPC: DPPG from about 15:1 to about 20:1.]

[ 34. The composition of claim 33, wherein the DEPC and the DPPG are present in the bupivacaine encapsulated MVLs in a mass ratio of DEPC: DPPG from about 15:1 to about 17:1. ]

[ 35. The composition of claim 7, wherein the DEPC and the DPPG are present in the final aqueous suspension in a mass ratio of DEPC: DPPG from about 7:1 to about 10:1.]

[ 36. The composition of claim 35, wherein the DEPC and the DPPG are present in the final aqueous suspension in a mass ratio of DEPC: DPPG of about 8:1.]

[ 37. The composition of claim 1, wherein the bupivacaine encapsulated MVLs have an internal lysine concentration of about 0.08 mg/mL.]

[ 38. The composition of claim 1, wherein the bupivacaine encapsulated MVLs have an internal lysine concentration of about 0.03 mg/mL.]

[ 39. The composition of claim 38, wherein the bupivacaine encapsulated MVLs have an internal pH of about 5.5.]

[ 40. The composition of claim 1, wherein the final aqueous suspension has a lysine concentration of about 0.12 mg/mL.]

[ 41. The composition of claim 1, wherein the bupivacaine encapsulated MVLs have an internal dextrose concentration from about 1.25 mg/mL to about 1.32 mg/mL.]

[ 42. The composition of claim 41, wherein the bupivacaine encapsulated MVLs have an internal lysine concentration of about 0.03 mg/mL.]

[ 43. The composition of claim 1, wherein the final aqueous suspension has a dextrose concentration from about 2.15 mg/mL to about 2.19 mg/mL.]

[ 44. The composition of claim 43, wherein the final aqueous suspension has a lysine concentration of about 0.12 mg/mL.]

[ 45. The composition of claim 1, wherein the composition has an increase in erucic acid concentration of no more than about 15 μg/mL per month on average over a period of time from (i) after being stored for one month at 25° C. to (ii) being stored for six months at 25° C.]

[ 46. The composition of claim 45, wherein the erucic acid concentration in the composition is from about 22 μg/mL to about 23 μg/mL after the composition is stored at 25° C. for one month.]

[ 47. The composition of claim 1, wherein the composition has an increase in erucic acid concentration of no more than about 15 μg/mL per month on average over a period of time from (i) after being stored for one month at 25° C. to (ii) being stored for two months at 25° C.]

[ 48. The composition of claim 47, wherein the erucic acid concentration in the composition is from about 22 μg/mL to about 23 μg/mL after the composition is stored at 25° C. for one month.]

[ 49. The composition of claim 1, wherein the composition has an increase in erucic acid concentration of no more than about 15 μg/mL per month on average over a period of time from (i) after being stored for two months at 25° C. to (ii) being stored for three months at 25° C.]

[ 50. The composition of claim 1, wherein the composition has an increase in erucic acid concentration of no more than about 15 μg/mL per month on average over a period of time from (i) after being stored for three months at 25° C. to (ii) being stored for six months at 25° C.]

[ 51. The composition of claim 1, wherein the composition increases in erucic acid concentration in accordance with changes in pH by no more than 104 μg/mL per pH unit on average from the second month to the sixth month of storage at 25° C.]

[ 52. The composition of claim 7, wherein the final aqueous suspension has a percent packed particle volume (% PPV) from about 32% to about 44%.]

[ 53. The composition of claim 52, wherein the final aqueous suspension has a percent packed particle volume (% PPV) from about 35% to about 40%.]

[ 54. The composition of claim 53, wherein the final aqueous suspension has a percent packed particle volume (% PPV) from about 36% to about 38%.]

[ 55. The composition of claim 7, wherein the volatile water-immiscible solvent solution, the second aqueous solution, and the saline solution are each filtered through a 0.2 μm filter.]

[ 56. The composition of claim 7, wherein the composition has an amount of free bupivacaine that is about 8% or less by weight of the total amount of the bupivacaine in the composition.]

[ 57. The composition of claim 56, wherein the composition has an amount of free bupivacaine that is about 5% or less by weight of the total amount of the bupivacaine in the composition.]

[ 58. A composition of bupivacaine encapsulated multivesicular liposomes (MVLs) prepared by a commercial scale process, the commercial scale process comprising:

(a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a water-in-oil first emulsion, wherein the volatile water-immiscible solvent solution comprises bupivacaine, 1, 2-dierucoylphosphatidylcholine (DEPC), 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), and at least one neutral lipid;

(b) mixing the water-in-oil first emulsion with a second aqueous solution to form a water-in-oil-in-water second emulsion, wherein the second aqueous solution comprises lysine and dextrose;

(c) removing the volatile water-immiscible solvent from the water-in-oil-in-water second emulsion to form a first aqueous suspension of bupivacaine encapsulated MVLs having a first volume;

(d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated MVLs by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated MVLs having a second volume;

(e) exchanging the aqueous supernatant of the second aqueous suspension with a saline solution by diafiltration to provide a third aqueous suspension of bupivacaine encapsulated MVLs having a third volume; and

(f) further reducing the third volume of the third aqueous suspension by microfiltration to provide a final aqueous suspension of bupivacaine encapsulated MVLs having a target concentration from about 12.6 mg/mL to about 17.0 mg/ml;

wherein all steps are carried out under aseptic conditions;

wherein the erucic acid concentration in the composition is from about 22 μg/mL to about 23 μg/mL after the composition is stored at 25° C. for one month; and

wherein the final aqueous suspension of bupivacaine encapsulated MVLs has a volume of about 150 L to about 250 L.]

[ 59. The composition of claim 58, wherein the final aqueous suspension of bupivacaine encapsulated MVLs has a volume of about 200 L.]

[ 60. The composition of claim 58, wherein the final aqueous suspension of bupivacaine encapsulated MVLs has a volume of about 225 L.]

[ 61. The composition of claim 58, wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for one month.]

[ 62. The composition of claim 58, wherein the erucic acid concentration in the composition is no more than about 38 μg/mL after the composition is stored at 25° C. for two months.]

[ 63. The composition of claim 62, wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for two months.]

[ 64. The composition of claim 58, wherein the erucic acid concentration in the composition is no more than about 54 μg/mL after the composition is stored at 25° C. for three months.]

[ 65. The composition of claim 64, wherein the composition has a pH of about 6.9 after the composition is stored at 25° C. for three months.]

[ 66. The composition of claim 58, wherein the erucic acid concentration in the composition is no more than about 99 μg/mL after the composition is stored at 25° C. for six months.]

[ 67. The composition of claim 66, wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.]

[ 68. The composition of claim 58, wherein the mixing in step (a) is performed using a first mixer at a high shear speed.]

[ 69. The composition of claim 68, wherein the high shear speed is from about 1100 rpm to about 1200 rpm.]

[ 70. The composition of claim 69, wherein the high shear speed is about 1150 rpm.]

[ 71. The composition of claim 70, wherein the mixing time in step (a) is about 65 to 75 minutes.]

[ 72. The composition of claim 58, wherein the mixing in step (b) is performed using a second mixer at a low shear speed.]

[ 73. The composition of claim 72, wherein the low shear speed is from about 450 rpm to about 510 rpm.]

[ 74. The composition of claim 73, wherein the low shear speed is about 495 rpm.]

[ 75. The composition of claim 74, wherein the mixing time in step (b) is about 60 to 65 seconds.]

[ 76. The composition of claim 58, wherein the concentration of bupivacaine in the composition is about 13.3 mg/mL.]

[ 77. The composition of claim 58, wherein the d₅₀of the multivesicular liposomes in the composition is about 27 μm.]

[ 78. The composition of claim 58, wherein the internal pH of the bupivacaine encapsulated MVLs in the composition is about 5.5.]

[ 79. The composition of claim 67, wherein the bupivacaine encapsulated MVLs have an internal pH of about 5.5.]

[ 80. The composition of claim 58, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for erucic acid concentration of no more than about 3.3 after being stored at 25° C. for each of 1 month, 3 months, and 6 months.]

[ 81. The composition of claim 58, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for erucic acid concentration of no more than about 2.5 after being stored at 25° C. for one month.]

[ 82. The composition of claim 58, wherein the erucic acid concentration in the composition is no more than about 38 μg/mL after the composition is stored at 25° C. for two months; and

[ 83. The composition of claim 58, wherein the erucic acid concentration in the composition is no more than about 54 μg/mL after the composition is stored at 25° C. for three months; and

[ 84. The composition of claim 58, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for erucic acid concentration of no more than about 0.6 after being stored at 25° C. for six months.]

[ 85. The composition of claim 58, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for supernatant pH of no more than about 0.8 after being stored at 25° C. for each of 1 month, 3 months, and 6 months.]

[ 86. The composition of claim 58, wherein the composition has a supernatant pH of about 7.4.]

[ 87. The composition of claim 58, wherein the composition is produced in the commercial scale process in at least three batches, and the at least three batches have a % relative standard deviation (RSD) for supernatant pH of no more than about 0.8 after being stored at 25° C. for 1 month.]

[ 88. The composition of claim 58, wherein the DEPC and the DPPG are present in the bupivacaine encapsulated MVLs in a mass ratio of DEPC: DPPG from about 15:1 to about 20:1.]

[ 89. The composition of claim 88, wherein the DEPC and the DPPG are present in the bupivacaine encapsulated MVLs in a mass ratio of DEPC: DPPG from about 15.1 to about 17:1.]

[ 90. The composition of claim 58, wherein the DEPC and the DPPG are present in the final aqueous suspension in a mass ratio of DEPC: DPPG from about 7:1 to about 10:1.]

[ 91. The composition of claim 90, wherein the DEPC and the DPPG are present in the final aqueous suspension in a mass ratio of DEPC: DPPG of about 8:1.]

[ 92. The composition of claim 58, wherein the bupivacaine encapsulated MVLs have an internal lysine concentration of about 0.08 mg/mL.]

[ 93. The composition of claim 58, wherein the bupivacaine encapsulated MVLs have an internal lysine concentration of about 0.03 mg/mL.]

[ 94. The composition of claim 93, wherein the bupivacaine encapsulated MVLs have an internal pH of about 5.50.]

[ 95. The composition of claim 58, wherein the final aqueous suspension has a lysine concentration of about 0.12 mg/mL.]

[ 96. The composition of claim 58, wherein the bupivacaine encapsulated MVLs have an internal dextrose concentration from about 1.25 mg/mL to about 1.32 mg/mL.]

[ 97. The composition of claim 96, wherein the bupivacaine encapsulated MVLs have an internal lysine concentration of about 0.03 mg/mL.]

[ 98. The composition of claim 58, wherein the final aqueous suspension has a dextrose concentration from about 2.15 mg/mL to about 2.19 mg/mL.]

[ 99. The composition of claim 98, wherein the final aqueous suspension has a lysine concentration of about 0.12 mg/mL.]

[ 100. The composition of claim 58, wherein the composition has an increase in erucic acid concentration of no more than about 15 μg/mL per month on average over a period of time from (i) after being stored for one month at 25° C. to (ii) being stored for six months at 25° C.]

[ 101. The composition of claim 58, wherein the composition has an increase in erucic acid concentration of no more than about 15 μg/mL per month on average over a period of time from (i) after being stored for one month at 25° C. to (ii) being stored for two months at 25° C.]

[ 102. The composition of claim 58, wherein the composition has an increase in erucic acid concentration of no more than about 15 μg/mL per month on average over a period of time from (i) after being stored for two months at 25° C. to (ii) being stored for three months at 25° C.]

[ 103. The composition of claim 58, wherein the composition has an increase in erucic acid concentration of no more than about 15 μg/mL per month on average over a period of time from (i) after being stored for three months at 25° C. to (ii) being stored for six months at 25° C.]

[ 104. The composition of claim 58, wherein the composition increases in erucic acid concentration in accordance with changes in pH by no more than 104 μg/mL per pH unit on average from the second month to the sixth month of storage at 25° C.]

[ 105. The composition of claim 58, wherein the final aqueous suspension has a percent packed particle volume (% PPV) from about 32% to about 44%.]

[ 106. The composition of claim 105, wherein the final aqueous suspension has a percent packed particle volume (% PPV) from about 35% to about 40%.]

[ 107. The composition of claim 106, wherein the final aqueous suspension has a percent packed particle volume (% PPV) from about 36% to about 38%.]

[ 108. The composition of claim 58, wherein the volatile water-immiscible solvent solution, the second aqueous solution, and the saline solution are each filtered through a 0.2 μm filter.]

[ 109. The composition of claim 58, wherein the composition has an amount of free bupivacaine that is about 8% or less by weight of the total amount of the bupivacaine in the composition.]

[ 110. The composition of claim 109, wherein the composition has an amount of free bupivacaine that is about 5% or less by weight of the total amount of the bupivacaine in the composition.]