DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. The response filed on January 21, 2026 to the restriction requirement of November 21, 2025 has been received. Applicant has elected for examination Group I, and the species of:
A. Stabilizer trehalose (claims 1, 4, 27);
B. Non-ionic surfactant poloxamer 188 (claims 1, 13, 27);
C. formulation further comprising L-arginine (claim 3);
D. formulation NOT further comprising anti-oxidant (withdraw claims 14-16);
E. formulation NOT further comprising metal chelator (withdraw claims 17-18); and
F. low dose pembrolizumab concentration of 25 mg/ml (claim 20).
Because Applicant did not distinctly and specifically point out any errors in the restriction requirement, the election has been treated as an election without traverse (MPEP 818.03(a)). Claims 1-30 are pending. The species of non-ionic surfactant polysorbate 80 (claim 11) has been rejoined for examination. Claims 22-26, 28-30 have been withdrawn from further consideration by the examiner under 35 CFR 1.142(b) as being drawn to non-elected inventions. Claims 5-10, 12, 14-18 and 21 are withdrawn as being drawn to non-elected species. Claims 1-4, 11, 13, 19, 20, and 27 are currently under prosecution as drawn to the elected and rejoined species.
Claim Objections
2. Claims 1 and 27 are objected to because of the following informalities: It appears the unit of measurement of “w/v” for “d) about 0.01% to about 0.10% non-ionic surfactant” is missing. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
3. Claim(s) 1-4, 11, 19, 20, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 9,220,776, Sharma et al, issued December 2015; in view of US Patent Application Publication 2016/0304607, Sadineni et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015).
Sharma teaches an aqueous (liquid) pharmaceutical formulation of anti-PD-1 antibody comprising:
(i) 25 mg/ml or 25-100 mg/ml anti-PD-1 antibody;
(ii) 70 mg/ml sucrose stabilizer;
(iii) about 1.55 mg/ml or 10 mM histidine buffer;
(iv) ~ 0.2 mg/ml (= 0.02 %) non-ionic surfactant polysorbate 80; and
(v) pH 5.0-6.0;
wherein the anti-PD-1 antibody is h409A11 comprising heavy and light chain SEQ ID NOs:31 and 36, which is also known as MK-3475 or pembrolizumab (col. 23, lines 45-56; claims 1-6; Tables 3-6; Example 1).
Sharma teaches cryoprotectants and lyoprotectants of the antibody formulation can be sucrose or trehalose (col. 13, lines 17-41).
Sharma additionally suggests adding amino acid arginine to the composition as a cryoprotectant that provides stability to the protein against freezing-induced stresses (col. 13, lines 24-25).
Sharma does not teach substituting in about 6% - about 8% weight/volume (w/v) trehalose for the sucrose stabilizer into the formulation.
Sharma does not teach the composition comprises about 1% to about 3% w/v L-arginine.
Sadineni suggest a pharmaceutical formulation comprising:
(i) an anti-PD-1 antibody
(ii) trehalose stabilizer ([21]; [163]; claim 39);
(iii) histidine at about 5mM to about 20 mM or at 20 mM (claims 31, 55, 57);
(iv) non-ionic surfactant polysorbate 80 at about 0.01% to about 0.10% ([23]; [163]; [167]; claims 41, 48, 49, 55); and
(v) pH about 5.0 to about 6.0 (claims 35, 55, 57);
wherein the anti-PD-1 antibody is pembrolizumab (MK-3475) ([9]; [111]; [119]; [135-137]; [148-149]; claim 3).
Sadenini additionally suggests adding arginine to the formulation as a stabilizing agent ([21]; claim 39).
Li teaches a pharmaceutical formulation comprising:
(i) an anti-PD-1 antibody in the range of 20-50 mg/ml (p. 7);
(ii) trehalose stabilizer in the amount of 60 to 90 mg/ml (= 6% to 9% w/v) (p. 3-4; p. 6; p. 8; Example 1, 4, 5, 6, 8);
(iii) histidine buffer 10 mM to 30 mM (p. 7);
(iv) non-ionic surfactant polysorbate 80 or polysorbate 20 or poloxamer (p. 3-4; p. 7; Examples 1, 4, 5, 6, 8); and
(v) pH in the range of 5.2 – 6.0 (p. 3-4; p. 7; Examples 1, 4, 5, 6, 8).
Li teaches (p. 18):
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Li further suggests adding amino acids including arginine at amounts of about 100 mM to about 150 mM (= 1.742% w/v to 2.613% w/v) (p. 8, lines 21-28).
Cosenza teaches an aqueous antibody pharmaceutical formulation comprising:
(i) a therapeutic antibody in the range of 20-150 mg/ml;
(ii) trehalose stabilizer at 120 (4% w/v) or 220 mM (7.5% w/v);
(iii) histidine buffer at 20 mM;
(iv) non-ionic surfactant polysorbate 20 or poloxamer 188 at 0.01% to 0.1% or 0.04%;
(v) pH in the range of 5.5 – 6.0; and
(vi) amino acid arginine-HCl (L-Arginine) at 50 mM (= 0.871% w/v).
See claims 1-24 and 35; Tables 5 and 16; paragraphs [9-63].
Cosenza teaches arginine-HCl functions as a stabilizer and buffer ([109]; [114]).
Bishop teaches an aqueous antibody pharmaceutical formulation comprising:
(i) a therapeutic antibody in the range of 10 mg/ml, 20 mg/ml, to 100 mg/ml;
(ii) trehalose stabilizer at 5%, 8% or 10%;
(iii) histidine buffer at 20 or 25 mM;
(iv) non-ionic surfactant polysorbate 80, polysorbate 20, or poloxamer 188 at 0.01 to 0.1%;
(v) pH in the range of 5.5 – 6.0; and
(vi) amino acid arginine-HCl (L-Arginine) at ([126]).
Also see paragraphs [30]; [32]; [48]; Figure 1; [85-109]; [114-117]; [127-129]; [137-148]; [452- 453]; claims 1, 5-9.
Bishop additionally teaches arginine is commonly added as an excipient that imparts beneficial physical property to the formulation ([30]).
Connolly established the stabilizing function of trehalose and optimizing effective ranges of trehalose for a monoclonal antibody composition, wherein the composition comprised 25 mg/ml antibody or 100 mg/ml antibody, 20 mM histidine at pH 6.0, and a range of trehalose from about 3.4% to about 6.8% w/v (Formula Composition p. 4171, col. 2; Table 3 and 4). Connolly teaches sucrose is a known alternative to trehalose (p. 4183, col. 1) and demonstrates comparing antibody composition stability with trehalose or sucrose (Figure 2).
Trehalose stabilizer at about 6% to about 8% w/v:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute trehalose stabilizer at 6-8% w/v for the sucrose stabilizer in the pembrolizumab composition of Sharma. One would have been motivated to, and have a reasonable expectation of success to because: (1) Sharma suggests using trehalose as a stabilizer; (2) all of Sharma, Sadineni, Li, Cosenza, Bishop, and Connolly teach and establish trehalose is a known stabilizer alternative to sucrose for antibody compositions and they are functional equivalents; (3) Li, Cosenza, Bishop, and Connolly teach or demonstrate known effective stabilizing amounts of trehalose in antibody compositions at about 6% to about 8% w/v; and (4) Sadineni, Li, Cosenza, Bishop, and Connolly teach or successfully demonstrate combining trehalose as the stabilizer with antibody, histidine buffer, non-ionic surfactant polysorbate 80; and at pH 5.0-6.0 to arrive at a stable antibody composition.
L-arginine at about 1% to about 3% w/v:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add amino acid L-arginine to the composition of Sharma and at about 1% to about 3% w/v. One would have been motivated to, and have a reasonable expectation of success to because: (1) Sharma suggests adding amino acid arginine to the composition as a stabilizer; and (2) Sadineni, Li, Consenza, and Bishop also teach additionally adding amino acid arginine or L-Arginine to the antibody composition as a common excipient, wherein Cosenza teaches arginine-HCl functions as a stabilizer and buffer and teaches adding Argining-HCl in the amount of about 1% w/v.
4. Claim(s) 13 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent 9,220,776, Sharma et al, issued December 2015; US Patent Application Publication 2016/0304607, Sadineni et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015), as applied to claims 1-4, 11, 19, 20, and 27 above, and further in view of Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
Sharma, Sadineni, Li, Bishop, and Connolly (the combined references) teach a pembrolizumab composition comprising:
(i) 25 mg/ml or 25-100 mg/ml anti-PD-1 antibody pembrolizumab;
(ii) about 6% to 8% w/v trehalose stabilizer;
(iii) about 10 mM histidine buffer;
(iv) about 0.02 % non-ionic surfactant polysorbate 80; and
(v) pH 5.0-6.0, as set forth above.
The combined references do not teach this specific composition comprises poloxamer 188 instead of polysorbate 80 as the non-ionic surfactant, however, Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers or poloxamer 188, as stated above.
Khan teaches the known and established function of polysorbate 80 and poloxamer 188 (P188) as non-ionic surfactants for reducing protein-protein interactions, reducing protein aggregates, and stabilizing protein or antibody formulations (Table 1; Figures 1 and 2). Khan also teaches methods for determining optimal concentration of surfactant are established. Khan teaches: “The most extensively used surfactants in biologics formulations are poly-oxy-ethylene (PEO) based surfactants, such as polysorbates 20 and 80 and poloxamer 188 (Fig. 1)” (section 2). Khan further teaches: “Typically, polysorbates are used in the range of 0.001–0.1% (w/v). The choice and concentrations of the surfactant are usually determined by screening for the lowest effective concentration which stabilizes the therapeutic protein upon interfacial stress. These concentrations are determined by stress studies generating air– water and/or ice–water interfaces, such as shaking, stirring or freezing/thawing at varied surfactant concentrations followed by aggregate and particulate analysis. The concentration chosen is usually significantly above the edge of failure to provide a sufficient safety margin and protection during real-time stress such as transportation, stirring, and freeze–thaw” (section 2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute poloxamer 188 for polysorbate 80 as the non-ionic surfactant in the antibody composition of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (2) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188 specifically and at 0.01 to 0.1%; and (3) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
5. Claims 1-4, 11, 13, 19, 20, and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 9,220,776 in view of US Patent Application Publication 2014/0234296, Sharma et al; US Patent Application Publication 2016/0304607, Sadineni et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015); and Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
U.S. Patent No. 9,220,776 claims:
1. A stable lyophilized pharmaceutical formulation of an anti-human PD-1 antibody, wherein the formulation made by lyophilizing an aqueous solution comprising:
a) 25-100 mg/mL of the anti-human PD-1 antibody;
b) about 70 mg/mL sucrose;
c) about 0.2 mg/mL polysorbate 80; and
d) about 10 mM Histidine buffer at about pH 5.0-pH 6.0, and
wherein the antibody, comprises:
i) a light chain comprising amino acid residues 20 to 237 of SEQ ID NO: 36; and
ii) a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO: 31.
2. The stable lyophilized pharmaceutical formulation of claim 1, wherein the anti-human PD-1 antibody is present at about 25 mg/mL in the aqueous solution.
3. The stable lyophilized pharmaceutical formulation of claim 1, wherein the aqueous solution has a pH of about 5.5.
4. The stable lyophilized pharmaceutical formulation of claim 1, wherein the aqueous solution comprises 25.0 mg/ml of the anti-human PD-1 antibody, 1.55 mg/ml histidine, 0.2 mg/ml polysorbate 80, 70 mg/ml sucrose, and has a pH of 5.5.
5. A stable liquid pharmaceutical formulation of an anti-human PD-1 antibody, comprising:
a) 25-100 mg/mL of the anti-human PD-1 antibody;
b) about 70 mg/mL sucrose;
c) about 0.2 mg/mL polysorbate 80; and
d) about 10 mM histidine buffer at pH 5.0-6.0,
wherein the antibody comprises:
i) a light chain comprising amino acid residues 20 to 237 of SEQ ID NO: 36; and
ii) a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO:31, and
wherein the liquid formulation has not been previously lyophilized.
6. The stable liquid pharmaceutical formulation of claim 5, which comprises 10 mM histidine, pH 5.5, 7% sucrose, 0.02% polysorbate 80, and 25.0 mg/ml of the anti-human PD-1 antibody.
7. A method of treating cancer in a human subject in need thereof, the method comprising administering an effective amount of a pharmaceutical formulation of an anti-human PD-1 antibody comprising:
a) 25-100 mg/mL of the anti-human PD-1 antibody, or antigen binding fragment thereof;
b) about 70 mg/mL sucrose;
c) about 0.2 mg/mL polysorbate 80; and
d) about 10 mM histidine buffer at pH 5.0-6.0,
wherein the antibody comprises:
i) a light chain comprising amino acid residues 20 to 237 of SEQ ID NO: 36; and
ii) a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO:31, and
wherein the pharmaceutical formulation is reconstituted from a stable lyophilized formulation or is a stable liquid formulation has not been previously lyophilized.
The US Patent does not claim the liquid pharmaceutical formulation of an anti-human PD-1 antibody comprises about 6% to about 8% w/v trehalose stabilizer, poloxamer 188 non-ionic surfactant, or further comprises about 1% to about 3% w/v L-arginine.
US Patent Application Publication 2014/0234296, Sharma, teaches an aqueous (liquid) pharmaceutical formulation of anti-PD-1 antibody comprising:
(i) 25 mg/ml or 25-100 mg/ml anti-PD-1 antibody;
(ii) 70 mg/ml sucrose stabilizer;
(iii) about 1.55 mg/ml or 10 mM histidine buffer;
(iv) ~ 0.2 mg/ml (= 0.02 % w/v) non-ionic surfactant polysorbate 80; and
(v) pH 5.0-6.0;
wherein the anti-PD-1 antibody is h409A11 comprising heavy and light chain SEQ ID NOs:31 and 36, which is also known as MK-3475 or pembrolizumab ([23-26]; [31-33]; claims 31-42; Tables 3-6; Example 1).
Sharma teaches cryoprotectants and lyoprotectants of the antibody formulation can be sucrose or trehalose ([76-78]).
Sharma additionally suggests adding amino acid arginine to the composition as a cryoprotectant that provides stability to the protein against freezing-induced stresses ([76]).
Sadineni, Li, Bishop, Connolly, and Khan teach as set forth above.
Trehalose stabilizer at about 6% to about 8% w/v (claims 1, 4, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute trehalose stabilizer at 6-8% w/v for the sucrose stabilizer in the pembrolizumab composition of U.S. Patent No. 9,220,776. One would have been motivated to, and have a reasonable expectation of success to because: (1) all of Sharma, Sadineni, Li, Cosenza, Bishop, and Connolly teach and establish trehalose is a known stabilizer alternative to sucrose for antibody compositions and they are functional equivalents; (3) Li, Cosenza, Bishop, and Connolly teach or demonstrate known effective stabilizing amounts of trehalose in antibody compositions at about 6% to about 8% w/v; and (4) Sadineni, Li, Cosenza, Bishop, and Connolly teach or successfully demonstrate combining trehalose as the stabilizer with antibody, histidine buffer, non-ionic surfactant polysorbate 80; and at pH 5.0-6.0 to arrive at a stable antibody composition.
L-arginine at about 1% to about 3% w/v (claim 3):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add amino acid L-arginine to the composition of U.S. Patent No. 9,220,776 and at about 1% to about 3% w/v. One would have been motivated to, and have a reasonable expectation of success to because: (1) Sharma suggests adding amino acid arginine to the composition as a stabilizer; and (2) Sadineni, Li, Consenza, and Bishop also teach additionally adding amino acid arginine or L-Arginine to the antibody composition as a common excipient, wherein Cosenza teaches arginine-HCl functions as a stabilizer and buffer and teaches adding Argining-HCl in the amount of about 1% w/v.
Non-ionic surfactant poloxamer 188 at about 0.01% to about 0.10% (claims 1, 13, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute poloxamer 188 for polysorbate 80 as the non-ionic surfactant in the antibody composition of U.S. Patent No. 9,220,776. One would have been motivated to, and have a reasonable expectation of success to because: (1) U.S. Patent No. 9,220,776 claims formulating the antibody composition with a non-ionic surfactant at 0.02% w/v (0.2 mg/ml polysorbate 80); (2) Sharma, Sadineni, Li, Consenza, and Bishop all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (3) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188 specifically and at 0.01 to 0.1%; and (4) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations.
6. Claims 1-4, 11, 13, 19, 20, and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,633,476 in view of US Patent Application Publication 2014/0234296, Sharma et al; US Patent Application Publication 2016/0304607, Sadineni et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015); and Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
U.S. Patent No. 11,633,476 claims:
1. An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
a) about 100 mg/mL to about 200 mg/mL of an anti-human PD-1 antibody, or antigen binding fragment thereof;
b) about 5 mM to about 20 mM histidine buffer;
c) about 6% to about 8% weight/volume (w/v) sucrose;
d) about 0.01% to about 0.10% polysorbate 80; and
e) about 1 mM to about 20 mM L-methionine, or a pharmaceutically acceptable salt thereof,
wherein the anti-human PD-1 antibody or antigen binding fragment thereof comprises three light chain CDRs comprising CDRL1 of SEQ ID NO:1, CDRL2 of SEQ ID NO:2 and CDRL3 of SEQ ID NO:3 and three heavy chain CDRs of CDRH1 of SEQ ID NO:6, CDRH2 of SEQ ID NO:7 and CDRH3 of SEQ ID NO:8.
2. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation has a pH between 5.0 and 6.0.
3. The anti-human PD-1 antibody formulation of claim 1, further comprising from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
4. The anti-human PD-1 antibody formulation of claim 1, comprising:
a) about 100 to about 200 mg/mL of an anti-human PD-1 antibody, or antigen binding fragment thereof;
b) 8 mM to about 12 mM histidine buffer;
c) about 5 mM to about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof;
d) about 6% to about 8% w/v sucrose; and
e) 0.01% to about 0.04% w/v polysorbate 80.
5. The anti-human PD-1 antibody formulation of claim 4, comprising:
a) about 125 to about 200 mg/mL of an anti-human PD-1 antibody, or antigen binding fragment thereof;
b) about 10 mM histidine buffer;
c) about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof;
d) about 7% w/v sucrose; and
e) about 0.02% to w/v polysorbate 80.
6. The anti-human PD-1 antibody formulation of claim 5, wherein the antioxidant is L-methionine HCl.
7. The anti-human PD-1 antibody formulation of claim 5, further comprising from about 1.25% to about 2.5% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
8. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation further comprises a metal chelator.
9. The anti-human PD-1 antibody formulation of claim 8, wherein the metal chelator is diethylenetriaminepentaacetic acid (DTPA), which is present at a concentration of about 10 μM to about 30 μM.
10. The anti-human PD-1 antibody formulation of claim 1 that is a reconstituted solution from a lyophilized formulation.
11. The anti-human PD-1 antibody formulation of claim 1, wherein the anti-human PD-1 antibody or antigen binding fragment thereof comprises a VL region which comprises the amino acid sequence set forth in SEQ ID NO:4, and a VH region which comprises the amino acid sequence set forth in SEQ ID NO:9.
12. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation comprises a light chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO: 10.
13. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation comprises an anti-human PD-1 antibody that is pembrolizumab.
14. The formulation of claim 13, wherein the formulation is contained in an injection device.
15. The formulation of claim 13, wherein the formulation is contained in a glass vial.
16. The anti-human PD-1 antibody formulation of claim 1, wherein the concentration of the anti-human PD-1 antibody or antigen binding fragment thereof is about 165 to about 170 mg/ml.
The US Patent does not claim the pharmaceutical formulation of an anti-human PD-1 antibody comprises 25 mg/ml antibody, about 6% to about 8% w/v trehalose stabilizer, and poloxamer 188 non-ionic surfactant.
Sharma, Sadineni, Li, Bishop, Connolly, and Khan teach as set forth above.
25 mg/ml pembrolizumab (claims 1, 20, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the formula of the US Patent to comprise 25 mg/ml of pembrolizumab. One would have been motivated to, and have a reasonable expectation of success to because Sharma teaches a pembrolizumab formulation, comprising the same excipients as recited in the claims of the US Patent, can also comprise 25 mg/ml of pembrolizumab.
Trehalose stabilizer at about 6% to about 8% w/v (claims 1, 4, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute trehalose stabilizer at 6-8% w/v for the sucrose stabilizer in the pembrolizumab composition of the U.S. Patent. One would have been motivated to, and have a reasonable expectation of success to because: (1) all of Sharma, Sadineni, Li, Cosenza, Bishop, and Connolly teach and establish trehalose is a known stabilizer alternative to sucrose for antibody compositions and they are functional equivalents; (3) Li, Cosenza, Bishop, and Connolly teach or demonstrate known effective stabilizing amounts of trehalose in antibody compositions at about 6% to about 8% w/v; and (4) Sadineni, Li, Cosenza, Bishop, and Connolly teach or successfully demonstrate combining trehalose as the stabilizer with antibody, histidine buffer, non-ionic surfactant polysorbate 80; and at pH 5.0-6.0 to arrive at a stable antibody composition.
Non-ionic surfactant poloxamer 188 at about 0.01% to about 0.10% (claims 1, 13, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute poloxamer 188 for polysorbate 80 as the non-ionic surfactant in the antibody composition of the U.S. Patent. One would have been motivated to, and have a reasonable expectation of success to because: (1) the U.S. Patent claims formulating the antibody composition with a non-ionic surfactant at about 0.01% to about 0.10%; (2) Sharma, Sadineni, Li, Consenza, and Bishop all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (3) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188, specifically, and at 0.01 to 0.1%; and (4) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations.
7. Claims 1-4, 11, 13, 19, 20, and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-61 of U.S. Patent No. 11,845,798 in view of US Patent Application Publication 2014/0234296, Sharma et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015); and Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
U.S. Patent No. 11,845,798 claims:
1. A formulation that comprises an anti-LAG3 antibody at a concentration of about 20-220 mg/ml, wherein the anti-LAG3 antibody comprises two heavy chains and two light chains, each light chain comprises SEQ ID NO: 35 and each heavy chain comprises a heavy chain variable region sequence of SEQ ID NO: 58 and an IgG4 constant region, and an excipient which is a) histidine, aspartate, glutamine, glycine, proline, methionine, or a combination thereof, at a total concentration of about 40-100 mM; b) arginine or a pharmaceutically acceptable salt thereof, NaCl, KCl, LiCl, or a combination thereof at a total concentration of about 40-150 mM; or a combination of a) and b); and a buffer that maintains the pH of the formulation at about 5.3 to 6.4.
2. The formulation of claim 1, wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-150 mM.
3. The formulation of claim 2 further comprising about 30-120 mg/mL sucrose or trehalose; and about 0.05-1.5 mg/mL polysorbate 80 or 20;
wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer.
5. The formulation of claim 1, wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-100 mM.
8. The formulation of claim 1, wherein the excipient is NaCl and L-arginine or a pharmaceutically acceptable salt thereof with a total concentration of about 70-100 mM.
10. The formulation of claim 1, wherein the excipient is L-histidine, L-aspartate, L-glutamine, or L-glycine at about 40-100 mM.
11. The formulation of claim 1, wherein the excipient is L-histidine at about 40-100 mM.
12. The formulation of claim 1, wherein the buffer is a histidine buffer, an acetate buffer or a citrate buffer.
13. The formulation of claim 12, wherein the buffer has a concentration of about 1-300 mM.
14. The formulation of claim 13, further comprising a surfactant selected from polysorbate 20 and polysorbate 80, and a sugar selected from sucrose and trehalose, or a combination thereof.
15. The formulation of claim 1 further comprising about 10-250 mg/mL sucrose, trehalose, mannitol, sorbitol, polyethylene glycol or glycerol; and about 0.005-2.0 mg/mL polysorbate 80 or 20; wherein the buffer is about 3-300 mM L-histidine, acetate or citrate buffer.
17. The formulation of claim 1 wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; and the excipient is about 40-150 mM NaCl; and wherein the formulation further comprises about 0.05-1.0 mg/mL polysorbate 80 or 20.
19. The formulation of claim 1 further comprising a sugar or polyol, and a non-ionic surfactant, or a combination thereof.
20. The formulation of claim 19, wherein the sugar is a non-reducing disaccharide.
21. The formulation of claim 20, wherein the sugar is trehalose or sucrose, or a combination thereof.
26. The formulation of claim 19, wherein the anti-LAG3 antibody is at about 20-30 mg/mL; the sugar is about 50-90 mg/mL sucrose or trehalose; the non-ionic surfactant is about 0.05-1.0 mg/mL polysorbate 80 or 20; the buffer is about 5-20 mM L-histidine, acetate or citrate buffer; and the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.
28. The formulation of claim 26 that is a liquid formulation.
34. The formulation of claim 26, further comprising an anti-PD-1 antibody that comprises two heavy chains and two light chains, wherein each light chain comprises SEQ ID NO: 5, and each heavy chain comprises a heavy chain variable region sequence of SEQ ID NO: 9 and an IgG4 constant region.
35. The formulation of claim 34, wherein the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.
36. The formulation of claim 34, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5 [which are the sequences of pembrolizumab].
38. A formulation comprising about 15-50 mg/mL of an anti-LAG3 antibody that comprises two heavy chains and two light chains, each light chain comprises SEQ ID NO: 35 and each heavy chain comprises a heavy chain variable region sequence of SEQ ID NO: 58 and an IgG4 constant region, about 50-90 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80 or 20; about 5-20 mM L-histidine, acetate or citrate buffer that maintains the pH of the formulation at about 5.3 to 6.4; and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; and an anti-PD-1 antibody that comprises two heavy chains and two light chains, wherein each light chain comprises SEQ ID NO: 5, and each heavy chain comprises a heavy chain variable region sequence of SEQ ID NO: 9 and an IgG4 constant region.
39. The formulation of claim 38, comprising about 20-30 mg/ml of the anti-LAG3 antibody, about 50-90 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80; about 5-20 mM L-histidine buffer; and about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof.
40. The formulation of claim 39, further comprising about 5-15 mM L-methionine.
41. The formulation of claim 40, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.
42. The formulation of claim 39 wherein the pharmaceutically acceptable salt of L-arginine is L-arginine-hydrochloride.
43. The formulation of claim 42, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.
44. The formulation of claim 39, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.
45. The formulation of claim 38, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.
46. A formulation that comprises:
an anti-LAG3 antibody at a concentration of about 20-220 mg/ml, wherein the anti-LAG3 antibody comprises two heavy chains and two light chains, each light chain comprises SEQ ID NO: 35 and each heavy chain comprises SEQ ID NO: 57;
an excipient which is a) histidine, aspartate, glutamine, glycine, proline, methionine, or a combination thereof, at a total concentration of about 40-100 mM; b) arginine or a pharmaceutically acceptable salt thereof, NaCl, KCl, LiCl, or a combination thereof at a total concentration of about 40-150 mM; or a combination of a) and b);
a buffer that maintains the pH of the formulation at about 5.3 to 6.4;
and an anti-PD-1 antibody that comprises two heavy chains and two light chains, each heavy chain comprises SEQ ID NO: 10 and each light chain comprises SEQ ID NO: 5.
47. The formulation of claim 46, wherein the anti-LAG3 antibody is at a concentration of about 20-30 mg/ml.
48. The formulation of claim 47, wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-150 mM.
49. The formulation of claim 47, wherein the excipient is NaCl and L-arginine or a pharmaceutically acceptable salt thereof with a total concentration of about 70-100 mM.
50. The formulation of claim 47, wherein the excipient is NaCl, KC1 or LiCl at about 40-100 mM.
51. The formulation of claim 47, wherein the excipient is L-histidine, L-aspartate, L-glutamine, or L-glycine at about 40-100 mM.
52. The formulation of claim 47, wherein the buffer is about 3-300 mM L-histidine, acetate or citrate buffer; and wherein the formulation further comprises about 10-250 mg/mL sucrose, trehalose, mannitol, sorbitol, polyethylene glycol or glycerol and about 0.005-2.0 mg/mL polysorbate 80 or 20.
53. The formulation of claim 47, wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-150 mM; the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; and wherein the formulation further comprises about 30-120 mg/mL sucrose or trehalose and about 0.05-1.5 mg/mL polysorbate 80 or 20.
54. The formulation of claim 47, wherein the excipient is about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof; the buffer is about 5-30 mM L-histidine, acetate or citrate buffer; and wherein the formulation further comprises about 50-90 mg/mL sucrose or trehalose and about 0.05-1.0 mg/mL polysorbate 80.
55. The formulation of claim 47, wherein the buffer is about 8-6 mM L-histidine, acetate or citrate buffer; and the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; and the formulation further comprises about 50-90 mg/mL sucrose or trehalose and about 0.05-1.0 mg/mL polysorbate 80 or 20.
56. The formulation of claim 47, wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; and the formulation further comprises about 20-200 mg/mL glycerol, sorbitol or PEG400 and about 0.05-1.0 mg/mL polysorbate 80 or 20.
57. The formulation of claim 47, wherein the excipient is about 40-100 mM L-glutamine, L-glycine, L-proline or L-methionine and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; and the formulation further comprises about 0.05-1.0 mg/mL polysorbate 80 or 20.
58. The formulation of claim 47, wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; the excipient is about 40-150 mM NaCl; and the formulation further comprises about 0.05-1.0 mg/mL polysorbate 80 or 20.
59. A formulation comprising:
about 15-50 mg/mL of an anti-LAG3 antibody that comprises two heavy chains and two light chains, and each light chain comprises SEQ ID NO: 35 and each heavy chain comprises SEQ ID NO: 57;
about 50-90 mg/mL sucrose or trehalose;
about 0.05-1.0 mg/mL polysorbate 80 or 20;
about 5-20 mM L-histidine, acetate or citrate buffer that maintains the pH of the formulation at about 5.3 to 6.4;
about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; and
an anti-PD-1 antibody that comprises two heavy chains and two light chains, and each heavy chain comprises SEQ ID NO: 10 and each light chain comprises SEQ ID NO: 5.
The US Patent does not claim the anti-PD1 antibody pembrolizumab is present at 25 mg/ml or substituting non-ionic surfactant poloxamer 188 for polysorbate 80.
Sharma, Sadineni, Li, Bishop, Connolly, and Khan teach as set forth above
25 mg/ml pembrolizumab (claims 1, 20, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the formula of the US Patent to comprise 25 mg/ml of pembrolizumab. One would have been motivated to, and have a reasonable expectation of success to because Sharma teaches a pembrolizumab formulation, comprising the same excipients as recited in the claims of the US Patent, can also comprise 25 mg/ml of pembrolizumab.
Non-ionic surfactant poloxamer 188 at about 0.01% to about 0.10% (claims 1, 13, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute poloxamer 188 for polysorbate 80 as the non-ionic surfactant in the antibody composition of the U.S. Patent. One would have been motivated to, and have a reasonable expectation of success to because: (1) the U.S. Patent claims formulating the antibody composition with a non-ionic surfactant polysorbate 80; (2) Sharma, Sadineni, Li, Consenza, and Bishop all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (3) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188, specifically, and at 0.01 to 0.1%; and (4) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations.
8. Claims 1-4, 11, 13, 19, 20, and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-71 of U.S. Patent No. 12,319,735 in view of US Patent Application Publication 2014/0234296, Sharma et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015); and Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
U.S. Patent No. 12,319,735 claims:
1. A pharmaceutical formulation comprising:
about 16-22 mg/mL of an anti-LAG3 antibody; about 3-7 mg/mL of an anti-PD-1 antibody; about 30-120 mg/mL of a non-reducing disaccharide; about 0.02-2.0 mg/mL polysorbate 80 or polysorbate 20; a buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5; and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8; wherein the molar ratio of the anti-LAG3 antibody to anti-PD-1 antibody is 4:1.
2. The pharmaceutical formulation of claim 1 comprising about 18-22 mg/mL of the anti-LAG3 antibody; about 4-7 mg/mL of the anti-PD-1 antibody; about 50-90 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; about 3-30 mM histidine buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5; and about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical formulation comprising: about 18-22 mg/mL of an anti-LAG3 antibody and about 3-7 mg/ml of an anti-PD-1 antibody at a molar ratio of 4:1 anti-LAG3 antibody to anti-PD-1 antibody, an excipient selected from histidine, aspartate, glutamine, glycine, proline, methionine, arginine or a pharmaceutically acceptable salt thereof, NaCl, and KCl, or a combination thereof, at a total excipient concentration of about 25-250 mM, and a buffer that maintains the pH of the pharmaceutical formulation at about 4.5-8, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.
9. The pharmaceutical formulation of claim 8, wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 25-250 mM.
10. The pharmaceutical formulation of claim 8, wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-100 mM.
11. The pharmaceutical formulation of claim 8, wherein the excipient is NaCl and L-arginine or a pharmaceutically acceptable salt thereof with a total excipient concentration of about 25-250 mM.
12. The pharmaceutical formulation of claim 11, wherein the NaCl to L-arginine concentration ratio is 1:1.
13. The pharmaceutical formulation of claim 12, wherein the NaCl concentration is about 35 mM and the L-arginine concentration is about 35 mM.
14. The pharmaceutical formulation of claim 12, wherein the NaCl concentration is about 50 mM and the L-arginine concentration is about 50 mM.
15. The pharmaceutical formulation of claim 8, further comprising a non-ionic surfactant that is a polysorbate.
16. The pharmaceutical formulation of claim 15, wherein the non-ionic surfactant is polysorbate 80 or polysorbate 20.
17. The pharmaceutical formulation of claim 8, further comprising a sugar that is a non-reducing disaccharide.
18. The pharmaceutical formulation of claim 17, wherein the sugar is trehalose or sucrose, or a combination thereof.
19. The pharmaceutical formulation of claim 18, wherein the sugar is at a concentration of about 10-200 mg/ml.
22. The pharmaceutical formulation of claim 8, further comprising about 10-250 mg/mL sucrose, trehalose, mannitol, sorbitol, polyethylene glycol or glycerol; about 0.005-2.0 mg/mL polysorbate 80 or polysorbate 20; and wherein the buffer is about 3-300 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5.
23. The pharmaceutical formulation of claim 9 or 11, further comprising about 30-120 mg/mL sucrose or trehalose and about 0.05-1.5 mg/ml polysorbate 80 or polysorbate 20; and wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5.
24. The pharmaceutical formulation of claim 8, further comprising about 50-90 mg/mL sucrose or trehalose and about 0.05-1.0 mg/mL polysorbate 80; and wherein the buffer is about 5-30 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5.
31. The pharmaceutical formulation of claim 1 that is a liquid formulation.
36. The pharmaceutical formulation of claim 1, wherein the anti-LAG3 antibody is Ab6 variant, and the anti-PD-1 antibody is pembrolizumab or pembrolizumab variant.
The US Patent does not claim the pembrolizumab is present at 25 mg/ml and non-ionic surfactant is poloxamer 188.
Sharma, Li, Bishop, Connolly, and Khan teach as set forth above.
25 mg/ml pembrolizumab (claims 1, 20, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the formula of the US Patent to comprise 25 mg/ml of pembrolizumab. One would have been motivated to, and have a reasonable expectation of success to because Sharma teaches a pembrolizumab formulation, comprising the same excipients as recited in the claims of the US Patent, can also comprise 25 mg/ml of pembrolizumab.
Non-ionic surfactant poloxamer 188 at about 0.01% to about 0.10% (claims 1, 13, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute poloxamer 188 for polysorbate 80 as the non-ionic surfactant in the antibody composition of the U.S. Patent. One would have been motivated to, and have a reasonable expectation of success to because: (1) the U.S. Patent claims formulating the antibody composition with a non-ionic surfactant at about 0.01% to about 0.10%; (2) Li, Consenza, and Bishop all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (3) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188, specifically, and at 0.01 to 0.1%; and (4) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations.
9. Claims 1-4, 11, 13, 19, 20, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-65 of copending Application No. 18/182,135 in view of US Patent Application Publication 2014/0234296, Sharma et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015); and Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
The copending application claims:
1. An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
a) about 100 mg/mL to about 200 mg/mL of an anti-human PD-1 antibody;
b) about 5 mM to about 20 mM buffer;
c) a stabilizer selected from the group consisting of:
i) about 6% to about 8% weight/volume (w/v) sucrose, trehalose or (2-hydroxypropyl)-β-cyclodextrin;
ii) about 3% to about 5% w/v mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; and
iii) about 1.8% to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof;
d) about 0.01 % to about 0.10% non-ionic surfactant; and
e) about 1 mM to about 20 mM L-methionine, or a pharmaceutically acceptable salt thereof;
wherein the anti-human PD-1 antibody comprises three light chain CDRs comprising CDRL1 of SEQ ID NO:1, CDRL2 of SEQ ID NO:2 and CDRL3 of SEQ ID NO:3 and three heavy chain CDRs of CDRH1 of SEQ ID NO:6, CDRH2 of SEQ ID NO:7 and CDRH3 of SEQ ID NO:8.
2. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation has a pH between 5.0 and 6.0.
3. The anti-human PD-1 antibody formulation of claim 1, wherein the buffer is a histidine buffer or an acetate buffer.
4. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 6% to about 8% trehalose.
5. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline and wherein the stabilizer is present at a concentration of about 3% to about 5% w/v.
7. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 3% to about 5% w/v L-arginine or L-arginine HCl and the pH of the formulation is from about 6.0 to about 6.4.
8. The anti-human PD-1 antibody formulation of claim 1, further comprising from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
9. The anti-human PD-1 antibody formulation of claim 1, further comprising from about 1.25 % to about 2.5 % w/v L-arginine, or a pharmaceutically acceptable salt thereof.
10. The anti-human PD-1 antibody formulation of claim 1, wherein the non-ionic surfactant is polysorbate 20, polysorbate 80 or F127.
15. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation comprises a light chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO: 10.
16. An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
a) about 100 mg/mL to about 200 mg/mL of pembrolizumab;
b) about 5 mM to about 20 mM buffer;
c) a stabilizer selected from the group consisting of:
i) about 6 % to about 8 % weight/volume (w/v) sucrose, trehalose or (2-hydroxypropyl)-β-cyclodextrin;
ii) about 3 % to about 5 % w/v mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; and
iii) about 1.8 % to about 2.2 % w/v glycine, or a pharmaceutically acceptable salt thereof;
d) about 0.01 % to about 0.10 % non-ionic surfactant; and
e) about 1 mM to about 20 mM L-methionine, or a pharmaceutically acceptable salt thereof.
17. The anti-human PD-1 antibody formulation of claim 16, wherein the formulation has a pH between 5.0 and 6.0.
18. The anti-human PD-1 antibody formulation of claim 16, wherein the buffer is a histidine buffer or an acetate buffer.
19. The anti-human PD-1 antibody formulation of claim 16, wherein the stabilizer is about 6% to about 8% trehalose.
20. The anti-human PD-1 antibody formulation of claim 16, wherein the stabilizer is mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline and wherein the stabilizer is present at a concentration of about 3% to about 5% w/v.
22. The anti-human PD-1 antibody formulation of claim 16, wherein the stabilizer is about 3% to about 5% w/v L-arginine or L-arginine HCl and the pH of the formulation is from about 6.0 to about 6.4.
23. The anti-human PD-1 antibody formulation of claim 16, further comprising from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
24. The anti-human PD-1 antibody formulation of claim 16, further comprising from about 1.25% to about 2.5% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
25. The anti-human PD-1 antibody formulation of claim 16, wherein the non-ionic surfactant is polysorbate 20, polysorbate 80 or F127.
30. The anti-human PD-1 antibody formulation of claim 16, wherein the concentration of pembrolizumab is about 165 mg/mL to about 170 mg/mL.
The copending application does not claim the pembrolizumab is present at 25 mg/ml and non-ionic surfactant is poloxamer 188.
Sharma, Li, Bishop, Connolly, and Khan teach as set forth above.
25 mg/ml pembrolizumab (claims 1, 20, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the formula of the copending application to comprise 25 mg/ml of pembrolizumab. One would have been motivated to, and have a reasonable expectation of success to because Sharma teaches a pembrolizumab formulation, comprising the same excipients as recited in the claims of the copending application, can also comprise 25 mg/ml of pembrolizumab.
Non-ionic surfactant poloxamer 188 at about 0.01% to about 0.10% (claims 1, 13, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute poloxamer 188 for polysorbate 80 as the non-ionic surfactant in the antibody composition of the copending application. One would have been motivated to, and have a reasonable expectation of success to because: (1) the copending application claims formulating the antibody composition with a non-ionic surfactant at about 0.01% to about 0.10% including polysorbate 80 as well as F27 which is a poloxamer; (2) Li, Consenza, and Bishop all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (3) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188, specifically, and at 0.01 to 0.1%; and (4) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations.
This is a provisional nonstatutory double patenting rejection.
10. Claims 1-4, 11, 13, 19, 20, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of copending Application No. 18/182,097 in view of US Patent Application Publication 2014/0234296, Sharma et al; US Patent Application Publication 2016/0304607, Sadineni et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015); and Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
The copending application claims:
1. An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
a) about 100 mg/mL to about 200 mg/mL of an anti-human PD-1 antibody;
b) about 5 mM to about 20 mM histidine buffer;
c) about 6% to about 8% weight/volume (w/v) sucrose;
d) about 0.01% to about 0.10% polysorbate 80; and
e) about 1 mM to about 20 mM L-methionine, or a pharmaceutically acceptable salt thereof,
wherein the anti-human PD-1 antibody comprises three light chain CDRs comprising CDRL1 of SEQ ID NO:1, CDRL2 of SEQ ID NO:2 and CDRL3 of SEQ ID NO:3 and three heavy chain CDRs of CDRH1 of SEQ ID NO:6, CDRH2 of SEQ ID NO:7 and CDRH3 of SEQ ID NO:8.
2. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation has a pH between 5.0 and 6.0.
3. The anti-human PD-1 antibody formulation of claim 1, further comprising from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
4. The anti-human PD-1 antibody formulation of claim 1, comprising:
a) about 100 mg/mL to about 200 mg/mL of the anti-human PD-1 antibody;
b) 8 mM to about 12 mM histidine buffer;
c) about 5 mM to about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof;
d) about 6% to about 8% w/v sucrose; and
e) 0.01% to about 0.04% w/v polysorbate 80.
5. The anti-human PD-1 antibody formulation of claim 4, comprising:
a) about 125 mg/mL to about 200 mg/mL of the anti-human PD-1 antibody;
b) about 10 mM histidine buffer;
c) about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof;
d) about 7% w/v sucrose; and
e) about 0.02% w/v polysorbate 80.
6. The anti-human PD-1 antibody formulation of claim 5, wherein the L-methionine is L-methionine HCl.
7. The anti-human PD-1 antibody formulation of claim 5, further comprising from about 1.25% to about 2.5% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
8. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation further comprises a metal chelator.
9. The anti-human PD-1 antibody formulation of claim 8, wherein the metal chelator is diethylenetriaminepentaacetic acid (DTPA), which is present at a concentration of about 10 μM to about 30 μM.
10. The anti-human PD-1 antibody formulation of claim 1 that is a reconstituted solution from a lyophilized formulation.
11. The anti-human PD-1 antibody formulation of claim 1, wherein the concentration of the anti-human PD-1 antibody is about 165 mg/mL to about 170 mg/mL.
12. The anti-human PD-1 antibody formulation of claim 1, wherein the anti-human PD-1 antibody comprises a VL region which comprises the amino acid sequence set forth in SEQ ID NO:4, and a VH region which comprises the amino acid sequence set forth in SEQ ID NO:9.
13. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation comprises a light chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO:10.
14. An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
a) about 100 mg/mL to about 200 mg/mL of pembrolizumab;
b) about 5 mM to about 20 mM histidine buffer;
c) about 6% to about 8% weight/volume (w/v) sucrose;
d) about 0.01% to about 0.10% polysorbate 80; and
e) about 1 mM to about 20 mM L-methionine, or a pharmaceutically acceptable salt thereof.
15. The anti-human PD-1 antibody formulation of claim 14, wherein the formulation has a pH between 5.0 and 6.0.
16. The anti-human PD-1 antibody formulation of claim 14, further comprising from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
17. The anti-human PD-1 antibody formulation of claim 14, comprising:
a) about 100 mg/mL to about 200 mg/mL of pembrolizumab;
b) 8 mM to about 12 mM histidine buffer;
c) about 5 mM to about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof;
d) about 6% to about 8% w/v sucrose; and
e) 0.01% to about 0.04% w/v polysorbate 80.
18. The anti-human PD-1 antibody formulation of claim 17, comprising:
a) about 125 mg/mL to about 200 mg/mL of pembrolizumab;
b) about 10 mM histidine buffer;
c) about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof;
d) about 7% w/v sucrose; and
e) about 0.02% w/v polysorbate 80.
19. The anti-human PD-1 antibody formulation of claim 14, wherein the L-methionine is L-methionine HCl.
20. The anti-human PD-1 antibody formulation of claim 14, further comprising from about 1.25% to about 2.5% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
21. The anti-human PD-1 antibody formulation of claim 14, wherein the formulation further comprises a metal chelator.
22. The anti-human PD-1 antibody formulation of claim 21, wherein the metal chelator is diethylenetriaminepentaacetic acid (DTPA), which is present at a concentration of about 10 μM to about 30 μM.
23. The anti-human PD-1 antibody formulation of claim 14 that is a reconstituted solution from a lyophilized formulation.
24. The anti-human PD-1 antibody formulation of claim 14, wherein the concentration of pembrolizumab is about 165 mg/mL to about 170 mg/mL.
27. An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
a) about 165 mg/mL of pembrolizumab;
b) about 10 mM histidine buffer,
c) about 7% w/v sucrose,
d) about 0.02% polysorbate 80, and
e) about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof, wherein the formulation has a pH between 5.0 and 6.0.
The copending application does not claim the formulation antibody formulation comprises 25 mg/ml of pembrolizumab, about 6% to about 8% w/v trehalose stabilizer, and poloxamer 188 non-ionic surfactant.
Sharma, Sadineni, Li, Bishop, Connolly, and Khan teach as set forth above.
25 mg/ml pembrolizumab (claims 1, 20, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the formula of the copending application to comprise 25 mg/ml of pembrolizumab. One would have been motivated to, and have a reasonable expectation of success to because Sharma teaches the composition comprising the same excipients as recited in the claims of the copending application can also comprise 25 mg/ml of pembrolizumab.
Trehalose stabilizer at about 6% to about 8% w/v (claims 1, 4, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute trehalose stabilizer at 6-8% w/v for the sucrose stabilizer in the pembrolizumab composition of the copending application. One would have been motivated to, and have a reasonable expectation of success to because: (1) all of Sharma, Sadineni, Li, Cosenza, Bishop, and Connolly teach and establish trehalose is a known stabilizer alternative to sucrose for antibody compositions and they are functional equivalents; (3) Li, Cosenza, Bishop, and Connolly teach or demonstrate known effective stabilizing amounts of trehalose in antibody compositions at about 6% to about 8% w/v; and (4) Sadineni, Li, Cosenza, Bishop, and Connolly teach or successfully demonstrate combining trehalose as the stabilizer with antibody, histidine buffer, non-ionic surfactant polysorbate 80; and at pH 5.0-6.0 to arrive at a stable antibody composition.
Non-ionic surfactant poloxamer 188 at about 0.01% to about 0.10% (claims 1, 13, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute poloxamer 188 for polysorbate 80 as the non-ionic surfactant in the antibody composition of the copending application. One would have been motivated to, and have a reasonable expectation of success to because: (1) the copending application claims formulating the antibody composition with a non-ionic surfactant polysorbate 80 at about 0.01% to about 0.10%; (2) Sharma, Sadineni, Li, Consenza, and Bishop all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (3) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188, specifically, and at 0.01 to 0.1%; and (4) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations.
This is a provisional nonstatutory double patenting rejection.
12. Claims 1-4, 11, 13, 19, 20, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 19/346,623 in view of CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015); and Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
The copending application claims:
1. An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
a) about 5 mg/mL to about 200 mg/mL of an anti-human PD-1 antibody [which encompasses about 5 mg/ml to about 100 mg/ml];
b) about 5 mM to about 20 mM histidine buffer;
c) a stabilizer selected from the group consisting of:
i) about 6% to about 8% weight/volume (w/v) trehalose or (2-hydroxypropyl)-β-cyclodextrin;
ii) about 3% to about 5% w/v mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; and
iii) about 1.8% to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof;
d) about 0.01% to about 0.10% non-ionic surfactant;
wherein the non-ionic surfactant is polysorbate 80, polysorbate 20, or poloxamer 188, and
wherein the anti-human PD-1 antibody is pembrolizumab.
2. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation has a pH between 5.0 and 6.0.
3. The anti-human PD-1 antibody formulation of claim 1, further comprising about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
4. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 6% to about 8% weight/volume (w/v) trehalose.
5. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 6% to about 8% weight/volume (w/v) (2-hydroxypropyl)-β-cyclodextrin.
6. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 3% to about 5% w/v mannitol.
7. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is 3% to about 5% w/v sorbitol.
8. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is 3% to about 5% w/v L-arginine, or a pharmaceutically acceptable salt of L-arginine.
9. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is 3% to about 5% w/v L-proline, or a pharmaceutically acceptable salt of L-proline.
10. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 1.8% to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof.
11. The anti-human PD-1 antibody formulation of claim 1, wherein the non-ionic surfactant is polysorbate 80.
12. The anti-human PD-1 antibody formulation of claim 1, wherein the non-ionic surfactant is polysorbate 20.
13. The anti-human PD-1 antibody formulation of claim 1, wherein the non-ionic surfactant is poloxamer 188.
14. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation further comprises about 1 mM to about 20 mM anti-oxidant.
15. The anti-human PD-1 antibody formulation of claim 14, wherein the anti-oxidant is L-methionine, or a pharmaceutically acceptable salt thereof.
16. The anti-human PD-1 antibody formulation of claim 15, wherein the L-methionine is L-methionine HCl.
17. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation further comprises a metal chelator.
18. The anti-human PD-1 antibody formulation of claim 17, wherein the metal chelator is diethylenetriaminepentaacetic acid (DTPA), which is present at a concentration of about 1 μM to about 30 μM.
19. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation is a liquid formulation.
20. The anti-human PD-1 antibody formulation of claim 1, wherein the concentration of pembrolizumab is about 25 mg/mL to about 100 mg/mL.
21. The anti-human PD-1 antibody formulation of claim 1, wherein the concentration of pembrolizumab is about 25 mg/mL.
22. The anti-human PD-1 antibody formulation of claim 1, wherein the concentration of pembrolizumab is about 165 mg/mL to about 170 mg/mL.
The copending claims render obvious all of the instant limitations of the claimed antibody formulation.
This is a provisional nonstatutory double patenting rejection.
13. Claims 1-4, 11, 13, 19, 20, and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 19/346,638 in view of US Patent Application Publication 2014/0234296, Sharma et al.
The copending application claims:
1. An anti-human programmed death receptor 1 (PD-1) antibody formulation, comprising:
a) about 5 mg/mL to about 200 mg/mL of an anti-human PD-1 antibody;
b) about 5 mM to about 20 mM acetate or citrate buffer;
c) a stabilizer selected from the group consisting of:
i) about 6% to about 8% weight/volume (w/v) sucrose, trehalose or (2-hydroxypropyl)-β-cyclodextrin;
ii) about 3% to about 5% w/v mannitol, sorbitol, L-arginine, a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; and
iii) about 1.8% to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof;
d) about 0.01% to about 0.10% non-ionic surfactant;
wherein the non-ionic surfactant is polysorbate 80, polysorbate 20, or poloxamer 188, and
wherein the anti-human PD-1 antibody is pembrolizumab.
2. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation has a pH between 5.0 and 6.0.
3. The anti-human PD-1 antibody formulation of claim 1, wherein the buffer is acetate.
4. The anti-human PD-1 antibody formulation of claim 1, wherein the buffer is citrate.
5. The anti-human PD-1 antibody formulation of claim 1, further comprising about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof.
6. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 6% to about 8% weight/volume (w/v) sucrose.
7. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 6% to about 8% weight/volume (w/v) trehalose.
8. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 6% to about 8% weight/volume (w/v) (2-hydroxypropyl)-β-cyclodextrin.
9. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 3% to about 5% w/v mannitol.
10. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is 3% to about 5% w/v sorbitol.
11. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is 3% to about 5% w/v L-arginine or a pharmaceutically acceptable salt of L-arginine.
12. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is 3% to about 5% w/v L-proline, or a pharmaceutically acceptable salt of L-proline.
13. The anti-human PD-1 antibody formulation of claim 1, wherein the stabilizer is about 1.8% to about 2.2% w/v glycine, or a pharmaceutically acceptable salt thereof.
14. The anti-human PD-1 antibody formulation of claim 1, wherein the non-ionic surfactant is polysorbate 80.
15. The anti-human PD-1 antibody formulation of claim 1, wherein the non-ionic surfactant is polysorbate 20.
16. The anti-human PD-1 antibody formulation of claim 1, wherein the non-ionic surfactant is poloxamer 188.
17. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation further comprises about 1 mM to about 20 mM anti-oxidant.
18. The anti-human PD-1 antibody formulation of claim 17, wherein the anti-oxidant is L-methionine, or a pharmaceutically acceptable salt thereof.
19. The anti-human PD-1 antibody formulation of claim 18, wherein the L-methionine is L-methionine HCl.
20. The anti-human PD-1 antibody formulation of claim 1, wherein the formulation is a liquid formulation.
21. The anti-human PD-1 antibody formulation of claim 1, wherein the concentration of pembrolizumab is about 25 mg/mL to about 100 mg/mL.
22. The anti-human PD-1 antibody formulation of claim 1, wherein the concentration of pembrolizumab is about 25 mg/mL.
23. The anti-human PD-1 antibody formulation of claim 1, wherein the concentration of pembrolizumab is about 165 mg/mL to about 170 mg/mL.
The copending application does not claim the buffer is 5mM to about 20 mM of histidine.
Sharma teaches the pembrolizumab formulation comprising 25 mg/ml antibody;
stabilizer; 10 mM histidine buffer; 0.02 % w/v non-ionic surfactant polysorbate 80; and
pH 5.0-6.0, as set forth above. Sharma teaches buffers to maintain pH 5.0 - 6.0 include histidine, acetate, or citrate buffers ([75]).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute histidine buffer at about 10 mM for the acetate or citrate buffer in the antibody composition of the copending application. One would have been motivated to, and have a reasonable expectation of success to because Sharma teaches all of these buffers serve the same function of maintaining pH 5.0- 6.0 in the pembrolizumab antibody composition, and Sharma teaches specifically including 10 mM of histidine buffer for pH 5.0- 6.0.
This is a provisional nonstatutory double patenting rejection.
14. Conclusion: No claim is allowed.
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/Laura B Goddard/Primary Examiner, Art Unit 1642