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 .
Status of the Claims
Claims 1, 17, 19, 22-23, and 27-31 are pending. Claim 15 was canceled and claim 1 was amended in the response filed January 5, 2026.
Priority
This application is a continuation of abandoned Application No. 15/779,237, filed May, 25, 2018, which is a 371 of PCT/US2016/064080, filed November 30, 2016, which claims benefit of US provisional application number 62/260,677, filed November 30, 2015. The earliest effective filing date of claims 1, 17, 19, 22-23, and 27-31 is November 30, 2015.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The previous rejection under 35 U.S.C. 103 over Chen et al. (WO 2004/055164 A2, Pub. July 1, 2004) in view of Grauschopf et al. (US-2012/0321638-A1, Pub. Dec. 20, 2012) and Chevrier et al. (US-2009/0081213-A1, Pub. Mar. 26, 2009) is withdrawn in view of the amendment to the claims filed January 5, 2026. A new rejection necessitated by amendment is made.
Claims 1, 17, 19, 22-23, and 27-31 are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US-2014/0234296 A1, Pub. Aug. 21, 2014) in view of Grauschopf et al. (US-2012/0321638-A1, Pub. Dec. 20, 2012) and Chevrier et al. (US-2009/0081213-A1, Pub. Mar. 26, 2009).
Sharma et al. teach stable formulations of antibodies against human programmed death receptor PD-1, or antigen binding fragments thereof (§ [0015]).
Sharma et al. teach a lyophilized formulation of an anti-human PD-1 antibody, or antigen binding fragment thereof, comprising: a) said anti-human PD-1 antibody, or antigen binding fragment thereof; b) histidine buffer; c) polysorbate 80; and d) sucrose, wherein the formulation has a pH between 5.0 and 6.0 when reconstituted (§ [0016]-[0017]). The lyophilized formulation enables reconstitution of the antibody, or antigen binding fragment thereof, at a concentration of between about 25 mg/mL and 100 mg/mL, and contains polysorbate 80 at a weight ratio of approximately 0.02% (w/v) and sucrose at a weight ratio of approximately 7% (w/v) (§ [0018]-[0020]). Sharma et al. teach that the lyophilized pharmaceutical formulation of an anti-human PD-1 antibody, or antigen binding fragment thereof, is made by lyophilizing an aqueous solution comprising: a) 25-100 mg/mL anti-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 (§ [0021]).
Sharma et al. teach a liquid pharmaceutical formulation of an anti-human PD-1 antibody, or antigen binding fragment thereof comprising: a) 25-100 mg/mL antibody, or antigen binding fragment thereof; b) about 70 mg/mL sucrose (a weight ratio of approximately 7% (w/v)); c) about 0.2 mg/mL polysorbate 80 (a weight ratio of approximately 0.02% (w/v)); and d) about 10 mM histidine buffer at pH 5.0-6.0 (§ [0025]-[0026]).
Sharma et al. meets the following limitations of instant claims 1 and 28:
A pharmaceutical composition which is an aqueous solution or lyophilizate consisting of
(1) a protein biomolecule that is an IgG1 antibody;
(2) a buffer;
(3) an amorphous stabilizing sugar compound which is sucrose; and
(4) a non-ionic detergent consisting of polysorbate-80.
The difference between Sharma et al. and instant claims 1 and 28 is the concentrations of components (1)-(4), the pH, and that in the prior art the buffer is histidine whereas in the claims the buffer is histidine-HCl. These differences are obvious over the prior art Sharm et al. and additional art which establishes histidine-HCl as a commonly used buffer in antibody.
MPEP § 2144.05(I) states: In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
In the instant case, the claimed range “about 50 mg/ml” and “about 100 mg/ml” of the IgG1 antibody overlap or lie inside the prior art range of 25-100 mg/ml. Therefore, the claimed range is prima facie obvious over the prior art.
In the instant case, the claimed range “about 0.5%, 1%, 1.5%, 2%, or 2.5% (w/v)” and “about 1%, 1.5%, 2%, or 2.5% (w/v)” of sucrose overlap or lie inside the prior art range of about 7% w/v. Therefore, the claimed range is prima facie obvious over the prior art.
In the instant case, the claimed range “pH 6.0 to 7.4” overlaps or lie inside the prior art range of about pH 5.0-6.0. Therefore, the claimed range is prima facie obvious over the prior art.
Regarding histidine-HCl, Grauschopf et al. teach a pharmaceutical composition comprising: a) 1 – 200 mg/mL of an antibody (a protein biomolecule); b) 1 – 100 mM of a histidine buffer (claim 6), wherein L-histidine hydrochloride is listed as a preferred buffer (See § [0041]); c) 0.001 to 1% surfactant; and d) 10 – 500 mM (approximately 0.34% – 17.11% w/v {Sucrose molecular weight = 342.3 g/mol}) of a stabilizer selected from the group consisting of sucrose and trehalose (claim 1), wherein the composition has a pH in the range of 4.0 – 7.0. (See claim 1).
Chevrier et al. teaches pharmaceutical formulations of therapeutic agents that are proteinaceous in nature, and comprise about 40- 140 mg/ mL of a therapeutic agent. See § [0400]. Chevrier et al. teaches concentrations of proteinaceous agents have suitable viscosity when the concentrations range between 0- 161.75 mg/ mL. See § [0423], including Table X. Chevrier et al. teach formulations comprise buffers resulting in formulations in the range between about 5 to about 7. See § [0401]. Preferred buffers include histidine in concentrations between about 5- 50 mM. See §§ [0405] and [0406]. The formulations include preferred surfactant polysorbate 80 at a preferred concentration between about 0.01% to about 0.03%. See § [0409]. Chevrier et al. teach formulations further comprising the cryoprotectant and lyoprotectant, sucrose, and exemplary formulations comprising 0.5% sucrose. See §§ [0411], [0425], and claim 16. The formulations are taught to comprise additional therapeutic agents suitably present in combination in amounts that are effective for the purpose intended; and additional immunomodulatory molecules administered together as a therapeutic mixture. See §§ [0414], [0432], [0440], and [0485]. Additional immunomodulatory molecules known in the art are taught, and include hormones. See § [0504]. Chevrier et al. teaches administration with growth factors. §§ [0528], [0532], [0539], and [0540]. Chevrier et al. teaches additional antibody based immunotherapeutics. See § [0534]- [0535]. Chevrier et al. teaches preferred embodiments comprising 0.74 mg/ml L-histidine, 1.1 mg/ml L-histidine monohydrochloride, 8.8 mg/ml NaCl, and 0.1 mg/ml polysorbate 80, at pH 6.0 (±0.5); another preferred embodiment formulated in 10 mM sodium citrate, 1.9% glycine, 0.5% sucrose, 0.01 % polysorbate 80, pH 6.5 (±0.3) for intravenous administration. See § [0417] and [0425], claim 16.
Chevrier et al. discloses formulations comprising glucose and glycine; as well as, histidine/ histidine HCl. Further, the addition of glucose as a cryoprotectant to the histidine/ histidine HCl would have necessarily resulted in a combination comprising an additional amino acid stabilizing agent. It would have been obvious to add glucose to the compositions comprising histidine and histidine HCl, because sucrose was taught as a cryoprotectant by Chevrier et al. and included at a concentration of 0.5% in exemplary pharmaceutical compositions for parenteral administration. See §§ [0411], [0425], and claim 16.
One having ordinary skill would have recognized the histidine/histidine-HCl buffers of Grauschopf et al. and Chevrier et al. as suitable substitutions for the histidine buffer of Sharma et al. before the effective filing date of the claimed invention, and would have expected that the optimized ranges taught by the respective references would have resulted in pharmaceutically acceptable composition for stabilizing antibody formulations buffered to a pH of 6, and suitable for administration or lyophilization and reconstitution, because: histidine buffer would have been expected to buffer to 6 and all references teach buffering to a pH of 6.
The resulting formulation satisfies all of the chemical and structural limitations of the formula of claims 1 and 28. With respect to the claimed property of drying time, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
With respect to claims 17 and 19, Sharma et al. teach that the anti-PD-1 antibodies and fragments can be used alone or in combination (§ [0057]). It would have been obvious to one having ordinary skill to combine the antibodies before the effective filing date of the claimed invention with a reasonable expectation that the combination formulation(s) would have resulted in a suitable formulation for parenteral administration for the conditions they are respectively intended to treat.
With respect to claim 22, Sharma et al. teach 10 mM buffer(§ [0021]), which falls within the claimed range.
With respect to claim 23, Sharma et al. teach that the buffer can further include succinate, citrate and other organic acid buffers (§ [0075]).
With respect to claim 27, Sharma et al. teach about 0.2 mg/mL polysorbate 80 (a weight ratio of approximately 0.02% (w/v)) (§ [0025]-[0026]).
With respect to claim 29, Sharma et al. teach that the formulation may be in a vial (§ [0108]).
With respect to claims 30-31, Sharma et al. teach that the formulations of anti-PD-1 antibodies are useful for treating various cancers and infectious diseases (§ [0045]).
The claims are rejected as prima facie obvious before the effective filing date of the claimed invention.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654