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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/26/2026 has been entered.
Application Status
Claims 4, 19, 69, 71, 79-80, and 90 are pending and examined on the merits herein.
Double Patenting
Rejection Maintained
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.
Claims 4, 19, 69, 71, 79-80, and 90 are rejected on the grounds of nonstatutory double patenting as being unpatentable over claim 1-16 of U.S. Patent No. US 10,279,038 B2 in view of Sadineni (CN107743401A; Espacenet English translation attached as NPL; cited in OA 09/15/2025) and Whitaker (J Pharm Sci. 2017 Nov;106(11):3230-3241; cited in OA 02/13/2025).
Regarding instant claims 4, 19 and 90, the ‘038 patent teaches an isolated monoclonal antibody to human CD137 with variable heavy and light chains comprising SEQ ID NOs: 4 and 6 respectively with 100% sequence identity to the instant claimed SEQ ID NOs: 4, 6, 48, 56, 68, 69, 78, and 89 (claim 1-9 and 13).
Regarding instant claims 4 and 90, the ‘038 patent teaches a pharmaceutical composition comprising the monoclonal antibody of claim 1 and an acceptable pharmaceutical carrier (claim 10-12 and 14-16).
The patented claims are silent on the specific components and concentrations of the pharmaceutical formulation.
Regarding claims 4, 19, and 90, Sadineni teaches a combination composition of an anti-PD-1 antibody and another antibody (claim 1), wherein the amount of the anti-PD-1 antibody is 240 mg (claim 6), wherein the second antibody is an anti-CD137 (claim 16), wherein the ratio of PD-1 to CD137 is 3:1 which results in 80 mg of CD137 (claim 10), wherein the composition is formulated in histidine buffer is about 20mM (claim 32), the pH is about 6 (claims 35-36), wherein the bulking agent is NaCl (claim 38) at a concentration of about 100mM (claim 43), wherein the stabilizing agent is sucrose (claim 39) at a concentration of 10% (claim 50), and wherein the surfactant is polysorbate 80 (claim 41) at a concentration of about 0.01% or 0.03% (claim 48). Sadineni further teaches wherein the composition is stable at 5°C, 40°C, 25°C for 1 week – 5 years (claims 66-68) and wherein the composition exhibits a change in the acidity peak after storage at about 5°C for about 6 months (claim 69) and 40°C or 25°C for about 3 months of less than about 15%-1% (claims 70-71).
Regarding claims 4 and 90, Whitaker teaches formulation development strategy for monoclonal antibodies to reduce viscosity at high concentrations (whole document). Whitaker screened 56 excipients and additives under accelerated and real time storage conditions over 6 months to identify formulations with pharmaceutically acceptable viscosity and stability when stored (abstract). Whitaker demonstrated “preferred range” viscosity for the IgG4 antibody and “acceptable rage” for the IgG1 antibody tested with 100mM NaCl in 10mM histidine at pH 5.75 with antibody concentrations between 135-160mg/ml. (Figure 1, condition 7). Whitaker further teaches that with increasing concentration of histidine and NaCl the viscosity of the solution decreases (Figure 3). Whitaker further teaches that due to the physicochemical differences inherit to individual monoclonal antibodies, high concentration formulation development studies to optimize protein stability and solution viscosity require either a detailed, but time-consuming and technically challenging mechanistic studies or a more rapid but empirical approach of excipient screening (or a combination of both approaches)(conclusion).
As detailed above one of ordinary skill in the art would recognize antibody concentration, pH, the concentrations of buffer, sucrose, polysorbate 80, and salt as result-effective variables and optimize them by routine experimentation in order to minimize peroxide formation for the stability of antibody formulation as well as to generate the best efficacy of therapy. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention with prior art that demonstrates good stability with an antibody that has the same target as a starting point for optimization.
Claims 4, 19, 69, 71, 79-80, and 90 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 11-19 of U.S. Patent No. US 10,279,039 B2 in view of Sadineni (CN107743401A; Espacenet English translation attached as NPL; cited in OA 09/15/2025) and Whitaker (J Pharm Sci. 2017 Nov;106(11):3230-3241; cited in OA 02/13/2025).
Regarding claims 4, 19, 71, and 90, the ‘039 patent teaches a method of treating cancer comprising administering an isolated monoclonal antibody to human CD137 with variable heavy and light chains comprising SEQ ID NOs: 4 and 6 respectively with 100% sequence identity to the instant claimed SEQ ID NOs: 4, 6, 48, 56, 68, 69, 78, and 89 (claim 1-9).
Regarding claims 4, 19, 69, 71, 79-80, and 90, the ‘039 patent teaches a method of treating cancer comprising administering a pharmaceutical composition comprising an isolated monoclonal antibody to human CD137 with variable heavy and light chains comprising SEQ ID NOs: 4 and 6 and an acceptable pharmaceutical carrier (claim 11-19).
The patented claims are silent on the specific components and concentrations of the pharmaceutical formulation.
Regarding claims 4, 19, and 90, Sadineni teaches a combination composition of an anti-PD-1 antibody and another antibody (claim 1), wherein the amount of the anti-PD-1 antibody is 240 mg (claim 6), wherein the second antibody is an anti-CD137 (claim 16), wherein the ratio of PD-1 to CD137 is 3:1 which results in 80 mg of CD137 (claim 10), wherein the composition is formulated in histidine buffer is about 20mM (claim 32), the pH is about 6 (claims 35-36), wherein the bulking agent is NaCl (claim 38) at a concentration of about 100mM (claim 43), wherein the stabilizing agent is sucrose (claim 39) at a concentration of 10% (claim 50), and wherein the surfactant is polysorbate 80 (claim 41) at a concentration of about 0.01% or 0.03% (claim 48). Sadineni further teaches wherein the composition is stable at 5°C, 40°C, 25°C for 1 week – 5 years (claims 66-68) and wherein the composition exhibits a change in the acidity peak after storage at about 5°C for about 6 months (claim 69) and 40°C or 25°C for about 3 months of less than about 15%-1% (claims 70-71).
Regarding claims 4 and 90, Whitaker teaches formulation development strategy for monoclonal antibodies to reduce viscosity at high concentrations (whole document). Whitaker screened 56 excipients and additives under accelerated and real time storage conditions over 6 months to identify formulations with pharmaceutically acceptable viscosity and stability when stored (abstract). Whitaker demonstrated “preferred range” viscosity for the IgG4 antibody and “acceptable rage” for the IgG1 antibody tested with 100mM NaCl in 10mM histidine at pH 5.75 with antibody concentrations between 135-160mg/ml. (Figure 1, condition 7). Whitaker further teaches that with increasing concentration of histidine and NaCl the viscosity of the solution decreases (Figure 3). Whitaker further teaches that due to the physicochemical differences inherit to individual monoclonal antibodies, high concentration formulation development studies to optimize protein stability and solution viscosity require either a detailed, but time-consuming and technically challenging mechanistic studies or a more rapid but empirical approach of excipient screening (or a combination of both approaches)(conclusion).
As detailed above one of ordinary skill in the art would recognize antibody concentration, pH, the concentrations of buffer, sucrose, polysorbate 80, and salt as result-effective variables and optimize them by routine experimentation in order to minimize peroxide formation for the stability of antibody formulation as well as to generate the best efficacy of therapy. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention with prior art that demonstrates good stability with an antibody that has the same target as a starting point for optimization.
Claims 69, 79, and 80 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 11-19 of U.S. Patent No. US 10,279,039 B2 in view of Sadineni (CN107743401A; Espacenet English translation attached as NPL; cited in OA 09/15/2025) and Whitaker (J Pharm Sci. 2017 Nov;106(11):3230-3241; cited in OA 02/13/2025) as applied to claims 4, 19, 69, 71, 79-80, and 90 above and further in view of Davis (US 2017/0174773 A1; IDS entered March 24, 2022).
The teachings of the ‘039 patent, Sadineni and Whitaker are detailed above.
The ‘039 patent, Sadineni, and Whitaker do not teach wherein the cancer is B cell lymphoma or use of the formulation to reduce or inhibit tumor growth.
Regarding claims 79 and 80, Davis teaches a method for treating cancer in an individual comprising administering to the individual a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) and a 4-1BB agonist (claim 1) wherein, the PD-1 antagonist and the 4-1BB agonist are administered simultaneously or sequentially (claim 2). Davis further teaches that wherein the PD-1 antagonist is formulated as a liquid medicament which comprises 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5 (claim 10). Davis further teaches that each therapeutic agent in the combination therapy may be administered simultaneously (e.g., in the same medicament or at the same time)(paragraph 0157), therefore the agonist 4-1BB antibody could be in the same formulation as the anti-PD-1 antibody. Davis further teaches wherein the cancer is bladder cancer, breast cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small-cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (FIL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL) (claim 18).
Regarding claim 69, Davis teaches the addition of 4-1BB agonists to in vitro cultures of B lymphoma cells with rituximab and NK cells resulted in increased lymphoma killing (paragraph 0008) and that “Treat” or “treating” a cancer as used herein means to administer a combination therapy of a PD-1 antagonist and a 4-1BB agonist to a subject having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth (paragraph 0133).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the anti-CD137 antibody formulation as taught by the ‘039 patent, Sadineni, and Whitaker into the method to treat B cell lymphoma as taught by Davis. The ordinary artisan would have been motivated to do so because this is a simple substitution of a similarly formulated antibody with the same binding target and Davis teaches the addition of 4-1BB agonists to in vitro cultures of B lymphoma cells with rituximab and NK cells resulted in increased lymphoma killing. Therefore substituting the antibody formulation has a reasonable expectation of success.
Claims 4, 19, 69, 71, 79-80, and 90 are rejected on the grounds of nonstatutory double patenting as being unpatentable over claim 1-14 of U.S. Patent No. US 10,434,175 B2 in view of Sadineni (CN107743401A; Espacenet English translation attached as NPL; cited in OA 09/15/2025) and Whitaker (J Pharm Sci. 2017 Nov;106(11):3230-3241; cited in OA 02/13/2025).
Regarding claims 4, 19, 71, and 90, the ‘039 patent teaches a method of treating cancer comprising administering an isolated monoclonal antibody to human CD137 with variable heavy and light chains comprising SEQ ID NOs: 4 and 6 respectively with 100% sequence identity to the instant claimed SEQ ID NOs: 4, 6, 48, 56, 68, 69, 78, and 89 (claim 1-14).
The patented claims are silent on a pharmaceutical composition comprising the monoclonal antibody to human CD137 and the specific components and concentrations of the pharmaceutical formulation.
It is necessary to formulate an antibody in a pharmaceutical composition prior to administration as a treatment for cancer.
Regarding claims 4, 19, and 90, Sadineni teaches a combination composition of an anti-PD-1 antibody and another antibody (claim 1), wherein the amount of the anti-PD-1 antibody is 240 mg (claim 6), wherein the second antibody is an anti-CD137 (claim 16), wherein the ratio of PD-1 to CD137 is 3:1 which results in 80 mg of CD137 (claim 10), wherein the composition is formulated in histidine buffer is about 20mM (claim 32), the pH is about 6 (claims 35-36), wherein the bulking agent is NaCl (claim 38) at a concentration of about 100mM (claim 43), wherein the stabilizing agent is sucrose (claim 39) at a concentration of 10% (claim 50), and wherein the surfactant is polysorbate 80 (claim 41) at a concentration of about 0.01% or 0.03% (claim 48). Sadineni further teaches wherein the composition is stable at 5°C, 40°C, 25°C for 1 week – 5 years (claims 66-68) and wherein the composition exhibits a change in the acidity peak after storage at about 5°C for about 6 months (claim 69) and 40°C or 25°C for about 3 months of less than about 15%-1% (claims 70-71).
Regarding claims 4 and 90, Whitaker teaches formulation development strategy for monoclonal antibodies to reduce viscosity at high concentrations (whole document). Whitaker screened 56 excipients and additives under accelerated and real time storage conditions over 6 months to identify formulations with pharmaceutically acceptable viscosity and stability when stored (abstract). Whitaker demonstrated “preferred range” viscosity for the IgG4 antibody and “acceptable rage” for the IgG1 antibody tested with 100mM NaCl in 10mM histidine at pH 5.75 with antibody concentrations between 135-160mg/ml. (Figure 1, condition 7). Whitaker further teaches that with increasing concentration of histidine and NaCl the viscosity of the solution decreases (Figure 3). Whitaker further teaches that due to the physicochemical differences inherit to individual monoclonal antibodies, high concentration formulation development studies to optimize protein stability and solution viscosity require either a detailed, but time-consuming and technically challenging mechanistic studies or a more rapid but empirical approach of excipient screening (or a combination of both approaches)(conclusion).
As detailed above one of ordinary skill in the art would recognize antibody concentration, pH, the concentrations of buffer, sucrose, polysorbate 80, and salt as result-effective variables and optimize them by routine experimentation in order to minimize peroxide formation for the stability of antibody formulation as well as to generate the best efficacy of therapy. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention with prior art that demonstrates good stability with an antibody that has the same target as a starting point for optimization.
Claims 69, 79, and 80 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-14 of U.S. Patent No. US 10,434,175 B2 in view of Sadineni (CN107743401A; Espacenet English translation attached as NPL; cited in OA 09/15/2025) and Whitaker (J Pharm Sci. 2017 Nov;106(11):3230-3241; cited in OA 02/13/2025) as applied to claims 4, 19, 69, 71, 79-80, and 90 above and further in view of Davis (US 2017/0174773 A1; IDS entered March 24, 2022).
The teachings of the ‘039 patent, Sadineni, and Whitaker are detailed above.
The ‘039 patent, Sadineni, and Whitaker do not teach wherein the cancer is B cell lymphoma or use of the formulation to reduce or inhibit tumor growth.
Regarding claims 79 and 80, Davis teaches a method for treating cancer in an individual comprising administering to the individual a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) and a 4-1BB agonist (claim 1) wherein, the PD-1 antagonist and the 4-1BB agonist are administered simultaneously or sequentially (claim 2). Davis further teaches that wherein the PD-1 antagonist is formulated as a liquid medicament which comprises 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5 (claim 10). Davis further teaches that each therapeutic agent in the combination therapy may be administered simultaneously (e.g., in the same medicament or at the same time)(paragraph 0157), therefore the agonist 4-1BB antibody could be in the same formulation as the anti-PD-1 antibody. Davis further teaches wherein the cancer is bladder cancer, breast cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small-cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (FIL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL) (claim 18).
Regarding claim 69, Davis teaches the addition of 4-1BB agonists to in vitro cultures of B lymphoma cells with rituximab and NK cells resulted in increased lymphoma killing (paragraph 0008) and that “Treat” or “treating” a cancer as used herein means to administer a combination therapy of a PD-1 antagonist and a 4-1BB agonist to a subject having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth (paragraph 0133).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to substitute the anti-CD137 antibody formulation as taught by the ‘039 patent, Sadineni and Whitaker into the method to treat B cell lymphoma as taught by Davis. The ordinary artisan would have been motivated to do so because this is a simple substitution of a similarly formulated antibody with the same binding target and Davis teaches the addition of 4-1BB agonists to in vitro cultures of B lymphoma cells with rituximab and NK cells resulted in increased lymphoma killing. Therefore substituting the antibody formulation has a reasonable expectation of success.
Claims 4, 19, 69, 71, 79-80, and 90 are rejected on the grounds of nonstatutory double patenting as being unpatentable over claim 1-28 of U.S. Patent No. US 10,350,292 B1 in view of Sadineni (CN107743401A; Espacenet English translation attached as NPL; cited in OA 09/15/2025) and Whitaker (J Pharm Sci. 2017 Nov;106(11):3230-3241; cited in OA 02/13/2025).
Regarding claims 4, 19, 69, 71, 79-80, and 90, the ‘292 patent teaches an isolated monoclonal antibody that specifically binds human CD137 with variable heavy and light chains comprising SEQ ID NOs: 4 and 6 respectively (claim 1-28), with 100% sequence identity to the instant claimed SEQ ID NOs: 4, 6, 48, 56, 68, 69, 78, and 89.
The patented claims are silent on a pharmaceutical formulation and the specific components and concentrations of the pharmaceutical formulation.
Regarding claims 4, 19, and 90, Sadineni teaches a combination composition of an anti-PD-1 antibody and another antibody (claim 1), wherein the amount of the anti-PD-1 antibody is 240 mg (claim 6), wherein the second antibody is an anti-CD137 (claim 16), wherein the ratio of PD-1 to CD137 is 3:1 which results in 80 mg of CD137 (claim 10), wherein the composition is formulated in histidine buffer is about 20mM (claim 32), the pH is about 6 (claims 35-36), wherein the bulking agent is NaCl (claim 38) at a concentration of about 100mM (claim 43), wherein the stabilizing agent is sucrose (claim 39) at a concentration of 10% (claim 50), and wherein the surfactant is polysorbate 80 (claim 41) at a concentration of about 0.01% or 0.03% (claim 48). Sadineni further teaches wherein the composition is stable at 5°C, 40°C, 25°C for 1 week – 5 years (claims 66-68) and wherein the composition exhibits a change in the acidity peak after storage at about 5°C for about 6 months (claim 69) and 40°C or 25°C for about 3 months of less than about 15%-1% (claims 70-71).
Regarding claims 4 and 90, Whitaker teaches formulation development strategy for monoclonal antibodies to reduce viscosity at high concentrations (whole document). Whitaker screened 56 excipients and additives under accelerated and real time storage conditions over 6 months to identify formulations with pharmaceutically acceptable viscosity and stability when stored (abstract). Whitaker demonstrated “preferred range” viscosity for the IgG4 antibody and “acceptable rage” for the IgG1 antibody tested with 100mM NaCl in 10mM histidine at pH 5.75 with antibody concentrations between 135-160mg/ml. (Figure 1, condition 7). Whitaker further teaches that with increasing concentration of histidine and NaCl the viscosity of the solution decreases (Figure 3). Whitaker further teaches that due to the physicochemical differences inherit to individual monoclonal antibodies, high concentration formulation development studies to optimize protein stability and solution viscosity require either a detailed, but time-consuming and technically challenging mechanistic studies or a more rapid but empirical approach of excipient screening (or a combination of both approaches)(conclusion).
As detailed above one of ordinary skill in the art would recognize antibody concentration, pH, the concentrations of buffer, sucrose, polysorbate 80, and salt as result-effective variables and optimize them by routine experimentation in order to minimize peroxide formation for the stability of antibody formulation as well as to generate the best efficacy of therapy. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention with prior art that demonstrates good stability with an antibody that has the same target as a starting point for optimization.
Response to Arguments
Applicant's arguments filed 06/26/2026 have been fully considered but they are not persuasive.
Applicant submits: Applicant submits that the doctrine of double patenting seeks to avoid unjustly extending patent rights at the expense of the public. Applicant submits that claims 4, 19, 69, 71, 79-80, and 90 of the present application to the formulation comprising the anti-CD137 antibody would not unjustly extend the terms of any of U.S. Patent No. 10,279,038, U.S. Patent No. 10,279,039, U.S. Patent No. 10,434,175, or U.S. Patent No. 10,350,292.
In Response: The extension of time for patent term is not a consideration for
patentability.
Consideration for double patenting must meet the conditions as set forth in
MPEP 1701 that Office personnel may not express an opinion regarding the expiration
date of any patent. Improper time-wise extension is not, however, the only reason for
requiring a terminal disclaimer. 37 CFR 1.321(c)(3) requires that a terminal disclaimer
filed to obviate a nonstatutory double patenting rejection based on commonly owned
conflicting claims must also include a provision that any patent granted on that
application be enforceable only for and during the period that the patent is commonly
owned with the application or patent which formed the basis for the rejection. A terminal
disclaimer to ensure common ownership at present is a requirement, and one which the
Federal Circuit in In re Cellect, LLC, 81 F.4th 1216, 2023 U.S.P.Q.2d 1011 (Fed. Cir.
2023) commented upon favorably (“We also agree with the USPTO that the Board did
not err in determining that a risk of separate ownership existed and, even in the
absence of separate ownership, that a terminal disclaimer would have been required to
ensure common ownership.” Id. at 1230).
Applicant submits: The Office's analysis impermissibly picks and chooses components from Sadineni without appreciating the full context of what it teaches, particularly when combined with Whitaker. As the Federal Circuit cautioned in In re Wess/au, 353 F.2d 238, 241 (CCPA 1965), it is impermissible within the framework of an obviousness analysis "to pick and choose from any one reference only so much so it as will support a given position, to the exclusion of other parts necessary to the full appreciation of what such reference fairly suggests to one of ordinary skill in the art."
To arrive at the claimed formulation, the Office picks components from among the claims of Sadineni without acknowledging or recognizing that Sadineni's formulation is specifically designed for an anti-PD-1 antibody and a second antibody, which is a fundamentally different therapeutic context than the single antibody anti-CD137 formulation of the present claims. Even among the choices of Sadineni, Applicant submits that the parameter values differ materially from Applicant's claimed formulation (e.g., sucrose 6% vs. claimed 10%, histidine 10 mM vs. claimed 20 mM, and context of dual-antibody composition vs. a single-antibody formulation). The differences in sucrose approaches a nearly 70% increase, which can significantly impact protein stabilization and aggregation. The histidine parameter is double what is taught in Sadineni, which directly affects buffering capacity and long term stability. MPEP § 2144.05(11)(8) states, "[A] particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation." Sadineni does not recognize the result-effective capability of these parameters. The teachings of Sadineni are far outside the parameters recited in the present claims. Thus, the claimed formulation falls far outside routine optimization in view of Sadineni. Therefore, the formulation of claims 4, 19, 69, 71, 79-80, and 90 of the present invention are patentably distinct from the anti-CD137 antibody and pharmaceutical formulations of U.S. Patent No. 10,279,038, U.S.
In response: A formulation is a composition without regard to therapeutic context; as independent claims 4 and 90 are drawn to the formulation the claims do not limit the formulation to specific therapeutic context. Further the independent claims both recite “a formulation comprising” which allows for additional elements to be present, including a second immunotherapeutic with broad applicability in cancer/ tumor treatment (anti PD-1 in regards to claims 69 and 71).
While Sadineni does not state the term “result-effective variable”, they do teach optimization of the drug product (page 59, para 2); as well as that sodium chloride, mannitol and PS80 are variables in the drug product that are not affected by pH (page 58, para 7). Further, this is an obvious type rejection wherein every element is not present in Sadineni.
Whitaker teaches formulation optimization strategy including optimization of histidine and sodium chloride concentration with goals of decreased viscosity and increased stability. Whitaker further teaches that optimization of formulation of monoclonal antibodies is required but can be expedited through an empirical approach of excipient screening.
Therefore it is still well within the skill of the ordinary artisan to optimize the formulation of the instant application and considered routine experimentation to do so.
USPTO MPEP § 2144.05 states that: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235
The Federal Circuit has affirmed that if a parameter (like pH or specific stabilizer concentration) is recognized as "result-effective" (i.e., affects stability), adjusting it to optimize results is obvious, Pfizer Inc. v. Sanofi Pasteur Inc. (2024).
Applicant submits: The unpredictability in the claimed anti-CD137 antibody formulation further demonstrates that one of ordinary skill in the art would not modify Sadineni's formulation to arrive at the claimed anti-CD137 antibody formulation with any reasonable expectation of success. Applicant also submits that it would be entirely unpredictable from the teachings of Sadineni, Whitaker, and Davis how the anti-CD137 antibody molecules would behave in any particular formulation even starting from the teachings of Sadineni. The art cited by the Office supports Applicant's position that it would be unpredictable whether the formulation of claims 4, 19, 69, 71, 79-80, and 90 would maintain the activity of the anti-CD137. As recognized by the Office Whitaker teaches that "due to the physicochemical differences inherent to individual monoclonal antibodies, high concentration formulation development studies to optimize protein stability and solution viscosity require that either a detailed, but time-consuming and technically challenging mechanistic studies or a more rapid but empirical approach of excipient screening (or a combination of both approaches)." (see Office action at p. 8, first paragraph). Whitaker directly confirms that the claimed anti-CD137 antibody formulation cannot simply be borrowed from one antibody formulation and applied to another.
In response: The applicant has not indicated any specific unpredictability in the instant claimed anti-CD137 antibody formulation and the instant specification does not indicate any unpredictable results. The instant specification indicates that it was surprising that the anti-CD137 antibody was stable at high concentrations and forced degradation conditions, but this argument was already addressed in the OA mailed 03/26/2026.
Whitaker specifically teach that “The generalized formulation development approach and workflow outlined in this work should be applicable to the rapid, empirical approach to the high concentration formulation development of many mAbs, especially those of the IgG1 and IgG4 subclasses...this case study provides a formulation platform approach that others can use in the future to rapidly identify optimized, ultra-high concentration mAb formulations that balance excipient effects on protein conformational stability, aggregation propensity, solution viscosity, and solution osmolality.” (Conclusion, last para). Which confirms the optimization of formulation as a necessary step in clinical antibody development while still using previously developed formulations as starting points for optimization and that there is a reasonable expectation of success for one of ordinary skill in the art.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
