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 .
Application Status
Claims 4, 19, 69, 71, 79-80, and 90 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
All previous objections and rejections of claims 6, 31-33, 43, and 45-46 are rendered moot by claim cancellation.
Previous rejection of claims 4, 19, 69, 71, 79-80, and 90 under NSDP are withdrawn in view of claim amendments.
Double Patenting
New Rejection Necessitated by Amendment
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). Sadenini 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). Sadenini 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). Sadenini 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). Sadenini 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 01/14/2026 have been fully considered but they are not persuasive.
Applicant submits: For at least the reasons presented below and without acquiescing in the Examiner's rejection, the applied references, whether taken alone or in any reasonable combination, fail to disclose or suggest at least a "formulation comprising ... (b) a buffer comprising histidine, wherein the buffer comprises about 20 mM histidine; (c) a salt, (d) a disaccharide sugar; and (e) a non-ionic surfactant, wherein the formulation has a pH of about 5.7-6.3, and wherein the salt is NaCl and the NaCl is at a concentration of about 100 mM, the disaccharide sugar is sucrose at about 10% weight/volume (w/v), and the non-ionic surfactant is polysorbate-80 at about 0.03% weight/volume (w/v)," as recited in amended independent claims 4 and 90.
In response: Contrary to the assertation that Sadenini does not teach the specific concentrations as claimed in the instant application, Sadenini does include those concentrations of the formulation in the disclosure as detailed in the new rejections above. They were not referenced in the prior office action as they were not relevant at the time.
Applicant submits: On pg. 6 of the Office Action, the Examiner characterizes these variables as "result-effective" and optimizable (citing In re Aller), but nonstatutory double patenting analysis still requires the claimed subject matter to be obvious over the reference patent's claims. Here, the precise numeric combination of four excipients at the recited concentrations within a narrow pH range-for the claimed antibody-is not taught by the patent claims and is not specifically suggested by Sadineni's dual-antibody context or Whitaker's general screenings. The Office's own description shows mismatches at key parameters (e.g., sucrose and histidine levels) and different clinical/formulation context (single-antibody vs. combination).
In response: Sadineni specifically teaches that the same formulation as the instant claims with an antibody targeting CD137 and Whitaker teaches IgG1 antibody formulated with 100mM NaCl in 10mM histidine (which still applies to instant claim 90) at pH 5.75 with antibody concentrations between 135-160 mg/ml as well as rapid and empirical excipient screening.
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: Moreover, evidence in the specification supports unexpected stability behavior within the claimed window. The Office Action quotes the specification (,I273) regarding surprising stability of anti-CD137 formulations in histidine buffer at pH ~5.8 and reduction in acidic/basic species at pH 6.0-6.5, and that addition of sucrose improves stability at elevated temperatures (see pg. 22 of the Office Action). While the Office Action questions commensurateness of scope, the amended claims now align tightly with the ranges demonstrated in the specification-histidine~20 mM, pH 5.7-6.3, sucrose present (10% w/v), polysorbate-80 0.03% w/v, NaCl ~100 mM.
In response: Sadineni teaches stability as well as maintenance of the acidic/ basic species of the composition over a range of temperatures from 4-40ºC and over a range of time periods of 1-3 months of an anti-CD137 and anti-PD-1 antibody composition in the same formulation.
Whitaker also teaches thermostability of antibody formulations with histidine, NaCl, polysorbate and sucrose, under elevated temperature up to 50 degrees Celsius (Figure 4). Whitaker also teaches maintenance of monomeric antibody in a range of temperatures, antibody concentrations and time, formulated in histidine buffer with NaCl (figure 6) as well as maintenance of acidic/ basic species at lower temperatures versus higher temperatures (figure 8).
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.
The claims are not drawn to degradation conditions of high temperature. As detailed below there was virtually no benefit to the addition of sucrose (or sorbitol) to the formulation other than sub visible particle formation which are later formed anyway by freeze thaw and “effectively removed by a needle with a 5um filter: (page 247); the antibody was not tested at the entire range of concentration claimed. Claim 90 does not teach the specific concentration of histidine; Claims 4 and 90 do not claim a specific pH, or a specific concentration of antibody but a range of each with a specific concentration of NaCl, sucrose and polysorbate. It was not demonstrated that the “unexpected results” achieved in the example would occur over the entire claimed range of concentrations or any combination of said variables so the “unexpected results” are not commensurate in scope of the independent claims.
Example 28 is drawn to 100mg/ml of antibody with SEQ ID NO: 4 and 6 at different pHs, buffers and temperatures at 8.5% sucrose with no NaCl or polysorbate; Example 29 is drawn to 5mg/ml of antibody with SEQ ID NO: 101 and 6 (which are not the CDRs claimed) with NaCl at 50 or 125mM, in various pHs, detergent, excipient and buffers and as shown in Table 7, there was no significant aggregation or degradation observed in any of the formulations tested. Example 30 is drawn to 21.8 mg/ml of SEQ ID NO: 4 and 6 with 100mM NaCl, 0.03% Polysorbate 80, 20 mM histidine at pH 6, 10% sucrose or 5 % sorbitol at different temperatures. As seen in table 8-12 the type and amount of sugar had no effect on stability, charge variants, or aggregation in various temperatures over time. Table 13 discloses that sucrose reduced the amount of sub-visible particles in the formulation.
Further the stability of the antibody formulation was maintained after 10 fold dilution at room temperature for 3 days in various dextrose and saline solutions. Figure 37 shows that there was no detectable increase in aggregation even with the 10 fold dilution of the stock formulation demonstrating that stability is maintained even over a wide range of concentrations of all factors.
Applicant submits: Finally, the nonstatutory double patenting combinations rely on retrospective assembly across disparate contexts. The Office Action's rationale stitches together: (i) reference patent claims that lack formulation detail; (ii) Sadineni's dual-antibody context and parameter examples; and (iii) Whitaker's general screening guidance, to reconstruct Applicant's single-antibody formulation at specific numeric values. The Office itself acknowledges that formulation optimization can be time-consuming and antibody-dependent, even under Whitaker's empirical approach-supporting that finding the exact "sweet spot" is non-trivial (see pg. 6 of the Office Action). In nonstatutory double patenting, where the reference patent claims do not include the specific excipient/concentration limitations, and the alleged obvious path requires selecting precise numeric points not taught by the references (and differs from Sadineni's values), the present claims remain patentably distinct.
In response: In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning (retrospective assembly), it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
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). While this does not render the optimization as “trivial” it does maintain that it can be rapid and efficient as a necessary step in clinical antibody development.
As detailed above Sadenini does teach the excipients at the specific concentrations in the newly amended instant claims, please see new rejection detailed above.
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.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643