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 .
The Amendments and Remarks filed 7/28/26 in response to the Office Action of 4/29/26 are acknowledged and have been entered.
Claims 43-48 have been added by Applicant.
Claims 20-24, 26-34, 39, 40, and 42-48 are pending.
Claims 20-24, 26-34, 39, 40, and 42 have been amended by Applicant.
Claims 20-24, 26-34, 39, 40, and 42-48 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The following Office Action contains NEW GROUNDS of rejections Necessitated by Amendments.
Rejections Withdrawn
The rejection of claims 20-24, 39, 40, and 42 under 35 U.S.C. 103(a) as being unpatentable over Zhang et al (US 2022/0324971 A1; 10/13/22; 3/6/26 IDS) in view of Tao et al (Oncology Research, 2017, 25: 1579-1587; 9/29/23 IDS) and Mimura et al (Fukushima J Med Sci, 2018, 64(2): 46-53) is withdrawn.
The rejection of claims 20-24 and 42 under 35 U.S.C. 103(a) as being unpatentable over Zhang et al (US 2022/0324971 A1; 10/13/22; 3/6/26 IDS) in view of Feliz-Mosquea et al (Breast Cancer Research and Treatment, 2018, 172: 69-82) is withdrawn.
The provisional rejection of claims on the ground of nonstatutory double patenting as being unpatentable over allowed claims 4-7, 9, 11, 12, 15, 17, 20, 25, and 31-39 of copending Application No. 17/640005 in view of Tao et al (Oncology Research, 2017, 25: 1579-1587) and Mimura et al (Fukushima J Med Sci, 2018, 64(2): 46-53) is withdrawn.
The provisional rejection of claims on the ground of nonstatutory double patenting as being unpatentable over claims 4-7, 9, 11, 12, 15, 17, 20, 25, and 31-39 of copending Application No. 17/640005 in view in view of Feliz-Mosquea et al (Breast Cancer Research and Treatment, 2018, 172: 69-82) is withdrawn.
Claims 39-40 are withdrawn from all previous rejections.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claim(s) 20-24, 26, 27, 31-34, and 42 remain rejected and claims 43 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (US 2022/0324971 A1; 10/13/22; 3/6/26 IDS) in view of Tao et al (Oncology Research, 2017, 25: 1579-1587; 9/29/23 IDS), Mimura et al (Fukushima J Med Sci, 2018, 64(2): 46-53), and Li et al (US 2019/0185569 A1; 6/20/19; 3/6/26 IDS).
Zhang et al teaches an anti-CD47 monoclonal antibody (6F7H1L1(hG4)) and antigen-binding fragment thereof with a heavy chain comprising SEQ ID NO:65 and a light chain comprising SEQ ID NO:66 ([0065], in particular). SEQ ID NO:65 is identical to instant SEQ ID NO:65 and comprises CDRs and VH of instant SEQ ID NOs: 5-7 and 12. SEQ ID NO:66 is identical to instant SEQ ID NO:66 and comprises CDRs and VL of instant SEQ ID NOs: 8-10 and 14. Zhang et al further teaches said antigen-binding fragment as a single-chain antibody ([0128], in particular). Zhang et al further teaches said antibody as humanized, chimeric, or multispecific ([0091], in particular). Zhang et al further teaches said antibody and antigen-binding fragments thereof are to be used to treat a hematological malignancy or a solid tumor, such as lymphoma, colon cancer, breast cancer, Hodgkin lymphoma, and B cell lymphoma ([0123], in particular). Zhang et al further demonstrates administration of said antibody to subjects with breast cancer therapeutically reduces tumor volume (Fig. 18 and Example 10, in particular). Zhang et al further teaches said antibodies provide therapeutic benefit by (1) binding to CD47 and blocking CD47 binding to its ligand SIRPa, which blocks CD47-SIRPa pathway to allow macrophages to perform phagocytosis and (2) exert tumor killing through DC cells and CD8+ T cells ([0004] and [0239], in particular).
Zhang et al does not specifically teach administering anti-CD47 antibody or binding fragment thereof of Zhang et al to subjects with esophageal squamous cell carcinoma in combination with bispecific anti-PD-1 X anti-CTLA-4 antibodies. However, these deficiencies are made up in the teachings of Tao et al, Mimura et al, and Li et al.
Tao et al teaches a method of treating subjects with esophageal squamous cell carcinoma comprising administering an anti-CD47 monoclonal antibody that blocks CD47 interaction with its ligand in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitory antibodies synergistically inhibits tumor volume and synergistically increases patient survival, as compared to anti-CD47 alone or a combination of anti-PD-1 and anti-CTLA-4 (Figure 4, in particular). Tao et al further teaches that in addition to increasing proinflammatory response and increased CD8+ T-cell infiltration of tumor tissue, treatment of CD8+ T cells with the anti-CD47 antibody results in an increase in PD-1 and CTLA-4 expression of the cells (page 1581 and Figure 3, in particular) – which are therapeutically targeted by anti-PD-1 and anti-CTLA-4.
Mimura et al teaches the anti-human CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have demonstrated tumor shrinkage and improved overall survival in patient with multiple cancer types (left column on page 46, in particular). Mimura et al further teaches studies administering the anti-PD-1 monoclonal antibody nivolumab to human esophageal squamous cell carcinoma patents that are refractory or intolerant to standard chemotherapy exhibited complete response or partial response to nivolumab (right column on page 49, in particular). Mimura et al further describes combination of anti-PD-1/anti-PD-L1 mAb with treatment such as anti-CTLA-4 mAb may be an “ideal and reasonable strategy” for esophageal squamous cell carcinoma therapy (left column on page 52, in particular).
Li et al teaches anti-CTLA-4 X anti-PD-1 bispecific antibodies comprising a VH immunoglobulin domain comprising SEQ ID NO:16 or 20 (SEQ ID NO:16 is the same as instant SEQ ID NOs: 87; SEQ ID NO:20 is the same as instant SEQ ID NOs: 121 and 129), a VL immunoglobulin domain comprising SEQ ID NO: 22 (same as instant SEQ ID NOs: 122 and 130) targeting PD-1, and a VH scFv domain comprising SEQ ID NO: 2, 6, or 10 (same as instant SEQ ID NOs: 95, 135, and 133), and a VL scFv domain comprising SEQ ID NO:4, 8, or 12 (same as instant SEQ ID NO: 96, 136, and 134) targeting CTLA-4 ([0044]-[0047], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to treat human subjects with esophageal squamous cell carcinoma comprising administering the anti-CD47 antibody of Zhang et al in combination with anti-CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibody nivolumab or pembrolizumab of Mimura et al because: Zhang et al teaches said anti-CD47 antibody functions by blocking interaction with CD47 to its ligand ([0004] and [0239], in particular) and is to treat solid tumors ([0123], in particular); Tao et al teaches a method of treating subjects with the solid tumor esophageal squamous cell carcinoma comprising administering an anti-CD47 monoclonal antibody that blocks CD47 interaction with its ligand in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitory antibodies synergistically inhibits tumor volume and synergistically increases patient survival (Figure 4, in particular); Tao et al teaches that in addition to increasing proinflammatory response and increased CD8+ T-cell infiltration of tumor tissue, treatment of CD8+ T cells with the anti-CD47 antibody results in an increase in PD-1 and CTLA-4 expression of the cells (page 1581 and Figure 3, in particular) – which are therapeutically targeted by anti-PD-1 and anti-CTLA-4; Mimura et al teaches the anti-human CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have demonstrated tumor shrinkage and improved overall survival in patient with multiple cancer types (left column on page 46, in particular); Mimura et al teaches studies administering the anti-PD-1 monoclonal antibody nivolumab to human esophageal squamous cell carcinoma patents that are refractory or intolerant to standard chemotherapy exhibited complete response or partial response to nivolumab (right column on page 49, in particular); and Mimura et al describes combination of anti-PD-1/anti-PD-L1 mAb with treatment such as anti-CTLA-4 mAb may be an “ideal and reasonable strategy” for esophageal squamous cell carcinoma therapy (left column on page 52, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143.
Further, of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-CTLA-4 and anti-PD-1 antibodies are administered as anti-CTLA-4 X anti-PD-1 bispecific antibodies because it is conventional and routine to administer two therapeutic antibodies as a single bispecific reagent. Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-CTLA-4 X anti-PD-1 bispecific antibodies of Li et al are substituted in place of the anti-CTLA-4 and anti-PD-1 antibodies of the combined method because the antibodies of the combined method are to treat cancer and Li et al teaches the anti-CTLA-4 X anti-PD-1 bispecific antibodies are to treat cancer. This is an example of s simple substitution of the anti-CTLA-4 X anti-PD-1 bispecific antibodies of Li et al in place of the anti-CTLA-4 and anti-PD-1 antibodies of the combined method with an expectation of success. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 7/28/26, Applicant cites Figure 9 and Example 9 of the specification and indicates the claims are non-obvious because anti-CD47 antibody in combination with anti-PD-1/anti-CTLA4 bispecific antibody unexpectedly demonstrates enhanced synergistic anti-tumor effects as compared to either antibody alone and none of the cited references teach or suggest administering anti-CD47 antibody in combination with anti-PD-1/anti-CTLA4 bispecific antibody would result in such synergistic anti-tumor effects.
The amendments to the claims and the arguments found in the Reply of 7/28/26 have been carefully considered, but are not deemed persuasive. In regards to the citation of Figure 9 and Example 9 of the specification and indication that the claims are non-obvious because anti-CD47 antibody in combination with anti-PD-1/anti-CTLA4 bispecific antibody unexpectedly demonstrates enhanced synergistic anti-tumor effects as compared to either antibody alone and none of the cited references teach or suggest administering anti-CD47 antibody in combination with anti-PD-1/anti-CTLA4 bispecific antibody would result in such synergistic anti-tumor effects, the examiner disagrees. The "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." See MPEP 716.02(d). In the instant case, the synergistic anti-tumor effects demonstrated in Figure 9 and Example 9 are neither commensurate in scope with the claims nor unexpected. The synergistic anti-tumor effects demonstrated in Figure 9 and Example 9 are from administering the anti-CD47 antibody “6FH1L1” in combination with anti-PD-1/anti-CTLA4 bispecific antibody “Cadonilimab” and the rejected claims not limited to administering 6FH1L1 and Cadonilimab. Further, one would expect administering anti-CD47 antibody in combination with anti-PD-1/anti-CTLA4 bispecific antibody would result in such synergistic anti-tumor effects because the prior art of Tao et al teaches a method of treating subjects with esophageal squamous cell carcinoma comprising administering an anti-CD47 monoclonal antibody that blocks CD47 interaction with its ligand in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitory antibodies synergistically inhibits tumor volume and synergistically increases patient survival, as compared to anti-CD47 alone or a combination of anti-PD-1 and anti-CTLA-4 antibodies (Figure 4, in particular). Tao et al further teaches that in addition to increasing proinflammatory response and increased CD8+ T-cell infiltration of tumor tissue, treatment of CD8+ T cells with the anti-CD47 antibody results in an increase in PD-1 and CTLA-4 expression of the cells (page 1581 and Figure 3, in particular) – which are therapeutically targeted by anti-PD-1 and anti-CTLA-4. One of skill in the art would expect the combined method that administers an anti-CD47 monoclonal antibody that blocks CD47 interaction with its ligand in combination with anti-PD-1/anti-CTLA4 bispecific antibodies would synergistically increase patient survival, as compared to anti-CD47 alone or anti-PD-1/anti-CTLA4 bispecific antibodies alone because Tao et al teaches anti-CD47 antibody and a combination of anti-PD-1 and anti-CTLA-4 antibodies demonstrates such synergy and substituting anti-PD-1/anti-CTLA4 bispecific antibodies in place of a combination of anti-PD-1 and anti-CTLA-4 antibodies is a simple substitution with an expectation of success to have such synergy because both (i) the combination of anti-PD-1 and anti-CTLA-4 antibodies and (ii) anti-PD-1/anti-CTLA4 bispecific antibodies function by inhibiting both PD-1 and CTLA-4.
Claim Rejections - 35 USC § 103
Claim(s) 20-24, 26-29, 31-34, and 42 remain rejected and claims 43 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (US 2022/0324971 A1; 10/13/22; 3/6/26 IDS) in view of Tao et al (Oncology Research, 2017, 25: 1579-1587; 9/29/23 IDS) and Mimura et al (Fukushima J Med Sci, 2018, 64(2): 46-53), and Xia et al (US 2022/0275089 A1; 9/1/22; 3/6/26 IDS).
Zhang et al teaches an anti-CD47 monoclonal antibody (6F7H1L1(hG4)) and antigen-binding fragment thereof with a heavy chain comprising SEQ ID NO:65 and a light chain comprising SEQ ID NO:66 ([0065], in particular). SEQ ID NO:65 is identical to instant SEQ ID NO:65 and comprises CDRs and VH of instant SEQ ID NOs: 5-7 and 12. SEQ ID NO:66 is identical to instant SEQ ID NO:66 and comprises CDRs and VL of instant SEQ ID NOs: 8-10 and 14. Zhang et al further teaches said antigen-binding fragment as a single-chain antibody ([0128], in particular). Zhang et al further teaches said antibody as humanized, chimeric, or multispecific ([0091], in particular). Zhang et al further teaches said antibody and antigen-binding fragments thereof are to be used to treat a hematological malignancy or a solid tumor, such as lymphoma, colon cancer, breast cancer, Hodgkin lymphoma, and B cell lymphoma ([0123], in particular). Zhang et al further demonstrates administration of said antibody to subjects with breast cancer therapeutically reduces tumor volume (Fig. 18 and Example 10, in particular). Zhang et al further teaches said antibodies provide therapeutic benefit by (1) binding to CD47 and blocking CD47 binding to its ligand SIRPa, which blocks CD47-SIRPa pathway to allow macrophages to perform phagocytosis and (2) exert tumor killing through DC cells and CD8+ T cells ([0004] and [0239], in particular).
Zhang et al does not specifically teach administering anti-CD47 antibody or binding fragment thereof of Zhang et al to subjects with esophageal squamous cell carcinoma in combination with bispecific anti-PD-1 X anti-CTLA-4 antibodies. However, these deficiencies are made up in the teachings of Tao et al, Mimura et al, and Xia et al.
Tao et al teaches a method of treating subjects with esophageal squamous cell carcinoma comprising administering an anti-CD47 monoclonal antibody that blocks CD47 interaction with its ligand in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitory antibodies synergistically inhibits tumor volume and synergistically increases patient survival, as compared to anti-CD47 alone or a combination of anti-PD-1 and anti-CTLA-4 (Figure 4, in particular). Tao et al further teaches that in addition to increasing proinflammatory response and increased CD8+ T-cell infiltration of tumor tissue, treatment of CD8+ T cells with the anti-CD47 antibody results in an increase in PD-1 and CTLA-4 expression of the cells (page 1581 and Figure 3, in particular) – which are therapeutically targeted by anti-PD-1 and anti-CTLA-4.
Mimura et al teaches the anti-human CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have demonstrated tumor shrinkage and improved overall survival in patient with multiple cancer types (left column on page 46, in particular). Mimura et al further teaches studies administering the anti-PD-1 monoclonal antibody nivolumab to human esophageal squamous cell carcinoma patents that are refractory or intolerant to standard chemotherapy exhibited complete response or partial response to nivolumab (right column on page 49, in particular). Mimura et al further describes combination of anti-PD-1/anti-PD-L1 mAb with treatment such as anti-CTLA-4 mAb may be an “ideal and reasonable strategy” for esophageal squamous cell carcinoma therapy (left column on page 52, in particular).
Xia et al teaches anti-CTLA-4 X anti-PD-1 bispecific antibodies comprising a VH immunoglobulin domain comprising SEQ ID NO:14 or 18 (same as instant SEQ ID NOs: 87 and 129) or a heavy domain comprising SEQ ID NO:40 (same as instant SEQ ID NOs: 82 and 139) and a VL immunoglobulin domain comprising SEQ ID NO: 16 or 20 (same as instant SEQ ID NOs: 88 and 130) or a light chain comprising SEQ ID NO:24 (same as instant SEQ ID NOs:80 and 84) targeting PD-1, and a VH scFv domain comprising SEQ ID NO: 2, 41, 10, 43, or 6 (same as instant SEQ ID NOs: 95, 135, 133, 137, and 131), and a VL scFv domain comprising SEQ ID NO:4, 42, 12, 44, or 8 (same as instant SEQ ID NO: 96, 136, 134, 138, and 132 ) targeting CTLA-4 ([0056]-[0057] and [0103], in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to treat human subjects with esophageal squamous cell carcinoma comprising administering the anti-CD47 antibody of Zhang et al in combination with anti-CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibody nivolumab or pembrolizumab of Mimura et al because: Zhang et al teaches said anti-CD47 antibody functions by blocking interaction with CD47 to its ligand ([0004] and [0239], in particular) and is to treat solid tumors ([0123], in particular); Tao et al teaches a method of treating subjects with the solid tumor esophageal squamous cell carcinoma comprising administering an anti-CD47 monoclonal antibody that blocks CD47 interaction with its ligand in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitory antibodies synergistically inhibits tumor volume and synergistically increases patient survival (Figure 4, in particular); Tao et al teaches that in addition to increasing proinflammatory response and increased CD8+ T-cell infiltration of tumor tissue, treatment of CD8+ T cells with the anti-CD47 antibody results in an increase in PD-1 and CTLA-4 expression of the cells (page 1581 and Figure 3, in particular) – which are therapeutically targeted by anti-PD-1 and anti-CTLA-4; Mimura et al teaches the anti-human CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have demonstrated tumor shrinkage and improved overall survival in patient with multiple cancer types (left column on page 46, in particular); Mimura et al teaches studies administering the anti-PD-1 monoclonal antibody nivolumab to human esophageal squamous cell carcinoma patents that are refractory or intolerant to standard chemotherapy exhibited complete response or partial response to nivolumab (right column on page 49, in particular); and Mimura et al describes combination of anti-PD-1/anti-PD-L1 mAb with treatment such as anti-CTLA-4 mAb may be an “ideal and reasonable strategy” for esophageal squamous cell carcinoma therapy (left column on page 52, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-CTLA-4 and anti-PD-1 antibodies are administered as anti-CTLA-4 X anti-PD-1 bispecific antibodies because it is conventional and routine to administer two therapeutic antibodies as a single bispecific reagent. Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-CTLA-4 X anti-PD-1 bispecific antibodies of Xia et al are substituted in place of the anti-CTLA-4 and anti-PD-1 antibodies of the combined method because the antibodies of the combined method are to treat cancer and Xia et al teaches the anti-CTLA-4 X anti-PD-1 bispecific antibodies are to treat cancer. This is an example of s simple substitution of the anti-CTLA-4 X anti-PD-1 bispecific antibodies of Xia et al in place of the anti-CTLA-4 and anti-PD-1 antibodies of the combined method with an expectation of success. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 7/28/26, Applicant repeat arguments addressed above.
Claim Rejections - 35 USC § 103
Claims 20-24 and 26-30 remain rejected and claims 43 and 47 are rejected under 35 U.S.C. 103(a) as being unpatentable over Zhang et al (US 2022/0324971 A1; 10/13/22; 3/6/26 IDS) in view of Xiong et al (International Journal of Molecular Sciences, 2018, 19(2900): 1-20).
Zhang et al teaches an anti-CD47 monoclonal antibody (6F7H1L1(hG4)) and antigen-binding fragment thereof with a heavy chain comprising SEQ ID NO:65 and a light chain comprising SEQ ID NO:66 ([0065], in particular). SEQ ID NO:65 is identical to instant SEQ ID NO:65 and comprises CDRs and VH of instant SEQ ID NOs: 5-7 and 12. SEQ ID NO:66 is identical to instant SEQ ID NO:66 and comprises CDRs and VL of instant SEQ ID NOs: 8-10 and 14. Zhang et al further teaches said antigen-binding fragment as a single-chain antibody ([0128], in particular). Zhang et al further teaches said antibody as humanized, chimeric, or multispecific ([0091], in particular). Zhang et al further teaches said antibody and antigen-binding fragments thereof are to be used to treat a hematological malignancy or a solid tumor ([0123], in particular).
Zhang et al does not specifically teach a combination of anti-CD47 antibody or binding fragment thereof and an anti-PD-1/anti-VEGFA bispecific antibody. However, these deficiencies are made up in the teachings of Xiong et al.
Xiong et al teaches a teaches an anti-PD-1/anti-VEGFA bispecific antibody that provides therapeutic benefit to subjects with a solid tumor (Figure 10, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate a combination comprising the anti-CD47 antibody of Zhang et al and the anti-PD-1/anti-VEGFA bispecific antibody of Xiong et al to treat solid tumors because both reagents have been shown to treat solid tumors. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 7/28/26, Applicant cites Figure 11 and Example 10 of the specification and indication the claims are non-obvious because the combination of anti-DD47 antibody “6FH1L1” and anti-PD-1Xanti-VEGFA bispecific antibody “VP101” more effectively inhibits tumor growth in a mouse model compared to either antibody administered individually or an isotype control and indicates the combination demonstrates enhanced synergistic anti-tumor effects compared to either antibody alone. Applicant further argues that cited references do not teach or suggest the combination of claimed antibodies would result in demonstrated synergistic anti-tumor effects or inhibit tumor growth exceeding the effect of each individual antibody. Applicant further states that VEGF165 of Xiong is an isoform of VEGFA and the anti-VEGF165 antibody of Xiong does not teach or suggest a recited anti-VEGFA antibody. Applicant further argues cited references do not suggest combining the antibodies of Zhang and Xiong for treatment of a tumor.
The amendments to the claims and the arguments found in the Reply of 7/28/26 have been carefully considered, but are not deemed persuasive. In regards to the citation of Figure 11 and Example 10 of the specification and indication the claims are non-obvious because the combination of anti-DD47 antibody “6FH1L1” and anti-PD-1Xanti-VEGFA bispecific antibody “VP101” more effectively inhibits tumor growth in a mouse model compared to either antibody administered individually or an isotype control, indication the claims are non-obvious because the combination demonstrates enhanced synergistic anti-tumor effects compared to either antibody alone, and indication the claims are non-obvious because cited references do not teach or suggest the combination of claimed antibodies would result in demonstrated synergistic anti-tumor effects or inhibit tumor growth exceeding the effect of each individual antibody, the examiner disagrees. Figure 11 and Example 10 does not demonstrate unexpected synergy; rather, Figure 11 and Example 10 exhibits a predicable additive therapeutic effect. See Figure 11:
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The "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." See MPEP 716.02(d). In the instant case, additive therapeutic benefit is expected because both reagents of the combined method are taught to treat tumors. Further, the additive anti-tumor effects demonstrated in Figure 11 and Example 10 are from administering the anti-CD47 antibody “6FH1L1” in combination with anti-PD-1/VEGFA bispecific antibody “VP101” and the rejected claims not limited to administering 6FH1L1 and VP101. Therefore, the evidences is neither unexpected nor commensurate in scope with the claims.
In regards to the argument that VEGF165 of Xiong is an isoform of VEGFA and the anti-VEGF165 antibody of Xiong does not teach or suggest a recited anti-VEGFA antibody, the examiner disagrees. Noting VEGF165 of Xiong is an isoform (i.e., species) of VEGFA, the anti-PD-1/anti-VEGFA bispecific antibody is a recited anti-PD-1/anti-VEGFA bispecific antibody.
Double Patenting
Claims 20-24, 26, 27, 31-34, and 42 remain provisionally rejected and claims 43 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over allowed claims 4-7, 9, 11, 12, 15, 17, 20, 25, and 31-39 of copending Application No. 17/640005 in view of Tao et al (Oncology Research, 2017, 25: 1579-1587), Mimura et al (Fukushima J Med Sci, 2018, 64(2): 46-53), and Li et al (US 2019/0185569 A1; 6/20/19).
The published copending Application No. 17/640005 is described above as Zhang et al (US 2022/0324971 A1; 10/13/22).
The copending claims and instant claims are drawn to the same anti-CD47 antibodies and methods of administering said antibodies. The copending claims do not specifically recite the antibodies are part of a composition comprising another therapeutic regent or that said composition is administered to a patient. These deficiencies are made-up in by the teachings of Tao et al, Mimura et al, and Li et al.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating human subjects with esophageal squamous cell carcinoma comprising administering the anti-CD47 antibody of the copending claims in combination with anti-CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibody nivolumab or pembrolizumab of Mimura et al because: the copending antibody functions by blocking interaction with CD47 to its ligand and is to treat solid tumors; Tao et al teaches a method of treating subjects with the solid tumor esophageal squamous cell carcinoma comprising administering an anti-CD47 monoclonal antibody that blocks CD47 interaction with its ligand in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitory antibodies synergistically inhibits tumor volume and synergistically increases patient survival (Figure 4, in particular); Tao et al teaches that in addition to increasing proinflammatory response and increased CD8+ T-cell infiltration of tumor tissue, treatment of CD8+ T cells with the anti-CD47 antibody results in an increase in PD-1 and CTLA-4 expression of the cells (page 1581 and Figure 3, in particular) - which are therapeutically targeted by anti-PD-1 and anti-CTLA-4; Mimura et al teaches the anti-human CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have demonstrated tumor shrinkage and improved overall survival in patient with multiple cancer types (left column on page 46, in particular); Mimura et al teaches studies administering the anti-PD-1 monoclonal antibody nivolumab to human esophageal squamous cell carcinoma patents that are refractory or intolerant to standard chemotherapy exhibited complete response or partial response to nivolumab (right column on page 49, in particular); and Mimura et al describes combination of anti-PD-1/anti-PD-L1 mAb with treatment such as anti-CTLA-4 mAb may be an “ideal and reasonable strategy” for esophageal squamous cell carcinoma therapy (left column on page 52, in particular).
Further, of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-CTLA-4 and anti-PD-1 antibodies are administered as anti-CTLA-4 X anti-PD-1 bispecific antibodies because it is conventional and routine to administer two therapeutic antibodies as a single bispecific reagent.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-CTLA-4 X anti-PD-1 bispecific antibodies of Li et al are substituted in place of the anti-CTLA-4 and anti-PD-1 antibodies of the combined method because the antibodies of the combined method are to treat cancer and Li et al teaches the anti-CTLA-4 X anti-PD-1 bispecific antibodies are to treat cancer. This is an example of s simple substitution of the anti-CTLA-4 X anti-PD-1 bispecific antibodies of Li et al in place of the anti-CTLA-4 and anti-PD-1 antibodies of the combined method with an expectation of success. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
In the Reply of 7/28/26, Applicant indicates use of secondary references in ODP rejection is only permitted to construe a reference claim and not to draw out disclosure of claim elements present in the pending claims and indicates this rejection should be withdrawn for relying on secondary reference teachings of antibodies in a manner that is “not permitted.”
The amendments to the claims and the arguments found in the Reply of 7/28/26 have been carefully considered, but are not deemed persuasive. In regards to the indication use of secondary references in ODP rejection is only permitted to construe a reference claim and not to draw out disclosure of claim elements present in the pending claims and indication this rejection should be withdrawn for relying on secondary reference teachings of antibodies in a manner that is “not permitted,” the examiner disagrees. While there are some limitations to what can be used from a copending specification of an application to reject claims of the instant application, there is no absolutely prohibition of using any secondary reference that is prior art to determine whether instant claims are obvious in view of copending claims.
Double Patenting
Claims 20-24, 26-29, 31-34, and 42 remain provisionally rejected and claims 43 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-7, 9, 11, 12, 15, 17, 20, 25, and 31-39 of copending Application No. 17/640005 in view of in view of Tao et al (Oncology Research, 2017, 25: 1579-1587), Mimura et al (Fukushima J Med Sci, 2018, 64(2): 46-53), and Xia et al (US 2022/0275089 A1; 9/1/22).
The published copending Application No. 17/640005 is described above as Zhang et al (US 2022/0324971 A1; 10/13/22).
The copending claims and instant claims are drawn to the same anti-CD47 antibodies and methods of administering said antibodies. The copending claims do not specifically recite the antibodies are part of a composition comprising another therapeutic regent or that said composition is administered to a patient. These deficiencies are made-up in by the teachings of Tao et al, Mimura et al, and Li et al.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating human subjects with esophageal squamous cell carcinoma comprising administering the anti-CD47 antibody of the copending claims in combination with anti-CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibody nivolumab or pembrolizumab of Mimura et al because: the copending antibody functions by blocking interaction with CD47 to its ligand and is to treat solid tumors; Tao et al teaches a method of treating subjects with the solid tumor esophageal squamous cell carcinoma comprising administering an anti-CD47 monoclonal antibody that blocks CD47 interaction with its ligand in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitory antibodies synergistically inhibits tumor volume and synergistically increases patient survival (Figure 4, in particular); Tao et al teaches that in addition to increasing proinflammatory response and increased CD8+ T-cell infiltration of tumor tissue, treatment of CD8+ T cells with the anti-CD47 antibody results in an increase in PD-1 and CTLA-4 expression of the cells (page 1581 and Figure 3, in particular) - which are therapeutically targeted by anti-PD-1 and anti-CTLA-4; Mimura et al teaches the anti-human CTLA-4 monoclonal antibody ipilimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have demonstrated tumor shrinkage and improved overall survival in patient with multiple cancer types (left column on page 46, in particular); Mimura et al teaches studies administering the anti-PD-1 monoclonal antibody nivolumab to human esophageal squamous cell carcinoma patents that are refractory or intolerant to standard chemotherapy exhibited complete response or partial response to nivolumab (right column on page 49, in particular); and Mimura et al describes combination of anti-PD-1/anti-PD-L1 mAb with treatment such as anti-CTLA-4 mAb may be an “ideal and reasonable strategy” for esophageal squamous cell carcinoma therapy (left column on page 52, in particular).
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-CTLA-4 and anti-PD-1 antibodies are administered as anti-CTLA-4 X anti-PD-1 bispecific antibodies because it is conventional and routine to administer two therapeutic antibodies as a single bispecific reagent.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method wherein the anti-CTLA-4 X anti-PD-1 bispecific antibodies of Xia et al are substituted in place of the anti-CTLA-4 and anti-PD-1 antibodies of the combined method because the antibodies of the combined method are to treat cancer and Xia et al teaches the anti-CTLA-4 X anti-PD-1 bispecific antibodies are to treat cancer. This is an example of s simple substitution of the anti-CTLA-4 X anti-PD-1 bispecific antibodies of Xia et al in place of the anti-CTLA-4 and anti-PD-1 antibodies of the combined method with an expectation of success. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
In the Reply of 7/28/26, Applicant indicates use of secondary references in ODP rejection is only permitted to construe a reference claim and not to draw out disclosure of claim elements present in the pending claims and indicates this rejection should be withdrawn for relying on secondary reference teachings of antibodies in a manner that is “not permitted.”
The amendments to the claims and the arguments found in the Reply of 7/28/26 have been carefully considered, but are not deemed persuasive. In regards to the indication use of secondary references in ODP rejection is only permitted to construe a reference claim and not to draw out disclosure of claim elements present in the pending claims and indication this rejection should be withdrawn for relying on secondary reference teachings of antibodies in a manner that is “not permitted,” the examiner disagrees. While there are some limitations to what can be used from a copending specification of an application to reject claims of the instant application, there is no absolutely prohibition of using any secondary reference that is prior art to determine whether instant claims are obvious in view of copending claims.
Double Patenting
Claims 20-24 and 26-30 are provisionally rejected and claims 43 and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-7, 9, 11, 12, 15, 17, 20, 25, and 31-39 of copending Application No. 17/640005 in view of in view of Xiong et al (International Journal of Molecular Sciences, 2018, 19(2900): 1-20).
The copending claims and instant claims are drawn to the same anti-CD47 antibodies and methods of administering said antibodies. The copending claims do not specifically recite the antibodies are part of a composition comprising an anti-PD-1/anti-VEGFA bispecific antibody. However, these deficiencies are made up in the teachings of Xiong et al.
Xiong et al teaches a teaches an anti-PD-1/anti-VEGFA bispecific antibody that provides therapeutic benefit to subjects with a solid tumor (Figure 10, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer a combination comprising the anti-CD47 antibody of the copending claims and the anti-PD-1/anti-VEGFA bispecific antibody of Xiong et al to treat solid tumors because both reagents have been shown to treat solid tumors. This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
In the Reply of 7/28/26, Applicant indicates use of secondary references in ODP rejection is only permitted to construe a reference claim and not to draw out disclosure of claim elements present in the pending claims and indicates this rejection should be withdrawn for relying on secondary reference teachings of antibodies in a manner that is “not permitted.”
The amendments to the claims and the arguments found in the Reply of 7/28/26 have been carefully considered, but are not deemed persuasive. In regards to the indication use of secondary references in ODP rejection is only permitted to construe a reference claim and not to draw out disclosure of claim elements present in the pending claims and indication this rejection should be withdrawn for relying on secondary reference teachings of antibodies in a manner that is “not permitted,” the examiner disagrees. While there are some limitations to what can be used from a copending specification of an application to reject claims of the instant application, there is no absolutely prohibition of using any secondary reference that is prior art to determine whether instant claims are obvious in view of copending claims.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 44-46 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 44-46 are rejected because claim 44 recites “…of the heavy chain of the immunoglobulin….” There is insufficient antecedent basis for “the heavy chain of the immunoglobulin” in the claims.
Claim Rejections - 35 USC § 103
Claim(s) 20-24, 26, 27, 31-34, 39, 40, 42, 43, and 48 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (US 2022/0324971 A1; 10/13/22; 3/6/26 IDS) in view of Tao et al (Oncology Research, 2017, 25: 1579-1587; 9/29/23 IDS), Mimura et al (Fukushima J Med Sci, 2018, 64(2): 46-53), and Li et al (US 2019/0185569 A1; 6/20/19; 3/6/26 IDS) as applied to claims 20-24, 26, 27, 31-34, 42, 43, and 48 above, and further in view of Yang et al (Oncotarget, 2017, 8(43): 74673-74687).
Teachings of Zhang et al, Tao et al, Mimura et al, and Li et al are discussed above.
Zhang et al, Tao et al, Mimura et al, and Li et al do not specifically teach administering an additional therapeutic agent that is an angiogenesis inhibitor to the subjects with esophageal squamous cell carcinoma. However, these deficiencies are made up in the teachings of Yang et al.
Yang et al teaches angiogenesis is necessary for tumor growth, metastasis, and constitutes an important point in the control of cancer progression (left column on page 74673, in particular) and metformin inhibits angiogenesis by suppressing the JAK/STAT3 signaling pathway when administered to subjects with esophageal squamous cell carcinoma – resulting in reduced tumor volume (Abstract and Figure 7, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Zhang et al, Tao et al, Mimura et al, and Li et al wherein the subjects of the combined method with esophageal squamous cell carcinoma are further administered an angiogenesis inhibitor such as metformin because Yang et al teaches angiogenesis is necessary for tumor growth, metastasis, and constitutes an important point in the control of cancer progression (left column on page 74673, in particular) and metformin inhibits angiogenesis by suppressing the JAK/STAT3 signaling pathway when administered to subjects with esophageal squamous cell carcinoma – resulting in reduced tumor volume (Abstract and Figure 7, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Double Patenting
Claims 20-24, 26, 27, 31-34, 39, 40, 42, 43, and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over allowed claims 4-7, 9, 11, 12, 15, 17, 20, 25, and 31-39 of copending Application No. 17/640005 in view of Tao et al (Oncology Research, 2017, 25: 1579-1587), Mimura et al (Fukushima J Med Sci, 2018, 64(2): 46-53) and Li et al (US 2019/0185569 A1; 6/20/19), as applied to claims 20-24, 26, 27, 31-34, 42, 43, and 48, and in further view of Yang et al (Oncotarget, 2017, 8(43): 74673-74687).
The combination of Zhang et al, Tao et al, Mimura et al, and Li et al is discussed above.
The combination does not specifically teach administering an additional therapeutic agent that is an angiogenesis inhibitor to the subjects with esophageal squamous cell carcinoma. However, these deficiencies are made up in the teachings of Yang et al.
Yang et al teaches angiogenesis is necessary for tumor growth, metastasis, and constitutes an important point in the control of cancer progression (left column on page 74673, in particular) and metformin inhibits angiogenesis by suppressing the JAK/STAT3 signaling pathway when administered to subjects with esophageal squamous cell carcinoma – resulting in reduced tumor volume (Abstract and Figure 7, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Zhang et al, Tao et al, Mimura et al, and Li et al wherein the subjects of the combined method with esophageal squamous cell carcinoma are further administered an angiogenesis inhibitor such as metformin because Yang et al teaches angiogenesis is necessary for tumor growth, metastasis, and constitutes an important point in the control of cancer progression (left column on page 74673, in particular) and metformin inhibits angiogenesis by suppressing the JAK/STAT3 signaling pathway when administered to subjects with esophageal squamous cell carcinoma – resulting in reduced tumor volume (Abstract and Figure 7, in particular). This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
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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