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 .
Detailed Action
The Amendments and Remarks filed 8/7/26 in response to the Office Action of 5/8/26 are acknowledged and have been entered.
Claims 13, 15-23, 25, 27, and 29 are pending.
Claims 13, 25, 27, and 29 have been amended by Applicant.
Claims 13, 15-23, 25, 27, and 29 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.
This Office Action contains New Rejections Necessitated by Amendments.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 13, 15-23, 25, 27, and 29 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Staunton et al (US 7,771,720 B2; 8/10/2010) in view of Kubala et al (Cancer Res, 2017, 77(13_Supp): 3061) and Suda (J Thorac Dis, 2017, 9(11): 4197-4200).
Staunton et al teaches PAI-1 protein is often expressed by cancer cells in non-invasive areas, suggesting PAI-1 plays a role in protecting tumor tissue against proteolytic degradation (lines 39-44 of column 66, in particular). Staunton et al further teaches a method of treating cancerous tumors comprising administering a compound comprising antibodies which bind and neutralize PAI-1 in combination with one or more additional therapeutic treatments (including one or a combination of anti-tumor chemotherapeutic treatments) to a cancer patient (columns 67-68, in particular). Further, one of skill in the art would recognize cancers tumors comprise tumor cells.
Staunton et al does not specifically describe a patient as expressing PD-L1. However, these deficiencies are made up in the teachings of Kubala et al and Suda.
Kubala et al teaches tumor-derived PAI-1 promotes the M2 macrophage polarization (Abstract, in particular).
Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197) and that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to treat a human subject with a cancerous tumor expressing PAI-1 by performing a combined method comprising administering an effective amount of compound comprising antibodies which bind and neutralize PAI-1 in combination with one or more additional therapeutic treatments (including one or a combination of anti-tumor chemotherapeutic treatments) to the subject because Staunton et al teaches PAI-1 protein is often expressed by cancer cells and likely plays a role in protecting tumor tissue against proteolytic degradation and Staunton et al teaches a method of treating cancerous tumors comprising administering a compound comprising antibodies which bind and neutralize PAI-1 in combination with one or more additional therapeutic treatments (including one or a combination of anti-tumor chemotherapeutic treatments) to a cancer patient.
Tumors of the combined method expressing PAI-1 are predictably in a tumor microenvironment comprising M2 macrophages expressing PD-L1 because Kubala et al teaches tumor-derived PAI-1 promotes M2 macrophage polarization (Abstract, in particular), Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), and Suda teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend).
Further, PAI-1-induced PD-L1 expression of macrophages in the tumor microenvironment of the subject of the combined method is predictably inhibited by the combined method because Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), Kubala et al teaches tumor-derived PAI-1 inhibits polarization to the M2 state (Abstract), and Suda et al teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend).
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 8/07/26, Applicant correctly states that a prior-art disclosure that a PAI-1 inhibitor may be administered to a cancer patient does not, without more, teach or suggest: 1) that PD-L1 expression in an immunosuppressive cell is induced by PAI-1, 2) that inhibiting PAI-1 will suppress PD-L1 expression in that immunosuppressive cell, 3) that the relevant biology occurs in a tumor-surrounding environment containing the specifically recited immunosuppressive cell populations, 4) that the mammal has tumor cells expressing PAI-1 in the claimed mechanistic context, or 5) that a person of ordinary skill in the art would have had a reasonable expectation that administration of a PAI-1 inhibitor would achieve that specific immunological effect. Applicant further argues Staunton does not teach inhibition of PAI-1-induced PD-L1 expression, in an immunosuppressive cell, in a tumor-surrounding environment, in a mammal having tumor cells expressing PAI-1, or in any of the presently recited cell types, namely M2 macrophages, tumor- associated macrophage, cancer-associated fibroblast, and regulatory T cells. Applicant further argues Staunton does not teach that, in a tumor-surrounding environment including tumor cells expressing PAI-1, PAI-1 is functionally linked to PD-L1 expression in immunosuppressive cells, and that a PAI-1 inhibitory compound can be used to inhibit that expression. Applicant further argues Kubala does not teach the claimed invention. Applicant further argues Kubala does not supply a missing mechanistic link. Applicant further correctly states an observation that PAI-1 may be associated with M2 polarization does not establish that: PD-L1 expression in such cells is PAI-1-induced, inhibition of PAI-1 will suppress PD-L1 expression, the same relationship applies across the presently claimed immunosuppressive cell populations, tumor cells expressing PAI-1 provide the claimed mechanistic context, or one of ordinary skill in the art would have expected such suppression to occur. The present claims are not rendered obvious if it is accepted that Suda proposes certain tumor-associated immunosuppressive cells, such as M2 tumor-associated macrophages, can express PD-L1. Applicant further correctly states Suda showing that PD-L1-expressing immunosuppressive cells can be present in a tumor microenvironment is fundamentally different from teaching that: PAI-1 induces PD-L1 expression in those cells, tumor cells expressing PAI-1 provide the relevant biological source or context for that induction, and a PAI-1 inhibitor can therefore be used to inhibit PD-L1 expression in those cells. Applicant further argues the rejection uses improper hindsight reconstruction to assemble separate observations from different references and then inferring, only in view of Applicants’ disclosure, that PAI-1 inhibition would inhibit PD-L1 expression in claimed immunosuppressive cells in a mammal having tumor cells expressing PAI-1. Applicant further agues cited references do not teach or suggest that administration of a PAI-1 inhibitor would inhibit PAI-1-induced PD-L1 expression in such immunosuppressive cells, in the claimed tumor-surrounding environment and in the presence of tumor cells expressing PAI-1, with a reasonable expectation of success. Applicant further argues a possibility that prior-art treatment might incidentally be performed in a patient who happens to have the recited immunological and tumor-related features does not establish obviousness of the claimed method. Applicant further correctly states that a cell's mere existence does not establish: suppression of its PD-L1 expression, that its PD-L1 expression is PAI-1-induced, that tumor-cell-derived or tumor-associated PAI-1 is responsible for that induction, that inhibition of PAI-1 causes suppression of that expression, or that such an effect would have been reasonably expected. Applicant further indicates the rejection improperly substitutes an observational fact for a claimed function limitation. Applicant further argues cited references do not yield a reasonable expectation that inhibiting PAI-1 would inhibit PAI-1-induced PD-L1 expression in the presently claimed immunosuppressive cells in the claimed tumor-surrounding environment.
The amendments to the claims and the arguments found in the Reply of 8/7/26 have been carefully considered, but are not deemed persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Arguments against reference individually include:
Staunton does not teach inhibition of PAI-1-induced PD-L1 expression, in an immunosuppressive cell, in a tumor-surrounding environment, in a mammal having tumor cells expressing PAI-1, or in any of the presently recited cell types, namely M2 macrophages, tumor- associated macrophage, cancer-associated fibroblast, and regulatory T cells;
Staunton does not teach that, in a tumor-surrounding environment including tumor cells expressing PAI-1, PAI-1 is functionally linked to PD-L1 expression in immunosuppressive cells, and that a PAI-1 inhibitory compound can be used to inhibit that expression;
Kubala does not teach the claimed invention;
Kubala does not supply a missing mechanistic link; and
The present claims are not rendered obvious if it is accepted that Suda proposes certain tumor-associated immunosuppressive cells, such as M2 tumor-associated macrophages, can express PD-L1.
In regard to the arguments (i) the rejection uses improper hindsight reconstruction to assemble separate observations from different references and then inferring, only in view of Applicants’ disclosure, that PAI-1 inhibition would inhibit PD-L1 expression in claimed immunosuppressive cells in a mammal having tumor cells expressing PAI-1, (ii) cited references do not teach or suggest that administration of a PAI-1 inhibitor would inhibit PAI-1-induced PD-L1 expression in such immunosuppressive cells, in the claimed tumor-surrounding environment and in the presence of tumor cells expressing PAI-1, with a reasonable expectation of success, and (iii) cited references do not yield a reasonable expectation that inhibiting PAI-1 would inhibit PAI-1-induced PD-L1 expression in the presently claimed immunosuppressive cells in the claimed tumor-surrounding environment: 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). Further, that PAI-1 inhibition would inhibit PD-L1 expression in macrophages in the tumor microenvironment is based on cited references. PAI-1-induced PD-L1 expression of macrophages in the tumor microenvironment of the subject of the combined method is predictably inhibited by the combined method because Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), Kubala et al teaches tumor-derived PAI-1 inhibits polarization to the M2 state (Abstract), and Suda et al teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend).
In regards to the argument that a possibility that prior-art treatment might incidentally be performed in a patient who happens to have the recited immunological and tumor-related features does not establish obviousness of the claimed method, the rejection is not based on a mere “possibility that prior-art treatment might incidentally be performed in a patient who happens to have the recited immunological and tumor-related features does not establish obviousness of the claimed method.”
In regards to the indication the rejection improperly substitutes an observational fact for a claimed function limitation, all recited limitations are addressed in the above rejection.
Claim Rejections - 35 USC § 103
Claims 13, 15-23, 25, 27, and 29 are rejected under 35 U.S.C. 103(a) as being unpatentable over Ando et al (US 10092537 B2; 10/9/18; 6/29/22 IDS), in view of Staunton et al (US 7,771,720 B2; 8/10/2010), Kubala et al (Cancer Res, 2017, 77(13_Supp): 3061), and Suda (J Thorac Dis, 2017, 9(11): 4197-4200).
Ando et al teaches a method of treating a tumor in a patient comprising administering to the patient low molecular weight inhibitors of PAI-1 (encompassed by instant claims 17-18 and 21-22) in combination with an anti-tumor agent (claim 1, in particular) that is at least one member selected from the group consisting of antimetabolites, microtubule inhibitors, antitumor antibiotics, topoisomerase inhibitors, platinum-based drugs, alkylating agents, hormone-like drugs, molecular targeted drugs, antibody drugs, cytokines, and non-specific immunostimulants (claim 4, in particular). Such alkylating agents of Ando et al include anti-tumor chemotherapeutics (column 110, in particular).
Ando et al does not specifically describe a patient as expressing PD-L1. However, these deficiencies are made up in the teachings of Staunton et al and Yadav et al.
Staunton et al teaches PAI-1 protein is often expressed by cancer cells in non-invasive areas, suggesting PAI-1 plays a role in protecting tumor tissue against proteolytic degradation (lines 39-44 of column 66, in particular). Staunton et al further teaches a method of treating cancerous tumors comprising administering inhibitors that neutralize PAI-1 in combination with one or more additional therapeutic treatments (including one or a combination of anti-tumor chemotherapeutic treatments) to a cancer patient (columns 67-68, in particular). Further, one of skill in the art would recognize cancers tumors comprise tumor cells.
Teachings of Kubala et al and Suda are discussed above.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to treat a human subject with a cancerous tumor expressing PAI-1 by performing a combined method comprising administering an effective amount of low molecular weight inhibitors of PAI-1 of Ando et al in combination with anti-tumor agent of Staunton and/or Ando et al to the subject because Staunton et al teaches PAI-1 protein is often expressed by cancer cells and likely plays a role in protecting tumor tissue against proteolytic degradation, Staunton et al teaches a method of treating cancerous tumors comprising administering a compound comprising antibodies which bind and neutralize PAI-1 in combination with one or more additional therapeutic treatments (including one or a combination of anti-tumor chemotherapeutic treatments) to a cancer patient (columns 67-68, in particular) to a cancer patient, and Ando et al teaches a method of treating a tumor in a patient comprising administering to the patient low molecular weight inhibitors of PAI-1 (encompassed by instant claims 7-8) in combination with anti-tumor agent (see claims 1 and 4, in particular).
Tumors of the combined method expressing PAI-1 are predictably in a tumor microenvironment comprising M2 macrophages expressing PD-L1 because Kubala et al teaches tumor-derived PAI-1 promotes M2 macrophage polarization (Abstract, in particular), Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), and Suda teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend).
Further, PAI-1-induced PD-L1 expression of macrophages in the tumor microenvironment of the subject of the combined method is predictably inhibited by the combined method because Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), Kubala et al teaches tumor-derived PAI-1 inhibits polarization to the M2 state (Abstract), and Suda et al teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend).
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 8/07/26, Applicant correctly states a prior-art disclosure that a PAI-1 inhibitor may be administered to a cancer patient does not, without more, teach or suggest: 1) that PD-L1 expression in an immunosuppressive cell is induced by PAI-1, 2) that inhibiting PAI-1 will suppress PD-L1 expression in that immunosuppressive cell, 3) that the relevant biology occurs in a tumor-surrounding environment containing the specifically recited immunosuppressive cell populations, 4) that the mammal has tumor cells expressing PAI-1 in the claimed mechanistic context, or 5) that a person of ordinary skill in the art would have had a reasonable expectation that administration of a PAI-1 inhibitor would achieve that specific immunological effect. Applicant further argues neither Ando nor Staunton teach or suggest inhibition of PAI-1-induced PD-L1 expression, in an immunosuppressive cell, in a tumor-surrounding environment, in a mammal having tumor cells expressing PAI-1, or in any of the presently recited cell types, namely M2 macrophages, tumor- associated macrophage, cancer-associated fibroblast, and regulatory T cells. Applicant further argues neither Ando nor Staunton teach that, in a tumor-surrounding environment including tumor cells expressing PAI-1, PAI-1 is functionally linked to PD-L1 expression in immunosuppressive cells, and that a PAI-1 inhibitory compound can be used to inhibit that expression. Applicant further argues Ando and Staunton do teach or suggest inhibition of PAI-1-induced PD-L1 expression, in an immunosuppressive cell, in a tumor-surrounding environment, in a mammal having tumor cells expressing PAI-1, or in any of the presently recited cell types, namely M2 macrophages, tumor- associated macrophage, cancer-associated fibroblast, and regulatory T cells. Applicant further argue Kubala does not teach the presently claimed invention. Applicant further correctly states there is a critical scientific and legal distinction between: involvement in macrophage polarization or macrophage phenotype, and regulation of PD-L1 expression in an immunosuppressive cell, much less PAI-1-induced PD-L1 expression in the claimed tumor-surrounding environment of a mammal having tumor cells expressing PAI-1. Applicant further argues Kubala does not supply a missing mechanical link because an observation that PAI-1 may be associated with M2 polarization does not establish that: PD-L1 expression in such cells is PAI-1-induced, inhibition of PAI-1 will suppress PD-L1 expression, the same relationship applies across the presently claimed immunosuppressive cell populations, tumor cells expressing PAI-1 provide the claimed mechanistic context, or one of ordinary skill in the art would have expected such suppression to occur. A proposition of Suda that certain tumor-associated immunosuppressive cells, such as M2 tumor-associated macrophages, can express PD-L1 does not render the present claims obvious. Applicant further correctly states showing that PD-L1-expressing immunosuppressive cells can be present in a tumor microenvironment is fundamentally different from teaching that: PAI-1 induces PD-L1 expression in those cells, tumor cells expressing PAI-1 provide the relevant biological source or context for that induction, and a PAI-1 inhibitor can therefore be used to inhibit PD-L1 expression in those cells. Applicant further argues the rejection uses improper hindsight reconstruction to assemble separate observations from different references and then inferring, only in view of Applicants’ disclosure, that PAI-1 inhibition would inhibit PD-L1 expression in claimed immunosuppressive cells in a mammal having tumor cells expressing PAI-1. Applicant further agues cited references do not teach or suggest that administration of a PAI-1 inhibitor would inhibit PAI-1-induced PD-L1 expression in such immunosuppressive cells, in the claimed tumor-surrounding environment and in the presence of tumor cells expressing PAI-1, with a reasonable expectation of success. Applicant further argues a possibility that prior-art treatment might incidentally be performed in a patient who happens to have the recited immunological and tumor-related features does not establish obviousness of the claimed method. Applicant further correctly states that a cell's mere existence does not establish: suppression of its PD-L1 expression, that its PD-L1 expression is PAI-1-induced, that tumor-cell-derived or tumor-associated PAI-1 is responsible for that induction, that inhibition of PAI-1 causes suppression of that expression, or that such an effect would have been reasonably expected. Applicant further indicates the rejection improperly substitutes an observational fact for a claimed function limitation. Applicant further argues cited references do not yield a reasonable expectation that inhibiting PAI-1 would inhibit PAI-1-induced PD-L1 expression in the presently claimed immunosuppressive cells in the claimed tumor-surrounding environment.
The amendments to the claims and the arguments found in the Reply of 8/7/26 have been carefully considered, but are not deemed persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Arguments against reference individually include:
Neither Ando nor Staunton teach or suggest inhibition of PAI-1-induced PD-L1 expression, in an immunosuppressive cell, in a tumor-surrounding environment, in a mammal having tumor cells expressing PAI-1, or in any of the presently recited cell types, namely M2 macrophages, tumor- associated macrophage, cancer-associated fibroblast, and regulatory T cells;
Neither Ando nor Staunton teach that, in a tumor-surrounding environment including tumor cells expressing PAI-1, PAI-1 is functionally linked to PD-L1 expression in immunosuppressive cells, and that a PAI-1 inhibitory compound can be used to inhibit that expression;
Kubala does not teach the presently claimed invention;
Kubala does not supply a missing mechanical link because an observation that PAI-1 may be associated with M2 polarization does not establish that: PD-L1 expression in such cells is PAI-1-induced, inhibition of PAI-1 will suppress PD-L1 expression, the same relationship applies across the presently claimed immunosuppressive cell populations, tumor cells expressing PAI-1 provide the claimed mechanistic context, or one of ordinary skill in the art would have expected such suppression to occur; and
A proposition of Suda that certain tumor-associated immunosuppressive cells, such as M2 tumor-associated macrophages, can express PD-L1 does not render the present claims obvious.
In regards to the argument that Ando and Staunton do teach or suggest inhibition of PAI-1-induced PD-L1 expression, in an immunosuppressive cell, in a tumor-surrounding environment, in a mammal having tumor cells expressing PAI-1, or in any of the presently recited cell types, namely M2 macrophages, tumor- associated macrophage, cancer-associated fibroblast, and regulatory T cells, this rejection is not solely based on Ando and Staunton.
In regards to the argument the rejection uses improper hindsight reconstruction to assemble separate observations from different references and then inferring, only in view of Applicants’ disclosure, that PAI-1 inhibition would inhibit PD-L1 expression in claimed immunosuppressive cells in a mammal having tumor cells expressing PAI-1, 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).
In regards to the arguments (i) cited references do not teach or suggest that administration of a PAI-1 inhibitor would inhibit PAI-1-induced PD-L1 expression in such immunosuppressive cells, in the claimed tumor-surrounding environment and in the presence of tumor cells expressing PAI-1, with a reasonable expectation of success and (ii) cited references do not yield a reasonable expectation that inhibiting PAI-1 would inhibit PAI-1-induced PD-L1 expression in the presently claimed immunosuppressive cells in the claimed tumor-surrounding environment: the examiner disagrees. PAI-1-induced PD-L1 expression of macrophages in the tumor microenvironment of the subject of the combined method is predictably inhibited by the combined method because Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), Kubala et al teaches tumor-derived PAI-1 inhibits polarization to the M2 state (Abstract), and Suda et al teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend).
In regards to the argument that a possibility that prior-art treatment might incidentally be performed in a patient who happens to have the recited immunological and tumor-related features does not establish obviousness of the claimed method, the rejection is not based on a mere “possibility that prior-art treatment might incidentally be performed in a patient who happens to have the recited immunological and tumor-related features.”
Double Patenting
Claims 13, 15-23, 25, 27, and 29 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10092537 B2 in view of Staunton et al (US 7,771,720 B2; 8/10/2010), Kubala et al (Cancer Res, 2017, 77(13_Supp): 3061), and Suda (J Thorac Dis, 2017, 9(11): 4197-4200).
The patent claims and the instant claims are both drawn to treating the same cancer patients by administering the same reagents. The instant claims and the patent claims differ in that the instant claims specify the cancer patients express PD-L1. Although the claims at issue are not identical, they are not patentably distinct from each other because it would have been obvious to perform the patent method wherein the patient has PAI-1 expressing tumor cells and a tumor microenvironment that comprises M1 macrophages and M2 macrophages expressing PD-L1 because Staunton et al teaches PAI-1 protein is often expressed by cancer cells and likely plays a role in protecting tumor tissue against proteolytic degradation, Staunton et al teaches a method of treating cancerous tumors comprising administering a compound comprising antibodies which bind and neutralize PAI-1 in combination with other therapeutic agents recited by the instant claims to a cancer patient, and the patent claims recite treating a tumor in a patient comprising administering to the patient low molecular weight inhibitors of PAI-1 (which, like antibodies of Staunton et al, also provides therapeutic benefit by inhibiting PAI-1) in combination with anti-tumor therapeutics encompassed by the claims; tumors of the combined method expressing PAI-1 are predictably in a tumor microenvironment where the macrophages of the tumor microenvironment comprise M1 macrophages and M2 macrophages expressing PD-L1 because Kubala et al teaches tumor-derived PAI-1 promotes M2 macrophage polarization (Abstract, in particular), Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), and Suda teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend). Tumors of the combined method expressing PAI-1 are predictably in a tumor microenvironment comprising M2 macrophages expressing PD-L1 because Kubala et al teaches tumor-derived PAI-1 promotes M2 macrophage polarization (Abstract, in particular), Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), and Suda teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend). Further, PAI-1-induced PD-L1 expression of macrophages in the tumor microenvironment of the subject of the combined method is predictably inhibited by the combined method because Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), Kubala et al teaches tumor-derived PAI-1 inhibits polarization to the M2 state (Abstract), and Suda et al teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend).
Response to arguments
In the Reply of 8/07/26, Applicant argues the pending claims are not merely an obvious variant of the subject matter claimed in the Ando patent. Applicant further correctly states a claim to general antitumor use of a PAI-1 inhibitor is not the same invention as a claim to suppressing PAI-1-induced PD-L1 expression in defined immunosuppressive cells under the claimed tumor-related context. Applicant further argues neither the Ando patent claims nor the cited references teaches or suggests: 1) that PAI-1 induces PD-L1 expression in the claimed immunosuppressive cells, 2) that inhibiting PAI-1 suppresses that expression, 3) that tumor cells expressing PAI-1 provide the claimed mechanistic context, or 4) that a skilled artisan would have expected the claimed immunological effect.
The amendments to the claims and the arguments found in the Reply of 8/7/26 have been carefully considered, but are not deemed persuasive. In regards to the argument the pending claims are not merely an obvious variant of the subject matter claimed in the Ando patent, the examiner disagrees for the reasons stated above.
In regards to the argument that argues neither the Ando patent claims nor the cited references teaches or suggests that PAI-1 induces PD-L1 expression in claimed immunosuppressive cells, that inhibiting PAI-1 suppresses that PD-L1 expression, that tumor cells expressing PAI-1 provide a claimed mechanistic context, or that a skilled artisan would have expected a claimed immunological effect: Tumors of the combined method expressing PAI-1 are predictably in a tumor microenvironment comprising M2 macrophages expressing PD-L1 because Kubala et al teaches tumor-derived PAI-1 promotes M2 macrophage polarization (Abstract, in particular), Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), and Suda teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend). Further, PAI-1-induced PD-L1 expression of macrophages in the tumor microenvironment of the subject of the combined method is predictably inhibited by the combined method because Suda teaches the tumor environment comprises M1 and M2 tumor associated macrophages (page 4197), Kubala et al teaches tumor-derived PAI-1 inhibits polarization to the M2 state (Abstract), and Suda et al teaches that M2 tumor associated macrophages (M2 TAMs) express PD-L1 (Figure 2 legend).
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 112
Claims 13, 15-23, 25, 27, and 29 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 13, 15-23, 25, 27, and 29 are rejected because claim 13 recites “…inhibiting…expression in an immunosuppressive cell…wherein the mammal has an immunosuppressive cell…wherein the immunosuppressive cell….” There is insufficient antecedent basis for “the immunosuppressive cell” in the claims.
Claim Objections
Claim 13 is objected to because of apparent typographical issues. Claim 13 recites “…wherein the immunosuppressive cell is at least one member selected from the group consisting of M2 macrophages…T cells.” The term “macrophages” (plural) should be replaced by “a macrophage” because “immunosuppressive cell” is singular. The term “T cells” (plural) should also be replaced by “T cell” because “immunosuppressive cell” is singular. Proper correction is required.
Claims 25, 27, and 29 are objected to because of apparent typographical issues. Claims 25, 27, and 29 each recite “…wherein the immunosuppressive cell is macrophages.” The term “macrophages” (plural) should be replaced by “a macrophage” because “immunosuppressive cell” is singular. Proper correction is required.
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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