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 1/14/26 in response to the Office Action of 8/14/25 are acknowledged and have been entered.
Claims 16-23 have been added by Applicant.
Claims 13 and 15-23 are pending.
Claims 13 and 15 have been amended by Applicant.
Claims 13 and 15-23 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.
Priority
As requested in the Reply of 1/14/23, the claim of foreign priority and receipt of a certified copy of a foreign priority document is acknowledged.
Rejections Withdrawn
The rejection of claim 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn.
The rejections of claims 13 and 15 under 35 U.S.C. 102(a)(1) are withdrawn.
The rejection of claims 13 and 15 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10092537 B2 is withdrawn.
The rejection of claims 13 and 15 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10092537 B2 is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 13 and 15 remain rejected and claims 16-23 are 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 Yadav et al (Annals of Oncology, 2018, Supp 6(vi35-vi36): 113P; 6/29/22 IDS).
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 Yadav et al.
Yadav et al teaches the expression pattern of PAI-1 was measured in 7858 samples from 32 cancer types and that PAI-1 expression was tightly correlated with PD-L1 expression (corr=0.29; p < 0.01).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to treat a 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 predictably comprise cells expressing PD-L1 because, based on a study examining the expression pattern of PAI-1 in 7858 samples from 32 cancer types, Yadav et al teaches expression of PAI-1 is highly correlated with PD-L1 (corr=0.29; p < 0.01).
Because the combined method administers the same reagents to the same subjects, the combined method is equivalent to: a method for inhibiting PD-L1 expression in a tumor or immunosuppressive cell in the patient; a method for inhibiting an immune escape of a tumor patient; a method for inhibiting exacerbation of tumor cells caused by PD-L1; and a method for enhancing an immunotherapeutic effect on tumors.
Further, recitation that the method of Staunton et al inhibits PD-L1 expression in cancer patients that happen to have any expression of PD-L1 is not sufficient to rebut obviousness when the combined method is expected to have a greater property of expected therapeutic benefit. See MPEP 716.02(c).
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 1/14/26, Applicant argues the combination of cited reference do not render the claimed invention obvious. Applicant argues Staunton is silent on PD-L1 and Yadav does not disclose functional consequences of PAI-1 inhibition on PD-L1 expression. Applicant further argues PAI-1 inhibition leading to PD-L1 suppression is not taught or suggested by cited references and would not have been reasonably expected by a person of ordinary skill in the art. Applicant further argues the invention provides an unexpected technical effect, where suppression of PD-L1 expression via PAI-1 inhibition enhances efficacy of immunotherapy, that is not disclosed or suggested by cited references.
The amendments to the claims and the arguments found in the Reply of 1/14/26 have been carefully considered, but are not deemed persuasive. In regards to the argument that the combination of cited reference does not render the claimed invention obvious, the examiner disagrees for the reasons stated above.
In regard to the arguments that Staunton is silent on PD-L1 and Yadav does not disclose functional consequences of PAI-1 inhibition on PD-L1 expression, 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).
In regards to the argument that PAI-1 inhibition leading to PD-L1 suppression is not taught or suggested by cited references and would not have been reasonably expected by a person of ordinary skill in the art, it is acknowledged the cited references do not teach the phenomena that PAI-1 inhibition results in suppressing PD-L1 expression. However, the examiner takes the position that PD-L1 expression is inhibited when a known cancer therapeutic that inhibits PAI-1 is administered is not a property having a significance greater than that of the expected property of the predicted therapeutic effect of the PAI-1 inhibitor. Recitation that the method of Staunton et al inhibits PD-L1 expression in cancer patients that happen to have any expression of PD-L1 is not sufficient to rebut obviousness when the combined method is expected to have a greater property of expected therapeutic benefit. See MPEP 716.02(c). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art. Further, see In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991), where the court held that the fact that another advantage would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
In regards to the argument that the cited references do not teach or suggest suppression of PD-L1 expression via PAI-1 inhibition enhances efficacy of immunotherapy, Applicant is arguing limitations not required by the claims. The claimed method does not require immunotherapy that is enhanced by PAI-1 inhibition of the claimed method.
Claim Rejections - 35 USC § 103
Claims 13 and 15 remain rejected and claims 16-23 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) and Yadav et al (Annals of Oncology, 2018, Supp 6(vi35-vi36): 113P; 6/29/22 IDS).
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.
Yadav et al teaches the expression pattern of PAI-1 was measured in 7858 samples from 32 cancer types and that PAI-1 expression was tightly correlated with PD-L1 expression (corr=0.29; p < 0.01).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to treat a 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 predictably comprise cells expressing PD-L1 because, based on a study examining the expression pattern of PAI-1 in 7858 samples from 32 cancer types, Yadav et al teaches expression of PAI-1 is highly correlated with PD-L1 (corr=0.29; p < 0.01).
Because the combined method administers the same reagents to the same subjects, the combined method is equivalent to: a method for inhibiting PD-L1 expression in a tumor or immunosuppressive cell in the patient; a method for inhibiting an immune escape of a tumor patient; a method for inhibiting exacerbation of tumor cells caused by PD-L1; and a method for enhancing an immunotherapeutic effect on tumors.
Recitation that the method of Ando et al inhibits PD-L1 expression in cancer patients that happen to have any expression of PD-L1 is not sufficient to rebut obviousness when the combined method is expected to have a greater property of expected therapeutic benefit. See MPEP 716.02(c).
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 1/14/2026, Applicant argues Ando does not teach tumors expressing PD-L1. Applicant further argues Staunton does not mention PD-L1, and Yadav does not disclose any functional effect of PAI-1 inhibition on PD-L1 expression. Applicant concludes that the combination of cited references does not render the claimed method obvious.
The amendments to the claims and the arguments found in the Reply of 1/14/2026 have been carefully considered, but are not deemed persuasive. In regards to the arguments that Ando does not teach tumors expressing PD-L1, Staunton does not mention PD-L1, and Yadav does not disclose any functional effect of PAI-1 inhibition on PD-L1 expression, it is first noted the claims do not recite tumors expressing PD-L1. Further, 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).
In regards to the conclusion that the combination of cited references does not render the claimed method obvious, the examiner disagrees. The examiner maintains one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to treat a 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 predictably comprise cells expressing PD-L1 because, based on a study examining the expression pattern of PAI-1 in 7858 samples from 32 cancer types, Yadav et al teaches expression of PAI-1 is highly correlated with PD-L1 (corr=0.29; p < 0.01). Because the combined method administers the same reagents to the same subjects, the combined method is equivalent to: a method for inhibiting PD-L1 expression in a tumor or immunosuppressive cell in the patient; a method for inhibiting an immune escape of a tumor patient; a method for inhibiting exacerbation of tumor cells caused by PD-L1; and a method for enhancing an immunotherapeutic effect on tumors. Further, recitation that the method of Ando et al inhibits PD-L1 expression in cancer patients that happen to have any expression of PD-L1 is not sufficient to rebut obviousness when the combined method is expected to have a greater property of expected therapeutic benefit. See MPEP 716.02(c).
Double Patenting
Claims 13 and 15 remain rejected and claims 16-23 are 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) and Yadav et al (Annals of Oncology, 2018, Supp 6(vi35-vi36): 113P; 6/29/22 IDS). 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 co-expresses PAI-1 and PD-1 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. Said combined method is equivalent to: a method for inhibiting PD-L1 expression in a tumor or immunosuppressive cell in the patient; a method for inhibiting an immune escape of a tumor patient; a method for inhibiting exacerbation of tumor cells caused by PD-L1; and a method for enhancing an immunotherapeutic effect on tumors.
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success to perform said combined method wherein the tumor expressing PAI-1 comprises cells expressing PD-L1 because Yadav et al teaches expression of PAI-1 is highly correlated with PD-L1.
Response to Arguments
In the Reply of 1/14/2026, Applicant argues the cited references do not teach or suggest PAI-1 inhibition leads to PD-L1 suppression.
The amendments to the claims and the arguments found in the Reply of 1/14/2026 have been carefully considered, but are not deemed persuasive. In regards to the argument that cited references do not teach or suggest PAI-1 inhibition leads to PD-L1 suppression, recitation that the method of the patent inhibits PD-L1 expression in cancer patients that happen to have any expression of PD-L1 is not sufficient to rebut obviousness when the combined method is expected to have a greater property of expected therapeutic benefit. See MPEP 716.02(c).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SEAN E AEDER/Primary Examiner, Art Unit 1642