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 .
Status of the Claims
Claims 1, 5-20, and 23-25 are pending in this application. Claims 2-4 and 21-22 have been cancelled by applicant.
Claims 1, 5-17, 19-20, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Bekker et al. (WO 2017/218544 A1 – previously cited) (“Bekker”); and Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867 – previously cited) (“Guzik”); in view of Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114 – previously cited) (“Gopinath”).
Regarding claim 1, Bekker discloses the compound Ib below (pages 3-4 and Bekker’s claims 1 and 3), which anticipates the compound in the instant amended claim.
PNG
media_image1.png
246
227
media_image1.png
Greyscale
Bekker discloses their compound as modulators of CCR2 chemokine ligand activity [0013]. Bekker discloses their compound may be administered with one or more additional therapeutic agents, including PD-1 and PD-L1 inhibitors (page 5, lines 2-4 and 17). Bekker further discloses the one or more additional therapeutic agent may be nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab (page 5, lines 34-35 and page 7, lines 1 and 3).
Regarding claim 11, Bekker discloses their compound of Formula Ib in a pharmaceutical composition for oral administration (page 8, line 8).
Regarding claims 12 and 20, Bekker discloses their oral formulation of compound of Formula Ib may be administered in effective amounts ranging from 50 to 300 mg, administered once or twice a day, anticipating the instantly claimed range. Regarding claim 20, for an average person weighing 70 kg, these dosage amounts would be about 0.7 to about 4.3 mg/ kg (once or twice a day), overlapping with the instantly claimed 0.001 to about 100 mg/ kg.
Applicant is advised that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding instant claims 13-17, Bekker discloses their compounds of Formula I may be administered together with one or more additional therapeutic agents, including PD-1 and PD-L1 inhibitors (page 5, lines 2-4 and 17).
Thus, with respect to the order of steps, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex Parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C. Therefore, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Regarding claim 19, Bekker discloses their compounds of Formula I as CCR2 inhibitors, capable of modulating human CCR2 proteins ([0013], last line) and that their pharmaceutical compositions can be administered to humans [0057].
While Bekker et al. does not specifically teach: (i) the treatment of glioma (claims 1-6, 11-17, and 19-22); (ii) nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab as PD-1 and/or PD-L1 inhibitors (claim 1); (iii) treatment of glioblastoma (claim 5); (iv) wherein the glioma is characterized as being CCR2+ (claim 6); (v) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (vi) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (vii) wherein the glioma is an immune checkpoint inhibitor resistant glioma (claim 23); the teachings of Guzik and Gopinath are relied upon for these disclosures.
Guzik teaches nivolumab, pembrolizumab, and atezolizumab as PD-1 and PD-L1 immune checkpoint protein inhibitors (page 5857, col. 1, para. 2, lines 2-4).
Gopinath discloses a study of chemokine receptor CCR2’s contributions to tumor progression in mouse models of glioma (col. 2, lines 6-8), disclosing administration of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors to glioma-bearing mice (col. 2, lines 8-10). Gopinath teaches that a CCR2 antagonist augmented the effects of either anti-PD-L1 or anti-PD-1 treatment to slow glioma progression, but had no effect when administered as a mono-therapy (col. 2, lines 15-18). Gopinath concludes that pharmacological inhibition of CCR2 augments the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression, and further states that their pre-clinical results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment on glioblastoma (col. 2, para. 1, last line).
Therefore, regarding the treatment of glioma with the instant compound in combination with nivolumab, pembrolizumab, or atezolizumab, as recited in instant claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Bekker’s CCR2 antagonist Ib in combination with Guzik’s PD-1 and PD-L1 inhibitors, in view of Gopinath, for the treatment of glioma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bekker’s disclosure of Ib as a CCR2 inhibitor, and their teachings of pharmaceutical compositions of Ib, suitable for humans in combination with one or more additional therapeutic agents (like nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab); Guzik’s teachings that nivolumab, pembrolizumab, and atezolizumab are FDA approved PD-1 and PD-L1 inhibitors; and Gopinath’s disclosure that CCR2 antagonists augment the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression.
Regarding claim 5, Gopinath discloses their results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment of glioblastoma patients (last three lines).
Regarding claim 6, Gopinath discloses a study of the impact of CCR2 deficiency or CCR2 inhibition, combined with PD-1/PD-L1 inhibition, for the treatment of glioma in mice. Gopinath discloses reduced presence of CCR2+ CD11b+ in gliomas of CCR2-deficient mice, suggesting a lack of need for CCR2 inhibition in CCR2-deficient gliomas. Gopinath also discloses that CCR2 inhibition (in CCR2+ gliomas) augmented the effects of the PD-1/ PD-L1 inhibitor treatment. Thus, Gopinath discloses treatment of CCR2+ gliomas.
Regarding claims 7-10 and 24-25, Applicant is advised that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
It is also noted that a “wherein” clause, such as that in claims 7-10 and 24-25, must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04.
Furthermore, it is noted that the courts have held that when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) Therefore, the phrases: (i) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (ii) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (iii) wherein administration increases the durability of overall response to treatment or reduces exhaustion in intra-tumoral T-cells (claims 24-25); clearly define the results of a use of the composition, and thus does not further distinguish the composition over the prior art. See MPEP 2112.02.
Regarding claim 23, Gopinath discloses that administration of CCR2 inhibitor in combination with anti-PD-1/PD-L1 treatment to KR158 glioma-bearing mice (immune checkpoint inhibitor resistant glioma – see claim interpretation), augmented the effects of the anti PD-1/PD-L1 treatment (col. 2, lines 13-16). These findings suggest that, even for previously immune checkpoint inhibitor resistant glioma, co-administration of a CCR2 inhibitor can augment the effects of the immune checkpoint inhibitor treatment.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Bekker et al. (WO 2017/218544 A1 – previously cited) (“Bekker”); and Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867 – previously cited) (“Guzik”); in view of Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114 – previously cited) (“Gopinath”); as applied to claims 1, 5-17, 19-20, and 23-25; further in view of FDA (Obtained from accessdata.fda.gov [retrieved on September 4th, 2025] <URL: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125527> - Revised December 2014 – previously cited) (“FDA”).
The teachings of Bekker, Guzik, and Gopinath are disclosed above and incorporated herein.
While Bekker and Guzik in view of Gopinath. does not specifically teach intravenous administration of their PD-1/PD-L1 inhibitor (nivolumab); the disclosures of the FDA are relied upon for these disclosures.
The FDA discloses that doses of nivolumab (OPDIVO®) may be administered at 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (page 1, col. 1, Dosage and Administration section).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the instant compound orally, as taught by Bekker, and the PD-1/PD-L1 inhibitor (nivolumab) as an intravenous injection, in view of the FDA. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bekker’s disclosure of compound Ib and oral formulations thereof, which may be co-administered with a PD-1/PD-L1 inhibitor such as nivolumab; further in view of the FDA’s specific directions for dosage amounts and methods of administration of nivolumab.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 5-17, 19-20, and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,251,888 B2 (US ‘888); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5-17, 19-20, and 23-25, US ‘888 claims a method of treating pancreatic cancer comprising administration of their compounds of Formula I below (US ‘888’s claims 1-7). US ‘888 claims their method further comprising a PD-1 or PD-L1 inhibitor (US ‘888’s claim 8).
PNG
media_image2.png
167
167
media_image2.png
Greyscale
PNG
media_image3.png
168
165
media_image3.png
Greyscale
While US ‘888 does not specifically teach: (i) the treatment of glioma (claims 1-6, 11-17, and 19-22); (ii) nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab as PD-1 and/or PD-L1 inhibitors (claim 1); (iii) treatment of glioblastoma (claim 5); (iv) wherein the glioma is characterized as being CCR2+ (claim 6); (v) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (vi) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (vii) wherein the glioma is an immune checkpoint inhibitor resistant glioma (claim 23); the teachings of Bekker, Guzik, and Gopinath et al. are relied upon for these disclosures.
Bekker discloses the compound Ib below (pages 3-4 and Bekker’s claims 1 and 3), as compounds that modulate CCR2 chemokine ligand activity [0013].
PNG
media_image1.png
246
227
media_image1.png
Greyscale
Guzik teaches nivolumab, pembrolizumab, and atezolizumab as PD-1 and PD-L1 immune checkpoint protein inhibitors (page 5857, col. 1, para. 2, lines 2-4).
Gopinath discloses a study of chemokine receptor CCR2’s contributions to tumor progression in mouse models of glioma (col. 2, lines 6-8), disclosing administration of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors to glioma-bearing mice (col. 2, lines 8-10). Gopinath teaches that a CCR2 antagonist augmented the effects of either anti-PD-L1 or anti-PD-1 treatment to slow glioma progression, but had no effect when administered as a mono-therapy (col. 2, lines 15-18). Gopinath concludes that pharmacological inhibition of CCR2 augments the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression, and further states that their pre-clinical results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment on glioblastoma (col. 2, para. 1, last line).
Therefore, regarding the treatment of glioma with US ‘888’s compounds of Formula I in combination with nivolumab, pembrolizumab, or atezolizumab, as recited in instant claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer US ‘888’s compounds of Formula I, taught by Bekker to be CCR2 antagonists, in combination with Guzik’s PD-1 and PD-L1 inhibitors, in view of Gopinath, for the treatment of glioma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘888’s disclosure of their compounds of Formula I; Bekker’s disclosure that the compounds of Formula I as CCR2 inhibitors, and pharmaceutical compositions thereof, suitable for humans in combination with one or more additional therapeutic agents (like nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab); Guzik’s teachings that nivolumab, pembrolizumab, and atezolizumab are FDA approved PD-1 and PD-L1 inhibitors; and Gopinath’s disclosure that CCR2 antagonists augment the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression.
Regarding instant claim 5, Gopinath discloses their results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment of glioblastoma patients (last three lines).
Regarding instant claim 6, Gopinath discloses a study of the impact of CCR2 deficiency or CCR2 inhibition, combined with PD-1/PD-L1 inhibition, for the treatment of glioma in mice. Gopinath discloses reduced presence of CCR2+ CD11b+ in gliomas of CCR2-deficient mice, suggesting a lack of need for CCR2 inhibition in CCR2-deficient gliomas. Gopinath also discloses that CCR2 inhibition (in CCR2+ gliomas) augmented the effects of the PD-1/ PD-L1 inhibitor treatment. Thus, Gopinath discloses treatment of CCR2+ gliomas.
Regarding instant claims 7-10 and 24-25, Applicant is advised that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claims 7-10 and 24-25, must give “meaning and purpose to the manipulative steps.”
Furthermore, it is noted that the courts have held that when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. Therefore, the phrases: (i) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (ii) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (iii) wherein administration increases the durability of overall response to treatment or reduces exhaustion in intra-tumoral T-cells (claims 24-25); clearly define the results of a use of the composition, and thus does not further distinguish the composition over the prior art.
Regarding instant claim 23, Gopinath discloses that administration of CCR2 inhibitor in combination with anti-PD-1/PD-L1 treatment to KR158 glioma-bearing mice (immune checkpoint inhibitor resistant glioma – see claim interpretation), augmented the effects of the anti PD-1/PD-L1 treatment (col. 2, lines 13-16). These findings suggest that, even for previously immune checkpoint inhibitor resistant glioma, co-administration of a CCR2 inhibitor can augment the effects of the immune checkpoint inhibitor treatment.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,251,888 B2 (US ‘888); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114); as applied to claims 1, 5-17, 19-20, and 23-25; further in view of FDA (Obtained from accessdata.fda.gov [retrieved on September 4th, 2025] <URL: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125527> - Revised December 2014). Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of US ‘888, Bekker, Guzik, and Gopinath are disclosed above and incorporated herein.
While US ‘888 in view of Bekker, Guzik, and Gopinath does not specifically teach intravenous administration of their PD-1/PD-L1 inhibitor (nivolumab); the disclosures of the FDA are relied upon for these disclosures.
The FDA discloses that doses of nivolumab (OPDIVO®) may be administered at 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (page 1, col. 1, Dosage and Administration section).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the instant compounds of Formula I orally, as taught by US ‘888 in view of Bekker, and the PD-1/PD-L1 inhibitor (nivolumab) as an intravenous injection, in view of the FDA. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘888’s disclosure of the compounds of Formula I, which may be co-administered with a PD-1/PD-L1 inhibitor; further in view of the FDA’s specific directions for dosage amounts and methods of administration of nivolumab.
Claims 1, 5-17, 19-20, and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10,398,685 B2 (US ‘685); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5-17, 19-20, and 23-25, US ‘685 claims a method of limiting overexpression of oncogenes comprising administration of their compounds of Formula I below (US ‘685’s claims 1-7). US ‘685 claims their method further comprising a PD-1 or PD-L1 inhibitor (US ‘685’s claims 16-17).
PNG
media_image2.png
167
167
media_image2.png
Greyscale
PNG
media_image3.png
168
165
media_image3.png
Greyscale
While US ‘685 does not specifically teach: (i) the treatment of glioma (claims 1-6, 11-17, and 19-22); (ii) nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab as PD-1 and/or PD-L1 inhibitors (claim 1); (iii) treatment of glioblastoma (claim 5); (iv) wherein the glioma is characterized as being CCR2+ (claim 6); (v) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (vi) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (vii) wherein the glioma is an immune checkpoint inhibitor resistant glioma (claim 23); the teachings of Bekker, Guzik, and Gopinath et al. are relied upon for these disclosures.
Bekker discloses the compounds of Formula I, Ia, Ib, and 1c below (pages 3-4 and Bekker’s claims 1 and 3), as compounds that modulate CCR2 chemokine ligand activity [0013].
PNG
media_image4.png
256
224
media_image4.png
Greyscale
PNG
media_image1.png
246
227
media_image1.png
Greyscale
PNG
media_image5.png
247
223
media_image5.png
Greyscale
Guzik teaches nivolumab, pembrolizumab, and atezolizumab as PD-1 and PD-L1 immune checkpoint protein inhibitors (page 5857, col. 1, para. 2, lines 2-4).
Gopinath discloses a study of chemokine receptor CCR2’s contributions to tumor progression in mouse models of glioma (col. 2, lines 6-8), disclosing administration of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors to glioma-bearing mice (col. 2, lines 8-10). Gopinath teaches that a CCR2 antagonist augmented the effects of either anti-PD-L1 or anti-PD-1 treatment to slow glioma progression, but had no effect when administered as a mono-therapy (col. 2, lines 15-18). Gopinath concludes that pharmacological inhibition of CCR2 augments the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression, and further states that their pre-clinical results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment on glioblastoma (col. 2, para. 1, last line).
Therefore, regarding the treatment of glioma with US ‘685’s compounds of Formula I in combination with nivolumab, pembrolizumab, or atezolizumab, as recited in instant claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer US ‘685’s compounds of Formula I, taught by Bekker to be CCR2 antagonists, in combination with Guzik’s PD-1 and PD-L1 inhibitors, in view of Gopinath, for the treatment of glioma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘685’s disclosure of their compounds of Formula I; Bekker’s disclosure that the compounds of Formula I as CCR2 inhibitors, and pharmaceutical compositions thereof suitable for humans in combination with one or more additional therapeutic agents (like nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab); Guzik’s teachings that nivolumab, pembrolizumab, and atezolizumab are FDA approved PD-1 and PD-L1 inhibitors; and Gopinath’s disclosure that CCR2 antagonists augment the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression.
Regarding instant claim 5, Gopinath discloses their results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment of glioblastoma patients (last three lines).
Regarding instant claim 6, Gopinath discloses a study of the impact of CCR2 deficiency or CCR2 inhibition, combined with PD-1/PD-L1 inhibition, for the treatment of glioma in mice. Gopinath discloses reduced presence of CCR2+ CD11b+ in gliomas of CCR2-deficient mice, suggesting a lack of need for CCR2 inhibition in CCR2-deficient gliomas. Gopinath also discloses that CCR2 inhibition (in CCR2+ gliomas) augmented the effects of the PD-1/ PD-L1 inhibitor treatment. Thus, Gopinath discloses treatment of CCR2+ gliomas.
Regarding instant claims 7-10 and 24-25, Applicant is advised that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claims 7-10 and 24-25, must give “meaning and purpose to the manipulative steps.”
Furthermore, it is noted that the courts have held that when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. Therefore, the phrases: (i) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (ii) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (iii) wherein administration increases the durability of overall response to treatment or reduces exhaustion in intra-tumoral T-cells (claims 24-25); clearly define the results of a use of the composition, and thus does not further distinguish the composition over the prior art.
Regarding instant claim 23, Gopinath discloses that administration of CCR2 inhibitor in combination with anti-PD-1/PD-L1 treatment to KR158 glioma-bearing mice (immune checkpoint inhibitor resistant glioma – see claim interpretation), augmented the effects of the anti PD-1/PD-L1 treatment (col. 2, lines 13-16). These findings suggest that, even for previously immune checkpoint inhibitor resistant glioma, co-administration of a CCR2 inhibitor can augment the effects of the immune checkpoint inhibitor treatment.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 10,398,685 B2 (US ‘685); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114); as applied to claims 1, 5-17, 19-20, and 23-25; further in view of FDA (Obtained from accessdata.fda.gov [retrieved on September 4th, 2025] <URL: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125527> - Revised December 2014). Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of US ‘685, Bekker, Guzik, and Gopinath are disclosed above and incorporated herein.
While US ‘685 in view of Bekker, Guzik, and Gopinath does not specifically teach intravenous administration of their PD-1/PD-L1 inhibitor (nivolumab); the disclosures of the FDA are relied upon for these disclosures.
The FDA discloses that doses of nivolumab (OPDIVO®) may be administered at 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (page 1, col. 1, Dosage and Administration section).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the instant compounds of Formula I orally, as taught by US ‘685 in view of Bekker, and the PD-1/PD-L1 inhibitor (nivolumab) as an intravenous injection, in view of the FDA. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘685’s disclosure of the compounds of Formula I, which may be co-administered with a PD-1/PD-L1 inhibitor; further in view of the FDA’s specific directions for dosage amounts and methods of administration of nivolumab.
Claims 1, 5-17, 19-20, and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,583,131 B2 (US ‘131); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5-17, 19-20, and 23-25, US ‘131 claims a method of controlling adenocarcinoma comprising administration of their compounds of Formula I below (US ‘131’s claims 1-4). US ‘131 claims their method further comprising a PD-1 or PD-L1 inhibitor (US ‘131’s claims 17-18).
PNG
media_image2.png
167
167
media_image2.png
Greyscale
PNG
media_image3.png
168
165
media_image3.png
Greyscale
While US ‘131 does not specifically teach: (i) the treatment of glioma (claims 1-6, 11-17, and 19-22); (ii) nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab as PD-1 and/or PD-L1 inhibitors (claim 1); (iii) treatment of glioblastoma (claim 5); (iv) wherein the glioma is characterized as being CCR2+ (claim 6); (v) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (vi) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (vii) wherein the glioma is an immune checkpoint inhibitor resistant glioma (claim 23); the teachings of Bekker, Guzik, and Gopinath et al. are relied upon for these disclosures.
Bekker discloses the compounds of Formula I, Ia, Ib, and 1c below (pages 3-4 and Bekker’s claims 1 and 3), as compounds that modulate CCR2 chemokine ligand activity [0013].
PNG
media_image4.png
256
224
media_image4.png
Greyscale
PNG
media_image1.png
246
227
media_image1.png
Greyscale
PNG
media_image5.png
247
223
media_image5.png
Greyscale
Guzik teaches nivolumab, pembrolizumab, and atezolizumab as PD-1 and PD-L1 immune checkpoint protein inhibitors (page 5857, col. 1, para. 2, lines 2-4).
Gopinath discloses a study of chemokine receptor CCR2’s contributions to tumor progression in mouse models of glioma (col. 2, lines 6-8), disclosing administration of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors to glioma-bearing mice (col. 2, lines 8-10). Gopinath teaches that a CCR2 antagonist augmented the effects of either anti-PD-L1 or anti-PD-1 treatment to slow glioma progression, but had no effect when administered as a mono-therapy (col. 2, lines 15-18). Gopinath concludes that pharmacological inhibition of CCR2 augments the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression, and further states that their pre-clinical results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment on glioblastoma (col. 2, para. 1, last line).
Therefore, regarding the treatment of glioma with US ‘131’s compounds of Formula I in combination with nivolumab, pembrolizumab, or atezolizumab, as recited in instant claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer US ‘131’s compounds of Formula I, taught by Bekker to be CCR2 antagonists, in combination with Guzik’s PD-1 and PD-L1 inhibitors, in view of Gopinath, for the treatment of glioma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘131’s disclosure of their compounds of Formula I; Bekker’s disclosure that the compounds of Formula I as CCR2 inhibitors, and pharmaceutical compositions thereof suitable for humans in combination with one or more additional therapeutic agents (like nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab); Guzik’s teachings that nivolumab, pembrolizumab, and atezolizumab are FDA approved PD-1 and PD-L1 inhibitors; and Gopinath’s disclosure that CCR2 antagonists augment the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression.
Regarding instant claim 5, Gopinath discloses their results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment of glioblastoma patients (last three lines).
Regarding instant claim 6, Gopinath discloses a study of the impact of CCR2 deficiency or CCR2 inhibition, combined with PD-1/PD-L1 inhibition, for the treatment of glioma in mice. Gopinath discloses reduced presence of CCR2+ CD11b+ in gliomas of CCR2-deficient mice, suggesting a lack of need for CCR2 inhibition in CCR2-deficient gliomas. Gopinath also discloses that CCR2 inhibition (in CCR2+ gliomas) augmented the effects of the PD-1/ PD-L1 inhibitor treatment. Thus, Gopinath discloses treatment of CCR2+ gliomas.
Regarding instant claims 7-10 and 24-25, Applicant is advised that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claims 7-10 and 24-25, must give “meaning and purpose to the manipulative steps.”
Furthermore, it is noted that the courts have held that when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. Therefore, the phrases: (i) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (ii) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (iii) wherein administration increases the durability of overall response to treatment or reduces exhaustion in intra-tumoral T-cells (claims 24-25); clearly define the results of a use of the composition, and thus does not further distinguish the composition over the prior art.
Regarding instant claim 23, Gopinath discloses that administration of CCR2 inhibitor in combination with anti-PD-1/PD-L1 treatment to KR158 glioma-bearing mice (immune checkpoint inhibitor resistant glioma – see claim interpretation), augmented the effects of the anti PD-1/PD-L1 treatment (col. 2, lines 13-16). These findings suggest that, even for previously immune checkpoint inhibitor resistant glioma, co-administration of a CCR2 inhibitor can augment the effects of the immune checkpoint inhibitor treatment.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,583,131 B2 (US ‘131); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114); as applied to claims 1, 5-17, 19-20, and 23-25; further in view of FDA (Obtained from accessdata.fda.gov [retrieved on September 4th, 2025] <URL: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125527> - Revised December 2014). Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of US ‘131, Bekker, Guzik, and Gopinath are disclosed above and incorporated herein.
While US ‘131 in view of Bekker, Guzik, and Gopinath does not specifically teach intravenous administration of their PD-1/PD-L1 inhibitor (nivolumab); the disclosures of the FDA are relied upon for these disclosures.
The FDA discloses that doses of nivolumab (OPDIVO®) may be administered at 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (page 1, col. 1, Dosage and Administration section).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the instant compounds of Formula I orally, as taught by US ‘131 in view of Bekker, and the PD-1/PD-L1 inhibitor (nivolumab) as an intravenous injection, in view of the FDA. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘131’s disclosure of the compounds of Formula I, which may be co-administered with a PD-1/PD-L1 inhibitor; further in view of the FDA’s specific directions for dosage amounts and methods of administration of nivolumab.
Claims 1, 5-17, 19-20, and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,116,756 B2 (US ‘756); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5-17, 19-20, and 23-25, US ‘756 claims a method of treating pancreatic cancer comprising administration of their compounds of Formula I below (US ‘756’s claim 1). US ‘756 claims their method further comprising a PD-1 or PD-L1 inhibitor (US ‘756’s claims 1).
PNG
media_image2.png
167
167
media_image2.png
Greyscale
PNG
media_image3.png
168
165
media_image3.png
Greyscale
While US ‘756 does not specifically teach: (i) the treatment of glioma (claims 1-6, 11-17, and 19-22); (ii) nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab as PD-1 and/or PD-L1 inhibitors (claim 1); (iii) treatment of glioblastoma (claim 5); (iv) wherein the glioma is characterized as being CCR2+ (claim 6); (v) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (vi) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (vii) wherein the glioma is an immune checkpoint inhibitor resistant glioma (claim 23); the teachings of Bekker, Guzik, and Gopinath et al. are relied upon for these disclosures.
Bekker discloses the compounds of Formula I, Ia, Ib, and 1c below (pages 3-4 and Bekker’s claims 1 and 3), as compounds that modulate CCR2 chemokine ligand activity [0013].
PNG
media_image4.png
256
224
media_image4.png
Greyscale
PNG
media_image1.png
246
227
media_image1.png
Greyscale
PNG
media_image5.png
247
223
media_image5.png
Greyscale
Guzik teaches nivolumab, pembrolizumab, and atezolizumab as PD-1 and PD-L1 immune checkpoint protein inhibitors (page 5857, col. 1, para. 2, lines 2-4).
Gopinath discloses a study of chemokine receptor CCR2’s contributions to tumor progression in mouse models of glioma (col. 2, lines 6-8), disclosing administration of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors to glioma-bearing mice (col. 2, lines 8-10). Gopinath teaches that a CCR2 antagonist augmented the effects of either anti-PD-L1 or anti-PD-1 treatment to slow glioma progression, but had no effect when administered as a mono-therapy (col. 2, lines 15-18). Gopinath concludes that pharmacological inhibition of CCR2 augments the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression, and further states that their pre-clinical results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment on glioblastoma (col. 2, para. 1, last line).
Therefore, regarding the treatment of glioma with US ‘756’s compounds of Formula I in combination with nivolumab, pembrolizumab, or atezolizumab, as recited in instant claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer US ‘756’s compounds of Formula I, taught by Bekker to be CCR2 antagonists, in combination with Guzik’s PD-1 and PD-L1 inhibitors, in view of Gopinath, for the treatment of glioma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘756’s disclosure of their compounds of Formula I; Bekker’s disclosure that the compounds of Formula I as CCR2 inhibitors, and pharmaceutical compositions thereof suitable for humans in combination with one or more additional therapeutic agents (like nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab); Guzik’s teachings that nivolumab, pembrolizumab, and atezolizumab are FDA approved PD-1 and PD-L1 inhibitors; and Gopinath’s disclosure that CCR2 antagonists augment the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression.
Regarding instant claim 5, Gopinath discloses their results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment of glioblastoma patients (last three lines).
Regarding instant claim 6, Gopinath discloses a study of the impact of CCR2 deficiency or CCR2 inhibition, combined with PD-1/PD-L1 inhibition, for the treatment of glioma in mice. Gopinath discloses reduced presence of CCR2+ CD11b+ in gliomas of CCR2-deficient mice, suggesting a lack of need for CCR2 inhibition in CCR2-deficient gliomas. Gopinath also discloses that CCR2 inhibition (in CCR2+ gliomas) augmented the effects of the PD-1/ PD-L1 inhibitor treatment. Thus, Gopinath discloses treatment of CCR2+ gliomas.
Regarding instant claims 7-10 and 24-25, Applicant is advised that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claims 7-10 and 24-25, must give “meaning and purpose to the manipulative steps.”
Furthermore, it is noted that the courts have held that when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. Therefore, the phrases: (i) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (ii) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (iii) wherein administration increases the durability of overall response to treatment or reduces exhaustion in intra-tumoral T-cells (claims 24-25); clearly define the results of a use of the composition, and thus does not further distinguish the composition over the prior art.
Regarding instant claim 23, Gopinath discloses that administration of CCR2 inhibitor in combination with anti-PD-1/PD-L1 treatment to KR158 glioma-bearing mice (immune checkpoint inhibitor resistant glioma – see claim interpretation), augmented the effects of the anti PD-1/PD-L1 treatment (col. 2, lines 13-16). These findings suggest that, even for previously immune checkpoint inhibitor resistant glioma, co-administration of a CCR2 inhibitor can augment the effects of the immune checkpoint inhibitor treatment.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,116,756 B2 (US ‘756); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114); as applied to claims 1, 5-17, 19-20, and 23-25; further in view of FDA (Obtained from accessdata.fda.gov [retrieved on September 4th, 2025] <URL: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125527> - Revised December 2014). Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of US ‘756, Bekker, Guzik, and Gopinath are disclosed above and incorporated herein.
While US ‘756 in view of Bekker, Guzik, and Gopinath does not specifically teach intravenous administration of their PD-1/PD-L1 inhibitor (nivolumab); the disclosures of the FDA are relied upon for these disclosures.
The FDA discloses that doses of nivolumab (OPDIVO®) may be administered at 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (page 1, col. 1, Dosage and Administration section).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the instant compounds of Formula I orally, as taught by US ‘756 in view of Bekker, and the PD-1/PD-L1 inhibitor (nivolumab) as an intravenous injection, in view of the FDA. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘756’s disclosure of the compounds of Formula I, which may be co-administered with a PD-1/PD-L1 inhibitor; further in view of the FDA’s specific directions for dosage amounts and methods of administration of nivolumab.
Claims 1, 5-17, 19-20, and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,890,276 B2 (US ‘276); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5-17, 19-20, and 23-25, US ‘276 claims a method of controlling adenocarcinoma comprising administration of their compounds of Formula I below (US ‘276’s claim 1). US ‘276 claims their method further comprising a PD-1 or PD-L1 inhibitor (US ‘276’s claims 1).
PNG
media_image2.png
167
167
media_image2.png
Greyscale
PNG
media_image6.png
167
161
media_image6.png
Greyscale
PNG
media_image3.png
168
165
media_image3.png
Greyscale
While US ‘276 does not specifically teach: (i) the treatment of glioma (claims 1-6, 11-17, and 19-22); (ii) nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab as PD-1 and/or PD-L1 inhibitors (claim 1); (iii) treatment of glioblastoma (claim 5); (iv) wherein the glioma is characterized as being CCR2+ (claim 6); (v) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (vi) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (vii) wherein the glioma is an immune checkpoint inhibitor resistant glioma (claim 23); the teachings of Bekker, Guzik, and Gopinath et al. are relied upon for these disclosures.
Bekker discloses the compounds of Formula I, Ia, Ib, and 1c below (pages 3-4 and Bekker’s claims 1 and 3), as compounds that modulate CCR2 chemokine ligand activity [0013].
PNG
media_image4.png
256
224
media_image4.png
Greyscale
PNG
media_image1.png
246
227
media_image1.png
Greyscale
PNG
media_image5.png
247
223
media_image5.png
Greyscale
Guzik teaches nivolumab, pembrolizumab, and atezolizumab as PD-1 and PD-L1 immune checkpoint protein inhibitors (page 5857, col. 1, para. 2, lines 2-4).
Gopinath discloses a study of chemokine receptor CCR2’s contributions to tumor progression in mouse models of glioma (col. 2, lines 6-8), disclosing administration of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors to glioma-bearing mice (col. 2, lines 8-10). Gopinath teaches that a CCR2 antagonist augmented the effects of either anti-PD-L1 or anti-PD-1 treatment to slow glioma progression, but had no effect when administered as a mono-therapy (col. 2, lines 15-18). Gopinath concludes that pharmacological inhibition of CCR2 augments the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression, and further states that their pre-clinical results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment on glioblastoma (col. 2, para. 1, last line).
Therefore, regarding the treatment of glioma with US ‘276’s compounds of Formula I in combination with nivolumab, pembrolizumab, or atezolizumab, as recited in instant claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer US ‘276’s compounds of Formula I, taught by Bekker to be CCR2 antagonists, in combination with Guzik’s PD-1 and PD-L1 inhibitors, in view of Gopinath, for the treatment of glioma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘276’s disclosure of their compounds of Formula I; Bekker’s disclosure that the compounds of Formula I as CCR2 inhibitors, and pharmaceutical compositions thereof suitable for humans in combination with one or more additional therapeutic agents (like nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab); Guzik’s teachings that nivolumab, pembrolizumab, and atezolizumab are FDA approved PD-1 and PD-L1 inhibitors; and Gopinath’s disclosure that CCR2 antagonists augment the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression.
Regarding instant claim 5, Gopinath discloses their results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment of glioblastoma patients (last three lines).
Regarding instant claim 6, Gopinath discloses a study of the impact of CCR2 deficiency or CCR2 inhibition, combined with PD-1/PD-L1 inhibition, for the treatment of glioma in mice. Gopinath discloses reduced presence of CCR2+ CD11b+ in gliomas of CCR2-deficient mice, suggesting a lack of need for CCR2 inhibition in CCR2-deficient gliomas. Gopinath also discloses that CCR2 inhibition (in CCR2+ gliomas) augmented the effects of the PD-1/ PD-L1 inhibitor treatment. Thus, Gopinath discloses treatment of CCR2+ gliomas.
Regarding instant claims 7-10 and 24-25, Applicant is advised that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claims 7-10 and 24-25, must give “meaning and purpose to the manipulative steps.”
Furthermore, it is noted that the courts have held that when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. Therefore, the phrases: (i) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (ii) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (iii) wherein administration increases the durability of overall response to treatment or reduces exhaustion in intra-tumoral T-cells (claims 24-25); clearly define the results of a use of the composition, and thus does not further distinguish the composition over the prior art.
Regarding instant claim 23, Gopinath discloses that administration of CCR2 inhibitor in combination with anti-PD-1/PD-L1 treatment to KR158 glioma-bearing mice (immune checkpoint inhibitor resistant glioma – see claim interpretation), augmented the effects of the anti PD-1/PD-L1 treatment (col. 2, lines 13-16). These findings suggest that, even for previously immune checkpoint inhibitor resistant glioma, co-administration of a CCR2 inhibitor can augment the effects of the immune checkpoint inhibitor treatment.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,890,276 B2 (US ‘276); in view of Bekker et al. (WO 2017/218544 A1); Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); and Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114); as applied to claims 1, 5-17, 19-20, and 23-25; further in view of FDA (Obtained from accessdata.fda.gov [retrieved on September 4th, 2025] <URL: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125527> - Revised December 2014). Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of US ‘276, Bekker, Guzik, and Gopinath et al. are disclosed above and incorporated herein.
While US ‘276 in view of Bekker, Guzik, and Gopinath et al. does not specifically teach intravenous administration of their PD-1/PD-L1 inhibitor (nivolumab); the disclosures of the FDA are relied upon for these disclosures.
The FDA discloses that doses of nivolumab (OPDIVO®) may be administered at 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (page 1, col. 1, Dosage and Administration section).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the instant compounds of Formula I orally, as taught by US ‘276 in view of Bekker, and the PD-1/PD-L1 inhibitor (nivolumab) as an intravenous injection, in view of the FDA. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘276’s disclosure of the compounds of Formula I, which may be co-administered with a PD-1/PD-L1 inhibitor; further in view of the FDA’s specific directions for dosage amounts and methods of administration of nivolumab.
Claims 1, 5-17, 19-20, and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,986,466 B2 (US ‘466); in view of Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114); and Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5-17, 19-20, and 23-25, US ‘466 claims a method of cutaneous T cell lymphoma comprising administration of their compounds of Formula I below (US ‘466’s claims 1-4). US ‘466 discloses their compounds as CCR2 inhibitors.
PNG
media_image2.png
167
167
media_image2.png
Greyscale
PNG
media_image6.png
167
161
media_image6.png
Greyscale
PNG
media_image3.png
168
165
media_image3.png
Greyscale
While US ‘466 does not specifically teach: (i) the treatment of glioma (claims 1-6, 11-17, and 19-22); (ii) co-administration with PD-1 and/or PD-L1 inhibitors, like nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab (claim 1); (iii) treatment of glioblastoma (claim 5); (iv) wherein the glioma is characterized as being CCR2+ (claim 6); (v) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (vi) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (vii) wherein the glioma is an immune checkpoint inhibitor resistant glioma (claim 23); the teachings of Gopinath and Guzik et al. are relied upon for these disclosures.
Gopinath discloses a study of chemokine receptor CCR2’s contributions to tumor progression in mouse models of glioma (col. 2, lines 6-8), disclosing administration of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors to glioma-bearing mice (col. 2, lines 8-10). Gopinath teaches that a CCR2 antagonist augmented the effects of either anti-PD-L1 or anti-PD-1 treatment to slow glioma progression, but had no effect when administered as a mono-therapy (col. 2, lines 15-18). Gopinath concludes that pharmacological inhibition of CCR2 augments the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression, and further states that their pre-clinical results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment on glioblastoma (col. 2, para. 1, last line).
Guzik teaches nivolumab, pembrolizumab, and atezolizumab as PD-1 and PD-L1 immune checkpoint protein inhibitors (page 5857, col. 1, para. 2, lines 2-4).
Therefore, regarding the treatment of glioma with US ‘466’s compounds of Formula I in combination with nivolumab, pembrolizumab, or atezolizumab, as recited in instant claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer US ‘466’s compounds of CCR2 inhibitors of Formula I in combination with a PD-1 or PD-L1 inhibitor for the treatment of glioma, in view of Gopinath. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘466’s disclosure of their compounds of their CCR2 inhibitors of Formula I; Gopinath’s disclosure that CCR2 antagonists augment the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression; and Guzik’s teachings that nivolumab, pembrolizumab, and atezolizumab are FDA approved PD-1 and PD-L1 inhibitors.
Regarding instant claim 5, Gopinath discloses their results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment of glioblastoma patients (last three lines).
Regarding instant claim 6, Gopinath discloses a study of the impact of CCR2 deficiency or CCR2 inhibition, combined with PD-1/PD-L1 inhibition, for the treatment of glioma in mice. Gopinath discloses reduced presence of CCR2+ CD11b+ in gliomas of CCR2-deficient mice, suggesting a lack of need for CCR2 inhibition in CCR2-deficient gliomas. Gopinath also discloses that CCR2 inhibition (in CCR2+ gliomas) augmented the effects of the PD-1/ PD-L1 inhibitor treatment. Thus, Gopinath discloses treatment of CCR2+ gliomas.
Regarding instant claims 7-10 and 24-25, Applicant is advised that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claims 7-10 and 24-25, must give “meaning and purpose to the manipulative steps.”
Furthermore, it is noted that the courts have held that when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. Therefore, the phrases: (i) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (ii) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (iii) wherein administration increases the durability of overall response to treatment or reduces exhaustion in intra-tumoral T-cells (claims 24-25); clearly define the results of a use of the composition, and thus does not further distinguish the composition over the prior art.
Regarding instant claim 23, Gopinath discloses that administration of CCR2 inhibitor in combination with anti-PD-1/PD-L1 treatment to KR158 glioma-bearing mice (immune checkpoint inhibitor resistant glioma – see claim interpretation), augmented the effects of the anti PD-1/PD-L1 treatment (col. 2, lines 13-16). These findings suggest that, even for previously immune checkpoint inhibitor resistant glioma, co-administration of a CCR2 inhibitor can augment the effects of the immune checkpoint inhibitor treatment.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,986,466 B2 (US ‘466); in view of Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114); and Guzik et al. (J. Med. Chem., 2017, 60, 5857−5867); as applied to claims 1, 5-17, 19-20, and 23-25; further in view of FDA (Obtained from accessdata.fda.gov [retrieved on September 4th, 2025] <URL: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125527> - Revised December 2014). Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of US ‘466, Gopinath, and Guzik et al. are disclosed above and incorporated herein.
While US ‘466 in view of Gopinath and Guzik et al. does not specifically teach intravenous administration of their PD-1/PD-L1 inhibitor (nivolumab); the disclosures of the FDA are relied upon for these disclosures.
The FDA discloses that doses of nivolumab (OPDIVO®) may be administered at 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (page 1, col. 1, Dosage and Administration section).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the instant compounds CCR2 inhibitors of Formula I, as taught by US ‘466, and the PD-1/PD-L1 inhibitor (nivolumab) as an intravenous injection, in view of the FDA. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘685’s disclosure of the compounds of Formula I, which may be co-administered with a PD-1/PD-L1 inhibitor; further in view of the FDA’s specific directions for dosage amounts and methods of administration of nivolumab.
Claim 1, 5-17, 19-20, and 23-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-13, 15-17, 20, 22-24, 26, 33, and 36 of copending Application No. 18/411,245 (Copending ‘245); in view of Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5-17, 19-20, and 23-25, Copending ‘245 claims a method of treating cancer in a mammal comprising co-administering a CCR2-inhibitor below (reading on the instant compounds of Formula Ic, with an immune-checkpoint inhibitor (PD-1 and/or PD-L1 inhibitor), such as nivolumab (Copending ‘245’s claim 1).
PNG
media_image7.png
181
352
media_image7.png
Greyscale
While Copending ‘245 does not specifically teach: (i) the treatment of glioma (claims 1-6, 11-17, and 19-22); (ii) treatment of glioblastoma (claim 5); (iii) wherein the glioma is characterized as being CCR2+ (claim 6); or (iv) wherein the glioma is an immune checkpoint inhibitor resistant glioma (claim 23); the teachings of Gopinath et al. are relied upon for these disclosures.
Gopinath discloses a study of chemokine receptor CCR2’s contributions to tumor progression in mouse models of glioma (col. 2, lines 6-8), disclosing administration of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors to glioma-bearing mice (col. 2, lines 8-10). Gopinath teaches that a CCR2 antagonist augmented the effects of either anti-PD-L1 or anti-PD-1 treatment to slow glioma progression, but had no effect when administered as a mono-therapy (col. 2, lines 15-18). Gopinath concludes that pharmacological inhibition of CCR2 augments the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression, and further states that their pre-clinical results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment on glioblastoma (col. 2, para. 1, last line).
Therefore, regarding instant claims 1 and 19, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘245’s CCR2 inhibitors with a PD-1/PD-L1 inhibitor, such as nivolumab, for the treatment of glioma, in view of Gopinath. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘245’s CCR2 inhibitors and pharmaceutical compositions thereof (Copending ‘245’s claim 33), suitable for humans (Copending ‘245’s claim 33) in combination with one or more additional therapeutic agents (like nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab) (Copending ‘245’s claim 1); and Gopinath’s disclosure that CCR2 antagonists augment the effects of immune checkpoint inhibitors (PD-1 and PD-L1 inhibitors) to slow glioma progression.
Regarding claim 5, Gopinath discloses their results support combining CCR2 antagonists with immune checkpoint inhibitors for the treatment of glioblastoma patients (last three lines).
Regarding claim 6, Gopinath discloses a study of the impact of CCR2 deficiency or CCR2 inhibition, combined with PD-1/PD-L1 inhibition, for the treatment of glioma in mice. Gopinath discloses reduced presence of CCR2+ CD11b+ in gliomas of CCR2-deficient mice, suggesting a lack of need for CCR2 inhibition in CCR2-deficient gliomas. Gopinath also discloses that CCR2 inhibition (in CCR2+ gliomas) augmented the effects of the PD-1/ PD-L1 inhibitor treatment. Thus, Gopinath discloses treatment of CCR2+ gliomas.
Regarding claims 7-10 and 24-25, Applicant is reminded that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claims 7-10 and 24-25, must give “meaning and purpose to the manipulative steps.”
Furthermore, it is noted that the courts have held that when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. Therefore, the phrases: (i) wherein the administering promotes a decrease in CD45hi/CD11b+/Ly6Chi cells in a tumor microenvironment and promotes an increase in CD45hi/CD11b+/Ly6Chi cells in bone marrow (claim 7); (ii) wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject, characterized as being CD45+/CD3+/CD4+ or CD45+/CD3+/CD8+ (claims 8-10); (iii) wherein administration increases the durability of overall response to treatment or reduces exhaustion in intra-tumoral T-cells (claims 24-25); clearly define the results of a use of the composition, and thus does not further distinguish the composition over the prior art.
Regarding claim 23, Gopinath discloses that administration of CCR2 inhibitor in combination with anti-PD-1/PD-L1 treatment to KR158 glioma-bearing mice (immune checkpoint inhibitor resistant glioma – see claim interpretation), augmented the effects of the anti PD-1/PD-L1 treatment (col. 2, lines 13-16). These findings suggest that, even for previously immune checkpoint inhibitor resistant glioma, co-administration of a CCR2 inhibitor can augment the effects of the immune checkpoint inhibitor treatment.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-13, 15-17, 20, 22-24, 26, 33, and 36 of copending Application No. 18/411,245 (Copending ‘245); in view of Gopinath et al. (Neuro-Oncology, 19, 2017, Page vi114); as applied to claims 1, 5-17, 19-20, and 23-25; further in view of FDA (Obtained from accessdata.fda.gov [retrieved on September 4th, 2025] <URL: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125527> - Revised December 2014).
The teachings of Copending ‘245 and Gopinath et al. are disclosed above and incorporated herein.
While Copending ‘245 in view of Gopinath et al. does not specifically teach intravenous administration of their PD-1/PD-L1 inhibitor (nivolumab); the disclosures of the FDA are relied upon for these disclosures.
The FDA discloses that doses of nivolumab (OPDIVO®) may be administered at 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (page 1, col. 1, Dosage and Administration section).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer the instant compounds of Formula Ic orally, as taught by Copending ‘245, and the PD-1/PD-L1 inhibitor (nivolumab) as an intravenous injection, in view of the FDA. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending 245’s disclosure of the compounds of Formula I and oral formulations thereof, which may be co-administered with a PD-1/PD-L1 inhibitor such as nivolumab; further in view of the FDA’s specific directions for dosage amounts and methods of administration of nivolumab.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Claims
Claim amendments are acknowledged. No new matter has been added.
Priority
Priority claim to parent application 16,824,585 is acknowledged.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive. Applicant argues that the combination of the prior art references is only motivated by hindsight, ignores evidence of non-obviousness, and does not enable a skilled artisan to practice the claimed invention. Applicant asserts that Gopinath is not “enabling art” because it is an abstract that omits critical information to be enabling. Namely, the abstract refers to a compound CCX598 with no chemical structure or any teaching regarding how to make use of CCX598. Applicant states one of ordinary skill cannot know whether CCX598 is structurally similar to the compound of claim 1 or the compounds disclosed by Gurzik or Bekker. Applicant states that post-filing evidence cannot be used to identify a compound and fill in any gaps of prior art and asserts that the office cannot rely on a prior art that omits structural information.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, 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).
Regarding applicant’s arguments that Gopinath is not enabling because it is an abstract that refers to a compound CCX558 without providing structural information about the compound, and that post-filing evidence cannot be used to identify a compound and fill in any gaps of prior art and asserts that the office cannot rely on a prior art that omits structural information; Applicant is advised that Gopinath’s disclosure of compound CCX558, and the structure of CCX558, was not considered in the context of the 103 rejection. Furthermore, no post-filing evidence was used to “fill in the gaps of prior art”, since Gopinath was disclosed in 2017, well before the filing of the instant application. Applicant is directed to the 103-rejection presented herein, wherein Gopinath is cited to establish that the combination of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors to glioma-bearing mice (col. 2, lines 8-10). Since Bekker teaches compound Ib as a CCR2 inhibitor and Guzik teaches nivolumab, pembrolizumab, and atezolizumab as PD-1 and PD-L1 immune checkpoint protein inhibitors; then it would have been obvious to one of ordinary skill, in view of Gopinath, to combine Bekker’s CCR2 inhibitor with Guzik’s PD-1 and PD-L1 inhibitors for the treatment of glioma.
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).
Therefore, while Gopinath, by itself, would not enable one of ordinary skill to arrive at the claimed invention; Bekker in view of Guzik and Gopinath render the claimed invention obvious.
The claims stand rejected over the art of record.
Double Patenting
Applicant's arguments filed 12/18/2025 have been fully considered but they are not persuasive.
For all the obviousness type double patenting (ODP) rejections of record, Applicant argues that the rejections are not proper because Gopinath is not “enabling art”.
Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references.
In the present case, Gopinath is cited to establish that the combination of a CCR2 antagonist in combination with PD-L1: PD-1 axis inhibitors has been reported to treat glioma-bearing mice (col. 2, lines 8-10). Since Bekker teaches compound Ib as a CCR2 inhibitor and Guzik teaches nivolumab, pembrolizumab, and atezolizumab as PD-1 and PD-L1 immune checkpoint protein inhibitors; then it would have been obvious to one of ordinary skill, in view of Gopinath, to combine Bekker’s CCR2 inhibitor with Guzik’s PD-1 and PD-L1 inhibitors for the treatment of glioma.
Therefore, while Gopinath, by itself, would not enable one of ordinary skill to arrive at the claimed invention; Bekker in view of Guzik and Gopinath render the claimed invention obvious.
Examiner thanks Applicant for pointing out the typographical error in the ODP rejection over U.S. Patent No. 11,116,756 B2 (US ‘756). This typographical error has been corrected herein.
The claims stand rejected over the ODP rejections of record.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
Examiner interviews are available via telephone and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L. Klinkel can be reached at (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JACKSON J HERNANDEZ/Examiner, Art Unit 1627 /Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627