Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
Claims 1-7, 9-14, 16-17, 19, 31-39, and 42-43 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
Previous rejection of claims 1-7, 9-14, 16-17, 19, 31-39, and 42-43 under 35 U.S.C. 103 are withdrawn in view of claim amendments.
Previous rejection of claims 1-7, 9-14, 16-17, 19, 31-39, and 42-43 under NSDP over copending application 17/631,277 are withdrawn in view of claim amendments.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-4, 9-17, 19, 23, 31-36, 38-39, and 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over King (WO 2014/160465 A2; IDS entered 06/11/2021) and Kwok (Human Vaccines & Immunotherapeutics, 12(11), 2777–2789; PTO-892).
Regarding claims 1, 4, 16-17, and 38, King teaches a method of inducing monocyte and/or neutrophil apoptosis in a subject comprising administering to said subject a pharmaceutical composition comprising negatively charged particles, wherein said particles are free from attached peptide or antigenic moieties, and a carrier (claim 1). King further teaches that the particles of the invention may also be used to decrease the inflammatory response associated with the development and/or growth of cancer cells and that the cancers that can be treated include melanoma (paragraph 0154), this is regulation of an anti-tumor response (instant claim 4). King further teaches that the subcutaneous injection of the particles of the invention prevents the accumulation of inhibitory neutrophils or monocyte derived suppressor cells, thereby enhancing or facilitating the tumor-specific immune response the cancer patient (paragraph 00154); this is an alteration of the MDSC or monocytes (instant claim 2). King further teaches that PLGA-IMP infusion (but not vehicle control) results in the expansion and induction of regulatory T cells that express anti-inflammatory proteins like PD-1 (paragraph 0050) and that these regulatory T cells are potent suppressors of T cell mediated immunity in a range of inflammatory conditions including, but not limited to, infectious disease, autoimmunity, pregnancy and tumors (para 0010). King further teaches wherein the diameter of said negatively charged particles is between about 0.5 µm to about 1 µm (claim 16), wherein the diameter of the said negatively charged particles is about 0.5 µm (claim 17). King further teaches that any mixture of particle sizes within these given ranges will be useful (para 0062). King further teaches that surprisingly, all that is necessary to dampen an inflammatory immune response, and treat inflammatory disease is the administration of negatively charged particles, without the need for coupling peptides thereto (para 0012).
Regarding claims 1 and 9, King teaches wherein said particles are PLGA particles (claim 5).
Regarding claims 10-11, King teaches in one embodiment the particles of the invention have about a 50:50 D,L-lactide:glycolide ratio (para 0089).
Regarding claim 12, King teaches wherein the particles are carboxylated (claim 6).
Regarding claims 13-14, King teaches wherein the particles have a zeta potential between -50 mV and - 40 mV (claim 10).
Regarding claim 32, King teaches wherein said composition is administered orally, nasally, intravenously, intramuscularly, ocularly, transdermally, or subcutaneously (claim 37).
Regarding claim 33, King teaches that subjects treated by the particles of the present invention are preferably human (para 00140).
Regarding claim 38, King further teaches that pharmaceutical compositions are provided, which comprise the particles and optionally comprise a pharmaceutically acceptable carrier and these compositions optionally further comprise one or more additional therapeutic agents (paragraph 00118).
King does not teach combination treatment with an anti-PD-1 antibody or reduction of tumor growth or size.
Regarding claims 1 and 39, Kwok teaches that melanoma is an aggressive malignancy in which chemotherapy is ineffective and that there are few treatment options for relapsing or non-responsive patients (page 2779, col 1, para 2). Kwok further teaches that clinical trial results have clearly indicated that pembrolizumab is active in advanced melanoma refractory to chemo-therapy, BRAF/MEK inhibitors and ipilimumab and is also superior to ipilimumab in both efficacy and safety profile and that pembrolizumab is approved by the USA FDA for the treatment of unresectable or metastatic melanoma with disease progression following ipilimumab and, ifBRAFV600 mutation positive, a BRAF inhibitor as well as for initial treatment of unresectable or metastatic melanoma (page 2780, col 2, para 2). Kwok further teaches that T cells play a critical role in immune responses against neoplasms but that after prolonged stimulation T cells may lose their effector functions and take on an exhausted state (introduction) and that PD1 is one of the inhibitory T cell receptors that suppress downstream signaling pathways for TCR stimulation (page 2777, col 1, para 2). Kwok further teaches that PD1 blockade can be used to enhance anti-tumor immunity by reversing T cell exhaustion and restoring T-cell mediated anti-tumor immunity by blocking interaction with the PD-L1 (page 2778, col 1, para 4) and further that PDL1 expression on tumor cells may be a critical predictor of response to PD1 blockade (page 2778, col 2, para 2). Kwok further teaches as activated T-cells infiltrate the tumor, the secretion of pro-inflammatory cytokines including interferon γ up-regulates PDL1 on tumor cells (page 2778, col 2, para 2) and that 80% of melanoma patients in one clinical trial were PDL1 positive (page 2779, last para). Kwok further teaches that other than being used as a single agent, pembrolizumab has also been combined with other drugs targeting different pathways (page 2786, col 2, para 3).
Regarding claims 3 and 34-36, Kwok further teaches that pembrolizumab has been extensively investigated in numerous malignancies and that specifically showed overall response rates of 21-34% in refractory melanoma (abstract).
Regarding claims 19, 23, and 42-43, Kwok teaches that pembrolizumab is a humanized monoclonal IgG4 kappa anti-PD1 antibody (page 2778, col 2, para 4).
Regarding claim 31, Kwok teaches that doses of pembrolizumab varied from 2 mg/kg every 3 weeks to 10 mg/kg every 2 or 3 weeks as a monotherapy in melanoma (page 2779, col 1, para 5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to combine the negatively charged particles to treat melanoma as taught by King with the anti-PD-1 antibody pembrolizumab as taught by Kwok. The ordinary artisan would have been motivated to do so because as King teaches that the negatively charged PLGA particles can be used to treat melanoma and prevent the accumulation of inhibitory neutrophils or monocyte derived suppressor cells, thereby enhancing or facilitating the tumor-specific immune response the cancer patient. King further teaches that PLGA-IMP infusion results in the expansion and induction of regulatory T cells that express anti-inflammatory proteins like PD-1 and Kwok teaches that that PD1 is one of the inhibitory T cell receptors that suppress downstream signaling pathways for TCR stimulation. Kwok further teaches that PD1 blockade by pembrolizumab can be used to enhance anti-tumor immunity by reversing T cell exhaustion and restoring T-cell mediated anti-tumor immunity by blocking interaction with the PD-L1. The ordinary artisan would have a reasonable expectation of success to enhance treatment with the negatively charged PLGA particles that deplete monocytes to treat cancer by combining it with anti-PD-1 therapy to enhance T cell mediated anti-cancer immunity.
Claims 2, 5, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over King (WO 2014/160465 A2; IDS entered 06/11/2021) and Kwok (Human Vaccines & Immunotherapeutics, 12(11), 2777–2789; PTO-892) as applied to claims 1, 3-4, 9-17, 19, 23, 31-36, 38-39, and 42-43 above, and further in view of Das (Indian J Med Res. 2016 Aug;144(2):181-193; PTO-892) as evidenced by Pozdnyakova (Cancer, 2009, 115: 1267-1275; PTO-892).
The teachings of King and Kwok regarding claims 1, 3-4, 9-17, 19, 23, 31-36, 38-39, and 42-43 are detailed above.
King and Kwok do not teach wherein the administration alters immune cells at/ in the tumor site or alters the stem cells in the subject.
Regarding claims 2 and 37, Das teaches that studies have demonstrated that topically applied NPs permeate much faster and reach higher concentrations in skin having follicles in comparison with skin having no follicles and that NPs of 320 nm in size were found to effectively penetrate deeper into the hair follicles when compared with the non-nanoparticulate forms (page 184, col 2). Das further teaches that the presence of a relatively tight barrier formed by the inter-follicular epidermis and the epithelium of the acro infundibulum hinders drug delivery to some extent, but the presence of a horny layer in the lower follicular tract makes the barrier rather incomplete, the corneocytes in this region being reduced and not completely differentiated (page 184, col 2). Das further teaches that poly-lactide-co-glycolide (PLGA), a copolymer of poly-lactic acid and poly-glycolic acid, provides an ideally suited performance-based design for better penetration into skin cells, thereby having a greater potential for the treatment of melanoma (abstract) and that PLGA has attained special importance for encapsulation of a wide variety of drugs as it is easily degradable, biocompatible and non-toxic in nature (page 185, col 1, para 2). Das further teaches that PLGA encapsulated NPs can closely contact the superficial junctions of corneocyte clusters and furrows (page 185, col 1, last para- col 2, 1st para). Das further teaches that it is now known that NP-delivered anti-cancer drugs are more target-specific as these concentrate more in tumor tissue, thus improving treatment efficacy and relatively reducing side effects (page 190, col 1, para 1). Das further teaches that targeting of specific mast cells and lymphocytes in the dermis can improve the therapeutic efficacy (page 190, col 1, para 1).
Regarding claim 5, Pozdnyakova teaches that follicular involvement by malignant melanoma is widely recognized (abstract/ background). Pozdnyakova further teaches that invasive tumors represent the subset of malignant melanomas with metastatic potential and that one characteristic of the lentiginous spread of melanoma is the extension of the tumor cells into the hair follicles (page 1268, para 1). Pozdnyakova further teaches that the hair bulge region contains several types of stem cells: epithelial, melanocytic, and mesenchymal and further that the bulge is contained within the isthmus region of the follicle (page 1268, col 1, para 2). Pozdnyakova further teaches 82% of melanoma cases examined had hair follicles involvement and 29.3% of melanoma cases examined showed melanoma tumor cells in the isthmus including the bulge (table 1; page 1270, col 1, para 1; Fig. 3). Penetration of the nanoparticles into the hair bulge would alter the mesenchymal stem cells present there by altering the inflammation and cell composition.
Regarding claims 6-7, Fujimara teaches that tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are significant components of the microenvironment of solid tumors in the majority of cancers and that TAMs sequentially develop from monocytes into functional macrophages (abstract). Fujimara further teaches that the stromal factor on each cancer stem cell is an important factor for TAM stimulation, leading to the induction of specific TAM phenotypes, investigating the immunomodulatory stromal cells in the tumor microenvironment is important for establishing the appropriate immunotherapy for each type of cancer (introduction). Fujimara further teaches that immune cells in the tumor microenvironment determine the aggressiveness of melanoma and that TAMs are prominent in the tumor stroma in melanoma where they secrete CCL17 and CCL22 to attract Tregs to the tumor site (page 2, col 2, para 1). Fujimara further teaches that MMPs play crucial roles in tumor progression and that MMPs can be produced by TAMs upon stimulation (page 3, col 2, para 2). Fujimara further teaches that TAMs produce not only chemokines that directly recruit immunosuppressive cells to the tumor microenvironment but also produce cytokines that stimulate other stromal cells such as fibroblasts to produce chemokines (page 4, col 1, para 2). Fujimara further teaches that TAMs express immune checkpoint modulators including PD-L1 (introduction). Fujimara further teaches that the anti-PD-1 Ab pembrolizumab is widely used to treat advanced cancer, including melanoma and one target of anti-PD-1 Abs in patients with advanced melanoma could be an immunomodulatory effect on TAM, which, in turn, might be correlated with both their effectiveness and the development of adverse events (page 4, col 1, para 2). The apoptosis of monocytes induced by the negatively charged particles, which are the precursor to TAMs combined with anti-PD-1 immunomodulation of TAMs would therefore have an effect on the stroma of melanoma.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use transdermal administration to enhance treatment in the tumor site as taught by Das, effecting mesenchymal stem cells in the tumor site as taught by Pozdnyakova and tumor associated stroma as taught by Fujimara, of the negatively charged particles PLGA and pembrolizumab to treat melanoma as taught by King and Kwok. The ordinary artisan would have been motivated to do so because Das teaches that nanoparticles are known to concentrate more in tumor tissue and that transdermal administration in skin with follicles increases penetration and that NPs of 320 nm in size were found to effectively penetrate deeper into the hair follicles. Pozdnyakova teaches that follicular involvement by malignant melanoma is widely recognized and includes the presence of melanoma cells in the stem cell containing bulge. Fujimara teaches that immune cells in the tumor microenvironment determine the aggressiveness of melanoma and that TAMs are prominent in the tumor stroma in melanoma. Fujimara further teaches that pembrolizumab has an immunomodulatory effect on TAMs which secrete MMPs to modulate the ECM and stimulatory cytokines to fibroblasts. The ordinary artisan has a reasonable expectation of success to use transdermal administration of the negatively charged PLGA particles to treat melanoma with penetration into the tumor through hair follicles in combination treatment with pembrolizumab that will alter the mesenchymal stem cells and tumor associated stroma in the subject.
Response to Arguments
Applicant's arguments filed 01/12/2026 have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant submits: Applicants have demonstrated, however, that the claimed combination therapy shows unexpected, synergistic benefits that would not have been predicted by one of skill in the art. As shown in Examples 1 and 2 of the specification, administration of the claimed negatively charged particles having the properties recited in the claims and that are free from antigens, peptides, or other bioactive materials in combination with anti-PD1 antibody achieved a significantly improved cancer treatment effect compared to anti-PD1 antibody or PLGA nanoparticles alone. Paragraph [0143] and Figure 2 describe that combination therapy with IMPs and anti-PD1 mAb resulted in a synergistic effect and enhanced inhibition of tumor growth compared to saline treatment or monotherapy with IMPs or anti-PD-1 mAb. Paragraph [0151] and Figures 3A-B describe that IMP survival efficacy was superior to anti-PD1, and combination therapy with IMP and anti-PD1 demonstrated a synergistic effect that resulted in enhanced survival when compared to respective monotherapies. The improved effects of the claimed combination therapy would not have been expected from the cited art, and a skilled artisan would not have found the significant improvement in efficacy achieved by use of the present PLGA particles in combination with an anti-PD-1 antibody was predictable prior to the present disclosure.
In response: Such unexpected results would overcome the 35 USC 103 rejection if commensurate in scope to the claims. Evidence showing unexpected results is capable of rebutting a prima facie case of obviousness (see MPEP § 716.02(a)).
In addition to demonstrating results that are unexpected, evidence of alleged unexpected results is required to be commensurate with the scope of the claims it is offered to support (See MPEP § 716.02(d)).
In the instant case applicant indicates Fig 2 and Fig 3 as demonstrating the unexpected synergy between the IMP particles and anti-PD-1 antibody treatment, however it is unclear that these examples are commensurate with the currently amended claim set in that the composition, zeta potential and diameter of the IMP particles in these examples is not disclosed in the instant specification. The disclosure includes embodiments that incorporate a wider range of diameters as well as alternate nanoparticle materials than those of the claim sets. As the particular embodiments that yielded the results in the figures are not disclosed they cannot overcome the obviousness rejection as it cannot be confirmed that they are commensurate with the scope of the current claims.
Double Patenting
New Rejection Necessitated by Amendment
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 9-14, 16-17, 19, 23, 31-39, and 42-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. US 11,045,492 B2 in view of Santoni (Biochim Biophys Acta Rev Cancer, 2018 Jan, 1869(1):78-84; cited in OA 07/11/2025), as evidenced by Nanda (J Clin Oncol, 2016 Jul 20, 34(21):2460-7; cited in OA 07/11/2025) and Williams (npj Breast Cancer, 2016, 2:15025; cited in OA 07/11/2025).
Regarding claims 1 and 16, the patented claims teach a method of treating cancer in a subject comprising administering to said subject a composition comprising negatively charged particles wherein said particles are free from therapeutic agents, wherein the negatively charged particles are selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), polystyrene particles, and poly (lactic-co-glycolic acid) (PLGA) particles, wherein the cancer is not leukemia or lymphoma (claim 1 and 25) and wherein administering the negatively charged particles induces monocyte and/or neutrophil apoptosis in the subject (claim 19). The patented claims further teach the patented claims teach wherein the average diameter of the negatively charged particles is between 0.1 μm to 10 μm (claim 11), wherein the average diameter of the negatively charged particles is between 0.2 μm to about 2 μm (claim 12 and 26). Although the ranges of the patent claims and the instant claims are not identical, the instant claims are entirely encompassed by the patented claims, as there is a broad range claimed by both claims sets there are a wide range of obvious size options.
Regarding claims 2 and 4, wherein administering the negatively charged particles reduces the cell population of monocytes, neutrophils, granulocytes and/or tumor-associated macrophages (TAMs) at the cancer site (claim 21).
Regarding claims 3, the patented claims teach wherein administering the negatively charged particles reduces tumor size and/or tumor growth in the subject (claim 5).
Regarding claims 9, the patented claims teach wherein the negatively charged particles are poly (lactic-co-glycolic acid) (PLGA) particles (claim 2).
Regarding claims 10 and 11, the patented claims teach wherein the negatively charged particles comprises 50:50 polylactic acid: polyglycolic acid (claim 7).
Regarding claim 12, the patented claims teach wherein the negatively charged particles are carboxylated (claim 8).
Regarding claims 13-14, the patented claims teach wherein the negatively charged particles have a zeta potential between −75 mV and −40 mV (claim 10).
Regarding claim 17, the patented claims teach a method of treating cancer in a subject comprising administering to said subject a composition comprising a negatively charged particles wherein said particles are free from therapeutic agents, wherein the negatively charged particles are selected from the group consisting of polyglycolic acid (PGA), polylactic acid (PLA), polystyrene particles, and poly (lactic-co-glycolic acid) (PLGA) particles, and wherein the subject has a cancer selected from the group consisting of brain cancer, melanoma, basal cell carcinoma breast cancer, prostate cancer, lung cancer, cervical cancer, central nervous system cancer, liver cancer, colon or rectal cancer, pancreatic cancer, endometrial cancer, ovarian cancer, bladder cancer, thyroid cancer, kidney cancer, and testicular cancer (claim 25).
Regarding claim 32, the patented claims teach wherein the negatively charged particles are administered intravenously, orally, nasally, intramuscularly, ocularly, transdermally, or subcutaneously (claim 13).
Regarding claim 33, the patented claims teach wherein the subject is human (claim 14).
Regarding claim 34, the patented claims teach wherein administering the negatively charged particles improves one or more symptoms of the cancer (claim 15).
Regarding claim 35, the patented claims teach wherein the one or more symptoms are selected from the group consisting of tumor size in the subject, tumor development, and levels of immune cells in the tumor (claim 16).
Regarding claim 37, the patented claims teach wherein administering the negatively charged particles reduces levels of monocytes, macrophages, granulocytes and/or neutrophils at the tumor (claim 18).
Regarding claim 38, the patented claims teach wherein the negatively charged particles are formulated in a composition comprising a pharmaceutical acceptable carrier, diluent or excipient (claim 20).
The patented claims are silent on using combination therapy of the negatively charged PLGA particles with an anti-PD-1 antibody.
Regarding claims 1, 2, 4, 37, Santoni teaches that Tumor-Associated Macrophages (TAMs) derive from peripheral blood monocytes recruited into the triple negative breast cancer (TNBC) microenvironment and TAMs promote tumor growth and progression by several mechanisms as well as directly and indirectly modulating PD-1/PD-L1 expression in tumor environment (abstract). Santoni teaches that that high PD-1+ immune cell infiltration correlated with significantly shorter patient survival (section 3, paragraph 1) and that PD-L1 overexpression has been reported in a large variety of human tumors and was predominantly defined as a negative prognostic factor (section 3, paragraph 3). Santoni further teaches that reducing TAM number represents the most promising strategy to enhance PD-1/PD-L1 effectiveness due to its marked effect on tumor microenvironment (section 8, paragraph 3).
Regarding claims 5-7, as evidenced by Williams, TAMs influence mammary cancer stem cell (CSC) functionality through analogous interactions as those performed with normal stem/progenitor cells during development and intercellular signaling between TAMs and CSCs through CD90 and Eph4A receptors induce activation of NF-κB and sustain the CSC phenotype (cancer stem cell support, page 5). Through the production of proteolytic enzymes and MMPs TAMs reorganize the extracellular matrix and degrade the basement membrane (angiogenesis, page 3). Therefore, targeting the TAMs would necessarily alter cancer stem cells, the tumor associated stroma and ECM.
Regarding claims 3, 19, 23, 33-35, 39, 42-43, Santoni teaches that pembrolizumab showed an acceptable safety profile and clinical activity in TNBC, with an overall response rate (ORR) of 18.5% and median time to response of 17.9 weeks in a phase Ib study KEYNOTE-112 as well as being evaluated in additional studies (section 5, paragraph 1; table 1). Nivolumab is also being evaluated in numerous studies for TNBC treatment (table 1). Clinical trials necessitate that the subject is a human and that an antibody is formulated in a pharmaceutical composition.
Regarding claims 31 and 36, as evidenced by Nanda, 37.5% of TNBC patients in KEYNOTE-012 study experienced a decrease in tumor burden ranging from ~30-85% (figure 1a). As further evidenced by Nanda, pembrolizumab was administered every 2 weeks to TNBC patients (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the patent to substitute the negatively charged particles to treat cancer through TAM depletion as taught by the patented claims with the anti-PD-1 antibody and TAM depletion treatment of TNBC as taught by Santoni. The ordinary artisan would have been motivated to do so because as the patented claims teach that the negatively charged PLGA particles induce reduce TAM numbers at the cancer site and Santoni teaches that pembrolizumab is clinically effective in treating TNBC and that reducing TAM number represents the most promising strategy to enhance PD-1/PD-L1 effectiveness due to its marked effect on tumor microenvironment. The ordinary artisan would have a reasonable expectation of success to enhance anti-PD-1 therapy by combining it with negatively charged PLGA particles that deplete TAMs to treat cancer.
Claims 1-7, 9-11, 13-14, 16-17, 19, 23, 31-39, and 42-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-14, 17-18, 22, 25, 35, 51, 97-98, 102, and 105 of copending Application No. 18/840,232 in view of Parveen (J Drug Target. 2008 Feb;16(2):108-23; PTO-892), Santoni (Biochim Biophys Acta Rev Cancer, 2018 Jan, 1869(1):78-84; cited in OA 07/11/2025), as evidenced by Nanda (J Clin Oncol, 2016 Jul 20, 34(21):2460-7; cited in OA 07/11/2025) and Williams (npj Breast Cancer, 2016, 2:15025; cited in OA 07/11/2025).
Regarding claims 1, 13-14, and 16, the copending claims teach a method of treating cancer in a subject in need thereof, comprising administering negatively charged particles at a dose ranging from about 0.1 mg/kg to about 15 mg/kg, wherein the negatively charged particles comprise: a) a zeta potential ranging from about -10 mV to -100 mV; and b) an average diameter ranging from about 100 nm to about 1500 nm, wherein the negatively charged particles are free from a therapeutic agent, thereby treating the cancer (claim 1, 97-98, and 102), wherein the negatively charged particles are administered alone or in combination with one or more additional cancer therapeutics (claim 18).
Regarding claims 3 and 34-35, the copending claims teach wherein the administering of the negatively charged particles reduces tumor size and/or tumor burden in the subject in need thereof (claim 22).
Regarding claims 2 and 4, the copending claims teach wherein the administering of negatively charged particles induces an anti-cancer immune response (claim 35).
Regarding claim 5, the copending claims teach wherein administering the negatively charged particles reduces the number of circulating tumor cells (CTCs) in the subject in need thereof, reduces the number of CTC clusters in the subject in need thereof, or reduces the number of CTC-leukocyte clusters in the subject in need thereof (claim 25).
Regarding claim 17, the copending claims teach wherein the cancer is selected from the group consisting of: brain cancer, skin cancer, eye cancer, breast cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, cervical cancer, liver cancer, colon cancer, bone cancer, uterine cancer, ovarian cancer, bladder cancer, stomach cancer, oral cancer, thyroid cancer, kidney cancer, or testicular cancer (claim 105).
Regarding claim 31, copending claims teach wherein the treatment cycle is a week in duration, and the negatively charged particles are administered once per week (claim 12-14).
Regarding claim 32, the copending claims teach wherein the negatively charged particles are administered intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, or orally (claim 17).
Regarding claim 38, the copending claims teach a composition comprising particles made by the method of claim 51 (claim 94), further comprising a pharmaceutically acceptable excipient (claim 95).
The copending application is silent on the additional therapeutic comprising an anti-PD-1 antibody or the specifics of that antibody.
Regarding claims 1 and 9-11, Parveen teaches that PLGA/ PLA polymers are the most commonly used polymers for this application are PLA and PLGA and that these polymers have been used in biomedical applications for more than 20 years and are known to be biodegradable, biocompatible and non-toxic (table 1; page 115). Parveen further teaches that the time required for degradation is related to the ratio of monomers used in the preparation, since higher the content of glycolide units, the lower is the time required for its degradation (page 115, col 1 last para to col 2 1st para) and further that PLGA is the most widely used and preferred polymer for the preparation of NPs (page 115, col 2, para 2).
Regarding claims 1, 2, 4, 37, Santoni teaches that Tumor-Associated Macrophages (TAMs) derive from peripheral blood monocytes recruited into the triple negative breast cancer (TNBC) microenvironment and TAMs promote tumor growth and progression by several mechanisms as well as directly and indirectly modulating PD-1/PD-L1 expression in tumor environment (abstract). Santoni teaches that that high PD-1+ immune cell infiltration correlated with significantly shorter patient survival (section 3, paragraph 1) and that PD-L1 overexpression has been reported in a large variety of human tumors and was predominantly defined as a negative prognostic factor (section 3, paragraph 3). Santoni further teaches that reducing TAM number represents the most promising strategy to enhance PD-1/PD-L1 effectiveness due to its marked effect on tumor microenvironment (section 8, paragraph 3).
Regarding claims 3, 19, 23, 33-35, 39, 42-43, Santoni teaches that pembrolizumab showed an acceptable safety profile and clinical activity in TNBC, with an overall response rate (ORR) of 18.5% and median time to response of 17.9 weeks in a phase Ib study KEYNOTE-012 as well as being evaluated in additional studies (section 5, paragraph 1; table 1). Nivolumab is also being evaluated in numerous studies for TNBC treatment (table 1). Clinical trials necessitate that the subject is a human and that an antibody is formulated in a pharmaceutical composition.
Regarding claims 31 and 36, as evidenced by Nanda, 37.5% of TNBC patients in KEYNOTE-012 study experienced a decrease in tumor burden ranging from ~30-85% (figure 1a). As further evidenced by Nanda, pembrolizumab was administered every 2 weeks to TNBC patients (abstract).
Regarding claims 5-7, Williams teaches that TAMs influence mammary cancer stem cell (CSC) functionality through analogous interactions as those performed with normal stem/progenitor cells during development and intercellular signaling between TAMs and CSCs through CD90 and Eph4A receptors induce activation of NF-κB and sustain the CSC phenotype (cancer stem cell support, page 5). Through the production of proteolytic enzymes and MMPs TAMs reorganize the extracellular matrix and degrade the basement membrane (angiogenesis, page 3). Therefore, targeting the TAMs would necessarily alter cancer stem cells, the tumor associated stroma and ECM.
Regarding claim 37, Williams teaches that macrophages within early neoplastic tissues are frequently tumoricidal and suppress tumor growth but prolonged
exposure to the TME during malignancy endows macrophages with tumorigenic properties and as such strategies to deliver immunogenic stimuli to reprogram macrophages within tumors have been pursued (page 8, col 2, para 1).
It would have been obvious to one of ordinary skill in the art to combine the negatively charged particles to treat cancer through immune activation as taught by the copending claims, to use PLGA particles as taught by Parveen, with the anti-PD-1 antibody treatment of TNBC as taught by Santoni. The ordinary artisan would have been motivated to do so because as the copending claims teach that the negatively charged particles induce immune activation at the tumor location and/or systemically and a reduction in tumor size from the same negatively charged particles. Parveen teaches that PLGA is the most widely used and preferred polymer for the preparation of NPs and that the ratio glycolide to lactic acid can be optimized to optimize the degradation of the nanoparticle. Williams teaches that new TAMs or reprograming of TAMs have antitumor properties. Santoni teaches that pembrolizumab is clinically effective in treating TNBC and that reducing TAM number represents the most promising strategy to enhance PD-1/PD-L1 effectiveness due to its marked effect on tumor microenvironment. The ordinary artisan would have a reasonable expectation of success to enhance anti-PD-1 therapy by combining it with negatively charged PLGA particles that increase immune activation and decrease tumor size to treat cancer.
Response to Arguments
Applicant's arguments filed January 12, 2026 have been fully considered but they are not persuasive.
Applicant submits: That the disclosure of US 11045492 is the same as that of King cited above. The '492 patent and King share all the same priority documents, and the US patent and the King PCT application have the same effective filing date. Applicant submits that the claims are not obvious over the '492 patent in view of the cited art for the same reasons as set out above in Section II with respect to King, Santoni, Danhier, Nanda and Williams since none of the cited art provides motivation of a reasonable expectation of success at arriving the present methods and their unexpected benefits.
In response: This argument was previously addressed in the office action mailed 07/11/2025; and included herein. While both applications claim priority to the same documents and appear to have the same disclosure the NSDP rejection is based off of the claims of the patent document which as a continuation of the PCT have a different scope than the original claim set. Further the NSDP rejection did not rely on Danhier and therefore the argument is not persuasive as it does not apply.
Applicant submits: Applicants have demonstrated, however, that the claimed combination therapy shows unexpected, synergistic benefits that would not have been predicted by one of skill in the art. As shown in Examples 1 and 2 of the specification, administration of the claimed negatively charged particles having the properties recited in the claims and that are free from antigens, peptides, or other bioactive materials in combination with anti-PD1 antibody achieved a significantly improved cancer treatment effect compared to anti-PD1 antibody or PLGA nanoparticles alone. Paragraph [0143] and Figure 2 describe that combination therapy with IMPs and anti-PD1 mAb resulted in a synergistic effect and enhanced inhibition of tumor growth compared to saline treatment or monotherapy with IMPs or anti-PD-1 mAb. Paragraph [0151] and Figures 3A-B describe that IMP survival efficacy was superior to anti-PD1, and combination therapy with IMP and anti-PD1 demonstrated a synergistic effect that resulted in enhanced survival when compared to respective monotherapies. The improved effects of the claimed combination therapy would not have been expected from the cited art, and a skilled artisan would not have found the significant improvement in efficacy achieved by use of the present PLGA particles in combination with an anti-PD-1 antibody was predictable prior to the present disclosure.
In response: The unexpected results as described and illustrated in the figures are not commensurate in scope with the claims of the application as the size of the particles which is the point of contention in the newly amended claims is not disclosed for any of the examples. Therefore the unexpected results do not overcome the obvious type NSDP rejection.
Applicant submits: With respect to the '322 application, Applicant request that the rejection be held in abeyance until such notification of allowable subject matter. Applicant will file any necessary terminal disclaimers as required.
In response: This rejection is maintained at this time.
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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/AMBER K FAUST/Examiner, Art Unit 1643