DETAILED ACTION
Status of the Claims
Claims 1, 3, 4, 6, 8-11, 15-17, 21-23, 25, 28-30 and 46 are pending in the instant application. Claims 29 and 30 have been withdrawn based upon Restriction/Election. Claims 1, 3, 4, 6, 8-11, 15-17, 21-23, 25, 28 and 46 are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The U.S. effective filing date has been determined to be 06/23/2020, the filing date of the U.S. Provisional Application No. 63/042,652.
Information Disclosure Statement
The information disclosure statements submitted on 12/22/2025 were filed after the mailing date of the first office action on the merits, however, Applicant has indicated the appropriate fees have been paid. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Objections
Claims 29 and 30 are objected to because these claims stand withdrawn and should have status identifiers indicating the same (MPEP 714(II)(C) – 37 CFR 1.121(c)). Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 10 and 11 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Instant claim 1 requires “a polymer conjugated to at least two immunomodulators.” dependent claim 10 recites “The composition of claim 1, wherein the at least two immunomodulators are conjugated to the same polymer molecule such that each polymer molecule comprises at least one molecule of each of the at least two immunomodulators.” which fails to further limit the subject matter of the parent claim which requires “a polymer conjugated to at least two immunomodulators.” of which the plain meaning is that “a polymer” is “conjugated to at least two immunomodulators”. And does not “(ii) then specify a further limitation of the subject matter claimed.” (MPEP §608.01(n)(III)).
Claim 1 is discussed above. Claim 11 recited “The composition of claim 1, wherein the at least two immunomodulators are conjugated to separate polymer molecules such that each polymer molecule comprises only one of the at least two immunomodulators.” which is broader in scope than claim 1 requiring “a polymer” is “conjugated to at least two immunomodulators”. MPEP §608.01(n)(III) makes clear that: “Following the statute, the test as to whether a claim is a proper dependent claim is that it shall include every limitation of the claim from which it depends and specify a further limitation of the subject matter claimed.” Claim 11 fails this test because it does not require “a polymer” is “conjugated to at least two immunomodulators”, but rather requires two different polymers each conjugated to one of the at least two immunomodulators.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3, 4, 6, 8-11, 15-17, 21-23, 28 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Yao et al. (“Efficient Simultaneous Tumor Targeting Delivery of All-Trans Retinoid Acid and Paclitaxel Based on Hyaluronic Acid-Based Multifunctional Nanocarrier,” 2013, ACS; Molecular Pharmaceutics, Vol. 10, pp. 1080-1091) in view of SHIMA (US 2016/0333073; published November, 2016); Tanita et al. (“Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma,” 2019, Frontiers in Oncology, Vol. 9, Article 907, pp. 1-10); Dosio et al. (“Hyaluronic acid for anticancer drug and nucleic acid delivery,” 2016, ELSEVIER, Advanced Drug Delivery Reviews, Vol. 97, pp. 204-236); Yoo et al. (“Hyaluronic acid Conjugates of TLR7/8 Agonists for Targeted Delivery to Secondary Lymphoid Tissue,” 2018; ACS Publications, Bioconjugate Chemistry, Vol. 29, pp. 2741-2754); Rook et al. (“Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma,” 2015, The American Society of Hematology, BLOOD, Vol. 126, No. 12, pp. 1452-1461); and Silva-Hirschberg et al. (“Cytotoxic impact of a perillyl alcohol-temozolomide conjugate, NEO212, on cutaneous T-cell lymphoma in vitro,”2019, Therapeutic Advances in Medical Oncology, Vol. 11, pp. 1-15).
Applicants Claims
Applicant claims a composition comprising a polymer conjugated to at least two immunomodulators (instant claim 1).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Yao et al. teaches “An amphiphilic hyaluronic acid (HA)-g-all-trans retinoid acid (HRA) conjugate was successfully developed as a tumor-targeting nanocarrier for potentially synergistic combination chemotherapy of all-trans retinoid acid (ATRA) and paclitaxel (PTX). The HRA conjugate was synthesized by an imine reaction between HA-COOH and ATRA-NH2. PTX-loaded HRA nanoparticles possessed a high loading capacity, nanoscale particle sizes, and good biocompatible characteristics.” (abstract, see whole document), including ATRA conjugated to HA by an amide bond (Scheme 1, p. 1084, col. 1, lines 8-10)(instant claims 1, 15-16, 21-23 and 46 – hyaluronic acid). Yao et al. teaches the “Hyaluronic acid (10 KDa)” (p. 1081, col. 2, last. paragraph , line 1)(instant claim 17).
Yao et al. teaches that: “It has been reported that the retinoid acid (ATRA), one of the retinoids which inhibits cell proliferation and induces differentiation in a variety of tumor cells, could enhance PTX induced death of tumor cells and the regression of tumor.” (p. 1080, col. 1, lines 10-14). And that: “However, some strategies are needed to overcome the obstacles which may prevent simultaneous delivery of PTX and ATRA, for example, the poor solubility of drugs, the aggregation and precipitation of drugs in aqueous medium, losing respective pharmaceutical activity, and raising a risk of embolisms.” (p. 1080, col. 2, lines 3-7).
Yao et al. teaches that: “Tumor cell targeting is a promising strategy for enhancing the therapeutic potential of chemotherapy agents. However, the polymer-drug conjugates often passively accumulate in the tumor as a result of the enhanced permeability and retention (EPR) effect. Therefore, it is essential to further improve the polymer selectivity of drug conjugates for cancer cells. Hyaluronic acid (HA), a low toxic, biodegradable, and biocompatible polyanionic polysaccharide, is distributed widely in the extracellular matrix and the joint liquid of mammalians. It has been proved that the HA conjugates were specifically and efficiently internalized into the malignant cells that overexpressed CD44 receptor and LYCE-1 receptor” (p. 1081, col. 2, lines 9-20). Yao et al. teaches in vivo antitumor activity - “In the subcutaneous B16F10 melanoma tumor model […].” (p. 1083, col. 2, 4th paragraph).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Yao et al. is that Yao et al. does not expressly teach the retinoid species bexarotene.
SHIMA teaches a drug delivery system including hyaluronic acid (HA) conjugates (see whole document), particularly teaching “hyaluronic acid conjugates comprising the same peptides and a therapeutic or diagnostic agent, and compositions and uses thereof.” (abstract, see whole document). And that: “In the collagen or hyaluronic acid binding conjugate of the invention, the therapeutic or diagnostic agent may be covalently or non-covalently bound to the peptide.” ([0036]). And further that: “The collagen or hyaluronic acid binding conjugate may contain a linker which binds the peptide to the therapeutic or diagnostic agent.” ([0038]).
SHIMA teaches the therapeutic agent is selected from retinoids, among others ([0046]), “Suitable retinoids include retinal, retinal, tretinoin (retinoic acid, Retin-A), isotretinoin, alitretinoin, etretinate and its metabolite acitretin, tazarotene, bexarotene, and adapalene.” [emphasis added]([0057]).
Tanita et al. teaches that: “Bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved for use in the treatment of both early and advanced cutaneous T-cell lymphoma (CTCL). Although bexarotene has been used for decades in the treatment of CTCL, little is known about the mechanisms underlying its anti-tumor effects in CTCL patients. This study therefore focused on the immunomodulatory effects of bexarotene in vivo using an EL4 mouse T-cell lymphoma model, followed by investigation in CTCL patients treated with bexarotene. Intraperitoneal injection of bexarotene significantly decreased expressions of CCL22, CXCL5, CXCL10, and p19 in the tumor microenvironment. Based on those results, we then evaluated serum levels of CCL22, CXCL5, and CXCL10 in 25 patients with CTCL, revealing that CCL22 was significantly increased in advanced CTCL compared with early CTCL. Next, we evaluated serum levels of CCL22, CXCL5, and CXCL10 in CTCL patients treated with bexarotene. Serum levels of CCL22 were significantly decreased in 80% of CTCL patients who responded to bexarotene therapy. In addition, immunofluorescence staining revealed CD163+ M2 macrophages as the main source of CCL22. Moreover, bexarotene decreased the production of CCL22 by M2 macrophages generated from monocytes in vitro. Our findings suggest that the clinical benefits of bexarotene are partially attributable to suppressive effects on the production of CCL22 by M2-polarized tumor-associated macrophages.” (abstract, see whole document).
Dosio et al. teaches hyaluronic acid anticancer drug delivery (title, see whole document), including HA-drug conjugates (pp. 207-214, §3). Dosio et al. teaches that: “The main advantages of this approach are that is i) increases the water solubility of low soluble or insoluble drugs, and therefore enhances drug bioavailability; ii) protects drugs from deactivation and preserves their activities during circulation; and iii) most importantly, that it actively targets the drug specifically to the site of action.” (p. 207, col. 2, 3rd paragraph). And that: “The benefit of using HA to design prodrugs is that it can act both as a hydrophilic carrier, available in a variety of molecular dimensions, and as a CD44 ligand targeting moiety.” (p. 207, col. 2, 4th paragraph; also see p. 206, 1st full paragraph).
Dosio et al. teaches that: “Further development of HA-BA has been proposed, in which other small molecules, such as 5-aza-2-deoxycytidine 3, retinoic acid, or 1a,25-dihydroxyvitamin D, are simultaneously bound to the same HA back bone.” (p. 209, col. 1, lines 20-24). And further: “A synergistic combination of topoisomerase I and II inhibitors (CPT and DOX) both linked to HA was recently proposed. HA (250 kDa) was sequentially derivatized with CPT and DOX, using the carbodiimide method, obtaining DL of 5.9 %mol CPT and 1.8 %mol DOX. Although not yet completely characterized, the CPT-HA-DOX conjugate, […].” (p. 210, col. 2, 4th paragraph)(instant claim 10).
Yoo et al. teaches HA-conjugates of TLR7/8 agonists (see whole document), and particularly that: “We envisioned that we could take advantage of the characteristics of HA, a natural biopolymer with an excellent record. clinical track
biodegradability, biocompatibility, high potential loading, and, importantly, its known propensity for trafficking to lymph nodes. We hypothesized that covalently coupled conjugates of HA bearing TLR7/TLR8 agonists, which we previously demonstrated to induce prominent Th1-biased responses could facilitate targeted delivery of these adjuvants to secondary lymphoid tissue while also minimizing systemic exposure of these small molecules with molecular properties that portend a large volume of distribution.” (p. 2742, col. 1, lines 16-27). And further that: “ We show that covalent conjugates of small-molecule TLR7/8 agonists with HA are entirely devoid of immunostimulatory activity in vitro. In murine models of immunization, however, such conjugates traffic to lymph nodes, where they are “unmasked” resulting in focused immunostimulation and potent adjuvantic effects with negligible systemic exposure.” (p. 2742, col. 1, 3rd paragraph).
Rook et al. teaches “Early-stage cutaneous T-cell lymphoma (CTCL) is a skin-limited lymphoma with no cure aside from stem cell transplantation. Twelve patients with stage IA-IIA CTCL were treated in a phase 1 trial of 0.03% and 0.06% topical resiquimod gel, a Toll-like receptor 7/8 agonist. Treated lesions significantly improved in 75% of patients and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions. Ninety-two percent of patients had more than a 50% improvement in body surface area involvement by the modified Severity-Weighted Assessment Tool analysis and 2 patients experienced complete clearing of disease. Four of 5 patients with folliculotropic disease also improved significantly. Adverse effects were minor and largely skin limited. T-cell receptor sequencing and flow cytometry studies of T cells from treated lesions demonstrated decreased clonal malignant T cells in 90% of patients and complete eradication of malignant T cells in 30%. High responses were associated with recruitment and expansion of benign T-cell clones in treated skin, increased skin T-cell effector functions, and a trend toward increased natural killer cell functions. In patients with complete or near eradication of malignant T cells, residual clinical inflammation was associated with cytokine production by benign T cells. Fifty percent of patients had increased activation of circulating dendritic cells, consistent with a systemic response to therapy. In summary, topical resiquimod is safe and effective in early-stage CTCL and the first topical therapy to our knowledge that can induce clearance of untreated lesions and complete remissions in some patients.” (abstract, see whole document).
Rook et al. teaches that: “Substantial emerging data indicate that host antitumor immunity plays a critical role in controlling CTCL disease progression. For example, the beneficial effects of recombinant interleukin-12 (IL-12) in CTCL are likely mediated through the induction of cellular immunity and cytotoxic T-cell responses. The imidazoquinolines are a class of small organic molecules with potent antiviral and anticancer activities. Imiquimod, a Toll-like receptor 7 (TLR7) agonist, is Food and Drug Administration–approved for the topical treatment of genital warts, basal cell carcinomas, and low-risk squamous cell carcinomas of the skin; there have also been reports of efficacy in cutaneous metastases of malignant melanoma, invasive squamous cell carcinomas, and MF. Imiquimod induces production of multiple inflammatory cytokines, including interferon-a (IFN-a), tumor necrosis factor-a (TNF-a), IL-1a, IL-6, and IL-8, from human plasmacytoid dendritic cells (PDCs), the only human dendritic cell (DC) population that expresses TLR7. PDCs are frequent in inflamed skin and skin cancers but are rare in healthy skin. In human basal cell carcinoma, the lack of PDCs in tumors was associated with imiquimod treatment failure. Resiquimod is an imidazoquinoline with potent TLR7 and TLR8 stimulating activity. In humans, TLR8 is expressed by myeloid-derived DCs, the dominant population of DCs in healthy and inflamed human skin; resiquimod but not imiquimod potently activates these cells. Given resiquimod’s ability to stimulate DC in both healthy and inflamed skin, we chose this medication to test in the treatment of CTCL.” (paragraph bridging pp. 1452-1453).
Silva-Hirschberg et al. “Primary cutaneous lymphomas are a heterogenous
group of extranodal non-Hodgkin lymphomas. In contrast to nodal non-Hodgkin lymphomas, most of which are B-cell derived, approximately 75% of primary cutaneous lymphomas are T-cell derived.1 Cutaneous T-cell lymphomas (CTCLs) are rare and they are characterized by the presence of malignant T lymphocytes in the skin.” (§Introduction, 1st paragraph).
Silva-Hirschberg et al. teaches that: “For patients at early stages who failed topical therapies, physicians can start using combinations with biologic agents, such as interferon alfa, retinoids (all-trans retinoic acid, isotretinoin), rexinoids (bexarotene), and methotrexate.” (p. 10, col. 2, lines 10-15). And that: “The current US Food and Drug Administration (FDA)-approved agents for the treatment of CTCL are bexarotene, vorinostat, denileukin diftitox (discontinued in the United States), romidepsin, brentuximab vedotin, and mogamulizumab.” (p. 10, col. 2, lines 30-35).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a HA-retinoid anticancer conjugate for cancer therapy, as suggested by Yao et al., the retinoid ATRA being substituted with bexarotene for cutaneous T-cell lymphoma (CTCL), as suggested by Tanita et al., and the bexarotene being an obvious variant of ATRA in a HA-conjugate, as suggested by SHIMA. The motivation for HA-anticancer conjugates being the increase solubility of the active agent and increased bioavailability as well as CD44 targeting which is overexpressed on many cancer cells. And further to combine the CTCL therapy with resiquimod imidazoquinoline with potent TLR7 and TLR8 stimulating activity also know for treating CTCL, as suggested by Rook et al. and Yoo et al. teaching HA-conjugates of TLR7/8 agonists. One skilled in the art would have been motivated to produce a combined HA-conjugate therapy with bexarotene and resiquimod because it is generally considered to be prima facie obvious to combine compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a composition that is to be used for an identical purpose. The motivation for combining them flows from their having been used individually in the prior art, and from the being recognized in the prior art as useful for the same purpose. As shown by the recited teachings, instant claims are no more than the combination of conventional components of CTCL therapeutic compositions. It therefore follows that the instant claims define prima facie obvious subject matter. Cf. In re Kerkhoven, 626 F.2d 848, 205 USPQ 1069 (CCPA 1980).
Additionally, Silva-Hirschberg et al. teaches bexarotene and vorinostat are FDA approved for treating CTCL, therefore one skilled in the art would have been motivated to produce a combined HA-conjugate therapy with bexarotene and vorinostat because it is generally considered to be prima facie obvious to combine compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a composition that is to be used for an identical purpose. The motivation for combining them flows from their having been used individually in the prior art, and from the being recognized in the prior art as useful for the same purpose. As shown by the recited teachings, instant claims are no more than the combination of conventional components of CTCL therapeutic compositions. It therefore follows that the instant claims define prima facie obvious subject matter. Cf. In re Kerkhoven, 626 F.2d 848, 205 USPQ 1069 (CCPA 1980).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because it would have required no more than an ordinary level of skill in the art to substitute the ATRA with bexarotene in the HA-ATRA conjugate of Yao et al. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Yao et al. in view of SHIMA; Tanita et al.; Dosio et al.; Yoo et al. ; Rook et al. and Silva-Hirschberg et al. as applied to claims 1, 3, 4, 6, 8-11, 15-17, 21-23, 28 and 46 above, and further in view of EVANS (WO 2019/139892 A1; published July, 2019, with priority to 01-2018) and Kelly et al. (“Targeted Liposomal Drug Delivery to Monocytes and Macrophages” Hindawi Publishing; Journal of Drug Delivery, Vol. 2011, Article ID 727241, pp. 1-11).
Applicants Claims
Applicant claims a composition comprising a polymer conjugated to at least one immunomodulator (instant claim 1). Applicant further claims a cellular composition comprising a composition of claim 1, and (a) adhered to or located on the surface of a macrophage or monocyte, or (b) present in a macrophage or monocyte (instant claim 25).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Yao et al. teaches an amphiphilic hyaluronic acid (HA)-g-all-trans retinoid acid (HRA) conjugate was successfully developed as a tumor-targeting nanocarrier for potentially synergistic combination chemotherapy of all-trans retinoid acid (ATRA), as discussed above and incorporated herein by reference.
SHIMA teaches a drug delivery system including hyaluronic acid (HA) conjugates, including a therapeutic agent such as bexarotene, as discussed above and incorporated herein by reference.
Tanita et al. teaches bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved for use in the treatment of both early and advanced cutaneous T-cell lymphoma (CTCL), as discussed above and incorporated herein by reference.
Dosio et al. teaches hyaluronic acid anticancer drug delivery, as discussed above and incorporated herein by reference.
Yoo et al. teaches HA-conjugates of TLR7/8 agonists, as discussed above and incorporated herein by reference.
Rook et al. teaches Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma, as discussed above and incorporated herein by reference.
Silva-Hirschberg et al. teaches Cutaneous T-cell lymphomas (CTCLs) are rare and they are characterized by the presence of malignant T lymphocytes in the skin, and that: “The current US Food and Drug Administration (FDA)-approved agents for the treatment of CTCL are bexarotene, vorinostat, [….]” as discussed above and incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Yao et al. is that Yao et al. does not expressly teach a cellular composition comprising a composition of claim 1, and (a) adhered to or located on the surface of a macrophage or monocyte, or (b) present in a macrophage or monocyte (instant claim 25).
EVANS teaches “polymeric particles and compositions (i.e., "backpacks") that can adhere to cells and provide delivery of payload immunomodulatory agents to those cells. For examples, the particles can adhere to macrophages and/or monocytes and release cytokines that promote an Ml or M2 phenotype to improve therapeutic efficacy of the cells.” (abstract, see whole document)(instant claim 25, item (a)). EVANS further teaches that: “Attachment of backpacks to monocytes can be mediated by various factors. In one mode, the polymers used to synthesize backpacks can exhibit affinity for monocytes. This property can be exhibited by hyaluronic acid, which exhibits affinity for CD44 on the surfaces of monocytes.” (p. 52, [00173]).
Kelly et al. teaches that: “As the role of monocytes and macrophages in a range of diseases including infectious disease, inflammatory diseases, cancer, and atherosclerosis is better understood, strategies to target these cell types are of growing importance both scientifically and therapeutically. As particulate carriers, liposomes naturally target cells of the mononuclear phagocytic system (MPS), particularly macrophages. Loading drugs into liposomes can therefore offer an efficient means of drug targeting to MPS cells. Physicochemical properties including size, charge, and lipid composition can have a very significant effect on the efficiency with which liposomes target MPS cells. Small, negatively charged liposomes appear to target macrophages most efficiently by interaction with scavenger receptors on the macrophage cell surface. MPS cells express a range of receptors including scavenger receptors, integrins, mannose receptors, and Fc-receptors that can be targeted by the addition of ligands to liposome surfaces. These ligands include peptides, antibodies, and lectins and have the advantages of increasing target specificity and avoiding the need for cationic lipids to trigger intracellular delivery. The goal for targeting monocytes/macrophages using liposomes includes not only drug delivery but also potentially a role in cell ablation and cell activation for the treatment of conditions including cancer, atherosclerosis, HIV, and chronic inflammation.” (abstract, see whole document).
Kelly et al. teaches that: “Mononuclear phagocytes such as monocytes, macrophages, and dendritic cells are intrinsically involved in innate immunity. As the designation denotes, the chief role of these cells is phagocytosis whereby cells will engulf and destroy apoptotic cells, pathogens, and other targets.” (p. 1, col. 1, lines 1-5). And that: “Due to its pivotal role in inflammation, the mononuclear phagocytic system (MPS) is an important target for drug delivery to treat disease. For certain diseases such as chronic obstructive pulmonary disease (COPD), asthma, atherosclerosis, and cancer […].” (p. 1, col. 1, 2nd paragraph). And further that: “Thus strategies aimed at targeting the MPS are highly attractive. In general however these cells are reputed to be difficult targets, particularly where intracellular delivery
of the active is required such as for gene delivery. Therefore the development of delivery systems that can target monocytes/macrophages intracellularly is crucial and could potentially open up new treatment paradigms for a range of diseases.” (p. 1, col. 2, 1st paragraph).
Kelly et al. teaches that: “In addition Tumour-Associated Macrophages (TAMs) are anM2-like macrophage population that promote tumour growth via angiogenesis and metastasis, at least in part, by the release of proangiogenic factors including vascular endothelial growth factor (VEGF) and matrix metalloproteinases. Thus targeting strategies aimed at discriminating against M1 and M2 macrophages may be very attractive for cancer chemotherapy in the future. With respect to cancer therapeutics, dendritic cells are major antigen presenting cells that play important roles in cancer detection and elimination through the activation of T cells, and interest lies in targeting these cells for cancer immunotherapies.” (p. 2, col. 2, 2nd paragraph).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a HA-retinoid anticancer conjugate for cancer therapy, as suggested by Yao et al., the retinoid ATRA being substituted with bexarotene for cutaneous T-cell lymphoma (CTCL), as discussed above, and further to produce a cellular delivery composition for delivery to monocytes and/or macrophages, as suggested by Kelly et al. for treatment of cancer, and as taught by EVANS for hyaluronic acid can exhibit affinity for monocytes which exhibits affinity for CD44 on the surfaces of monocytes.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 12/22/2025 have been fully considered but they are not persuasive.
Applicant’s argument that “a prima facie modification rationale requires that the modification provides only predictable results. For example, MPEP 2143.0l(III) is clear that "The mere fact that references can be combined or modified does not render the resultant combination obvious unless the results would have been predictable to one of ordinary skill in the art." As the MPEP states at 716.02(a), "superiority of a property shared with the prior art is evidence of nonobviousness."” (p. 6, 1st full paragraph).
In response the examiner argues that instant claim 1 is directed to “A composition comprising a polymer conjugated to at least two immunomodulators.” and that one of ordinary skill would have easily predicted that one could have conjugated (see Specification, p. 11, [0048]) at least two immunomodulator molecules to a polymer with a reasonable expectation of success because polymer conjugation was well-known before the time of the claimed invention. MPEP 2143.02 makes clear that: “Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness.” Applicant has cited no evidence that one of ordinary skill in the art would have had no reasonable expectation of success.
Applicant further argues that: “Even if the Office's characterization of the art and the motivation were credited, merely en argudeno, the instantly claimed compositions provide more than would be expected on the basis of the prior art and do exhibit superior properties and are therefore not obvious.” (p. 8, 3rd paragraph). And specifically that: “The instant specification demonstrates that "a composition comprising a polymer conjugated to at least one two immunomodulators" exhibits synergism. See instant Figs. 7Cl6C, 16D, 17A, 17B and paragraphs [00175]-[00176], [00229]-[00230].” And further that: “The instant specification demonstrates that "a composition comprising a polymer conjugated to at least one two immunomodulators" exhibits fewer side effects on healthy cells, e.g., fibroblasts and keratinocytes as compared to combinations of free drugs. See instant Figs. 19A-19B and paragraph [00233]. Compositions "comprising a polymer conjugated to at least one two immunomodulators" also showed lower toxicity than compositions comprising a polymer conjugated to only one immunomodulator. See instant paragraph [00164].” “ (p. 8, last two paragraphs).
Firstly, Yao et al. clearly teaches that: “An amphiphilic hyaluronic acid (HA)-g-all-trans retinoid acid (HRA) conjugate was successfully developed as a tumor-targeting nanocarrier for potentially synergistic combination chemotherapy of all-trans retinoid acid (ATRA) and paclitaxel (PTX). […] Furthermore, PTX-loaded HRA nanoparticles exhibited greater tumor growth inhibition effect in vivo with reducing the toxicity. Therefore, HRA nanoparticles can be considered as a promising targeted codelivery system for combination cancer chemotherapy.” [emphasis added](abstract). Lower toxicity of a toxic free drug compared to the same drug conjugated to a polymer such as Hyaluronic acid (HA) would have been predictable to one of ordinary skill before the time of the claimed invention as suggested by Yao et al., as would “potentially synergistic combination of chemotherapy” drugs. Secondly, the burden is on Applicant to establish their results are unexpected and significant (“Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”) and any unexpected results must be commensurate in scope with the claimed invention (MPEP §706.02). In the instant case the Applicant claims “A composition comprising a polymer conjugated to at least two immunomodulators.” and points to Figures that are alleged to include unexpected results. Figure 16A compares BEX to HA-BEX; Figure 16B compares VOR to HA-VOR; Figure 16C compares BEX:VOR at ratios of 1:1, 2:1, and 3:1; Figure 16 compares HA-BEX, HA-VOR and the combination HA-BEX + HA-VOR(2:1 ratio); Figure 17A-B include similar combinations of HA-BEX/HA-VOR; Figures 19A and 19B each include BEX compared to HA-BEX and VOR compared to HA-VOR, as well as the combination BEX:VOR(2:1) and HA-BEX:HA-VOR(2:1). Where HA is Hyaluronic acid, BEX is bexarotene, and VOR is vorinostat. The specification further discloses that: “50 kDa HA was selected as a backbone.” (p. 47, [00196], lines 4-5; p. 51, [00224], line 1). The examiner sees no result within the scope of claim 1 which requires “a polymer conjugated to at least two immunomodulators.” where “HA-BEX” is a polymer conjugated to an immunomodulator, and HA-VOR is a polymer conjugated to an immunomodulator. Where is the example of HA-BEX-VOR which is a polymer conjugated to two immunomodulators. Given the results pointed to by Applicant does not include “a polymer conjugated to at least two immunomodulators” the results cannot be relied upon to overcome the prima facie case of obviousness.
Conclusion
Claims 1, 3, 4, 6, 8-11, 15-17, 21-23, 25, 28 and 46 are pending and have been examined on the merits. Claims 29 and 30 are objected to (improper status identifiers); claims 10 and 11 are rejected under 35 U.S.C. 112(d); and claims 1, 3, 4, 6, 8-11, 15-17, 21-23, 25, 28 and 46 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619