Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Oct. 09, 2025. Claims 1, 3, 8-18, 20, 22, 27-30 and 38-50 are pending and are currently examined.
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
(Previous rejection- withdrawn) Claims 14-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
This rejection is withdrawn in view of the amendment file on Oct. 09, 2025.
Claim Rejections - 35 USC § 112 (Written Description)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(Previous rejection- withdrawn) Claims 1, 3, 8-20, 22, 27-30 and 38-41 and 43-48 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection is withdrawn in view of the amendment file on Oct. 09, 2025.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(Previous rejection- withdrawn) Claims 1, 3, 8-20, 22, 27-30 and 38-41 and 43-48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating AB1 mesothelioma and melanoma using a pharmaceutical composition comprising rMVTT and an antibody 1A8 that induces depletion of tumor- induced bone marrow myeloid-derived suppressor cells of PMN- MDSCs, does not reasonably provide enablement for a method of treating any cancer using an oncolytic MVTT. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
This rejection is withdrawn in view of the amendment file on Oct. 09, 2025.
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.
(Previous rejection- withdrawn) Claims 8-11, 14-17, 39-42, 46-47 and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (US 2020/0385758 A1, published on Dec. 10, 2020, claimed provisional application filed on Jan. 5, 2018) as applied to claims 1, 3, 12-13, 18-20, 22, 43-45 and 48 above and in view of Liu et al. (Nat Commun. 2017 Mar 27; 8:14754).
This rejection is withdrawn in view of the amendment file on Oct. 09, 2025.
(New Rejection-necessitated by amendment) Claims 1, 3, 9-22 and 39-50 are rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (US 2020/0385758 A1, published on Dec. 10, 2020, claimed provisional application filed on Jan. 5, 2018) in view of in view of Liu et al. (Nat Commun. 2017 Mar 27; 8:14754), Zhao et al. (Int Immunopharmacol. 2015 Jun;26(2):314-21) and Najjar et al. (Clin Cancer Res. 2017 May 1;23(9):2346-2355).
The amended base claim 1 is directed to a method of treating melanoma or mesothelioma in a subject, the method comprising administering to the subject:
(a) a pharmaceutical composition comprising an oncolytic virus, and
(b) a therapy that induces depletion of tumor-induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN-MDSCs), wherein the oncolytic virus is a vaccinia TianTan virus, wherein the vaccinia TianTan virus is modified to comprise a deletion of one or more genes that are necessary for replication selected from the group consisting of MIL, M2L, K1L, and K2L, wherein the therapy that induces depletion of tumor-induced PMN-MDSCs specifically induces depletion of CXCR2+ tumor-induced PMN-MDSCs, and wherein the method is effective to treat or alleviate one or more symptoms of melanoma or mesothelioma in the subject.
The amended base claim 20 is directed to a pharmaceutical composition comprising an oncolytic viruses and a pharmaceutically acceptable carrier, wherein the oncolytic virus is a modified vaccinia TianTan viruses, wherein the vaccinia TianTan virus is modified to comprise a deletion of one or more genes that are necessary for replication selected from the group consisting of MIL, M2L, K1L, and K2L, and wherein the vaccinia TianTan virus is present in the pharmaceutical composition in an amount effective to treat or alleviate one or more symptoms of melanoma or mesothelioma in a subject.
The base claim 42 is directed to a system comprising: a first composition comprising an oncolytic virus and a pharmaceutically acceptable carrier, wherein the oncolytic virus is a vaccinia TianTan virus, wherein the vaccinia TianTan virus is modified to comprise a deletion of one or more genes that are necessary for replication selected from the group consisting of MIL, M2L, K1L, and K2L; and a second composition comprising a therapeutic agent that specifically induces depletion of tumor-induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN-MDSCs), and a pharmaceutically acceptable carrier.
The base claim 49 is directed to a method of generating an immune response to a tumor antigen in a subject comprising administering to the subject: (a) a first composition comprising an oncolytic virus and a pharmaceutically acceptable carrier, wherein the oncolytic virus is a vaccinia TianTan virus, wherein the vaccinia TianTan virus is modified to comprise a deletion of one or more genes that are necessary for replication selected from the group consisting of MIL,M2L, K1L, and K2L, and wherein the first composition is administered in an effective amount to recruit myeloid-derived suppressor cells of polymorphonuclear type (PMN-MDSCs) to a tumor site; and(b) a second composition comprising a therapeutic agent that specifically induces depletion of tumor-induced myeloid-derived suppressor cells of polymorphonuclear type (PMN- MDSCs), and a pharmaceutically acceptable carrier, wherein administration of the first composition and the second composition is effective to activate dendritic cells and stimulate an immune response to the tumor antigen in the subject, and wherein the administering occurs multiple times over a period of two to fourteen days.
Bell et al. discloses using of Copenhagen-derived Vaccinia virus vectors for the treatment of cancer including melanoma. In particular, the disclosure is based in part on the surprisingly enhanced oncolytic activity, spread of infection, and safety results engendered when a vaccinia virus is genetically modified to contain deletions in some or all, of the following genes: C2L, ClL, NIL, N2L, MIL, M2L, KIL, K2L, K3L, K4L, K5L, K6L, K7R, FIL, F2L, F3L…and B9R (see [0006] [0008] and [0021]), and also teaches a method of administering to a subject (e.g., a patient) a pharmaceutical composition containing a recombinant vaccinia virus vector described herein to treat cancer such as melanoma and mesothelioma (See e.g., [0159], [0187]). Bell et al. further teaches that while it is possible for the recombinant vaccinia virus vector of the invention to be administered alone, it may also be administered as a pharmaceutical formulation in combination with excipients, carriers, and optionally, additional therapeutic agents (See [0160]). Among the vaccinia viruses used for cancer treatment, Five Vaccinia wild type strains (Copenhagen, TianTan, Lister, Wyeth, and Western Reserve) are studied in Bell’s invention (See [0165]). In Fig. 36, Bell et al. discloses the Tiantan virus as claimed (See Fig. 36 and below), where "5P3P", “3P” and “5P” are deletions including MIL, M2L, K1L, and K2L (See Table 1 and below; [0146]).
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Accordingly, Bell et al. teaches a method to administer a pharmaceutical composition treating melanoma, where the composition comprises the modified Vaccinia virus such as TianTan virus with a deletion selected from the group consisting of M1L, M2L, K1L, and K2L. Although Bell et al. uses the modified Copenhagen strain of vaccinia virus as an example virus to treat cancer in the invention, it would be obvious for one of ordinary skill in the art to treat cancer using the modified Tiantan virus as well. One of ordinary skill in the art would be motivated to do so given that Bell et. al made constructs of Tiantan (and other viruses) with 5p, 3p and 5p3p deletions and demonstrated that the modified TianTan viruses have cytotoxic effects in HeLa cells (See Fig. 36 and below). There would be a reasonable expectation of success given the findings for the Copenhagen strain and given the teachings and finds regarding the TianTan virus (see Fig. 36). Further, given the teachings of Bell et al., one of ordinary skill in the art is motivated to try any of the modified viruses.
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However, Bell et al. does not teach claim 1 (b) at “a therapy that induces depletion of tumor-induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN-MDSCs)”.
Liu et al. describes a rational combination of oncolytic vaccinia virus and PD-L1 blockade that works synergistically to enhance therapeutic efficacy. Liu et al. teaches that both anti-PD1/PD-L1 therapy and oncolytic virotherapy have demonstrated promise, yet have exhibited efficacy in only a small fraction of cancer patients. Furthermore, the treatment reduces the virus-induced PD-L1+ DC, MDSC, TAM and Treg, as well as co-inhibitory molecules-double-positive, severely exhausted PD-1+ CD8+ T cells, leading to reduced tumour burden and improved survival. This combinatorial therapy may be applicable to a much wider population of cancer patients (See Abstract). Anti-mouse PD-L1 Ab (clone 10F.9G2) (See page 9, right column, paragraphs 2 & 3), but also teaches a
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regimen for treating a Rodent tumor (See page 10, left column, paragraph 3; Page 10, Figure 8; Figure 8C above, modified by the examiner). Liu et al. teaches that the dual therapy enhances beneficial repertoire of anti-tumor T cells (See page 4, left column, paragraph 3), and demonstrates that that an oncolytic vaccinia virus markedly upregulates PD-L1 in the TME, and thereby synergizes with a-PD-L1 treatment leading to over 40% cures in aggressive models of peritoneal carcinomatosis. Multiple histologies tested demonstrated similar upregulation of PD-L1 in response to vaccinia virus infection (See page 9, right column, paragraph 1).
Accordingly, Liu et al. teaches a method of treating a cancer including the melanoma in a subject (Mice), comprising administering to the subject a combination of an oncolytic virus, vaccinia virus, and a therapy (anti-PD-L1 antibody) that induces depletion of tumor- induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN- MDSCs, also known as G-MDSCs).
Based on the description above, Bell and Liu teach a method of treating melanoma claimed by the base claim 1 at both (a) and (b); Teach the base claim 20 at a pharmaceutical composition comprising an oncolytic virus and a pharmaceutically acceptable carrier (See [0149]); Teach the base claim 42 at a system comprising a first composition comprising an oncolytic virus and a pharmaceutically acceptable carrier (See [0181]); Teach the base claim 49 by teaching a combination of oncolytic vaccinia virus and PD-L1 for working synergistically to exert cytotoxicity to cancer cells, eliminate immunosuppressive cells (including MDSC, TAM, Treg and exhausted CD8+ T cells), and elicit more potent and sustained systemic anti-tumor immunity, thus achieving better therapeutic efficacy (See page 9, right column, paragraph 1).
As for the new specific limitation “CXCR2+ tumor-induced PMN-MDSCs”, Zhao et al. teaches that CXCR2 is essential for the recruitment of MDSCs to the tumor site (See page 319, right column, paragraph 3) and was most highly expressed in PMN-MDSCs (See page 319, right column, paragraph 2). Najjar et al. teaches anti-CXCR2 and anti-PD1 synergized to reduce tumor weight and enhanced CD4+ and CD8+ T cell infiltration in a Renca murine model, suggesting that CXCR2+ PMN-MDSC are important in reducing activity of anti-PD-1 antibody (See Abstract) and treating mice bearing Renca tumors with CXCR2 antagonist enhanced the efficacy of anti-PD-1 therapy (See page 8, paragraph 2).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine both teachings from Bell, Liu, Zhao and Najjar to arrive at the invention as claimed. One of skill in the art would have been motivated to use the combination therapy of the modified Tiantan virus and PD-L1 blockade for working synergistically to enhance therapeutic efficacy as described above, which can eliminate bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN- MDSCs) as claimed in the instant application. Also, one of skill in the art would have been motivated to study the depletion of the CXCR2+ PMN-MDSC and their roles in cancer treatment. There would have been a reasonable expectation of success based on these teachings to develop a method, a pharmaceutical composition or a system to treat melanoma by inducing a depletion of PMN-MDSCs and generating an immune response to a tumor antigen in a subject.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 3 and 22, Bell et al. teaches that the virus is replication competent (See [0175]).
Regarding claim 8, it requires that the method of claim 1, wherein the therapy that induces depletion of tumor-induced PMN-MDSCs is administered multiple times over a period of two to fourteen days. Liu et al. teaches a method of treating a cancer in a subject (Mice), comprising administering to the subject a combination of an oncolytic virus, vaccinia virus, and a therapy (anti-PD-L1 antibody) that induces depletion of tumor- induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN- MDSCs, also known as G-MDSCs) (See Figure 8, page 10). In Figure 8 C (See above), Liu teaches administering multiple times over a period of two to fourteen days.
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce Liu’s method of combination of vaccinia virus and PD-L1 blockade into Bell’s study to arrive at an invention as claimed. One of skill in the art would have been motivated to use the combination of the Bell’s virus and PD-L1 blockade to work synergistically to enhance therapeutic efficacy as described above, which can eliminate bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN- MDSCs) as claimed in the instant application. There would have been a reasonable expectation of success based on the teachings of Bell and Liu to develop a method to treat melanoma by inducing a depletion of PMN-MDSCs to treat or alleviate one or more symptoms of melanoma in the subject.
Regarding claims 9-11 and 50, based on the description above, although Bell et al. does not teach a therapy that induces depletion of tumor-induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN-MDSCs), Liu et al. teaches that the grouped mice were intraperitoneally injected with anti-PD-L1 Ab (clone 10F.9G2, 200 mg per injection), VV plus anti-PD-L1 Ab, or PBS (100 ml) per mouse, respectively. In some experiments, anti-CD8 Ab at 250 mg per injection (clone 53-6.7; Bio X Cell), anti-CD4 Ab (clone GK1.5, Bio X Cell; 150 mg per injection), or anti-IFN-g Ab (clone XMG1.2, Bio X Cell; 200 mg per injection) were intraperitoneally injected into mic (See page 10, left column, paragraph 4), where anti-PD-L1 antibody is a PMN-MDSC/G-MDSC depleting antibody (See Figure 5-d, page 7 and below). In Figure 5-C, Liu et al. teaches that the PD-L1+G-MDSC is defined as Ly6G+, which is also known as the lymphocyte antigen 6 complex locus G6D (LY6G6D), and further teaches that the antibody targeting Ly6G+ is clone 1A8 (See page 10, right column, paragraph 2).
It would be obvious for one of ordinary skill in the art to apply the PD-L1 Ab into Bell’s invention to enhance the therapeutic efficacy. One of skill in the art would have been motivated to use the combination therapy based on the advantages described above. There would have been a reasonable expectation of success based on the teachings of Bell and Liu.
Regarding claim 12, Bell et al. teaches the pharmaceutical composition may be administered to the subject in one or more doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or more) per a specified time interval (e.g., weekly, daily, or hourly).
Regarding claim 13, Bell et al. teaches that the route of administration may vary with the location and nature of the cancer, and may include, e.g., intradermal, transdermal, parenteral, intravenous, intramuscular, intranasal, subcutaneous and etc. (See [0150]).
Regarding claims 14-17, Liu et al. teaches that the PD-L1 is the additional anti-cancer therapy to the subject as claimed in claim 14, and PD-L1 is a check-point inhibitor as claimed in claim 15 and 16. Liu et al. also teaches the inhibitor of PD-L1 is an antibody that bind to PD-L1 as claimed in claim 17 (See page 9, right column, paragraph 1). Although Bell et al. does not teach the additional anti-cancer therapies to the subject, it would be obvious for one of ordinary skill in the art to introduce the PD-L1 therapy into Bell’s invention, and the result for the dual cancer treatments would be predictable.
Further, the courts have said: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose . . . . [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.) See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). (See MPEP §2144.06(I) – Combining Equivalents Known For The Same Purpose). In this case, applicant is combining two known cancer treatments to form a third composition to be used for the very same purpose. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Regarding claim 18, Bell et al. teaches that in some embodiments, the mammalian patient is a human patient (See [0057]).
Regarding claim 39, Liu et al. teaches that the antibody against Ly6G is 1A8 (See page 10, right column, paragraph 2).
Regarding claims 40 and 41, they require that the oncolytic virus and therapy that induces depletion of tumor-induced PMN-MDSCs are administered before or simultaneously or consecutively. Liu et al. teaches that they tested whether different time points for the reagent administration could impact the therapeutic effect elicited by the combination therapy. They fixed the first treatment time at day 5 post tumor cell injection and applied treatment using different timing schemes: (1) a-PD-L1 Ab followed in 2 days by VV treatment; (2) VV treatment followed in 2 days by a-PD-L1 Ab therapy; and (3) simultaneous administration of both a-PD-L1 Ab and VV. The survival data showed that the simultaneous administration achieved the best therapeutic effect (See page 3, left column, paragraph 2 and right column, paragraph 1).
It would be obvious for one of ordinary skill in the art to apply the administration regimen into Bell’s invention to enhance the therapeutic efficacy. One of skill in the art would have been motivated to use the combination therapy based on the advantages described above. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated and commonly used as evidenced by the prior art teachings.
Regarding claims 43, Bell et al. teaches that administration of the vaccinia virus to a patient having cancer induce oncolysis, kill cells, inhibit growth, inhibit metastases, decrease tumor size and otherwise reverse or reduce the malignant phenotype of tumor cells (See [0150]).
Reducing claims 44-45 and 48, Bell et al. teaches that Nude CD-1 (Crl:CDl-Foxnlnu) mice were seeded with HT-29 human colon cancer xenograft (5e6 cells). Once subcutaneous tumors have established an approximate 5 mmx5 mm size, mice were treated three times (dashed lines) 24h apart with 1x 10^7 PFU of either vaccinia virus intravenously. Mice were measured approximately every other day for tumor size and weight loss (see FIG. 14) (See [0179]), where the tumor size (cubic millimeters (mm³)) has over 50% reduction at day 16 with the administration. Bell et al. also teaches Unit dose of the present invention may conveniently be described in terms of plaque forming units (pfu) for a viral construct. Unit doses may range from 1x 10^6, 1x10^7… to 1x 10^13 pfu and higher (See [0154]).
Regarding claims 46-47, Liu et al. teaches that the PD-1 is injected intratumorally (See e.g. page 2, right column, paragraph 4). Liu et al. also teaches that a-PD-L1 Ab, 200ug (0.2mg ) per 100 ml, was injected every 2 days for a total of four times (See Figure 4, page 5). Although Liu’s dose does not use the same unit mg/kg as claimed, it is a common knowledge in the art that the unit can be covert to mg/kg, and it would be obvious for one of ordinary skill in the art to optimize the unit based on the subject’s body weight and the result would be predictable to reach a dose ranging from 0.01 mg/kg to 200 mg/kg as claimed.
It would be obvious for one of ordinary skill in the art to apply the administration dose into Bell’s invention based on the subject’s body weight to reach a better treatment result for enhancing the therapeutic efficacy. One of skill in the art would have been motivated to use the combination therapy based on the advantages described above. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated and commonly used as evidenced by the prior art teachings.
(New Rejection-necessitated by amendment) Claims 27-30 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (US 2020/0385758 A1, published on Dec. 10, 2020, claimed provisional application filed on Jan. 5, 2018) in view of in view of Liu et al. (Nat Commun. 2017 Mar 27; 8:14754), Zhao et al. (Int Immunopharmacol. 2015 Jun;26(2):314-21) and Najjar et al. (Clin Cancer Res. 2017 May 1;23(9):2346-2355) as applied to claims 1, 3, 9-22 and 39-50 above and further in view of Simpson et al. (Oncolytic Virother. 2016 Jan 6;5:1-13) and Ma et al. (Journal of Leukocyte Biology, Volume 99, June 2016, pages 794-706).
Claims 27-30, depend on claim 20, require that the pharmaceutical composition/method that induces depletion of tumor-induced PMN-MDSCs specifically induces depletion of tumor-induced PMN-MDSCs without affecting tumor-induced M-MDSCs, and the composition includes other antibody and antitumor compounds.
Based on the teaching of Bell et al. described above, Bell et al. teaches a method for administrating a subject a pharmaceutical composition comprising the modified vaccinia TianTan virus for cancer treatment, and teaches a system comprising a first composition comprising an oncolytic virus and a pharmaceutically acceptable carrier, wherein the oncolytic virus is a vaccinia TianTan virus (See e.g.[0181], [0158]). Also, Bell et al. teaches a method of generating an immune response to a tumor antigen in a subject comprising administering to the subject with the modified Tiantan virus because Bell et al. discloses that the ability of modified Tiantan virus for inducing an anti-tumor immune response (See e.g. [0174]). Liu teaches a method to further comprise administrating to the subject a therapy that induces depletion of tumor-induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN-MDSCs) and further generate an immune response.
Accordingly, both Bell and Liu teach a method of treating a cancer in mice using the combination of the modified Tiantan and a therapy (anti-PD-L1) that induces depletion of tumor- induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN- MDSCs, also known as G-MDSCs). However, they are silent on teaching the current claims regarding a composition of antibody is Ly6G and its antibody 1A8, inducing PMN-MDSC without affecting M-MDSC and a selection of the compound that induces depletion of tumor-induced PMN-MDSCs.
Simpson et al. reviews the cancer immunotherapy via combining oncolytic virotherapy with chemotherapy. It teaches that scientists have investigated many ways to increase the immunogenic effects seen with OVs (oncolytic viruses), but it is becoming clearer that one way to complement the ICD (immunogenic cell-death) mechanisms and the immunomodulatory effects (Table 1) seen with either therapy alone is to combine both OVs and chemotherapy to achieve either at least an additive or (even better) a synergistic result (See page 4, right column, paragraph 1). Simpson et al discloses that In vivo studies with either HSV or reovirus in combination with gemcitabine improved the survival compared with either treatment alone. These therapeutic combinations also demonstrate that gemcitabine limits the reovirus/HSV-1-induced accumulation of MDSCs in the tumor microenvironment (See page 5, right column, paragraph 2).
Ma et al. describes a “Invisible” MDSC in tumor bearing individuals after antibody depletion. Ma et al. teaches that Murine MDSCs can be divided into 2 major subgroups: granulocytic CD11b+Ly6G+Ly6Clow (G-MDSC/ PMN-MDSCs) and monocytic CD11b+Ly6G2Ly6Chigh (M-MDSC) (See page 794, left column, paragraph 1). Ma et al. discloses that a widely used method to study the in vivo function of the CD11b+Ly6G+ cells is antibody-mediated depletion of these cells. Two different antibodies are commonly used for this approach: anti-Ly6G (clone 1A8) and anti-Gr1 (clone RB6-8C5). Several investigators have used RB6-8C5 for the depletion of MDSCs. Targeted depletion of G-MDSC but not M-MDSC has been achieved using 1A8 in KPC mice bearing spontaneous pancreatic ductal adenocarcinoma (See page 794, Middle column, paragraph 1).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine all teachings from Bell, Liu, Simpson and Ma to arrive at an invention as claimed. Because anti-Ly6G (1A8) can deplete G-MDSC but not M-MDSC and the Gemcitabine of Simpson can also Decreases MDSCs. Therefore, one of skill in the art would have been motivated to do so to introduce gemcitabine of Simpson and the anti- Ly6G antibody (1A8) of Ma into Liu’s composition, and there would be a reasonable expectation of success to develop a composition comprising an oncolytic virus and 1A8 that induces depletion of PMN-MDSCs and includes a pharmaceutically acceptable carrier as claimed in the instant application.
Regarding claim 38, it is directed to a method of claim 8 and claim 1, wherein the therapy specifically induces depletion of tumor-induced PMN-MDSCs without affecting tumor-induced M-MDSCs.
Both Bell and Liu teach a method of treating a cancer in subject using the combination of modified Tiantan virus and a therapy (anti-PD-L1) that induces depletion of tumor- induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN- MDSCs, also known as G-MDSCs). Liu et al. teaches that using Ly6G antibody 1A8 to induce the depletion of tumor-induced PMN-MDSCs (See page 3, right column paragraph 3). Based on the evidence of Ma, antibody 1A8 does not affect the tumor-induced M-MDSCs. Ma et al. describes a “Invisible” MDSC in tumor bearing individuals after antibody depletion. Ma et al. teaches that Murine MDSCs can be divided into 2 major subgroups: granulocytic CD11b+Ly6G+Ly6Clow (G-MDSC/ PMN-MDSCs) and monocytic CD11b+Ly6G-Ly6Chigh (M-MDSC) (See page 794, left column, paragraph 1). Ma et al. discloses that a widely used method to study the in vivo function of the CD11b+Ly6G+ cells is antibody-mediated depletion of these cells. Two different antibodies are commonly used for this approach: anti-Ly6G (clone 1A8) and anti-Gr1 (clone RB6-8C5). Several investigators have used RB6-8C5 for the depletion of MDSCs. Targeted depletion of G-MDSC but not M-MDSC has been achieved using 1A8 in KPC mice bearing spontaneous pancreatic ductal adenocarcinoma (See page 794, Middle column, paragraph 1). Therefore, 1A8 antibody induced the PMN-MDSCs in Liu does not affect the M-MDSC. Further, because the prior art method has the same steps as claim 8, the method of the prior art will produce the same effects to induce depletion of tumor-induced PMN-MDSCs without affecting tumor-induced M-MDSCs as claim 38.
Responses to Applicant’s Remarks
Applicant’s arguments filed on Oct. 09, 2025 has been received and fully considered.
Regarding the Rejection Under 35 U.S.C. § 112(b), applicant’s amendment is considered. The rejection is withdrawn.
Regarding the Rejections Under 35 U.S.C. § 112(a), Applicant’s arguments are considered. The rejections are withdrawn.
Regarding the rejection Under 35 U.S.C. § 103, Applicant’s arguments are not found persuasive. With a new rejection-necessitated by amendment is issued for claims 1, 3, 12-13, 18-20, 22, 43-45 and 48, the previous 103 rejections on claims 8-11, 14-17, 39-42, 46-47 and 49-50 are withdrawn and incorporated into the new rejection-necessitated by amendment on claims 3, 12-13, 18-20, 22, 43-45 and 48. The responses to the Applicant’s arguments are as follows:
1). Applicant argued that Bell does not describe or contemplate a therapy
that induces depletion of tumor-induced bone marrow myeloid-derived suppressor cells of polymorphonuclear type (PMN-MDSCs), let alone a method of use thereof for treating melanoma or mesothelioma in a subject (See Remarks, bridging pages 13-14).
The argument is not persuasive.
Although Bell does not describe or contemplate a therapy that induces depletion of PMN-MDSCs regarding the new amendment, Bell combined with the prior art references of Liu, Zhao and Najjar together teach the newly added limitations. Accordingly, a new rejection-necessitated by amendment is issued for the claims 1, 3, 12-13, 18-20, 22, 43-45 and 48.
2). Applicant argued the Tian Tan demonstrating poor replication based on the prior art Bell [0166]- [0167] and allegedly states that Bell's data explicitly teach away from selecting TianTan virus for further modification in an oncolytic context (See Remarks, page 15).
The argument is not persuasive.
First, Bell teaches that the Tiantan virus can be one of the oncolytic vaccinia viruses to be used for treating melanoma and mesothelioma.
Second, Bell does not teach that TianTan virus cannot be selected for further modification in an oncolytic context. Actually, it is common knowledge in the art that Tiantan virus is actively researched for its potential as an oncolytic agent. This can be evidenced by Deng’s study. Deng1 (Cancer Lett. 2016 Mar 28;372(2):251-7) teaches that VG9 (Tian Tan strain Guang9)-GMCSF induces strong tumoricidal activity, providing a potential therapeutic strategy for combating cancer (See Abstract). Therefore, one of skill in the art would have been motivated to select the TianTan virus as well.
Third, the Office does not have the facilities and resources to provide the factual evidence needed in order to establish that the TianTan virus can be one of the oncolytic vaccinia viruses to be selected for further modification in an oncolytic context. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed invention is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
3). Applicant argued that Bell's modified Copenhagen virus requires numerous deletions, spanning both terminal regions, to achieve the reported tumor-reducing activity, and Applicant has demonstrated that deletion of only four genes, MlL, M2L, KlL, and K2L, in the Tian Tan vaccinia strain is sufficient to increase oncolysis of mesothelioma (AB1) and melanoma (B16F10) cancer cells (See Remark, page 17).
The argument is not persuasive.
First, the instant application does not limit a specific method to be used for making the deletions.
Second, the Table 1 of Bell listed the possible genes can be deleted in the Vaccinia virus including Tiantan virus. One of skilled in the art can selected the claimed four genes, M1L, M2L, KlL, and K2L based on the research goal because Bell teaches that in another aspect, the invention features a nucleic acid that includes a recombinant vaccinia virus genome, wherein the recombinant vaccinia virus genome has a deletion of at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 genes selected from the group consisting of C2L, ClL, NIL, N2L, MIL, M2L, KIL, K2L, K3L, K4L, K5L, K6L, K7R, FIL, F2L, F3L (See [0008]), which the deletion is selectable. In addition, there are prior arts for specifically teaching the four deletions in the Tiantan virus. This can be evidenced by Zhu’s study. Zhu2 teaches that a modified VTT (MVTT2-GFP) was constructed by replacing the viral M1L-K2L genes with a GFP gene for generating an attenuated vaccinia Tian Tan vaccine vector (See Abstract) and this virus can be developed further to become a live vaccine vector for infectious pathogens or tumors (See page 24, right column, paragraph 2). Thus, one of ordinary skill in the art reading Bell and Zhu would have selected the TianTan strain for further modifications. Because the structural of Zhu is identical to the claimed TianTan virus structures, a similar function on antitumor efficacy should be achieved.
4). Applicant argued the Bell's oncolytic Copenhagen vaccinia virus is engineered to have extensive gene deletions to achieve selective replication and oncolytic efficacy in specific human cancer cells. The therapeutic principle underlying Bell's construct is attenuation through gene deletion, not immune activation through cytokine expression.
The argument is not persuasive.
First, the instant application does not require the immune activation is though cytokine expression.
Second, Bell’s deletion is based on a selection. Bell teaches that the present disclosure describes the use of Copenhagen-derived Vaccinia virus vectors for the treatment of cancer. In particular, the disclosure is based in part on the surprisingly enhanced oncolytic activity, spread of infection, and safety results engendered when a vaccinia virus is genetically modified to contain deletions in some or all, of the following genes: C2L, ClL, NIL, N2L, MIL, M2L, KIL, K2L, K3L, K4L, K5L, K6L, K7R, FIL, F2L, F3L, B14R, B15R, B16R, B17L, B18R, B19R, B20R, KORF A, K ORF B, B ORF E, B ORF F, B ORF G, B21R, B22R, B23R, B24R, B25R, B26R, B27R, B28R, and B29R (See [0004]). Plus, the Zhu’s study teaches making a TianTan virus with the claimed four deletions.
5). Applicant argued the vvDD-CXCL11 (VV) used in Liu et al. and alleged that the therapeutic mechanism in Liu therefore depends entirely on the addition of the CXCL11 transgene to induce PD-L1 expression and sensitize tumors to anti-PD-L1 therapy. Without this insertion, Liu's anti-PD-L1 antibody is ineffective (See Remarks, pages 19-22).
The argument is not persuasive.
First, the instant claims do not limit if the vaccinia TianTan virus has insertion or not. Therefore, the application does not limit if the Tiantan virus is inserted with CXCL11 or not.
Second, Liu teaches that “because vvDD-CXCL11 has previously been demonstrated to be superior to vvDD by attracting an increased number of effector T cells, we have used this virus (short-named as VV in the figures) in the remaining experiments. It should be noted, however, that direct comparisons between vvDD and VV when combined with a-PD-L1 Ab did demonstrate only a trend of better, yet not statistically significant difference in therapeutic efficacy for the CXCL11 virus” (See page 3, left column, paragraph 1), which indicates the CXCL11 may not as “insertion of CXCLll is essential for recruiting T cells” as alleged by the applicant’s argument (See page 19, paragraph 2). Furthermore, the Figs. 2A-2B of Liu teaches PD-L1 being elevated in cancer tissue post vvDD treatment in vivo, where there is no CXCL11 insertion in the vvDD.
Third, some earlier studies have already shown the possibility of the oncolytic vaccinia virus for inducing the depletion of PMN-MDSCs. For example, Kilinc (J Transl Med. 2016 Dec 20;14(1):340) teaches that PMN-MDSCs were the main producer of NO through iNOS and NO provided a beneficial antitumor effect, The results strongly support an important novel role for VACV infection in the tumor microenvironment. VACV convert tumor-promoting MDSCs into tumor-killing cells by inducing higher NO production (See Conclusions, page 1).
6). Applicant’s arguments on claims 27-30 and 38 are not found persuasive. The prior art references of Simpson and Ma are used for teaching the specific limitation by supporting the teachings of Bell and Liu. It is applicable for the combination to teach the compound that induces depletion of tumor-induced PMN-MDSCs specifically induces depletion of tumor-induced PMN-MDSCs without affecting tumor-induced M-MDSCs.
Conclusion
No claims are allowed.
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 extension fee 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 date of this final action.
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/RUIXUE WANG/Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/Primary Examiner, Art Unit 1672
1 Deng is cited solely to respond to applicant’s argument and not to reject any claim.
2 Zhu is cited solely to respond to applicant’s argument and not to reject any claim.