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 March 16, 2026. Claims 1, 2, 9, 14-18, and 22-25 are pending and are currently examined.
Claim Rejections - 35 USC § 112
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(Previous rejection- withdrawn) Claims 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and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This rejection is withdrawn in view of the amendment filed on March 16, 2026.
(New) Claims 1-2 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.
The amended base claim 1 recites a term “configured” that renders the claims indefinite. It is not clear how the pharmaceutical composition is “configured” to be administered at a specific dose and pfu.
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 of this title, 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-maintained) Claims 1, 2, 9 and 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Evans et al. (US 8679509 B2, patented on Mar. 25, 2014) as evidenced by Thorne et al. (CA3070146A1, published on Jan. 25, 2018) in view of McCart et al. (US 7208313 B2, patented on Apr. 24, 2007), Boucher et al. (Gene Ther. 2002 Aug;9(15):1023-30.), Panicali et al. (Proc Natl Acad Sci U S A. 1982 Aug;79(16):4927-31) and Mackett et al. (Proc Natl Acad Sci U S A. 1982 Dec;79(23):7415-9).
The amended base claim 1 is directed to a pharmaceutical composition
an oncolytic virus;
hydroxyurea; and
a physiologically acceptable carrier, an excipient, and/or a diluent,
wherein the oncolytic virus is a recombinant vaccinia virus with modifications with respect to a wild-type vaccinia virus, wherein the modifications comprise a deletion of thymidine kinase gene and an insertion of herpes simplex virus type 1 thymidine kinase gene.
wherein the pharmaceutical composition comprises the oncolytic virus in an amount of 1x10^5 pfu to 1x10^10 pf and the hydroxyurea in an amount configured to be administered at a dose of 10 mg/kg to 90 mg/kg.
The amended base claim 9 is directed to a method for treating cancer in a subject in need thereof consisting of:
administering, to the subject, a first composition consisting of an oncolytic virus and a physiologically acceptable carrier, an excipient, and/or a diluent; and a second composition consisting of hydroxyurea and a physiologically acceptable carrier, an excipient, and/or a diluent,
wherein the oncolytic virus is a recombinant vaccinia virus with modifications with respect to a wild-type vaccinia virus, wherein the modifications comprise a deletion of thymidine kinase gene and an insertion of herpes simplex virus type 1 thymidine kinase gene.
wherein the oncolytic virus-containing composition is administered at a dose of 1x 10^5 pfu to 1x10^10 pfu, and wherein the hydroxyurea-containing composition is administered at a dose of 10 mg/kg/day to 90 mg/kg/day.
Evans et al. describes the oncolytic viruses and methods for treating neoplastic disorders. Evans et al. teaches that their invention provides mutant ribonucleotide reductase strains of poxviruses including for example vaccinia viruses. The disclosure also provides methods and for the use of these mutant ribonucleotide reductase strains of vaccinia viruses in oncolytic virotherapy (See Abstract). Evans et al. also discloses that a composition comprising the isolated optionally recombinant virus disclosed herein and a pharmaceutically acceptable diluent or carrier. In an embodiment, the composition further comprises hydroxyurea, gemcitabine and/or a nucleoside analog (See Column 3, lines 18-22), where in an embodiment, the recombinant virus is an oncolytic virus and the one of the oncolytic viruses is vaccinia viruses, and the neoplastic disorders is cancer (See Column 3, lines 28-41). Evans et al. also discloses that in a further aspect, the disclosure provides a method of treating a neoplastic disorder comprisingisolated or recombinant virus or composition including hydroxyurea disclosed herein to a subject in need thereof. In an embodiment, the virus is an oncolytic virus. In another embodiment, the neoplastic disorder is cancer. In yet another embodiment, the cancer is selected from breast cancer, lung cancer, colorectal cancer, hepatic cancer such as hepatocellular carcinoma, pancreatic cancer, skin cancer such as melanoma…cancer. In an embodiment, the cancer is a carcinoma. In another embodiment, the cancer is an epithelioid carcinoma (See Column 3, lines 28-41). Evans et al. also teaches that Vaccinia viruses for example are useful as oncolytic agents. Vaccinia viruses can infect a wide range of human tissues and there is a large body of knowledge about its biology and extensive experience with it clinically as part of the smallpox vaccination program. Accordingly, in a preferred embodiment, the poxvirus is a vaccinia virus (See Column 17, lines 34-44).
Evan et al. also teaches that the disclosure provides a composition comprising the isolated optionally recombinant virus disclosed herein and a pharmaceutically acceptable diluent or carrier. In an embodiment, the composition further comprises hydroxyurea, gemcitabine and/or a nucleoside analog. (See column 3, lines 18-22), which indicates that both vaccinia virus and hydroxyurea are with a pharmaceutically acceptable diluent or carrier during the administration. Evans et al. also teaches that in another embodiment, the subject is also administered hydroxyurea wherein the hydroxyurea is administered prior to, contemporaneously with, or following administration of the isolated or recombinant virus or composition of the disclosure (See e.g., column 3, lines 60-67), where the “following administration of the isolated or recombinant virus or composition” indicates that the sequential administration can be performed by using oncolytic virus composition as the first composition and use the hydroxyurea composition as a second composition.
As for the amended consisting of “physiologically acceptable carrier, an excipient, and/or a diluent”, it should be considered as comparable as pharmaceutical acceptable carrier, an excipient, and/or a diluent as Evans taught. As an evidence, Thorne et al. teaches that the terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" can refer to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material (See [0060]).
Based on the description above, Evans teaches the amended base claim 1 at “an oncolytic virus”, “hydroxyurea” and “a physiologically acceptable carrier, an excipient, and/or a diluent”, and also teaches the amended base claim 9 by disclosing a method for treating cancer by administrating the first composition of vaccinia virus and the second composition of hydroxyurea.
As for the thymidine kinase gene deletion as claimed, Evans et al. teaches that in an embodiment, the isolated or recombinant virus further comprises a functionally inactivated R1 gene, thymidine kinase gene and/or vaccinia virus growth factor gene (See column 3, lines 14-16). Evans et al. also teaches that VACV encodes a thymidine kinase (J2R) involved in the alternative and complementary salvage pathway (See Example 1), therefore, the J2R deletion is actually the thymidine kinase gene deletion. Evans et al. discloses that it is also demonstrated herein that vaccinia viruses comprising a functionally inactivated R2 gene, alone or in combination with functionally inactivated R1 and/or J2R genes, preferentially replicate and induce death in cancer cells having increased RR levels. Such viruses are useful for treating neoplastic disorders (See column 2, lines 7-15). The table 1 of Evans et al. summarize the VACV strains (vaccinia virus) with the J2R/ thymidine kinase gene deletion (See the table 1 in the following).
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As for the required limitation of “…thymidine kinase gene is deleted with respect to a wild-type vaccinia virus…”, Evans et al. teaches that the functionally inactivated J2R gene comprises a disruption in the J2R ORF such that an insertion is made in between nucleotides 81001 and 81002 in the WR genome (See column 18, lines 40-47), where the WR genome is a vaccinia virus strain selected from GenBank accession: NC 006998 (See column 2, lines 58-63). The GenBank accession: NC 006998 shows that the WR genome is from the Western Reserve (WR) strain that is a wild-type vaccinia virus (VACV).
Accordingly, Evans et al. teaches the base claims 1 and 9 by using a pharmaceutical composition for cancer treatments, where the pharmaceutical composition consist of a recommended oncolytic virus of vaccinia virus with J2R/thymidine kinase gene deletion and hydroxyurea, where the method of treating cancer comprises administering an effective amount of the oncolytic virus/vaccina virus and hydroxyurea to a subject in need, and the vaccinia virus and hydroxyurea can be administered in a sequential order.
It is noted that Evans et al. performs the thymidine kinase gene deletion from the wild type WR strain to make the construct ΔJ2R alone strain. They evaluate its viral titer and plaque size with other mutant strains as disclosed in Table 1 above. Although Evans et al. does not include the ΔJ2R strain alone in their susceptibility Table 2 of VACV RR mutant strains to cidofovir (CDV), hydroxyurea (HU) and phosphonoacetic acid (PAA) and in the survivors’ experiments (See Table 2, column 37; Figure 10), it would be obvious for one of ordinary skill in the art to set up experiment to test the function of the combination of ΔJ2R strain and hydroxyurea in cancer treatment if needed. Furthermore, the ΔJ2R of Evan teaches a comparable vaccinia virus strain structure compared to the vaccinia virus with thymidine kinase gene deletion as claimed in base claims 1 and 9, a similar function should be achieved for cancer treatment through routine experimental optimization.
However, Evans et al. is silent on the insertion of the herpes simplex virus type 1 thymidine kinase (TK) gene for constructing the recombinant vaccinia virus as claimed in the amended claims.
McCart et al. teaches that Herpes Simplex Virus 1 (HSV-1) thymidine kinase (TK) is a widely used suicide gene in cancer therapy. By introducing the HSV-1 TK gene into tumor cells, they become sensitive to GCV. When GCV is administered, the HSV-1 TK enzyme converts it into a toxic form that disrupts tumor cell DNA and leads to cell death. Many strategies for delivering the HSV-TK gene have been employed including liposomal transfections, retroviral transductions, and adenoviral infections. The vaccinia virus of McCart’s invention represents an additional method of delivering the gene (HSV-TK), where the vaccinia virus vector here is negative thymidine kinase virus (See column 1, lines 15-26). One advantage of this system is that only dividing cells are affected so systemic toxicity is minimal. Another advantage is that GCV has been shown to be safe in humans and is readily available (See column 8, lines 36-54). McCart et al. also discloses the evidence that the HSV-TK gene is the most widely used suicide gene, which has been inserted into different oncolytic virus backbones as the follows: 1). In vitro treatment of glioma cells with a non-replicating adenovirus carrying HSV-TK (See column 8, lines 55-65). 2). In vivo treatment of subcutaneous sarcomas in BALB/c mice by retrovirally transduced HSV-TK gene. 3). Inhibition hepatic metastases by IP injection of retrovirus expressing HSV-TK. 4). Non-replicating, recombinant adenovirus carrying the HSV-TK gene has been used in many tumor models (See column 9, lines 1-26). McCart et al also referred a reference studying a Replication Competent Recombinant Vaccinia Vector Expressing HSV-TK for the Treatment of Tumors in Vivo (See page 12, left column). Accordingly, McCart et al. teaches the antitumor effect of HSV-TK gene and discloses that HSV-TK gene is the most widely used suicide gene, which has been inserted into different virus for cancer treatment, where the virus include the vaccina virus and the vaccina virus McCart taught lacks the TK gene with negative thymidine kinase phenotype.
Boucher et al, teaches that hydroxyurea significantly enhances tumor growth delay in vivo with herpes simplex virus thymidine kinase/ganciclovir gene therapy (See Title). This teaching provides a motivation to combine the HSV TK with the hydroxyurea together for cancer treatment.
In addition, Panicali et al. and Mackett et al. teaches a method for inserting the HSV-TK gene into the TK-gene deleted vaccinia virus.
Panicali et al. teaches constructing recombinant vaccinia viruses containing the thymidine kinase gene from herpes simplex virus. The gene was inserted into the genome of a variant of vaccinia virus that had undergone spontaneous deletion as well as into the 120-megadalton genome of the large prototypic vaccinia variant (See Abstract), where the constructs vP3 and vP4 containing the HSV TK in the TK-deleted S variant vaccinia virus genome (See page 4930, right column, paragraph 2).
Mackett et al. teaches that they modified the Vaccinia Virus TK Gene by inserting a foreign DNA and be inactivated, and then the Herpesvirus TK Gene is inserted and expressed into the TK-deleted Vaccinia Virus Genome (See, page 7416, left column; page 7417).
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 the teachings of Evans, Thorne, McCart, Boucher, Panicali and Mackett to arrive at an invention as claimed. McCart teaches that the HSV-TK is a widely used suicide gene in cancer therapy and is the most widely used suicide gene that has been inserted into different virus including Vaccinia virus with backbone for cancer treatment. Boucher teaches the combined application of Hydroxyurea and HSV-TK can enhance cancer treatment, Panicali and Mackett teaches the feasibility and method of inserting the HSV-TK gene into the TK-gene deleted vaccinia virus. Therefore, one of skill in the art would have been motivated to set up an experiment to construct a recombinant vaccinia virus with TK-deletion and HSV-TK insertion, and further test its capability for cancer treatment with hydroxyurea as Evans and Boucher taught. 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.
As for the new limitation on “the pharmaceutical composition comprises the oncolytic virus in an amount of 1x10^5 pfu to 1x10^10 pf and the hydroxyurea in an amount configured to be administered at a dose of 10 mg/kg to 90 mg/kg”, it is related to a concentration in the claim. Although Evan et al. is silent on the doses of oncolytic virus and hydroxyurea, Thorne et al. teaches the oncolytic vaccinia virus can be administered at a dosage of 10^6 PFU/mL to about 10^8 PFU/mL (See [0024]), which teaches the dose range as claimed.
Boucher et al. teaches that the amount of hydroxyurea administered to a mice can be at 500, 1000 or 1500 mg/kg (See page 1026, left column, paragraph 2). At the same time, Evans et al. also teaches that the dosage administered will vary depending on the use and known factors such as the pharmacodynamic characteristics of the particular substance, and its mode and route of administration, age, health, and weight of the individual recipient, nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Dosage regime may be adjusted to provide the optimum therapeutic response. The term "subject" as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans (See Column 15, lines 1-24).
According to section 2144.05 of the MPEP, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). Based on the teaching of Evan, Thorne and Boucher, one of ordinary skills would be able to test for an optimal administration amount of vaccinia virus and hydroxyurea through routine experimentation. Therefore, the claimed dose of oncolytic virus and hydroxyurea for administration would have been obvious unless there is evidence showing that they produce unexpected results.
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 2 and 14, they require the pharmaceutical composition of the pharmaceutical composition of wherein the oncolytic virus and the hydroxyurea are contained in separate containers and administered simultaneously, sequentially, or in reverse order (claim 2) or wherein the hydroxyurea is administered at least once before, during, or after administration of the oncolytic virus (claim 14). Evans et al. teaches that in another embodiment, the subject is also administered hydroxyurea wherein the hydroxyurea is administered prior to, contemporaneously with, or following administration of the isolated or recombinant virus or composition of the disclosure (See Column 3, lines 60-67), and also discloses that as used herein, "contemporaneous administration" and "administered contemporaneously" means that two substances are administered to a subject such that they are both biologically active in the subject at thesubstance within 24 hours of administration of the other, if the pharmacokinetics are suitable (See Column 15, lines 12-24), which is obvious that the oncolytic virus and the hydroxyurea are contained in separate containers and it is also obvious that the hydroxyurea is administered at least once.
Regarding claims 15 and 16, they are directed to a method wherein the hydroxyurea-containing composition is administered once a day starting from 3 to 5 days before administration of the oncolytic virus, skipped on the day of the oncolytic virus administration, and administered once a day for 9 to 28 days starting from 24 hours after the administration of the oncolytic virus-containing composition (claim 15), and the oncolytic virus-containing composition is administered to the individual at intervals of 7 to 30 days (claim 16) respectively.
Evans et al. discloses the regimen of the schedules for administrating the pharmaceutical composition of oncolytic virus/vaccinia virus and hydroxyurea into the subject. It teaches that the isolated and/or recombinant viruses and the combined agents such as the hydroxyurea described herein may be administered at least once a week, from about one time per week to about once daily for a given treatment or the isolated or recombinant poxviruses and/or compositions described herein may be administered twice daily. As another example, the isolated or recombinant poxvirus/vaccina virus is administered once only, or for example every 3 weeks for 4 cycles (See Column 14, lines 50-57). Evans et al. also discloses that in another embodiment, the subject is also administered hydroxyurea wherein the hydroxyurea is administered prior to, contemporaneously with, or following administration of the isolated or recombinant virus or composition of the disclosure (See Column 20, lines 44-53). Therefore, Evans et al. teaches a similar administration schedule as claimed even though they are not identical. Nevertheless, Evans et al. teaches that the length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration, the activity of the isolated or recombinant poxviruses and/or compositions described herein, and/or a combination thereof. It will also be appreciated that the effective dosage used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required (See Column 14, lines 57-67), which indicates that the claimed administration courses can be modified based on the applied condition through routine experimental optimization unless there is an unexpected result under the claimed conditions.
Regarding claim 17, Evans et al. teaches that in another embodiment, the neoplastic disorder is cancer. In yet another embodiment, the cancer is selected from breast cancer, lung cancer, colorectal cancer, hepatic cancer such as hepatocellular carcinoma, pancreatic cancer, skin cancer such as melanoma, esophageal cancer, leukemia, ovarian cancer, head and neck cancer, gliomas and gastric cancer. In an embodiment, the cancer is a carcinoma. In another embodiment, the cancer is an epitheliod carcinoma (See Column 3, lines 28-40).
(Previous rejection-maintained) Claims 18 and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Evans et al. (US 8679509 B2, patented on Mar. 25, 2014) as evidenced by Thorne et al. (CA3070146A1, published on Jan. 25, 2018) in view of McCart et al. (US 7208313 B2, patented on Apr. 24, 2007), Boucher et al. (Gene Ther. 2002 Aug;9(15):1023-30.), Panicali et al. (Proc Natl Acad Sci U S A. 1982 Aug;79(16):4927-31) and Mackett et al. (Proc Natl Acad Sci U S A. 1982 Dec;79(23):7415-9) as applied to claims 1, 2, 9 and 14-17 above, and further in view of Heinemann et al. (Mol Ther. 2010 Dec;18(12):2085-93. Epub 2010 Sep 14) and Yu et al. (Mol Cancer. 2009 Jul 6; 8:45).
Claims 18 and 22-23 require that oncolytic virus-containing composition and the hydroxyurea are administered intratumorally or intraperitoneally.
Evans et al. teaches a method of using a pharmaceutical composition to treat cancers, where the pharmaceutical composition comprises an oncolytic virus/vaccina virus and hydroxyurea. However, it is silent on the administrating route as claimed.
Heinemann et al. describes the effect of cell cycle synchronization on tumor sensitivity to Reovirus oncolysis. It teaches a study on the potential for increased sensitivity of tumor cells to oncolytic reovirus by altering the normal cell cycle using clinically available pharmacological agents. It teaches that B16.F10 mouse melanoma cells were partially synchronized with hydroxyurea, thymidine, or by mitotic shake-off (See Abstract). It teaches that C57Bl/6 mice bearing subcutaneous B16.F10 flank tumor were treated with 8 mg hydroxyurea intraperitoneally followed 0, 6, 12, 18, or 24 hours later by a single intratumoral injection of 3 × 10^8 plaque-forming unit (pfu) reovirus (See Page 2087, left column, paragraph 1), where the administered dose of oncolytic virus and hydroxyurea is in the claimed range, and the administered route of oncolytic virus and hydroxyurea is same as claimed as well.
Yu et al. studies the oncolytic vaccinia therapy of squamous cell carcinoma. Yu et al. teaches that they examined the therapeutic effects of an attenuated, replication-competent vaccinia virus (GLV-1h68) as an oncolytic agent against a panel of six human head and neck SCC cell lines. A single injection of GLV-1h68 (5 × 10^6 pfu) intratumorally into MSKQLL2 xenografts in mice exhibited localized intratumorally luciferase activity peaking at days 2–4, with gradual resolution over 10 days and no evidence of spread to normal organs. Treated animals exhibited near-complete tumor regression over a 24-day period without any observed toxicity, while control animals demonstrated rapid tumor progression (See Abstract).
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 Evans, Heinemann and Yu to test different dosage with different administering route, and then develop a pharmaceutical composition and method to treat cancers using oncolytic virus and hydroxyurea as claimed in the instant application.
(Previous rejection-maintained) Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Evans et al. (US 8679509 B2, patented on Mar. 25, 2014) as evidenced by Thorne et al. (CA3070146A1, published on Jan. 25, 2018) in view of McCart et al. (US 7208313 B2, patented on Apr. 24, 2007), Boucher et al. (Gene Ther. 2002 Aug;9(15):1023-30.), Panicali et al. (Proc Natl Acad Sci U S A. 1982 Aug;79(16):4927-31) and Mackett et al. (Proc Natl Acad Sci U S A. 1982 Dec;79(23):7415-9) as applied to claims 1, 2, 9 and 14-17 above, and further in view of Lawson et al. (Expert Opin Biol Ther. 2012 Jul;12(7):891-903) and Vaha-Koskela et al. (Mol Ther Oncolytics. 2015 Jan 7; 1:14006).
Claim 24 requires the subject shows resistance to oncolytic virus alone treatment.
Evans et al. teaches a method of using a pharmaceutical composition to treat cancers, where the pharmaceutical composition comprises a vaccinia virus with thymidine kinase gene deletion and hydroxyurea. However, it is silent on the individual showing resistance to oncolytic virus alone treatment.
Lawson et al. reviews the oncolytic virotherapy for renal cell carcinoma and teaches that the known responsiveness of mRCC (metastatic renal cell carcinoma) to immunotherapy and the molecular aberrations characteristic of this disease make it an attractive malignancy for treatment with oncolytic viruses (OVs), as these agents are capable of usurping common oncogenic signaling pathways and generating anti-tumor immune responses (See Abstract). It discloses that in vivo barriers to oncolytic virotherapy: role of the RCC tumor microenviroment in mediating resistance to OVs by stating that effective oncolytic targeting and destruction of cancer cells by viruses relies on both their ability to selectively replicate and induce cell death, as well as priming of an anti-tumor immune response. However, the lack of success of OVs as cancer monotherapies in early clinical trials suggests that immune clearance of virus as well as other barriers to oncolytic virotherapy exist. Interestingly, the RCC-specific tumor microenvironment is characterized by OV-restrictive factors, which likely act to limit the therapeutic efficacy of these agents through suppression of anti-tumor immunity and prevention of effective intratumoral viral delivery (See page 897, right column, paragraph 2). Lawson et al. also teaches that it is likely that rationale combination therapies that overcome these microenvironmental barriers and augment the oncolytic and immunotherapeutic effects of these agents hold the greatest potential for future clinical use against RCC (See page 899, left column, paragraph 2).
Vähä-Koskela et al. describes a study on overcoming tumor resistance by heterologous adeno-poxvirus combination therapy. Vähä-Koskela et al. teaches that successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. They demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Their results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer (See Abstract). Vähä-Koskela et al. discloses that addition of vaccinia virus injections into the weekly adenovirus regimen caused a significant retardation of tumor growth compared to adenovirus alone (Figure 3a). Interestingly, the SKOV3Luc tumors seemed to eventually generate resistance also to vaccinia virus, which has not been reported before (See page 2, right column, paragraph 3).
Accordingly, Lawson teaches RCC tumor microenviroment in mediating resistance to oncolytic viruses and suggests a combination therapy to overcome the resistance to oncolytic virus alone treatment. Vähä-Koskela teaches that a tumors cell can eventually generate resistance to vaccinia virus. 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 understand that the resistance of cancer cells to oncolytic viruses such as vaccinia virus can eventually occurs if applying the treatment using the virus alone.
(Previous rejection -maintained) Claims 25 is rejected under 35 U.S.C. 103 as being unpatentable over Evans et al. (US 8679509 B2, patented on Mar. 25, 2014) as evidenced by Thorne et al. ( CA3070146A1, published on Jan. 25, 2018) in view of McCart et al. (US 7208313 B2, patented on Apr. 24, 2007), Boucher et al. (Gene Ther. 2002 Aug;9(15):1023-30.), Panicali et al. (Proc Natl Acad Sci U S A. 1982 Aug;79(16):4927-31) and Mackett et al. (Proc Natl Acad Sci U S A. 1982 Dec;79(23):7415-9) as applied to claims 1, 2, 9 and 14-17 above, and further in view of Heinemann et al. (Mol Ther. 2010 Dec;18(12):2085-93. Epub 2010 Sep 14)
Regarding the amended claim 25, it is directed to a method of enhancing efficacy of oncolytic virus treatment in a cancer patient who had received, receives, or will receive an oncolytic virus treatment as compared with only the oncolytic virus treatment, said method consisting of administering an effective amount of a composition consisting of hydroxyurea and a physiologically acceptable carrier, an excipient, and/or a diluent to the cancer patient,
wherein the oncolytic virus is a recombinant vaccinia virus with modifications with respect to a wild-type vaccinia virus, wherein the modifications comprise a deletion of thymidine kinase gene and an insertion of herpes simplex virus type 1 thymidine kinase gene.
wherein the oncolytic virus-containing composition is administered at a dose of 1x 10^5 pfu to 1x10^10 pfu, and wherein the hydroxyurea-containing composition is administered at a dose of 10 mg/kg/day to 90 mg/kg/day.
Evans et al. teaches that the term "treating" or "treatment" as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more isolated or recombinant poxvirus or compositions described in the present application and optionally consists of a single administration, or alternatively comprises a series of applications (See Column 14, right column, lines 26-67). Evans et al. also teaches that in an embodiment, the subject is also administered effective amount of hydroxyurea wherein the hydroxyurea is administered prior to, contemporaneously with, or following administration of the isolated or recombinant virus or composition of the disclosure (See Column 20, lines 44-53). Evans et al. also teaches that the length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration, the activity of the isolated or recombinant poxviruses and a combination of hydroxyurea, gemcitabine and/or a nucleoside analog (See e.g., Column 14, lines 55-67), and the F4L mutant strains such as the li.F4L and Y300F F4-expressing strains could form a logical component of combined therapy whereby patients are first treated with HU ( or gemcitabine) followed by treatment with one of these oncolytic VACV strains to target remaining drug-resistant tumor tissue (See Column 31, lines 1-31).
As for the required limitation of “…thymidine kinase gene is deleted from a wild-type vaccinia virus…”, Evans et al. teaches that the functionally inactivated J2R gene comprises a disruption in the J2R ORF such that an insertion is made in between nucleotides 81001 and 81002 in the WR genome (See column 18, lines 40-47), where the WR genome is a vaccinia virus strain selected from GenBank accession: NC 006998 (See column 2, lines 58-63). The GenBank accession: NC 006998 shows that the WR genome is from the Western Reserve (WR) strain that is a wild-type vaccinia virus (VACV).
Accordingly, Evans et al. teaches a method of treating a cancer patient with the combination treatment comprising the vaccinia virus with TK gene deletion from the wild-type vaccinia virus and hydroxyurea. Evans et al. also discloses that hydroxyurea is widely used to treat leukemia, ovarian cancers, and head and neck cancers, suggesting that these tumor types also exhibit elevated RR activity and would be amendable to treatment with the aforementioned oncolytic poxviruses (See Column 31, lines 7-11), which indicates an enhancing oncolytic virus treatment with hydroxyurea.
Nevertheless, Heinemann teaches that In vivo combination of hydroxyurea followed by intratumoral reovirus resulted in reduced tumor growth and increased survival compared to monotherapy (P = 0.0041) at 15 days (See Abstract). Heinemann also teaches that combination therapy of hydroxyurea/reovirus can educed tumor growth and prolonged survival (See Figure 6, page 2090 and below). Although Heinemann uses Reovirus in his teaching, it is obvious for a person skilled in the art to introduce the teaching of Heinemann into Evans’s invention on vaccinia virus application and further test the roles of the combination therapy of Vaccinia virus and hydroxyurea in enhancing cancer treatment.
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As for the amended limitations on “…herpes simplex virus type 1 thymidine kinase gene is inserted…), McCart et al. teaches that Herpes Simplex Virus 1 (HSV-1) thymidine kinase (TK) is a widely used suicide gene in cancer therapy. By introducing the HSV-1 TK gene into tumor cells, they become sensitive to GCV. When GCV is administered, the HSV-1 TK enzyme converts it into a toxic form that disrupts tumor cell DNA and leads to cell death. Many strategies for delivering the HSV-TK gene have been employed including liposomal transfections, retroviral transductions, and adenoviral infections (See column 8, lines 36-54). McCart et al. teaches that their invention for vaccinia virus expression vector with a negative thymidine kinase phenotype can be an additional method of delivering the HSV-TK gene and further teaches that HSV-TK)/Gancyclovir (GCV) system has been shown to be safe in humans and is readily available (See e.g. column 8, lines 53-54).
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 the teachings of Evans, Thorne, McCart, Boucher, Panicali, Mackett and Heinemann to arrive at an invention as claimed. Based on the description above, McCart teaches that the HSV-TK is a widely used suicide gene in cancer therapy and is the most widely used suicide gene that has been inserted into different virus including Vaccinia virus with backbone for cancer treatment. Boucher teaches the combined application of Hydroxyurea and HSV-TK can enhance cancer treatment, Panicali and Mackett teaches the feasibility and method of inserting the HSV-TK gene into the TK-gene deleted vaccinia virus. Therefore, one of skill in the art would have been motivated to set up an experiment to construct a recombinant vaccinia virus with TK-deletion and HSV-TK insertion, and further test the capability for cancer treatment with hydroxyurea. 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.
As for the new limitation on “the pharmaceutical composition comprises the oncolytic virus in an amount of 1x10^5 pfu to 1x10^10 pf and the hydroxyurea in an amount configured to be administered at a dose of 10 mg/kg/day to 90 mg/kg/day”, it is related to a concentration in the claim. Although Evan et al. is silent on the doses of oncolytic virus and hydroxyurea, Thorne et al. teaches the oncolytic vaccinia virus can be administered at a dosage of 10^6 PFU/mL to about 10^8 PFU/mL (See [0024]). Boucher et al. teaches that the amount of hydroxyurea administered to a mice can be 500, 1000 or 1500 mg/kg for 5 days (See page 1026, left column, paragraph 2). At the same time, Evans et al. also teaches that the dosage administered will vary depending on the use and known factors such as the pharmacodynamic characteristics of the particular substance, and its mode and route of administration, age, health, and weight of the individual recipient, nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Dosage regime may be adjusted to provide the optimum therapeutic response. The term "subject" as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans (See Column 15, lines 1-24).
According to section 2144.05 of the MPEP, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). Based on the teaching of Evan, Thorne and Boucher, one of ordinary skills would be able to test for an optimal administration amount of vaccinia virus and hydroxyurea through routine experimentation. Therefore, the claimed dose of oncolytic virus and hydroxyurea for administration would have been obvious unless there is evidence showing that they produce unexpected results.
Responses to Applicant’s Remarks
Applicant’s arguments filed on March 16, 2026 has been received and fully considered.
Applicant’s amendment regarding the rejections under 35 U.S.C. §112 (b) is considered. The rejection is withdrawn.
Applicant’s arguments on the rejection under 35 U.S.C. §103 are not persuasive as the following points:
1). Applicant argued that a person of ordinary skill in the art would not be motivated to modify the therapeutic oncolytic virus of Evans with the teachings of Panicali and Mackett (See Remarks, page 8).
Applicant’s argument is not persuasive.
Evan already teaches that the J2R deletion is actually the thymidine kinase gene deletion. Evan in view of Panicali and Mackett teaches a method for inserting the herpes simplex virus type I thymidine kinase gene into the J2R deleted vaccinia virus. It is applicable for Panicali and Mackett used as a combined teachings to teach the claimed limitation with Evan. Also, McCart teaches that the HSV-TK is a widely used suicide gene in cancer therapy and is the most widely used suicide gene that has been inserted into different virus including Vaccinia virus with backbone for cancer treatment that provide a motivation for inserting the HSV-TK into the J2R deleted vaccinia virus of Evan.
2). Applicant argued that the asserted references, either individually or in combination, do not provide any guidance on a safe dose window for combination therapy with an oncolytic virus, particularly yyTK-/HSVTK+.
Applicant’s argument is not persuasive.
Applicant added the new limitation of the dose in the base claim 1, however, it did not add limitation for a dose that is specific for a specific subject such as a patient or for a specific cancer type such as lung cancer (See bridging pages 8 and 9). Therefore, the dose of the clamed virus can vary based on the condition and the subject. In addition, according to section 2144.05 of the MPEP, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). Based on the teaching of Evan, Thorne and Boucher, one of ordinary skills would be able to test for a safe dose window for combination therapy with an oncolytic virus, particularly yyTK-/HSVTK through routine experimentation. Therefore, the claimed dose of oncolytic virus and hydroxyurea for administration would have been obvious unless there is evidence showing that they produce unexpected results.
Also, the instant claims do not recite the limitation “safe dose window”.
Applicant’s substantive data and arguments presented in the instant Remarks filed on March 16, 2026 are fully considered. However, the arguments on the unexpected results commensurate in scope is not persuasive as follows:
(Please note: the <Summary of Experimental Data> table in page 11 is difficult to read).
1). Based on the claims 9 and 25, applicant argued that a person skilled in the art would not be able to derive from these references that HU should be limited to approximately 10-90 mg/kg, nor that such a range would provide a balanced therapeutic window between efficacy and systemic/reproductive toxicity when combined with an oncolytic virus. Such a dose window could not have been predicted without actually performing the experiments described in the present application (See Remarks, page 10).
Applicant’s argument is not persuasive.
As described above, Evan in view of Thorne and Boucher teach a pfu and dose for administration although the administration dose of oncolytic virus and the HU can vary depending on different subject and cancer types. According to section 2144.05 of the MPEP, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). Based on the teaching of Evan, Thorne and Boucher, one of ordinary skills would be able to test an predict a dose window through routine experimentation. Therefore, the claimed dose of oncolytic virus and hydroxyurea for administration would have been obvious unless there is evidence showing that they produce unexpected results.
2). Applicant’s Data 1: Dose-Dependent Toxicity of HU in Combination with VVTK-/HSVTK+ in Normal Mice is not persuasive (See Remarks, page 12).
First, the dose showed in the data in page 12 is dependent on a fixed pfu dose of 4 x 10^6 pfu that is different from the claimed limitation with a range of the pfu amount.
Second, the data for the mg/kg actually showed a difference at dose ≥120 mg/kg. However, the claims require the dose is at 10 mg/kg to 90 mg/kg/ (the base claim 1) and 10 mg/kg/day to 90 mg/kg/day (claims 9 and 25). Also, claim 25 is for a cancer patient, the Data 1 is for mice. Boucher is also for mice and teaches that at with 500, 1000 or 1500 mg/kg HU for 5 days without any observed adverse behavior effects or weight loss during treatment or 100 days following treatment (See page 1026, left column, paragraph 2), which indicates the lower dose such as 10 mg/kg to 90 mg/kg would not produce the adverse behavior effects or weight loss.
3) It is not persuasive on the Data 2: Survival Evaluation in a CT26 Tumor Model (See Remarks, page 14).
First, claims 1 and 9 are directed to a generic subject and no limitation on days of administration. So, the specific dose in the CT-26 cannot provide the support for the claimed dose limitation at 10mg/kg to 90 mg/kg or mg/kg/ day to 90 mg/kg/ day.
Second, claim 25 has the limitation on a cancer patient, the dose of the CT-26 model cannot represent the dose claimed in claim 25 in human.
4) It is not persuasive on the Data 3: Survival Evaluation in a CT26 Tumor Model (See Remarks, page 15).
First, the survival data with the HU dose is based on a single oncolytic virus pfu amount that is different with the limited range at Ix 10^5 pfu to Ix 10^10 pfu. Also, the instant claims do not limit the claimed dose based on the survival evaluation.
Second, the CT-26 model data does not support a generic subject in claim 1 and 9, and also does not support the claim 25 that required a cancer patient subject.
5) It is not persuasive on the Data 4: Survival According to VV Dose in Combination Therapy (See Remarks, page 16).
First, the VV dose in CT-26 mice model does not provide a support for the claims on a generic subject in claims 1 and 9, and does not teach the claimed VV dose claimed for cancer patient in claim 25.
Second, the VV dose is tested based on a single fixed HU dose at 90mg/kg, which is different from the limitation of the HU dose is at a range of 10 mg/kg to 90 mg/kg (claim 1) and 10 mg/kg/day to 90 mg/kg/day (claim 9 and 25).
6) It is not persuasive on the Data 5: Evaluation of tumor size when combined with VVTK-/HSVTK+ and HU in the Renea mouse tumor model (See Remarks, pages 17-20).
First, the instant claims do not limit the administered dose of virus and HU being based on the tumor size.
Second, data from the Renca mouse model does not provide support for a generic subject in claims 1 and 9, and does not teach a dose for cancer patient in claim 25.
Third, Evan in view of Thorne teach a VV administration dose at 10^6 PFU/mL to about 10^8 PFU (See page 9), which is in the claimed VV range.
7) It is not persuasive on the Data 6: Toxicity Evaluation of Combined Administration of VVTK-/HSVTK+ and HU in a VX2 Rabbit Tumor Model (See Remarks, page 20).
First, the administration dose of VV and HU are not limited by the toxicity, and a VX2 Rabbit Tumor Model does not provide the support for a generic subject claim (claims 1 and 9) and does not teach a cancer patient (claim 25).
Second, the conclusion “a single dose of yyTK-/HSVTK+ at Ix 10^8 pfu/head is considered a toxicologically acceptable dose even in combination with HU at 80 or 60 mg/kg/day” (See Remarks, page 25) is not consistent with a range claim at Ix 10^5 pfu to Ix 10^10 pfu.
Lastly, applicant’s data appear to be assays to determine toxicity limits (e.g., highest dose that will not cause toxicity). Toxicity assays do not demonstrate unexpected results, but instead demonstrate the limits of HU doses that will or will not cause toxicity. Accordingly, applicant’s argument on the unexpected results is not found persuasive.
In addition, as to applicant’s arguments about unexpected results, as an initial matter, “the burden of showing unexpected results rests on he who asserts them. Thus, it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted). Applicant’s attention is directed to MPEP 716.02(b)-(e) for how unexpected results can be established. E.g., to evaluate if the claimed invention produces unexpected results, one must consider if the results produced by the claimed invention are commensurate in scope with the claims and how the results compare with the closest prior art. See MPEP Section 716.02(d) and (e). Here, applicant has not provided sufficient information for the Office to consider if the results produced by the claimed invention are commensurate in scope with the claims and how the results compare with the closest prior art.
Conclusion
No claims are allowed.
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
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