DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 4, 2026 has been entered.
3. Claims 1-9, 11-21 and 26-31 are pending.
Claims 1-9 and 11, drawn to non-elected inventions and non-elected species are withdrawn from examination.
Claim 25 has been cancelled.
Claim 12 has been amended.
Claims 26-31 have been added.
Claims 12-21 and 26-31 are examined on the merits with species, vaccinia virus.
New and Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
4. 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.
5. The rejection of claim(s) 12-21 and new claims 26-31 under 35 U.S.C. 103 as being unpatentable over Zitvogel et al., US 2017/0143780 A1 (published May 25, 2017), and further in view of Fishbein et al., (Clinical Pharmacology & Therapeutics 5(5): 537-672, 4 January 2016) is maintained and made. Claim 25 has been cancelled.
The declaration under 37 CFR 1.132 filed May 4, 2026 is insufficient to overcome the rejection of claims 12-21 and 26-31 based upon Zitvogel et al., US 2017/0143780 A1 (published May 25, 2017), and further in view of Fishbein et al., (Clinical Pharmacology & Therapeutics 5(5): 537-672, 4 January 2016) applied under 35 U.S.C. 103 as set forth in the last Office action because: the showing of Experiment 1 (Figure A) cited on page 2 of the declaration (page 9 of the Remarks) continues not to be commensurate in scope with the claims. Figure D cited on page 5 (page 12 of the Remarks) and Figure E cited on page 6 (page 13 of the Remarks) also are not commensurate in scope with the claims.
Claim 1 has been amended to read on a host of cancers and continues to read on a host of immune checkpoint inhibitors. The claims read broadly on a number of cancers, as well as a number of immune checkpoint inhibitors, while Figure A reads on the treatment of renal cancer with three administered therapeutic agents, “the group receiving the combination of Wyeth VVtk- (oncolytic virus), anti-PD-LI (immune checkpoint inhibitor), and hydroxyurea (HU) [, which] showed a significant tumor-suppression effect compared to groups receiving the Wyeth VVtk- alone, the PD-L1 inhibitor alone, the combination of Wyeth VVtk⁻ and the PD-L1 inhibitor, or the combination of Wyeth VV²⁻ and HU.”, see segment 8 spanning pages 2 and 3 of the declaration. The Examiner does concur with Applicant, Figure A does evidence synergism, this evidence is limited to the treatment of renal cancer with Wyeth VVtk- (oncolytic virus), anti-PD-LI and HU, see segments 5-8 spanning pages 2 and 3 of the declaration.
The additional showing presented on page 3 is Figure B, results rendered with the administration of VVtk- (oncolytic virus) and hydroxyurea (HU) to mouse-renal cell-implanted mice (Renca II), wherein the tumor volume is lower for VVtk-treated. Figure C also presents results wherein Western Reserve (WR) VVtk- and HU is administered and volume is lower in the VVtk- treated. However, it can only be assumed that the cancer treated was renal cancer, given it is cited as a similar experiment, see page 3, segment 11.
The lines within Figure D, Figure E and Figure F are discernable on pages 5, 6 and 7, respectively. All these figures utilize anti-PD-L1 with the treatment of colorectal cancer.
Applicant states in conclusion, “[c]onsidering the results in Experiments 1-4 above, it is clear that the inventive methods of administering the "oncolytic virus," the "hydroxyurea" and the "immune checkpoint inhibitor" as separate compositions leads to a synergistic effect that reduces tumor volume and improves survival of a subject with cancer, and that this improvement is not merely an additive effect of the individual drugs. Hwang 2 Declaration, ¶ 30.”, see Remarks submitted May 4, 2026, paragraph (para.) bridging pages 14 and 15; and para. before Conclusion segment.
Applicant’s declaration and arguments have been carefully considered, but fail to persuade.
As stated in the preceding paragraphs (paras.) are the reasons why the rejection does not fall.
Zitvogel teaches therapeutic agents independently and separately placed in a solvent, diluent and/or composition, see abstract; page 2, section 0019; and page 12, sections 0133 and 0136.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine of teachings of Zitvogel and Fishbein to have three independent compositions comprising each the oncolytic virus, HU and ICI as active ingredients, separately because each reference teaches such.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the teachings of both, Zitvogel and Fishbein, as well as what is known in the art, active agents in independent compositions ensure stability of the active agent, as well as limit premature interactions prior to point(s) of administration. Hence, the rejection is maintained and made.
Zitvogel teaches “…methods to treat, prevent, or inhibit proliferative diseases, especially cancer” with an oncolytic virus in combination with one or more immune checkpoint modulator(s), see page 1, section 0001; page 2, sections 0011 and 0016; sections 0038-0041 spanning pages 3 and 4; and page 8, section 0080. “[I]n the context of the present invention is coupling of the immune checkpoint modulator to an external agent such as radiosensitizer agent,” for instance hydroxyurea, see page 11, section 0124.
“[T]he one or more immune checkpoint modulator(s) is an antagonist molecule that antagonizes the activity of PD-1, PD-L1 or CTLA4 ...”, see page 2, section 0016.
The oncolytic virus and the immune checkpoint modulator, which is coupled to hydroxyurea may be administered at the same time or sequentially, see page 12, section 0133. Moreover, the immune checkpoint modulator may be administered first and oncolytic virus second, see page 14, section 0146. As well as, the hydroxyurea coupled to the immune checkpoint modulator can be administered before, during or after administration of the oncolytic virus. “Intervals between each administration can be from several hours to one year (e.g. 24 h, 48 h, 72 h, weekly, every two weeks, monthly or yearly). Intervals can also be irregular (e.g. following the measurement of monoclonal antibodies in the patient blood levels). The doses can vary for each administration within the range described above.”, see page 14, section 0146.
“In a preferred embodiment, the oncolytic virus and the immune checkpoint modulator(s) are administered sequentially (separately or interspersed), with a specific preference for the virus starting first followed by the immune checkpoint modulator(s). The period of time between the first administration of the oncolytic virus and the first administration of the immune check point modulator(s) may vary from approximately several hours (at least 6 hours) to several week(s). In a preferred embodiment, the method of the present invention comprises at least one administration of the oncolytic virus before starting administration of the immune checkpoint modulator(s), with a specific preference for at least 2 viral administrations followed by 2 to 5 administrations of the immune check point modulator(s) (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days separating the second viral administration from the first immune checkpoint modulator administration). Another preferred therapeutic scheme involves from 2 to 5 (e.g. 3) intravenous or intratumoral administrations of 108 or 109 pfu of oncolytic vaccinia virus [VV] at approximately 1 or 2 weeks interval followed by or interspersed with 2 to 5 (e.g. 3 or 4) intravenous administrations of 3 to 10 mg/kg of anti-immune checkpoint antibody(ies) every 2 or 3 weeks.”, see page 14, section 0147.
Additional VV strains include “Wyeth, Copenhagen and Western Reserve strains.”, see page 5, section 0052.
“Suitable dosage for the oncolytic virus varies from approximately 105 to approximately 1013 vp (viral particles), iu (infectious unit) or pfu (plaque-forming units) depending on the virus and the quantitative technique used. As a general guidance, vaccinia virus doses from approximately 105 to approximately 1013 pfu are suitable, preferably from approximately 106 pfu to approximately 1011 pfu, more preferably from approximately 107 pfu to approximately 5×109 pfu; doses of approximately 108 pfu to approximately 109 pfu being particularly preferred (e.g. dose of 108, 2×108, 3×108, 4×108, 5×108, 6×108, 7×108, 8×108, 9×108 or 109 pfu) especially for human use. On the same line, doses reduced by a factor of 10 to 100 may be considered for local intratumoral injection(s) of the oncolytic virus.”, see page 13, section 0142.
The oncolytic virus is a VV engineered to lack thymidine kinase (TK) activity, see page 2, section 0014; page 5, sections 0051, 0053, 0054 and 0057; page 7, sections 0077 and 0078. There may also be “the disruption of the A56R gene coding for hemagglutinin, eventually in combination with TK deletion (Zhang et al., 2007, Cancer Res. 67: 10038-46). Disruption of interferon modulating gene(s) may also be advantageous (e.g. the B8R or B18R gene) or the caspase-1 inhibitor B13R gene.”, see page 5, section 0056.
“In an alternative and also preferred embodiment, the oncolytic virus for use in the invention is a vaccinia virus (preferably from the Wyeth strain) defective for TK activity (resulting from inactivating mutations in the virus J2R gene). More preferably, said vaccinia virus is armed with an immunostimulatory therapeutic gene with a special preference for the human GM-CSF gene described herein.”, see page 7, section 0078.
A “suicide gene”, “a gene coding for a protein able to convert a precursor of a drug into a [cytotoxic] compound includes genes coding protein having a cytosine deaminase activity, as well as thymidine kinase activity, see page 6, sections 0062-0064 and Table 1 within the said sections.
“[T]he proliferative disease treated by the method of the invention is cancer and especially melanoma, renal cancer, prostate cancer, breast cancer, colorectal cancer, lung cancer and liver cancer.”, see page 2, section 0018; and page 3, section 0036.
Zitvogel does not teach the claimed method of treatment, wherein a first composition comprising an oncolytic virus as an active ingredient, a second composition comprising hydroxyurea as an active ingredient, and a third composition comprising an immune checkpoint inhibitor as an active ingredient is administered. Moreover, Zitvogel does not teach the hydroxyurea is administered 3 to 5 days before administration of the oncolytic virus and is continuously administered once a day for 9 to 28 days after administration of the oncolytic virus, wherein the hydroxyurea dosage is 10 mg/kg/day to 90 mg/kg/day and delivered intraperitoneally or intravenously.
Zitvogel does not teach the claimed method of treatment, wherein the immune checkpoint inhibitor is continuously administered at least once a week for 1 week to 10 weeks after administration of the oncolytic virus.
However, Zitvogel teaches therapeutic agents in an effective amount of an active agent may be administered in a single composition, separate composition, see page 12, section 0133; and page 15, section 0166. Fishbein teaches an individual composition comprising hydroxyurea as an active ingredient for the treatment of a malignant disease, see entire document. And Zitvogel teaches therapeutic agents independently and separately placed in a solvent, diluent and/or composition, see abstract; page 2, section 0019; and page 12, sections 0133 and 0136.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine of teachings of Zitvogel and Fishbein to have three independent compositions comprising each the oncolytic virus, HU and ICI as active ingredients, separately because each reference teaches such.
Zitvogel further teaches the immune checkpoint modulator may be administered first and oncolytic virus second and vice versa, see page 14, section 0146. The hydroxyurea uncoupled to the immune checkpoint modulator is able to be administered 3 to 5 days prior to the administration of the oncolytic virus and the hydroxyurea can be continuously administered once a day for 9 to 28 days after administration of the oncolytic virus and a dose of 10 mg/kg/day to 90 mg/kg/day. As well as, the immune checkpoint inhibitor is able to be continuously administered at least once a week for 1 week to 10 weeks after administration of the oncolytic virus.
Likewise, the hydroxyurea uncoupled to the immune checkpoint modulator is also able to be administered via the same preferred routes as the immune checkpoint modulator(s), intravenously (e.g. intravenous injection or infusion), intratumorally and intraperitoneally as a separate composition, see page 13, section 0145.
In addition, Fishbein teaches administration of hydroxyurea (HU) to patients with malignant disease, see abstract; Table 1 on page 575; and the entire document. Daily dosages ranged from “…30 mg. per kilogram per day (range 15 to 66 mg. per kilogram per day)”, as well as in daily doses varying from 15 to 100 mg. per kilogram.”, see Table II on page 576; page 577, 1st column; page 578, 1st column; and paragraph bridging 578 and 579.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine of teachings of Zitvogel and Fishbein to treat cancer with the administration of the three therapeutic agents as separate compositions and the desired times and dosages as stated in the claims, especially since Zitvogel states “Intervals between each administration can be from several hours to one year (e.g. 24 h, 48 h, 72 h, weekly, every two weeks, monthly or yearly)... The doses can vary for each administration within the range described above.”, see page 14, section 0146.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the teachings of both, Zitvogel and Fishbein to administer separate combinations of each therapeutic agents as an active agent to render synergistic immune responses, see page 1, section 0008; page 2, section 0011; section 0038 spanning pages 3 and 4; and Combination Therapy segment spanning pages 12 and 13; and sections 0194 and 0195 on page 17. Moreover, hydroxyurea has exhibited considerable and reproducible antitumor activity, as well as has been well tolerated over a wide dose range in patients with proliferative diseases, see both documents in their entireties; and especially Fishbein, pages 574 and 575.
6. The rejection of claim(s) 12-21 and new claims 26-29 and 31 under 35 U.S.C. 103 as being unpatentable over Nakao et al., US 2021/0315951 (effective filing date September 26, 2018, see English Translation of JP2018-0179632), and further in view of Coffey et al., US 6,596,268 B1 (issued July 22, 2003) and Fishbein et al., (Clinical Pharmacology & Therapeutics 5(5): 537-672, 4 January 2016) is maintained and made. Claim 25 has been cancelled.
The declaration under 37 CFR 1.132 filed May 4, 2026 is insufficient to overcome the rejection of claims 12-21, 26-29 and 31 based upon Nakao et al., US 2021/0315951 (effective filing date September 26, 2018, see English Translation of JP2018-0179632), and further in view of Coffey et al., US 6,596,268 B1 (issued July 22, 2003) and Fishbein et al., (Clinical Pharmacology & Therapeutics 5(5): 537-672, 4 January 2016) applied under 35 U.S.C. 103 as set forth in the last Office action because: the showing of Experiment 1 (Figure A) cited on page 2 of the declaration (page 9 of the Remarks) continues not to be commensurate in scope with the claims. Figure D cited on page 5 (page 12 of the Remarks) and Figure E cited on page 6 (page 13 of the Remarks) also are not commensurate in scope with the claims.
Claim 1 has been amended to read on a host of cancers and continues to read on a host of immune checkpoint inhibitors. The claims read broadly on a number of cancers, as well as a number of immune checkpoint inhibitors, while Figure A reads on the treatment of renal cancer with three administered therapeutic agents, “the group receiving the combination of Wyeth VVtk- (oncolytic virus), anti-PD-LI (immune checkpoint inhibitor), and hydroxyurea (HU) [, which] showed a significant tumor-suppression effect compared to groups receiving the Wyeth VVtk- alone, the PD-L1 inhibitor alone, the combination of Wyeth VVtk⁻ and the PD-L1 inhibitor, or the combination of Wyeth VV²⁻ and HU.”, see segment 8 spanning pages 2 and 3 of the declaration. The Examiner does concur with Applicant, Figure A does evidence synergism, this evidence is limited to the treatment of renal cancer with Wyeth VVtk- (oncolytic virus), anti-PD-LI and HU, see segments 5-8 spanning pages 2 and 3 of the declaration.
The additional showing presented on page 3 is Figure B, results rendered with the administration of VVtk- (oncolytic virus) and hydroxyurea (HU) to mouse-renal cell-implanted mice (Renca II), wherein the tumor volume is lower for VVtk-treated. Figure C also presents results wherein Western Reserve (WR) VVtk- and HU is administered and volume is lower in the VVtk- treated. However, it can only be assumed that the cancer treated was renal cancer, given it is cited as a similar experiment, see page 3, segment 11.
The lines within Figure D, Figure E and Figure F are discernable on pages 5, 6 and 7, respectively. All these figures utilize anti-PD-L1 with the treatment of colorectal cancer.
Applicant states in conclusion, “[c]onsidering the results in Experiments 1-4 above, it is clear that the inventive methods of administering the "oncolytic virus," the "hydroxyurea" and the "immune checkpoint inhibitor" as separate compositions leads to a synergistic effect that reduces tumor volume and improves survival of a subject with cancer, and that this improvement is not merely an additive effect of the individual drugs. Hwang 2 Declaration, ¶ 30.”, see Remarks submitted May 4, 2026, paragraph (para.) bridging pages 14 and 15; and para. before Conclusion segment.
Applicant’s declaration and arguments have been carefully considered, but fail to persuade.
As stated in the preceding paragraphs (paras.) are the reasons why the rejection does not fall. Applicant’s declaration and arguments have been carefully considered, but fail to persuade.
As stated in the preceding paragraphs (paras.) are the reasons why the rejection does not fall. Furthermore, Nakao teaches active ingredients may be contained separately in different compositions, see page 2, sections 0036 and 0037. And Fishbein teaches an individual composition comprising hydroxyurea as an active ingredient for the treatment of a malignant disease, see entire document.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine of teachings of Nakao and Fishbein to have three independent compositions comprising separately, each, the oncolytic virus, HU and ICI as active ingredients because both, Nakoa and Fishbein teach independent and separate pharmaceutically active ingredients may be in different compositions, see Nakoa, page 2, sections 0036 and 0037; and entire Fishbein reference.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the teachings of all the references, as well as what is known in the art active agents in independent compositions ensure stability of the active agent, as well as limit premature interactions prior to point of administration. Hence, the rejection is maintained.
Nakao teaches a cancer therapy with a combination of a genetically modified oncolytic vaccinia virus (VV) and an immune checkpoint inhibitor, page 1, sections 0006 and 0007; page 2, sections 0016, 0017, 0020, 0022, 0028, 0032, 0033, 0035, 0038 and 0039; and entire document. The VV implemented in the method can be defective in function of thymidine kinase (TK), see page 4, section 0057. “Examples of the strain of the vaccinia virus to be used in the present invention include, but are not limited to, Lister strain, New York City Board of Health (NYBH) strain, Wyeth strain, Copenhagen strain, Western Reserve (WR) strain, …Tian Tan strain”, as well as LC16m8 strain, see page 3, section 0055.
Nakao teaches “…a method for treating cancer in a subject (for example, patient) in need thereof, comprising administering a pharmaceutical composition containing the vaccinia virus to be used in the present invention and an immune checkpoint inhibitor to the subject, wherein the cancer is, for example, solid cancer, for example but not limited to, a cancer selected from the group consisting of malignant melanoma, lung cancer, lung adenocarcinoma, small cell lung cancer, lung squamous cell carcinoma, kidney cancer, bladder cancer, head and neck cancer, breast cancer, esophagus cancer, glioblastoma, neuroblastoma, … ovarian cancer, colorectal cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, … and stomach cancer.”, see page 10, sections 0152-0154, 0158, 0159 and 0162-0164.
“In an embodiment, vaccinia viruses are administered, and then, the immune checkpoint inhibitor is administered.”, see page 10, section 0158. The immune checkpoint inhibitor includes checkpoint inhibitors that block a signal through PD-1, checkpoint inhibitors that block a signal through CTLA-4, “an antibody that can neutralize the binding between PD-1 and PD-L1 or PD-L2 and an antibody that can neutralize the binding between CTLA-4…”, see page 2, section 0039; and sections 0112-0120 spanning pages 7 and 8.
The vaccinia virus may be administered at a desired time interval, see page 10, section 0162; and page 12, lines 12-14. “[T]he vaccinia viruses…and the immune checkpoint inhibitor…are sequentially administered, they may be administered continuously or at a time interval.”, see page 10, sections 0158 and 0162; section 0186 spanning pages 11 and 12; and page 12, section 0188.
The vaccinia virus may be defective in function of vaccinia virus growth factor (VGF), vaccinia virus defective in functions of TK, HA and F14.5L and vaccinia virus defective in functions of TK and B18R, see page 4, section 0057.
The virus to be administered in combination may be at a dose of
“a plaque formation unit (PFU) of about 102 to 1010 can be used.”, see page 10, section 0150.
Nakoa does not teach a method for treating cancer comprising administering a first composition comprising an oncolytic virus as an active ingredient, a second composition comprising hydroxyurea as an active ingredient, and a third composition comprising an immune checkpoint inhibitor as an active ingredient is administered.
Moreover, Nakoa does not teach administering hydroxyurea with the taught VV (having a deleted TK gene) and an immune checkpoint inhibitor.
Nakoa does not teach the manner of administering the hydroxyurea, as well as the dosages limited in claims 14, 15, 17, 18, 20 and 21.
However, Nakao teaches active ingredients may be contained separately in different compositions, see page 2, sections 0036 and 0037. Coffey teaches formulating compositions in unit dosage form and/or a single dose, see column 15. And Fishbein teaches an individual composition comprising hydroxyurea as an active ingredient for the treatment of a malignant disease, see entire document.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine of teachings of Nakao and Fishbein to have three independent compositions comprising separately, each, the oncolytic virus, HU and ICI as active ingredients because Nakoa, Coffey and Fishbein teach independent and separate pharmaceutically active ingredients may be in different compositions, see Nakoa, page 2, sections 0036 and 0037; Coffey, column 15; and entire Fishbein reference.
Coffey teaches treating neoplastic diseases with a modified VV in conjunction with or in addition to chemotherapeutic agents, such as hydroxyurea, see column 4, 1st paragraph (para.); column 7, lines 32-67; column 15, lines 11-27; and the para. bridging columns 15 and 16.
Coffey teaches continuous infusion of the taught virus in controlled amounts via transdermal patches, as well as by intravenous injection, see column 10, lines 59-64; and column 14, lines 3-12.
Moreover, Fishbein teaches administration of hydroxyurea (HU) to patients with malignant disease, see abstract; Table 1 on page 575; and the entire document. Daily dosages ranged from “…30 mg. per kilogram per day (range 15 to 66 mg. per kilogram per day)”, as well as in daily doses varying from 15 to 100 mg. per kilogram.”, see Table II on page 576; page 577, 1st column; page 578, 1st column; and paragraph bridging 578 and 579.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine of teachings of Nakoa and Fishbein to treat cancer with the addition of hydroxyurea to the therapeutic combination of Nakoa at the desired times, routes of administration and dosages as stated in the claims, especially since Nakoa states “[t]he combination [various therapeutic agents may be non-immunotherapeutic drugs] use may include simultaneous administration, separate and continuous administration, separate administration at a desired time interval. In the case of simultaneous administration, the pharmaceutical composition of the present invention may be a combined preparation or a combination of separate preparations.”, see section 0186 bridging pages 11 and 12.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the teachings of all references, Nakoa, Coffey and Fishbein to add an independent hydroxyurea composition to the medicines of Nakoa and administer each therapeutic agent as an active agent for treatment, see all references. Moreover, hydroxyurea has exhibited considerable and reproducible antitumor activity, as well as has been well tolerated over a wide dose range in patients with proliferative diseases, see both documents in their entireties; and especially Fishbein, pages 574 and 575.
7. Claim(s) 12-17, 20, 21 and 26-31 are rejected under 35 U.S.C. 103 as being unpatentable over Nakao et al., US 2021/0315951 (effective filing date September 26, 2018, see English Translation of JP2018-0179632), and further in view of Zitvogel et al., US 2017/0143780 A1 (published May 25, 2017). Nakao teaches a cancer therapy with a combination of a genetically modified oncolytic vaccinia virus (VV) and an immune checkpoint inhibitor, page 1, sections 0006 and 0007; page 2, sections 0016, 0017, 0020, 0022, 0028, 0032, 0033, 0035, 0038 and 0039; and entire document. The VV implemented in the method can be defective in function of thymidine kinase (TK), see page 4, section 0057. “Examples of the strain of the vaccinia virus to be used in the present invention include, but are not limited to, Lister strain, New York City Board of Health (NYBH) strain, Wyeth strain, Copenhagen strain, Western Reserve (WR) strain, …Tian Tan strain”, as well as LC16m8 strain, see page 3, section 0055.
Nakao teaches “…a method for treating cancer in a subject (for example, patient) in need thereof, comprising administering a pharmaceutical composition containing the vaccinia virus to be used in the present invention and an immune checkpoint inhibitor to the subject, wherein the cancer is, for example, solid cancer, for example but not limited to, a cancer selected from the group consisting of malignant melanoma, lung cancer, lung adenocarcinoma, small cell lung cancer, lung squamous cell carcinoma, kidney cancer, bladder cancer, head and neck cancer, breast cancer, esophagus cancer, glioblastoma, neuroblastoma, … ovarian cancer, colorectal cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, … and stomach cancer.”, see page 10, sections 0152-0154, 0158, 0159 and 0162-0164.
“In an embodiment, vaccinia viruses are administered, and then, the immune checkpoint inhibitor is administered.”, see page 10, section 0158. The immune checkpoint inhibitor includes checkpoint inhibitors that block a signal through PD-1, checkpoint inhibitors that block a signal through CTLA-4, “an antibody that can neutralize the binding between PD-1 and PD-L1 or PD-L2 and an antibody that can neutralize the binding between CTLA-4…”, see page 2, section 0039; and sections 0112-0120 spanning pages 7 and 8.
The vaccinia virus may be administered at a desired time interval, see page 10, section 0162; and page 12, lines 12-14. “[T]he vaccinia viruses…and the immune checkpoint inhibitor…are sequentially administered, they may be administered continuously or at a time interval.”, see page 10, sections 0158 and 0162; section 0186 spanning pages 11 and 12; and page 12, section 0188.
The vaccinia virus may be defective in function of vaccinia virus growth factor (VGF), vaccinia virus defective in functions of TK, HA and F14.5L and vaccinia virus defective in functions of TK and B18R, see page 4, section 0057.
The virus to be administered in combination may be at a dose of
“a plaque formation unit (PFU) of about 102 to 1010 can be used.”, see page 10, section 0150.
Nakoa does not teach a method for treating cancer comprising administering a first composition comprising an oncolytic virus as an active ingredient, a second composition comprising hydroxyurea as an active ingredient, and a third composition comprising an immune checkpoint inhibitor as an active ingredient is administered.
Moreover, Nakoa does not teach administering hydroxyurea with the taught VV (having a deleted TK gene) and an immune checkpoint inhibitor.
Nakoa does not teach the manner of administering the hydroxyurea, as well as the dosages limited in claims 14, 15, 17, 18, 20 and 21.
Zitvogel teaches “…methods to treat, prevent, or inhibit proliferative diseases, especially cancer” with an oncolytic virus in combination with one or more immune checkpoint modulator(s), see page 1, section 0001; page 2, sections 0011 and 0016; sections 0038-0041 spanning pages 3 and 4; and page 8, section 0080. “[I]n the context of the present invention is coupling of the immune checkpoint modulator to an external agent such as radiosensitizer agent,” for instance hydroxyurea, see page 11, section 0124.
“[T]he one or more immune checkpoint modulator(s) is an antagonist molecule that antagonizes the activity of PD-1, PD-L1 or CTLA4 ...”, see page 2, section 0016.
The oncolytic virus and the immune checkpoint modulator, which is coupled to hydroxyurea may be administered at the same time or sequentially, see page 12, section 0133. Moreover, the immune checkpoint modulator may be administered first and oncolytic virus second, see page 14, section 0146. As well as, the hydroxyurea coupled to the immune checkpoint modulator can be administered before, during or after administration of the oncolytic virus. “Intervals between each administration can be from several hours to one year (e.g. 24 h, 48 h, 72 h, weekly, every two weeks, monthly or yearly). Intervals can also be irregular (e.g. following the measurement of monoclonal antibodies in the patient blood levels). The doses can vary for each administration within the range described above.”, see page 14, section 0146.
“In a preferred embodiment, the oncolytic virus and the immune checkpoint modulator(s) are administered sequentially (separately or interspersed), with a specific preference for the virus starting first followed by the immune checkpoint modulator(s). The period of time between the first administration of the oncolytic virus and the first administration of the immune check point modulator(s) may vary from approximately several hours (at least 6 hours) to several week(s). In a preferred embodiment, the method of the present invention comprises at least one administration of the oncolytic virus before starting administration of the immune checkpoint modulator(s), with a specific preference for at least 2 viral administrations followed by 2 to 5 administrations of the immune check point modulator(s) (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days separating the second viral administration from the first immune checkpoint modulator administration). Another preferred therapeutic scheme involves from 2 to 5 (e.g. 3) intravenous or intratumoral administrations of 108 or 109 pfu of oncolytic vaccinia virus [VV] at approximately 1 or 2 weeks interval followed by or interspersed with 2 to 5 (e.g. 3 or 4) intravenous administrations of 3 to 10 mg/kg of anti-immune checkpoint antibody(ies) every 2 or 3 weeks.”, see page 14, section 0147.
Additional VV strains include “Wyeth, Copenhagen and Western Reserve strains.”, see page 5, section 0052.
“Suitable dosage for the oncolytic virus varies from approximately 105 to approximately 1013 vp (viral particles), iu (infectious unit) or pfu (plaque-forming units) depending on the virus and the quantitative technique used. As a general guidance, vaccinia virus doses from approximately 105 to approximately 1013 pfu are suitable, preferably from approximately 106 pfu to approximately 1011 pfu, more preferably from approximately 107 pfu to approximately 5×109 pfu; doses of approximately 108 pfu to approximately 109 pfu being particularly preferred (e.g. dose of 108, 2×108, 3×108, 4×108, 5×108, 6×108, 7×108, 8×108, 9×108 or 109 pfu) especially for human use. On the same line, doses reduced by a factor of 10 to 100 may be considered for local intratumoral injection(s) of the oncolytic virus.”, see page 13, section 0142.
The oncolytic virus is a VV engineered to lack thymidine kinase (TK) activity, see page 2, section 0014; page 5, sections 0051, 0053, 0054 and 0057; page 7, sections 0077 and 0078. There may also be “the disruption of the A56R gene coding for hemagglutinin, eventually in combination with TK deletion (Zhang et al., 2007, Cancer Res. 67: 10038-46). Disruption of interferon modulating gene(s) may also be advantageous (e.g. the B8R or B18R gene) or the caspase-1 inhibitor B13R gene.”, see page 5, section 0056.
“In an alternative and also preferred embodiment, the oncolytic virus for use in the invention is a vaccinia virus (preferably from the Wyeth strain) defective for TK activity (resulting from inactivating mutations in the virus J2R gene). More preferably, said vaccinia virus is armed with an immunostimulatory therapeutic gene with a special preference for the human GM-CSF gene described herein.”, see page 7, section 0078.
A “suicide gene”, “a gene coding for a protein able to convert a precursor of a drug into a [cytotoxic] compound includes genes coding protein having a cytosine deaminase activity, as well as thymidine kinase activity, see page 6, sections 0062-0064 and Table 1 within the said sections.
Zitvogel further teaches the immune checkpoint modulator may be administered first and oncolytic virus second and vice versa, see page 14, section 0146. The hydroxyurea uncoupled to the immune checkpoint modulator is able to be administered 3 to 5 days prior to the administration of the oncolytic virus and the hydroxyurea can be continuously administered once a day for 9 to 28 days after administration of the oncolytic virus and a dose of 10 mg/kg/day to 90 mg/kg/day. As well as, the immune checkpoint inhibitor is able to be continuously administered at least once a week for 1 week to 10 weeks after administration of the oncolytic virus.
Likewise, the hydroxyurea uncoupled to the immune checkpoint modulator is also able to be administered via the same preferred routes as the immune checkpoint modulator(s), intravenously (e.g. intravenous injection or infusion), intratumorally and intraperitoneally as a separate composition, see page 13, section 0145.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine of teachings of Nakoa and Zitvogel to treat cancer with the administration of the three therapeutic agents as separate compositions and the desired times and dosages as stated in the claims, especially since Zitvogel states “Intervals between each administration can be from several hours to one year (e.g. 24 h, 48 h, 72 h, weekly, every two weeks, monthly or yearly)... The doses can vary for each administration within the range described above.”, see page 14, section 0146.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the teachings of both, Nakoa and Zitvogel to administer separate combinations of each therapeutic agents as an active agent to render synergistic immune responses, see page 1, section 0008; page 2, section 0011; section 0038 spanning pages 3 and 4; and Combination Therapy segment spanning pages 12 and 13; and sections 0194 and 0195 on page 17. Moreover, hydroxyurea has exhibited considerable and reproducible antitumor activity, as well as has been well tolerated over a wide dose range in patients with proliferative diseases, see both documents in their entireties.
Conclusion
8. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached on 8AM-8PM, Monday through Friday.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
10 September 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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