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
Claims 1-11, 14-24, 27-31, 36-46, and 48-52 are pending.
Claims 12 and 13 are canceled.
Claims 49-52 are newly added.
Claims 1, 3, 8, 14, 17-21, 23, 27-31, 36-40, 43, 44, and 48 are currently amended.
Claim 48 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/29/2025.
Claims 27 and 37-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/29/2025.
Claims 1-11, 14-24, 28-31, 36, 41-46, and 49-52 are under examination on the merits.
Rejections Maintained
35 U.S.C. 103
The rejection of claims 1-4, 6-11, 14-24, 36, and 41-46 under 35 U.S.C. 103 as being unpatentable over Lala et al. (WO 2019/160755, international filing date: 02/08/2019) in view of Sznol et al. (J Clin Oncol, volume 38, number 15, suppl., 2020), as evidenced by Russell et al. (U.S. PAT 9,428,736, issue date: 08/30/2016) is maintained. Claims 12 and 13 are canceled.
The rejection of claims 1 and 5 under 35 U.S.C. 103 as being unpatentable over Lala et al. (WO 2019/160755, international filing date: 02/08/2019) in view of Silverman et al. (US PG PUB 20130071432, publication date 03/21/2013) is maintained.
The rejection of claims 28-31 under 35 U.S.C. 103 as being unpatentable over Lala et al. (WO 2019/160755, international filing date: 02/08/2019) in view of Sznol et al. (J Clin Oncol, volume 38, number 15, suppl., 2020), as evidenced by Russell et al. (U.S. PAT 9,428,736, issue date: 08/30/2016), as applied to claims 1-4, 6-24, 36, and 41-46, and further in view of Papadopoulos et al. (US PAT 9,987,500, issue date: 06/05/2018) is maintained. Newly added claims 49-52 are added to this rejection.
Nonstatutory Double Patenting
The nonstatutory double patenting rejections of record have been maintained.
Response to Arguments
In Applicant Arguments, dated 05/01/2026, Applicant asserts that one of ordinary skill in the art would not have been motivated to combine the teachings of Lala et al., Sznol et al., and Russel et al. to arrive at the claimed invention. “Lala discloses the use of pembrolizumab and an anti-CTLA4 antibody to treat various cancers. Lala does not disclose or suggest any combination therapies that include an oncolytic virus let alone a triple combination therapy, wherein the combination of an oncolytic virus, an anti-PD-1 antibody or antigen-binding fragment thereof, and an anti-CTLA4 antibody or antigen-binding fragment thereof are administered concurrently, as presently claimed… Sznol discloses the use of the oncolytic virus Voyager V1 and cemiplimab to treat specific malignancies. Sznol does not disclose or suggest any triple combination therapies, let alone a combination with an anti-CTLA4 antibody. Sznol also fails to teach or suggest a triple combination therapy, wherein the combination of an oncolytic virus, an anti-PD-1 antibody or antigen-binding fragment thereof, and an anti-CTLA4 antibody or antigen-binding fragment thereof are administered concurrently, as presently claimed… Russell discloses the design of Voyager V1 and its anti-tumor efficacy. The only combination therapy mentioned in Russell is administration of the virus ‘in combination with pharmacological agents that facilitate viral replication and spread within cancer cells or agents that protect non-cancer cells from viral toxicity.’ See Russell, column 10, lines 3-7. Russell fails to teach or suggest a triple combination of an oncolytic virus, an anti-PD-1 antibody, and an anti- CTLA4 antibody, let alone a combination therapy wherein the three pharmaceutical agents are administered concurrently, as presently claimed.”
These arguments have been fully considered but are not deemed persuasive. It is initially noted that “[o]ne cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).” It is also noted that Russel et al. is an evidentiary reference used to demonstrate that Voyager V1 meets the limitations of an oncolytic VSV that expresses a cytokine (IFNβ), which is positioned between the viral M and G genes, and NIS, which is positioned between the viral M and G genes, as indicated at p. 7 of the Non-Final Rejection, dated 02/03/2026.
With respect to the teachings of Lala et al. and Sznol et al., as indicated at p. 7 of the Non-Final Rejection, one of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to combine the teachings of Lala et al. and Sznol et al. to develop a method of treating cancer, such as NSCLC by administering an oncolytic virus, such as VSV, in combination with an anti-PD-1 antibody and an anti-CTLA4 antibody to a subject in need thereof. One of ordinary skill in the art would have been motivated to do so, because Lala et al. teach a method of treating various cancers, including NSCLC, by administering an anti-PD-1 antibody and an anti-CTLA4 antibody to a subject in need thereof. Furthermore Sznol et al. teach or suggest the treatment of cancers, such as NSCLC, by administering an anti-PD-1 antibody in combination with Voyager V1, an oncolytic VSV engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and an anti-PD-1 antibody. As such one of ordinary skill in the art would have been motivated to modify the method of Lala et al. to comprise the administration of Voyager V1, as taught by Sznol et al., because there would have been a reasonable expectation the resultant invention would be effective in treating various cancers, such as NSCLC, by combining the administration of multiple anti-cancer medicaments. Furthermore one of ordinary skill in the art would appreciate that when administering a combination of medicaments, said medicaments may be administered concurrently or sequentially, and one of ordinary skill in the art would have been motivated to determine which administration regimen results in safe and efficacious therapy. The combination of references cited renders obvious a method of treating cancer, comprising 1) selecting a cancer patient and 2) concurrently administering to said patient a combination of an oncolytic virus, an anti-PD-1 antibody, and an anti-CTLA4 antibody, as recited in claim 1.
Applicant also discusses a study where “mice were implanted with 3 X 10⁵ MC38 [colon cancer cell line] tumor cells at Day 0. Treatment was initiated at Day 15, when tumors reached an average volume of approximately 150 mm³. Among the treatment groups, one group of mice were administered one dose of the oncolytic virus VSV-M51R-GFP at Day 15, and four doses of anti-PD-1 antibody and anti-CTLA4 antibody were administered at Days 15, 18, 22, and 25; and the control group was administered vehicle (PBS) and isotype antibody controls. See Specification, ¶¶[170]; Table 5. Tumor volume was measured approximately twice per week; complete tumor clearance was assessed on Days 29 and 45; and survival was recorded until end of experiment, at Day 60. See Specification, ¶[170]; Table 6. Mice administered one dose of VSV-M51R-GFP concurrently with anti-PD-1 and anti-CTLA4 on Day 15, followed by three additional doses of both antibodies showed outstanding inhibition of tumor growth as early as Day 22. See Fig. 6. Remarkably, at Day 29, when all mice were still alive, while the average tumor volume of control mice was 2404 mm³, the average tumor volume of mice administered the triple-combination therapy was only 40 mm³ (- i.e., a 98.3% reduction). See Table 6. Complete tumor clearance and survival of mice administered the triple-combination therapy was also dramatic, with 8/8 mice tumor-free by Day 45 and 100% surviving to end of experiment at Day 60. In comparison, no control mice had survived even to Day 32, let alone exhibited any tumor clearance. See Specification, Table 6. Thus, Example 3 shows that a therapy having the therapeutic components and administration regimen representative of the claims dramatically inhibited tumor growth, induced complete tumor regression, and improved survival as compared untreated subjects.”
Table 6 is shown below:
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322
623
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It is noted that the anti-PD-1/anti-CTLA4 group demonstrated an improvement in tumor volume compared to control samples; however the VSV (oncolytic virus)/anti-PD-1/anti-CTLA4 demonstrated a much improved reduction in tumor volume and tumor-free mice at days 29 and 45. This evidence demonstrates the surprising efficacy of VSV (oncolytic virus)/anti-PD-1/anti-CTLA4 treatment for colon cancer cells. Applicant points to similar results in Figures 14 and 15.
Additional evidence of surprising or unexpected results is provided at Table 8, which is shown below:
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429
626
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While the administration of VSV in combination with an anti-PD-1 antibody only slightly reduced tumor volume with no test subjects surviving at day 29 or 42 post-treatment, the administration of VSV in combination with an anti-PD-1 antibody and an anti-CTLA4 antibody led to an impressive reduction in tumor volume with 42.9% and 38.6% of test subjects surviving at days 29 and 42, respectively.
While Applicant has provided evidence of unexpected or surprising results, said evidence is not sufficient to overcome the rejection of the claims under 35 U.S.C. 103. According to MPEP 716.02(d), “[w]hether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)…”
The VSV strain used in in the experiments described by Applicant are either the VSV-M51R-Fluc strain or the VSV-mIFNb-NIS (mVV1) strain. Furthermore it appears that the anti-PD-1 antibody used is the anti-mouse PD-1 rat IgG2a antibody (clone 29F1.A12 from Bioxcell), and the anti-CTLA4 antibody used is the anti-mouse CTLA4-mlgG2a antibody (clone 9D9). Applicant has not demonstrated that the observed unexpected or surprising results occur with the use of any other VSV strain, anti-PD-1 antibody, or anti-CTLA4 antibody. Applicant has also not demonstrated that the observed unexpected or surprising results occur with cell types other than colon cancer cells. Additionally one of ordinary skill in the art would not expect the observed unexpected or surprising results to occur for any cancer type following the administration of any VSV strain, any anti-PD-1 antibody, and any anti-CTLA4 antibody. For example the claims encompass agonist and antagonist anti-PD-1 antibodies, and while antagonist anti-PD-1 antibodies would be expected to stimulate T cell responses, agonist anti-PD-1 antibodies would be expected to inhibit T cell responses. As indicated at [0279] of Shen et al. (US PG PUB 2019/0373868, publication date: 12/12/2019), “[i]n some embodiments, the genetically modified animals can be used for determining whether an anti-PD-1 antibody is a PD-1 agonist or antagonist. In some embodiments, the methods as described herein are also designed to determine the effects of the agent (e.g., anti-PD-1 antibodies) on PD-1, e.g., whether the agent can stimulate immune cells or inhibit immune cells (e.g., T cells), whether the agent can increase or decrease the production of cytokines, whether the agent can activate or deactivate immune cells (e.g., T cells, macrophages, B cells, or DC), whether the agent can upregulate the immune response or downregulate immune response…” As such Applicant’s evidence of unexpected or surprising results is not commensurate in scope with the claims.
Applicant further asserts that neither Silverman et al. nor Papadopoulos et al. remedy the deficiencies of Lala et al. or Sznol et al., and Applicant further asserts that the cited references do not provide a basis for the nonstatutory obviousness-type double patenting rejections of record; however as indicated above one of ordinary skill in the art would have been motivated to modify the method of Lala et al. to comprise the administration of Voyager V1, as taught by Sznol et al., because there would have been a reasonable expectation the resultant invention would be effective in treating various cancers, such as NSCLC, by combining the administration of multiple anti-cancer medicaments. Furthermore one of ordinary skill in the art would appreciate that when administering a combination of medicaments, said medicaments may be administered concurrently or sequentially, and one of ordinary skill in the art would have been motivated to determine which administration regimen results in safe and efficacious therapy. The combination of references cited renders obvious a method of treating cancer, comprising 1) selecting a cancer patient and 2) concurrently administering to said patient a combination of an oncolytic virus, an anti-PD-1 antibody, and an anti-CTLA4 antibody, as recited in claim 1. As such the claim rejections under 35 U.S.C. 103 and the nonstatutory obviousness-type double patenting rejections of record are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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