DETAILED ACTION
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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/6/2026 has been entered.
Claims 1-11 and 16-17 have been canceled, and claims 12-15 and 18-19 have been considered on the merits. All arguments have been considered.
Response to Amendment
The declaration under 37 CFR 1.132 filed 2/6/2026 is insufficient to overcome the rejection of claims 12-19 based upon Ahn et al. in view of Pardoll and Rojas et al. as set forth in the last Office action.
The declaration showed evidence supporting the synergistic effect of the combination as claimed (i.e. IL12/shVEGF and anti-PD-1) in three different cancer types including melanoma, ovarian cancer and breast cancer in a mouse model. Along with the previous declaration filed on 7/16/2025, and the data shown in the instant specification (i.e. Figures 3 and 5), applicant has shown that there is a synergistic effect from combining IL-12/shVEGF expression in a recombinant oncolytic adenovirus and anti-PD-1 or anti-PD-L1 antibody.
However, as discussed in the previous OA, the synergism between blockage of PD-1 and VEGFR in treating a cancer is known in the art according to Yasuda et al. (2013, Clin. Exp. Immunol.; of record). The teaching of Yasuda et al. would indicate that there would be a synergism expected when PD-1 and VEGFR are blocked in the method of treating a caner. Hato et al. (2015, Immunotherapy; of record) also teach the synergy is achieved when combining anti-VEGF therapy with immunotherapy, i.e. immune checkpoint blockade, and refers to the teaching of Yasuda et al. (p.306, 2nd col.; p.307, 2nd col.; Fig. 3). Based on these teachings a synergistic effect is expected from the combination of anti-VEGF and anti-PD-1 or anti-PD-L1 in treating a cancer.
MPEP716.02(a)(I) states “[h]owever, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage.”
If the alleged synergistic effect is expected, then the synergistic effect per se cannot be unexpected results. Thus, the synergism present in the combination as claimed cannot be considered unexpected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 12-15 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Ahn et al. (2016, Oncotarget; IDS ref.) in view of Pardoll (2016, Nat Rev Cancer; of record), Rojas et al. (2015, Clin. Cancer Res.; IDS ref.), Tugues et al. (2015, Cell Death and Differentiation; of record) and Hamanishi et al. (2016, Int J Clin Oncol; of record)
Ahn et al. teach an oncolytic adenovirus (Ad) co-expressing IL-12 and VEGF-specific short hairpin ribonucleic acid (RdB/IL12/shVEGF) for antitumor treatment (Abstract). The oncolytic Ad of Ahn et al. was injected in PBS, i.e. pharmaceutically acceptable carrier (Fig. 5).
Ahn et al. do not teach a step of administering to an individual an immune checkpoint inhibitor. However, it is well known in the art at the time of filing that there are several agents that block the immune-checkpoint pathways according to Pardoll including PD1 antibody (MDX-1106) (see Table 1 at p.31), and they are used for anti-cancer treatment.
It would have been obvious to a person skilled in the art to combine the blocking agents of immune checkpoint pathway taught by Pardoll with the oncolytic Ad of Ahn et al. with a reasonable expectation of success in treating a cancer. A person of ordinary skilled in the art would have been motivated to do so both the oncolytic Ad of Ahn et al. and the blocking agents of the immune checkpoint pathway would produce anti-tumor effect and thus, the combining the two approaches is for the same purpose of treating a cancer. See M.P.E.P. §2144.06 In re Kerkhoven.
Furthermore, it is known in the art that a combination of immune checkpoint blockage and oncolytic virotherapy is used for treating a cancer according to Rojas et al. (see entire document). Thus, one skilled in the art would have a reasonable expectation of success in combining the method of Ahn et al. utilizing the oncolytic Ad and the method of blocking immune checkpoint taught by Pardoll.
Regarding the new limitation of claim 1 directed to the type of cancer, i.e. melanoma, ovarian cancer or breast cancer, Ahn et al. in view of Pardoll do not particularly disclose the type of cancer being treated. However, it would have been obvious to a person skilled in the art to use the agents of Ahn et al. and Pardoll for any of the claimed cancer types with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because Ahn et al. teach IL-12 induces T helper type 1 (Th1) immunity and cytolysis by cytotoxic T-lymphocyte, and it stimulates production of interferon-gamma from T and natural killer cells, and it showed potent antitumor activity in a number of in vivo murine tumor models by inducing immunomodulatory effect (p.84965, Introduction), and Tugues et al. teach that IL-12 can be used in metastatic renal carcinoma, melanoma, colon carcinoma, recurrent ovarian cancer, and neck and head carcinoma (p.241). Pardoll teaches early-stage clinical trials suggest that blockade of the PD1 pathway induces sustained tumor regression in various tumor types (p.23, At a glance), and Table 1 shows PD1 blockade was used in clinical trials for lung cancer, melanoma, renal cancer, or multiple cancers. Thus, one skilled in the art would recognize that the use of IL-12 and immune checkpoint inhibitors can be used for the claimed types of cancers.
Regarding claims 13-14, the oncolytic Ad of Ahn et al. is identical to the claimed recombinant adenovirus and Ahn et al. teach that the oncolytic Ad lacks E1B and E3, and IL-12 and shVEGF were inserted into E1 and E3 region, respectively (Fig. 1).
Regarding claim 15 directed to the composition and the immune checkpoint inhibitor being administered simultaneously, separately or sequentially, Ahn et al. in view of Pardoll do not teach the limitation.
However, it would have been obvious to a person skilled in the art that there are only three options that these two agents (i.e. oncolytic Ad of Ahn et al. and immune checkpoint blocking agents of Pardoll) would be administered, and those three options are administering them simultaneously, separately or sequentially.
Regarding claim 18 directed to the recurrent cancer, Ahn et al. in view of Pardoll do not teach the limitation. Tugues et al. teach recurrent ovarian cancer as discussed above (p.241). Furthermore, Hamanishi et al. teach the use of PD-1/PD-L1 blockage in cancer treatment including recurring cancers including lung cancer (p.454). Thus, it would have been obvious to a person skilled in the art to treat a recurrent cancer using the oncolytic Ad of Ahn et al. and PD-1 checkpoint inhibitor of Pardoll for a recurrent cancer with a reasonable expectation of success.
Regarding claim 19, the limitation is considered as a result which does not require any active step other than the steps of claim 12, and thus, claim 19 is interpreted the same as claim 12.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
It is noted that the Ahn reference cited in the above claim rejection is an intervening reference published before the filing date of the instant application but after the filing of the foreign priority document. Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Claim(s) 12-15 and 18-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yun et al. (WO2015/163622; English translation attached; of record) in view of Pardoll (supra), Rojas et al. (supra), Tugues et al. (supra) and Hamanishi et al. (supra)
Regarding claim 12, Yun et al. teach an anticancer treatment method comprising administering a therapeutically effective amount of a polymer-virus complex for the cancer including lung cancer, breast cancer, ovarian cancer, etc. (p.2, Claims 5, 10-11). Yun et al. teach that the a pharmaceutically acceptable carrier (p.1, Claim 4).
Regarding claims 13-14, Yun et al. teach that the virus can be adenovirus (Ad) which is oncolytic (p.2, claim 8; p.3-4; p.6; p.9), and the adenovirus has E1B or E3 region deleted and decorin gene is inserted (p.3, last para.). Yun et al. also teach an adenovirus expressing shVEGF (RdB/shVEGF) (p.6).
Yun et al. also teach that the virus disclosed therein may further comprise the therapeutic genes, and the therapeutic genes include IL-12 (p.4).
It would have been obvious to a person skilled in the art to insert IL-12 gene into the RdB/shVEGF to express both IL-12 and shVEGF with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated shVEGF has anti-tumor effect and IL-12 is one of several therapeutic gene that can be co-expressed along with shVEGF according to Yun et al. One skilled in the art would recognize based on the teaching of Yun et al. that E1B and E3 region are two sites where transgenes can be inserted upon the deletion of the regions, and IL-12 and shVEGF genes can be inserted E1B and E3 regions of the adenovirus, respectively.
Yun et al. do not teach the administration of the immune checkpoint inhibitor (claim 12).
However, it is well known in the art at the time of filing that there are several agents that block the immune-checkpoint pathways according to Pardoll including PD1 antibody (MDX-1106) (see Table 1 at p.31), and they are used for anti-cancer treatment.
It would have been obvious to a person skilled in the art to combine the blocking agents of immune checkpoint pathway taught by Pardoll with the oncolytic Ad of Yun et al. with a reasonable expectation of success in treating a cancer. A person of ordinary skilled in the art would have been motivated to do so both the oncolytic Ad of Yun et al. and the blocking agents of the immune checkpoint pathway would produce anti-tumor effect and thus, the combining the two approaches is for the same purpose of treating a cancer. See M.P.E.P. §2144.06 In re Kerkhoven.
Furthermore, it is known in the art that a combination of immune checkpoint blockage and oncolytic virotherapy is used for treating a cancer according to Rojas et al. (see entire document). Thus, one skilled in the art would have a reasonable expectation of success in combining the method of Yun et al. utilizing the oncolytic Ad and the method of blocking immune checkpoint taught by Pardoll.
Regarding claim 15 directed to the composition and the immune checkpoint inhibitor being administered simultaneously, separately or sequentially, Yun et al. in view of Pardoll do not teach the limitation.
However, it would have been obvious to a person skilled in the art that there are only three options that these two agents (i.e. adenovirus of Yun et al. and immune checkpoint blocking agents of Pardoll) would be administered, and those three options are administering them simultaneously, separately or sequentially.
Regarding claim 18 directed to the recurrent cancer, Yun et al. in view of Pardoll do not teach the limitation. Tugues et al. teach recurrent ovarian cancer as discussed above (p.241). Furthermore, Hamanishi et al. teach the use of PD-1/PD-L1 blockage in cancer treatment including recurring cancers including lung cancer (p.454). Thus, it would have been obvious to a person skilled in the art to treat a recurrent cancer using the oncolytic Ad of Yun et al. and PD-1 checkpoint inhibitor of Pardoll for a recurrent cancer with a reasonable expectation of success.
Regarding claim 19, the limitation is considered as a result which does not require any active step other than the steps of claim 12, and thus, claim 19 is interpreted the same as claim 12.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 12-15 and 18-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 17/587,973 in view of Pardoll (supra), Rojas et al. (supra), Tugues et al. (supra) and Hamanishi et al.(supra). The claims of the ‘973 application disclose a method for treating cancer by administering a recombinant oncolytic adenovirus expressing IL-12 and shRNA suppressing VEGF. They do not disclose the administration of an immune checkpoint inhibitor. However, it is well known in the art at the time of filing that there are several agents that block the immune-checkpoint pathways according to Pardoll including PD1 antibody (MDX-1106) (see Table 1 at p.31), and they are used for anti-cancer treatment.
It would have been obvious to a person skilled in the art to combine the blocking agents of immune checkpoint pathway taught by Pardoll with the oncolytic adenovirus for the method of treating cancer of the ‘973 application for the same purpose of treating a cancer. See M.P.E.P. §2144.06 In re Kerkhoven. Furthermore, it is known in the art that a combination of immune checkpoint blockage and oncolytic virotherapy is used for treating a cancer according to Rojas et al. (see entire document). Thus, one skilled in the art would have a reasonable expectation of success in combining the method of the claims of the ‘973 application and the method of blocking immune checkpoint taught by Pardoll.
Regarding the types of cancer being treated (claim 12), claim 7 of the ‘973 application discloses the claimed cancers.
Regarding the recurrent cancer, the claims of the ‘973 application do not teach the limitation. However, Tugues et al. and Hamanishi et al. teach the treatment of the recurrent cancer using IL-12 and immune checkpoint inhibitor (PD1 blockage) would be used for a cancer treatment.
Thus, the claims of the ‘973 application in view of the cited references render the claims of the instant application obvious.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 2/6/2026 have been fully considered but they are not persuasive.
As discussed above in response to the declaration, the Examiner has determined that there is a synergistic effect of the combined treatment using the oncolytic virus expressing IL-12 and shRNA against VEGF (RdB/IL12/shVEGF), and a PD-1 or PD-L1 antagonist in treating melanoma, ovarian cancer or breast cancer in mice based on the data shown in the declaration and the instant application. However, the synergism of the claimed invention is considered expected.
Applicant argued that the teachings of Yasuda et al. and Hato et al. for the general concept of combining anti-VEGF and anti-PD-1 therapies are distinguishable because they teach systemic administration of anti-VEGF agents, not the localized, tumor-microenvironment-remodeling effects of an oncolytic virus co-expressing shVEGF and the potent immunostimulant IL-12. Applicant alleged that the synergy is achieved in the instant application through a distinct mechanism: the oncolytic virus lyses tumor cells, releasing tumor antigens, while simultaneously expressing shVEGF to normalized tumor vasculature and IL-12 to microenvironment that is then exquisitely sensitive to the effects of PD-1/PD-L1 blockage.
The Examiner is not convinced by the applicant’s arguments. This is because there is no establishment that the other factors indicated by applicant (oncolytic virus; releasing tumor antigens, IL-12, etc.) contribute to the synergism shown between the oncolytic vector expressing IL-12/shVEGF and anti-PD-1/PD-L1 antibodies. The declaration and the data shown in the instant specification does not point out that other factors are necessary for the synergism as the synergistic effects were shown by comparing RdB/IL12/shVEGF and a-PD-1 or a-PD-L1. Furthermore, based on the data shown with regard to the RdB/IL12/GMCSF-TK and aPD-L1, which does not support any synergism, indicate that IL12 or oncolytic virus does not provide anything to the synergism between RdB/IL12/shVEGF and a-PD-1. Therefore, it is the Examiner’s position that the synergism shown by the instant declaration and the specification is expected based on the teaching of Yasuda et al. and Hato et al.
Applicant has shown data that the synergism is present in two additional cancers in addition to melanoma shown in the figures of the instant specification. It would be considered unexpected if applicant shows that the synergism is only in the claimed types of cancer whereas not other types of cancers, if there is any evidence supporting this.
Regarding the double patenting rejection, applicant asserted that based on the unexpected and synergistic effect, the claims of the ‘973 application do not anticipate or render the claims of the instant application obvious. The Examiner respectfully disagrees with this assertion. As the 103 rejection is maintained due to the “expected” synergism as discussed above, the same rationale is applied to the combined teachings of the claims of the ‘973 application in view of Pardoll, Rojas, Tugues and Hamanishi.
Conclusion
No claims are allowed.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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