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 .
Claim Status
Claim listing filed on September 15, 2025 is pending. Claims 2, 9-10, 12-14, 19-20, and 27-46 are canceled. Claims 1, 5-8, and 17-18 are amended. Claim 48 is new. Claims 5, 21-26, and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions or species. Claims 1, 3-4, 6-8, 11, 15-18, and 48 are examined upon their merits.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 2, 9, 12-14, and 19-20 have rendered all previous objections or rejections directed to these claims moot.
The objections to the drawings are withdrawn in view of Applicant’s amended drawings filed 09/15/2025.
The rejection of claims 7-8 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments. In particular, the indefinite term “about” has been removed from the claims.
The rejection of Claims 1, 3-4, 7-8, and 16-17 under 35 U.S.C. 102(a)(1) as being anticipated by Cervera-Carrascon et al. Oncoimmunology 2018 is withdrawn in view of Applicant’s amendments. Specifically, Cervera-Carrascon does not teach the specific structure of the oncolytic adenoviral vector required by amended Claim 1.
The rejection of Claims 1-4, 7-8, and 16-18 under 35 U.S.C. 103 as being unpatentable over Cervera-Carrascon et al. Oncoimmunology 2018 is withdrawn in view of Applicant’s amendments. Specifically, Cervera-Carrascon does not teach the specific structure of the oncolytic adenoviral vector required by amended Claim 1.
The rejection of Claims 1-4, 6-9, 11-12, 14, and 16-17 under 35 U.S.C. 103 as being unpatentable over Cervera-Carrascon et al. Oncoimmunology 2018 in view of Varga et al. Gynecol Oncol. 2018 is withdrawn in view of Applicant’s amendments. Specifically, the references do not teach the specific structure of the oncolytic adenoviral vector required by amended Claim 1.
The rejection of Claims 1-4, 7-8, 11, 13, and 16-17 under 35 U.S.C. 103 as being unpatentable over Cervera-Carrascon et al. Oncoimmunology 20180 in view of Varga et al. Gynecol Oncol. 2018, and further in view of Saito et al. Gastric Cancer 2011 and Riccardi et al. Expert Opin Ther Targets 2018 is withdrawn in view of Applicant’s amendments. Specifically, the references do not teach the specific structure of the oncolytic adenoviral vector required by amended Claim 1.
The rejection of Claims 1-4, 7-8, 15-17, and 19-20 under 35 U.S.C. 103 as being unpatentable over Cervera-Carrascon et al. Oncoimmunology 2018, and further in view of Hemminki WO 2014/170389 and White et al. Mol Cell Biol 1992 is withdrawn in view of Applicant’s amendments. Specifically, the references do not teach the treatment of ovarian cancer as required by amended Claim 1.
Claim Rejections - 35 USC § 112 (Maintained)
Claims 1, 3-4, 6-8, 11, 15-18, and 48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for ameliorating ovarian cancer, does not reasonably provide enablement for treating ovarian cancer, which the disclosure defines as encompassing prevention (Claim 1). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As on record in the non-final office action filed 03/13/2025, the specification defines “treating” as “for purposes which include not only complete cure but also prophylaxis, amelioration, or alleviation of disorders or symptoms related to a cancer or tumor” (page 14, lines 32-34). Because prophylaxis is listed in the definition, “treating” is interpreted as both ameliorating an established cancer and preventing the onset of cancer. The World Health Organization teaches that only 30-50% of cancer cases are preventable, and prevention primarily comprises risk management such as avoiding tobacco, alcohol, obesity, and carcinogens (“Preventing Cancer”; of record). The state of the art shows a continued lack of predictability even after the effective filing date of the instant invention in administering therapeutics prophylactically to prevent the onset of ovarian cancer, and there is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in preventing ovarian cancer.
Applicant's arguments filed September 15, 2025 have been fully considered but they are not persuasive. Applicant argues that limiting the scope of Claim 1 to specifically treating ovarian cancer overcomes the 112(a) enablement rejection of record. Examiner maintains that “treating” is still directed to both therapeutically treating an established cancer and prophylactically preventing the onset of cancer based on the definition of “treating” provided in the instant specification (page 14, lines 32-34). As there is no basis for preventing ovarian cancer by prophylactically administering an oncolytic adenoviral vector encoding TNFalpha and/or IL-2 and one or more immune checkpoint inhibitors in the art prior to filing and no working examples of preventing cancer provided in the specification, the disclosure is not enabled for treating ovarian cancer.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
Claims 1, 3-4, 6-8, 11, 15-18, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Cervera-Carrascon et al. Oncoimmunology (of record) as evidenced by Jackson Laboratory (of record) in view of Hemminki WO 2014/170389 (of record) and White et al. Mol Cell Biol 1992 (of record), and further in view of Varga et al. Gynecol Oncol. 2018 (of record) and Havunen et al. Mol Ther Oncolytics 2017 (of record in IDS filed 10/24/2022).
In regard to Claim 1, Cervera-Carrascon teaches administering oncolytic adenovirus vectors encoding TNFalpha and IL-2 in combination with an anti-PD-1 antibody to treat mice models of melanoma (abstract). In regard to Claims 3-4 and 7, the viral treatments were given intratumorally with doses of 0.05-1 X 108 VP (Materials and methods – Treatments). In regard to Claim 8, 0.1 mg of the anti-PD-1 antibody was injected (Figure 1 caption) to 5–7-week-old C57 BL/6J mice (Materials and methods – In vivo studies). According to The Jackson Laboratory (accessed 2025), C57 BL/6J mice from 5-7 weeks old across both sexes weigh 20 grams on average. Administering 0.1 mg anti-PD-1 antibody to a 20 gram mouse is equivalent to 5 mg/kg (0.1 mg/0.02 kg). In regard to Claim 16, Cervera-Carrascon teaches that the preclinical mouse studies provide the rationale and schedule for a clinical trial where oncolytic adenovirus coding for TNFalpha and IL-2 can be administered to melanoma patients receiving an anti-PD-1 antibody (abstract). In regard to Claim 17, in one experimental arm the virus and the anti-PD-1 were administered simultaneously (Results section 4, paragraph 1 and Figure 4A).
In regard to Claim 18, Cervera-Carrascon teaches an experimental arm wherein the virus was administered on Days 0 and 1 followed by the combination of virus and anti-PD-1 administered on Days 3, 6, 9, etc. (Results section 4, paragraph 1 and Figure 4A). Cervera-Carrascon teaches that it is beneficial to administer the virus before the anti-PD-1 in a “prime-boost approach” as it resulted in 100% of tumors to regress and all mice to survive (abstract). Therefore, Cervera-Carrascon teaches an advantage to sequentially administering the virus before the anti-PD-1, and separating their administration by exactly 24 hours is considered routine optimization. MPEP § 2144.05 II states “It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
The teachings of Cervera-Carrascon as they apply to Claims 1, 3-4, 7-8, and 16-18 are outlined above. Cervera-Carrascon does not explicitly teach administering an additional therapy selected from radiotherapy or chemotherapy (Claim 15); wherein said oncolytic adenoviral vector encoding TNFalpha and IL-2 comprises (1) a 5/3 chimeric fiber knob, (2) E2F1 promoter for tumor specific expression of E1A, (3) a 24 bp deletion (D24) in the Rb binding constant region 2 of adenoviral E1, (4) a nucleic acid sequence deletion of viral pg19k and 6.7k reading frames, and (5) a nucleic acid sequence encoding at least TNFalpha and IL-2 in the place of the deleted pg19k/6.7k in the E3 region resulting in replication-associated control of transgene expression under the viral E3 promoter (Claim 1); or wherein the adenoviral vector further comprises a deletion of E1B19k (Claim 1).
Hemminki teaches a method of treating cancer by administering an oncolytic adenoviral vector (Claim 30, page 51) wherein the oncolytic adenoviral vector comprises (1) a 5/3 chimeric fiber knob, (2) E2F1 promoter for tumor specific expression of E1A, (3) a 24 bp deletion (D24) in the Rb binding constant region 2 of adenoviral E1, (4) a nucleic acid sequence deletion of viral pg19k and 6.7k reading frames, and (5) a nucleic acid sequence encoding at least one cytokine transgene in the place of the deleted pg19k/6.7k in the E3 region resulting in replication-associated control of transgene expression under the viral E3 promoter wherein the cytokines are TNFalpha and IL-2 (Claim 23, page 50). Hemminki teaches that the method can further comprise administration of concurrent radiotherapy, monoclonal antibodies, or chemotherapy (page 29, lines 3-7) which supports the concept of combination treatments in oncology that is well understood in the art. Hemminki does not teach the deletion of E1B19k.
White teaches that expression of E1B19k by viral infection blocks the action of TNFalpha and enables adenovirus to evade TNFalpha-dependent immune surveillance (abstract). When the E1B19k gene is deleted, TNFalpha activity is restored (Results paragraph 5).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to modify the method for treating cancer comprising administering an oncolytic adenoviral vector encoding TNFalpha and IL-2 in combination with an anti-PD-1 antibody as taught by Cervera-Carrascon to comprise the specific adenovirus construct taught by Hemminki and White. Hemminki teaches an identical oncolytic adenovirus vector construct comprising TNFalpha and IL-2 as presently claimed except for the deletion of E1B19k. White teaches that the deletion of E1B19k is necessary to preserve TNFalpha activity. Therefore, it would have been obvious to combine prior art elements according to known methods to yield predictable results. Specifically, it would have been obvious to substitute a known adenovirus construct into a known method of treating cancer wherein the adenovirus construct has a known E1B19k deletion to preserve TNFalpha activity.
The teachings of Cervera-Carrascon in view of Hemminki and White as they apply to Claims 1, 3-4, 7-8, and 15-18 are outlined above. Cervera-Carrascon further teaches that immune checkpoint inhibitors are known to work well in “hot” tumors characterized by high immunogenicity and high CD8+ T cell function whereas “cold” tumors characterized by suppressed immune systems do not respond well to immune checkpoint inhibitors (Introduction paragraph 1). Cervera-Carrascon teaches that when the immune system is primed with pre-treatment of the oncolytic adenovirus vectors comprising TNFalpha and IL-2, the following anti-PD-1 treatment has a stronger anti-tumor effect than anti-PD-1 treatment alone (Figure 4). Specifically, the virus treatment synergizes with the anti-PD-1 treatment (Discussion paragraph 2), meaning that the agents work better together than they do as monotherapy treatments.
Cervera-Carrascon in view of Hemminki and White do not explicitly teach wherein the immune checkpoint inhibitor is pembrolizumab (Claims 6 and 48); wherein the cancer is ovarian cancer (Claim 1); or wherein the subject has failed at least one previous chemotherapy or immunotherapy treatment (Claim 11).
Varga teaches clinical trial results wherein ovarian cancer patients who failed previous chemotherapy were administered the anti-PD-1 antibody pembrolizumab (Abstract and Table 1).
Further, Havunen teaches administering an oncolytic adenovirus encoding TNFalpha and IL-2 to treat ovarian cancer cell lines (SKOV3-Luc) (Fig. 1B) and mouse models of ovarian cancer (Fig. 3).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to apply the method for treating cancer comprising administering an oncolytic adenoviral vector encoding TNFalpha and IL-2 in combination with an anti-PD-1 antibody as taught by Cervera-Carrascon to the patient population taught by Varga and Havunen. Varga teaches that ovarian cancer can be treated with an anti-PD-1 antibody, and Havunen teaches that ovarian cancer can be treated with the oncolytic adenoviral vector encoding TNFalpha and IL-2. Because Cervera-Carrascon teaches that the oncolytic adenoviral vector synergizes with anti-PD-1 therapy, it would be obvious to use the combination in ovarian cancer patients who already receive the anti-PD-1 antibody pembrolizumab in the refractory setting. Cervera-Carrascon teaches that immune checkpoint inhibitor non-responders have immunologically “cold” tumors where CD8+ T cells are not active, but priming a subject’s immune system with the virus increases the response to anti-PD-1 treatment. Therefore, it is obvious to administer the combination treatment of virus and anti-PD-1 therapy in patient populations where immune checkpoint inhibitors are standard practice but patients may have “cold” tumors to improve the anti-tumor effect of anti-PD-1.
Response to Arguments
Applicant's arguments filed September 15, 2025 have been fully considered but they are not persuasive.
Applicant argues that the teaching of MD Anderson Cancer Center in the non-final office action filed 03/13/2025 does not teach wherein ovarian cancer is treated with immune checkpoint inhibitors. Applicant further argues that nothing cited in the art would have reasonably provided an expectation that the claimed method of treatment would have been effective in treating ovarian cancer. As recited in the rejection above, Varga teaches that ovarian cancer can be treated with an anti-PD-1 antibody, and Havunen teaches that ovarian cancer can be treated with the oncolytic adenoviral vector encoding TNFalpha and IL-2. Because Cervera-Carrascon teaches that the oncolytic adenoviral vector synergizes with anti-PD-1 therapy, it would be obvious to use the synergistic combination in ovarian cancer patients who already receive the anti-PD-1 antibody in order to improve the efficacy of the therapy.
Applicant argues that the results of treating ovarian cancer with the oncolytic adenoviral vector and anti-PD-1 were unexpected and cites a publication emphasizing their synergistic relationship. These results are not unexpected in view of Varga and Havunen that teach that the two therapies independently have anti-tumor activity in ovarian cancer and in view of Cervera-Carrascon that teaches that the combination is synergistic.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) 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.
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/SARAH COOPER PATTERSON/ Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675