DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicants’ amendments to the claims filed on August 5, 2026, have been received and entered. Claim 1 has been amended, while claims 2-5 have been canceled. Claims 1, 6-16 are
under consideration.
Withdrawn-Claim Rejections - 35 USC § 112-Biological deposit
Claims 1, 6-16 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. Applicants’ submission of a declaration under 37 C.F.R. § 1.808 signed by the inventor, providing the required assurances including that the deposited biological material would be made available to the public upon grant of the patent is found persuasive, therefore, previous rejection of claims 1, 6-16 is hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 1, 6, 8, 11-14 and 16 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al (CN102146418B, dated 1/15/2014). In view of Applicants’ amendment of base claim 1, introducing the limitation of claims 2-5, that was previously not included in the rejection, obviates the basis of the rejection. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are, however, subject to new rejections over the prior art of record, as set forth below.
Claims 1, 6-9, 11-15 and 16 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al (Journal for Immuno Therapy of Cancer 2021;9:e002224, 1-10). ). In view of Applicants’ amendment of base claim 1, introducing the limitation of claims 2-5, that was previously not included in the rejection, obviates the basis of the rejection. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are, however, subject to new rejections over the prior art of record, as set forth below.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 1-9, 11-16 were rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (Journal for Immuno Therapy of Cancer 2021;9:e002224, 1-10) as evidenced by ClinicalTrials.gov ID NCT 04386967, posted 5/13/2020), Hu-Lieskovan (J Clin Oncol 36, 2018 (suppl; abstract TPS9603), Zhu (Molecular Therapy: Oncolytics 2019Vol. 15. 201-213). In view of Applicant’s amendments to the claims incorporating the limitation from dependent claims and introducing limitation of “subject is a human subject”, that was previously not required by claims, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are, however, subject to new rejections over the prior record of art.
Claims 1-5, 9-12 were rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (Journal for Immuno Therapy of Cancer 2021;9:e002224, 1-10) as evidenced by ClinicalTrials.gov ID NCT 04386967, posted 5/13/2020), Hu-Lieskovan (J Clin Oncol 36, 2018 (suppl; abstract TPS9603), Zhu (Molecular Therapy: Oncolytics 2019Vol. 15. 201-213) as applied above for claim 1, and further in view of Chesney et al (Journal of Clinical Oncology, 2018, 36, 1658-1667). The rejection is withdrawn for the reasons discussed above.
New-Claim Rejections - 35 USC § 103- necessitated by amendments
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.
Claims 1, 6-16 remain rejected under 35 U.S.C. 103 as being unpatentable over Shoushtari et al (Clinical Cancer Research, 2023, 100-109), Zhu (Molecular Therapy: Oncolytics 2019Vol. 15. 201-213, art of record) Zhang et al (Journal for Immuno Therapy of Cancer 2021;9: e002224, 1-10) and further in view of Chesney et al (Journal of Clinical Oncology, 2018, 36, 1658-1667).
Claim interpretation: Recitation of capable of infecting and thus killing melanoma cells is interpreted as an implicit property of the oHSV2. To the extent, prior art teaches use of same virus capable of infecting melanoma cell, it necessarily be capable of killing melanoma cell.
With respect to claims 1, 6, Shoushtari teaches intratumorally administering either sequentially or in combination with oncolytic virus in patients with melanoma resistant to prior PD-1 blockade (see abstract and page 101, within box), wherein the patient is enrolled in US and Norway and, all patients had received previous anti–PD-1 therapy (≥,2 cycles), 12 (57%) and patient is at disease stage IV-IVM1c ) (see .page 102, col. 2, last para. table 1). The results show oncolytic virus promoted T-cell infiltration, particularly cytotoxic CD8þ T cells, which persisted at Week 9, driving clinical benefit (abstract). Shoushtari contemplated longer treatment duration and follow-up in a larger cohort of patients with anti–PD-1 resistant melanoma to inform the durability of clinical responses (see page 107, col. 2, para. 2). Shoushtari differs from claimed invention by not disclosing delivering oncolytic oHSV2 in a human having melanoma that is resistant to anti-PD-1 monoclonal antibody.
Zhu teaches proof of concept of oHSV2 based therapeutics by disclosing a melanoma tumor-bearing mice (B16R, is a variant developed to be resistant to anti-PD-1 monoclonal therapy) are treated with PBS, oHSV2, or oHSV2-aPD1 every other day via intertumoral injection (see page 204, col. 1, para. 1). It is disclosed that both CD4+ and CD8+ memory T cells increased significantly following oncolytic virus treatments (Figures 4E and 4F). Moreover, the percentage of dendritic cells (DCs) was also enhanced in the OV groups (Figure 4G). The combination of reference differs from claimed invention by not disclosing delivering oncolytic oHSV2.
Zhang cure the deficiency by teaching a method for treating a subject with melanoma, comprising: intratumorally administering the subject a therapeutically effective amount of an antitumor drug, wherein the antitumor drug comprises recombinant oncolytic herpes simplex virus type II (oHSV2)) (see page2, col. 2, para. 2). It is further disclosed that oHSV2 (OH2) is a novel oncolytic virus derived from the wild-type HSV-2 strain HG52. In the construction of this virus, the ICP34.5 neurovirulence gene was deleted to attenuate the toxicity and enhance tumor selectivity. The ICP47 gene is removed to help present tumors associated with antigens and promote oncolytic activity. The gene encoding the human granulocyte-macrophage colony-stimulating factor (GM-CSF) is added to potentiate antitumor immunity similar to oHSV2 deposited in the instant application (see page 1, col. 2, last para to page 2, col. 1, para. 1) (limitation of claim 16). Zhang teaches subject has malignant melanoma and has been tested for terminal phase III -IV (see page 1, col. 1, para. 2) as evidenced by NCT 04386967 who reported subject with stage III or stage IV malignant melanoma are included in the study (see inclusion criterion, page 4) (claim 1). With respect to claim 7, Zhang teaches intra-tumoral injection is performed either directly for cutaneous or subcutaneous lesions, or with ultrasound guidance for deep-located nodes or organ metastases (see page 2, col. 2, para. 2). Regarding claim 8., Zhang teaches that HSV2 is formulated in a pharmaceutically acceptable carrier or excipient (see para. 151). With respect to claim 9, Zhang teaches HSV2 is delivered at three dose levels (106, 107 and 108 CCID50/mL) every 2 weeks (see page 2, col. 1, last para.).
With respect to claims 11-15, Zhang teaches that HSV2 is administered at a dose of at doses (106, 107 and 108 CCID50/mL) as single agent or with fixed-dose HX008. (anti-{D1 antibody). It is further disclosed that the volume injected to each lesion is based on the longest diameter of the tumor (≤1.5 cm, up to 1 mL; >1.5 to ≤2.5 cm, up to 2 mL; >2.5 to ≤5.0 cm, up to 4 mL; >5.0 cm, up to 8 mL) (limitation of claim 12) (see page 2, col. 2, para. 2).
Regarding claim 14, Zhang teaches HSV2 is administered in multiple doses at days 1, 4 and 7 (example 4, para. 288). The combination of references differs from claimed invention by not disclosing administering HSV2 to a subject having anti PD-1 resistant melanoma.
The combination of reference differs from claimed invention by not disclosing antitumor drug is administered with an administration period of ≥ 6 months with a dose of 106 CCID50/ml, 107 CCID50/ml or 108 CCID50/ml with a single administration volume from 1 to 8 ml.
Before the effective filing date of instant application, Chesney teaches administering genetically modified oHSV1 plus ipilimumab or ipilimumab alone in a subject with advance melanoma of disease stage IIIB/IIIC/IVM1a v IVM1b to better distinguish effects between patients whose disease had or had not spread beyond the skin and/or lymph nodes. (see page 1659, col. 2, para. 1). Further teaches administering the treatment every 2 weeks at 108 plaque-forming units/mL (< 4.0 mL) (see page 1659, col. 2, para. 2). It is disclosed that oHSV treatment continued until complete response and all injectable tumors had disappeared (See page 1659, col. 2, para. 2. The median time to response was 5.8 months to 10.9 months (see table 2) (limitation of claims 9-12).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art by modifying the method of treating a human subject having stage IV-IVM1c melanoma that is resistant to PD-1 therapy as disclosed in Shoushtari by using anti-PD1 therapy proof of concept model as suggested in Zhu by substituting the oncolytic virus disclosed in Shoushtari with equivalent oncolytic virus disclosed in Zhang, to successfully treat advanced stage melanoma that is resistant to anti PD-1 antibody, as instantly claimed, with a reasonable expectation of success, at the time of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art suggested that in PD-1–resistant melanoma, PD-1 blockade alone is insufficient, but a combination strategy could be pursued in humans (see Shoushtari and Zhu). One of skill in the art would have been expected to have a reasonable expectation of success in treating a subject with melanoma that is resistant to anti-PD-1 therapy with oHSV2 because prior art reported successful reduction in tumor burden as evident from the teaching of Zhu. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support the finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Response to arguments
To the extent that Applicants’ arguments are pertinent to the new rejection, they are addressed as follows:
Applicants disagree with the rejection arguing that none of subjects with melanoma has experienced a failed PD-1 monoclonal antibody treatment and is in the clinical stage of terminal phases III-IVMIa and is resistant to the treatment with at least one anti-PD1 monoclonal antibody. Applicant argues that Zhang fails to teach clinical protocol suggests that specific patient subpopulation of PD1 refractory and recited stage patient. Zhu employs a genetically engineered murine tumor model B16R for targeted pharmacodynamic evaluation. This model does not recapitulate the clinical drug resistance profiles observed in human patients, nor has it been evaluated using oHSV2-administered in the absence of anti-PD-1 antibody-as described in the present application. Applicants continue to argue that Zhu teaches away from the claimed invention and cannot support an obvious finding. Zhu is directed to a different virus engineered to express an anti-PD-1 monoclonal antibody. Thus, the teaching of Zhu is that combination therapy (oHSV2 + PD-1 antibody) is superior to oHSV2 monotherapy, and that oHSV2 alone is insufficient to effectively combat PD-1- resistant tumors. This is a teaching away from the claimed invention, which uses oHSV2 monotherapy in PD-1-refractory patients. Applicant argues that B16R mouse model does not represent clinical PD-1-resistant patients who have experienced failed PD-1 monoclonal antibody treatment and are in the clinical stage of terminal phases III-IVMIa. Thus, Zhu not only fails to provide any teaching toward the claimed invention involving oHSV2 for treating the specific patient subpopulation at stage III-IVMIa of melanoma, but its actual data constitutes a teaching away from the claimed subject matter. Applicants’ arguments have been fully considered but are not found persuasive.
In response, as an initial matter, claim 1 as amended is broad and recites a single active method step of administering via any route any effective amount of any antitumor drug comprising oHSV2 to a subject and wherein the subject with melanoma has experienced a failed PD1 monoclonal antibody treatment and wherein the subject is human. It is in this context, newly cited prior art explicitly teaches a clinical protocol in humans that recites a single step of intratumorally administering an oncolytic virus in combination with another antitumor agent to a human subject, wherein human subject has experienced a failed anti PD1 therapy.
In response to applicants’ argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e. use of oHSV2 monotherapy) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, claimed method requires administering the subject a therapeutically effective amount of an antitumor drug comprising a recombinant oncolytic herpes simplex virus type II. MPEP 2111.03 states “transitional term "comprising", is synonymous with "including," "containing," is inclusive or open-ended and does not exclude additional, unrecited elements. Therefore, recitation of phrases a therapeutically effective amount of an antitumor drug comprising a recombinant oncolytic herpes simplex virus type II does not exclude additional therapy. Therefore, applicants’ argument that pending claims are limited to oHSV2 monotherapy is not persuasive as claims ae not so limited.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicants have further engaged in selective reading of the teachings of Zhu to formulate the grounds for teaching away. It should be noted that the ultimate goal of using a genetically engineered oHSV2 injection as an antitumor therapy for melanoma, especially advanced and PD-1-resistant disease. As indicated above, Shoushtari teaches a clinical protocol in humans that recites a single step of intratumorally administering an oncolytic virus in combination with another antitumor agent to a human subject, wherein human subject has experienced a failed PG1 therapy. The study reported clinical outcomes and tumor microenvironment changes in this resistant cohort, it did not conclude that PD-1 blockade itself is ineffective; instead, it focused on overcoming resistance by combining with a new agent. A variety of animal models as proof of concept suitable for this purpose are well-known in the art, including one disclosed in Zhu. melanoma tumor-bearing mice (B16R, is a variant developed to be resistant to anti-PD-1 monoclonal therapy) are treated with PBS, oHSV2, or oHSV2-aPD1 every other day via intertumoral injection (see page 204, col. 1, para. 1). Thus, Zhu cures the deficiency in Shoushtari for using oHSV2 as therapy for resistant melanoma. Zhang teaches a method for treating a subject with melanoma, comprising: intratumorally administering the subject a therapeutically effective amount of an antitumor drug, wherein the antitumor drug comprises recombinant oncolytic herpes simplex virus type II (oHSV2)) (see page2, col. 2, para. 2). To the extent that Zhu and Zhang describe the use of oHSV2 to treat melanoma, the rejection is applicable to the instant case. Applicants' selective reading of Zhu ignores the teachings of the primary reference of Shoushtari. There is no requirement for Zhu to teach that which is clearly taught by Shoushtari. A person of skill in the art would be motivated to use of oHSV2 as disclosed in Zhu or Zhang in the clinical protocol disclosed in Shoushtari, because the method would allow to clinically oHSV2 in treating late-stage metastatic melanoma that is resistant to anti PD-1 therapy in human, with a reasonable expectation of success.
On pages 9 and 10 of the applicant’s argument, Applicants argue of unexpected superior results by asserting that the present invention is the first clinical identification of a specific patient subpopulation that derives significant benefit from oHSV2 monotherapy. As demonstrated in the Specification (see page 20, lines 6-22 of the specification), in the Phase Ib subgroup of PD-1-failed, stage III-IVMIa melanoma patients, oHSV2 treatment achieved an ORR of 62.5% and a DCR of 87.5%. These results are remarkably superior to existing PD-1 monoclonal antibody therapies. As shown in Table 3 of the Specification, the ORRs of pembrolizumab (16.7%), toripalimab (17.3%), and pucotenlimab (20.17%) in similar patient populations are only about 16-20%. Applicants’ arguments have been fully considered but are not found persuasive.
In response, it should be noted that unexpected results have to be commensurate with the scope of the invention. "Whether 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)." Example (pages 12, 20-21 and table 3) discloses an intratumor injection of oHSV2 with a deposit number of CGMCC No. 3600 directly into melanoma of terminal phases III-IVMIa and is resistant to treatment with anti-PD-1 monoclonal antibody in human. The claims are not so limited.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Pi et al (Cancer, 2022, 14, 4134, 1-15) teaches B16F10-R tumor resistant to anti PD-1 therapy model. Liu (CN102146418B, dated 1/15/2014) teaches a method for treating a subject with melanoma, comprising: intratumorally administering the subject (mouse) a therapeutically effective amount of an antitumor drug, wherein the antitumor drug comprises recombinant oncolytic herpes simplex virus type II (oHSV2, (HG52dICP47d34.5-hGM-CSP with the ICP34.5gene knocked out)) (example 4 and para. 282, 288-289), thereby reducing the tumor load (table 5). It is further disclosed that oHSV2 is deposited as accession number CGMCC No. 3600 (see para. 77). Liu teaches that HSV2 is formulated in a pharmaceutically acceptable carrier or excipient (see para. 151). Liu teaches that HSV2 is administered at a dose of 10³ pfu to 10⁸ pfu in 500ml to 10 ml (see para. 203 and 288). Liu teaches HSV2 is administered in multiple doses at days 1, 4 and 7 (example 4, para. 288).
THIS ACTION IS MADE FINAL. Applicants are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
