CTNF 18/653,847 CTNF 101369 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Liu, TC et al. 2006 and further in view of Ahrens, T., et al. 2001, Chen C, et al. 2018, and Vázquez-Arreguín K, et al. 2025 . Liu, TC et al. 2006 discloses, “Herein, we describe the effect of incorporating a therapeutic transgene, dnFGFR, which inhibits the FGF signaling pathway, into an oncolytic HSV vector.” (paragraph 1, discussion section). It does not disclose using the soluble, extracellular domain of CD44 as a therapeutic transgene in HSV-1. It also does not disclose that oncovirus infection makes tumor cells more susceptible to radiation and chemotherapies. Ahrens, T., et al. 2001 discloses, “Thus, the secretion of soluble CD44s efficiently inhibits tumor cell proliferation in vivo, extending the results observed in vitro. This suppression of tumor development is critically dependent on the interaction of soluble CD44s with hyaluronic acid. These data suggest that solCD44 interferes with processes which lead to cell proliferation that are usually initiated by the interaction of cell surface CD44 with hyaluronic acid.” (paragraph titled “Expression of soluble CD44s results in suppression of melanoma tumor growth in vivo”). Therefore, a person of ordinary skill in the art, before the effective filing date, would find it obvious to take the HSV-1 oncovirus expressing a dominant negative FGFR as disclosed in Liu, TC et al. 2006, and insert the transgene encoding the soluble extracellular domain of CD44 (sCD44) disclosed in Ahrens, T et al. 2001. Expression of sCD44 will sequester hyaluronic acid ligands, thereby preventing its binding to tumor cell CD44. Normal tumor cell CD44 activation results in the expression of anti-apoptotic proteins, as supported by Chen C, et al. 2018. Therefore, inhibition of CD44 activation abrogates tumor cell’s ability to circumvent programed cell death. Additionally, oHSV1 infection induces host cell DNA damage and results in sequestration of host DDR proteins to viral replication compartments, thereby inhibiting DDR protein’s ability to repair host DNA damage, as supported by Vázquez-Arreguín K, et al. 2025. This two-pronged approach prevents tumor cells from stopping/reversing the therapeutic effects of chemo/radiation therapy, and abrogates tumor cells’ ability to inhibit chemo/radiation therapy-induced cell death. Combining a DDR pathway inducing oncolytic virus with the expression of sCD44 results in synergistic tumor cell sensitization to radio/chemotherapies. Therefore, claims 1-7 are obvious . 07-22-aia AIA Claim s 8-12,15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Liu, TC et al. 2006, and Ahrens, T., et al. 2001 as applied to claim 1 above, and further in view of US 6428968 B1 and Wennier ST, et al. 2012 . Liu, TC et al. 2006, and Ahrens, T., et al. 2001 render claim 1 obvious, as outlined above. However, they do not provide a pharmaceutical composition, or a method of treating a subject with cancer by using intertumoral injection to deliver the composition containing the oncolytic virus of claim 1 to the subject. They also do not disclose the use of a secondary treatment wherein the secondary agent is a DNA damage-inducing chemotherapeutic. Additionally, they do not show that the oncolytic virus treatment increases; 1) tumor cell susceptibility, 2) immune cell infiltration, and, 3) downregulation of MAPK signaling, thereby inhibiting growth. US 6428968 B1 discloses, “The invention relates to a method of killing tumor cells in a subject having tumor cells. The method comprises administering a chemotherapeutic agent and an oncolytic virus to the subject.” (paragraph 1, Summary of the invention section). Furthermore, “…the chemotherapeutic agent is selected from the group consisting of…a purine analog, a pyrimidine analog….” (paragraph 2, Summary of the invention section). Additionally, “The kit differs from the pharmaceutical composition in that the agent and virus in the kit need not be combined before or during administration to the subject, but may instead be administered to the subject at different times (e.g. within days, hours, or seconds).” (paragraph 1 in the Pharmaceutical Compositions and Kits section). Importantly, “…it is preferred that one or both…may be injected directly into the tumor tissue…” (paragraph 2 in the Pharmaceutical Compositions and Kits section). Therefore, it would be obvious to a person of ordinary skill in the art, before the effective date, to use the composition containing the oHSV-1 vector expressing sCD44 as disclosed by Liu, TC et al. 2006 and Ahrens, T., et al. 2001 as the therapeutic oncolytic virus in the method of treating a subject with cancer by administering an oncolytic virus via intertumoral injection, then administering a purine analog (aka a DNA-damaging-inducing chemotherapeutic) as a second treatment disclosed by US 6428968 B1. Direct, intertumoral injection of the sCD44-expressing oHSV-1 is a much more efficient and effective method of delivery compared to infusion, subdermal injection, and other routes of administration. Intertumoral injection circumvents the need for viral migration/homing to the tumor. Furthermore, the addition of a secondary treatment using a purine analog is obvious to try because it works synergistically with oHSV-1 by acting as a second DNA damage agent. Their combined therapeutic effects work together to trigger apoptosis in cancer cells, as supported by Wennier ST, et al. 2012. This renders claims 8-12, and 20 obvious. Claims 15-19 claim subject matter that is not considered patentable because the limitations are inherently present in the prior art. A prior art reference need not expressly disclose a limitation if that limitation is the natural result of what is explicitly taught. In this case, treating cancer with an HSV-1 oncolytic virus inevitably results in increased tumor cell susceptibility, immune cell infiltration into the tumor driven by the release of tumor antigens and cytokines into the tumor microenvironment by oncolytic cell lysis, decreased stem cell properties, DNA damage, and downregulation of MAPK. These are inevitable outcomes from oncolytic virus treatments, and in particular, treatments comprising oHSV-1 variants. Therefore, claims 15-19 are rejected as obvious since the claimed limitations are inherent results from HSV-1 oncolytic viral treatment . 07-22-aia AIA Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Liu, TC et al. 2006, Ahrens, T., et al. 2001, US 6428968 B1 and Wennier ST, et al. 2012 as applied to claim 11 above, and further in view of US 2013287688 A1 and H. Zou, et al 2023 . Liu, TC et al. 2006, Ahrens, T., et al. 2001, US 6428968 B1 and Wennier ST, et al. 2012 disclose a method of treating a subject with cancer wherein a first therapeutic (aka an oncolytic HSV-1 virus encoding sCD44) is administered via intertumoral injection, and subsequently administering a second treatment comprising a DNA-damaging agent. However, they do not disclose using an HIF-1a inhibitor in the second therapy composition. US 2013287688 A1 discloses, “…the administration of…the microenvironment modulator is sequential…with the therapy, e.g., the cancer therapy…” (paragraph 0142). Furthermore, “In one embodiment, the therapy is chosen from …a viral cancer therapeutic agent (e.g., an oncolytic herpes simplex virus (HSV)…” (paragraph 0146). Additionally, “…the microenvironment modulator includes…an agent that inhibits hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α)” (paragraph 0153). Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to incorporate an HIF-1a inhibitor, as disclosed by US 2013287688 A1, into the second treatment composition used in the method of treating cancer in a subject as disclosed in Liu, TC et al. 2006, Ahrens, T., et al. 2001, US 6428968 B1 and Wennier ST, et al. 2012. This is a case of combining known elements to achieve predictable results. It is known that hypoxia-inducing factor 1 (HIF-1α) is an essential factor in hypoxia that can enhance angiogenesis and tumor cell metastasis, as supported by H. Zou, et al 2023. Therefore, including an HIF-1a inhibitor in the secondary treatment composition results in additional benefits that would not occur if a sCD44-encoding oHSV-1 and a DNA-damaging agent were the only components of the therapeutic compositions. Therefore, claim 14 is obvious . 07-22-aia AIA Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Liu, TC et al. 2006, Ahrens, T., et al. 2001, US 6428968 B1 and Wennier ST, et al. 2012 as applied to claim 11 above, and further in view of Market, J et al. 2014 . Liu, TC et al. 2006, Ahrens, T., et al. 2001, US 6428968 B1 and Wennier ST, et al. 2012 disclose a method of treating a subject with cancer wherein a first therapeutic (aka an oncolytic HSV-1 virus encoding sCD44) is administered, and subsequently administering a second treatment comprising a DNA-damaging agent. They do not disclose the use of radiation as the DNA damaging agent used in the second treatment composition. Market, J et al. 2014 discloses, “G207, a mutant herpes simplex virus (HSV) type 1…We conducted a phase 1 trial of G207 to demonstrate the safety of stereotactic intratumoral administration when given 24 hours prior to a single 5 Gy radiation dose in patients with recurrent malignant glioma.” (Abstract). Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to take the secondary radiation treatment disclosed in Market, J et al. 2014, and substitute it for the secondary treatment composition containing a chemotherapeutic used in the method of treating cancer disclosed by Liu, TC et al. 2006, Ahrens, T., et al. 2001, US 6428968 B1 and Wennier ST, et al. 2012. This is a case of simple substitution of one known element for another to achieve predictable results. sCD44- expressing oHSV-1 sensitizes cancer cells to DNA damaging chemotherapeutics (like purine analogs), and DNA damaging radiation treatments. Both secondary treatment options result in DNA damage that is synergistic with oHSV-1 induced DNA damage. Therefore, claim 13 is obvious. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Adam M Smith whose telephone number is (571)272-7517. The examiner can normally be reached Monday- Friday 10:30AM-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, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638 Application/Control Number: 18/653,847 Page 2 Art Unit: 1638 Application/Control Number: 18/653,847 Page 3 Art Unit: 1638 Application/Control Number: 18/653,847 Page 4 Art Unit: 1638 Application/Control Number: 18/653,847 Page 5 Art Unit: 1638 Application/Control Number: 18/653,847 Page 6 Art Unit: 1638 Application/Control Number: 18/653,847 Page 7 Art Unit: 1638 Application/Control Number: 18/653,847 Page 8 Art Unit: 1638 Application/Control Number: 18/653,847 Page 9 Art Unit: 1638 Application/Control Number: 18/653,847 Page 10 Art Unit: 1638
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