CTNF 18/449,841 CTNF 89236 DETAILED ACTION This action is in reply to papers filed 8/15/2023. Claims 15-33 are pending and examined herein. Notice of Pre-AIA or AIA Status 07-03-fti AIA The present application is being examined under the pre-AIA first to invent provisions. Examiner’s Note All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240277764A1, Published 8/22/2024. Claim Rejections - 35 USC § 112 07-30-01 AIA The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-03 AIA Claim s 15-21 and 23-33 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 a method of treating a metastatic neuroblastoma in a patient in need thereof, wherein said method comprises administering a therapeutically effective number of engineered natural killer T-cells comprising a viral vector encoding at least IL-15, wherein the administered cells engraft at a site at or near the neuroblastoma , does not reasonably provide enablement for treatment of any cancer with a viral vector that does not encode for at least IL-15 . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue.’ Not ‘experimentation;” (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to: • (A) The breadth of the claims; • (B) The nature of the invention; • (C) The state of the prior art; • (D) The level of one of ordinary skill; • (E) The level of predictability in the art; • (F) The amount of direction provided by the inventor; • (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below. The Nature of the Invention : The inventive concept in the instant application is a method of treating neuroblastomas with an NKT cell transduced with at least an IL-15 cytokine. The Breadth of the Claims : The breadth of the claims is excessive with regard to treatment of any type of cancer. Amount of Direction Provided by Inventor/Working Examples : Relevant to the claimed invention, the specification discloses ‘Example 7’ and ‘Example 12.’ Starting at para. 123, ‘Example 7’ sought to examine whether NKTs/IL-15 have a therapeutic advantage. As such, a metastatic NB model in hu-NSG mice was utilized. Three and half months after SCT and upon confirmation of human hematopoietic reconstitution (FIG. 9B,C), mice were i/v injected with luciferase-transduced human NB cells, CHLA-255/luc. The therapeutic groups also received a single injection of either NKTs or NKTs/IL15. NSG mice that did not receive human CD34+ stem cells were used as a control group to assess the overall effect of human hematopoietic cells on the tumor growth. The specification teaches FIG. 6A demonstrates that metastatic growth in hu-NSG mice was dramatically enhanced compared with NSG mice, providing further support for the prominent role of BM-derived cells in enhancing NB growth. The immunotherapy with NKTs had significant but short-lived inhibitory effect on the metastatic growth. In contrast, a single injection of NKTs/IL-15 completely abrogated the tumor-promoting effect of the human hematopoietic environment (FIG. 6A,B). Example 12, an exemplary study (para. 185), sought to examine whether IL-15 and CAR.GD2 coexpression enhances NKT cell tumor homing and persistence, one can transduce NKTs with eGFP-ffLuc followed by transduction with CAR.GD2/IL-15. Continuing, the specification teaches Hu-NSG mice are grafted with human NB xenografts and i/v injected with CAR.GD2, IL-CAR.GD2/IL-15 or control NKTs (10 7 cells/mouse). NKT-cell tumor localization is monitored at 1, 2, 3, 5, and 7 days using BL imaging followed by sacrifice and FACS analysis in blood, spleen, liver, bone marrow, and tumor tissues. The distribution of infiltrating NKTs within the tumor tissues is analyzed by confocal microscopy, including quantitative analysis of their frequency in hypoxic areas using EF5 staining (Liu et al., 2012). NKTs expressing IL-15 and CAR.GD2 will have a superior in vivo expansion and persistence as well as enhanced accumulation and survival at the tumor site including hypoxic areas. It is noted that the specification at para. 55 admits that to work well, NKTs must survive in the hostile environment . Continuing, the specification teaches that upon genetic engineering with a survival factor such as IL-15 and/or with a cancer -targeting molecule called CAR.GD2, NKTs will survive at the tumor site and have antitumor efficacy both by killing the cancer directly and by disrupting the supporting environment. Independent claim 15 recites IL-15 as optional. Thus, Applicant’s own specification casts significant doubt as to whether transplanted non-IL-15 transduced NKT cells would be able to survive the hostile tumor environment long enough to provide a therapeutic benefit to the patient with cancer. The State of the Prior Art: As background, Nelson et al. (Cancers (Basel). 2021 Oct; 13(20): 5174.; Ref 104 in IDS filed 8/15/23) teach that it is well established that iNKT (type I NKT) cells have a direct role in anti-tumor immunity and immunosurveillance. In humans, cancer patients often present with reduced numbers of iNKT cells and/or impaired iNKT cell function. In contrast, iNKT cell infiltration into tumors is associated with a good prognosis in chronic lymphocytic leukemia, neuroblastomas, colorectal carcinoma, and pancreatic adenocarcinoma. iNKT cell immunosurveillance is likely mediated by inflammatory cytokines or recognition of tumor-associated glycolipids or stress-induced glycolipid antigens presented by CD1d positive tumor cells, or by antigen-presenting cells (APCs). CD1d positive tumors are more susceptible to iNKT cell-mediated lysis compared to CD1d negative tumors, and cancer cells often avoid detection by downregulating CD1d (Pg. 2 of 26, para. 2). Brettschneider et al. (Cells 2021, 10(7), 1641; Ref 33 in IDS filed 8/15/23) adds NKT cells recognize lipid antigens presented by non-classical class Ib MHC CD1d antigen-presenting molecules. Brettschneider et al. notes that these cells may play an especially intriguing role in the regulation of brain cancer immune landscapes, as the brain is one of the most highly lipid-enriched organs in the body. However, Brettschneider et al. cautions that much is still unclear about how NKT cells contribute to the GBM TME, interact with existing immunotherapies, and may be manipulated to improve GBM outcomes (Pg. 2 of 23, para. 1-2). Metelitsa (Clin Immunol. 2011 Aug; 140(2): 119–129; Ref 98 in IDS filed 8/15/23 ) concludes that despite the progress in the understanding of NKT-cell biology and their role in tumor immunity, many important questions remain unanswered that impedes translation of NKT-cell anti-tumor potential into effective immunotherapies in cancer patients. Specifically, in order to determine whether a certain tumor can be targeted for direct NKT-cell cytotoxicity , primary tumors need to be screened for CD1d expression on the surface of tumor cells. Metelitsa notes that so far only a few types of solid tumors in humans have been characterized for CD1d expression . However, Metelitsa cautions that there could be a heterogeneity of CD1d expression within the same type of tumor like we observed in medulloblastoma so that only a subset of patients may have CD1d-positive tumors. The functional status of CD1d expression (e.g. the ability to present αGalCer to NKTs) on the tumor cells need to be tested using established cell lines of the same tumor type or short-term cultures of primary tumor cells when it is possible. Those types of cancer that express functional CD1d could be targeted for direct NKT-cell cytotoxicity using either synthetic NKT ligands or/and ex-vivo expanded NKTs (paragraph bridging Pg. 6 and Pg. 7). The teachings of Brettschneider et al. and Metelitsa highlight an unpredictability associated with the claimed invention. First, it is clear that not all cancers can be treated by transplanted NKT cells. Additionally, the art makes clear that even within the same type of tumor, only a subset of patients may have CD1d-positive tumors. This is critical because Metelitsa teaches only those types of cancer that express functional CD1d could be targeted for direct NKT-cell cytotoxicity. And while the majority of solid tumors (such as neuroblastomas) are CD1d-negative such that those tumor cells cannot be a direct target for NKT-cell cytotoxicity, para. 5 of the PgPub indicates that tumor-associated monocytes/macrophages (TAMs) in neuroblastoma tumors have detectable CD1d expression and therefore could be targeted. The claims are neither limited to CD1d-positive tumors nor tumors that have detectable CD1d expression. Corroborating the specification at para. 55, Pereira et al. (Cancer J. 2022 Jul-Aug;28(4):263-269.; Ref 107 in IDS filed 8/15/23) teach tumors induce an environment that is favorable to tumor cell growth and resistant to immune responses, known as the TME. In the course of rapid tumor growth that outstrips vascular supply, the TME has progressively restricted access to both glucose and oxygen, creating a nutrient-poor and hypoxic environment (Pg. 267, Col. 1, para. 1). Li et al. (Successes and Challenges of NK Immunotherapy. Academic Press, 2021. 63-80.; Ref 84 in IDS filed 8/15/23) notes that both mouse and human studies have highlighted the central role of IL-15 in iNKT cell homeostasis. So far, Li teaches transgenic expression of IL-15 in adoptively transferred iNKT cells have improved iNKT in vivo persistence without causing significant toxicity, and is therefore a potential approach for general application to maximize NKT persistence and efficacy (Pg. 74, para. 3). Taking a broader view, Ishikawa et al. (In: Yamanaka, R. (eds) Glioma. Advances in Experimental Medicine and Biology, vol 746.; Ref 71 in IDS filed 8/15/23) teach cell therapies have two common major problems: (1) difficulty of ex vivo cell expansion and expense and (2) the antitumor effect is temporary because the transferred cells frequently fail to engraft and persist(Pg. 110, para. 2-3). The level of Predictability in the Art / Conclusion: The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. Due to the large quantity of experimentation necessary to establish the claimed method can treat any cancer, the breadth of the claims which encompasses treatment of any cancer, the state of the art which establishes (1) only cancers that express functional CD1d can be therapeutically targeted with NKT cells (2) IL-15 is required for in vivo persistence of transplanted NKT cells and (3) antitumor effect of cell therapies often fail because the cells fail to engraft and persist, the lack of guidance or evidence in the specification or in the art regarding the treatment of any cancer with IL-15 transduced NKT cells, it would have required undue experimentation for one skilled in the art at the time of the invention to practice over the full scope of the invention claimed. Thus, limiting the claimed invention to the scope above would be proper . Claim Rejections - 35 USC § 112 07-30-02 AIA The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. 07-34-01 Claims 17-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 17 recites “the inducible suicide gene” on line 2. There is no antecedent basis for this limitation. This is because claim 17 directly depends from claim 15 which does not recite an inducible suicide gene. Claim 16 does recite such a limitation; however, claim 17 is not dependent upon claim 16. Note that claims 18-21 are included in this rejection as they refer (either directly or indirectly) to the inducible suicide gene of claim 17. Claim 22 refers to the method of claim 9. Claim 9 is canceled. See below. PNG media_image1.png 71 750 media_image1.png Greyscale PNG media_image2.png 69 293 media_image2.png Greyscale As such, the metes and bounds of claim 22 are unclear. Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In this regard, claim 20 is drawn to the method of claim 17, wherein the inducible suicide gene is thymidine kinase (sr39 TK). The inclusion of ‘sr39TK’ within parentheses is being interpreted as a preference for type of thymidine kinase. This lends confusion to the claim because it is unclear if sr39TK is actually required by the claims or not. Note that, per Kim et al . (Ref. 78 in IDS filed 8/15/2023), ‘thymidine kinase’ is not interchangeable with ‘sr39 TK’ as Kim teaches sr39TK is mutant of thymidine kinase that was created by a five codon substitution from thymidine kinase (Pg. 1263, Col. 2, para. 1). Appropriate correction is required. Claim Rejections - 35 USC § 102 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 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. 07-07-fti The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-fti 07-08 (a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent. Prior Art Rejection 1 07-15-fti Claim (s) 15, 23 and 26-27 rejected under pre-AIA 35 U.S.C. 102 (a) as being anticipated by Liu et al. (J Immunol 1 April 2011 ; 186 (1_Supplement): 48.7.; Ref 86 in IDS filed 8/15/23) . Liu discloses Vα24-invariant Natural Killer T cells (NKTs) are important for antitumor immunity and immunotherapy. Liu previously demonstrated that NKTs inhibit tumor growth indirectly via targeting tumor-associated monocytes/macrophages (TAMs) in neuroblastoma (NB), suggesting that tumor progression requires an escape from NKTs via yet unknown mechanism. Here, Liu demonstrate that NB cells via membrane-bound TNFα induce CCL20 production in monocytes and this effect is amplified in hypoxia. Anti-CCL20 neutralizing mAb strongly inhibited NKT-cell in vitro migration towards tumor-conditioned hypoxic monocytes and in vivo localization in NB/TAM xenografts in NOD/SCID mice. The immunofluorescent staining of primary NB tumors revealed selective CCL20 accumulation in TAMs. Liu also found that hypoxia impairs NKT-cell function, suggesting that NKT-cell trafficking toward CCL20-producing TAMs may serve as a hypoxic trap for tumor-infiltrating NKTs and other T cells. IL-15 protected NKTs from hypoxia in vitro and IL-15-transduced NKTs more efficiently inhibited tumor growth in metastatic NB model in humanized NOD/SCID/IL2rgamma(null) mice compared with parental NKTs (as in claim 15, claim 23 , claim 26 and claim 27 ). Thus, Liu concludes that CCL20 production in hypoxic TAMs and consequent inhibition of NKTs reveals what is believed to be a novel mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15-transduced NKTs. Thus, Liu anticipates the claimed invention . 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-fti The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action: (a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made. 07-23-fti The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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-fti This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a). Examiner’s Note: In view of the 112 (b) rejection above, and in order to practice compact prosecution, claims 17-21 are being interpreted as depending from claim 16. Similarly, claim 22 is being interpreted as depending from claim 15. Prior Art Rejection 2 07-21-fti Claim s 16-19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Liu et al. (J Immunol 1 April 2011 ; 186 (1_Supplement): 48.7.; Ref 86 in IDS filed 8/15/23) as applied to claims 15, 23 and 26-27 and further in view of Tey et al. (Biol Blood Marrow Transplant. 2007 May 29;13(8):913–924.) . The teachings of Liu et al. are relied upon as detailed above. However, Liu et al. fails to teach the NK-T cell comprises an inducible suicide gene (as in claim 16), wherein the inducible suicide gene is inducible caspas-9 suicide gene (as in claim 18). Before the effective filing date of the claimed invention, Tey et al. teach suicide gene-modification of T cells circumvents the biological uncertainty of graft-versus-host-disease in addback of unmanipulated donor T cells (Abstract). Tey teaches this is because effective T cell doses can be administered to all patients safe in the knowledge that any GVHD that develops can be effectively controlled by activation of the suicide gene mechanism (Pg. 2, para. 1). Towards this end, Tey investigated the suitability of an alternative suicide gene, inducible caspase 9 (iCasp9) (as in claim 16, claim 17 and claim 18 ) (Pg. 2, para. 3). Tey teaches suicide gene functionality was assessed by adding a small molecule synthetic homodimerizer, AP20187 (as in claim 19 ) (paragraph bridging Pg. 4 and Pg. 5). When taken with the teachings of Liu et al., wherein Liu teaches IL-15-transduced NKTs more efficiently inhibited tumor growth in metastatic NB model in humanized NOD/SCID/IL2rgamma(null) mice compared with parental NKTs, one of ordinary skill in the art would have found it prima facie obvious to modify the NKTs of Liu such that they include the iCasp9 suicide gene of Tey et al. The skilled artisan would have found it prima facie obvious to do so because Tey teaches inclusion iCasp9 circumvents the biological uncertainly of graft-versus-host-disease raised in adding back donor T cells to a subject as the induction of iCasp9 gene would effectively kill the donor cells. Thus, the modification would have been prima facie obvious. Prior Art Rejection 3 07-21-fti Claim s 9, 16-17 and 20-22 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Liu et al. (J Immunol 1 April 2011 ; 186 (1_Supplement): 48.7.; Ref 86 in IDS filed 8/15/23) as applied to claims 15, 23 and 26-27 and further in view of Sangiolo et al. (Gene Therapy volume 14, pages1549–1554 (2007).) . The teachings of Liu et al. are relied upon as detailed above. However, Liu et al. fails to teach the NK-T cell comprises an inducible suicide gene (as in claim 16), wherein the inducible suicide gene is thymidine kinase (as in claim 20). Before the effective filing date of the claimed invention, Sangiolo et al. teach that to improve the safety of gene therapy, it is helpful to eliminate transduced cells if their activity is not needed. The inducible suicide gene herpes simplex virus-1 thymidine kinase (HSV-TK) has been used to control cell survival by permitting killing of transduced cells with the prodrug ganciclovir. Sangiolo notes that following allogeneic HCT, donor T cells facilitate engraftment and induce graft-versus-tumor effects, but alloreactive donor T cells can also cause fatal graft- versus-host disease. Gene modification of donor T cells with HSV-TK renders alloreactive T cells sensitive to ablation with ganciclovir (Abstract; paragraph bridging Pg. 1549-1550). Towards this end, Sangiolo combined the in vivo selection potential of MMF (an immunosuppressive drug) resistance with the inducible suicide gene ΔCD34/TK (as in claim 16 , claim 17 , claim 20, and claim 22 ) in one vector. Sangiolo studied the in vitro function of a bicistronic lentiviral vector (LV) that rendered transduced cells both resistant to the anti-metabolite immunosuppressive drug MMF and sensitive to ganciclovir (as in claim 21 ). Sangiolo hypothesized that after in vivo infusion of transduced T cells that were MMF-resistant and ganciclovir-sensitive, administration of MMF would favor the proliferation of ΔCD34/TK cells over non-transduced cells and could also potentially suppress immune responses against the vector transgenes. Sangiolo teaches administration of ganciclovir would allow for rapid and specific ablation of transduced cells if needed. Sangiolo notes that cells transduced with LV-ΔCD34/TK.IMPDH IY were efficiently enriched by immunomagnetic selection for CD34, proliferated in 0.5–5 μM MMF, and were killed by 0.5–25 μg ml −1 ganciclovir (Pg. 1550, Col. 1, para. 1). When taken with the teachings of Liu et al., wherein Liu teaches IL-15-transduced NKTs more efficiently inhibited tumor growth in metastatic NB model in humanized NOD/SCID/IL2rgamma(null) mice compared with parental NKTs, one of ordinary skill in the art would have found it prima facie obvious to modify the NKTs of Liu such that they include the thymidine kinase suicide gene of Sangiolo et al. The skilled artisan would have found it prima facie obvious to do so because Sangiolo teaches gene modification of donor T cells with HSV-TK renders alloreactive T cells sensitive to ablation with ganciclovir and would effectively kill the donor cells, in case graft-versus-tumor effects are induced. Thus, the modification would have been prima facie obvious. Prior Art Rejection 4 07-21-fti Claim s 24-25 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Liu et al. (J Immunol 1 April 2011 ; 186 (1_Supplement): 48.7.; Ref 86 in IDS filed 8/15/23) as applied to claims 15, 23 and 26-27 and further in view of Fardin et al. (Mol Cancer. 2010 Jul 12;9:185.) . The teachings of Liu et al. are relied upon as detailed above. However, Liu fails to teach the tumor microenvironment is hypoxic (as in claim 24) and said microenvironment comprises less than 15% O 2 (as in claim 25). Before the effective filing date of the claimed invention, to examine the relationship between hypoxia and neuroblastoma, Fardin et al. generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome. Specifically, Fardin obtained the gene expression profile of 11 hypoxic neuroblastoma cell lines and derived a robust 62 probesets signature (NB-hypo) taking advantage of the strong discriminating power of the l1-l2 feature selection technique combined with the analysis of differential gene expression. Fardin’s results show that hypoxia, 1% O 2 , is negatively correlated with tumors' outcome (as in claim 25 (Abstract; paragraph bridging Pg. 2-3). When taken with the teachings of Fardin, wherein Fardin teaches hypoxia is negatively correlated with tumors' outcome, one of ordinary skill in the art would have found it prima facie obvious to administer the IL-15-transduced NKTs of Liu into a hypoxic neuroblastoma in vivo environment (as in claim 24 ) in order to determine if the transduced NKTs could inhibit tumor growth and/or improve the tumors’ outcome. The skilled artisan would have found it prima facie obvious to do so because, although Liu teach inhibition of tumor growth in an NB mouse model, Liu et al. was silent as to the level of oxygen in the model. Thus, the modification would have been prima facie obvious. Prior Art Rejection 5 07-21-fti Claim s 28-33 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Liu et al. (J Immunol 1 April 2011 ; 186 (1_Supplement): 48.7.; Ref 86 in IDS filed 8/15/23) as applied to claims 15, 23 and 26-27 and further in view of Paul, S. (PgPub US20050063945A1, Published 3/24/2005) . The teachings of Liu et al. are relied upon as detailed above. However, Liu et al. fails to teach the IL-15 is human IL-15 (as in claim 28), the natural killer T-cell is derived from cells from the subject (as in claim 29), the administration is systemic (as in claim 29), the administration is parenteral (as in claim 30) or NKT cells are administered locally to the tumor (as in claim 32). Before the effective filing date of the claimed invention, Paul teach methods of administering host cells comprising novel nucleic aids for the treatment of tumors in vivo (Abstract; Pg. 20, para. 153). In one embodiment, Paul teaches the nucleic acid comprises human IL-15 (as in claim 28 ) (Pg. 4,para. 34;Pg. 5,para. 41) and the host cells are autologous (as in claim 29 ) (Pg. 22, para. 164). Paul teaches means of administering said composition by a variety of modes of administration including systemic (as in claim 30 ), topical and localized administration (as in claim 32 ). For systemic administration, Paul teaches injection is preferred, e.g. subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, intracardiac (as in claim 31 ) (Pg. 19, para. 146). Paul teaches the cells can be administered alone or, if desired, in conjunction with presently or conventional therapeutic modalities (e.g., radiation, chemotherapy and/or surgery) (as in claim 33 ) (Pg. 23,para. 168). When taken with the teachings of Liu et al., wherein Liu teaches IL-15-transduced NKTs more efficiently inhibited tumor growth in metastatic NB model in humanized NOD/SCID/IL2rgamma(null) mice compared with parental NKTs, one of ordinary skill in the art would have found it prima facie obvious to modify the NKTs of Liu such that, when a human is treated, the IL-15 is a human IL-15 and the NKT cells are derived from said human. The modification would have been prima facie obvious in order to avoid an adverse immune reaction to transplanted allogeneic or xenogenic NKT cells transduced with a non-human IL-15 gene. Thus, the modification would have been prima facie obvious. Authorization to Initiate Electronic Communications The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided , Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to TITILAYO MOLOYE whose telephone number is (571)270-1094. The examiner can normally be reached Working Hours: 5:30 a.m-3:00 p.m. M-F. Off first Friday of biweek.. 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. 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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. /TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632 Application/Control Number: 18/449,841 Page 2 Art Unit: 1632 Application/Control Number: 18/449,841 Page 3 Art Unit: 1632 Application/Control Number: 18/449,841 Page 4 Art Unit: 1632 Application/Control Number: 18/449,841 Page 5 Art Unit: 1632 Application/Control Number: 18/449,841 Page 6 Art Unit: 1632 Application/Control Number: 18/449,841 Page 7 Art Unit: 1632 Application/Control Number: 18/449,841 Page 8 Art Unit: 1632 Application/Control Number: 18/449,841 Page 9 Art Unit: 1632 Application/Control Number: 18/449,841 Page 10 Art Unit: 1632 Application/Control Number: 18/449,841 Page 11 Art Unit: 1632 Application/Control Number: 18/449,841 Page 12 Art Unit: 1632 Application/Control Number: 18/449,841 Page 13 Art Unit: 1632 Application/Control Number: 18/449,841 Page 14 Art Unit: 1632 Application/Control Number: 18/449,841 Page 15 Art Unit: 1632 Application/Control Number: 18/449,841 Page 16 Art Unit: 1632 Application/Control Number: 18/449,841 Page 17 Art Unit: 1632 Application/Control Number: 18/449,841 Page 18 Art Unit: 1632 Application/Control Number: 18/449,841 Page 19 Art Unit: 1632 Application/Control Number: 18/449,841 Page 20 Art Unit: 1632