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 .
Election/Restrictions
Applicant cancelled claims 94-95 and 97-99, which were directed to the non-elected invention in the reply filed on 16 September 2025.
Claim Status
Claim 71 is currently amended, claims 4-5, 7, 9-11, 14, 16, 18, 20-37, 39, 41, 43, 45, 47-48, 52-56, 58-62, 64-65, 68-69, 72-77, 79-83, 86-87, 91, and 93-100 were previously cancelled, and claims 1-3, 6, 8, 12-13, 15, 17, 19, 38, 40, 42, 44, 46, 49-51, 57, 63, 66-67, 70-71, 78, 84-85, 88-90, and 92 have been considered on their merits.
Withdrawn Rejections
The rejection under 35 USC § 112(b) has been withdrawn due to applicant’s amendment to the claim.
The objection to the specification is repeated for the same reasons of record as set forth in the Official Action mailed 17 October 2025. It is noted, in the response filed 15 January 2026, Applicant acknowledged the objection and stated if and when required the disclosure will be amended.
Specification
The incorporation of essential material in the specification by reference to an unpublished
U.S. application, foreign application or patent, or to a publication is improper. Applicant is
required to amend the disclosure to include the material incorporated by reference, if the material
is relied upon to overcome any objection, rejection, or other requirement imposed by the Office.
The amendment must be accompanied by a statement executed by the applicant, or a practitioner
representing the applicant, stating that the material being inserted is the material previously
incorporated by reference and that the amendment contains no new matter. 37 CFR l.57(g).
For example, the following foreign patent documents are listed as incorporated by
reference at instant paragraph [0063]: WO 05/060721, WO 05/060721, WO 05/045039, WO
05/059134, WO 05/045041, WO 05/045040, WO 05/045039, WO 05/027980, WO 05/014837,
WO 05/002594, WO 04/085645, WO 04/078181, WO 04/076623, and WO 04/04635.
Response to Remarks
In the response filed 15 January 2026, section II(B)(1), Applicant noted the Office Action contained a statement regarding joint inventors. This paragraph was inadvertently included in the rejection and does not apply to this application, as Dr. Thomas Ichim is the sole inventor of the present application. The remainder of the response to any traversal is included following the applicable rejections below.
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.
Claims 1, 3, 6, 8, 12-13, 15, 17, 19, 38, 40, 42, 44, 46, 49-51, 57, 63, 66-67, 70-71, 78, 84-85, 88-90, and 92 are rejected under 35 U.S.C. 103 as being unpatentable over Ichim et al. (US 2017/0304418, published 26 October 2017, IDS ref.), and in view of Inoue et al. (International Journal of Oncology 49, 2016, IDS ref.) as evidenced by An et al. (J Cell Mol Med. 2020; 24, published online 23 October 2019).
This rejection is repeated with regard to claims 1, 3, 6, 8, 12-13, 15, 17, 19, 38, 40, 42, 44, 46, 49-51, 57, 63, 66-67, 70-71, 78, 84-85, 88-90, and 92 for the same reasons of record as set forth in the Official Action mailed 17 October 2025. A response to applicant’s traversal follows the reiterated rejection below.
Regarding claim 1, Ichim et al. teach the use cord blood cells as starting cell populations for generation of killer cells that possess selectivity to tumor tissues (para. [0002]). Ichim et al. teach lymphocytes derived from umbilical cord blood are gene silenced or gene edited to reduce, or completely abolish expression of checkpoint inhibitor genes (claim 1(c)) (para. [0013]). Ichim et al. teach a method of producing a population of activated natural killer (NK) cells, comprising: (a) seeding a population of hematopoietic stem or progenitor cells in a first medium comprising interleukin-15 (IL-15) and one or more of stem cell factor (SCF) and interleukin-7 (IL-7), such that the population expands, and a plurality of hematopoietic stem or progenitor cells within said population of hematopoietic stem or progenitor cells differentiate into NK cells during said expanding; and (b) expanding the cells from step (a) in a second medium comprising interleukin-2 (IL-2), to produce a population of activated NK cells (para. [0060]). Ichim et al. teach natural killer (NK) cells are CD3-negative/CD56-positive mononuclear cells and have a cytotoxic activity against cells in which express MHC class I molecules is reduced or the expression is lost (para. [0014]). NK cell expansion to produce an activated NK cell population reads as isolating mononuclear cells from a cord blood sample (claim 1(a)). Ichim et al. teach the NK cells and the cell therapy of the disclosed method can be applied to treatment and/or prevention of various diseases having sensitivity to NK cells (claim 1(d)) (para. [0055]).
Ichim et al. is silent to co-culturing mononuclear cells with cancer-associated fibroblasts (claim 1(b)).
Inoue et al. teach cancer-associated fibroblasts (CAFs) were cocultured with natural killer (NK) cells (Abstract). Inoue et al. teach CAFs regulate not only carcinogenesis, but also the immune evasion of cancer in the tumor microenvironment (TME), which facilitates cancer cell proliferation, expansion, and metastasis (p. 1297, Introduction). Inoue et al. teach CAFs suppress the NK cell-killing activity by decreased PVR cell surface expression, a ligand of an NK activating receptor (p. 1302, Discussion). Inoue et al. teach ligands of the receptors, PVR, a ligand of DNAM-1, was observed to be ubiquitously expressed on the cell-surface of CAFs and it is known DNAM-1 activates NK cell activity (p. 1303, 1st column). Inoue et al. teach some studies demonstrated PVR interacts with higher affinity to TIGIT (inhibitor) than DNAM-1 (activator) (p. 1303, 1st column). Inoue et al. teach soluble poliovirus receptor (PVR/CD155) may be used as a potential agent to activate NK cell activity in the TME (p. 1303, Discussion). Inoue et al. teach the reduction of PVR expression in CAFs is critical for CAF-induced suppression of NK cell activity (p. 1303, 1st column).
Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Inoue et al. with the method of Ichim et al., wherein mononuclear cells and cultured with CAFs, with a reasonable expectation of success because Inoue et al. teach a mechanism to circumvent the suppressive nature CAFs impose on NK killing activity when co-cultured with CAFs which would further enhance the cytotoxic activity of the NK cells. One would be motivated to combine the teachings of Inoue et al. with the method of Ichim et al. because it is well known in the art NK cells play an important role in cancer immunity in the tumor microenvironment, thus, recovering one of the known inhibitory pathways imposed by CAFs on NK cells would be expected to enhance the cytotoxic activity of said mononuclear cells and Ichim et al. teach the use cord blood cells as starting cell populations for generation of killer cells that possess selectivity to tumor tissues, which would be improved by co-culturing CAFs with NK cells.
Regarding claim 3, Ichim et al. teach gene silencing of an immunological checkpoint in mononuclear cells comprises induction of RNA interference, administration of short interfering RNA (siRNA), or short hairpin RNA (para. [0080]-[0083]).
Regarding claim 6, Ichim et al. teach said immunological checkpoint is selected from the group comprising NRDF6, PD-1, TIM-3, CTLA-4, CD200, STAT6, indolamine 2,3, deoxygenase (IDO) (para. [0111]).
Regarding claim 8, Ichim et al. teach the factors capable of enhancing cytotoxic activity of the mononuclear cells are selected from the group consisting of IL-2, anti-CD3/anti-CD28 beads, IL-7, IL-12, IL-17, IL-15, IL-18, and IL-33 (para. [0112]).
Regarding claims 12-13, 15, 17, and 19, Ichim et al. teach said factors endowing cord blood with tumor cytotoxic activity are toll like receptors, wherein the toll like receptor is TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, or TLR-9 (para. [0113]-[0148]). Ichim et al. teach wherein the activator of TLR-1 is Pam3CSK4 (claim 13), wherein the activator of TLR-2 is HKLM (claim 15), wherein the activator of TLR-3 is Poly:IC (claim 17), wherein the activator of TLR-4 is Buprenorphine, wherein the activator of TLR-4 is Carbamazepine, wherein the activator of TLR-4 is Fentanyl, wherein the activator of TLR-4 is Levorphanol, wherein the activator of TLR-4 is Methadone, wherein the activator of TLR-4 is Cocaine, wherein the activator of TLR-4 is Morphine, wherein the activator of TLR-4 is Oxcarbazepine wherein the activator of TLR-4 is Oxycodone, wherein the activator of TLR-4 is Pethidine, wherein the activator of TLR-4 is, Glucuronoxylomannan from Cryptococcus, wherein the activator of TLR-4 is Morphine-3-glucuronide, wherein the activator of TLR-4 is lipoteichoic acid, wherein the activator of TLR-4 is β-defensin 2, wherein the activator of TLR-4 is small molecular weight hyaluronic acid, wherein the activator of TLR-4 is fibronectin EDA, wherein the activator of TLR-4 is snapin, wherein the activator of TLR-4 is tenascin C (claim 19) (para. [0122]-[0139]). The aforementioned activators of TLR read as TLR agonists (claim 12).
Regarding claim 38, Ichim et al. teach wherein the activator of TLR-5 is flagellin (para. [0141]).
Regarding claim 40, Ichim et al. teach wherein the activator of TLR-6 is FSL-1 (para. [0143]).
Regarding claim 42, Ichim et al. teach wherein the activator of TLR-7 is imiquimod (para. [0145]).
Regarding claim 44, Ichim et al. teach wherein the activator of TLR-8 is ssRNA40/LyoVec (para. [0147]).
Regarding claim 46, Ichim et al. teach wherein the activator of TLR-9 is a CpG oligonucleotide, ODN2006, or Agatolimod (para. [0149]-[0151]).
Regarding claim 49, Ichim et al. teach wherein an antigen presenting cell is added to the culture system (para. [0152])
Regarding claim 50, Ichim et al. teach wherein the antigen presenting cell is a dendritic cell, a B cell, a neutrophil, an endothelial cell, or an artificial antigen presenting cell (para. [0153], and [0156]-[0159]).
Regarding claim 51, Ichim et al. teach wherein the dendritic cell is a myeloid dendritic cell or a lymphoid dendritic cell (para. [0154]-[0155]).
Regarding claim 57, Ichim et al. teach wherein the antigen presenting cell is activated to enhance immunogenicity, wherein enhanced immunogenicity is augmentation of HLA antigens, TAP expression, CD80, CD86, or IL-12 expression (para. [0160]-[0165]).
Regarding claim 63, Ichim et al. teach wherein said culture additionally consists of soluble inhibitors to immunosuppressive factors (para. [0166]).
Regarding claim 66, Ichim et al. teach wherein immunosuppressive factors are selected from the group comprising HLA-G, IL-10, IDO, cyclo-oxygenases, and IL-20 (para. [0168]).
Regarding claim 67, Ichim et al. teach wherein a chemotherapeutic agent is administered prior to administration of said therapeutic cells with the intent of reducing tumor burden prior to administration of cellular therapy (para. [0169]).
Regarding claim 70, the phrase “capable of inducing and immunological response in the subject” is considered an intended use statement and thus is not considered limiting because the phrase does not add structure to the claimed method and is considered an inherent property of said mononuclear cells. Therefore, the claim is interpreted the same as claim 1 and is rejected for the same reasons. If this phrase was considered limiting, Ichim et al. teach a method of inducing an anticancer immune response wherein an immune cell provides an inhibitory signal to said immune cell’s ability to induce an immunological response (para. [0192]).
Regarding claim 71, Ichim et al. teach wherein said immunological response is cell proliferation, expression of CD69, CD25, perforin, granzyme, Fas ligand, or a tumor inhibitory cytokine (para. [0194]-[0200]).
Regarding claim 78, Ichim et al. teach wherein said tumor inhibitory cytokine induces cell cycle arrest of tumor cells, apoptosis of tumor cells, autophagy of tumor cells, necrosis of tumor cells, wherein the cytokine is interferon gamma, TNF-α, TRAIL, IL-2, IL-12, IL-17, IL-18, IL-21, IL-33, or HMGB1 (para. [0201]-[0218]).
Regarding claims 84-85, Ichim et al. teach a method of producing a population of activated natural killer (NK) cells (claim 85) (para. [0060]). NK cells read as the mononuclear cells are immune cells (claim 84).
Regarding claim 88, Ichim et al. teach a cord blood derived allogeneic T cell endowed with enhanced antitumor activity capacity, wherein the T cell comprise a protein comprising a targeting moiety, which specifically binds to cell-surface antigen on said T cell (para. [0230] and [0237]). Therefore, Ichim et al. in view of Inoue et al. teach providing to the T cells a cancer-associated fibroblast antigen since the combination of the teachings of Ichim et al. and Inoue et al. are considered obvious and co-culturing CAF of Inoue et al. with the T cell of Ichim et al. would necessarily result in the presentation of antigens of said CAFs to said T cells.
Regarding claim 89, Ichim et al. in view of Inoue et al. are silent to a specific CAF antigen, however, fibroblast activated protein 1 (FAP) is a commonly known maker for activated CAFs as evidenced by An et al. (Fig. 2 and p. 15, 1st column). Therefore, FAP would necessarily be present in the CAF of Inoue et al., thus the antigen would be presented to the T cell of Ichim et al. when co-cultured with the CAF of Inoue et al.
Regarding claim 90, Ichim et al. teach wherein T cells are expanded possessing a Th1 phenotype (para. [0177]). Ichim et al. teach the Th1 phenotype includes cell expressing markers to include CD4, CD94, CD119 (IFNγ R1), CD183 (CXCR3), CD186 (CXCR6), CD191 (CCR1), CD195 (CCR5), CD212 (IL-12Rβ1&2), CD254 (RANKL), CD278 (ICOS), IL-18R, MRP1, NOTCH3, or TIM3 (para. [0178]).
Regarding claim 92, Ichim et al. teach a T cell (a mononuclear cell), wherein said T cell has been treated with agents capable of inducing chromatin remodeling, wherein said agents capable of inducing chromatin remodeling are selected from a group comprising a histone deacetylase inhibitor (para. [0319]).
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.
Response to Traversal
Applicant's arguments filed 15 January 2026 have been fully considered but they are not persuasive.
Regarding the remarks on page 13 which reference the lack of articulate reasoning with some rational underpinning to support the conclusion of obviousness, Applicant notes Ichim teaches NK cells can be used for cell therapy of cancer on their own. While this may not be required for NK cells to be utilized in cancer cell therapy, it does not exclude the possibility to improve upon the methods which were known in the art.
Regarding the remarks on pages 13-14, Applicant argues a skilled artisan would not have been motivated to combine the teachings of Inoue with Ichim, while Inoue does teach co-culturing CAF with NK cells reduces the cytotoxic effect of NK cells, Inoue investigates the mechanisms involved and points to possible strategies to overcome this immune evasion system in the tumor microenvironment (TME). In uncovering the mechanisms related to this suppressive nature Inoue suggests the data from their investigation could provide a novel strategy for inhibiting the immune evasion system in the TME (p. 1303, Discussion), which provides the appropriate motivation to combine the teachings of Inoue and Ichim. MPEP 2141.02 (VI) states that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
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).
Regarding the remarks on page 14 which reference a surprising technical effect of improved cytotoxicity of the claimed CAFs with activated NK cells, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Furthermore, in submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964).
The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter "as a class" relative to the prior art subject matter "as a class." In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971 ); In re Hostettler, 429 F.2d 464, 166 USPQ 558 (CCPA 1970). See, also, In re Lindner, 457 F.2d 506, 173 USPQ 356 (CCPA 1972).
It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D'Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
Regarding the rejection of the dependent claims, Applicant has not set forth any specific arguments pertaining to these rejections.
Claims 2 is rejected under 35 U.S.C. 103 as being unpatentable over Ichim et al. (US 2017/0304418, published 26 October 2017, IDS ref.) and in view of Inoue et al. (International Journal of Oncology 49, 2016, IDS ref.) as applied to claims 1, 3, 6, 8, 12-13, 15, 17, 19, 38, 40, 42, 44, 46, 49-51, 57, 63, 66-67, 70-71, 78, 84-85, 88-90, and 92 above, and further in view of Ohno et al. (Cytotechnology, 1997, IDS ref.).
This rejection is repeated with regard to claim 2 for the same reasons of record as set forth in the Official Action mailed 17 October 2025. A response to applicant’s traversal follows the reiterated rejection below.
Regarding claim 2, Ichim et al. in view of Inoue et al. are silent to mitotically inactivating the cancer-associated fibroblasts.
However, Ohno et al. teach induction of allogeneic cytotoxic T lymphocytes (CTL) from PBMC against human lung cancer cells, wherein, the PBMCs were co-cultured on X-ray irradiated live SQ-5 cells (p. 198, 1st column). Irradiation is a well-known method of mitotically inactivating cancer cells. Ohno et al. teach after coculturing and subsequence subculturing, allogeneic CTL grown from the PBMC killed SQ-5 cells but not other human cancer cell lines (p. 198, 1st column). Ohno et al. teach the CTL, named SQ-5-CTL, could be routinely subcultured on unirradiated target SQ-5 cells wherein the SQ-5 cells disappeared within 1 day after addition of the SQ-5-CTL (p. 198, 1st column). Which suggests an effective method of inducing mononuclear cells against cancer cells of any type, to include CAFs.
Therefore, it would have been obvious to one of ordinary skill in the art to mitotically inactivate the cancer-associated fibroblasts of Ichim et al. in view of Inoue et al. with the method disclosed by Ohno et al. with a reasonable expectation of success because mitotically inactivating cancer cells halts the tumor cells' ability to proliferate while preserving their antigenic properties. One would be motivated to mitotically inactivate the cancer-associated fibroblasts of Ichim et al. in view of Inoue et al. because active cancer cells can proliferate rapidly and outcompete immune cells for nutrients and space.
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.
Response to Traversal
Regarding the remarks on page 16 which reference the assertion “[i]rradiation is a well-known method of mitotically inactivating cancer cells” which lacks a citation, this conclusion was drawn from the teachings of Ohno. Ohno teaches utilization of irradiated cancer cells, while Ohno does not specifically point to mitotic inactivation while utilizing this process it was thought that radiation techniques to halt and regulate the development, spread, and multiplication of cancerous tumor cells was well-known. Radiation is a well-known cancer treatment method which can be used to damage cancer cells so severely that they are unable to complete cell division and grow, thus mitotic inactivation, as cells with unrepaired DNA often arrest in mitosis or undergo apoptosis during division.
Regarding the remarks directed to Ohno not supporting an effective method of inducing mononuclear cells against cancer cells of any type, to include CAFs; Ohno summarizes their work by stating induction and large scale culture of specific CTL against tumor cells are important for adoptive immunotherapy and whenever epitope-peptides presented on the surface of tumor cells, successful induction of CTL responses with peptide-pulsed dendritic cells illustrates the potential use of antigen-presenting cells for vaccination protocols in human tumor (p. 201, Conclusion). Thus, it would have been obvious to extend this conclusion to any type of cancer cell, to include CAFs.
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 1, 3, 49-50, 57, 63, 66, 85, and 88-90 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,141,471 in view of Inoue et al. (International Journal of Oncology 49, 2016, IDS ref.).
This rejection is repeated with regard to claims 1, 3, 49-50, 57, 63, 66, 85, and 88-90 for the same reasons of record as set forth in the Official Action mailed 17 October 2025. A response to applicant’s traversal follows the reiterated rejection below.
Claims 1, 3, 49-50, 57, 63, 66, 85, 88-90 are rejected on the ground of nonstatutory double patenting over claims 1-13 of U.S. Patent No. 11,141,471 since the claims, if allowed, would improperly extend the “right to exclude” already granted in the patent.
Although the claims at issue are not identical, they are not patentably distinct from each
other because the patented claims render obvious the instant claims.
Regarding claim 1, patented claim 1 recites a method of inducing anticancer activity in mononuclear cells comprising the steps of: a) obtaining a cord blood sample; b) isolated mononuclear cells from said cord blood sample; c) culturing said mononuclear cells to induce gene silencing of an immunological checkpoint; and d) continuing said culture in the presence of a factor capable of endowing and/or augmenting said cord blood mononuclear cells with tumor cytotoxic activity.
However, patented claim 1 does not recite culturing said mononuclear cells with cancer-associated fibroblasts and administering said mononuclear cells to a subject in need.
Inoue et al. disclose cancer-associated fibroblasts (CAFs) were cocultured with natural killer (NK) cells (Abstract). Inoue et al. teach CAFs regulate not only carcinogenesis, but also the immune evasion of cancer in the tumor microenvironment (TME), which facilitates cancer cell proliferation, expansion, and metastasis (p. 1297, Introduction). Inoue et al. teach CAFs suppress the NK cell-killing activity by decreased PVR cell surface expression, a ligand of an NK activating receptor (p. 1302, Discussion). Inoue et al. teach ligands of the receptors, PVR, a ligand of DNAM-1, was observed to be ubiquitously expressed on the cell-surface of CAFs and it is known DNAM-1 activates NK cell activity (p. 1303, 1st column). Inoue et al. teach some studies demonstrated PVR interacts with higher affinity to TIGIT (inhibitor) than DNAM-1 (activator) (p. 1303, 1st column). Inoue et al. teach soluble poliovirus receptor (PVR/CD155) may be used as a potential agent to activate NK cell activity in the TME (p. 1303, Discussion). Inoue et al. teach the reduction of PVR expression in CAFs is critical for CAF-induced suppression of NK cell activity (p. 1303, 1st column).
Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Inoue et al. with the method of patent ‘471, wherein mononuclear cells and cultured with CAFs, with a reasonable expectation of success because Inoue et al. teach a mechanism to circumvent the suppressive nature CAFs impose on NK killing activity when co-cultured with CAFs which would further enhance the cytotoxic activity of the NK cells. One would be motivated to combine the teachings of Inoue et al. with the method of patent ‘471 because it is well known in the art NK cells play an important role in cancer immunity in the tumor microenvironment, thus, recovering one of the known inhibitory pathways imposed by CAFs on NK cells would be expected to enhance the cytotoxic activity of said mononuclear cells and Ichim et al. teach the use cord blood cells as starting cell populations for generation of killer cells that possess selectivity to tumor tissues, which would be improved by co-culturing CAFs with NK cells. Additionally, it would have been obvious to one or ordinary skill in the art to administer said modified mononuclear cells to a subject in need because patent ‘471 in view of Inoue et al. would necessarily induce an immune response to cancer-associated fibroblasts in a subject. See MPEP § 2144.07, Art Recognized Suitability for an Intended Purpose. As the intended purpose of the modified mononuclear cells would be for administering to a subject.
Regarding claim 3, patented claim 2 disclose wherein gene silencing comprises induction of RNA interference.
Regarding claim 49, patented claim 3 disclose wherein an antigen presenting cell is added during culturing.
Regarding claim 50, patented claim 4 disclose wherein said antigen presenting cell is a dendritic cell.
Regarding claim 57, patented claims 5 and 6 disclose wherein said antigen presenting cell is activated to enhance immunogenicity wherein said enhanced immunogenicity is augmentation of HLA antigens.
Regarding claim 63, patented claim 7 disclose wherein said culture additionally comprises soluble inhibitors to immunosuppressive factors.
Regarding claim 66, patented claims 8 and 9 disclose wherein said soluble inhibitors are selected from the group consisting of: a) small molecules; and b) antibodies, wherein said immunosuppressive factor is HLA-G.
Regarding claims 85 and 88, patented claim 10 disclose wherein said mononuclear cells are T cells, selectively expanded from cord blood progenitors from the cord blood sample, said T cells are then expanded using the culture with a tumor antigen.
Regarding claim 89, patented claim 11 disclose wherein said tumor antigen is prostate stem cell antigen.
Regarding claim 90, patented claims 12 and 13 disclose wherein said mononuclear cels are T cells possessing a Th1 phenotype wherein said Th1 phenotype includes cells expressing the marker. The patent discloses at column 36 lines 19-25, Th1 phenotype includes cells expressing markers selected from a group comprising; CD4, CD94, CD119, CD183, CD186, CD191, CD195, CD212, CD254, CD278, IL-18R, MRP1, NOTCH3, and TIM3.
Response to Traversal
Applicant's arguments filed 15 January 2026 have been fully considered but they are not persuasive.
Regarding the remarks on page 17 which reference the ‘471 Patent teaches NK cells can be used for cell therapy of cancer on their own. While this may not be required for NK cells to be utilized in cancer cell therapy, it does not exclude the possibility to improve upon the methods which were known in the art.
Regarding the remarks on pages 17-18, Applicant argues a skilled artisan would not have been motivated to combine the teachings of Inoue with the ‘471 Patent, while Inoue does teach co-culturing CAF with NK cells reduces the cytotoxic effect of NK cells, Inoue investigates the mechanisms involved and points to possible strategies to overcome this immune evasion system in the tumor microenvironment (TME). In uncovering the mechanisms related to this suppressive nature Inoue suggests the data from their investigation could provide a novel strategy for inhibiting the immune evasion system in the TME (p. 1303, Discussion), which provides the appropriate motivation to combine the teachings of Inoue and the ‘471 Patent. MPEP 2141.02 (VI) states that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
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).
Regarding the remarks on page 18 which reference a surprising technical effect of improved cytotoxicity of the claimed CAFs with activated NK cells, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Furthermore, in submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964).
The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter "as a class" relative to the prior art subject matter "as a class." In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971 ); In re Hostettler, 429 F.2d 464, 166 USPQ 558 (CCPA 1970). See, also, In re Lindner, 457 F.2d 506, 173 USPQ 356 (CCPA 1972).
It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D'Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
Regarding the remarks on page 18 which reference administering the mononuclear cells to a subject and that this would not have been obvious, further pointing to Inoue as not teaching administering nor measuring immune response. Patent ‘471 teaches administration of cord blood killer cells to initiate a cascade of antitumor immune responses (Abstract). The rejection was base on the combination of references, not Inoue alone. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Regarding the rejection of the dependent claims, Applicant has not set forth any specific arguments pertaining to these rejections.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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