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 .
DETAILED ACTION
This action is in response to the papers filed on May 11, 2026. Claims 1-20 are currently under examination.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2019/048311 filed on August 27, 2019. Applicants' claim for the benefit of a prior-filed application parent provisional applications 62/820,636 filed on March 19, 2019 and 62/723,105 filed on August 27, 2018 under 35 U.S.C. l 19(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The disclosures of the prior-filed provisional application 62/723,105 fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Specifically, 62/723,105 does not support the claimed subject matter of the newly amended claim 20, such as expression of CD117, CD105, etc. CD117, CD105, and expression of the rhodamine 123 efflux activity is not mentioned or taught in the specification of 62/723,105.
Thus, the earliest possible priority for claims 1-19 is March 19, 2019.
Withdrawn- Specification Objection
In view of the concurrent submission of a substitute specification, removing hyperlinks the objections to the specification have been withdrawn.
Maintained Claim Rejections - 35 USC§ 102
Claims 1-2 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kang (CN108795877A, published Nov. 13, 2018), evidenced by Cords et al. (Nat Commun. 2023 Jul 18;14:4294.) and Schulze et al. (Thorac Cancer. 2020 Jan;11(1):120-129.). Applicants’ arguments filed on May 11, 2026 have been fully considered but they are not persuasive.
Regarding claims 1-2, Kang discloses an engineered fibroblast expressing CAR, or CAR-F cell (Abstract; claim 1). Kang additionally discloses the antigen-specific targeting region, transmembrane domain, intracellular signaling domain, and scFV (pg. 2, para. 3-4 and last para.)
Kang discloses the fibroblast cell expressing the CAR for treatment of tumor diseases (Abstract; pg. 2, para. 3). Where the fibroblast is a species which is administered to, or exists in, a physiological inflammatory or cancer state/environment, the fibroblast can naturally or inherently express CD34, as evidenced by Cords et al. and Schulze. These fibroblasts are commonly termed inflammatory associated fibroblasts (iCAFs) or cancer-associated fibroblasts (CAFs). The disclosure of Cords evidence that a fibroblast cell inherently expresses the cell-surface marker CD34, along with other cell surface markers selected from conventional fibroblast markers, such as vimentin (pg. 2-3, bridging para.; Fig. 4; Table 1). Likewise, the disclosure of Schulze evidence markers including CD34 and SMA are inherently expressed by fibroblasts (Abstract; pg. 126-127, bridging para.). Thus, fibroblast cell subtypes inherently express markers such as CD34, as well as conventional fibroblast markers such as vimentin.
Maintained Claim Rejections - 35 USC § 102
Claims 1-3, 7, and 16-20 remain rejected under 35 102(a)(1)(2) as being anticipated by Shiku et al. (US 2014/0242701 A1, patented Aug. 28, 2014), evidenced by Cords et al. (Nat Commun. 2023 Jul 18;14:4294.) and Schulze et al. (Thorac Cancer. 2020 Jan;11(1):120-129.). Applicants’ arguments filed on May 11, 2026 have been fully considered but they are not persuasive.
Regarding claims 1 and 20, Shiku discloses a fibroblast, where said fibroblast expresses a chimeric antigen receptor (CAR), and wherein the chimeric antigen receptor comprises at least one antigen-specific targeting region, at least one transmembrane domain, and at least one intracellular signaling domain ([0011]; [0014]; [0083]).
Shiku discloses the cell expressing the CAR for administration or use as a therapeutic agent for diseases including inflammatory disease and cancer ([0091]). Where the fibroblast is a species which is administered to, or exists in, a physiological inflammatory or cancer state/environment, the fibroblast can naturally or inherently express CD34, as evidenced by Cords et al. and Schulze. These fibroblasts are commonly termed inflammatory associated fibroblasts (iCAFs) or cancer-associated fibroblasts (CAFs). The disclosure of Cords evidence that a fibroblast cell inherently expresses the cell-surface marker CD34, along with other cell surface markers selected from conventional fibroblast markers, such as vimentin (pg. 2-3, bridging para.; Fig. 4; Table 1). Likewise, the disclosure of Schulze evidence markers including CD34 and SMA are inherently expressed by fibroblasts (Abstract; pg. 126-127, bridging para.). Thus, fibroblast cell subtypes inherently express markers such as CD34, as well as conventional fibroblast markers such as vimentin.
Regarding claim 2, dependent on claim 1, Shiku discloses a chimeric antigen receptor comprising an extracellular domain capable of binding to an antigen, a transmembrane domain,
and at least one intracellular domain ([0014]).
Regarding claim 3, dependent on claim 1-2, Shiku discloses the antigen-specific targeting region is an scFv, stating that a domain capable of binding to an antigen or a ligand can be used, preferably a scFv (Fig. 1-2, [0004], [0029-0030], [0052], and [0055]).
Regarding claim 7, dependent on claim 1, Shiku discloses that the cell expressing a chimeric antigen receptor, which are useful in the field of adoptive immunity gene therapy for tumors and an effect of the invention is adoptive immunity gene therapy targeting an antigen such as a tumor antigen ([0001]; [0028]).
Regarding claim 16-18, dependent on claim 1, Shiku discloses that the cell is a human cell collected, isolated, purified or induced from a body fluid, a tissue or an organ such as blood (peripheral blood, umbilical cord blood etc.) or bone marrow ([0083]).
Regarding claim 19, dependent on claim 1, Shiku discloses cells, in the plural ([0031-0047]).
Maintained Claim Rejections - 35 USC§ 103
Claims 1-20 remain rejected, under 35 U.S.C. 103 as being unpatentable over Wagner et al. (US 2016/0237407 A1, patented Aug. 18, 2016), in view of Denu et al. (Acta Haematol. 2016; 136(2): 85-97.), Ichim et al. (J Transl Med (2018) 16:212), and Kang (CN108795877A, published Nov. 13, 2018), as evidenced by Cords et al. (Nat Commun. 2023 Jul 18;14:4294.) and Schulze et al. (Thorac Cancer. 2020 Jan;11(1):120-129. Epub 2019 Nov 24.). Applicants’ arguments filed on May 11, 2026 have been fully considered but they are not persuasive.
Regarding claims 1 and 20, Wagner teaches universal donor chimeric allogeneic cells useful for the treatment of cancer, including mesenchymal stem cells which are transfected with CAR (CAR-MSC) to enhance migration into tumors and induce tumor death, reduction of inflammation, or immune sensitization, (Abstract and claims 18-36). Furthermore, Wagner teaches where the mesenchymal stem cell expressing CAR (claim 18) with antigen binding domains for Wt1 (claim 19).
Additionally, where the fibroblast is a species which is administered to, or exists in, a physiological inflammatory or cancer state/environment, the fibroblast can naturally or inherently express CD34, as evidenced by Cords et al. and Schulze. These fibroblasts are commonly termed inflammatory associated fibroblasts (iCAFs) or cancer-associated fibroblasts (CAFs). The disclosure of Cords evidence that a fibroblast cell inherently expresses the cell-surface marker CD34, along with other cell surface markers selected from conventional fibroblast markers, such as vimentin (pg. 2-3, bridging para.; Fig. 4; Table 1). Likewise, the disclosure of Schulze evidence markers including CD34 and SMA are inherently expressed by fibroblasts (Abstract; pg. 126-127, bridging para.). Thus, fibroblast cell subtypes inherently express markers such as CD34, as well as conventional fibroblast markers such as vimentin.
While Wagner teaches a CAR-MSC, or mesenchymal stem cells expressing CAR, Wagner never explicitly teaches a fibroblast cell expressing a chimeric antigen receptor (CAR).
However, in view of Denu and Ichim, which teach fibroblast as a practical and interchangeable alternative to MSCs, including for therapeutic use, a person of ordinary skill in the art would have found it obvious to employ fibroblasts, rather than mesenchymal stem cells, as taught by Wagner, as the CAR-expressing cellular platform or substitute fibroblast in place of mesenchymal stem cells as the CAR-expressing cell type.
Denu teaches that fibroblasts and mesenchymal stromal/stem cells are phenotypically indistinguishable. Moreover, Denu teaches that human mesenchymal stromal/stem cells (MSCs), derived from many different tissues, are characterized by a fibroblast-like morphology, possess ability to differentiate into adipocytes, chondrocytes, osteoblasts, express certain cell surface markers like CD105, and produce of vimentin, a canonical fibroblast marker (abstract; pg. 6, para. 1; pg. 8, para. 3). Denu states that fibroblast, as well as MSCs express vimentin,
“Prior studies have also presented evidence that MSCs exhibit properties typically thought to characterize fibroblasts. One study showed that bone marrow MSCs express the same types of collagens as skin fibroblasts. Another study demonstrated that adipose tissue-derived MSCs make collagen type I, fibronectin, vimentin, and nestin matrices similar to those of dermal fibroblasts, and another report demonstrated these same findings in bone marrow MSCs compared to adult bronchial and fetal lung fibroblasts.”
Likewise, Ichim teaches fibroblast as a practical and effective therapeutic substitute for mesenchymal stem cells, recognizing their similar immunophenotypic properties and efficacy in cell therapy. Ichim explicitly states,
“While the most commonly used MSC source, the bone marrow provides relatively little starting material for cellular expansion, and requires invasive extraction means, fibroblasts are easily harvested in large numbers from various biological wastes. Additionally, in vitro expansion of fibroblasts is significantly easier given the robustness of these cells in tissue culture and shorter doubling time compared to typical MSC. In this paper we put forward the concept that in some cases, fibroblasts may be utilized as a more practical, and potentially more effective cell therapy than mesenchymal stem cells (abstract).”
“Accordingly, tissue sources, such as fibroblasts, in which larger numbers of cells may be originally extracted, may serve as an attractive alternative to MSC (pg. 2, column 1, para 3).”
“Based on currently accepted definitions for cultured human MSCs and fibroblasts, the investigators could not find any immunophenotypic property that could make a characteristic distinction between MSCs and fibroblasts (pg. 5, column 1, para. 2).”
Furthermore, the teachings of Kang demonstrate that the prior art already taught and recognized the utility of engineered fibroblast CAR cells, or fibroblasts as the CAR-expressing cellular platform. Kang teaches a chimeric antigen receptor fibroblast and establishing method and application thereof for treating tumor diseases (abstract; claim 1).
Hence, prior to the effective filing date of the instant application, one of ordinary skill in the art, would have found it obvious to simply substitute the fibroblasts, rather than mesenchymal stem cells, as taught by Wagner, as the CAR-expressing cellular platform, motivated by the teachings of Denu and Ichim, to achieve the predictable result of obtaining a CAR-Fibroblast cellular composition suitable to treat cancer. This substitution would have obtained the predictable result of producing a fibroblast cell expressing a chimeric antigen receptor (CAR), with a reasonable expectation of success, further in view of Kang.
Regarding claim 2, the combined teachings of Wagner, Denu, Ichim and Kang render claim 1 obvious. Wagner additionally teaches the expression of an antigen binding domain, a transmembrane domain, and an intracellular signaling domain (claim 1).
Regarding claim 3, the combined teachings of Wagner, Denu, Ichim and Kang render claims 1 and 2 obvious. Wagner additionally teaches CARs are usually generated by joining a single chain antibody (scFv) to an intracellular signaling domain, and the antigen binding affinity of scFv is typically much higher than the binding moiety of most TCRs ([0006-0007]).
Regarding claim 4, the combined teachings of Wagner, Denu, Ichim and Kang render claims 1 and 2 obvious. Wagner additionally teaches antigen binding domain binds antigens selected from the group comprising of TEM-1, TEM-2, TEM-3, TEM-4, TEM-5, TEM-6, TEM-7, TEM-S, ROBO-4, VEGFR2, CD109, survivin, and CD93 (claim 32).
Regarding claim 5, the combined teachings of Wagner, Denu, Ichim and Kang render claims 1 and 2 obvious. Notably, Wagner additionally teaches the engineered cell, where said intracellular signaling domain of the TLR-4 protein is linked to an activator of molecular pathways. This activator, the functional portion of the TLR-4 protein, triggers TLR4 signaling transduction, thereby endowing the cell with an MSC-1 phenotype (claims 20 and 33-36).
An MSC-1 phenotype is characterized by an enhanced ability to stimulate a mixed lymphocyte reaction, which correlates with improved anti-cancer activity (claims 20-24). The prior art’s disclosure of CAR-fibroblasts is significant because fibroblasts, as disclosed by Denu and Kang, offer unique advantages: they are readily isolated and modified, can persist in the tumor microenvironment, and may influence tissue architecture in ways that further support anti-cancer responses. Therefore, integrating the intracellular TLR4 domain into CAR-fibroblasts is desirable. It is reasonable to expect that such modification would enhance the anti-cancer ability of these cells by combining the robust immune-stimulatory effects of TLR4 signaling with the advantageous properties of fibroblasts as a therapeutic cell type.
Thus, it would have been obvious to further modify the CAR-fibroblasts by incorporating the intracellular TLR4 domain, with the expectation that this modification would enhance their anti-cancer capabilities.
Regarding claim 6, the combined teachings of Wagner, Denu, Ichim and Kang render claims 1 and 2 obvious. intracellular domain containing CD3 zeta chain and at least one shRNA domain encoding a transcript which generates at least one siRNA capable of inhibiting expression of HLA I and/or HLA II (abstract).
Regarding claim 7, the combined teachings of Wagner, Denu, Ichim and Kang render claim 1 obvious. Wagner additionally teaches that CARs are capable of endowing the cells with ability to trigger a T cell mediated immune response ([0031]).
Regarding claim 8, the combined teachings of Wagner, Denu, Ichim and Kang render claim 1 and 7 obvious. Wagner additionally teaches CAR is utilized to activate T cells to endow cytokine production or to stimulate cytotoxicity against tumors ([0009-0010]). Moreover, Wagner teaches an appropriate amount of soluble agent to be added will vary with the specific agent but can be determined by assaying different amounts of the soluble agent in T cell cultures and measuring the extent of co-stimulation by proliferation assays or production of cytokines ([0029]).
Regarding claim 9, the combined teachings of Wagner, Denu, Ichim and Kang render claim 1, 7, and 8 obvious. Wagner additionally teaches the utilization of IL-12 and IL-21 as tumor targeting agents delivered by the cells ([0011]).
Regarding claim 10 and 11, the combined teachings of Wagner, Denu, Ichim and Kang render claims 1 and 5 obvious. Wagner additionally teaches the enhanced ability of the cells expressing the TLR4 intracellular domain to stimulate NK cells as compared to a naive cell, wherein the NK cells are CD94+ and/or CDI 17 + and/or CD 161- and/or NKG2D+ and/or NKp46+ and/or CD226+ and/or CD57+ (claims 23-31).
Regarding claim 12-15, the combined teachings of Wagner, Denu, Ichim and Kang render claim 1 obvious. Wagner additionally taches the CAR cells are transfected with anti-apoptotic proteins to enhance in vivo longevity, and a method of using CAR-MSC that have been cultured under conditions to express increased amounts of at least one anti-apoptotic protein as a therapy to inhibit or prevent apoptosis. Furthermore, Wagner teaches the CAR cells have been contacted with an apoptotic cell secrete high levels of at least one anti-apoptotic protein, including but not limited to, STC-1, BCL-2, XIAP, Survivin, and Bcl-2XL ([0035] and claims 19 and 32).
Regarding claim 16-18, the combined teachings of Wagner, Denu, Ichim and Kang render claim 1 obvious. Kang teaches that fibroblasts are the most common cells in connective tissues (p. 1). Isolating fibroblasts from any connective tissue, including human placental connective tissue would have been obvious.
Regarding claim 19, the combined teachings of Wagner, Denu, Ichim and Kang render claim 1 obvious. Wagner additionally teaches that the cell can be expanded to obtain a plurality of cells ([0021] and [0026]).
***
Claims 12-15 remain additionally rejected under 35 U.S.C. 103 as being unpatentable over Shiku et al. (US 2014/0242701 A1), evidenced by Cords et al. and Schulze et al. as applied to claims 1-3, 7, and 16-20 above, in view of Wagner et al. (US 2016/0237407 A1). Applicants’ arguments filed on May 11, 2026 have been fully considered but they are not persuasive.
Regarding claim 12-15, dependent on claim 1, Shiku discloses claim 1, as clarified above, and that the cell is capable of binding to a tumor antigen such as survivin ([0060]). Shiku further discloses that a "tumor antigen" means a biological molecule having antigenicity, expression of which comes to be newly recognized in association with canceration of a cell. The tumor antigen in the present invention includes a tumor specific antigen (an antigen which is present only in tumor cells and is not found in other normal cells), and a tumor-associated antigen (an antigen which is also present in other organs and tissues or heterogeneous and allogeneic normal cells, or an antigen which is expressed on the way of development and differentiation) ([0050]).
Shiku does not teach anti-apoptotic proteins or that survivin is an anti-apoptotic protein.
However, Wagner taches the CAR cells are transfected with anti-apoptotic proteins to enhance in vivo longevity, and a method of using CAR-MSC that have been cultured under conditions to express increased amounts of at least one anti-apoptotic protein as a therapy to inhibit or prevent apoptosis. Furthermore, Wagner teaches the CAR cells have been contacted with an apoptotic cell secrete high levels of at least one anti-apoptotic protein, including but not limited to, STC-1, BCL-2, XIAP, Survivin, and Bcl-2XL ([0035]).
Thus, prior to the effective filing date, one of ordinary skill in the art would have found it obvious to apply the known anti-apoptotic function of survivin and other anti-apoptotic proteins, as taught by Wagner, to improve the similar method of utilizing tumor antigenecity of the cell, as taught by Shiku, ready for improvement. This would have yielded the predicable result of exposing, expressing, the known anti-apoptotic proteins with the CAR-fibroblast, with a reasonable expectation of success.
Response to Applicants’ arguments as they apply to the rejection of Claims 1 -20 under 35 USC § 102 & 103
Applicant's arguments filed May 11, 2026, have been fully considered but they are
not persuasive.
At pages 6-11 of the remarks filed on May 11, 2026, Applicants essentially argue
the following:
Applicant argues that the cited evidence shows that some fibroblast subtypes are CD34-negative and therefore CD34 expression cannot be inherent.
This argument is not persuasive because the argument is not commensurate with the scope of claim 1. Claim 1 is directed to “a fibroblast cell” expressing a CAR and comprising cell-surface marker expression of CD34. The claim is directed to a single fibroblast cell possessing the recited characteristics. Applicant’s evidence establishes, at most, that fibroblast populations are heterogenous and that CD34 expression levels may vary among fibroblast subtypes or in various biological contexts. Still, the evidence of record establishes CD34 expression as a recognized endogenous fibroblast phenotype. The fact that certain fibroblast subpopulations may differ in CD34 expression patterns or levels does not detract from the disclosures of a CD34+ fibroblast cell encompassed by claim 1.
Inherency does not require that the prior art expressly recognize the inherent property, and a newly appreciated property of an old product does not confer patentability where the property is present in the prior-art product. As set forth in MPEP § 2112(II), an inherent feature need not be disclosed or recognized in the prior art so long as the feature is necessarily present in the disclosed subject matter. The fact that marker expression may vary or differ in level by cell subtype, tissue source, culture condition, activation state, or physiological environment does not obviate the rejection because claim 1 does not exclude the CD34-positive fibroblast phenotypes evidenced by the record.
Claim 1 is encompassed by any CAR-expressing fibroblast having CD34 expression. The applied references disclose CAR-expressing fibroblasts, while the evidentiary references demonstrate CD34 expression as a natural fibroblast phenotype, known and recognized in the art. Applicants present no evidence that this is not the case, and applicants own discussion of Cords acknowledges CD34-high iCAFs, and applicant’s discussion of Schulze acknowledges evaluation of CD34+ fibroblasts staining in tumor stroma. The possibility that levels of CD34 expression varied among various populations or groups of fibroblast does not distinguish a claim that encompasses a CD34+ fibroblast cell.
Additionally, Applicant has not provided objective evidence showing that the fibroblast cells disclosed or rendered obvious by Kang, Shiku, or the combination of Wagner, Denu, Ichim, and Kang are necessarily CD34-negative or incapable of CD34 expression. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence, and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Conclusion
Claims 1-20 stand rejected. 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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/J.D.L./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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