DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment filed on August 17, 2026 is acknowledged.
Claims 1-20 are pending.
Claims 16-20 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 13, 2026.
Claims 1-15 are currently under consideration as they read on the elected invention.
3. In view of applicant’s amendment, only following rejections are set forth.
4. 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.
5. 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
6. This is a New Ground of Rejection necessitated by applicant’s amendment to the claims. Claims 1-6 and 8-15 are rejected under 35 U.S.C. 103 as being unpatentable over Repellin et al. (Adv. Biosyst. 2018 1800210:1-8, first published September 14, 2018) in view of Zhang et al. (Frontiers in Immunology 2017, May 8;533:1-17).
The amended claims are now drawn to a genetically engineered natural killer (NK) cell comprising an exogenous polynucleotide in operative association:
a receptor element comprising a CAR linked to a transmembrane domain, an intracellular and a signaling domain, wherein the intracellular signaling domain includes an intracellular signaling portion of a CD28, an intracellular signaling portion of a 4-1BB, and an intracellular signaling portion of a CD3ζ
an actuator element encodes a transcription factor binding site, and
an effector element encodes the effector protein operably linked to a signal peptide.
Repellin et al. teach a T cell biofactory comprising polynucleotide encoding an artificial cell-signally pathway in T cells (a population of Jurkat T cells) comprising:
a) CAR comprising antigen binding domain that binds folate receptor alpha (FRα) or mesothelin (MSLN) (VH and VL) that recognize an antigen on target cells, a transmembrane domain from CD28 transmembrane domain and 4-1BB and CD3 zeta signaling domain,
b) an actuator comprising six copies of NFAT-RE nucleotides,
c) effector comprising IFN alpha-2 signal peptide linked upstream to a reporter transgene Nluc (a non-human effector and non-native to the effector protein) that can be exchanged with a therapeutic transgene to neutralize pathology that triggered the T cell biofactory (e.g. see Figure 1B or copy below, and Generation of T-cell Biofactories in left col. in page 6).
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Repellin et al. teach that the receptor, effector and actuator are designed as a single DNA sequence for ease of manufacture and clinical translation (e.g. see right col. in page 1).
Repellin et al. teach that the T cell biofactory autonomously synthesizes the release of effector protein upon engaging its target ligand on the surface of antigen-presenting disease cells such as human ovarian cancer cells expressing FRα and MSLN (e.g. see left col. in page 4) and the effector protein activity from the FRα specific T-cell Biofactories was proportional to the target cell mass (e.g. see right col. in page 4 and Figure 2D).
Repellin et al. teach that the receptor, actuator, and secretor are constant domains and effector and sensor (the extracellular domain) are variable domains (e.g. see Figure 1B legend in page 2).
Repellin et al. teach T cell-Biofactories population of 12,500 cells (e.g. see Legend for Figure 2 (A)-(C) in page 3).
Repellin et al. teach that the T cell Biofactories can synthesize and deliver therapeutics (effectors) with spatiotemporal resolutions because they can synthesize and secret an effector protein upon binding to a specific cell surface target, thereby prevent systemic toxicity by synthesizing biologic molecules only when and where required and minimizing their delivery to non-target cells (e.g. see 2.6. in left col. in page 5).
Repellin et al. conclude that the T-cell Biofactories will circumvent the need to rely on passive diffusion of drugs in fused in excess, and will instead autonomously synthesize calibrated amounts of engineered therapeutic proteins from human or nonhuman origin directly at the disease site and limit damage to normal tissues (e.g. see last paragraph in right col. in page 5).
Repellin et al. teach that the modularity of this pathway enables reprogramming of the T cell Biofactory to target biomarkers on different disease cells and leads to a “living drug” that extravasates to the disease sites, assesses the disease burden and synthesizes the calibrated amount of engineered therapeutic proteins upon stimulation by the disease cells and reduces targeting of normal cells (e.g. see Abstract).
Repellin teaches intracellular portion of the CAR having CD28, 4-1BB, and CD3 ζ (e.g. see Figure 1). Thus, Repellin teaches receptor element, actuator element, and effector element that are identical to the instant claims.
The reference teachings differ from the instant invention by not describing NK cells including NK cell.
Zhang et al. teach CAR-NK-92 cells as an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Specifically, Zhang et al. teach advances from the CAR T cell field enables the generation of tumor specific CAR-NK cells. The CAR design evolved from the basic CAR with scFv fused to CD3ζ to including of costimulatory protein domains derived from CD28 and 41-BB or their combination in addition to CD3ζ to improve T cell activation, proliferation and persistence (e.g. see left col. in page 3). Zhang et al. teach that the first generation of CAR comprising scFv fused to CD3ζ was demonstrated to be functional in NK cells. Zhang et al. teach variety of CARs comprising intracellular signaling elements of CD3ζ, CD28, and CD137 (41-BB) for T cells have been successfully used for NK-92 cells (e.g. see Table 1 and left col. in page 3). Zhang et al. teach third generation CD28-CD137-CD3ζ has been used successfully with NK-92 cells (e.g. see Table 1 and right col. in page 3).
Zhang et al. teach CAR-engineered NK-92 offers a valid and cost-effective alternatives to primary CAR NK or T cells. Methodology for continuous good manufacturing practice (GMP)-compliant expansion can be readily extended from unmodified NK-92 cells to CAR-engineered NK-92 cells (e.g. see right col. in page 5).
It would thus be obvious to one of ordinary skill in the art at the time the invention was filed to combine the teachings of Repellin et al. and Zang et al. to switch the T cell disclosed in Repllin et al. to the NK92 cells taught by Zang et al. One of ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, because Repellin et al. teach a T cell biofactory comprising genetically engineered T cells comprising a single NDA sequence comprising the receptor, effector, and actuator, wherein the T cell biofactory autonomously synthesizes the release of effector protein upon engaging its target ligand on the surface of antigen-presenting disease cells and Zhang teach that third generation CAR comprising intracellular CD28-CD137-CD3ζ for T cells has been used successfully with NK-92 cells.
Given that Repellin et al. teach that the modularity of the T cell biofactory enables reprogramming of the T cell Biofactory to target biomarkers on different disease cells and leads to a “living drug” that extravasates to the disease sites, and in view of the benefit of CAR-NK-92 and the evidence shown in Zhang that CAR designed for T cells can be successfully adapted to use in NK-92 to generate tumor targeting CAR-NK-92 cells, an ordinary skill in the art would have been motivated to use the biofactory disclosed by Repellin et al. in the more beneficial NK 92 cells with a reasonable expectation of success.
Applicant’s arguments relevant to the new ground of rejection have been fully considered but have not been found persuasive.
Applicant argues Repellin is directed to a T-cell biofactory using T cells not NK cells. Applicant further asserts that one of ordinary skill in the art would not have a reasonable expectation of success modifying Repellin to arrive the claimed invention.
Furthermore, applicant asserts that NK cell is not a predictable system with changes in different variables impacting cell viability and ability to incorporate a single construct. A skill in the art would know CAR-based T-cell and CAR-based NK cell composition may bring about different effects and functionality of the CAR and/or the genetically engineered cell and would not expect the element in Repellin would retain its functions in NK cells.
Thus, applicant asserts that NK cells are not the same as T cells and there would not be a reasonable expectation of success to use the construct used in a T cell of Repellin with a NK cell. Moreover, applicant asserts that page 35 of the instant specification as-filed discloses that it was surprising that the genetically engineered NK cells can utilize at lease some modular architecture used to modified T cells.
This is not found persuasive for following reasons:
Note that regarding the newly added limitation of “wherein the intracellular domain includes an intracellular portion of CD28, an intracellular signaling portion of 4-1BB, and intracellular signaling portion of CD3 zeta”, note that Repellin teaches intracellular portion of the CAR having CD28, 4-1BB, and CD3 ζ (e.g. see Figure 1). Thus, Repellin teaches receptor element, actuator element, and effector element that are identical to the instant claims.
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). In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, rather than require each reference to teach the claimed limitation, the question remains whether the claims are obvious in view of the teachings of both Repellin Zhang.
It was well known in the art at the time the instant invention was filed that advances from CAR T field enables the generation of tumor-specific NK cells and CARs used in T cells would be functional in NK-92 cells. For example, the third generation CAR CD28-CD137 (41-BB)-CD3ζ recognizing CD3 or CD5 for elimination of malignant T cells has been used successfully with NK-92 (e.g. see first full paragraph in right col. in page 3 of Zhang et al.).
Further, contrary to applicant’s arguments relying upon the surprising results of CAR of T cells also works in NK cells, note that there is abundant evidence disclosed in Zang to show that constructs from CAR-T are functional in NK cells. For example, Zang listed preclinical studies of CAR-NK-92 cells in Table 1 that showed CAR having CD28-4-1BB-CD3ζ has been used for NK-92 for T cell malignancies.
Given that the modularity of the T cell biofactory enables reprogramming of the T cell Biofactory to target biomarkers on different disease cells and leads to a “living drug” that extravasates to the disease sites as taught by Repellin et al., and in view of the knowledge that
CARs designed for T cells have been successfully adapted to use in NK-92 to generate tumor targeting CAR-NK-92 cells, an ordinary skill in the art would have been motivated to use the biofactory disclosed by Repellin et al. in the more beneficial NK 92 cells in Zhang with a reasonable expectation of success.
As such, applicant’s arguments have not been found persuasive.
7. Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Repellin et al. (Adv. Biosyst. 2018 1800210:1-8, first published September 14, 2018) in view of Zhang et al. (Frontiers in Immunology 2017, May 8;533:1-17) as applied to claim 1 above, and further in view of You et al. (Am. J. Cancer Res. 2019, Jan 1;9:64-78) as evidenced by the ATCC catalog page for NK-92MI.
The teachings of Repellin et al. and Zang et al. have been discussed, supra.
The reference teachings differ from the instant invention by not describing NK-92 MI cell from ATCC CRL-2408.
You et al. teach that CAR T therapy has shown promising results as adoptive immunotherapy in treating several solid and hematological cancers (e.g. see last paragraph in right col. in page 64). However, several challenges such as harvesting adequate number of autologous T cells from patients with refractory disease without contamination by malignant T cells have limited the use of CAR-T in treating T cell malignancies (e.g. see last col. in page 65). You et al. teach NK-92 cells line derived from peripheral blood mononuclear cells from a non-Hodgkin’s lymphoma patient has been tested in clinical trials for immunotherapy and its safely and expansion feasibility have been validated in Phase I clinical trial (e.g. see last paragraph in left col. in page 65).
You et al. further teach that NK-92 MI cells are derived from NK-92 cell line by stably transfecting an IL-2 gene, making them IL-2-independent but have the same characteristics to activated NK cells as the parent NK-92 cells (e.g. see right col. in page 65).
You et al. constructed two CD7-CAR-NK92MI cell lines using monovalent and bivalent CD7 nanobody, each joined to the signal peptide, Fc hinge, CD28 transmembrane and intracellular domain, and intracellular domain of 4-1BB and CD3 zeta (e.g. see first paragraph in left col. in page 66 and Figure 1 in page 67). You et al. teach that in vitro and in vivo, the CD7-CAR-NK92 MI cells recognized and eliminated primary T-cell acute lymphoblastic leukemia (T-ALL) primary tumor cells from T-ALL patients (e.g. see right col. in page 72 and left col. in page 74).
You et al. teach that since NK-92 or NK-92MI cells are off-the-shelf cell products, repeated administration of these cells engineered to express CAR to patients are another option for T-ALL treatment (e.g. see paragraph spanning pages 74-75).
As evidenced by the ATCC Catalog page, NK-92MI has a deposit number of ATCC CRL-2408.
It would thus be obvious to one of ordinary skill in the art at the time the instant invention was filed to use NK-92MI to construct the CAR NK cells. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since the combined teachings of Repellin et al. and Zang et al. would have motivated an skill in the art to construct CAR NK92 cells using the T-cell biofactory and You et al. teach that NK-92MI, a modified NK-92 cell that is IL-2 independent. As such, making CAR-NK92MI using the polypeptide sequence disclosed by Repellin et al. would have been well within the skill of an ordinary artisan. Such engineered CAR NK-92 MI cells would be expected to be beneficial in eliminating the cytokine release syndrome associated with CAR-T cells, and more suitable for treating T-ALL.
Applicant’s arguments and the Examiner’s rebuttal are essentially the same as discussed above.
8. No claim is allowed.
9. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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