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 election with traverse of Group I (drawn to a genetically engineered natural killer (NK) cell) in the Response filed on March 13, 2026 is acknowledged.
The traversal is on the ground that the Examiner has not established a search burden for both the product and the methods. Applicant asserts that independent claim 16 recites the method of contacting the NK cell of Group I with target cells and the international search report has already listed search results. As such, applicant asserts that there is no burden to search all claims and thus the restriction requirement should be withdrawn.
This is not found persuasive for following reasons:
Contrary to applicant’s arguments relying upon lack of burden, note that the search burden is not a consideration in applications entering the National Stage under 35 U.S.C. 371. The inventions of Groups I-II lack the same or corresponding special technical feature that is a contribution over the prior art Valamehr et al. for the reasons set forth in the Office Action mailed on January 15, 2026.
Applicant is reminded that where applicant elects claims directed to the product, and product claims are subsequently found allowable, withdrawn process claims that depend from or otherwise include all the limitations of the allowable product claim will be considered for rejoinder. All claims directed a nonelected process invention must require all the limitations of an allowable product claim for that process invention to be rejoined. See 37 CFR 1.104 and MPEP § 821.04(b). Additionally, in order to retain the right to rejoinder in accordance with the above policy, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product claims. Failure to do so may result in a loss of the right to rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Claims 1-20 are pending.
Claims 16-20 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected invention.
Claims 1-15 are currently under consideration as they read on the elected invention.
3. 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.
4. Claim 7 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
It is apparent that NK cell NK-92MI is required to practice the claimed invention. As a required element, it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, a deposit of the cell line may satisfy first paragraph. See 37 CFR 1.801-1.809.
If the deposit(s) ha(ve)s been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the NK-92 MI has been deposited under the Budapest Treaty and that the NK-92 MI will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806. If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit(s) was/were made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the NK-92MI described in the specification as filed are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
It is noted that the instant specification discloses on paragraph [Symbol font/0x5B]0121] (PG PUB of instant application US 2023/0398215) that the NK-92MI is from ATCC Cat # CRL-2408). Amending claim 7 to recite NK-92 MI from ATCC CRL-2408 would obviate this rejection.
5. 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.
6. 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.
7. 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 Wang et al. (Cancer Letter March 2020, 472:175-180, reference on IDS).
The claims are 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,
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).
The reference teachings differ from the instant invention by not describing NK cells including NK cell.
Wang et al. teach that while researches on CAR-T cells have made major breakthrough in treatment of recurrent refractory B-cell malignant tumors, cytokine release syndrome or other side effects restrict their further clinical uses (e.g. see 1st paragraph in left col. in page 175). Wang et al. further teach that NK cells are an alternative to CAR T cells as NK cells inherently lack these drawn backs and are safer (see 1st paragraph in left col. in page 175). Wang et al. teach similar to CAR-T, CAR-NK cells are composed of an extracellular signaling domain that recognizes specific antigens on tumors and a transmembrane domain, and an intracellular domain.
Wang et al. teach CAR NK cells contains CD3 zeta, CD28,and 4-1BB (e.g. see paragraph spanning pages 175-176). Wang et al. teach CAR-NK92 cells had been safely administered (e.g. see left col. in page 177 and Table 3 in page 178).
Wang et al. teach the recent understanding of NK cell immunobiology has paved way for novel CAR NK cell therapy where the NK cells recognize tumor-associated antigen independently of patients’ HLA phenotype, making it possible to prepare NK cell banks instead of constructing individualized CAR-NK cells (e.g. see paragraph spanning pages 178-179).
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 Wang et al. to switch the T cell disclosed in Repllin et al. to the NK92 cells taught by Wang 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 Wang et al. teach CAR NK cells are an alternative to CAR T cells as NK cells inherently lack drawn backs of CAR T cells such as cytokine release syndrome and are safer than CAR T cells. Further, Wang et al. teach CAR NK cells and CAR T cells share similar structures including an extracellular signaling domain that recognizes specific antigens on tumors and a transmembrane domain, and an intracellular domain.
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 NK CAR and the similarity in structure between CAR T and CAR NK, 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.
8. 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 Wang et al. (Cancer Letter March 2020, 472:175-180, reference on IDS) as applied to claim 1 above, and further in view of You et al. (Am. J. Cancer Res. 2019, Jan 1;9:64-78).
The teachings of Repellin et al. and Wang et al. have been discussed, supra.
The reference teachings differ from the instant invention by not describing NK-92 MI cell.
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).
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 Wang 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, construct 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 eliminate the cytokine release syndrome associated with CAR-T cells, and more suitable for treating T-ALL.
9. No claim is allowed.
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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