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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant’s response filed September 16, 2025 has been received and entered into the application file. All arguments have been fully considered.
Claims 1, 3-5, 10-11, 13-14, 17-18, 20-21, 24, 34-35, 37-38 and 67 from the claim set filed September 16, 2025 are pending. Claims 2, 6-9, 12, 15-16, 19, 22-23, 25-33, 36, and 39-66 are cancelled. Claims 3, 10-11, 13-14, 17, 35, and 38 are withdrawn. Claims 1, 4-5, 18, 20-21, 24, 34, 37, and 67 are being examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/16/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Rejection(s) Withdrawn
Claim Rejections - 35 USC § 103
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.
RE: Claims 1-2, 4-5, 8, 12, 18, 20-22, 34, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (Liu, et al., Leukemia (2017) 32(2): 520-531; IDS filed 1/3/2023), in view of Denman (Denman, et al., PLoS ONE (2012) 7(1): e30264; IDS filed 7/25/2023) and Bajgain (Bajgain et al., Methods & Clinical Development (2014) 1: 14015; previously cited). Claim 12 is rejected under 35 USC 103 as being unpatentable over Liu, in view of Denman and Bajgain, as evidenced by MDACC (https://www.mdanderson.org/donors-volunteers/other-ways-to-help/give-blood/donation-instructions.html, retrieved from the web 12/10/2024; previously cited).
Examiner notes Applicant amendment has cancelled claims 2, 8, 12, and 22 thus making the rejection of said claims moot.
Applicant amended claim 1 to now require the limitations from now cancelled claims 8, 25, and 19. Examiner notes claims 25 and 19 were not included in the previously filed rejection, and as such, the previously filed rejections are withdrawn.
However, Applicant’s amendment has necessitated new grounds of rejection as set forth below.
RE: Claim 19 is rejected under 35 U.S.C. 103 as being obvious over Liu, in view of Denman and Bajgain, and further in view of Gonzalez-Cabrero (Gonzalez-Cabrero et al., Proc. Natl. Acad. Sci. (1999) 96(3):1019-23; IDS filed 4/4/2024) and Kumaresan (Kumaresan et al., Mol Immunol (2002) 39(1-2):1-8; IDS filed 4/4/2024).
Applicant amendment has cancelled claim 19, thus making the rejection of said claim moot.
RE: Claims 24 and 25 are rejected under 35 U.S.C. 103 as being obvious over Liu, in view of Denman and Bajgain, and further in view of Rham (Rham et al., Arthritis Res Ther (2007) 9(6): R125; previously cited).
Applicant amendment has cancelled claim 25, thus making the rejection of said claim moot. For the reasons discussed above, the obviousness rejection over Liu, in view of Denman and Bajgain is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn. However, Applicant amendment has necessitated new grounds of rejection, as set forth below.
New ground(s) of Rejection, necessitated by Amendment
Claim Rejections - 35 USC § 103
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.
Claims 1, 4-5, 18, 20-21, 24, 34, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (previously cited), in view of Malaer (Malaer, et al., Am J Cancer Res (2017) 7(8): 1637-1641; PTO 892).
In regards to claim 1, Liu teaches cord blood derived NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity (Title). Liu teaches CARS have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results but extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Liu teaches NK cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Additionally, Liu teaches cord blood (CB) offers an attractive, allogeneic, off-the-shelf source of NK cells for immunotherapy. Liu teaches of transducing CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9) and teaches the efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Additionally, Liu teaches IL-15 production by the transduced CB-NK cells critically improved their function. Liu teaches iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. Thus, Liu teaches of engineered CB-derived NK cells which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. Liu teaches said approach should greatly improve the logistics of delivering this therapy to large numbers of patients, which is a major limitation to current CAR-T-cell therapies (Abstract).
In regards to culturing said CB-NK cells, Liu teaches of K562-based feeder cells expressing membrane bound IL21 and CD137 (i.e., 41BBL). Said K-562 feeder cells are named Clone9.mbIL21 and as a POSITA will appreciate are well known APCs. Further, Liu teaches said APCs were recently reported to promote peripheral blood and CB-NK cell expansion. Liu additionally teaches CB-NK cells were stimulated (i.e., cultured with) clone 9 (i.e., APCs) and IL-2 (i.e., at least one cytokine) (Materials and Methods, Generation of CAR-modified NK cells). Further, Liu teaches of the expansion of CB-NK cells in the presence of clone9 APCs and IL-2 (Materials and Methods, Cell Lines).
Thus, Liu teaches claim 1 with the exception of Liu does not teach said clone9 APCs are engineered to express CD48 or CS1 (CD319).
Malaer teaches CS1 was identified as a NK cell receptor regulating immune functions and teaches CS1 (i.e., SLAMF7, i.e., CD319) as an effective immunotherapeutic target (Abstract). Malaer teaches CS1 activates NK cell cytoxicity. Malaer teaches CS1 is a self-ligand and homophilic interaction of CS1 activates NK cell function (p1638, 2nd column, CS1 activates NK cell cytoxicity).
As is well known in the art, and as a POSITA will appreciate, the primary purpose of culturing immune cells, such as NK cells, with engineered feeder cells, such as APCs, is to induce their optimal proliferation, activation, and enhanced killing function (i.e., cytotoxicity) for therapeutic applications. Thus, as Malaer teaches CS1 is a self-ligand that activates NK cell function, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Liu and Malaer. As Liu teaches the use of engineered APCs in regards to NK cells expansion, a POSITA would have been motivated to combine the teachings of Liu with the teachings of Malaer due to Malaer teaching of CS1 as an activator of NK cell cytotoxicity. A POSITA would have been motivated to engineer said APCs to express mbIL-21 and 41BB ligand (as taught by Liu) as well as to express CS1 (as taught by Malaer) in order to have the most proliferative and cytotoxic NK cells as possible. A POSITA would have had a reasonable expectation of success in combining said teachings due to both Liu and Malaer studying NK cells.
Therefore, the claim is obvious and is properly rejected.
In regards to claim 4, Liu and Malaer teach the method of claim 1. Neither Liu nor Malaer teaches of performing HLA matching. Thus, it is considered that HLA matching is not performed, hence meeting the limitation of claim 4.
Therefore, the claim is obvious and is properly rejected.
In regards to claim 5, Liu and Malaer teach the method of claim 1. Further, Liu teaches “wherein the engineered NK cells express a CAR.” Liu teaches cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR (Title).
Thus, the claim is obvious and is properly rejected.
In regards to claim 18, Liu and Malaer teach the method of claim 1. As defined in the instant specification, [0077], universal antigen presenting cells (uAPCs) refer to antigen presenting cells designed for the optimized expansion of immune cells, specifically, NK cells. The uAPCs may be generated by a unique combination of co-stimulatory molecules to overcome inhibitory signals and induce optimal and specific NK cell killing function. Exemplary APCs are generated by enforced expression of membrane bound IL-21 (mbIL21) and 4-1BB ligand in the NK cell -sensitive K562 antigen presenting cell line.
Liu teaches of K562-based feeder cells expressing membrane bound IL21 and CD137 (i.e., 41BBL). Said K-562 feeder cells are named Clone9.mbIL21 and as a POSITA will appreciate are well known APCs. Further, Liu teaches said APCs were recently reported to promote peripheral blood and CB-NK cell expansion. Liu additionally teaches CB-NK cells were stimulated (i.e., cultured with) clone 9 (i.e., APCs) and IL-2 (i.e., at least one cytokine) (Materials and Methods, Generation of CAR-modified NK cells). Further, Liu teaches of the expansion of CB-NK cells in the presence of clone9 APCs and IL-2 (Materials and Methods, Cell Lines). Thus, Liu teaches of “wherein the APCs are universal APCs.”
Therefore, the claim is obvious and is properly rejected.
In regards to claims 20 and 21, Liu and Malaer teach the method of claim 1. Further, Liu teaches the NK cells and the APCs are present at a 1:2 ratio (p521, 1st column, Generation of CAR-modified NK cells).
Thus, the claims are obvious and are properly rejected.
In regards to claim 24, Liu and Malaer teach the method of claim 1. Further, Liu teaches the culturing and/or expanding of the NK cells is in the presence of IL-21 (i.e., bound to the engineered APCs, i.e., clone 9) and IL-2. Liu teaches NK cells were stimulated (i.e., cultured) with irradiated clone 9 and recombinant human IL-2 (p521, 1st column, Generations of CAR-modified NK cells).
Thus, the claim is obvious and is properly rejected.
In regards to claim 34, Liu and Malaer teach the method of claim 1. Further, Liu teaches on day +14, CAR-transduced NK cells were collected for use (p521, Generation of CAR-modified NK cells).
Examiner notes, that absent any teaching of criticality by the Applicant concerning the time period in which the cells are cultured and expanded, it would be obvious that one of ordinary skill in the art would recognize said culturing and expansion is a result effective variable. “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. “In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05).
Thus, the claim is obvious and is properly rejected.
In regards to claim 37, Liu and Malaer teach the method of claim 1. Further, Liu teaches wherein the CAR has antigenic specificity for CD19 (i.e., CD19-targeted CAR) (Title).
Thus, the claim is obvious and is properly rejected.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Liu (previously cited), in view of Malaer and further in view of Bajgain (previously cited).
In regards to claim 67, Liu and Malaer teach the method of claim 1. Liu and Malaer do not teach wherein step (a) occurs in a gas-permeable bioreactor.
Bajgain teaches the broader implementation of cell-based therapies has been hindered by the logistics associated with the expansion of clinically relevant cell numbers ex vivo. To overcome this limitation, Wilson Wolf Manufacturing developed the G-Rex, a cell culture flask with a gas-permeable membrane at the base that supports large media volumes without comprising gas exchange, i.e., a gas-permeable bioreactor (Abstract). Bajgain teaches of the G-Rex M series and specifically teaches of G-Rex 100M (Figure 5), and further teaches said cell culture system can reliably produce a 100-fold cell expansion in only 10 days using 1L of medium. Bajgain teaches the G-Rex M series is linearly scalable and adaptable as a closed system, allowing an easy translation of preclinical protocols into the good manufacturing practice (Abstract). Further, Bajgain specifically teaches superior natural killer cell expansion (i.e., via culturing) when using the G-Rex (Introduction, 2nd paragraph).
Thus, a POSITA would have been motivated before the effective filing date of the claimed invention, to combine the teachings of Liu, Malaer and Bajgain in order to culture (step a) and expand (step c) the above discussed NK cells (as taught by Liu and Malaer) in a gas-permeable bioreactor (as taught by Bajgain) in the presence of APCs and at least one cytokine (as taught by Liu) in order to obtain an expanded population of NK cells. Said combination of teachings would have been obvious due to Bajgain teaching of superior NK cell expansion (i.e., via culturing). A POSITA would have had a reasonable expectation of success in combining said teachings due to all working in the field of natural killer cell production.
Thus, the claim is obvious and is properly rejected.
Conclusion
No claim is allowed. No claim is free of the prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE R SMALL whose telephone number is (703)756-4783. The examiner can normally be reached Monday - Friday 8:30am-4pm.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633