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 .
Applicant's amendments to the claims filed on 04-27-2023 have been received and entered. Claims 1-30 have been canceled. Claims 31-50 are pending in the instant application.
Election/Restrictions
Applicant's election with traverse of Group I (claims 31-37) in the reply filed on 10-13-2025 is acknowledged. The traversal is on the ground(s) that “the present application is a 371 National Stage filing and thus unity of invention rules applies to the restriction. Specifically, it is rule 37 C.F.R. § 1.475 that discusses the determination of unity of invention. In particular, 37 C.F.R. § l.475(b) states that "claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations” (remarks filed on 10-13-2025, page 1).
This is not found persuasive because as applicant admitted that the present application is a 371 National Stage filing and thus unity of invention rules applies to the restriction. In accordance with 37 CFR 1.499, applicant is required to elect a single invention to which the claims must be restricted: Group I , claim(s) 31-37, drawn to an engineered feeder cell capable of generating a natural killer (NK) cell resistant to TGF-β. Group II , claim(s) 38-41, drawn to a method of generating TGF- β resistant natural killer (NK) cells. Group III , claim(s) 42-43, drawn to a TGF- β resistant NK cell. Group IV , claim(s) 44-50, drawn to a method of treating a cancer in a subject with TGF-β resistant NK cells. The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features: Group I-IV lack unity of invention because even though the inventions of these groups require the technical feature of a natural killer (NK) cell resistant to TGF-β incubated with the engineered feeder cells, this technical feature is not a special technical feature as it does not make a contribution over the prior art as explained and described in the Restriction office action mailed on 08-11-2025, and will be further discussed in the 35 USC§ 103 below.
The requirement is still deemed proper and is therefore made FINAL.
Claim 38-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10-13-2025.
Claims 31-37 are under consideration.
Priority
This application is a 371 of PCT/US2021/030142 filed on 04/30/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10-28-2022 and 05-19-2025 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
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.
Claim(s) 31-36 are rejected under 35 U.S.C. 103 as being unpatentable over Foltz et al (Cancers 2018, 10, 423; doi:10.3390/cancers10110423, Published: 5 November 2018) (Applicant own work) in view of Nagy et al (WO 2018/227286 Al, International Publication Date: 20 December 2018).
Regarding to claim 31, Foltz et al teach TGFβ imprinting during activation promotes
natural killer cell cytokine hypersecretion (title), and the stimulation of natural killer (NK) cells with pro-inflammatory cytokines decreases NK cell sensitivity to TGFβ (Abstract). Foltz et al stated that “To investigate the effect of chronic TGFβ stimulation during NK cell propagation and activation, NK cells were isolated from healthy peripheral blood and TGFβ imprinted (TGFβi) for 14 days by culturing with both IL-2 and 10 ng/mL TGFβ (a concentration previously reported to activate TGFβ signaling and suppress NK cell function) in combination with a weekly stimulation with irradiated K562 feeder cells expressing membrane-bound IL-21 (mbIL21) and 4-1BBL, which are known to induce robust NK cell proliferation and activation, resulting in a median ~2,500-fold expansion in 14 days” (Page 2, 5th para.). Foltz et al stated that “although acute overnight TGFβ treatment inhibited the degranulation of control NK cells against HOS, TGFβi NK cells were not inhibited by the acute TGFβ treatment”(Page 6, last para.).
Although Foltz et al teach culturing K562 feeder cells expressing membrane-bound IL-21 (mbIL21) and 4-1BBL with NK cells in presence of TGF- β to make TGFβ imprinted (TGFβi) NK cells (decreasing NK cell sensitivity to TGFβ suppression), Foltz et al do not specifically teach feeder cells that have been engineered to express TGF- β. Nagy et al cure the deficiency.
Nagy et al teach a genetically modified cell that comprises a set of transgenes, each transgene encoding a gene product that is cytoplasmic, membrane bound, or local acting (Abstract) and the cell comprising transgene TGF-β (Claim 4, page 204). The cell is a K562 human erythroid leukemia cell line or a natural killer cell (page 8 lines 6-7). Nagy et al teach inducible systems for expression of therapeutic agents: “the therapeutic agent can be expressed using a constitutive promoter …. (e.g., CAG, CMV, or another constitutive promoter). ….. it can be expressed by an inducible promoter, which provides the capability of expressing the therapeutic agent only when it is needed.” (Page 62, 1st para., lines 4-9).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Foltz et al by using genetically modified K562 and or NK cells expressing transgene TGF-β as taught by Nagy et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Nagy et al teach that the nucleic acid vectors described herein may include a Woodchuck Posttranscriptional Regulatory Element (WPRE). The WPRE acts at the transcriptional level, by promoting nuclear export of transcripts and/or by increasing the efficiency of polyadenylation of the nascent transcript, thus increasing the total amount of mRNA in the cell. The addition of the WPRE to a vector can result in a substantial improvement in the level of transgene expression from several different promoters, both in vitro and in vivo (Page 46 1st para, lines 1-6). Nagy et al teach that the genetically modified cells’ function is one or more of: to mitigate antigen presenting cell activation and function; to mitigate graft attacking leukocyte activity or cytolytic function; to mitigate macrophage cytolytic function and phagocytosis of allograft cells; to induce apoptosis in graft attacking leukocytes; to mitigate local inflammatory proteins; and to protect against leukocyte-mediated apoptosis (Abstract). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Nagy et al were successful in generating genetically modified cells expressing transgene such as TGF-β, with working examples and data.
Regarding to claims 32, 33, 34, and 36, Foltz et al teach K562 feeder cells expressing membrane-bound IL-21 (mbIL21) and 4-1BBL, (Page 2, 5th para.).
Regarding to claims 35, Foltz et al teach “K562 feeder cells were derived by transducing K562, a chronic myelogenous leukemia cell line, with human 4-1BBL and membrane-bound human IL-21” (Page 14, 2nd para.).
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Foltz et al (Cancers 2018, 10, 423; doi:10.3390/cancers10110423, Published: 5 November 2018) (Applicant own work) in view of Nagy et al (WO 2018/227286 Al, International Publication Date: 20 December 2018) as applied to claims 31-36 above, and further in view of Copik et al (Pub .No.: US 2017/0333479 A1, Pub. Date: Nov. 23, 2017).
The teachings of Foltz et al and Nagy et al above are incorporated herein in their entirety.
The above references do not teach a plasma membrane particle or exosome. Copik et al cure the deficiency.
Copik et al teach “novel compositions and methods for stimulation of and the production or expansion of natural killer (NK ) cells. Numbers of NK cells can be increased following contact with exosomes modified with one or more stimulatory peptides. Methods and compositions for the production of exosomes, wherein the exosomes comprise stimulatory peptides are also described” (Abstract). Copik et al teach the exosomes can be an extracellular product of exosome-secreting cells produced in vitro such as feeder cells ([0009], page 1), and in some cases, the cell line is a leukemia cell line, such asK562 cells that has been engineered to express the one or more stimulatory peptides, such as 4 -1BBL and IL – 21 ([0011], page 1).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of Foltz et al and Nagy et al by generating and using exosomes for the production or expansion of natural killer (NK) cells as taught by Copik et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Copik et al stated that “Disclosed herein are methods for improved technologies for enhancing the activity of natural killer (NK ) cells . In certain embodiments the methods disclosed herein result in increased number of NK cells . In certain embodiments the methods disclosed herein result in NK cells having improved activity . In certain embodiments, the methods disclosed herein result in increased numbers of NK cells with improved activity.” ([0008], page 1). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Copik et al were successful in generating and using exosomes for the production or expansion of natural killer (NK) cells, with working examples and data.
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632