DETAILED ACTION
Status of the Claims
1. Claims 1-60 are the original claims filed on 7/10/2023. In the Preliminary Amendment of 1/22/2024, claims 1-2, 8-9, 12-13, 16, 18, 20-21 and 60 are amended and claims 10-11, 14-15, 17, 19, 24-25, 27-29 and 31-59 are canceled.
Claims 1-9, 12-13, 16, 18, 20-23, 26, 30 and 60 are the pending claims.
Priority
2. USAN 18/271,632, filed 07/10/2023, is a National Stage entry of PCT/US2022/ 013422, International Filing Date: 01/21/2022, PCT/US2022/013422 Claims Priority from Provisional Application 63/140,118, filed 01/21/2021. The priority filing date for 01/21/2021 is granted for the claimed inventions.
Election/Restrictions
3. Applicant’s election of Group I in the reply filed on 7/8/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
4. Claims 20-23, 26 and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/8/2026.
5. Claims 1-9, 12-13, 16, 18, and 60 are the claims under examination.
Information Disclosure Statement
6. As of 8/26/2026, a total of three (3) IDS are filed: 8/18/2023; 9/20/2023; and 7/14/2026. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Drawings
7. The drawing sheet for Figure 20 is objected to because the use of the term ATCC, which is a trade name or a mark used in commerce, has been noted in the figure. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Corrected drawing sheet(s) in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
8. The disclosure is objected to because of the following informalities:
a) The use of the term ATCC, FACSCalibur, NCBI, FASTA, FlowJo, FACSAria, BioTek, Cytofix/Cytoperm, GenBank, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) The disclosure is objected to because it contains three (3) embedded hyperlinks and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
9. Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 16 recites “The combination of claim 12, further comprising an inhibitor of FDPS.” Claim 12 recites an aminobisphosphonate drug that is an art-recognized category of FDPS inhibitors. Drugs like nitrogen-containing bisphosphonates (e.g., zoledronate) inhibit FDPS (Nada et al. (PTO 892)). Accordingly, a generic inhibitor of FDPS in dependent claim 16 is broadening from an aminobisphosphonate drug in Claim 12.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
10. Claim(s) 1-2 is/are rejected under 35 U.S.C. 102 (a)/(1) and (a)(2) as being anticipated by Zeng et al., (US 12410400 B2; priority to 2/7/2018).
Zeng teaches and claims a method of producing a modified natural killer (NK) cell, comprising an NK cell that expresses at least one T cell receptor, wherein the at least one T cell receptor comprises at least one γ chain and at least one δ chain, wherein the NK cell further comprises at least one NK cell receptor selected from NKp30, NKp44, NKp46 and NKG2D.
Zang claiming “1. A method of generating gamma-delta natural killer T cells (γδ NKT cells), the method comprising: (a) expanding γδ T cells of human peripheral blood cells in PBMC culture medium containing an amino-bisphosphonate and interleukin 2 (IL2); (b) transducing the expanded γδ T cells with reprogramming transcription factors to generate induced pluripotent stem cells (iPSCs); (c) screening the TCRG and TCRD gene configuration of the iPSCs to identify γδ T cell-derived iPSCs; (d) co-culturing γδ T cell-derived iPSCs with a stromal cell line deficient in expressing macrophage colony stimulating factor (M-CSF) to generate innate immune cell progenitors; (e) co-culturing the innate immune cell progenitors with a stromal cell line deficient in expressing M-CSF and ectopically expressing Notch ligand, Delta like 1 (DLL1) in a media comprising stem cell factor (SCF), Fins-related tyrosine kinase 3 ligand (FLT3L), interleukin 7 (IL7) and interleukin 15 (IL15) to generate differentiated gamma-delta NKT cells; (f) passaging the differentiated gamma-delta NKT cells weekly for 3 to 5 weeks to obtain gamma-delta NKT cells expressing gamma-delta TCRs (γδ TCRs); and (g) detecting the expression profile of the gamma-delta NKT cells obtained in step (f); wherein the γδ NKT cells expressing gamma-delta TCRs (γδ TCRs), express NKp30 in 99% of the cells, NKp44 in 99% of the cells, NKp46 in 97% of the cells, NKG2D in 84% of the cells, DNAM-1 in 97% of the cells, TRAIL in 89% of the cells, and NKG2A/CD94 in 83% of the cells in combination with expression of at least any one of CD56, CD16, FASL and less than 5% expression of killer cell immunoglobulin-like receptors (KIR) are γδ NKT cells.”
Zeng is effective art in teaching and anticipating the generic claims 1 and 2 of the instant invention.
11. Claim(s) 1 is/are rejected under 35 U.S.C. 102 (a)/(1) and (a)(2) as being anticipated by GORCHAKOV et al., (RU 2757353 C1 (published 10/14/2021) with priority to RU 2020133421 A (10-12-2020).
GORCHAKOV teaches “As used herein, the term "host cell" includes transduced human peripheral blood T and / or NK lymphocytes (both autologous and allogeneic with respect to patient cells) transduced with the following constructs, as well as transplanted human NK cell lines (such as NK-92, NK-92mi, YT, KHYG, NKL, etc.). In specific embodiments, the T lymphocytes can be CD4 +, CD8 +, or Treg lymphocytes, and the NK cells include NKT and gamma-delta NK cells.
GORCHAKOV is effective art in teaching and anticipating the generic claims 1 and 2 of the instant invention.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
12. Claim(s) 1-9, 12-13, 16 and 60 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zeng et al., (US 12410400 B2; priority to 2/7/2018) as evidenced by Nada et al (J Immunother Cancer 2017 Feb 21:5:9. doi: 10.1186/s40425-017-0209-6. eCollection 2017).
AS regards claims 1-2, Zeng teaches and claims a method of producing a modified (“mimetic”) natural killer (NK) cell, comprising an NK cell that expresses at least one T cell receptor, wherein the at least one T cell receptor comprises at least one γ chain and at least one δ chain, wherein the NK cell further comprises at least one NK cell receptor selected from NKp30, NKp44, NKp46 and NKG2D.
Zeng claiming “1. A method of generating gamma-delta natural killer T cells (γδ NKT cells), the method comprising: (a) expanding γδ T cells of human peripheral blood cells in PBMC culture medium containing an amino-bisphosphonate and interleukin 2 (IL2); (b) transducing the expanded γδ T cells with reprogramming transcription factors to generate induced pluripotent stem cells (iPSCs); (c) screening the TCRG and TCRD gene configuration of the iPSCs to identify γδ T cell-derived iPSCs; (d) co-culturing γδ T cell-derived iPSCs with a stromal cell line deficient in expressing macrophage colony stimulating factor (M-CSF) to generate innate immune cell progenitors; (e) co-culturing the innate immune cell progenitors with a stromal cell line deficient in expressing M-CSF and ectopically expressing Notch ligand, Delta like 1 (DLL1) in a media comprising stem cell factor (SCF), Fins-related tyrosine kinase 3 ligand (FLT3L), interleukin 7 (IL7) and interleukin 15 (IL15) to generate differentiated gamma-delta NKT cells; (f) passaging the differentiated gamma-delta NKT cells weekly for 3 to 5 weeks to obtain gamma-delta NKT cells expressing gamma-delta TCRs (γδ TCRs); and (g) detecting the expression profile of the gamma-delta NKT cells obtained in step (f); wherein the γδ NKT cells expressing gamma-delta TCRs (γδ TCRs), express NKp30 in 99% of the cells, NKp44 in 99% of the cells, NKp46 in 97% of the cells, NKG2D in 84% of the cells, DNAM-1 in 97% of the cells, TRAIL in 89% of the cells, and NKG2A/CD94 in 83% of the cells in combination with expression of at least any one of CD56, CD16, FASL and less than 5% expression of killer cell immunoglobulin-like receptors (KIR) are γδ NKT cells.”
As regards claims 2-7, Zeng teaches mimetic NK cells comprising iPSC-derived γδ NKT cells have features of NK cells such as expression of at least one of CD56, CD16, NKp30, NKp44, NKp46, NKG2D, DNAM-1, FASL, TRAIL, NKG2A/CD94, or a combination thereof and new features such as no or low expression of killer cell immunoglobulin-like receptors (KIR) but also features of γδ T cells such as CD3+ and/or γδ T cell receptors such as V gamma 9V delta 2 (Vγ9Vδ2).
As regards claim 8, Zeng teaches downregulation of CD16 expression on cultured mimetic NK cells at “With a starting NK cell number of 10.sup.6, a 74-fold expansion was observed on day 9, although no further expansion was achieved by extending the co-culture to 14 days (FIG. 11a). Interestingly, although there was no obvious change in phenotype except the down-regulation of CD16 expression (FIG. 11c), these expanded NK cells became more potent in killing K562 cells (FIG. 11d), probably due to their further functional maturation during expansion. These data indicate that it is feasible to produce functional iPSC-derived NK cells in clinical-scale through expansion with feeder cells.”
As regards 9, Zeng teaches the NK cell comprises a primary NK cell at
FIG. 5 and FIG. 6 teach PB-γδ T cells and PB-NK cells were expanded from PBMCs of a healthy donor. Phenotypes of iPSC-γδ T cells (a), expanded PB-γδ T cells (b) and expanded PB-NK cells (c) were analyzed by flow cytometry. And “To derive PB-NK cells, 2×10.sup.6 PBMCs from healthy donors.”
As regards claims 12-13 and 16, Zeng teaches and claims compositions for expanding γδ T cells of human peripheral blood cells in PBMC culture medium containing an amino-bisphosphonate and interleukin 2 (IL2) to further generate the gamma-delta NK cell (Zeng claim 1) where the amino-bisphosphonate is zoledronic acid (Zeng claim 4). AS regards claim 16 and as evidenced by Nada, an aminobisphosphonate drug is an art-recognized category of FDPS inhibitors. Drugs like nitrogen-containing bisphosphonates (e.g., zoledronate) inhibit FDPS.
As regards claim 60, Zeng teaches the manufacture of mimetic innate immune cells, gamma-delta NK cell, for use in therapy.
Current generation of high-purity NK cell products requires a prolonged procedure that not only compromises the recovery of NK cells but also affects their viability and potency. With a low recovery rate, it is difficult to obtain sufficient NK cells from a single leukapheresis product. Zeng teaches using a reliable, unlimited and standardizable starting cell source of human pluripotent stem cells such as induced pluripotent stem cells (iPSCs) to generate mimetic innate immune cells, i.e., gamma-delta NK cells, for use in immunotherapy treatment. Zeng teaches viability of expanded NK cells after freeze/thaw procedure. a promising starting material to produce mimetic innate immune cells such as mimetic natural killer (NK) cells and mimetic γδ T-cells for cancer immunotherapy. To facilitate consistent mass production, an overall manufacturing scheme to make mimetic innate immune cells from human pluripotent stem cells (hPSCs) was designed and demonstrated. Particularly, a robust protocol to differentiate hPSCs into mimetic NK cells or mimetic γδ T-cells with NK properties through sequential hematopoietic differentiation on OP9 cells and lymphoid commitment on OP9-DLL1 cells without employing CD34+ cell enrichment and spin embryoid body formation. Accordingly, Zeng renders obvious the instant claims because Zeng teaches the need for stable NK cell populations that mimic features of the gamma-delta- T cells with killing capacity for cancer cells. Zeng demonstrates the predictability of the gamma-delta NK cells insofar as production, stability and expansion for use in treatment methods to provide a reasonable assurance of success.
13. Claim(s) 1, 12 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zeng et al., (US 12410400 B2; priority to 2/7/2018) as applied to claims 1 and 12 above, and further in view of Hoeres et al (Frontiers in Immunol. 9:1-18; April 19, 2018).
AS regards claims 1 and 12, Zeng teaches compositions comprising the gamma-delta NK cell much less one expressing Vγ9Vδ2 subset and drugs like nitrogen-containing bisphosphonates (e.g., zoledronate). As regards claim 18, Inhibition of farnesyl diphosphate synthase (FDPS) and activation or engagement of CD16 (FcγRIII) functionally overlap in Vγ9Vδ2 γδ T cells and Natural Killer (NK) cells during anti-tumor immune responses and bisphosphonate-based immunotherapy. When FDPS is inhibited by drugs like zoledronate, the accumulated IPP sensitizes tumor cells or activates γδ T cells via butyrophilin molecules (BTN3A1/BTN2A1). Simultaneously, CD16 can bind to the Fc portion of therapeutic monoclonal antibodies (such as anti-tumor IgG). In view of Hoeres, and NK-cell expression of CD16 that acts as a low-affinity Fc receptor that triggers ADCC, it would be obvious to include a CD16 antagonist to regulate the NK cell engagement of receptors.
Rejections Maintained
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
14. The rejection of Claim(s) 1-3, 9, and 60 under 35 U.S.C. 103 as being unpatentable over Niazi (US 20200354679; published 2020-11-12; (IDS 8/18/2023, #120)) is maintained.
Applicants have not responded to the outstanding grounds for rejection.
AS regards claims 1 and 3, Niazi teaches a modified natural killer (NK) cell, wherein the modified NK cell expresses at least one T cell receptor, wherein the at least one T cell receptor comprises at least one γ chain and at least one δ chain at
[0048] NK cell expressing a recombinant T cell receptor complex: The inventors contemplate that NK cells can be genetically modified by introducing a recombinant nucleic acid composition encoding a protein complex to the NK cells. Most typically, the protein complex includes at least one or more distinct peptides having an extracellular domain of a T cell receptor, and at least one or more distinct peptides of the intracellular domain of a T cell receptor. For example, one preferred protein complex includes an α chain of a T cell receptor, a β chain of a T cell receptor, at least a portion of CD3δ (preferably cytoplasmic domain), and at least a portion of CD3γ (preferably cytoplasmic domain). In another example, the protein complex may include a γ chain T cell receptor and a δ chain T cell receptor instead of the α and β chains of T cell receptors. Additionally, the protein complex may include in one or more instances, at least a portion of a CD3ξ and at least a portion of a CD3ζ.
As regards claims 2 and 9, Naizi teaches [0037] The genetically engineered NK cell may also be an NK92 derivative that is modified to express the high-affinity Fcγ receptor (CD16) and that [0035] NK92 cells exhibit an unusual receptor expression profile, expressing a relatively large number of activating (e.g., NKp30, NKp46, 2B4, NKGD, E, CD28) receptors.
AS regards claim 9, Naizi teaches transfecting a starting population of NK-92 cells to produce a gamma-delta NK cell at
[0084] The inventors transfected control natural killer NK-92 cells with mRNA encoding GFP to verify transfection efficiency and transfected other natural killer NK-92 cells with mRNA encoding the T cell receptor mRNA encoding a T cell receptor α chain separated by a 2A sequence followed by mRNA encoding a T cell receptor β chain and with a second T cell receptor RNA encoding a T cell receptor γ chain followed by a 2A sequence and another mRNA encoding a T cell receptor δ chain.
As regards claim 60, Naizi teaches a pharmaceutical composition
[0019] In still another aspect of the inventive subject matter, the inventors contemplate a pharmaceutical composition containing a plurality of genetically modified immunocompetent cells such as NK cells expressing a recombinant protein complex.
Accordingly, it is prima facie obvious that Niazi provides the motivation to generate immunocompetent cells such as NK cells that are genetically modified to express a T cell receptor or a portion thereof that specifically binds to a tumor specific or tumor associated antigen, a neoepitope, and/or a self-lipid of the tumor, which consequently triggers a cellular immune response against the tumor. As more NK cells are recruited near the tumor, the NK cells are expected to alter the microenvironment of the tumor via their immunesurveillance function (e.g., by locally releasing cytokines, etc.).
Niazi demonstrates the reasonable predictability of success in generating such engineered NK cell constructs where T cells have been engineered with success by similar engineering:
[0012] More recently, genetically engineered receptors, chimeric antigen receptors (CARs), have been developed by grafting antigen specific binding portions onto signaling portions to so drive immune cells carrying the CAR to the targeted cells (e.g., infected cells, cancer cells, etc.). Notably, however, such approach has traditionally been used to genetically modify T cells to specifically elicit T cell response to a molecule that the expressed CAR recognizes (e.g., CAR-T cells). Thus, even though genetic modification of T cells with recombinant CAR molecule is known in the art.
Conclusion
15. No claims are allowed.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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