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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant’s claim to priority from International Application No. PCT/CN2022/085416 filed 04/06/2022 and from Foreign Application No. PCT/CN2021/085619 filed 04/06/2021 is hereby acknowledged.
Election/Restrictions
Applicant's election with traverse of Invention Group I (claims 1-4, 6, 8, 10, 22-
29, 32, 34 and 35) in the reply filed on 06/26/2026 is acknowledged. The traversal is on the ground(s) that the inventions “Group I and II are technically linked by the same general inventive concept of improving and stabilizing viral transduction of γδ T cells by using an agent capable of inhibiting innate anti-virus activity during transduction”. This is not found persuasive because Invention Group II is clearly not a method, it is a composition, a product. Although both inventions can be linked as product and process and making, the two are distinct and separate inventions, each one patentable on their own rights if the claims are found allowable. The reasons for restriction and requirement were elaborated and explained in the previous Office Action dated 04/27/2026.
The requirement is still deemed proper and is therefore made FINAL.
Applicant’s election of Species Group A ((2) ; a VSV-G pseudotyped lentiviral vector) and Species Group B (a TAK1 inhibitor ; (5Z)-7-Oxozeaenol) in the reply filed on 06/26/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election of Species has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 47 and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06/26/2026.
Application Status
This Application is a National Phase entry under 35 U.S.C. §371 from International Application No. PCT/CN2022/085416 filed 04/06/2022.
This Office Action is in response to Amendments and Remarks filed 06/26/2026.
Claims filed 06/26/2026 are hereby acknowledged.
Claims 5, 7, 9, 11-21, 30-31, 33, 36-46, and 49-52 are cancelled. Claims 1-4, 6, 8, 10, 22-29, 32, 34-35, 47 and 48 are pending. Claims 47 and 48 are withdrawn from consideration, therefore, claims 1-4, 6, 8, 10, 22-29, 32 and 34-35 are under consideration in this Office Action.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on10/05/2023,
07/15/2025 and 04/03/2026 are hereby acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
However, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The Drawings filed 10/05/2023 are hereby acknowledged and are acceptable.
Specification
The use of the terms “Ficoll-Paque” and “Ficoll-Paque Plus” (page 1, last paragraph of “Background” section; page 15, “Primary cell culture” section), “Dynabeads” (page 1, last paragraph of “Background” section), “RetroNectin” (page 16, lines 2, 4), “Gibco” (page 16, lines 13, 29), “FACSCalibur” and “Biolegend” (page 16, “Flow cytometry” section) which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear 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.
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.
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.
Claims 1-4, 8, 10, 22-29, 32, and 34 are rejected under 35 U.S.C. § 103 as being unpatentable over Liang (Liang, B. et al. WO 2016/007827 A1- published January 14, 2016; previously cited; cited in IDS filed 04/03/2026) in view of Leek (Leek, M.D. et al. WO 2016/166544 A1, published October 20, 2016, previously cited; cited in IDS filed 10/05/2023).
Regarding claims 1 and 24, Liang teaches a method of transducing T cells with a viral vector, comprising contacting the T cell with a viral vector and an agent capable of inhibiting the innate anti-virus activity of the T cell (see [0004]).
Liang teaches the use of agents capable of inhibiting the innate immune system of primary T cells such as inhibitors of IKKɛ, IkB kinase, TBK1 or PKR (see [0007]). Liang specifically teaches the use of BX795 or 2-aminopurine (2-AP) (see [0007]-[0008]).
Liang teaches that contacting the compound (BX795 or 2-AP) with the lymphocytes enhances the transduction efficiency with a vector, that can be a viral vector, or a retroviral vector (see [0008]).
Liang does not specify which type of T cells to use, stating “primary T lymphocytes”, meaning T lymphocytes that have been isolated from subjects directly ( see [0006]-[0008]).
However, Leek teaches the preparation and the use of gamma delta T cells (γδ T cells), suitable to use in allogeneic or autologous transplantation for treating conditions including infections and cancers, and more specifically the use of chimeric antigen receptors (CARs) modified γδ T cells (page 1, lines 5-13).
Leek teaches that autologous transplantation strategies of γδ T cells have been utilized to overcome the disadvantages associated with allogeneic stem cell transplantation. Leek teaches that as part of such autologous transplantation techniques, methods of inducing and culturing sufficient numbers of γδ T cells for exerting therapeutic effect autologously have been previously disclosed; alternative and/or improved treatment strategies using γδ T cells are thus required (see pages 1 (lines 31-33) and 2 (lines 1-4). Leek teaches that CAR transduction of γδ T cells can be advantageous, increasing the potency of the γδ T cells (see page 2, lines 16-18; lines 29-31).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the T cells taught by Liang, with a more potent subset of T cells such as the γδ T cells taught by Leek and have conditioned the cells with an inhibitor such as BX795 or 2-AP to enhance the transduction by a viral vector for CAR expression as taught by Liang. One with ordinary skills in the art motivated in avoiding the disadvantages of autologous transplantation and optimizing the lymphocytes before transplantation, could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Regarding claims 2-3 and 26-28, Leek teaches that the γδ T cells comes from peripheral blood, and that the majority of γδ T cells are of Vgamma9 Vdelta2 (Vγδ9 Vδ2) isotype (see page 2, lines 20-21; page 3, lines 28-30).
The obviousness of combining the references Liang and Leek is described above. Therefore, the combination of references renders elements of claims 2-3 and 26-28 obvious.
Regarding claims 4 and 29, Liang teaches that the viral vector for CAR T cell derivation can be a retroviral vector or a lentiviral vector (see [0004]). Leek teaches transduction of peripheral blood lymphocytes with lentiviral vectors containing classical CAR sequence 9see page 39, lines 11-12; claims 25 and 45, pages 46 and 50).
The obviousness of combining the references Liang and Leek is described above. Therefore, the combination of references renders elements of claim 4.
Regarding claims 8, 10, 22, 32 and 34, Liang teaches the use of agents capable of inhibiting the innate immune system of primary T cells such as inhibitors of IKKɛ, IkB kinase, TBK1 or PKR (see [0007]). Liang specifically teaches the use of BX795 (TBK1 and IKKɛ inhibitor) or 2-aminopurine (2-AP; PKR inhibitor) (see [0007]-[0008]). Liang teaches culturing transduced cells with an agent capable of inhibiting the innate immune system, i.e., the anti-virus activity of primary T cells ( see [0030]-[0031]; [0065]-[0067]; see page 25, section 6.3.2, [0070]).
The obviousness of combining the references Liang and Leek is described above. Therefore, the combination of references renders elements of claims 8, 10, 22, 32 and 34 obvious.
Regarding claim 23, Liang teaches transducing a viral vector comprising a nucleotide sequence encoding for a chimeric antigen receptor (CAR) (see [0012], [0015]). Leek teaches a lentiviral construct comprising a CAR encoding nucleic acid sequence (see page 11, lines 8-10; page 39, lines 11-13; page 40, lines 5-8; claims 25 and 45, pages 46 and 50).
The obviousness of combining the references Liang and Leek is described above. Therefore, the combination of references renders elements of claim 23 obvious.
Regarding claim 25, Liang teaches that non-limiting examples of cells that can be used in the method of producing CAR T cells can include peripheral blood cells (see [0005], [0023]-[0024]). Liang teaches that primary T lymphocytes can be transduced with a transformation reagent which includes Interleukin-2 (IL-2) ([0014]-[0018], [0029]).
Leek teaches that γδ T cells can be expanded from peripheral blood mononuclear cells (PBMCs) (see page 13, lines 30-33). Leek teaches that the Vgamma9 subtype may be expanded/selected from PBMCs using chemically defined culture medium, including IL-2, and can be activated using aminobisphosphonate such as Zoledronic acid (see page 14, lines 6-9).
Leek also teaches that the γδ T cells comes from peripheral blood, and that the majority of γδ T cells are of Vgamma9 Vdelta2 (Vγδ9 Vδ2) isotype (see page 2, lines 20-21; page 3, lines 28-30).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have added Zoledronic acid to the culture medium for expansion/selection of γδ T cells containing IL-2 taught by Liang and obtained an expanded and activated subset of Vgamma9 Vdelta2 (Vγδ9 Vδ2) isotype T cells as taught by Leek, prior to the cells conditioning using a kinase inhibitor to potentiate transduction as taught by Liang. One with ordinary skills in the art could have performed this modification with a reasonable expectation of success and would have arrived to the claimed invention.
Claims 6 and 35 are rejected under 35 U.S.C. § 103 as being unpatentable over Liang (Liang, B. et al. WO 2016/007827 A1- published January 14, 2016; previously cited; cited in IDS filed 04/03/2026) in view of Leek (Leek, M.D. et al. WO 2016/166544 A1, published October 20, 2016, previously cited; cited in IDS filed 10/05/2023) as applied to claims 1 and 24 above, and further in view of Simmons ( Simmons, A. et al. “Use of recombinant lentivirus pseudotyped with vesicular stomatitis virus glycoprotein G for efficient generation of human anti-cancer chimeric T cells by transduction of human peripheral blood lymphocytes in vitro”. Virology Journal, Vol. 3, No. 8 (2006); doi:10.1186/1743-422X-3-8 (pages 1-10)).
The rejections of claims 1 and 24 are described above. The obviousness of combining the references Liang and Leek is described above. The combination of references renders elements of claims 1 and 24 obvious.
However, regarding claims 6 and 35, the combination of references does not render obvious a lentivirus vector that is a VSV-G pseudotyped lentiviral vector.
However, Simmons teaches the use of a recombinant lentivirus pseudotyped with VSV-G for production of anti-cancer chimeric T cells in vitro (see title and abstract).
Simmons teaches the use of the chimeric lentiviral vector to lead to about 100% transduction efficiency (see abstract).
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention, to have substituted the lentiviral vector taught by Liang modified by Leek, with a recombinant VSV-G pseudotyped lentiviral vector as taught by Simmons. One with ordinary skills in the art motivated in increasing the efficiency of transduction could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
The following rejections are necessitated by Applicant’s selection of Species Group B (a TAK1 inhibitor ; (5Z)-7-Oxozeaenol) in the response filed 06/26/2026:
Claims 6, 8, 10, 32 and 34-35 are rejected under 35 U.S.C. § 103 as being unpatentable over Liang (Liang, B. et al. WO 2016/007827 A1- published January 14, 2016; previously cited; cited in IDS filed 04/03/2026) in view of Leek (Leek, M.D. et al. WO 2016/166544 A1, published October 20, 2016, previously cited; cited in IDS filed 10/05/2023), as applied to claims 1 and 24 above, and in further view of Kawai (Kawai, T. et al. “Innate immune recognition of viral infection”. Nature Immunology, Vol. 7, No. 2 (2006), pp: 131-137), Kobayashi (Kobayashi, A. et al. “TAK1 inhibition ameliorates survival from graft-versus-host disease in an allogeneic murine marrow transplantation model”. International Journal of Hematology, Vol. 107 (2018), pp: 222-229) and Alici (Alici, E. et al. WO 2017/059177 A2, published April 6, 2017).
The rejections of claims 1 and 24 are described above. The obviousness of combining the references Liang and Leek is described above. The combination of references renders elements of claims 1 and 24 obvious.
Liang does teach that “the innate immune system comprises proteins (e.g., retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), IKB kinase ɛ (IKKɛ),
TANK-binding kinase 1 (TBKI))” and “In another embodiment, transduction (e.g., retroviral transduction, for example lentiviral transduction) of T lymphocytes (e.g., primary human T lymphocytes) can be enhanced by the addition of compounds, for example small molecules, that inhibit innate immune signaling (see [0030]).
However, claims 8 and 32 recite “wherein the agent is an inhibitor of IKKα,
IKKβ, IKKɛ, IƙB kinase, TBK1, PKD1, NF-ƙB, Akt, PKR, TAK1, IRAK1/4 or proteasome” ; and claims 10 and 34 recite “wherein the agent is selected from the
group consisting of BX795, BAYll-7082, Curcumin, Dexamethasone, 2-Aminopurine, (SZ)-7-Oxozeaenol, IRAK1/4 Inhibitor I, and Bortezomib.”
Claims 6 and 35 recite “wherein the viral vector is a VSV-G pseudotyped lentiviral vector”.
Therefore, regarding claims 6, 8, 10, 32 and 34-35, the combination of references Liang and Leek does not render obvious an agent that is a TAK1 inhibitor. The combination of references does not teach (5Z)-7-Oxozeaenol. The combination of references does not teach a VSV-G pseudotyped lentiviral vector either.
However, Kawai teaches signal pathways involved in innate immune response to viral infection (see title). Kawai teaches that TAK1 activates the canonical IƙB kinases (IKKs) IKKα and IKKβ which leads to the phosphorylation and degradation of IƙB, allowing NF-kB to translocate into the nucleus (see page 132, right column, “Signaling via TLR7, TLR8 and TLR9” section, lines 14-17).
Therefore, Kawai teaches that TAK1 is acting upstream from IKKs and is part of the same signaling pathway (see pages 132-132, Figures 1 and 2).
Kobayashi teaches that TAK1 and TAK1 inhibitor can have an impact on innate
immune response, since 5Z-7-oxozeaenol, a selective inhibitor of TAK1, is capable of ameliorating the immune response, graft-versus-host disease, via immunosuppression of T cells in an allogeneic murine marrow transplantation model (see title and abstract; page 227, “Discussion” section, right column, lines 2-5).
Therefore, Kobayashi teaches that a TAK1 inhibitor can be used to inhibit T cell
mediated innate immune response signaling (page 227, “Discussion” section, right column, lines 2-5).
Alici teaches that gene RNA-based vector delivery can be enhanced to Natural Killer cells, hematopoietic stem cells and macrophages using specific compound inhibitor, (5Z)-7-oxozeaenol (see title and abstract).
Alici teaches that Natural Killer cells (NK cells) are lymphocytes of the innate immune system, and transfection of these cells with a viral vector is enhanced using (5Z)-7-Oxozeaenol (see [004]-[005]).
Alici specifically teaches VSV-G pseudotyped lentiviral vector transduction of NK cells, using IL-2 in maintenance medium in culture, and using BX795 and (5Z)-7-Oxozeaenol (iX) (see [033]-[034], [038]-[041]).
Alici teaches that using BX795 dramatically increases transduction efficiency in NK cells ( [047]-[049]). Alici also teaches that using TAK1 inhibitor iX enhances lentiviral transduction to a further extent compared to BX795, proving a statistically significant improvement in gene delivery (see [050]). Alici teaches that iX shows a dose-dependent effect with minimal toxicity to NK cells ( [053]-[056]).
It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the small molecule inhibitor, i.e., 2-AP or BX795, used by Liang to counteract the antiviral immune response against the recombinant lentivirus construct and enhance the lentiviral transduction of T lymphocytes, with a TAK1 inhibitor, i.e., (5Z)-7-oxozeaenol (iX) as taught by Kawai, Kobayashi and Alici, in the method taught by Liang modified by Leek. It would be substituting one potent inhibitor of the IkB signaling with another potent inhibitor of the same signaling pathway. One with ordinary skills in the art motivated in assaying the bioequivalence of inhibitors of the same signaling pathway on specific T cells subsets and avoiding toxicity to the cells could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
It would also have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention, to have substituted the lentiviral vector taught by Liang and Leek, to a pseudotyped VSV-G lentiviral vector for which an enhanced transduction with minimal toxicity method using iX inhibitor is available and taught by Alici. One with ordinary skills in the art motivated in a proven and safe method and material could have performed this substitution with a reasonable expectation of success and would have arrived at the claimed invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA G DACE DENITO whose telephone number is (703)756-4752. The examiner can normally be reached Monday-Friday, 8:30-5:00EST.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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