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 and arguments filed on 06-10-2026 have been received and entered. Claims 61, 69, 70 have been amended. Claims 1-45, 47-48, 50-53, 57, 60, 62 have been canceled. Claims 46, 49, 54-56, 58-59, 61, 63-72 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-4, 7-8, 11-13, 16, 39-43) in the reply filed on 10-24-2024 is acknowledged. However, claims 1-45 have been canceled, and claims 46-71 have been added.
Claims 46, 49, 54-56, 58-59, 61, 63-72 are under consideration.
Priority
This application is a 371 of PCT/CN2020/098930 filed on 06/29/2020 that claims priority from foreign application CN 201910576425.X filed on 06/28/2019 and CN 201910809425.X filed on 08/29/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Certified translations filed on 04-15-2025 of foreign application CN 201910576425.X and CN 201910809425.X are also acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06-10-2026 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
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.
Claims 46, 49, 54-56, 58-59, 61 and 72 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (Pub. No.: US 2021/0332101 A1, Foreign Application Priority Data: Nov. 1 , 2018 , CN 201811297174.3, and Dec. 18, 2018, CN 201811549651.0) in view of Busser et al (Pub. No.: US 2020/0237823 Al, Foreign Application Priority Data: Oct. 19, 2017) and Campana et al (Pub. No .: US 2021/0046112 A1, Provisional application No. 62/112,765 , filed on Feb. 6 , 2015).
Claim interpretation :
The specification of the claimed invention teaches that HLA-I gene is one or more selected from the group consisting of: HLA-A, HLA-B, HLA-C, and B2M; preferably, the HLA-I gene is B2M (Page 3, lines 7-8). Thus, HLA-I gene is interpreted as B2M and vice versa.
The specification of the claimed invention teaches that the first protein specifically recognizes one or more NK cell surface antigens selected from the group consisting of: NKG2A, NKG2D, NKP30, NKP44, and NKP46 (Page 2, lines 26-27). Thus, according to the specification of the claimed invention, NKG2A, NKG2D, NKP30, NKP44, and NKP46 are interpreted as NK cell surface antigens.
The specification of the claimed invention teaches that a first protein and a second protein may be in a chimeric receptor, i.e., preferably, the chimeric receptor comprises an antibody (the first protein) recognizing immune effector cells of the host, an antibody (the second protein) recognizing tumor antigens or pathogen antigens … (Page 4, lines 12-15). Thus, according to the specification of the claimed invention, chimeric receptor can comprise both a first protein and a second protein which are antibodies.
Regarding to claims 46 and 72, Wang et al provides an engineered immune cell comprising a CAR or engineered TCR, which CAR or engineered TCR can comprise a first antigen binding domain and a second antigen binding domain. The engineered immune cells of the present disclosure, when administered into a subject, can inhibit the host immune cells such as T cells and/or NK cells and enhance the survival and persistence of the engineered immune cells in vivo, thereby exhibiting more effective tumor killing activity (Abstract). Wang et al teach CARs can comprise an extracellular antigen recognition region, for example, a scFv (single-chain variable fragment), a transmembrane region, and an intracellular costimulatory signal region ([0118], Page 12).
Wang et al teach that transmembrane regions of particular use in the present disclosure may be derived from (e.g., comprise at least the transmembrane region(s) of) the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD8 etc. ([0125], page 13). Wang et al teach that the cytoplasmic domain of the CAR can be designed to comprise the CD3-zeta (ζ) signaling domain by itself or combined with any other desired cytoplasmic domain(s) useful in the context of the CAR of the present disclosure ([0130], page 14), CD3ζ is a cytoplasmic signaling sequence derived from CD3ζ ([0135], page 14) and human CD3ζ intracellular region ([0392], page 53).
Wang et al teach that the expression of one or more endogenous HLA genes of the engineered immune cell may be knocked out or partially knocked out. For example, HLA-I, HLA-II or both can be knocked out, ([0172], page 19). However, Wang et al did not specifically mention B2M (which is an HLA-I gene). Busser et al cure the deficiency.
Busser et al teach “successfully generating β2m deficient CAR T-cells, in which an exogenous sequence encoding NK inhibitor has been inserted by site directed gene editing for its expression during T-cell activation” ([0019], page 2), and “It consists in a simultaneous TALEN mediated knock-out of B2M and TCR in the presence of AAV6 repair vectors delivering the CAR at the TRAC locus and an NK inhibitor at the B2M locus. This method prevents CAR T-cell to attack host tissues in a non-specific and TCR-mediated manner (graft versus host attack) and to divert host T- and NK-cells-mediated depletion of CAR T-cells.” ([0460], page 63).
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 Wang et al by using TALEN mediated knock-out of B2M to generate β2m deficient CAR T-cells as taught by Busser 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 Busser et al teach that “This example describes methods to improve the therapeutic outcome of CAR T-cell therapies by extending their persistence in vivo. It consists in a simultaneous TALEN mediated knock-out of B2M and TCR in the presence of AAV6 repair vectors delivering the CAR at the TRAC locus and an NK inhibitor at the B2M locus. This method prevents CAR T-cell to attack host tissues in a non-specific and TCR-mediated manner (graft versus host attack) and to divert host T- and NK-cells-mediated depletion of CAR T-cells” ([0460], page 63). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Busser et al teach “successfully generating β2m deficient CAR T-cells, in which an exogenous sequence encoding NK inhibitor has been inserted by site directed gene editing for its expression during T-cell activation” ([0019], page 2) with detailed instructions and working examples.
Although Wang et al teach that a CAR comprises an antigen binding domain that can target both an immune cell antigen ([0133], page 14) such as CD159a (NKG2A) ([0141], page 15), and Busser et al teach inactivation of checkpoint receptors ([0362], page 22), these references do not clearly teach a single-chain fragment variable (scFv) recognizes NKG2-A/NKG2-B type II integral membrane protein (NKG2A) (an immune checkpoint receptor). Campana et al cure the deficiency.
Campana et al teach an engineered immune cell comprising a nucleic acid comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR) and a nucleic acid comprising a nucleotide sequence encoding an antibody linked to a localizing domain (LD) (See claim 23, page 33). Campana et al teach the localizing domain (LD)-linked target-binding molecule binds to a target expressed on the surface of an immune cell. In some embodiments, the LD-linked target binding molecule inhibits the activity or function of the target molecule . By way of example, as disclosed herein , the LD -linked target-binding molecule can be designed to bind to e.g., NKG2A ([0067], page 8). Campana et al teach “chimeric antigen receptor (CAR) and a nucleic acid comprising a nucleotide sequence encoding a single-chain variable fragment (scFv)” ([0082], page 9), and “Cloning of scFv against Human NKG2A …. the sequence of scFv was designed by connecting variable light (VL) region and variable heavy (VH) region with linker sequence . The synthesized gene consisting of CD8 signal peptide, scFv against human NKG2A, CD8 hinge and transmembrane, and KKMP sequence was subcloned into EcoRI and Xhol sites of the MSCV - IRES -GFP vector.” ([0103]-[0104], page 10).
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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 Wang et al and Busser et al by using a single-chain fragment variable (scFv) that recognizes (NKG2A- an immune checkpoint receptor) as taught by Campana 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 Campana et al provide explicit advantage of LD - linked target binding molecule inhibits the activity or function of NKG2A ([0067], page 8) and the engineered immune cells of the invention have enhanced therapeutic efficacy which refers to one or more of reduced graft- versus-host disease (GvHD ) in a host , reduced or elimination of rejection by a host, extended survival in a host , reduced inhibition by the tumor in a host, reduced self-killing in a host, reduced inflammatory cascade in a host , or sustained CAR-mediated signal transduction in a host ([0068], page 8). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Campana et al were successful in generation of engineered immune cells having enhanced therapeutic efficacy with detailed instructions and working examples.
Regarding to claim 49, Wang et al teach that in some embodiments, the engineered immune cell is an autologous cell or an allogeneic cell ([0020], page 6).
Regarding to claim 54, Wang et al teach that the cytoplasmic domain is designed to comprise the signaling domain ofCD3-zeta and the signaling domain of 4-lBB. In yet another embodiment, the cytoplasmic domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD28 and 4-1BB ([0132], page 14).
Regarding to claim 55, Wang et al teach that one or more endogenous genes (e.g., a gene encoding a subunit of a TCR, or a gene encoding a cell surface marker) of the engineered immune cell can be inactivated ([0163], page 18). The endogenous T cell receptor (TCR) of the engineered immune cell can be inactivated ([0164], page 18).
Regarding to claims 56, 58, Wang et al teach that one or more chimeric antigen receptors (CARs) comprising a binding moiety, wherein the binding moiety comprises a first antigen binding domain capable of binding to an immune cell antigen and a second antigen binding domain capable of binding to a disease-associated antigen ([0008], page 3). In some embodiments, the disease-associated antigen is a tumor-associated antigen. In some embodiments, the tumor-associated antigen is CD19, CD20, CD22, CD38, BCMA etc., and the second antigen binding domain binds to CD19 ([0012], page 4 , right column).
Regarding to claims 59, 61, Wang et al teach that the engineered immune cell comprises a first CAR and a second CAR, each targeting a different antigen ([0163], page 18). The engineered immune cell can comprise one or more chimeric antigen receptors (CARs) comprising a binding moiety. The binding moiety can comprise a first antigen binding domain capable of binding to an immune cell antigen and a second antigen binding domain capable of binding to a disease-associated antigen. Each CAR of the one or more CARs may further comprise a transmembrane domain and an intracellular signaling domain ([0164], page 18). In some embodiments, the disease-associated antigen is a tumor-associated antigen. In some embodiments, the tumor-associated antigen is CD19, CD20, CD22, CD38, BCMA etc., and the second antigen binding domain binds to CD19 ([0012], page 4 , right column).
Wang et al teach that transmembrane regions of particular use in the present disclosure may be derived from (e.g., comprise at least the transmembrane region(s) of) the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD8 etc. ([0125], page 13). Wang et al teach that the cytoplasmic domain of the CAR can be designed to comprise the CD3-zeta (ζ) signaling domain by itself or combined with any other desired cytoplasmic domain(s) useful in the context of the CAR of the present disclosure ([0130], page 14), CD3ζ is a cytoplasmic signaling sequence derived from CD3ζ ([0135], page 14) and human CD3ζ intracellular region ([0392], page 53).
Claim 63 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (Pub. No.: US 2021/0332101 A1, Foreign Application Priority Data: Nov. 1 , 2018 , CN 201811297174.3, and Dec. 18, 2018, CN 201811549651.0) in view of Busser et al (Pub. No.: US 2020/0237823 Al, Foreign Application Priority Data: Oct. 19, 2017) and Campana et al (Pub. No .: US 2021/0046112 A1, Provisional application No. 62/112,765 , filed on Feb. 6 , 2015) as applied to claims 46, 49, 54-56, 58-59, 61 above, and further in view of Andre et al (Pub. No.: US 2019/0322744 A1, Provisional application No. 62/067,642, filed on Oct. 23 , 2014 .)
The teachings of Wang et al, Busser et al, Campana et al above are incorporated herein in their entirety.
Although the above references teach that the immune cell antigen can be NKG2A, they do not teach the antigen binding region that specifically recognizes NKG2A comprising SEQ ID NO: 10, 11, 12, 13, 14, 15. Andre et al cure the deficiency.
Regarding to claims 63, Andre et al teach treatment of cancers using anti-NKG2A agents (Title). Andre et al teach SEQ ID NO: 8 which is 100% identical to SEQ ID NO: 10 of the claimed invention; SEQ ID NO: 11 which is 100% identical to SEQ ID NO: 11 of the claimed invention; SEQ ID NO: 12 which is 100% identical to SEQ ID NO: 12 of the claimed invention (see [100], page 10). SEQ ID NO: 13 which is 100% identical to SEQ ID NO: 13 of the claimed invention; SEQ ID NO: 14 which is 100% identical to SEQ ID NO: 14 of the claimed invention; SEQ ID NO: 15 which is 100% identical to SEQ ID NO: 15 of the claimed invention (see [101], page 10). Thus, a person of ordinary skill in the art before the effective filing date of the rejected claims who is looking to treat cancer would be motivated to use the antigen binding region that specifically recognizes NKG2A comprising sequences identical to SEQ ID NO: 10, 11, 12, 13, 14, 15 as claimed.
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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 Wang et al, Busser et al, Campana et al by using the anti-NKG2A antibody is an antibody comprising sequences identical to SEQ ID NO: 10, 11, 12, 13, 14, 15 as taught by Andre 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 Andre et al teach that blockade of inhibitory receptor NKG2A using an anti-NKG2A antibody enables NK cells to effectively eliminate head and neck cancer cells. In particular, in head and neck cancer HLA- E is serving as a tumor escape mechanism, even when the cancer is being treated with other therapeutic agents, and including in HPV positive patients. It is shown herein that head and neck cancer cells express HLA-E at levels which are causing inhibition of NKG2A-expression NK and/or T cells , and an anti-NKG2A antibody can reverse such inhibition ([0011], page 1-2). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Andre et al provided proof of principle and a method of increasing the likelihood of survival over a relevant period of a human patient diagnosed with head and neck squamous cell carcinoma (HNSCC) ([0136], page 14).
Claim 64 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (Pub. No.: US 2021/0332101 A1, Foreign Application Priority Data: Nov. 1 , 2018 , CN 201811297174.3, and Dec. 18, 2018, CN 201811549651.0) in view of Busser et al (Pub. No.: US 2020/0237823 Al, Foreign Application Priority Data: Oct. 19, 2017) and Campana et al (Pub. No .: US 2021/0046112 A1, Provisional application No. 62/112,765 , filed on Feb. 6 , 2015) as applied to claims 46, 49, 54-56, 58-59, 61 above, and further in view of Cornen et al (Pub. No.: US 2020/0369764 Al, Provisional application No. 62/530,454, filed on Jul. 10, 2017.)
The teachings of Wang et al, Busser et al, Campana et al above are incorporated herein in their entirety.
Although the above references teach that the immune cell antigen NKG2A can be targeted, the above references do not teach a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1, and a light chain variable region having the amino acid sequence of SEQ ID NO:2. Cornen et al cure the deficiency.
Cornen et al teach “combination therapy using antibody to human siglec-9 and antibody to human NKG2A for treating cancer” (Title). Cornen et al teach heavy chains VH1 with SEQ ID NO: 172 (page 34) is 100% identical to SEQ ID NO: 1 of the claimed invention, and light chain variable region SEQ ID NO: 182 (Page 35) is 100% identical to SEQ ID NO: 2 of the claimed invention (see below).
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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 Wang et al, Busser et al, Campana et al by using the SEQ ID NO: 172 which is 100% identical to SEQ ID NO: 1 of the claimed invention, and light chain variable region SEQ ID NO: 182 which is 100% identical to SEQ ID NO: 2 of the claimed invention as taught by Cornen 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 Cornen et al teach “antibodies that bind and neutralize the inhibitory activity of human Siglec-9 (and that optionally further bind and neutralize the inhibitory activity of human Siglec- 7) exhibit a highly increased ability to cause immune mediated (e.g. NK cell mediated) elimination of target cells (e.g. tumor cells, infected cells) when used in combination with an agent that neutralizes the activity of the human NKG2A polypeptide. In particular, the inventors have observed that Siglec polypeptides are inhibiting the cytotoxic activity of NKG2A-expressing NK cells towards HLA-E expressing tumor cells when the inhibitory activity of NKG2A is neutralized” ([0016], page 2), and “The ability to enhance the cytotoxicity of such Siglec-9 low-expressing NK cells has the advantage of being able to additionally mobilize this population of cells against disease target cells, e.g. tumor cells and/or bacterial cells” ([0025], page 4). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Cornen et al were successful in generating and using antibody agents for treating an individual having a cancer or an infectious disease, with detailed instructions and working examples.
Claim(s) 66, 67, 69, 70 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (Pub. No.: US 2021/0332101 A1, Foreign Application Priority Data: Nov. 1 , 2018 , CN 201811297174.3, and Dec. 18, 2018, CN 201811549651.0) in view of Busser et al (Pub. No.: US 2020/0237823 Al, Foreign Application Priority Data: Oct. 19, 2017) and Campana et al (Pub. No .: US 2021/0046112 A1, Provisional application No. 62/112,765 , filed on Feb. 6 , 2015) as applied to claims 46, 49, 54-56, 58-59, 61 above, and further in view of Wang et al ( herein after Wang-2, Pub. No.: US 2019/0359726 A1, Foreign Application Priority Data, Jan. 23, 2017).
The teachings of Wang et al, Busser et al, Campana et al above are incorporated herein in their entirety.
Although the above references teach that tumor-associated antigens include BCMA, the above references do not teach antigen binding region that specifically recognizes BCMA comprising SEQ ID NO: 16, 17, 18, 19, 20, 21. Wang-2 cure the deficiency.
Regarding to claims 66, 69 Wang-2 teaches that the present invention belongs to the field of tumor immunotherapy or diagnosis; and in particular, the present invention relates to an antibody that targets BCMA and uses thereof ([0001], page 1). Wang-2 teaches SEQ ID NO: 60 which is 100% identical to SEQ ID NO: 16 of the claimed invention; teach SEQ ID NO: 61 which is 100% identical to SEQ ID NO: 17 of the claimed invention; teach SEQ ID NO: 5 which is 100% identical to SEQ ID NO: 18 of the claimed invention, teach SEQ ID NO: 6 which is 100% identical to SEQ ID NO: 19 of the claimed invention; teach SEQ ID NO: 7 which is 100% identical to SEQ ID NO: 20 of the claimed invention; teach SEQ ID NO: 10 which is 100% identical to SEQ ID NO: 21 of the claimed invention (see Page 18 and page 24, Sequence listing, and page 12)
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Regarding to claims 67, 70 Wang-2 teaches SEQ ID NO: 56 which is 100% identical to SEQ ID NO: 22 of the claimed invention; teaches SEQ ID NO: 67 which is 100% identical to SEQ ID NO: 23 of the claimed invention
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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 Wang et al by using an antibody that targets BCMA comprising sequences identical to SEQ ID NO: 16, 17, 18, 19, 20, 21, 22, 23 as taught by Wang-2 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 Wang-2 teaches that the BCMA binding portion of a CAR is a scFv antibody fragment that retains an equivalent binding affinity, for example it binds to the same antigen with comparable efficacy, as compared with the IgG antibody from which it is derived. The antibody fragment is functional, thereby providing a biochemical reaction, which can include, but is not limited to, activating an immune response, inhibiting the initiation of signaling from its target antigen, inhibiting kinase activity, and the like. Accordingly, a BCMA-CAR which comprises a WT binding domain and engineered into a T cell, and a method for using it in adoptive immunotherapy are provided in the present invention ([0143], page 8). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Wang-2 teaches that the antibody of the present invention is capable of efficiently binding to tumor cells expressing BCMA, and the immune effector cells of the present invention exhibit significant killing ability against tumor cells expressing BCMA, and therefore, the antibody and immune effector cells of the present invention can be efficiently and safely applied to the treatment of multiple myeloma, thereby constituting a material foundation for the treatment of multiple myeloma ([0157], page 9).
Claim Objections
Claims 65, 68, and 71 are objected to as being dependent upon a rejected base claim, but would be free of prior arts if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Response to Arguments
Applicant's arguments filed on 06-10-2026 have been fully considered but they are not persuasive.
1. Applicants argue that
“independent claims 46 and 72 are not rendered obvious by Wang in view of Busser and Campana”,
“Busser appears to describe knocking out the endogenous B2M gene to eliminate surface MHC class I from the engineered cell, thereby evading host T-cell rejection; however, the resulting MHC-class-I-null phenotype renders the cell vulnerable to NK-cell attack (See, e.g., Busser ,[0049]-[0050] and FIG. 17; FIG. 18, copied below, first step.)”,
“Campana teaches that "KKMP" is an endoplasmic reticulum/Golgi retention sequence of the "KKXX" family, the function of which is to retain the scFv-target complex intracellularly and "thereby downregulat[e] the cell surface" expression of the target "through ... localizing/targeting the molecules for degradation and/or internalization." (Campana ,r[0067], [0076].) As such, Campana's anti-NKG2A construct was retained intracellularly and used to downregulate surface NKG2A on the engineered cell” (Campana ,[0020]; FIG. 11)”.
(Remarks, page 6-7)
Response to Arguments:
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Wang et al provides an engineered immune cell comprising a CAR or engineered TCR, which CAR or engineered TCR can comprise a first antigen binding domain and a second antigen binding domain. The engineered immune cells of the present disclosure, when administered into a subject, can inhibit the host immune cells such as T cells and/or NK cells and enhance the survival and persistence of the engineered immune cells in vivo, thereby exhibiting more effective tumor killing activity (Abstract). One of ordinary skill in the art would have been motivated to combine teachings of Wang et al with Busser et al because
Busser et al teach that “the method of the invention provides with the genetic insertion of exogenous coding sequence(s) encoding NK inhibitors to prevent allogeneic T-cells rejection from patient's NK cell” ([0001], page 1). Thus, Busser et al concerned about inhibiting NK cell for improved immune cells therapy.
Busser et al teach that “The different aspects developed above to enhance persistence of the cells are particularly preferred, when the exogenous coding sequence is introduced by disrupting an endogenous gene encoding β2m or another MHC component” ([0132], page 11)
Busser et al teach that “one gene editing step is to reduce or prevent the expression of the β2m protein and/or another protein involved in its regulation such as C2TA (Uniprot P33076) or in MHC recognition, such as HLA proteins. This permits the engineered immune cells to be less alloreactive when infused into patients” ([0359], page 22).
Busser et al teach that “methods to improve the therapeutic outcome of CAR T-cell therapies by extending their persistence in vivo. It consists in a simultaneous TALEN mediated knock-out of B2M and TCR in the presence of AAV6 repair vectors delivering the CAR at the TRAC locus and an NK inhibitor at the B2M locus. This method prevents CAR T-cell to attack host tissues in a non-specific and TCR-mediated manner (graft versus host attack) and to divert host T- and NK-cells-mediated depletion of CAR T-cells” ([0460], page 63).
Busser et al were successful in prevent allogeneic T-cells rejection with improved immune cells therapy because Busser et al teach that “the insertion of the coding sequence has the effect of reducing or preventing the expression of genes involved into self and non-self-recognition to reduce host versus graft disease (GVHD) reaction or immune rejection upon introduction of the allogeneic cells into a recipient patient. For instance, one of the sequence-specific reagents used in the method can reduce or prevent the expression of TCR in primary T-cells, such as the genes encoding TCR-alpha or TCR-beta.” ([0358], page 21-22).
With regard to Campana et al reference, it appears applicant have engaged in selective reading of the teachings of Campana et al to formulate the grounds for Campana's anti-NKG2A construct was retained intracellularly and used to downregulate surface NKG2A on the engineered cell. It seems applicant argue localizing domain (LD), such as a "KKMP" or "EEKKMP" sequence is to retain the scFv-target complex intracellularly and does not recognize NKG2A. This is not persuasive because:
It is noted that Campana et al teach an engineered immune cell comprising a nucleic acid comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR) and a nucleic acid comprising a nucleotide sequence encoding an antibody linked to a localizing domain (LD) (See claim 23, page 33). Campana et al teach the localizing domain (LD)-linked target-binding molecule binds to a target expressed on the surface of an immune cell. In some embodiments, the LD-linked target binding molecule inhibits the activity or function of the target molecule . By way of example, as disclosed herein , the LD -linked target-binding molecule can be designed to bind to e.g., NKG2A ([0067], page 8). It is noted that scFv is part of localizing domain: Campana et al teach “FIG . 1B shows the combined expression of CAR with different formats of compartment-directed scFv ( an example of a target-binding molecule linked to a localizing domain)” ([0010], page 1).
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Campana et al teach “chimeric antigen receptor (CAR) and a nucleic acid comprising a nucleotide sequence encoding a single-chain variable fragment (scFv)” ([0082], page 9), and “Cloning of scFv against Human NKG2A …. the sequence of scFv was designed by connecting variable light (VL) region and variable heavy (VH) region with linker sequence . The synthesized gene consisting of CD8 signal peptide, scFv against human NKG2A, CD8 hinge and transmembrane, and KKMP sequence was subcloned into EcoRI and Xhol sites of the MSCV - IRES -GFP vector.” ([0103]-[0104], page 10).
One of ordinary skill in the art would have been motivated combine the above references with Campana et al because Campana et al provide explicit advantage of LD - linked target binding molecule inhibits the activity or function of NKG2A ([0067], page 8) and the engineered immune cells of the invention have enhanced therapeutic efficacy which refers to one or more of reduced graft- versus-host disease (GvHD ) in a host , reduced or elimination of rejection by a host, extended survival in a host , reduced inhibition by the tumor in a host, reduced self-killing in a host, reduced inflammatory cascade in a host , or sustained CAR-mediated signal transduction in a host ([0068], page 8).
2. Applicants argue no motivation to combine:
“a POSITA would not have been motivated to combine the cited references in the manner recited in the instant claims. Starting from Wang: Instead ofB2M knockout, Wang took an alternative approach to overcome host T-cell rejection, namely, by expressing an immune-cell-targeting CAR, such as a CD3- or CD7-targeting CAR (Wang ,r,r[0l 19], [0221]). Wang's working examples appear to show that its CD3- or CD7-targeting CAR sufficiently overcame T-cell rejection, without causing NK-cell rejection (as the B2M was intact and therefore normal surface MHC class I was displayed)”.
“Wang's own disclosure further teaches away from the proposed modification. In the same paragraph that reports the success of the CD3-targeting CAR alone, Wang reports that CAR-T cells combining the CD3-targeting CAR with B2M silencing "were not able to survive long"”.
“Starting from Busser, a POSITA likewise had no motivation to arrive at the claimed cells. Busser proposes to overcome host T-cell rejection by the B2M knockout, and then the resulting host NK-cell rejection by the inhibitory trimer. Busser provides no reason for a POSITA to further introduce an immune cell-targeting CAR”
(Remarks, page 8)
Response to Arguments:
It is noted that Wang et al teach “…. an endogenous HLA can be knocked out to reduce T cell killing activity but keep anti-NK killer function. …… an endogenous HLA can be knocked out with co-expression of killer/phagocyte inhibitor(s). For example, HLA-I, HLA-II, or both can be knocked out with coexpression of killer/phagocyte inhibitors…..” ([0172], page 19) (Note: B2M is an HLA-I gene). Wang et al provides an engineered immune cell comprising a CAR or engineered TCR, which CAR or engineered TCR can comprise a first antigen binding domain and a second antigen binding domain. The engineered immune cells of the present disclosure, when administered into a subject, can inhibit the host immune cells such as T cells and/or NK cells and enhance the survival and persistence of the engineered immune cells in vivo, thereby exhibiting more effective tumor killing activity (Abstract). One of ordinary skill in the art would have been motivated to combine teachings of Wang et al with Busser et al because Busser et al teach that “The different aspects developed above to enhance persistence of the cells are particularly preferred, when the exogenous coding sequence is introduced by disrupting an endogenous gene encoding β2m or another MHC component” ([0132], page 11). Busser et al teach that “one gene editing step is to reduce or prevent the expression of the β2m protein and/or another protein involved in its regulation such as C2TA (Uniprot P33076) or in MHC recognition, such as HLA proteins. This permits the engineered immune cells to be less alloreactive when infused into patients” ([0359], page 22). Busser et al teach that “methods to improve the therapeutic outcome of CAR T-cell therapies by extending their persistence in vivo. It consists in a simultaneous TALEN mediated knock-out of B2M and TCR in the presence of AAV6 repair vectors delivering the CAR at the TRAC locus and an NK inhibitor at the B2M locus. This method prevents CAR T-cell to attack host tissues in a non-specific and TCR-mediated manner (graft versus host attack) and to divert host T- and NK-cells-mediated depletion of CAR T-cells” ([0460], page 63). Busser et al were successful in prevent allogeneic T-cells rejection with improved immune cells therapy because Busser et al teach that “the insertion of the coding sequence has the effect of reducing or preventing the expression of genes involved into self and non-self-recognition to reduce host versus graft disease (GVHD) reaction or immune rejection upon introduction of the allogeneic cells into a recipient patient. For instance, one of the sequence-specific reagents used in the method can reduce or prevent the expression of TCR in primary T-cells, such as the genes encoding TCR-alpha or TCR-beta.” ([0358], page 21-22).
3. Applicants argue no reasonable expectation of success:
“the B2M-silenced cells "were not able to survive long." (Wang ,r[0333]; see also ,r[0221].) A POSITA would thus lack a reasonable ground to expect that combining B2M knockout and an NKG2A-targeting CAR would yield a cell resistant to host NK rejection”
“Busser's functional NK-resistance assay is prophetic-it describes only that NK resistance "can be assayed." (Busser ,r[0463].) Busser thus does not demonstrate that its proposed approach in fact protects cells from NK killing, much less that swapping in an NKG2A-targeting scFv on top ofB2M knockout would do so”
“Campana appears completely silent on expressing a CAR incorporating an anti-NKG2A scFv on the cell surface, therefore providing no reasonable expectation that the structurally and functionally different claimed cell would achieve the claimed property”
(Remarks, page 9-10)
Response to Arguments:
As evidenced by applicant own work, B2M knockout and/or TCR/B2M dual knockout cells are viable and can be used: Example 3 of the instant disclosure teaches preparation of NKG2A UCAR-T Cells: Knockout of TCR and B2M Genes and Screening of TCR/B2M Double Negative Cells (See example 3, page 26-27 of the instant specification). Since Wang et al teach the same step of knockout of B2M gene in T-cells, it is expected to have the same results as the claimed invention: Wang et al teach in vitro HVG study with TCR/B2M dual knockout cells ([0333], page 44). Furthermore, Wang et al teach “…. an endogenous HLA can be knocked out to reduce T cell killing activity but keep anti-NK killer function. …… an endogenous HLA can be knocked out with co-expression of killer/phagocyte inhibitor(s). For example, HLA-I, HLA-II, or both can be knocked out with coexpression of killer/phagocyte inhibitors ….” ([0172], page 19). It is also noted that Wang et al did not make any mention to avoid knocking out of B2M or HLA-I genes. Thus, Wang et al clearly teach embodiments of knocking out of HLA-I such as B2M gene as same as the claimed invention.
Additionally, as described above, one of ordinary skill in the art would have been motivated to combine teachings of Wang et al with Busser et al because Busser et al teach that “The different aspects developed above to enhance persistence of the cells are particularly preferred, when the exogenous coding sequence is introduced by disrupting an endogenous gene encoding β2m or another MHC component” ([0132], page 11) and “one gene editing step is to reduce or prevent the expression of the β2m protein and/or another protein involved in its regulation such as C2TA (Uniprot P33076) or in MHC recognition, such as HLA proteins. This permits the engineered immune cells to be less alloreactive when infused into patients” ([0359], page 22). Busser et al teach that “methods to improve the therapeutic outcome of CAR T-cell therapies by extending their persistence in vivo. It consists in a simultaneous TALEN mediated knock-out of B2M and TCR in the presence of AAV6 repair vectors delivering the CAR at the TRAC locus and an NK inhibitor at the B2M locus. This method prevents CAR T-cell to attack host tissues in a non-specific and TCR-mediated manner (graft versus host attack) and to divert host T- and NK-cells-mediated depletion of CAR T-cells” ([0460], page 63). Busser et al were successful in prevent allogeneic T-cells rejection with improved immune cells therapy because Busser et al teach that “the insertion of the coding sequence has the effect of reducing or preventing the expression of genes involved into self and non-self-recognition to reduce host versus graft disease (GVHD) reaction or immune rejection upon introduction of the allogeneic cells into a recipient patient. For instance, one of the sequence-specific reagents used in the method can reduce or prevent the expression of TCR in primary T-cells, such as the genes encoding TCR-alpha or TCR-beta.” ([0358], page 21-22).
It is noted that Campana et al teach an engineered immune cell comprising a nucleic acid comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR) and a nucleic acid comprising a nucleotide sequence encoding an antibody linked to a localizing domain (LD) (See claim 23, page 33). Campana et al teach “ localizing domain (LD)-linked target-binding molecule binds to a target expressed on the surface of an immune cell. … , the LD -linked target-binding molecule can be designed to bind to e.g., NKG2A ([0067], page 8). It is noted that scFv is part of localizing domain: Campana et al teach “FIG . 1B shows the combined expression of CAR with different formats of compartment-directed scFv ( an example of a target-binding molecule linked to a localizing domain)” ([0010], page 1). Campana et al teach “chimeric antigen receptor (CAR) and a nucleic acid comprising a nucleotide sequence encoding a single-chain variable fragment (scFv)” ([0082], page 9), and “Cloning of scFv against Human NKG2A …. the sequence of scFv was designed by connecting variable light (VL) region and variable heavy (VH) region with linker sequence . The synthesized gene consisting of CD8 signal peptide, scFv against human NKG2A, CD8 hinge and transmembrane, and KKMP sequence was subcloned into EcoRI and Xhol sites of the MSCV - IRES -GFP vector.” ([0103]-[0104], page 10). One of ordinary skill in the art would have been motivated combine the above references with Campana et al because Campana et al provide explicit advantage of LD - linked target binding molecule inhibits the activity or function of NKG2A ([0067], page 8) and the engineered immune cells of the invention have enhanced therapeutic efficacy which refers to one or more of reduced graft- versus-host disease (GvHD ) in a host , reduced or elimination of rejection by a host, extended survival in a host , reduced inhibition by the tumor in a host, reduced self-killing in a host, reduced inflammatory cascade in a host , or sustained CAR-mediated signal transduction in a host ([0068], page 8).
As per MPEP 716.01(c), arguments by applicant cannot take the place of evidence, Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Conclusion
Claims 46, 49, 54-56, 58-59, 61, 63-64, 66, 67, 69, 70 and 72 are rejected.
Claims 65, 68 and 71 are objected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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