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 .
DETAILED ACTION
Amendments
In the reply filed 03/11/2026, Applicant has amended claims 1, 3, 14, 15, 17, 21-24, 37 and 39, and added new claim 50.
Claim Status
Claims 1, 3, 7-8 and 12-50 are pending.
Claims 8, 25-27, 38 and 40-49 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on 09/05/2025.
Claims 1, 3, 7, 12-24, 28-37, 39 and 50 are considered on the merits.
Withdrawn Claim Objections
The prior objection to claims 1, 3, 14, 17 and 22 is withdrawn in light of Applicant’s amendment to the claims.
New Claim Objections
Claim 23 is objected to because of the following informalities:
Claim 23 recites “a the CD16” in line 2, which contains a typographical error. It is recommended to change to “the CD16”.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 21, 23, 24, 37 and 39 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment to the claims and Applicant’s argument that the particular mutations of F176V and S197P (recited in claim 24 (a)) are known to those skilled in the art and sequence of CD16 is provided in WO2015148926 which is incorporated by reference (Remarks, p. 17-18). Applicant’s argument has been fully considered and it is persuasive. Thus, the prior rejection over claim 24 under 35 U.S.C. 112(b) is withdrawn.
Maintained Claim Rejections - 35 USC § 102
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.
Claims 1, 3, 7, 12-13, 15-21 and 35 stand rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Zhuang et al., (Cancer Immunol Res. 2019 April; 7(6): 939-951 and suppl. p. 1-9. Prior art of record).
It is noted that the prior 102 rejection is maintained. The following rejection is edited to discuss the new limitation “recombinant” in claim 1.
With respect to claim 1, Zhuang teaches a CD28H chimeric antigen receptor (CD28H-CAR) consisting of full-length CD28H fused to the cytoplasmic domain of T-cell receptor ζ chain (see e.g., abstract and Fig 6A), in which the full-length CD28H comprises an extracellular domain (“EC” in Fig 6A, equivalent to claimed ectodomain), a transmembrane domain (“TM” in Fig 6A) and a cytoplasmic domain (“CD” in Fig 6A, equivalent to claimed endodomain). Zhuang teaches CD28H has a single extracellular immunoglobulin domain and its ligand is B7H7 (e.g., p. 939, right col, para 2), thus teaches the ectodomain of CD28H comprises an antigen recognition domain. Zhuang teaches the cytoplasmic domain of CD28H is required for its activity (see e.g., abstract and p. 947, left col.) and teaches CD28H activates NK cells and T cells (e.g., p. 942, “Results”, para 1 and p. 945, “Discussion”, para 1), thus teaches the endodomain of CD28H comprises a signaling domain, and this signaling domain is originated from a cytoplasmic domain of a signal transducing protein (i.e., CD28H) specific to T and NK cell activation.
In regard to the new limitation a “recombinant” ectodomain, the instant specification does not provide a special definition for the term “recombinant”, thus the term “recombinant” is given its plain meaning, i.e., the ordinary and customary meaning by those of ordinary skill in the art at the relevant time (see MPEP 2111.01 (I)). One of ordinary skill in the art would have understood that the term “recombinant” in genetics, describes DNA, proteins, cells, or organisms that are made by combining genetic material from two different sources. In the instant case, Zhuang teaches “CD28H cDNA was amplified and cloned into the EcoRI and NotI cloning sites of pCDH-EF1-T2A-Puro lentivirus vector for transduction of human cell lines” (e.g., p. 940, left col, para “Plasmids”), thus clearly teaches that the CD28H protein is made by combining genetic material from two different sources, i.e., from human and lentivirus, thus is recombinant. This interpretation of “recombinant” is further evidenced by Zhang’s teaching that the NK cells are cultured with “10% purified IL2 (Hemagen) and 100 units/mL recombinant IL2 (Roche)” (p. 940, right col, para “Cells”), in which the “purified” IL2 (Hemagen) is purified from fresh pooled human peripheral blood leukocytes from donors while the “recombinant” IL2 (Roche) is cloned in an expression plasmid and transformed into E. coli for expression and isolation. Therefore, one of ordinary skill in the art would have immediately acknowledged that Zhuang’s CD28H CAR comprises a recombinant CD28H ectodomain, a recombinant CD28H transmembrane domain and a recombinant CD28H endodomain.
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Regarding the CAR comprising a form of CD28H-CD28H-CD3ζ wherein the transmembrane domain is indicated in bold text and the endodomain is indicated in italicized text, as stated supra, Zhuang teaches the CD28H CAR comprising full-length CD28H fused to the cytoplasmic domain of T-cell receptor ζ chain (i.e., CD3ζ), thus teaches the CAR comprises a form of a CD28H transmembrane domain-CD28H signaling domain-CD3ζ signaling domain (see Fig 6A for a diagram of the CAR attached).
With respect to claim 3 directed to the endodomain comprising an ITAM, the instant specification discloses that “all CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain” ([000121]). Zhuang’s endodomain comprises the cytoplasmic domain of T-cell receptor ζ chain (i.e., CD3ζ), thus comprises an ITAM.
With respect to claim 7 directed to the endodomain comprising two different signaling domains comprising fused cytoplasmic domains, as stated supra, Zhuang teaches the endodomain of the CAR comprises the cytoplasmic domain of CD28H fused to the cytoplasmic domain of T-cell receptor ζ chain (see abstract and Fig 6A).
With respect to claim 12 directed to the CAR comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 60, Zhuang teaches the amino acid sequence of the CD28H-TCRζ CAR (see Supple. Fig 7A in Supple. p. 9), in which the sequence of amino acid numbers 151-395 is 100% identical to instant SEQ ID NO: 60 (see attached below, it is noted that Zhuang’s sequence has amino acid number 332 that is not recited in the instant SEQ ID NO: 60).
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With respect to claim 13 directed to the antigen recognition domain specifically binding an antigen associated with a disease or a liquid tumor, as stated supra, Zhuang teaches CD28H specifically binds its ligand B7H7 that is broadly expressed in tumor tissues (e.g., see abstract), for example, is expressed by K562 cells (p. 943, right col, para 1), which is a leukemia cell line. Thus, Zhuang teaches the antigen recognition domain specifically binds an antigen associated with a disease or a liquid tumor.
With respect to claim 15 (ii) directed to the ectodomain comprising a signal peptide, as stated supra, Zhuang teaches the amino acid sequence of the CD28H-TCRζ CAR (see Supple. Fig 7A in Supple. p. 9), in which the amino acid number 1-22 is the CD28H signal peptide.
With respect to claim 16 directed to the CAR encoded by a polynucleotide comprised in a bi-cistronic construct co-expressing an exogenous cytokine, it is noted that this limitation is directed to a product-by-process claim. The applicant is reminded that “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” See MPEP § 2113. In the instant case, the claimed product itself, the CAR comprising a recombinant ectodomain and a CD28H-CD28H-CD3ζ transmembrane-endodomain domain in the instant claim, is the same as the CD28H-TCRζ CAR of Zhuang, thus the claim is unpatentable even though the prior product was made by a different process (being encoded by a polynucleotide vector, see Zhuang, p. 940, para “Plasmids”).
With respect to claim 17 directed to the CAR being expressed in a derivative effector cell differentiated from an iPSC and the derivative effector cell being chosen from a list of cells, and claim 18 directed to the derivative effector cell expressing the CAR and comprising a functional feature, it is noted that this limitation is directed to a product-by-process claim. The claimed product itself, the CAR comprising an ectodomain and a CD28H-CD28H-CD3ζ transmembrane-endodomain domain in the instant claim, is the same as the CD28H-TCRζ CAR of Zhuang, thus the claims are unpatentable even though the prior product was made by a different process (the CAR of Zhuang being expressed in a human NK cell line NKL cell, see p. 945, left col., “NK cells with a CD28H-CAR”).
With respect to claim 19 directed to a cell being an immune cell and comprising at least one CAR of claim 1, Zhuang teaches a human NK cell comprising the CD28H CAR (see e.g., p. 945, left col, para “NK cells with a CD28H-CAR”).
With respect to claim 20 (i) directed to the CAR being NK cell specific, Zhuang teaches CD28H is expressed in NK cells (p. 942, “Results” para 1) and is a strong activator of NK cells through selective synergy with NK cell receptors NKp46 and 2B4 and also enhances NK-cell activation through CD16 for antibody-dependent cellular cytotoxicity (p. 939, last para), thus teaches the CD28H CAR is NK cell specific.
With respect to claim 21 (iv) directed to the cell further comprising a CD16, Zhuang teaches the NK cell expresses CD16 that mediates antibody-dependent cellular cytotoxicity (ADCC) and CD28H enhances CD16-mediated ADCC (p. 943, right col, para “CD28H enhances CD16-mediated ADCC”). Thus, Zhuang teaches the cell further comprises an endogenous CD16.
With respect to claim 35 directed to a composition comprising the cell of claim 19, Zhuang teaches human NK cells are transfected with the CD28H CAR and show specific lysis of tumor cells in an in vitro assay (see p. 945, left col, para “NK cells with a CD28H-CAR” and Fig 6), thus teaches a composition comprising the cell of claim 19.
Accordingly, Zhuang anticipates instant claims.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged.
Applicant argues that the present application describes numerous recombinant proteins in which the ectodomain is among the recombinant sequences. The alleged "CAR" of Zhuang has a "full-length" (native) CD28H extracellular domain, transmembrane domain, and cytoplasmic domain. In particular, Zhuang states that "[w]e constructed two CD28H CARs by fusing full-length or cytoplasmic domain-truncated (ΔCD) CD28H with the signal transduction domain of the TCR ζ chain" (Zhuang, pg. 8). The cited receptor of Zhuang is therefore only recombinant in the intracellular domain, not the extracellular domain, as presently claimed (Remarks, p. 18-19).
Applicant’s arguments have been fully considered but they are not persuasive. As discussed above, the instant specification does not provide a special definition for the term “recombinant”, thus the term “recombinant” is given its plain meaning by those of ordinary skill in the art at the relevant time (see MPEP 2111.01 (I)). One of ordinary skill in the art would have understood that the term “recombinant” in genetics, describes DNA, proteins, cells, or organisms that are made by combining genetic material from two different sources. Therefore, the fact that Zhuang’s CAR has a "full-length" (native) CD28H extracellular domain, transmembrane domain, and cytoplasmic domain does not negate Zhuang’s CAR being recombinant. In fact, Zhuang teaches “CD28H cDNA was amplified and cloned into the EcoRI and NotI cloning sites of pCDH-EF1-T2A-Puro lentivirus vector for transduction of human cell lines” (e.g., p. 940, left col, para “Plasmids”), thus clearly teaches that the CD28H protein is made by combining genetic material from two different sources, i.e., from human and lentivirus, thus is recombinant (while being full-length wild-type). This interpretation of “recombinant” is further evidenced by Zhang’s teaching that the NK cells are cultured with “10% purified IL2 (Hemagen) and 100 units/mL recombinant IL2 (Roche)” (p. 940, right col, para “Cells”), in which the “purified” IL2 (Hemagen) is purified from fresh pooled human peripheral blood leukocytes from donors (thus being natural and endogenous), while the “recombinant” IL2 (Roche) is cloned in an expression plasmid and transformed into E. coli for expression and isolation (thus being recombinant while being identical to the natural wildtype human IL2). Therefore, one of ordinary skill in the art would have immediately acknowledged that Zhuang’s CD28H CAR comprises a recombinant CD28H ectodomain, a recombinant CD28H transmembrane domain and a recombinant CD28H endodomain.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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, 3, 7, 12-21, 35 and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Zhuang et al., (Cancer Immunol Res. 2019 April; 7(6): 939-951 and suppl. p. 1-9. Prior art of record).
It is noted that the prior 103 rejection of claims 1, 3, 7, 12-21 and 35 is maintained. The following rejection is edited to discuss the new claim 50.
Claims 1, 3, 7, 12-13, 15-21 and 35 are anticipated by Zhuang, thus Zhuang makes obvious instant claims.
With respect to claim 14 directed to antigen recognition domain being specific to CD19, and new claim 50 directed to the recombinant ectodomain comprising a single-chain variable fragment (scFv) polypeptide, however, Zhuang is silent on the CAR having an antigen recognition domain specific to CD19 in claim 14 or the recombinant ectodomain comprising a scFv in claim 50.
Nevertheless, Zhuang teaches several antigen-specific CARs, incorporating single-chain antibodies specific for tumor antigens CD19, CD20, and CD138, have been tested in NK cells and exemplifies two CARs expressed in NK cells, CD19scFv-CD28-TCRζ and CD19scFv-CD28-OX40-TCRζ (p. 949, both columns), thus teaches a NK CAR comprising an antigen recognition domain specific to CD19 in claim 14 and the recombinant ectodomain comprising a scFv in claim 50. Zhuang teaches the study raises the possibility of utilizing CD28H for design of NK-CARs in order to overcome signaling by inhibitory receptors (e.g., p. 950, last para.).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CD28H CAR expressed in NK cells for cancer immunotherapy disclosed by Zhuang, by substituting the antigen recognition domain with a single-chain variable fragment (scFv) specific for tumor antigens such as CD19 as suggested by Zhuang with a reasonable expectation of success. Since Zhuang suggests the NK-based CARs incorporating single-chain antibodies specific for tumor antigens CD19, CD20, and CD138 have been tested in NK cells and exemplifies two NK-CARs comprising CD19scFv (p. 949, both columns), and teaches the study raises the possibility of utilizing CD28H for design of NK-CARs in order to overcome signaling by inhibitory receptors (p. 950, last para.), one of ordinary skill in the art would have had a reason to make this substitution in order to treat tumors expressing tumor antigens such as CD19.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged.
Applicant firstly argues that cited reference does not disclose or suggest the presently claimed invention because Zhuang fails to teach or even suggest a CAR comprising a recombinant ectodomain and also fails to provide even a motivation to modify the extracellular domain of the cited receptor, and certainly no basis for reasonably predicting the results of doing so (Remarks, 20, para 1).
Applicant’s arguments have been fully considered but they are not persuasive. As discussed above, the term “recombinant” is given its plain meaning by those of ordinary skill in the art at the relevant time, and one of ordinary skill in the art would have immediately acknowledged that Zhuang’s CD28H CAR comprises a recombinant CD28H ectodomain, a recombinant CD28H transmembrane domain and a recombinant CD28H endodomain.
Additionally, Zhuang teaches several antigen-specific CARs, incorporating single-chain antibodies specific for tumor antigens CD19, CD20, and CD138, have been tested in NK cells and exemplifies two CARs expressed in NK cells, CD19scFv-CD28-TCRζ and CD19scFv-CD28-OX40-TCRζ used in in vitro and in mice, but are sensitive to inhibition by HLA-E on target cells (p. 949, both columns). Zhuang teaches the study raises the possibility of utilizing CD28H for design of NK-CARs in order to overcome signaling by inhibitory receptors (e.g., p. 950, last para.). Therefore, Zhuang provides teaching (the CD28H CAR and e.g., the CD19scFv) and motivation to modify, by using CD28H for design of NK-CARs (e.g., CD19CAR that is sensitive to inhibition) in order to overcome signaling of inhibitory receptors with a reasonable expectation of success.
Applicant additionally argues that modification of the cited reference would render it unsatisfactory for its intended purpose because Zhuang uses natural receptors for binding their natural ligands as an alternative to scFv-based CARs (Zhuang, pgs. 949-50). Thus modification of Zhuang to use a scFv would change the principle of operation of using natural receptors and their ligands (Remarks, p. 20, last para).
Applicant’s arguments have been fully considered but they are not persuasive. In the paragraphs recited by Applicant where Zhuang recites "[a]n alternative and more natural way to reprogram NK cells is by engineering receptors that are activated by recognition of their ligands on tumor cells" (see Zhuang, p. 950, left col, para 2, and Remarks, p. 20, last para), Zhuang continues to teach “expression of the CD28H-TCRζ CAR in NKL cells resulted in very efficient lysis of HDML-2 cells, whereas neither the CD28H cytoplasmic tail nor the TCRζ chain on their own could overcome inhibition. The natural transmembrane domain and cytoplasmic tail of CD28H can now be added to the list of CAR components for use in NK cells” (p. 950, left col, para 2, emphasized by examiner), and Zhuang teaches the study raises the possibility of utilizing CD28H for design of NK-CARs in order to overcome signaling by inhibitory receptors (e.g., p. 950, last para.). Therefore, Zhuang’s principle of operation is not limited to using natural receptors and their ligands, but rather, is aimed to use CD28H as a component of NK-based CARs for cancer immunotherapy (see e.g., abstract), in combination with scFv-based CARs.
Applicant finally argues that no basis in Zhuang for reasonably predicting the results of making a claimed CAR because Zhuang does not provide any reason to have expected any particular advantage from combining a recombinant extracellular domain with the particular combinations of transmembrane and endodomains as presently claimed. By contrast, the present application teaches that CAR constructs in accordance with present claim 1 are among those shown in the present application to provide higher levels of cell surface expression and higher levels of expression for the specific combinations of transmembrane domain and endodomains as presently claimed could not have been reasonably predicted based on the cited references (remarks, p. 21, para 1).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, Zhuang suggests to use CD28H, especially the natural transmembrane domain and cytoplasmic tail of CD28H, as a component of NK-based CARs for cancer immunotherapy in order to overcome signaling by inhibitory receptors and acknowledges a CD19scFv in NK-CARs (see above). Thus, Zhuang provides a particular advantage (i.e., to overcome signaling by inhibitory receptors) from combining a recombinant extracellular domain (e.g., a CD19scFv) with the particular combination of transmembrane and endodomain (e.g., the natural transmembrane domain and cytoplasmic tail of CD28H).
In regard to the argument that Applicants identify CAR constructs in accordance with present claim 1 could provide higher levels of cell surface expression, MPEP 2145 (II) states that “mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”, and “the fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. In instant case, prior art Zhuang teaches utilizing CD28H for design of NK-CARs in order to overcome signaling by inhibitory receptors (e.g., p. 950, last para.). Thus, the fact that applicant has recognized another advantage (i.e., higher levels of cell surface expression) cannot be the basis for patentability when the differences would otherwise be obvious over Zhuang.
Claims 1, 3, 7, 12-13, 15-22, 28-31, 35-37 and 39 stand rejected under 35 U.S.C. 103 as being unpatentable over Zhuang et al., (Cancer Immunol Res. 2019 April; 7(6): 939-951 and suppl. p. 1-9. Prior art of record) in view of Li et al., (Cell Stem Cell. 2018; 23: 181-192. Cited in IDS 03/01/2024) evidenced by Scaria et al., (Blood. 2014; 124 (21): 5816. Prior art of record).
Claims 1, 3, 7, 12-13, 15-21 and 35 are anticipated by Zhuang, thus Zhuang makes obvious instant claims.
With respect to claims 19, 20, 22, 28-31, 36, 37 and 39, directed to a derivative effector cell obtained from differentiating an iPSC, however, Zhuang teaches the CAR is expressed in a human NK cell line NKL cell (see p. 945, left col., “NK cells with a CD28H-CAR”), but is silent on the cell being a derivative effector cell obtained from differentiating an iPSC in claims 19, 20, 22, 28-31, 36, 37 and 39.
Nevertheless, Zhuang teaches the development of induced pluripotent stem cell (iPSC)-derived NK cells provides a resource for NK-based cancer immunotherapy (47) (p. 950, para. 1).
Li, being the cited reference #47 of Zhuang, teaches utilizing human iPSCs to produce NK cells with chimeric antigen receptors that specifically target cancer cells in an antigen-specific manner (see e.g. cover page, para “In Brief”) and teaches human iPSC-derived NK cells provide an ‘‘off-the-shelf’’ resource for cancer therapy (see e.g., cover page, para “Highlights”).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the NK cell line cells expressing the CD28H CAR for cancer immunotherapy disclosed by Zhuang, by substituting NK cell line cells with human iPSC-derived NK cells taught by Li with a reasonable expectation of success. Since Zhuang refers to Li and acknowledges the development of induced pluripotent stem cell (iPSC)-derived NK cells provides a resource for NK-based cancer immunotherapy (p. 950, para. 1), and since Li teaches human iPSC-derived NK cells provide an ‘‘off-the-shelf’’ resource for cancer therapy (see e.g., cover page, para “Highlights”) and reduces to practice a derivative NK cell obtained from differentiating a human iPSC having CARs that specifically target cancer cells in an antigen-specific manner (see e.g. cover page, para “In Brief”), one of ordinary skill in the art would have had a reason to make this substitution in order to obtain human NK cells from an ‘‘off-the-shelf’’ resource for cancer therapy.
With respective to claim 20 directed to the derivative effector cell comprising longer telomers in comparison to primary cells obtained from peripheral blood, Scaria evidences that telomere length in NK cells derived from iPSCs is much longer (200-300kb/diploid genome) compared to those expanded from peripheral blood (<50kb/diploid genome) (p. 2, lines 2-3). Accordingly, one of ordinary skill in the art would have immediately appreciated that the derivative NK cell obtained from differentiating a human iPSC suggested by Zhuang in view of Li would have comprised longer telomers in comparison to primary NK cells obtained from peripheral blood as evidenced by Scaria.
With respect to claim 22 directed to the derivative effector cell having increased cytotoxicity, Zhuang teaches NK cells transfected with CD28H-TCRζ CAR have increased cytotoxicity to B7H7+ tumor cells by overcoming NKG2A-mediated inhibition (see Fig 6G and p. 945, left col, para “NK cells with a CD28H-CAR”). Accordingly, one of ordinary skill in the art would have immediately appreciated that the derivative NK cell having the CAR would have had increased cytotoxicity.
With respect to claim 28 directed to wherein the derivative effector cell is capable of recruiting T cells and wherein the derivative effector cell is capable of reducing tumor immunosuppression in the presence of checkpoint inhibitors, claim 29 directed to the checkpoint inhibitors being antagonists to checkpoint molecules, and claim 30 directed to the checkpoint inhibitors comprising a list of antibodies, it is noted that these wherein clauses simply express the intended result of the derivative effector cell being engineered to comprise the CAR. Therefore, these wherein clauses do not provide any patentable weight in determining patentability of the claimed product. Furthermore, the second wherein clause is directed to contingent limitations based on the condition in the presence of checkpoint inhibitors, and does not limit the structure of the claimed derivative effector cell. Thus, the wherein clause does not provide any patentable weight in determining patentability of the claimed product. See MPEP 2111.04 II. Accordingly, the derivative NK cell comprising the claimed CAR obtained from differentiating a human iPSC suggested by Zhuang in view of Li would have made obvious instant claims 28-30.
With respect to claim 31 directed to the derivative effector cell being a derivative NK cell, as stated supra, Zhuang suggests and Li teaches a derivative NK cell differentiated from a human iPSC (see Li, cover page, para “In Brief” and “Highlights”).
With respect to claim 36 directed to a composition comprising the derivative effector cell of claim 19 and a therapeutic agent, claim 37 directed to the therapeutic agent comprising an antibody, and claim 39 directed to the antibody comprising an anti-CD20 antibody, as stated supra, Zhuang in view of Li suggest a derivative NK cell differentiated from a human iPSC and comprising the claimed CAR. Zhuang teaches the CD28H-TCRζ NK cells show specific lysis of tumor cells in an in vitro assay (see p. 945, left col, para “NK cells with a CD28H-CAR” and Fig 6), and teaches the study holds promise as a component of NK-based CARs for cancer immunotherapy (abstract), thus teaches a composition for therapeutic use comprising the derivative NK cell of claim 19.
Regarding an additional therapeutic agent being an anti-CD20 antibody, Zhuang teaches to treat some tumor cells that co-express the tumor antigen CD20 (such as Daudi and 221 cells), an anti-CD20 antibody (rituximab) is used to induce NK cell-mediated ADCC, and CD28H–B7H7 interaction enhances lysis of 221 and Daudi cells through rituximab-induced ADCC (p. 943, right col, para 1 and also Fig 4D and 4E).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition for therapeutic use comprising the derivative NK cell of claim 19 as suggested by Zhuang in view of Li, by combining a therapeutic agent such as an anti-CD20 antibody as suggested by Zhuang with a reasonable expectation of success. Since Zhuang teaches some tumor cells co-express B7H7 and tumor antigen CD20, and CD28H-B7H7 interaction enhances lysis of those tumor cells through anti-CD20 antibody rituximab-induced ADCC (p. 943, right col, para 1 and also Fig 4D and 4E), one of ordinary skill in the art would have had a reason to combine an anti-CD20 antibody as a combinatory therapeutic agent with the NK cells comprising the CD28H-TCRζ CAR in order to induce ADCC to tumor cells co-expressing B7H7 and CD20 for enhanced cancer immunotherapy.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged.
Applicant argues that Li and Scaria fail to provide the missing teaching. Scaria does not disclose any CARs at all. None of the CAR constructs of Li comprise a combination of transmembrane domain and endodomain as presently claimed, and none of the references provide any motivation to use an ectodomain of Li in a construct of Zhuang, nor any basis to predict the results thereof. Zhuang expressly describes the constructs therein as an alternative to scFv-based designs like those of Li, and fails to provide any basis for concluding that advantages attributed to such "more natural" approach would translate in any way to scFv-based approaches (Remarks, p. 22, para “B”).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, Zhuang teaches a CAR construct comprising a combination of transmembrane domain and endodomain as presently claimed in claim 1. The only difference between the claims in this section (claims 19, 20, 22, 28-31, 36, 37 and 39) and Zhuang is that Zhuang uses a human NK cell line NKL cell but is silent on the cell being a derivative effector cell obtained from differentiating an iPSC. Li is cited to make obvious a derivative effector cell (e.g., a derivative NK cell) obtained from differentiating an iPSC (see above). Thus, Applicant’s argument regarding Zhuang’s teaching of scFv-based designs or advantages does not negate substituting Zhuang’s NK cell line cell with Li’s hiPSC-derived NK cells.
Claims 1, 3, 7, 12-13, 15-21, 23, 24 and 35 stand rejected under 35 U.S.C. 103 as being unpatentable over Zhuang et al., (Cancer Immunol Res. 2019 April; 7(6): 939-951 and suppl. p. 1-9. Prior art of record) in view of Jochems et al., (Oncotarget. 2016; 7(52): 86359-86373. Prior art of record) and Jing et al (PLoS ONE. 2015; 10(3): e0121788, p. 1-14. Prior art of record).
Claims 1, 3, 7, 12-13, 15-21 and 35 are anticipated by Zhuang, thus Zhuang makes obvious instant claims.
With respect to claim 21 directed to a CD16 variant, claim 23 directed to the CD16 variant, and claim 24 directed to the CD16 variant comprising F176V and S197P in ectodomain domain of CD16, however, Zhuang is silent on a CD16 variant comprising F176V and S197P in ectodomain.
Jochems teaches a NK cell is engineered to express an exogenous CD16 variant, a high affinity CD16 V158 FcγRIIIa receptor (see e.g., abstract. Note that this V158 (i.e. F158V) CD16 variant is equivalent to a F176V variant depending on exclusion or inclusion of the signal peptide in the amino acid count). Jochems teaches high affinity NK cells have a higher killing frequency on tumor cells than healthy donor NK cells (p. 86363, left col, last para – right col, para 1, see Fig 6).
Jing teaches a human iPSC is engineered to express an exogenous non-cleavable CD16 variant S197P and is differentiated into an NK cell (p. 4, para 1-2). Jing teaches the engineered mutation in CD16a prevents its down-regulation in NK cells when activated with various stimuli while does not disrupt IgG binding or cell activation by CD16a, indicating that the receptor remains functional (p. 2, para 4, see Figs 3-5).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the NK cell comprising the CD28H CAR for cancer immunotherapy disclosed by Zhuang, by combining an exogenous CD16 variant comprising high affinity F176V and non-cleavable S197P in ectodomain domain as taught by Jochems and Jing with a reasonable expectation of success. Since Jochems teaches high affinity NK cells expressing F176V CD16 variant have a higher killing frequency on tumor cells than healthy donor NK cells (p. 86363, left col, last para-right col, para 1, Fig 6), and since Jing teaches the engineered non-cleavable CD16a prevents its down-regulation in NK cells when activated with various stimuli while remains functional (p. 2, para 4, Figs 3-5), one of ordinary skill in the art would have had a reason to combine the CD16 variant taught by Jochems and Jing in order to obtain NK cells with enhanced tumor killing ability for cancer immunotherapy.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged.
Applicant argues that Jochems and Jing fail to provide the missing teaching. For example, neither Jochems nor Jing disclose any CAR at all, much less a CAR comprising the transmembrane and endodomain combinations presently claimed (Remarks, p. 22-23).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, Zhuang teaches a CAR construct comprising a combination of transmembrane domain and endodomain as presently claimed in claim 1. The only difference between the claims in this section (claims 21 and 23-24) and Zhuang is that Zhuang is silent on a CD16 variant comprising F176V and S197P in ectodomain. Jochems and Jing are cited to make obvious a CD16 variant comprising high affinity F176V and non-cleavable S197P in ectodomain.
Claims 1, 3, 7, 12-13, 15-21 and 32-35 stand rejected under 35 U.S.C. 103 as being unpatentable over Zhuang et al., (Cancer Immunol Res. 2019 April; 7(6): 939-951 and suppl. p. 1-9. Prior art of record) in view of Eyquem et al (Nature. 2017, 543: 113-117. Prior art of record).
Claims 1, 3, 7, 12-13, 15-21 and 35 are anticipated by Zhuang, thus Zhuang makes obvious instant claims.
With respect to claims 32 directed to the cell comprising one exogenous polynucleotides integrated in a selected gene locus, claim 33 directed to the selected gene locus being TCR, and claim 34 directed to the TCR locus being a constant region of TCR alpha, however, Zhuang is silent on targeted integration of the CAR in a selected gene locus of a constant region of TCR alpha.
Eyquem teaches targeting a CAR in the T-cell receptor α constant (TRAC) locus enhances tumor rejection (title, abstract). Eyquem teaches integrating the CAR in the TRAC locus results in uniform CAR expression with enhanced potency and reduced tonic signaling (see e.g., Figs 1-2). Eyquem teaches targeting CARs to the TRAC locus provides a safer therapeutic (by minimizing the risks of insertional oncogenesis and TCR-induced autoimmunity and alloreactivity), a better defined cell product (by yielding constant CAR expression and avoiding position-effect variegation and vector copy number variation) and a more potent effector cell (by reducing constitutive signaling and delaying exhaustion) (p. 117, left col, line 7).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the NK cell comprising the CD28H CAR by random integration for cancer immunotherapy disclosed by Zhuang, by substituting the random integration with targeted integration of the CAR in the TCR alpha constant (TRAC) locus as taught by Eyquem with a reasonable expectation of success. Since Eyquem teaches targeting CARs to the TRAC locus provides a safer therapeutic (by minimizing the risks of insertional oncogenesis and TCR-induced autoimmunity and alloreactivity), a better defined cell product (by yielding constant CAR expression and avoiding position-effect variegation and vector copy number variation) and a more potent effector cell (by reducing constitutive signaling and delaying exhaustion) (p. 117, left col, line 7), one of ordinary skill in the art would have had a reason to make this substitution in order to obtain safer, better defined, and more potent CD28H-CAR-NK cells for cancer immunotherapy.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged.
Applicant argues that Eyquem fails to provide the missing teaching. The lone CAR construct of Eyquem does not have a combination of transmembrane domain and endodomain as presently claimed, and none of the references provide any motivation to use an ectodomain of Eyquem in a construct of Zhuang, nor any basis to predict the results thereof. On the contrary, Zhuang expressly describes the constructs therein as an alternative to scFv-based designs like that of Eyquem, and fails to provide any basis for concluding that advantages attributed to such "more natural" approach would translate in any way to scFv-based approaches (Remarks, p. 23).
Applicant’s arguments have been fully considered but they are not persuasive. As stated supra, Zhuang teaches a CAR construct comprising a combination of transmembrane domain and endodomain as presently claimed in claim 1. The only difference between the claims in this section (claims 32-34) and Zhuang is that Zhuang is silent on targeted integration of the CAR in a selected gene locus of a constant region of TCR alpha. Eyquem is cited to make obvious the targeted integration of a CAR in the gene locus of a constant region of TCR alpha. Thus, Applicant’s argument regarding Zhuang’s teaching of scFv-based designs or advantages does not negate substituting Zhuang’s random integration with targeted integration of the CAR in the TCR alpha constant (TRAC) locus as taught by Eyquem.
Withdrawn Double Patenting Rejections
The prior rejection of claims 1, 3, 7, 13-24, 28-37 and 39 on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of US Patent No. 12,203,098 and over claims 1-16 of US Patent No. 12,122,846 is withdrawn in light of Applicant’s argument filed on 03/11/2026 stating that the subject application should be analyzed under the two-way test, and the rejections fail the "two-way test" for nonstatutory double patenting (Remarks, p. 24-25).
Applicant’s arguments have been fully considered and they are persuasive. Since the CDR sequences in the independent claim of Patents 12,203,098 and 12,122,846 are free of art, the claims of the reference patents are not obvious over the claims of the instant application. Therefore, the prior nonstatutory double patenting rejection over Patents 12,203,098 and 12,122,846 is withdrawn.
Maintained Provisional Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 3, 7, 12-24, 28-37, 39 and 50 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims of US Application No. 17/769,651 in view of Jochems et al., (Oncotarget. 2016; 7(52): 86359-86373. Prior art of record), Jing et al (PLoS ONE. 2015; 10(3): e0121788, p. 1-14. Prior art of record), Eyquem et al (Nature. 2017, 543: 113-117. Prior art of record) and Zhuang et al., (Cancer Immunol Res. 2019 April; 7(6): 939-951 and suppl. p. 1-9. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims of ‘651 recite a CAR comprising a recombinant ectodomain comprising at least one antigen recognition domain, a transmembrane domain and an endodomain comprising at least one signaling domain, and the transmembrane domain-(endodomain) comprising a form from a list including DNAM1-(DNAM1-CS1) (reference claims 1, 7, and 12, see the same form recited in instant claim 1), with the sequences of the endodomains of DNAM1 and CS1 being recited in reference claim 2 and claim 5, and the transmembrane domain sequence of DNAM1 being recited in reference claim 10. The cytoplasmic domain comprises an ITAM (reference claim 3). The antigen recognition domain binds an antigen associated with a disease and is specific to a list of antigens including CD19 (reference claims 13-14). The ectodomain comprises a signal peptide (reference claim 15). The CAR is co-expressed with additional cytokines (reference claim 16. It is noted that the cytokines are therapeutic agents). A derivative effector cells from iPSC differentiation, including a derivative NK cell, comprising the CAR, and a composition comprising the cell and one or more therapeutic agents (reference claims 17-19).
Thus, the copending claims recite a CAR that is identical to the CAR in the instant claims 1, 3, 7 and 13-18, and a derivative effector cell comprising the CAR, and a composition in instant claims 19, 20, 22, 28-31, 35-37.
However, the copending claims are silent on the cell further comprising a CD16 variant having F176V and S197P in ecdodomain in instant claims 21, 23 and 24, nor recite the CAR is integrated in a selected TCR alpha constant gene locus in instant claims 32-34, or the composition further comprises a anti-CD20 antibody in instant claim 39.
Jochems teaches a NK cell is engineered to express an exogenous CD16 variant, a high affinity CD16 V158 FcγRIIIa receptor (see e.g., abstract. Note that this V158 (i.e. F158V) CD16 variant is equivalent to a F176V variant depending on exclusion or inclusion of the signal peptide in the amino acid count). Jochems teaches high affinity NK cells have a higher killing frequency on tumor cells than healthy donor NK cells (p. 86363, left col, last para – right col, para 1, see Fig 6).
Jing teaches a human iPSC is engineered to express an exogenous non-cleavable CD16 variant S197P and is differentiated into an NK cell (p. 4, para 1-2). Jing teaches the engineered mutation in CD16a prevents its down-regulation in NK cells when activated with various stimuli while does not disrupt IgG binding or cell activation by CD16a, indicating that the receptor remains functional (p. 2, para 4, see Figs 3-5).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have recited an exogenous CD16 variant comprising high affinity F176V and non-cleavable S197P in ectodomain domain as taught by Jochems and Jing with a reasonable expectation of success. Since Jochems teaches high affinity NK cells expressing F176V CD16 variant have a higher killing frequency on tumor cells than healthy donor NK cells (p. 86363, left col, last para-right col, para 1, Fig 6), and since Jing teaches the engineered non-cleavable CD16a prevents its down-regulation in NK cells when activated with various stimuli while remains functional (p. 2, para 4, Figs 3-5), one of ordinary skill in the art would have had a reason to combine the CD16 variant taught by Jochems and Jing in order to obtain NK cells with enhanced tumor killing ability for cancer immunotherapy.
Eyquem teaches targeting a CAR in the T-cell receptor α constant (TRAC) locus enhances tumor rejection (title, abstract). Eyquem teaches integrating the CAR in the TRAC locus results in uniform CAR expression with enhanced potency and reduced tonic signaling (see e.g., Figs 1-2). Eyquem teaches targeting CARs to the TRAC locus provides a safer therapeutic (by minimizing the risks of insertional oncogenesis and TCR-induced autoimmunity and alloreactivity), a better defined cell product (by yielding constant CAR expression and avoiding position-effect variegation and vector copy number variation) and a more potent effector cell (by reducing constitutive signaling and delaying exhaustion) (p. 117, left col, line 7).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have recited targeted integration of the CAR in the TCR alpha constant (TRAC) locus of the immune cell as taught by Eyquem with a reasonable expectation of success. Since Eyquem teaches targeting CARs to the TRAC locus provides a safer therapeutic (by minimizing the risks of insertional oncogenesis and TCR-induced autoimmunity and alloreactivity), a better defined cell product (by yielding constant CAR expression and avoiding position-effect variegation and vector copy number variation) and a more potent effector cell (by reducing constitutive signaling and delaying exhaustion) (p. 117, left col, line 7), one of ordinary skill in the art would have had a reason to recite targeted integration in order to obtain safer, better defined, and more potent CAR-engineered immune cells for cancer immunotherapy.
Zhuang teaches a CAR-engineered NK cell for cancer immunotherapy (e.g. abstract). Zhuang teaches to treat some tumor cells that co-express the tumor antigen CD20 (such as Daudi and 221 cells), an anti-CD20 antibody (rituximab) is used to induce NK cell-mediated ADCC resulting in lysis of those tumor cells (p. 943, right col, para 1 and also Fig 4D and 4E).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have recited an anti-CD20 antibody as the additional therapeutic agents in the composition as suggested by Zhuang with a reasonable expectation of success. Since Zhuang teaches some tumor cells co-express the tumor antigen CD20, and an anti-CD20 antibody (rituximab) is used to induce NK cell-mediated ADCC resulting in lysis of those tumor cells (p. 943, right col, para 1 and also Fig 4D and 4E), one of ordinary skill in the art would have had a reason to combine an anti-CD20 antibody as a combinatory therapeutic agent with the CAR-NK cells in order to induce ADCC to tumor cells co-expressing CD20.
Since the instant application claims are obvious over cited application claims, in view of Jochems, Jing, Eyquem and Zhuang, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged.
Applicant requests that the provisional double patenting rejections be held in abeyance until allowable subject matter is identified. This is not found persuasive therefore the rejections are maintained. Applicant is reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. Such a response is required even when the nonstatutory double patenting rejection is provisional. See MPEP 804.I.B.1.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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