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 on 05/04/2026, Applicant has amended claims 1-3, 5, 12, 14 and 17-19, newly canceled claim 9, and added new claim 50.
Claim Status
Claims 1-8, 10, 12-19, 36 and 50 are pending.
Claim 6 has been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim.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 09/29/2025.
Claims 1-5, 7-8, 10, 12-19, 36 and 50 are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/04/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Withdrawn Claim Objections
The prior objection to claims 1, 12 and 14 because of minor informalities is withdrawn in light of Applicant’s amendment to the claims.
New Claim Objections
Claim 14 is objected to because of the following informalities:
Claim 14, line 4 from bottom, recites the phrase “oncofetal antigen (h5T4)”, which seems to refer to human 5T4 oncofetal antigen. If so, it is recommended to change to “oncofetal antigen h5T4”, i.e., to remove the parentheses.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112(b)
The prior rejection of claims 1-5, 7-10, 12-16, 19 and 36 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s cancellation of claim 9 and removal of claim 2c, and removal of the subjective term in claim 1.
Withdrawn Claim Rejections - 35 USC § 112(d)
The prior rejection of claims 2-3 and 5 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn in light of Applicant’s amendment to the claims to remove the molecules not recited in claim 1.
New 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 1-5, 7-8, 10, 12-19, 36 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) in view of Li et al., (Cell Stem Cell. 2018 Aug; 23: 181-192. Cited in IDS 03/18/2024).
It is noted that the 103 rejection in the prior Office action mailed on 01/16/2026 is maintained. The following rejection is edited to include the discussion on the new limitation “recombinant” in claim 1 and is edited to address the amendments to claims 2-3 and 17-18. The new claim 50 is rejected as follows.
With respect to claim 1, Zhuang teaches a CD28H chimeric antigen receptor (CD28H-CAR) comprising 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.) to activate 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 (e.g., 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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In regard to the CAR comprising the transmembrane domain and endodomain (TM-(endodomain)) in the form of CD28H-(CD28H-2B4-CD3ζ), 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).
However, Zhuang is silent on the endodomain comprising a 2B4 signaling domain linked to the 5’ end of the CD3ζ signaling domain.
Nevertheless, Zhuang tests NK-cell degranulation induced by CD28H alone and CD28H coengaged with other receptors using the redirected cytotoxicity assay and teaches that strong NK-cell degranulation occurs only after coengagement of CD28H with either 2B4 or NKp46 (p. 942, last para “CD28H synergizes with 2B4 and NKp46” – p. 943, para 1, also see Fig. 2A and B).
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Li tests different constructs of CARs in NK cells (see Table 1) and teaches CARs containing the 2B4 co-stimulatory domain and the CD3ζ signaling domain mediate strong antigen-specific NK cell signaling (e.g., abstract and Fig 2B CAR4(meso) comprising a 2B4-CD3ζ endodomain). Specifically, Li compares CAR9 comprising CD137-2B4-CD3ζ endodomain to CAR5 comprising CD137-CD3ζ endodomain, with the only difference being a 2B4 signaling domain linked to the 5’ end of the CD3ζ signaling domain (compare CAR9 to CAR5 in Table 1). The result shows the CAR9 with the 2B4 signaling domain has significantly greater cytotoxicity to tumor cells than the CAR5 without the 2B4 signaling domain (see Fig 1C and 1E to compare the CAR9 (purple line) to the CAR5 (brown line) and see Fig 1F and 1G for the bar graphs, modified and attached for clarity). Thus, Li teaches a NK-CAR comprising an endodomain comprising the 2B4 co-stimulatory domain linked to the 5’ end of the CD3ζ signaling domain mediates strong antigen-specific NK cell signaling (e.g., abstract), related to the endodomain recited in claim 1.
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 chimeric antigen receptor comprising an endodomain comprising a CD28H signaling domain linked to a CD3ζ signaling domain disclosed by Zhuang, by combining a 2B4 signaling domain linked to the 5’ end of the CD3ζ signaling domain as suggested by Li with a reasonable expectation of success. Since Zhuang teaches that CD28H synergizes with 2B4 to enhance the cytotoxicity of NK cells (p. 942, last para “CD28H synergizes with 2B4 and NKp46” – p. 943, para 1, also see Fig. 2A and B), and since Li teaches an endodomain comprising the 2B4 co-stimulatory domain linked to the 5’ end of the CD3ζ signaling domain mediates strong antigen-specific NK cell signaling (e.g., abstract and Fig 1C, 1E, 1F and 1G), one of ordinary skill in the art would have had a reason to combine a 2B4 signaling domain linked to the 5’ end of the CD3ζ signaling domain to obtain a CD28H CAR comprising a CD28H transmembrane domain and an endodomain comprising three signaling domains (i.e., CD28H TM-(CD28H-2B4-CD3ζ)) in order to take advantage of the synergistic effect between CD28H and 2B4 to mediate stronger antigen-specific NK cell signaling.
With respect to amended claim 2 directed to the signaling domain comprising an amino acid sequence that has at least about 85% identity to the cytoplasmic domain of CD28H represented by SEQ ID NO: 26, Zhuang teaches the amino acid sequence of the CD28H-TCRζ CAR comprising the cytoplasmic domains of CD28H and CD3ζ (see Supple. Fig 7A in Supple. p. 9), in which amino acids 172-282 directed to the CD28H cytoplasmic domain is 100% identical to instant SEQ ID NO: 26 (attached below).
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With respect to claim 3 directed to the cytoplasmic domain comprising an ITAM, the instant specification discloses that “all CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain” ([000122]). As stated supra, Zhuang teaches the endodomain comprises the cytoplasmic domains of CD28H and CD3ζ, thus Zhuang’s cytoplasmic domains comprise an ITAM.
With respect to claim 4 directed to the endodomain comprising a first, a second and a third signaling domains that are different, as discussed above, Zhuang, in view of Li, suggests an endodomain comprising three signaling domains (i.e., CD28H-2B4-CD3ζ) that are different.
With respect to claim 5 directed to the second or the third signaling domain comprising an amino acid sequence that has at least about 85% identity to the cytoplasmic domain of CD28H represented by SEQ ID NO: 26, as stated supra, Zhuang teaches the amino acid sequence of the CD28H-TCRζ CAR comprising the cytoplasmic domains of CD28H and CD3ζ (see Supple. Fig 7A in Supple. p. 9), in which amino acids 172-282 directed to the CD28H cytoplasmic domain is 100% identical to instant SEQ ID NO: 26 (attached above).
With respect to claim 7 directed to the endodomain comprising two different signaling domains comprising fused cytoplasmic domains in the form of CD28H-2B4, as discussed above, Zhuang, in view of Li, suggests an endodomain (i.e., CD28H-2B4-CD3ζ) that comprises two different signaling domains comprising fused cytoplasmic domains of CD28H-2B4.
With respect to claim 8 directed to the endodomain comprising three different signaling domains comprising fused cytoplasmic domains in the form of CD28H-2B4-CD3ζ, as discussed above, Zhuang, in view of Li, suggests an endodomain comprising three different signaling domains comprising fused cytoplasmic domains in the form of CD28H-2B4-CD3ζ (see above).
With respect to claim 10 directed to the transmembrane domain comprising an amino acid sequence that has at least about 85% identity to a transmembrane region of CD28H represented by SEQ ID NO: 6, as stated supra, Zhuang teaches the amino acid sequence of the CD28H-TCRζ CAR comprising the transmembrane region of CD28H (see Supple. Fig 7A in Supple. p. 9), in which amino acids 151-171 directed to the CD28H transmembrane region is 100% identical to instant SEQ ID NO: 6 (attached below).
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With respect to claim 12 directed to the CAR comprising the transmembrane domain and the endodomain (TM-(endodomain)) in the form of CD28H-(CD28H-2B4-CD3ζ), as discussed above, Zhuang, in view of Li, suggests a CAR comprising a CD28H transmembrane domain and an endodomain comprising three signaling domains CD28H-2B4-CD3ζ (see discussion with respect to claim 1).
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 14 directed to the antigen recognition domain being specific to CD19 or mesothelin, however, Zhuang is silent on the CAR having an antigen recognition domain specific to CD19 or mesothelin.
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 (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.).
Li teaches a NK-CAR comprising a scFv specific for mesothelin (see e.g., Table 1 and Fig 1) and teaches anti-CD19-CAR-expressing NK cells are being developed for clinical trials (e,g, p. 190, left col, para 2).
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 suggested by Zhuang in view of Li, by substituting the antigen recognition domain with a single-chain antibody specific for tumor antigens such as CD19 and mesothelin as suggested by Zhuang and Li 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 (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.), and since Li reduces to practice an anti-mesothelin NK CAR (e.g., Table 1) and teaches anti-CD19-CAR-expressing NK cells are being developed for clinical trials (e,g, p. 190, left col, para 2), 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 or mesothelin.
With respect to claim 15 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 acids 1-22 is the CD28H signal peptide.
With respect to claim 16 directed to the CAR being comprised in a bi-cistronic construct co-expressing an exogenous cytokine, this is examined as the CAR being 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 an ectodomain and a CD28H-(CD28H-2B4-CD3ζ) (transmembrane-(endodomain)) domain in the instant claim, is obvious over the CAR suggested by Zhuang in view of Li, thus the claim is unpatentable even though the prior product was made by a different process (the CAR of Zhuang being encoded by a polynucleotide vector, see p. 940, para “Plasmids”).
With respect to amended claims 17 and 18 directed to the CAR being encoded by a polynucleotide in a derivative effector cell differentiated from an iPSC and the derivative effector cell expressing the CAR, similarly, this limitation is directed to a product-by-process claim. See MPEP § 2113. In the instant case, the claimed product itself, the CAR comprising an ectodomain and a CD28H-(CD28H-2B4-CD3ζ) (transmembrane-(endodomain)) domain in the instant claim, is obvious over the CAR suggested by Zhuang in view of Li, thus the claim is unpatentable even though the prior product was made by a different process (the CAR of Zhuang being encoded by a polynucleotide in a human cell line NKL cell, see p. 940, para “Plasmids”). Nevertheless, Li teaches that an anti-meso NK-CAR, when stably expressed in human iPSCs, enables differentiation of the CAR-expressing iPSCs to derivative CAR-NK cells (i.e., a derivative effector cell) and the derivative effector cell expresses the CAR (see p. 183, last para “Expression and Function of NK-CARs in iPSC-Derived NK Cells” and Fig 3A GFP expression as a marker of CARs).
Claim 19 is directed to a cell being a derivative effector cell obtained from differentiating the iPSC and comprising a polynucleotide encoding at least one CAR of claim 1. Claim 36 is directed to a composition comprising the derivative effector cell of claim 19 and optionally one therapeutic agent. Applicant is reminded that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See MPEP 2111.04 I.
However, Zhuang is silent on the cell being a derivative effector cell obtained from differentiating the iPSC in claim 19 or a composition comprising the derivative effector cell in claim 36.
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 an anti-meso NK-CAR is engineered in human iPSCs and the iPSCs are differentiated into derivative effector cells (derivative NK cells) (see p. 183, last para “Expression and Function of NK-CARs in iPSC-Derived NK Cells”). The iPSC-derived CAR-NK cells (i.e., the derivative immune effector cells) comprise the polynucleotide encoding the CAR and express the CAR (see e.g., Fig 3A GFP expression as a marker of CARs) and demonstrate an antigen-specific increase in cytotoxicity against tumor cells in comparison to control NK cells (p. 184, right col., para 1, see Fig 3B). Thus, Li teaches a derivative effector cell obtained from differentiating the iPSC and comprising the polynucleotide encoding the CAR in claim 19, and teaches a composition for therapeutic use comprising the derivative effector cell in claim 36. Li teaches the derivative immune effector cells can be produced from a standardized iPSC population to provide a homogeneous NK cell population that can be grown to clinical scale (p. 182, left col, para 1).
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 cell expressing the CAR for cancer immunotherapy suggested by Zhuang in view of Li, by substituting the NK cell line cell with a derivative effector NK cell obtained from differentiating the iPSC as suggested by Li with a reasonable expectation of success. Since Li reduces to practice a method of genetically modifying an iPSC with a polynucleotide encoding a CAR and differentiating the iPSC into a derivative effector CAR-NK cell, and teaches a standardized iPSC population can provide a homogeneous NK cell population that can be grown to clinical scale (p. 182, left col, para 1), one of ordinary skill in the art would have had a reason to make this substitution in order to obtain a clinical-scale homogeneous NK cell population from differentiating the iPSCs for therapeutic use.
With respect to the new claim 50, it is noted that these limitations are directed to generic characteristics of chimeric antigen receptors, as evidenced by prior art Li et al. Li demonstrates that an anti-meso NK-CAR, when stably expressed in human iPSCs, enables differentiation of the CAR-expressing iPSCs to derivative CAR-NK cells (p. 183, last para “Expression and Function of NK-CARs in iPSC-Derived NK Cells”), and the iPSC-derived CAR-NK cells demonstrate an antigen-specific increase in cytotoxicity against tumor cells in comparison to control NK cells (p. 184, right col., para 1, see Fig 3B). Accordingly, one of ordinary skill in the art would have immediately understood that the chimeric antigen receptor of Zhuang in view of Li, when comprised in an iPSC, would have promoted differentiation of the iPSC to a derivative NK cell, and the iPSC-derived NK cell expressing the CAR would have had increased cytotoxicity in comparison to a primary NK cell (see e.g., Zhuang p. 945, left col, para “NK cells with a CD28H-CAR kill B7H7+ tumor cells”, and Fig 6B and 6G).
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 05/04/2026 are acknowledged.
Applicant argues that (1) the cited references do not disclose or suggest the presently claimed invention. Specifically, the alleged "CAR" of Zhuang has a "full-length" (native) CD28H extracellular domain, transmembrane domain, and cytoplasmic domain. The cited receptor of Zhuang is only recombinant in the intracellular domain, not the extracellular domain, as presently claimed. Li fails to remedy the deficiencies of Zhuang. None of the CAR constructs of Li comprise a combination of transmembrane domain and endodomain as presently claimed. (Remarks, p. 12). (2) Modifications of Zhuang would render it unsatisfactory for its intended purpose. Zhuang intended to provide “an alternative and more natural way to reprogram NK cells by engineering receptors that are activated by recognition of their ligands on tumor cells”. Any modification to use a recombinant extracellular domain would impermissibly change the express principle of operation of using natural receptor and ligands (Remarks, p. 13, para 1). (3) No basis for reasonably predicting the results of modification. Zhuang and Li do not provide any reason to have expected any advantage. 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. 13-14).
Applicant’s arguments have been fully considered but they are not persuasive.
In response to the argument (1) and also the argument regarding modifications of ectodomain in arguments (2) and (3), all the arguments are based on that Zhuang’s chimeric antigen receptor does not comprise a “recombinant” ectodomain. 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 indeed “recombinant” (while being full-length wild-type). This interpretation of “recombinant” is further evidenced by Zhuang’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.
Furthermore, in response to the argument (1) that Li fails to remedy the deficiencies of Zhuang because none of the CAR constructs of Li comprise a combination of transmembrane domain and endodomain as presently claimed (Remarks, p. 12), Applicant is reminded that a 35 U.S.C. § 103 based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, Zhuang has taught a CAR comprising the cited combination of transmembrane domain and endodomain, i.e., CD28H TM-(CD28H-CD3ζ). The only difference between Zhuang and the instant application is that Zhuang’s endodomain does not have a 2B4 domain on the 5’ of the CD3ζ domain. Li is cited to make obvious a three-element endodomain that comprises a 2B4-CD3ζ, which induces significantly greater cytotoxicity to tumor cells than the CAR without the 2B4 signaling domain (see modified and attached Fig 1C and 1E to compare the CAR9 (purple line) to the CAR5 (brown line) and see Fig 1F and 1G for the bar graphs). Thus, one of ordinary skill in the art would have had a reason to combine a 2B4 domain on the 5’ of the CD3ζ domain to arrive at the claimed combination of transmembrane domain and endodomain, , i.e., CD28H TM-(CD28H-2B4-CD3ζ).
In response to the argument (2) that Zhuang intended to use natural receptor and ligands (Remarks, p. 13, para 1), 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. 13, para 1), 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 contemplated to use CD28H as a component of NK-based CARs for cancer immunotherapy (see e.g., abstract), in combination with scFv-based CARs.
In response to the argument (3) that Zhuang and Li do not provide any reason to have expected any advantage (Remarks, p. 13, last para.), 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. Thus, Zhuang provides a particular advantage, i.e., to overcome signaling by inhibitory receptors. Li teaches a CAR comprising a three-element endodomain that comprises a 2B4-CD3ζ induces significantly greater cytotoxicity to tumor cells than the CAR without the 2B4 signaling domain (see modified and attached Fig 1C, 1E, 1F and 1G), thus provides a particular advantage, i.e., to induce greater cytotoxicity on tumor cells. Therefore, both Zhuang and Li provide particular advantages of the combination of ectodomain, transmembrane domain and endodomain.
Furthermore, 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.), and Li teaches a CAR comprising a three-element endodomain that comprises a 2B4-CD3ζ induces significantly greater cytotoxicity to tumor cells (see above). 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 in view of Li.
Withdrawn Double Patenting Rejections
The prior rejection of claims 1-5, 7-8, 10, 12-19 and 36 on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of US Patent No. 12,203,098 in view of Li et al., (Cell Stem Cell. 2018 Aug; 23: 181-192. Cited in IDS 03/18/2024), and over claims 1-16 of US Patent No. 12,122,846 in view of Li et al., is withdrawn in light of Applicant’s argument filed on 05/04/2026 arguing 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. 15-16).
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, in view of Li, 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 1-5, 7-8, 10, 12-19, 36 and 50 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims of US Application No. 17/766,513. Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims of ‘513 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 selected from a list including CD28H-CD28H-2B4-CD3ζ (reference claim 1). The cytoplasmic domain comprises an ITAM (reference claim 3). The endodomain comprises two different signaling domains comprising fused cytoplasmic domains (reference claim 7). The endodomain comprises three different signaling domains comprising fused cytoplasmic domains (reference claim 8). The chimeric antigen receptor comprises an amino acid sequence that has at least 90% identity to a list of sequences (reference claim 12, thus teaches the amino acid sequences of transmembrane domain and signaling domains in instant application). 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 encoded by a polynucleotide comprised in a bi-cistronic construct co-expressing exogenous cytokines (reference claim 16. It is noted that the cytokines are therapeutic agents). The CAR is expressed in a derivative effector cell differentiated from an iPSC and the derivative effector cell is a derivative NK cell (reference claim 17). The derivative effector cell expresses the CAR and comprises at least one functional feature that is not present in a primary NK cell (reference claim 18). 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 claim 19). A composition for therapeutic use comprising the derivative effector cell of claim 19 and one or more therapeutic agents (reference claim 36).
The difference between the cited application claims and the instant claims lies in the fact that the cited application claims are much more specific. Thus the invention of said claims of the cited application are in effect “species” of the “generic” invention of the instant claim. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Since the instant application claims are anticipated by cited application claims, 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.
Claims 1-5, 7-8, 10, 12-19, 36 and 50 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of US Application No. 18/854,905 in view of Li et al., (Cell Stem Cell. 2018; 23: 181-192. Cited in IDS 03/18/2024). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims in ‘905 recite a CAR comprising an ectodomain comprising an antigen binding domain recognizing a HER2, a transmembrane domain and an endodomain comprising at least one signaling domain, wherein the at least one signaling domain responds specifically to binding of the CAR to a HER2 antigen expressed on a cancer cell thereby generating a cancer antigen specific response (reference claim 1), the endodomain comprises two different signaling domains, and wherein said endodomain domain comprises fused cytoplasmic domains in any form from a list including CD28H-CD3ζ/1XX (it is noted that this CD3ζ/1XX includes either CD3ζ or CD3ζ1XX) (reference claim 4), the transmembrane domain sequence is identical to a list of genes including CD28H (reference claim 5), the transmembrane domain and its immediately linked signaling domain are from a same protein (reference claim 6, thus encompasses the transmembrane domain-(endodomain) in a form of CD28H-(CD28H-CD3ζ). It is noted that CD3ζ signaling domain comprises at least one ITAM). The signaling domains comprise a signaling domain of 2B4, CD28H and CD3ζ, and comprise an amino acid sequence having at least about 85% identity to CD28H cytoplasmic domain represented by SEQ ID NO: 42 (reference claim 3, the sequence is 100% identical to instant SEQ ID NO: 26). The ectodomain comprises a signal peptide and a spacer (reference claim 7). The CAR of claim 1, wherein the cancer antigen specific responses comprise cytolysis and cytokine production (reference claim 13). A polynucleotide and a vector encoding the CAR (reference claims 15-16).
However, application claims are silent on the endodomain comprising a 2B4 signaling domain linked to the 5’ end of the CD3ζ signaling domain.
Li tests different constructs of CARs in NK cells (see Table 1) and teaches CARs containing the 2B4 co-stimulatory domain and the CD3ζ signaling domain mediate strong antigen-specific NK cell signaling (e.g., abstract and Fig 2B CAR4(meso) comprising a 2B4-CD3ζ endodomain). Specifically, Li compares an endodomain comprising three signaling domains (such as CAR9 comprising CD137-2B4-CD3ζ endodomain) to an endodomain comprising two signaling domains (such as CAR5 comprising CD137-CD3ζ endodomain), with the only difference being a 2B4 signaling domain linked to the 5’ end of the CD3ζ signaling domain (compare CAR9 to CAR5 in Table 1). The result shows the CAR9 having the 2B4 signaling domain has significantly greater cytotoxicity to tumor cells than the CAR5 without the 2B4 signaling domain (see Fig 1C and 1E to compare the CAR9 (purple line) to the CAR5 (brown line) and see Fig 1F and 1G for the bar graphs). Thus, Li teaches a NK-CAR comprising an endodomain comprising the 2B4 co-stimulatory domain linked to the 5’ end of the CD3ζ signaling domain mediates strong antigen-specific NK cell signaling (e.g., abstract), related to the endodomain recited in instant claim 1.
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 chimeric antigen receptor comprising the transmembrane domain-(endodomain) in a form of CD28H-(CD28H-CD3ζ) recited in the application claims, by combining a 2B4 signaling domain linked to the 5’ end of the CD3ζ signaling domain as suggested by Li with a reasonable expectation of success. Since Li teaches an endodomain comprising the 2B4 co-stimulatory domain linked to the 5’ end of the CD3ζ signaling domain mediates strong antigen-specific NK cell signaling (e.g., abstract and Fig 1C, 1E, 1F and 1G comparing CAR9 and CAR5), one of ordinary skill in the art would have had a reason to combine a 2B4 signaling domain linked to the 5’ end of the CD3ζ signaling domain to obtain a CAR comprising a CD28H transmembrane domain and an endodomain comprising three signaling domains (i.e., CD28H TM-(CD28H-2B4-CD3ζ)) in order to mediate stronger antigen-specific NK cell signaling.
However, application claims are silent on the CAR being comprised in a derivative immune effector cell obtained from differentiating iPSCs or a composition comprising the derivative immune effector cell.
Li teaches an anti-meso NK-CAR is engineered in human iPSCs and the iPSCs are differentiated into derivative effector cells (derivative NK cells) (see p. 183, last para “Expression and Function of NK-CARs in iPSC-Derived NK Cells”). The iPSC-derived CAR-NK cells (i.e., the derivative immune effector cells) express the CARs (see e.g., Fig 3A GFP expression as a marker of CARs) and demonstrate an antigen-specific increase in cytotoxicity against tumor cells in comparison to control NK cells (p. 184, right col., para 1, see Fig 3B). Thus, Li teaches a derivative effector cell obtained from differentiating the iPSC and comprising the CAR, and teaches a composition for therapeutic use comprising the derivative effector cell. Li teaches the derivative immune effector cells can be produced from a standardized iPSC population to provide a homogeneous NK cell population that can be grown to clinical scale (p. 182, left col, para 1).
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 CAR for cancer treatment recited in application claims, by combining a derivative effector NK cell obtained from differentiating the iPSC genetically engineered with the CAR polynucleotide as suggested by Li with a reasonable expectation of success. Since Li reduces to practice a method of genetically modifying an iPSC with a CAR polynucleotide and differentiating the iPSC into a derivative effector CAR-NK cell, and teaches a standardized iPSC population can provide a homogeneous NK cell population that can be grown to clinical scale (p. 182, left col, para 1), one of ordinary skill in the art would have had a reason to combine the method of Li in order to obtain a clinical-scale homogeneous CAR-NK cell population from differentiating the iPSCs for therapeutic use.
Since the instant application claims are obvious over cited application claims, in view of Li, 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 05/04/2026 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
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