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
Election/Restriction
In the reply filed on 09/29/2025, Applicant elects CD28H-(CD28H-2B4-CD3ζ) as the species of transmembrane domain and endodomain in the form of (TM-(endodomain)), a signaling domain comprising SEQ ID NO: 26 as an amino acid sequence for a signaling domain, and a transmembrane domain comprising SEQ ID NO: 6 as an amino acid sequence for a transmembrane domain.
Applicant’s election with traverse is acknowledged. The traversal is on the ground(s) that (1) the examiner does not identify the special technical feature for each of the groups; (2) with regard to combinations of domains, each alternative shares the general structure and function.
This is not found persuasive because (1) the examiner has identified the special technical feature of each group in the prior Office action mailed on 07/29/2025 (see e.g., p. 2-3 of the action); (2) with regard to each alternative combination of domains shares the general structure and function, one of ordinary skill in the art would have understood that the combinations of transmembrane domain and endodomains can significantly influence the level of CAR expression on the cell surface and each signaling domain in the endodomains provides distinct stimulatory signaling to the host immune cell, thus they do not share the same function. Furthermore, since the signaling domains are derived from different proteins (such as CD28H, 2B4 or CD3ζ), they do not have the same structure.
The requirement is still deemed proper and is therefore made FINAL.
Claim 6 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Status
Claims 1-10, 12-19 and 36 are pending.
Claim 6 is withdrawn.
Claims 1-5, 7-10, 12-19 and 36 are considered on the merits.
Priority
This application is a 371 of PCT/US2020/056387 (filed on 10/19/2020), which is a CIP of PCT/US20/54601 (filed on 10/07/2020), which claims benefit from Application 62/916,468 (filed on 10/17/2019). The priority claim of the instant application has been granted and the earliest benefit date is 10/17/2019 from the application 62/916,468.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/18/2024 and 09/29/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Claim Objections
Claims 1, 12 and 14 are objected to because of the following informalities:
Claim 1, line 8 recites “the iPSC-derived effector cell differentiated from the iPSC”. The limitation “the iPSC-derived” and the limitation “differentiated from the iPSC” are repetitive. It is recommended to delete one of the limitations.
Furthermore, claim 1, last wherein clause recites “wherein the chimeric antigen receptor comprises a transmembrane domain and an endodomain”. Since claim 1 has already recited a transmembrane domain and an endodomain, it is recommended to change the last wherein clause to “wherein the chimeric antigen receptor comprises the transmembrane domain and the endodomain”.
Claim 12, the first wherein clause recites repetitive limitations to those recited in claim 1 last wherein clause. It is recommended to rewrite claim 12 as follows: “The chimeric antigen receptor of claim 1, wherein the chimeric antigen receptor comprises the transmembrane domain and the endodomain (TM-(endodomain)) comprising one of the forms: CD28H-(CD28H-2B4), CD28H-(CD28H-2B4-CD3ζ), DNAM1-(DNAM1-CS1), and NKG2D-(2B4-CS1).
Claim 14 (ii), line 7 recites "EGFRvIII" and "EGFR-VIII". It seems they refer to the same EGFR variant III. If they do, it is suggested to remove one.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 7-10, 12-16, 19 and 36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, line 7 recites the term “desired”, which renders the claim indefinite because it is a subjective term. A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. See MPEP § 2173.05(b). Claims 2-5, 7-10, 12-16, 19 and 36 are rejected as being dependent from claim 1 but not resolving the ambiguity.
Furthermore, claim 2 (c) recites the at least one signaling domain comprises an amino acid sequence that has at least about 85% … identity to the cytoplasmic domain, or a portion thereof, of 2B4, … or a combination thereof. Claim 9 recites the transmembrane domain comprises an amino acid sequence that has at least about 85% … identity to a transmembrane region, or a portion thereof, of CD28H, DNAM1, KIR2DS2, or NKG2D. Since the recited molecules have multiple isoforms or polymorphic variants across multiple species that have distinct amino acid sequences, it is unclear which reference sequences Applicant intends to compare to in order to arrive at the claimed “at least about 85%” identity. A claim may be rendered indefinite by reference to term of an object that is variable (see MPEP 2173.05(b), II). The reference sequences required to determine the claimed amino acid sequences are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For the sake of compact prosecution, the signaling domain in claim 2 (c) is examined as the signaling domain of CD28H comprising SEQ ID NO: 26, and the transmembrane domain in claim 9 is examined as the transmembrane domain of CD28H comprising SEQ ID NO: 6.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-3 and 5 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 (a) (b) and (c), claim 3 and claim 5 all recite signaling domains or signal transducing proteins that have sequence identity to a list of molecules such as 4-1BB. However, claim 1 has recited the signaling domains in one of the forms in the last wherein clause that do not recite some of the molecules, such as 4-1BB recited in claims 2-3 and 5. Therefore, claims 2-3 and 5 fail to further limit the subject matter of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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, 7-10, 12-19 and 36 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) in view of Li et al., (Cell Stem Cell. 2018 Aug; 23: 181-192. Cited in IDS 03/18/2024).
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. Zhuang teaches a human NK cell comprising the CD28H CAR has enhanced killing of tumor cells expressing the target B7H7 (see e.g., p. 945, left col, para “NK cells with a CD28H-CAR kill B7H7+ tumor cells”, and see Fig 6B and 6G).
In regard to the limitations wherein the chimeric antigen receptor, when comprised in an induced pluripotent stem cell (iPSC), promotes differentiation of the iPSC directed to a derivative effector cell, and wherein the iPSC-derived effector cell has increased cytotoxicity in comparison to a primary immune cell, 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 Zhuang’s chimeric antigen receptor, when comprised in an iPSC, would have promoted differentiation of the iPSC directed to a derivative NK cell, and the iPSC-derived NK cell expressing Zhuang’s 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).
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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).
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 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 claim 2 directed to the signal transducing protein comprising CD28H, as stated supra, Zhuang teaches the CD28H CAR comprising full-length CD28H fused to the cytoplasmic domain of T-cell receptor ζ chain (see e.g., Fig 6A), thus teaches the CAR comprises the signal transducing protein of CD28H.
With respect to claim 3 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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In regard to the cytoplasmic domains 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 9 and 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 ton 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 claim 17 directed to the derivative effector cell comprising a derivative immune effector cell, and claim 18 directed to the iPSC-derived immune effector cell expressing the CAR and comprising a functional feature, as stated supra, these limitations are directed to generic characteristics of a CAR as evidenced by Li. Specifically, 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 (i.e., a derivative immune effector cell, see p. 183, last para “Expression and Function of NK-CARs in iPSC-Derived NK Cells”), and the iPSC-derived CAR-NK cells (i.e., the iPSC-derived 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 (i.e., a functional feature not present in a primary NK cell, 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 suggested by Zhuang in view of Li, when comprised in an iPSC, would have promoted differentiation of the iPSC directed to a derivative immune effector cell (a derivative NK cell), and the iPSC-derived immune effector cell (iPSC-NK cell) would have expressed the CAR suggested by Zhuang in view of Li, and would have comprised one functional feature of increased antigen-specific cytotoxicity that is not present in 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).
Claim 19 is directed to a cell being a derivative effector cell obtained from differentiating the iPSC and comprising 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) 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 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 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.
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.
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, 7-10, 12-19 and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of US Patent No. 12,203,098 (‘098) in view of Li et al., (Cell Stem Cell. 2018 Aug; 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.
Patented claims in ‘098 recite a cell, being an immune cell or a derivative effector cell obtained from differentiating an iPSC, comprising 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 (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 molecules 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: 59 (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 cell further comprises a solid tumor targeting backbone comprising an exogenous CD16 or a variant comprising a high affinity non-cleavable CD16 or comprising F176V and S197P in ectodomain domain of CD16 (reference claims 11-12 and 21). The derivative cell comprises a list of cells including a derivative NK cell (reference claim 26). The CAR is inserted at a TCR locus being a constant region of TCR alpha or beta (reference claims 23-24). The NK lineage cell or the T lineage cell has improved infiltration and/or retention at tumor sites (reference claim 27). A composition comprising the cell (reference claim 28). The composition further comprises therapeutic agents comprising a list of agents including an antibody (reference claim 29).
However, patent 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 patent 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.
Since the instant application claims are obvious over cited patent claims in view of Li, said claims are not patentably distinct.
Claims 1-5, 7-10, 12-19 and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of US Patent No. 12,122,846 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.
Patent claims in ‘846 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, patent 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 patent 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, patent 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 patent 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 patent claims, in view of Li, said claims are not patentably distinct.
Provisional Double Patenting Rejections
Claims 1-5, 7-10, 12-19 and 36 are 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 an 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, 7-10, 12-19 and 36 are 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.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631