DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/21/2025 has been entered.
Applicant’s amendments to the claims filed on November 21, 2025 have been received and entered. Claims 1, 3-4, 8-12, 16-18 have been amended, whereas 2, 5-7, 13-15 have been canceled. Claims 1, 3-4, 8-12, 16-21 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 1-12 (group I) in the reply filed on August 1, 2024 was acknowledged. Upon further consideration restriction requirement between invention of group I and II is hereby withdrawn and claims 13-17 (group II) were rejoined with the elected invention of claims 1-12 of group I.
Claims 18-21 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 1, 2024.
Claims 1, 3-4, 8-12, 16 and 17 are under consideration.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 1-6, 8-17 remain rejected under 35 U.S.C. 103 as being unpatentable over Davila (WO2019010383, dated 1/10/2019) as evidenced by Sadelain (USP 7446190, 11/4/2008) and Pagan et al (The Journal of Immunology, 2012, 189: 2909–2917). Applicant’s amendments to the base claim 1, obviates the basis of the rejection. the previous rejections of claims 1-6, 8-17 are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below:
New-Claim Rejections - 35 USC § 103- necessitated by amendments
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3-4, 8-12, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Davila (WO2019010383, dated 1/10/2019, art of record) as evidenced by Sadelain (USP 7446190, 11/4/2008, art of record ), Guo (J Immunol. 2008 August 15; 181(4): 2285–2291) as evidenced by Okkenhaug et al (Nature Immunology, 2001, 2(4), 325-332) and Semple et al (Blood, 2011, 17(11):3096-3103).
With respect to claim 1, Davila teaches an immune effector cells comprising an chimeric antigen receptor (CAR) polypeptide, comprising a ligand binding domain, a transmembrane domain, an intracellular signaling domain, and a co-stimulatory signaling region, wherein the co-stimulatory signaling region comprises a mutated form of a cytoplasmic domain of CD28 that enhances CAR-T cell fusion , wherein the co-stimulatory signaling region comprises a cytoplasmic domain of CD28 having a null mutation in the YMNM subdomain and wherein the co-stimulatory signaling region comprises a cytoplasmic domain of CD28 having a null mutation in the PRRP subdomain. It is noted that Davila teaches that CD28 having a null mutation in the tyrosine amino acid of the YMNM subdomain, and a null mutation in the proline amino acids of the PRRP subdomain (see Mut 6, Fig. 2A claims 1-3, ‘383). Davila teaches that mutated form of the cytoplasmic domain of CD28 reduces CAR-T cell exhaustion (See claim 7 of ‘383).
Regarding claim 4, wherein the null mutations in the proline amino acids of the PRRP subdomain are alanine for proline substitutions (see fig.2A, Mut 6).
With respect to claim 10, Davila teaches that the CAR polypeptide is defined by the formula: SP- TAA-HG-TM- CSR-ISD; or SP- TAA - HG-TM-ISD-CSR, wherein "SP" represents a signal peptide, wherein "TAA" represents a tumor associated antigen-binding region, wherein "HG" represents and optional hinge domain, wherein "TM" represents a transmembrane domain, wherein "CSR" represents the co-stimulatory signaling region, wherein "ISD" represents an intracellular signaling domain, and wherein "-" represents a bivalent linker (see claim 5 of ‘383).
Regarding claim 11, Davila teaches that the intracellular signaling domain comprises a CD3 zeta (CD3z) signaling domain (see claim 6 of ‘383).
With respect to claim 12, Davila teaches that mutated form of the cytoplasmic domain of CD28 reduces CAR-T cell exhaustion (See claim 7 of ‘383).
Regarding claims 16-17, Davila teaches that the cell is selected from the group consisting of an abT cell, gdT cell, a Natural Killer (NK) cells, a Natural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), a cytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), a lymphokine activated killer (LAK) cell, a regulatory T cell, or any combination thereof (see claim 10-11 of ‘383).
With respect to claim 17, Davila teaches that the cell exhibits an anti-tumor immunity when the antigen binding domain of the CAR binds to TAA (see claim 12 of ‘383). Sadelain teaches sequence of co-stimulatory signaling region comprises a cytoplasmic domain of CD28 as set forth in SEQ ID NO: 9 (RSKRSRLLHSDYMNMTPRRPGPTRKH YQPYAPPRDFAAYRS) (see the highlighted domain sequences. While Davila teaches that CD28 having a null mutation in the tyrosine amino acid of the YMNM subdomain, and a null mutation in the proline amino acids of the PRRP subdomain (see Mut 1, Mut 6, Fig. 2A claims 1-3, ‘383) but differs from claimed invention by not disclosing mutation in the tyrosine amino acid of the YMNM subdomain is a phenylalanine for tyrosine substitution and alanine for proline in PRRP motif.
Before the effective filing date of instant application, Guo teaches intracellular domain of CD28 contains multiple motifs that can recruit and activate many kinases, including PI3K, IL-2-inducible T cell kinase (Itk), and Lck, which are responsible for various functions of CD28 receptor. Guo teaches CD28 with a mutation in Y170F that abrogated PI3K binding (CD28 –170); CD28 with mutations in P175A and P178A (N-terminal proline residues) that abrogated Itk binding (CD28-NP) (see page 2289, col. 1, para. 2) (limitation of claim 3-4, 8-9). Guo did not specifically report CAR-T cells design but reported selectively mutating CD28 motif to optimize activation, persistence of T cells. This is further supported by Okkenhaug who reported Y170F mutated form of CD28 prevents the induction of anergy and promotes T cell proliferation, interleukin 2 secretion (see abstract, page 327, col. 2, last para to page 328, col. 1, para. 2), while Semple reported that CD28 with a mutation in Y170F abrogates PI3K binding (CD28-PI3K); and CD28 with mutations in P175A and P178A that abrogate Itk binding (CD28-Itk) (see page 3098, col. 2, last para).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the CAR comprising s a cytoplasmic domain of CD28 having a null mutation in the tyrosine amino acid of the YMNM subdomain and proline substitution in PRRP subdomain as disclosed Davila by substituting tyrosine with phenylalanine in YMNM subdomain and proline with alanine in PRRP as suggested by Guo and Semple, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art recognized that co-stimulatory signaling region having a mutated form of a cytoplasmic domain of CD28 enhances CAR• T cell function, by reducing CAR• T cell exhaustion (see Davila abstract), while Okkenhaug reported mutated form of CD28 prevents the induction of T cells anergy (see abstract). One of skill in the art would have been expected to have a reasonable expectation of success in studying the modifications in YMNM and PRRP subdomain of CD28 as it could serve as refinements in CAR design by optimizing the mutation in YMNM and PRRP subdomain to improve response rates, reduce relapse relates to improve survival for patients because prior art recognized that any and all null mutations are contemplated and one of ordinary skill in the art would have reasonably predicted that any other conservative amino acids such as one disclosed in Guo, Okkenhaug and Semple could be used to inactivate the YMNM and PRRP subdomain of CD28. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. Uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Response to arguments
To the extent that Applicants’ arguments are pertinent to the new rejections, they are addressed as follows:
Applicant disagree with the rejection arguing Davila did not teach this specific mutation or provide a reasonable expectation for its success. Specifically, Davila did not teach or suggest which residues within the YMNM and PRRP are sufficient to mutate in order to get the benefits of the mutant. Applicant further assert that Guo did not teach or suggest that mutating any of these targets in a CAR would enhance CAR-T cell function, e.g. reduce exhaustion. Applicants’ arguments have been fully considered, but are not found persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicants have further engaged in selective reading of the teachings of Guo to formulate the grounds for teaching away. It should be noted that the ultimate goal of mutating specific residue within the YMNM and PRRP subdomain of CD28 to reduce CAR-T cell exhaustion. As previously indicated, Davila et al. in describing CART cells with a CD28 co-stimulatory domain reported that they are prone to low-level tonic signaling and an exhaustion phenotype and mutating certain CD28 subdomains does not eliminate CAR signaling or cytokine production (see page 2 lines 5-7). Davila teaches CARs comprise a costimulatory signaling region comprising a mutated form of the cytoplasmic domain of CD28 that enhances CAR-T cell function (see page 2, line 10-12). Davila teaches the CD28 domain includes 3 intracellular subdomains (YMNM (SEQ ID N0:1), PRRP (SEQ ID N0:2) regulate signaling pathways post TCR-stimulation. It is further disclosed that CAR comprises mutation or one or more of these subdomains that enhances CAR-T cell function, e.g. reducing CAR-T cell exhaustion. A variety of substitution mutation in these CD28 subdomains are are well-known in the art, including YMNM and PRRP as evident from the teaching of Guo. Guo et al. cure the deficiency in Davila by disclosing specific mutation Y170F that abrogated PI3K binding (CD28 –170); and P175A and P178A (N-terminal proline residues) in PRRP subdomain that abrogated Itk binding (CD28-NP) (see page 2289, col. 1, para. 2). While Guo did not specifically report CAR-T cells design but reported selectively mutating CD28 motif to optimize activation, persistence of T cells. To the extent that Guo describe the specific mutation in CD28 subdomain, the rejection is applicable to the instant case. Applicants' selective reading of Guo. ignores the teachings of the primary reference of Davila. There is no requirement for Guo to teach that which is clearly taught by Davila. A person of skill in the art would be motivated to optimize the substitution mutation is CD28 subdomain as suggested in Davila using specific mutation disclosed in Guo, Okkenhaug and Semple, because this would allow for a mutated cytoplasmic domain of CD28 that enhances CAR-T cell function, with a reasonable expectation of success.
New-Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-4, 8, 10-12, 16 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163 states “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). "A representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
The claims embrace a chimeric antigen receptor (CAR)-T cell with reduced cell exhaustion, comprising an immune effector cell expressing a CAR polypeptide, wherein the CAR polypeptide comprising a ligand binding domain, a transmembrane domain, an intracellular signaling domain, and a co-stimulatory signaling region with a mutated CD28 domain comprises the amino acid sequence RSKRSRLLHSDX1 MNMTX2RRX3GPTRKHYQPYAPPRDF AAYRS, wherein X1 is not Y, and wherein X2 and X3 are not P (SEQ ID NO:4). Dependent claims limit the X1 is phenylalanine and X2 is alanine and X3 is alanine (claims 3-4). Claim 8 limits the CAR-T cells, wherein the X1, X2, and X3 are conservative substitutions.
The specification teaches a chimeric antigen receptor (CAR) polypeptide that can be used with adoptive cell transfer to target and kill cancers. The disclosed CARs comprise a costimulatory signaling region comprising a mutated form of the cytoplasmic domain of CD28 that enhances CAR-T cell function. In some embodiments, the mutated form reduces CAR-T cell exhaustion. The CD28 domain includes 3 intracellular subdomains (cd28 and (SEQ ID NO:3)) that regulate signaling pathways post TCR-stimulation (see page 2 of the specification). Example 3 discloses the CD28 domain that includes 3 intracellular subdomains (YMNM (SEQ ID NO:1), PRRP (SEQ ID NO:2), and PYAP (SEQ ID NO:3)) that regulate signaling pathways post TCR-stimulation. The hmut06 mutant produced had mutations of the tyrosine and proline residues in the YMNM and PRRP subdomains that enhances CAR-T cell function, e.g. reducing CAR-T cell exhaustion. In particular, the hmut06 sequence had the amino acid sequence RSKRSRLLHSDFMNMTARRAGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO:5). Each CAR used the human FMC63 anti-CD19 scFv. Consistent with mouse data, human (h)mut06 had no appreciable effect on cell viability or proliferation (Fig. 14A). Hmut06 CAR T cells had significantly decreased expression of LAG3 and TIM3 compared with those with h1928z (Fig. 14C). Hmut06 CAR T cells were better able to control lymphoma growth in NSG mice compared with CAR T cells with h1928z (Fig. 15). Thus, in view of foregoing it is apparent that guidance provided in the specification is limited to the use of mutated CD28 domain comprises the amino acid set forth in SEQ ID NO: 5.
The genus of immune effector cell ( abT cell, gd T cell, a Natural Killer (NK) cells, a Natural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), a mast cells, a cytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), a lymphokine activated killer (LAK) cell, .a regulatory T cell) expressing a CAR polypeptide, wherein the CAR polypeptide comprising a mutated CD28 domain comprising the amino acid sequence RSKRSRLLHSDX1 MNMTX2RRX3 GPTRKHYQPYAPPRDFAAYRS, wherein X1 is not Y, and wherein X2 and X3 are not P (SEQ ID NO:4), wherein X1, X2 and/or X3 are any non-conservative substitution, other than the sequence consisting of SEQ ID NO: 5 in T cells encompassed within the genus of mutated CD28 domain have not been disclosed. The specification has not disclosed any other substitution at X1, X2 and/or X3 of mutated CD28 domain in genus of immune effector cells. The specification does not provide a representative number of species of mutated CD28 in any other immune effector cells (mast cell or B cell). The possible structural variations are limitless to domain comprising any conservative and/or non-conservative substitution of amino acid at positions X1, X2 and/or X3 of the CD28. In the instant case, substituting Y in YMNM subdomain of CD28 with F that is structurally similar to tyrosine and preserve the motif structure but will prevent tyrosine phosphorylation, however, substituting Y with any other genus of amino acid that includes non-conservative amino acid substitution would disrupt the motif and thereby affect the folding and interaction with signaling protein . This random substitution in plurality of different immunocyte may abolish the ability of subdomain to bind SH2 domain protein. In this context, Harada teaches that a Y189F mutant of CD28 disrupts binding by PI3K, and the YMNM deletion mutant both demonstrate reduced but significant activity for IL-2 promoter activation. In contrast, the N191A mutant, which retains PI3K binding ability, resulted in a complete abrogation of activity (see abstract, Harada et al The Journal of Biological Chemistry, 2001, 276, 12, 9003-9008). The claims lack written description because there is no disclosure of a correlation between function and structure of the different species of mutated CD28 domain in different immune effector cells beyond those mutated CD28 as set forth in SEQ ID NO: 5 showing contemplated biological activity in T- cells that are exemplified in the specification. The specification lacks sufficient number of species to reflect this variance in the genus showing contemplated biological activity. While having written description of a mutated CD28 consisting of the amino acid sequence as set forth in SEQ ID NO: 5, identified in the specification and examples, the specification does not provide sufficient descriptive support for the myriads of other immune effector cells comprising the mutated CD28 sequences embraced by the breadth of the claims. In view of the above considerations one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by member of the genus of mutated CD28 domain sequence, other than the amino acid sequence as set forth in SEQ ID NO: 5. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
New-Claim Rejections - 35 USC § 112- necessitated by amendments
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, 3-4, 8-12, 16 and 17 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 is vague and indefinite to the extent the claim recites a chimeric antigen receptor T cell comprising an immune effector cell expressing a CAR polypeptide. The T cell is species of a broader immune effector cells and therefore a narrower T-cells cannot comprise a broader immune effector cell that includes NK cell or a B cell. In fact, the specification teaches CAR-T cells are created using ab T cells, however gd T cells may also be used. In some embodiments, the described CAR constructs, domains, and engineered features used to generate CAR-T cells could similarly be employed in the generation of other types of CAR-expressing immune cells including NK (natural killer) cells, B cells, mast cells, myeloid-derived phagocytes, and NKT cells (see page 46, lines 3-8). There appears to be more than one meaning for a term in view of the specification, it is incumbent upon applicant to it make clear on record which meaning is being relied upon to claim the invention. Therefore, the metes and bounds of the phrase CAR-T cells comprising an immune effector cell could not be ascertained. Claims 3-4, 8-12, 16 and 17 are included in the rejection because they directly or indirectly depend from the rejected base claim. Recitation of a chimeric antigen receptor (CAR)- immune effector cell comprising a nucleic acid encoding a CAR polypeptide comprising a ligand binding domain, a transmembrane domain, an intracellular signaling domain, and a co-stimulatory signaling region comprising a mutated CD28 domain would obviate the basis of the rejection. Appropriate correction and/or clarification on record is required.
Withdrawn- Double Patenting
Claims 1, 2-4, 8-12, 16 and 17 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No.18003922. Applicant’s argument that pending claim in 922 do not contain CD28 mutant as claimed in the instant application is found persuasive. Therefore, previous rejection is hereby withdrawn. Claims 11-6, 8-17 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10-14, 96-105 of copending Application No. 18/361,056. Applicant’s argument is found persuasive; therefore, previous rejection is hereby withdrawn.
Claims 1, 2-4, 8-12, 16 and 17 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of copending Application No. 18262287. Applicants’ terminal disclaimer dated November 20, 2025, the previous rejections are rendered moot and hereby withdrawn.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANOOP K SINGH/ Primary Examiner, Art Unit 1632