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 .
Applicant’s amendments to the claims filed on April 14, 2026 have been received and entered. Claims 1, and 16 have been amended, whereas 2-9, 13-15 have been canceled. Claims 1, 10-12, 16-20 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 Upon further consideration restriction requirement between invention of group I and II is hereby withdrawn and claims 13-17 (group II) were rejoined with the elected invention of claims 1-12 of group I.
Claims 18-21 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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, 10-12, 16 and 17 are under consideration.
Maintained -Claim Rejections - 35 USC § 103- in modified form
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, 10-12, 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 a chimeric antigen receptor (CAR) T cell comprising 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), 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
Applicant disagree with the rejection arguing Guo evaluated which of the kinases PI3K, IL-2-inducible T cell kinase (ltk), and Lck, are responsible for CD28 in Treg differentiation by mutating their respective targets (e.g. Y170, P175, P178, P187, and P190). Applicant continue to argue that these mutants, Guo further demonstrated that recruitment and activation of Lck, not PI3K or Itk, is accountable for CD28 function in iTreg generation. Office has not shown that CD28 functions in CAR-T cell activation and exhaustion by the same mechanism as Treg differentiation. These are very different cells with different activities. Moreover, CAR polypeptides are chimeric proteins with their own unique properties. Even if, arguendo, PI3K and Itk binding are involved in CD28 activation in CAR-T cells, there is no reason for one of ordinary skill in the art to presume that this binding is both necessary and sufficient. 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. It is in this context, the primary art of 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 that the mutant CD28 co-stimulatory domains comprise mutations that perturb either a single or multiple kinase binding domains (page 42-43). Davila teaches that the CD28 co-stimulatory domain used in CART cells is from the cytoplasmic tail of CD28, which has no intrinsic enzymatic activity but contains subdomains or motifs that regulate T cell signaling (see example 1, page 42, lines 15-page 43). The three-kinase binding domain that are the targets of null mutations includes YMNM, PRRP, and PYAP (page 3 lines 29-34 and figure 2a). It is further disclosed that CAR comprises mutation in one or more of these subdomains that enhances CAR-T cell function, e.g. reducing CAR-T cell exhaustion. In view of foregoing, it is apparent that Davila explicitly teaches CD28 functions in CAR-T cell activation and exhaustion. Davila exemplified an anti-CD19 CAR T cell comprising a CD28 double null mutant, null YMNM and null PRRP motifs that performed better than a comparable CAR T cell population comprising the wild-type CD28 cytoplasmic domain (page 44 and figure 10).
In view of foregoing, it is apparent that Davila alone shows that by disrupting two out of three kinase binding domains within the cytoplasmic tail of the CD28 co-stimulatory domain, in the context of a CAR element, one is able to produce CAR T cells with enhanced in vivo efficacy. Davila contemplated CAR comprises mutation of one or more of these subdomains that enhances CAR-T cell function, e.g. reducing CAR-T cell exhaustion (see page 2, lines 15-18). Thus, Davila contemplated a finite number of mutations of one or more of these subdomains that would enhances CAR-T cell function.
A variety of substitution mutation in these CD28 subdomains are well-known in the art, including YMNM and PRRP. 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. However, prior art recognized that the Y170F mutant of CD28 that cannot bind PI3K, still drives T cell activation (see Guo, and Andres Digestive Disease Week Abstracts and Itinerary Planner, (2003) Vol. 2003, pp. Abstract No. S1104, cited as evidence without relying on the rejection).
To the extent that Guo describe the specific mutation in CD28 subdomain, the rejection is applicable to the instant case. Applicants' selective reading of Davila ignores the teachings of the Guo. It is relevant to note that Guo cites Tai et al who teaches systematic mutation of the three kinase binding domains found within the cytosolic tail of CD28 to identify the effects that each motif has on Treg generation. It is disclosed that the PYAP motif is essential for Treg generation and Lck binding (figure 2 in Tai) (see page 2289, col. 1, to col. 2 and 2290, col. ,1 para. 2) The null mutations used to perform this experiment were conservative mutations, relative to those taught by Davila (figure 2 of Tai). It would have been obvious to one skilled in the art to combine the teachings of use a mutated CD28 cytosolic tail cells taught by Davila in view of Guo as evidenced by Tai (cited in Guo as reference 7). One of ordinary skill in the art at the time of filing would have been motivated to incorporate the mutated CD28 domain, with the known advantage of enhanced survival duration and reduced exhaustion, as taught by Davila. There is no requirement for Guo to teach that which is clearly taught by Davila. Additionaly, applicant should note that “Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976)”. To the extent, Davila contemplated a finite number of mutations of one or more of these subdomains with known conservative substitution as disclosed in Guo that would enhances CAR-T cell function, it is applicable to the rejection. Absent evidence of any unexpected and/or superior results, 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 to use the conservative kinase binding motif mutations due to the decreased possibility of unintended interactions or structural perturbations that would have resulted from non-conservative substitutions resulting in enhanced CAR-T cell function, with a reasonable expectation of success.
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.
.Withdrawn -Claim Rejections - 35 USC § 112
Claims 1, 3-4, 8, 10-12, 16 and 17 were 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. In view of Applicants’ amendment of base claims limiting the scope of the mutated CD28 to SEQ ID NO: 5, the previous rejection is rendered moot and hereby withdrawn.
Withdrawn -Claim Rejections - 35 USC § 112
Claims 1, 3-4, 8-12, 16 and 17 were 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. Applicant’s amendments to the base claim obviates the basis of the rejection. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Tai et al (Nat Immunol. 2005 Feb;6(2):152-62 , IDS) systematically mutate the three kinase binding domains found within the cytosolic tail of CD28 to identify the effects that each motif has on Treg generation. (figure 2). The null mutations used to perform this experiment were conservative mutations, relative to those taught by Davila
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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