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
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This Action is in response to the papers filed on April 16, 2026. Claims 1-3, 5-6, 8-9, 14-15, 34, 41-42, 53-54, 65, 69-70, 81-82, 88, 92-94, 107-108, 116 and 121-122 are currently pending of which claims 1, 41, 54, 65, have been amended in Applicant’s amendment filed on April 16, 2026. No claims have been cancelled, and no claims have been added.
Claims 81, 88, 92, 107-108, 116 and 121-122 were withdrawn in the previous Office Action. The restriction requirement between Groups I-VIII is maintained for reasons of record, and hereby made FINAL.
Therefore, claims 1-3, 5-6, 8-9, 14-15, 34, 41-42, 53-54, 65, 69-70, 82 and 93-94 are currently under examination to which the following grounds of rejection are applicable.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US2021/025932, filed on April 6, 2021. Applicant’s claim for the benefit of a prior-filed parent provisional application 63/005,824 filed on April 6, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is April 6, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 16, 2026 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Maintained Objections/Rejections in response to Applicants' arguments or amendments:
Claim Rejections - 35 USC § 102
Claim 1 remains rejected under 35 U.S.C. 102(a)(1)(2) as being anticipated by Novartis. (US-2016/0340406-A1).
Regarding claim 1, Novartis teaches a polynucleotide (“Accordingly, in one aspect, the invention provides a T cell comprising nucleic acid, e.g., exogenous nucleic acid” (par 0006)) encoding a) a 4-1 BB ligand (4-1 BBL) or a functional portion thereof (“(b) the nucleic acid comprises a second nucleic acid sequence encoding a polypeptide which enhances T cell priming,” (par 0008); “In an embodiment, the costimulatory molecule ETP is selected from the group consisting of ... CD137L (4-1BBL)” (par 0028)), and b) a chimeric antigen receptor (CAR) comprising an extracellular target-binding domain comprising a B7-H3-binding moiety, a transmembrane domain and a cytoplasmic domain comprising a signaling domain (“(a) the nucleic acid comprises a first nucleic acid sequence encoding a chimeric antigen receptor (CAR) comprising an extracellular domain, a transmembrane domain, and an intracellular signaling domain,” (par 0007); Accordingly, the present invention provides CARs that target the following cancer associated antigens (tumor antigens): ... B7H3, (par 0170)).
Response to Applicants' Arguments as they apply to rejection of claim 1 rejected under 35 USC § 102
Starting on page 9 of the remarks filed on April 16, 2026, Applicants essentially argue the following:
In relation to claim 1, Applicants' state:
“Novartis does not teach all elements of amended claim 1, much less the particular combination of elements as required by claim 1. In particular, Novartis does not expressly or inherently describe the exclusion of 4-lBB costimulatory domain from the cytoplasmic domain. To contrary, all CAR constructs experimentally exemplified in Novartis include a 4-1BB costimulatory domain (See e.g., Novartis, Example 1, ,i [0370]). Novartis does not clearly teach or require the omission of 4-1BB costimulatory domain in any disclosed CAR construct.”
In response to the argument it has been fully considered but is not persuasive due to Novartis clearly teaching the of 4-1BB costimulatory domain as being in the alternative, particularly CD28 or 4-1BB (CD137) (par 0002), or rather other options as listed in paragraph 0055. Secondly, in reference to the examples primarily using CARs with 4-1BB as the costimulatory domain, Novartis still maintains that this domain is not required. Novartis describes third-generation versions of CARs constructed utilizing the CD28 signaling domain (par 0370), and therefore it can be understood that CARs are not to limited to only 4-1BB. Therefore, this argument is not persuasive with respect to amended claim 1.
Claim Rejections - 35 USC § 103
Claims 1-3, 5-6, 8-9, 14-15, 34, 41-42, 53-54, 65, 69-70, 82 and 93-94 remain rejected under 35 U.S.C. 103 as being unpatentable over Mackall et al. (US 10,562,952 B2) in view of Ma et al. (US 2018/0162939 A1). This is a modified rejection necessitated by Applicants' amendments to the claims in the response filed on April 16, 2026.
Claim 1 is directed to a polynucleotide encoding
a 4-1BB ligand ( 4-lBBL) or a functional portion thereof, and
a chimeric antigen receptor (CAR) comprising an extracellular target-binding domain comprising a B7-H3-binding moiety, a transmembrane domain and a cytoplasmic domain comprising a signaling domain, wherein the cytoplasmic domain does not comprise a 4-1BB costimulatory domain.
Mackall teaches a CAR comprising an extracellular target-binding domain comprising a B7-H3-binding moiety (“The CARs of the invention have antigen specificity for CD276 (also known as B7-H3)” (col 5, par 2)), a transmembrane domain (“In an embodiment of the invention, the CAR comprises a transmembrane (TM) domain.” (col 6, par 6)) and a cytoplasmic domain comprising a signaling domain, wherein the cytoplasmic domain does not comprise a 4-1BB costimulatory domain. (“In an embodiment of the invention, the CAR comprises an intracellular T cell signaling domain.” (col, par 2); Fig1C depicts the cytoplasmic domain as not comprising 4-1BB (Col ln 5-10)).
Mackall does not teach a polynucleotide encoding a 4-1BB ligand (4-1BBL) or a functional portion thereof.
Ma teaches a polynucleotide that encodes a CAR construct with a 4-1BBL (CD137L) enhancer linked by a P2A peptide, further stating , “Upon cleavage of this P2A peptide, A CAR construct with 4-1BBL splits to a CAR polypeptide and the full length of 4-1BBL protein… 4-1BBL provides a synergistic effect of T cell activation or anti-tumor activity with CD28 or 4-1BB. CAR is more powerful when equipped with 4-1BBL.” (par 0366).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the nucleotide that encodes a CAR as taught by Mackall et al. to further include a nucleotide sequence encoding 4-1BBL as taught by Ma because it would have been obvious to combine prior art elements according to known methods to yield predictable results. The CAR taught by Mackall includes an extracellular target-binding domain comprising a B7-H3-binding moiety, but lacks a sequence for 4-1BBL, but by incorporating this sequence there is a reasonable expectation there would an increased T cell activation or anti-cancer activity as described by Ma when using the 4-1BBL enhancer.
Regarding claim 2, dependent on claim 1, Ma teaches wherein the functional portion of 4-1BBL comprises an ectodomain of the 4-1BBL as seen in the claim 1 rejection because the enhancer is the full length of the polypeptide.
Regarding claim 3, dependent on claim 1, Ma teaches wherein the 4-1BBL comprises the amino acid sequence of SEQ ID NO: 1 as seen in the STIC sequence search provided wherein the sequence alignment is 100% for Result #6 (A longer version of the STIC Search will be provided in the Office Action).
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Regarding claims 5 and 6, both dependent on claim 1, Mackall teaches wherein the B7-H3-binding moiety is an anti-B7-H3 single chain variable fragment (scFv), and furthermore, wherein the anti-B7-H3 scFv is derived from antibodies MGA271, 376.96, 8H9, or humanized 8H9 (“The antigen binding domain may comprise any antigen binding portion of the MGA271 antibody. For example, the antigen binding domain may be a… single-chain variable region fragment (scFv). In a preferred embodiment, the antigen binding domain is an scFv.” (col 5, par 5)).
Regarding claim 8, dependent on claim 5, Mackall teaches wherein the anti-B7-H3 scFv comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 5 as seen in the STIC sequence search provided below in which the sequence alignment is 100% for Result #4 (A longer version of the STIC Search will be provided in the Office Action).
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Regarding claim 9, dependent on claim 8, Mackall teaches wherein the polynucleotide comprises a nucleotide sequence encoding the anti-B7-H3 heavy chain variable region (VH) comprising the nucleotide sequence of SEQ ID NO: 6, or a nucleotide sequence having at least 80% sequence identity thereof as seen in the STIC sequence search provided below in which the sequence alignment is 89% for Result #1 (A longer version of the STIC Search will be provided in the Office Action).
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Regarding claim 14, dependent on claim 5, Mackall teaches wherein the anti-B7-H3 scFv comprises the amino acid sequence of SEQ ID NO: 27 as seen in the STIC sequence search provided below in which the sequence alignment is 100% for Result #1 (A longer version of the STIC Search will be provided in the Office Action).
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Regarding claim 15, dependent on claim 14, Mackall teaches wherein the polynucleotide comprises a nucleotide sequence encoding the anti-B7-H3 scFv comprising the nucleotide sequence of SEQ ID NO: 28, or a nucleotide sequence having at least 80% sequence identity thereof as seen in the STIC sequence search provided below in which the sequence alignment is 87% for Result #1 (A longer version of the STIC Search will be provided in the Office Action).
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Regarding claim 34, dependent on clam 1, Mackall teaches wherein the transmembrane domain is derived from CD8 or CD28 (col 6, ln 62-66) and the signaling domain is derived from CD3ζ (col 7).
Regarding claim 41, dependent on claim 1, Ma teaches wherein the extracellular target-binding domain further comprises a hinge domain between the single-chain variable fragment (scFv) region and the transmembrane domain (Fig. 96A; par 0178).
Regarding claim 42, dependent on claim 41, Ma teaches wherein the hinge domain is derived from CD8a stalk, CD28 or IgG1 (par 0261-0263).
Regarding claims 53 and 54, both dependent on claim 1, Mackall teaches wherein the cytoplasmic domain further comprises one or more costimulatory domains, and wherein the one or more costimulatory domains are derived from CD28,, CD27, CD40, CD134, CD226, CD79A, ICOS, or MyD88, or any combination thereof (“In an embodiment of the invention, the CAR comprises an intracellular T cell signaling domain. The intracellular T cell signaling domain may comprise an intracellular T cell signaling domain of any one or more of CD28, 4-1 BB, and CD3 zeta (ζ).” (col 7, par 2)). Moreover, Ma teaches “CAR also has costimulatory domain (including, but not limited to, CD28 or 4-1BB) and intracellular signaling, CD3 zeta chain while 4-1BBL does not bear these components.” (par 0178).
Regarding claim 65, dependent on claim 1, Mackall teaches wherein the CAR comprises the amino acid sequence of any of SEQ ID NOs: 41, 43, or an amino acid sequence having at least 80% sequence identity thereof as seen in the STIC sequence search provided below in which the sequence alignment is around 87% for Result to instant SEQ ID NO: 41, and respectively around 95% for instant SEQ DI NO: 43 (A longer version of the STIC Search will be provided in the Office Action).
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Regarding claims 69 and 70, both dependent on 1, Ma teaches wherein the sequence encoding the 4-lBBL or a functional portion thereof is operably linked to the sequence encoding the CAR via a sequence encoding a self-cleaving peptide and/or an internal ribosomal entry site (IRES) (Figure 96A (“P2A”), par 0178; par 0440, 01172).
Regarding claim 82, 93 and 94, all dependent on claim 1, the rejection to claim 1 above is applied herein. In particular, Mackall states, “Further embodiments of the invention provide related nucleic acids, recombinant expression vectors, host cells,” (col 1).
Response to Applicants' Arguments as they apply to rejection of claims 1-3, 5-6, 8-9, 14-15, 34, 41-42, 53-54, 65, 69-70, 82 and 93-94 rejected under 35 USC § 103
Starting on page 10 of the remarks filed on April 16, 2026, Applicants essentially argue the following:
In relation to Mackall’s teachings, Applicants' state:
“Mackall does not teach or suggest the exclusion of the 4-1BB costimulatory domain from the cytoplasmic domain. To the contra[r]y, Mackall teaches that inclusion of 4-1BB intracellular T cell signaling domain is preferred…As such, Mackall teaches away from the presently claimed polynucleotide, which expressly requires that the cytoplasmic domain does not comprise a 4-1BB costimulatory domain.”
The Applicant argues in favor of superior and unexpected results that were obtained, stating,
“The data of record demonstrate that the claimed polynucleotide configuration performs materially better than would have been reasonably anticipated from the teachings of Mackall and Ma.”
In response to the first argument it has been fully considered but is not persuasive. Mackall clearly teaches examples wherein the intracellular T cell signaling domain as not comprising 4-1BB as stated in the cited section. This is further depicted in Figure 1C wherein such domain is CD28, and the CAR is characterized as “CD276.17.CH2CH3.28.” Moreover, the preference by Mackall as using 4-1BB does not teach away from the claimed combination of elements, but is merely a preference of the prior art references. Furthermore, the motivation to combine need not be the preferred or most optimal combination over other alternatives. The Applicant further argues that Ma et al. also does not teach the exclusion of the 4-1BB domain, yet as described above for Mackall, Ma teaches the alternative of using 4-1BB, and such teaching is sufficient despite not explicitly stating 4-1BB is to not be included. Altogether, it can be seen with both reference, that it is widely known that CARs’ cytoplasmic domains need not be limited to 4-1BB, but may contain other domains, e.g. CD28.
In response to the second argument it has been fully considered but is not persuasive.
Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e. Secondly, the argued unexpected results appear to be based on the CAR structure that is depicted in Fig 4A labeled ‘41BBL’ which does not comprise a 4-1BB cytoplasmic domain and has 4-1BB ligand. Claim 1 as currently recited is not limited to this particular structure as select elements are not recited, and therefore arguments pertaining to unexpected results are not convincing when the structure that led to unexpected findings is not fully claimed.
Conclusion
Claims 1-3, 5-6, 8-9, 14-15, 34, 41-42, 53-54, 65, 69-70, 82 and 93-94 are rejected. No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/ Examiner, Art Unit 1634
/TERESA E KNIGHT/ Primary Examiner, Art Unit 1634
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