DETAILED ACTION
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 .
Applicant’s remarks, filed 7/20/2026, are acknowledged and entered into the record. Applicants amended claim 1, 3, 6, 8 and 14-15, and canceled claim 5, in the remarks of 7/20/2026.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2021/64408, filed 12/20/2021; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/129340, filed 12/22/2020.
Election/Restrictions
Applicant’s election without traverse of Group I, encompassing claims 1-3, 5-6, 8-10 and 14-15, in the reply filed on 3/20/2026 is acknowledged. Claims 16-20 and 25-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II and III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/20/2026. Applicant’s election of species is acknowledged; applicants elected the extracellular domain of SEQ ID NO: 12, the transmembrane domain of SEQ ID NO: 5, the signaling domain of SEQ ID NO: 1, the full CAR construct of SEQ ID NO: 36 and nucleic acid of SEQ ID NO: 35. Claims 2 and 9-10 are withdrawn as they do not read on the elected species.
Status of Claims
Claims 1-3, 6, 8-10, 14-20 and 25-29 are pending; claims 2, 9-10, 16-20 and 25-29 are withdrawn; claims 1, 3, 6, 8 and 14-15 are being examined on the merits.
Claim Rejections – Withdrawn
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 3, 5-6, 8, 14, and 15 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn.
Applicants amended claim 1 to remove the “antibody-binding portion” terminology, thus obviating the indefiniteness issues associated with such language.
Applicants amended claims 1, 3, 8 and 14 to delete “having” and “has” language and replaced it with “comprising” or “consisting of” language, thus obviating the indefiniteness issues.
Applicants amended claim 6 to remove the “optionally” language, thus obviating the indefiniteness issues.
Claim Rejections - 35 USC § 102
The rejection of claims 1 and 3 under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hwang et al., (US 2019/0336533; published 11/7/2019), is withdrawn. Applicants amended instant claim 1 to require the IC signaling domain of instant SEQ ID NO: 1. Hwang does not teach a signaling domain of SEQ ID NO: 1, thus the embodiments of Hwang do not anticipate the constructs of the amended claims.
Claim Rejections – New, necessitated by amendment
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.
Claims 1, 3, 6, 8 and 14-15 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 recites a chimeric antigen receptor comprising an antibody binding domain comprising a polypeptide with a sequence of SEQ ID NO: 12. Similarly, claim 14 recites “wherein the chimeric antigen receptor comprise an amino acid sequence of SEQ ID NO: 36,” and claim 15 recites a nucleic acid having a nucleotide sequence of SEQ ID NO: 35. Use of the terminology “a sequence” or “an amino acid sequence” is open-ended and may read on as little as 2-3 amino acids of any of the claimed sequences. That is, the claims do not require the full length sequences of the sequence identifiers, it is not close-ended and definite, defined by the recites SEQ ID NOs. Rather, that any 2-3 consecutive amino acid residues, constituting a “sub-sequence”, can be interpreted as constituting “an amino acid sequence of”. Amended claim 1 further recites “comprising the peptide sequence of SEQ ID NO: 5” and “comprising the peptide sequence of SEQ ID NO: 1.” Thus, it is clear that the construct must comprise all of SEQ ID NOs: 1 and 5; this is definite claim language, as opposed to indefinite claiming of “a”, “an” or “any” subsequence of SEQ ID NO: 12. It is unclear which amino acid residues of SEQ ID NO: 12 are required to meet the limitations of the claim. Similarly, for claim 14, it is unclear which amino acid residues, of SEQ ID NO: 36, are required to meet the claim limitations to a CAR comprising an amino acid sequence of SEQ ID NO: 36. Is any CAR construct comprising, for example, the TM domain sequence within SEQ ID NO: 36, encompassed by the claim, even if the construct has entirely different extracellular domains? The structures of instant claims 1 and 14-15 are limited by the recited amino acid sequences, however the clam language is unclear with regard to how the required amino acid sequences are defined. As the metes and bounds of the claim limitations are unclear, claims 1 and 14-15 are rejected for indefiniteness. As claims 3, 6 and 8 depend from clam 1, but fail to rectify the indefiniteness issues, claims 3, 6 and 8 are also rejected.
It is suggested that applicants use definitive language, such as “comprising the amino acid sequence of” the representative SEQ ID NO, or “the nucleotide sequence of” the representative nucleic acids sequences, such that there is no ambiguity as to what domain sequences the construct must necessarily comprise. Further, as some embodiments utilize only a portion of instant SEQ ID NO: 12, applicants may delineate the minimum required sub-sequence of SEQ ID NO: 12 that is necessary for the invention, in definitive language. For example, “wherein the CAR comprises an antibody binding domain comprising the peptide sequence of residues 1-206 of SEQ ID NO: 12”.
Claim Rejections – Maintained, Amended
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.
Claims 1, 3, 6, 8 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Hwang et al., (US 2019/0336533; published 11/7/2019) and Patakas et al., (US 2020/0289564; published 9/17/2020) .
Claims 1, 3, 6, 8 and 14-15 are drawn to a chimeric antigen receptor (CAR) comprising and extracellular domain of CD16, which binds to an antibody Fc region, a transmembrane domain (TM) of human CD28, and an intracellular signaling domain (ICD) of FcεRIγ. In the elected instant embodiment of the CAR, the CD16 extracellular domain is derived from the CD16 polypeptide of SEQ ID NO: 12, specifically amino acids 1-206 of SEQ ID NO: 12; the TM domain is SEQ ID NO: 5, and the ICD signaling domain is SEQ ID NO: 1. Thus the amino acid sequence of the CAR construct of instant claim 14 (SEQ ID NO: 36), is the combination of SEQ ID NO: 12 (residues 1-206) + SEQ ID NO: 5 + SEQ ID NO: 1.
Hwang et al. teaches CARs and natural killer (NK) cells expressing the CARs (abstract). Hwang teaches the CAR may include an Fc receptor as the extracellular domain and thus may be used to associate with different antibodies depending on cell types of cancer to be treated; the Fc receptor may be any one selected from CD16, CD32, CD64, CD23 and CD89; and specifically, may be the whole or portion of the CD16 V158 variant (pg. 4, para. 0077). Hwang teaches the TM domain may include the whole of a portion of CD8α or CD28 (pg. 4, para. 0080). Hwang teaches the CAR may comprise one or more intracellular signaling domains, linked in various orders, and which may include the whole, of portions of, well known ICs such as OX40, CD28, 4-1BB or CD3zeta (pg. 4, para. 0083; pg. 5, para. 0084). Specifically, Hwang teaches the CD16V amino acid sequence of SEQ ID NO: 5 (pg. 9, Table 2) which is 100% identical to the first 206 amino acids of instant SEQ ID NO: 12, as well as the first 206 amino acids of the full embodiment of the CAR of instant SEQ ID NO: 36. Hwang teaches the CD28 TM domain sequence of SEQ ID NO: 11, which comprises the amino acid sequence of instant SEQ ID NO: 5 with 100% sequence identity. Hwang teaches various embodiments of a CAR comprising the CD16V ECD, a CD28 TM and 2-3 alternative IC signaling domains (see Table 1, pg. 7). Thus, each of the embodiments of the CAR of Hwang SEQ ID NOs: 33, 41, 43, 45, 47, 49 and 51 (see Table 2, pg. 9; pg. 86, claim 60), which comprise the “CD16V-28” ECD-TM domains, also comprise the ECD (i.e. antibody-binding portion) of the first 206 amino acids of instant SEQ ID NO: 12, as well as the TM of instant SEQ ID NO: 5; or together, the ECD-TM portions (amino acids 1-234) of CAR of instant SEQ ID NO: 36.
Thus, the CAR constructs of Hwang et al. comprise the ECD and TM domains of instant SEQ ID NOs: 12 (re. claim 1) and 5 (re. claim 3), respectively, and include one or more ICD signaling domains. However, the CAR constructs of Hwang do not comprise the IC signaling domain of instant SEQ ID NO: 1.
Patakas et al. teaches modified CAR T cells, including gamma-delta T cells or NK cells, which express a CAR incorporating the signaling domain of a Fcγ receptor (abstract). Patakas teaches CAR constructs comprise a cancer antigen specific scFv ECD, and further comprise a CD28 TM domain and a Fcγ common chain activation domain (Figure 1). Patakas teaches that common CAR constructs utilize similar signaling domains as alpha beta T cells; however, the effector functions of gamma-delta T cells and NK cells are unlike alpha beta T cells, and instead are linked to molecules such as FcγRs. Thus, the inventors determined that gamma delta T cells or NK cells expressing a CAR that includes stimulatory domains of Fcγ receptor common chain will result in increased effector functions (pgs. 1-2, paras. 0007-0008). Patakas teaches the CARs may comprise an intracellular signaling domain of SEQ ID NO: 1 or functional variants or fragments thereof (pg. 2, para. 0017). Patakas SEQ ID NO: 1 comprises the amino acid sequence of instant SEQ ID NO: 1 with 100% sequence identity; specifically the last 41 amino acids of Patakas SEQ ID NO: 1 are identical to instant SEQ ID NO: 1. Patakas teaches a CAR construct comprising an anti-CD19 scFv ECD, a CD28 TM domain and a Fcγ receptor IC signaling domain, of SEQ ID NO: 5 (pg. 4, para. 0044). Patakas SEQ ID NO: 5 comprises the CD28 TM domain of instant SEQ ID NO: 5 and the Fcγ receptor IC signaling domain of instant SEQ ID NO: 1, with 100% amino acid sequence identity, with no gaps or inserts. That is, the last 69 amino acids of Patakas SEQ ID NO: 5 are the combination of instant SEQ ID NO: 5 (TM) + SEQ ID NO: 1 (ICD) exactly. Thus, the CAR constructs of Patakas et al. comprise the TM-IC signaling domains of instant SEQ ID NOs: 5 and 1, respectively.
It would have been obvious to one of skill in the art to modify the CAR constructs comprising a CD16V ECD and CD28 TM domain, of Hwang et al., to comprise a Fcγ receptor IC signaling domain, of Patakas et al. One would have been motivated to do so given that expression of CAR constructs in NK cells, whereby the intracellular signaling domain is a Fcγ receptor IC signaling domain imparts increased effector functions to the CAR-expressing NK cells. There would have been a reasonable expectation for success given that the CD16V ECD is taught with 100% identity in a CAR construct by Hwang et al., the FcγR ICD is taught with 100% identity in a CAR construct by Patakas et al., and both Hwang and Patakas teach the CAR constructs comprise the CD28 TM domain with 100% identity, and both Hwang and Patakas teach the CAR constructs for expression in NK cells. Thus, the invention as a whole was prima facie obvious to one of skill in the art at the time the invention was made.
Regarding instant claims 1, 3, 6, 8 and 14-15. The combination CAR of Hwang and Patakas comprises a CD16V antibody-binding portion as the ECD, a CD28 TM domain and a FcγR ICD; whereby the CD16V ECD comprises the antibody-binding portion of instant SEQ ID NO: 12, the TM comprises instant SEQ ID NO: 5 and the ICD comprises instant SEQ ID NO: 1 with 100% identity. Further, the combination CAR of Hwang and Patakas encodes the CAR of instant SEQ ID NO: 36 with 100% sequence identity. Thus the combination CAR of Hwang and Patakas make obvious the CAR of instant claims 1, 3, 8 and 14, as well as the nucleic acid sequence encoding the CAR of instant SEQ ID NO: 35, of claim 15.
Regarding claim 6, Patakas teaches the CAR may comprise one or more Fcγ receptor signaling domains (pg. 21, claim 1). Further, Patakas teaches “in embodiments of the invention, the activation endodomains of the Fcγ receptors can be combined with other activation domains including CD28, CD2,” or others (pg. 6, para. 0063). Thus, Patakas makes obvious CARs comprising a first signaling domain of instant SEQ ID NO: 1 and a second signaling domain, wherein the second signaling domain is distinct from the first signaling domain. Thus the combination of Hwang and Patakas make obvious instant claim 6.
Response to Arguments
Applicant's arguments filed 7/20/2026 have been fully considered but they are not persuasive. First, applicants contend Patakas does not suggest selecting FcεRIγ for the claimed CAR (Remarks, pg. 7). Applicants contend that Fcγ and Fcε receptors are not the same and are not interchangeable (pg. 7, para. 4-5); and that Patakas teaches away from using FcεRIγ in CARs (pg. 7, last paragraph – pg. 8). Thus, there is no teaching, suggestion, or motivation provided by the references. Second, applicants contend Patakas uses a fundamentally different targeting architecture (pg. 8). Applicants contend that Patakas uses an anti-tumor antigen scFv construct, which is fundamentally different than using a CD16 Fc-binding domain, and thus there is no motivation to substitute different extracellular binding domains. Third, applicants contend that the rejection does not establish a reasonable expectation for success (pg. 9). That the cited references provide no basis for expecting that combining the domains would produce a functional CAR.
First, the examiner points out that while Fcγ receptors and Fcε receptors may be different proteins, the claims are drawn to a CAR comprising the “intracellular signaling domain” of the Fcε receptor. The FcεRIγ signaling domain is the common Fc receptor gamma chain and serves as a shared signaling adaptor subunit for various Fc receptors, including Fcγ receptors. Thus, the FcεRIγ intracellular signaling domain, for use in a CAR construct, is dissociable from the function of full Fcγ or Fcε receptors, and is interchangeable as an intracellular signaling domain of an engineered Fcy construct.
Regarding applicants contention that Patakas teaches away from using FcεRIγ signaling domain in a CAR, the examiner disagrees. The recited excerpt from Patakas is discussing the history of CARs, and their expression in alpha-beta T cells. As recited in the rejection above, Patakas specifically teaches using an FcεRIγ signaling domain in gamma-delta T cells and NK cells will enhance their effector function because the FcεRIγ signaling domain is more complementary to the innate activation signaling of gamma-delta T cells and NK cells versus alpha-beta T cells. Patakas, in no way, teaches away from using the FcεRIγ signaling domain in a CAR construct; the entire disclosure of Patakas centers on the benefits of using the FcεRIγ signaling domain in CARs- when they are to be expressed in gamma-delta T cells or NK cells. As described in the rejection above, both of Hwang and Patakas teach expressing the CAR in NK cells. Thus, Patakas provides the motivation for a skilled artisan to select the FcεRIγ signaling domain when constructing a CAR that will be used to generate genetically engineered NK cells expressing the CAR, and wherein the engineered NK cells are to have therapeutic efficacy. Applicants arguments are unpersuasive.
Regarding applicant’s contention that the CAR construct of Patakas use anti-tumor antigen scFvs and not Fc receptors, the examiner contends that the rejection is based on the obviousness of the combination of Hwang and Patakas. 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). The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Here, both Hwang and Patakas teach CAR constructs, for expression in genetically engineered NK cells, whereby each of the extracellular, transmembrane and intracellular domains may be selected from various Markush groupings of alternatives. Hwang is relied on for teaching extracellular domain may be Fc receptors, and that use of such extracellular domains was known in the prior art, and was in the public domain at the time of the invention. Thus, the use of Fc receptor extracellular domains in a CAR is not a patentable point of novel of the instant invention. Patakas utilizes the more common scFv formats of the extracellular domain of CARs, whereby the scFv comprises the antigen binding domain of an tumor antigen-targeting construct. Hwang specifically teaches the extracellular domain is a domain to be specifically linked to an antibody or so specifically recognize an antigen, and may include, for example, an Fc receptor or an antigen-binding fragments such as a scFv,” (pg. 4, para. 0076). Thus, Hwang contemplates the interchangeability of Fc receptor and antigen-specific scFvs for use as the extracellular domain of the CAR. The teachings of Hwang may be bodily incorporated into the CARs of Patakas, and vice versa, as the obviousness is based on the combined teachings of CAR constructs of Hwang and Patakas. The motivation to substitute an Fc receptor versus an scFv is inherent in the desire of the artisan, as to what target molecule they want the CAR, and thus the cells expressing the CAR, to be directed. As both Hwang and Patakas teach that various extracellular domains may be chosen for use in the construct, as well as the transmembrane and intracellular domain, all of which were known in the art before the instant invention, the artisan more than a reasonable expectation for success that the recombinant CAR will function and the NK cells expressing the CAR will be viable anti-cancer therapeutics. The degree to which they are expressed, functional or the engineered cells being efficacious is not a claimed feature. The artisan needs only a reasonable expectation for success; the vast amount of art on engineering CAR construct with various EDs linked to various TMs linked to various IC domains, across generations of CARs, provides more than a reasonable expectation for success in generating the CAR construct of the combination of Hwang and Patakas. Applicant’s arguments are not persuasive, and the rejections are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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 JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
