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 .
Claim Status
The claim set filed on 16 October 2023 contains claims 1-20, which are currently pending.
Election/Restrictions
Applicant’s election without traverse of Invention I (claims 1-10) in the reply filed on 13 July 2026 is acknowledged. Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 13 July 2026. Claims 1-10 will be examined on the merits herein.
Priority
The instant application claims priority to foreign applications KR 10-2022-0146397 (filed 4 November 2022), KR 10-2023-0009038 (filed 20 January 2023), and KR 10-2023-0103122 (filed 7 August 2023). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, because no certified translation of the foreign priority document was provided, the foreign priority claim has not been perfected. Therefore, for the purposes of searching the prior art, the effective filing date of instant claims 1-10 is 16 October 2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 16 October 2023 and 16 January 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, each information disclosure statement is being considered by the examiner.
Claim Objections
Claim 2 is objected to because of the following informalities: there are two periods at the end of the claim. 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.
Claim 3 is 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 3 recites, “wherein the ITAM domain is derived from CD3 zeta.” The phrase “derived from” is not defined by the claim or in the instant specification. As written, one of ordinary skill in the art cannot determine the scope of ITAM structures encompassed by the claim. In the interest of compact prosecution, the claim is interpreted such that a sequence taught by the art as being derived from CD3 zeta meets the claim and that any CD3 zeta sequence in part or in whole or a partial or whole CD3 zeta sequence that has been mutated is considered as being “derived from” CD3 zeta. Clarification is requested.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 6-8, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou et al. (2022, Front. Cell Dev. Biol.; cited in IDS; herein “Zhou”) as evidenced by Wange et al. (1993, J. Biol. Chem.; herein “Wange”) and Bajar et al. (2016, Sensors; herein “Bajar”).
Regarding claims 1 and 3, Zhou teaches a FRET-biosensor for monitoring CAR T cell activity (pg. 2, right col., para. 2), comprising an antigen-binding receptor domain, thyroid-stimulating hormone receptor (TSHR)-targeting scFvs (pg. 4, left col., para. 2), a transmembrane domain, a CD3 zeta domain, a FRET domain comprising GFP and also ECFP (enhanced cyan fluorescence protein) or YPet (a yellow fluorescence protein) as fluorescence donors and acceptors, and a ZAP70 domain (Figure 1A, pg. 2, right col., para. 2-3 and pg. 7 – 8), which comprises the ZAP-SH2 domain, as evidenced by Wange (Abstract). Zhou also teaches that upon antigen binding, ZAP70 is recruited to the phosphorylated CD3 zeta subunits, which leads to downstream signal (i.e., detectable FRET signal) amplification (pg. 2, right col., para. 3).
Regarding claim 2, Zhou teaches that there is a CD28 “hinge” (i.e., a spacer) between the scFv antigen-binding domain and the CD28 transmembrane domain (Figure 1A) and that the scFv was able to target TSHR (pg. 4-7).
Regarding claim 6, Zhou teaches that the antigen-binding receptor domain is a single-chain variable fragment (scFv) for a thyroid cancer antigen, thyroid-stimulating hormone receptor (TSHR) (pg. 4, left col., para. 2) and that the FRET domain includes the cyan fluorescent protein, ECFP, and the yellow fluorescent protein, YPet, (pg. 7-8, as evidenced by Bajar, section 3.1). Zhou also teaches that upon binding of TSHR to the scFv, ZAP70 is recruited to the phosphorylated CD3 zeta subunits, which leads to downstream signal (i.e., detectable FRET signal) amplification, thereby detecting cancer antigen binding and activation of T cells (pg. 2, right col., para. 3).
Regarding claim 7, Zhou teaches that the FRET signal is measured by a FRET ratio or change thereof (pg. 3, right col., para. 3).
Regarding claim 8, Zhou teaches that the FRET-based biosensor is present on a membrane of a CAR cell (as is evident by the presence of a “transmembrane” domain, Figure 1A) and successfully detects CAR activity in a cell environment (pg. 7 – 9 and Figures 3-4) when interacting with a cell expressing a target antigen (pg. 3, right col., para. 2).
Regarding claim 10, Zhou teaches that the biosensor comprises a module comprising the scFv antigen-binding domain, the CD3 zeta domain, and GFP (i.e., a fluorescence donor or acceptor) and another module comprising the ZAP70 (comprising ZAP-SH2) and ECFP or YPet (i.e., fluorescence donors or acceptors).
Claim Rejections - 35 USC § 103
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.
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 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou (2022, Front. Cell Dev. Biol.; cited in IDS) as evidenced by Wange (1993, J. Biol. Chem.) and Bajar (2016, Sensors) in view of Sivaramakrishnan and Kim (US 2021/0179692 A1; herein “Sivaramakrishnan”), Juillerat et al. (US 10,239,948 B2; herein “Juillerat”), and Wu et al. (US 10,105,391 B2; herein “Wu”).
The teachings of Zhou are set forth in para. 12-17 above and teaches all limitations of claims 1-3, 6-8, and 10.
However, Zhou does not teach that the fluorescence donor protein and the fluorescence acceptor protein are connected by a first linker and one end of the FRET domain is connected to the ZAP-SH2 domain by a linker, as in claim 4, or wherein the first linker is an ER/K linker of SEQ ID NO: 18, the second linker is a GSG(7) linker of SEQ ID NO: 6, the transmembrane domain has an amino acid sequence of SEQ ID NO: 8, the ITAM domain has a sequence of SEQ ID NO: 1, and the ZAP-SH2 domain has an amino acid sequence of SEQ ID NO: 2, as in claim 5.
Regarding claims 4-5, Sivaramakrishnan teaches a FRET pair in which the fluorescence donor and acceptor are separated by an ER/K linker sequence with an amino acid sequence of SEQ ID NO: 2 (para. 9 and FIG. 1A), which is identical to instant SEQ ID NO: 18 (see Figure 1 for alignment below).
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Figure 1: Alignment of instant SEQ ID NO: 18 (Qy) with Sivaramakrishnan’s ER/K linker, SEQ ID NO: 2 (Db).
Regarding claim 4-5, Wu teaches a chimeric antigen receptor comprising an antigen-binding domain, a transmembrane domain, a co-stimulatory domain, a dimerizer binding pair, and an intracellular signaling domain (FIG. 17). Wu also teaches that the CAR may comprise linkers and that linkers may be glycine-serine polymers (of which the GSG(7) linker is an obvious variant), an ITAM intracellular signaling domain that may be CD3 zeta having an amino acid sequence of SEQ ID NO: 26, which is identical to instant SEQ ID NO: 1 (para. bridging col. 29-30 and FIG. 3B; see Figure 2 for alignment below), and a ZAP70 intracellular signaling domain consisting of an amino acid sequence of SEQ ID NO: 36, which comprises an amino acid sequence identical to instant SEQ ID NO: 2 (col. 35, lines 28-60; see Figure 3 for alignment below).
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Figure 2: Alignment of instant SEQ ID NO: 1 (Qy) with Wu’s CD3 zeta sequence, SEQ ID NO: 26 (Db).
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Figure 3: Alignment of instant SEQ ID NO: 2 (Qy) with Wu’s ZAP70 sequence, SEQ ID NO: 36 (Db).
Regarding claim 5, Juillerat teaches a chimeric antigen receptor comprising an antigen-targeting domain, a transmembrane domain, and co-stimulation domain (FIG. 23), wherein the transmembrane domain may be a CD8a transmembrane domain having a sequence of SEQ ID NO: 42 (col. 15, lines, 17-21), which is identical to instant SEQ ID NO: 8 (see Figure 4 for alignment below). Juillerat also teaches that he antigen-targeting domain may be an scFv, and that the co-stimulation domain may be ZAP70, which activates CD3 zeta (col. 15, lines 6-7 and para. bridging cols. 15-16).
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Figure 4: Alignment of instant SEQ ID NO: 8 (Qy) with Juillerat’s CD8a transmembrane domain, SEQ ID NO: 42 (Db).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to modify the FRET-based biosensor taught by Zhou by using the ER/K linker sequence taught by Sivaramakrishnan as the linker between the fluorescent donor and acceptor, using the GSG linker taught by Wu and Harwood as a linker between the FRET domain and the ZAP70 domain, using the CD8a transmembrane domain sequence taught by Juillerat as the transmembrane domain, using the CD3 zeta sequence taught by Wu as the ITAM domain, and using the ZAP70 sequence taught by Wu as the ZAP70 domain, thereby arriving at the invention of claims 1-8 and 10. The person of ordinary skill in the art would have been motivated to make the modification because Zhou is silent on the sequences of each domain, and each of the sequences taught by Sivaramakrishnan, Wu, and Juillerat are known in the art to function as linkers, a transmembrane domain, a CD3 zeta domain, and a ZAP70 domain in CAR T cells and/or in FRET sensors. Therefore, the combination is also desirable (see MPEP 2144(II)). The person of ordinary skill in the art would have had a reasonable expectation of success because the sequences making up to domains taught by Sivaramakrishnan, Wu, and Juillerat are the same domains used in the FRET-based biosensor of Zhou, and one would have predicted that one domain could be successfully replaced with another. Therefore, the combination leads to expected results because each element performs the same function as is does individually.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., FRET-based biosensor, linkers, e.g., ER/K linker and GSG(7) linker, transmembrane domain, CFP, YFP, CD3 zeta domain, and ZAP-SH2 domain, etc.) were known in the art. In addition, combining these elements yields a composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Regarding claim 9, Zhou is silent on whether their FRET-based biosensor provides a “tonic signal” of a CAR by detecting a level of activation of T cells by the scFv in the absence of a cancer antigen. However, because the modified FRET-based biosensor of Zhou, Sivaramakrishnan, Wu, and Juillerat contains all of the same domains as the FRET-based biosensor described in para. 131 of the instant specification, it is presumed that it has the same properties as the biosensor described in the specification to give a tonic signal detecting a level of activation of T cells in the absence of a cancer antigen, described in para. 138 and FIG. 4A-B of the present disclosure. MPEP 2112.01 states: “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). ‘When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.’ In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433.”
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY M MORGAN whose telephone number is (703)756-5388. The examiner can normally be reached M-F 9-5 ET.
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/BAILEY M MORGAN/Examiner, Art Unit 1645
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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