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 .
Response to Amendment
The amendment filed 23 April 2026 is acknowledged. Applicant amends claims 166, 169-179, 182 and 184 are amended. Claims 168 and 181 are cancelled.
Claim Status
Claims 166-167, 169-180, and 182-185 are pending and under examination in the instant office action.
Information Disclosure Statement
Applicants are kindly reminded of their duty to disclose pursuant to 37 C.F.R. 1.56 which encompasses the citation of references material to patentability of which Applicants are aware, such as references that may have been cited in the International Search Report of the parent applicant or in the specification.
Withdrawal of Rejections
The rejection of claims 170-177, 181-182, and 184 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), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the invention is withdrawn in view of the amendment to the claims.
The rejection of claims 166-185 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of the amendment to the claims.
The rejection of claims 166-185 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because of scope of enablement is withdrawn in view of the amendment to the claims.
The rejection of claims 166-168, 175, 177, and 185 under 35 U.S.C. 102(a)(2) as being anticipated by U.S. 20190203227 to Ho et. al as evidenced by Uniprot O43561 LAT_Human and Lo, WL., Shah, N.H., Ahsan, N. et al. Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT. Nat Immunol 19, 733–741 (2018). https://doi.org/10.1038/s41590-018-0131-1 is withdrawn in view of the amendment to the claims.
The rejection of claims 166, 167, 170-172, 174, 181, 182, 183, and 185 under 35 U.S.C. 103 as being unpatentable over U.S. 20190345220 to Qi et. al. effectively filed 11 January 2016 in view of Baeumler, Toni A., et. al. "Engineering synthetic signaling pathways with programmable dCas9-based chimeric receptors." Cell reports 20.11 (2017): 2639-2653 as evidenced by Batey, Sarah, et. al. "Studying the folding of multidomain proteins." HFSP journal 2.6 (2008): 365-377 and GFP Antibody #2555 sold by Cell Signaling Technologies (15 July 2015) is withdrawn in view of the amendment to the claims.
The rejection of claim 176 under 35 U.S.C. 103 as being unpatentable over U.S. 20190345220 to Qi et. al. effectively filed 11 January 2016 in view of Baeumler, Toni A., et. al. "Engineering synthetic signaling pathways with programmable dCas9-based chimeric receptors." Cell reports 20.11 (2017): 2639-2653 as applied to claim 166 above, and further in view of WO2008060483 to Taylor et. al. published 22 May 2000 is withdrawn in view of the amendment to the claims.
The rejection of claims 178 and 180 under 35 U.S.C. 103 as being unpatentable over U.S. 20190345220 to Qi et. al. effectively filed 11 January 2016 in view of Baeumler, Toni A., et. al. "Engineering synthetic signaling pathways with programmable dCas9-based chimeric receptors." Cell reports 20.11 (2017): 2639-2653 as applied to claim 166 above, and further in view of Balagopalan, Lakshmi, et al. "Enhanced T-cell signaling in cells bearing linker for activation of T-cell (LAT) molecules resistant to ubiquitylation." Proceedings of the National Academy of Sciences 108.7 (2011): 2885-2890 is withdrawn in view of the amendment to the claims.
The rejection of claims 178 and 179 under 35 U.S.C. 103 as being unpatentable over U.S. 20190345220 to Qi et. al. effectively filed 11 January 2016 in view of Baeumler, Toni A., et. al. "Engineering synthetic signaling pathways with programmable dCas9-based chimeric receptors." Cell reports 20.11 (2017): 2639-2653 as applied to claim 166 above, and further in view of Gringhuis, Sonja I., et al. "Effect of redox balance alterations on cellular localization of LAT and downstream T-cell receptor signaling pathways." Molecular and cellular biology 22.2 (2002): 400-411 is withdrawn in view of the amendment to the claims.
The rejection of claim 184 under 35 U.S.C. 103 as being unpatentable over U.S. 20190345220 to Qi et. al. effectively filed 11 January 2016 in view of Baeumler, Toni A., et. al. "Engineering synthetic signaling pathways with programmable dCas9-based chimeric receptors." Cell reports 20.11 (2017): 2639-2653 as applied to claims 166 and 183 are above, and further in view of Wu, Xiuqi, et al. "A fusion receptor as a safety switch, detection, and purification biomarker for adoptive transferred T cells." Molecular Therapy 25.10 (2017): 2270-2279” is withdrawn in view of the amendment to the claims.
Specification- Maintained
The disclosure is objected to because of the following informalities:
The instant specification at least at paragraphs [0009], [0017], [0035], [0110], [0141] teaches that an NES comprises a "polynucleotide pattern" and then contradicts the teachings of a "polynucleotide pattern" by disclosing particular amino acids and polypeptide sequences.
The instant specification re-defines the amino acid abbreviation “L” as “a hydrophobic amino acid residue” and “the hydrophobic amino acid residue is selected from the group consisting of leucine, isoleucine, valine, phenylalanine, and methionine” at least at paragraphs [0009], [0017], [0035], [0110], [0141]. However, the specification also teaches particular sequences SEQ ID NO: 2 and 3, wherein “L” is defined as leucine (see sequence listing and Standards ST.26, Annex I ‘Controlled Vocabulary’). “L” is art-understood to designate the particular amino acid leucine; it is repugnant in the art to uses "L" to mean anything other than leucine when describing an amino acid residue. The wildcard to define “a hydrophobic amino acid” should be designated as another letter or symbol not art-understood as a single amino acid.
The specification at Example 8 and Example 9 teaches, for example, “In some examples, the systems 110 and 130 as illustrated in FIG. 1A may be expressed in immune cells (e.g. T cells), and the engineered immune cells may be tested in vivo in a mouse tumor model to study their anti-tumor efficacy. The system 110 may be referred to as “Conv CAR” in this Example” ([0330], also see similar language in [0342]). Later, the Examples teach “conventional HER2-CAR-transduced T cells” [0332]. This is objected to because it is not possible to discern in the Example and Figures whether wildtype LAT is overexpressed (exogenous LAT) as in one embodiment of system 110, or if the cells labeled “Conv CAR” are only transduced with HER2-CAR and rely on endogenous levels of LAT.
Appropriate correction is required.
Response to Arguments
Applicant states that applicant will address the objections upon indication of allowable subject matter (Remarks 4/ 23/2026 p. 8, top). Because the objections have not been addressed, the objections are maintained.
Claim Objections
Claim 184 is objected to because of the following informalities: Claim 184 recites "the recognition moiety is configured to bind the antibody such that the chimeric polypeptide mediates (i) antibody-dependent cellular cytotoxicity, or (ii) complement-dependent cytotoxicity of the cell". The claim is informal because it would be the antibody binding to the chimeric polypeptide that mediates ADCC or CDC; there would still be no structure of the chimeric polypeptide that could mediate ADCC or CDC. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)- New, necessitated by amendment
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 170-177, 182, and 184 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.
Claims 170-174 and 182 are rejected for recitation of intended result/effect without conferring some structural, material, or manipulative difference on the scope of the claim. Claim 170 recites “wherein the plurality of heterologous NES domains is configured to inhibit nuclear translocation of the receptor, such that upon introduction into a cell comprising the receptor, the chimeric polypeptide prolongs or enhances signaling of the receptor in the cell (i) delays degradation of the receptor, or (ii) increases the duration of phosphorylation of one or more signaling cascade protein of the receptor, as compared to the wild-type adaptor protein without the plurality of heterologous NES domains”; claim 171 recites “The chimeric polypeptide of claim 170, wherein the plurality of heterologous NES domains is configured to enhance translocation of the adaptor protein into a membrane of the cell.”; claim 172 recites “wherein the plurality of heterologous NES domains is configured to reduce displacement of the adaptor protein from a membrane of the cell during the signaling of the receptor”; claim 173 recites “wherein the plurality of heterologous NES domains is configured to reduce degradation of the adaptor protein during the signaling of the receptor”; and claim 174 recites “wherein the plurality of heterologous NES domains is configured to stabilize the adaptor protein in a membrane of the cell, as compared to the wild-type adaptor protein without the plurality of heterologous NES domains”. Apart from the structure of the chimeric protein comprising adaptor protein comprising full-length LAT and a plurality of heterologous NESs, wherein the adaptor protein is disposed between an at least a first NES and a second NES (as recited in claim 166), there is no further structure described in the claim or the specification that would apprise a person of ordinary skill in the art which structures are encompassed by the claim.
Claim 182 is directed towards the chimeric polypeptide of claim 166 comprising one additional polypeptide, “wherein upon introduction of the chimeric polypeptide into a cell, a charge, size, and/or position of the at least one additional polypeptide relative to the chimeric polypeptide is sufficient to inhibit or reduce the interaction between the adaptor protein and a cellular component of the cell”. Absent specific structures in the claims or specification that are clearly linked to these functions, it is unclear how these claims further limit the scope of the parent claim. MPEP 2173.05(g) states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim' and thus be indefinite.” It further states: “Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim” (emphasis added). Since the claims fail to meet all (3) criteria set forth in MPEP 2173.05(g), then claims 170-174 and 182 are rejected.
Claims 170, 174, and 182 are indefinite for the recitation of “as compared to the wild-type adaptor protein without the plurality of heterologous NES domains” and “as compared to the wild-type adaptor protein without the at least one additional polypeptide” (claim 182 part a). This is unclear because claim 166 from which claims 170, 174, and 182 depend recites “a chimeric polypeptide comprising a plurality of heterologous nuclear export signal (NES) domains linked to an adaptor protein of a receptor”, but it does not recite an adaptor protein comprising a plurality of heterologous NES domains and it does not recite an adaptor protein comprising at least one additional polypeptide; rather, it is understood that the chimeric polypeptide comprises these elements but not the adaptor protein. Therefore, it is unclear whether the claim requires a control of the chimeric polypeptide without the NES domains or at least one additional polypeptide, just the adaptor protein without the NES domains or at least one additional polypeptide, or something else. The Examiner recommends amended the claim to recite either the wild-type adaptor protein of the receptor (which by definition does not comprise the NES domains) or to recite compared to a control chimeric polypeptide without either the NES domains or the additional polypeptide.
Claims 175-177 are indefinite for the recitation of a heterologous NES domain comprising a polynucleotide sequence. Nuclear export signal (NES) domains are understood to be a polypeptide domain, and further the instant claims recite the polynucleotide comprising particular amino acids. Therefore, the metes and bounds of the claim are unclear.
Claims 175-177 are indefinite for the recitation of “having the pattern […] wherein each x is a hydrophobic amino acid residue selected from the group consisting of leucine, isoleucine, valine, phenylalanine, and methionine”. The specification both that “L” is any hydrophobic amino acid residue ([0009]) and teaches particular sequences SEQ ID NO: 2 and 3, wherein “L” is defined as leucine (see sequence listing and Standards ST.26, Annex I ‘Controlled Vocabulary’). Because “L” is defined in the specification in two ways, it is unclear what the metes and bounds of the claim are. “L” is art-understood to designate the particular amino acid leucine; it is repugnant in the art to uses "L" to mean anything other than leucine when describing an amino acid residue. The wildcard to define “a hydrophobic amino acid” should be designated as another letter or symbol not art-understood as a single amino acid.
The term “configured to reduce” in claim 182 is a relative term which renders the claim indefinite. The term “configured to reduce” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear the degree to which reduction or inhibition of the interaction between the adaptor protein and a cellular component of the cell or reduction of degradation of the adaptor protein in the cell must occur in order to meet the limitations of the claims.
Claim 182 recites the limitation "the cellular component" in line 13. There is insufficient antecedent basis for this limitation in the claim.
Claim 184 recites the limitation "the cell" in line 5. There is insufficient antecedent basis for this limitation in the claim.
Response to Arguments
Applicant argues “Without acquiescing to the merits of these rejections and solely to advance prosecution, present reply addresses the rejection of claims 166 to 185 under 35 U.S.C. 112(a) for failure to comply with the written description requirement” (Remarks p. 8). Applicant does not address the 112(b) rejections in the arguments. As described in the new rejections necessitated by amendment above, the claims are still indefinite for failing to particularly point out and distinctly claim the subject matter which the Applicant regards as the invention.
Claim Rejections - 35 USC § 112(a)- New Matter- New, necessitated by amendment
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 175-177 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. This is a "new matter" rejection.
Claims 175-177, as presently amended, recite wherein a heterologous NES domain of the plurality of heterologous NES domains comprises a polynucleotide sequence having the particular pattern of L and x, “wherein each x is a hydrophobic amino acid residue selected from the group consisting of leucine, isoleucine, valine, phenylalanine, and methionine”. However, it is noted that the specification only defines “x” as any amino acid (p. 32) and never as the hydrophobic amino acids in particular. There is no support for the sequence as claimed being a nuclear export signal.
Allowable Subject Matter
Claims 166-167, 169, 178-180, 183, and 185 are allowed.
Claim interpretation: Claim 166 is directed towards a chimeric polypeptide comprising a plurality of heterologous nuclear export signal (NES) domains linked to an adaptor protein of a receptor, wherein the adaptor protein comprises full-length Linker for Activation of T cells (LAT); wherein the plurality of heterologous NES domains comprises at least a first and second NES domain, wherein the adaptor protein is disposed between the first heterologous NES domain and the second heterologous NES domain. The instant application defines a nuclear export signal functionally as an amino acid sequence capable of directing a polypeptide containing it to be exported from the nucleus of a cell [110]. Because full-length LAT is a transmembrane protein, claim 166 is interpreted to require an extracellular nuclear export sequence because the full-length LAT is disposed between the first and second nuclear export sequences.
The following is an examiner’s statement of reasons for allowance: The closest prior art is Qi et. al. effectively filed 11 January 2016 (PTO-892 10/24/2025) in view of Baeumler, Toni A., et. al. "Engineering synthetic signaling pathways with programmable dCas9-based chimeric receptors." Cell reports 20.11 (2017): 2639-2653 (PTO-892 10/24/2025) as described in the Non-Final Office action dated 24 October 2026. Qi et. al. in view Baeumler et. al. Qi et. al. in view of Baeumler et. al. fails to teach the chimeric polypeptide wherein at least one NES domain is on the N-terminus of LAT and at least one is on the C-terminus because the Qi et. al. in view of Baeumler et. al. teach that the NES can be N- or C-terminus of the adaptor, but it would be expected to be in a cytoplasmic domain of the adaptor protein. Therefore, the art does not make obvious the instantly claimed chimeric polypeptide with the two NES domains disposed around full-length LAT, resulting in one of the NESs being extracellular.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
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 Kathleen CunningChen whose telephone number is (703)756-1359. The examiner can normally be reached Monday - Friday 11-8:30 ET.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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