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 .
Status of Application, Amendments and/or Claims
The amendment of 13 May 2026 has been entered in full. Claims 1, 6, 9, 10, and 17 are amended. Claim 11 is cancelled.
Claims 16 and 18 are withdrawn from further consideration further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 09 October 2025.
Claims 1-10, 12-15, and 17 are under consideration in the instant application as they read upon the elected invention of Group I (an artificial membrane protein).
Drawings
The replacement drawings were received on 13 May 2026. These drawings are acceptable.
Withdrawn Objections and/or Rejections
1. The objections to the drawings as set forth at page 4 of the previous Office Action of 13 February 2026 are withdrawn in view of the submission of replacement drawings (13 May 2026).
2. The objections to the specification as set forth at page 4 of the previous Office Action of 13 February 2026 are withdrawn in view of the amended specification (13 May 2026).
3. The objections to claims 9, 10, and 17 as set forth at page 5 of the previous Office Action of 13 February 2026 are withdrawn in view of the amended claims (13 May 2026).
4. The rejections of claims 6-7 and 17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph as set forth at pages 6-7 of the previous Office Action of 13 February 2026 are withdrawn in view of the amended claims (13 May 2026). Please see remaining rejection set forth below.
5. The rejection of claims 1, 2, 3, 6, 8, 12-15 under 35 U.S.C. 102(a)(2) as being anticipated by Mackall et al. (US 2022/0041686 and WO 2020/118076; priority to 06 December 2018) as set forth at page 8 of the previous Office Action of 13 February 2026 is withdrawn in view of the amended claims (13 May 2026). Specifically, Mackall et al. do not teach that the intracellular signaling domain is configured to interact with the cAMP pathway or with the ERK signaling pathway.
6. The rejection of claims 1, 3, 6, 8, 12-15 under 35 U.S.C. 102(a)(1) as being anticipated by Eyckerman et al. (US 2003/0100021 or WO 01/090188) as set forth at pages 8-9 of the previous Office Action of 13 February 2026 is withdrawn in view of the amended claims (13 May 2026). Specifically, Eyckerman et al. do not teach that the intracellular signaling domain is configured to interact with the cAMP pathway or with the ERK signaling pathway.
7. The rejection of claims 1, 3, 5, 6, 8, 10, 12-15 under 35 U.S.C. 102(a)(1) as being anticipated by Juillerat et al. (WO 2017/032777) as set forth at page 10 of the previous Office Action of 13 February 2026 is withdrawn in view of the amended claims (13 May 2026). Specifically, Juillerat et al. do not teach that the intracellular signaling domain is configured to interact with the cAMP pathway or with the ERK signaling pathway.
8. The rejection of claims 1, 3, 6, 7, 10, and 12-15 under 35 U.S.C. 102(a)(1) as being anticipated by Kiefer et al. (Biochem 35: 16077-16084, 1996) as set forth at page 11 of the previous Office Action of 13 February 2026 is withdrawn in view of the amended claims (13 May 2026). Specifically, Kiefer et al. do not teach that the intracellular signaling domain is configured to interact with the cAMP pathway or with the ERK signaling pathway.
9. The rejection of claims 1, 3, 6, 8, 9, and 12-15 under 35 U.S.C. 102(a)(1) as being anticipated by Schonfeld et al. (EP 3115373; 01 November 2017) as set forth at pages 11-12 of the previous Office Action of 13 February 2026 is withdrawn in view of the amended claims (13 May 2026). Specifically, Schonfeld et al. do not teach that the intracellular signaling domain is configured to interact with the cAMP pathway or with the ERK signaling pathway.
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.
10. Claims 1-10, 12-15, and 17 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. The basis for this rejection is set forth at pages 5-6 of the previous Office Action of 13 February 2026.
10a. Regarding claims 1-10, 12-15, and 17, the phrases “is configured to interact with” (claim 1, 17); “is configured to bind to” (claim 1, 17); “configured to facilitate” (claim 2); “is configured to establish” (claim 3); “configured for interacting” (claim 10); and “configured for intracellular or intravesicular biomolecular interaction” (claim 17) render the claims indefinite. The term "configured” is not defined by the claims, 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 not clear what specific layout/arrangement, elements, or components are included or excluded. For example, how is a receptor structure arranged/configured to interact with an intracellular or intravesicular component? How is the extracellular or extravesicular binder structure arranged/configured to bind to membrane recognition elements and to establish a covalent bond? How is an affinity tag arranged/configured for interacting with membrane recognition elements? How is a protein of interest arranged/configured for intracellular or intravesicular biomolecular interaction? Are amino acid substitutions, deletions, insertions involved? Post-translational modifications? Or, something else altogether?
(i) At the middle of page 11 of the Response of 13 May 2026, Applicant argues that there is no prohibition on the use of the term “configured to” or “configured for” in the MPEP. Applicant submits that contrary to the Examiner’s position that the specification does not provide any guidance, in addition to the skilled person knowing what this encompasses (e.g. the binding of an antibody to an antigen or a nucleophile to an electrophile), suitable examples are at least discussed on page 11, line 14 to line 21 of the specification. Applicant asserts that the same holds true for an element that is suitable for interacting with another element. For example, a small molecule may bind to a receptor which is clearly understood by the skilled person as a biological interaction. Applicant contends that therefore, the receptor is configured to interact with the small molecule, as shown by the Example discussed in Figure 4d. Applicant states that while Grb2 is configured to interact with the Grb2-targeting protein within the cell, eYFP is not. Applicant concludes that the term is clear to the skilled person and not indefinite.
Applicant’s arguments have been fully considered but are not found to be persuasive. Below is the excerpt from page 11, lines 11-21 of the originally filed specification of 08 April 2022 highlighted in Applicant’s response:
In further embodiments, the extracellular or extravesicular binder structure is configured to establish a covalent bond to the membrane recognition elements arranged along a plurality of predetermined lines of the biomolecular detection device. For example, the extracellular or extravesicular binder structure may comprise a chemical moiety that enables the generation of a covalent bond, such as an electrophile, a nucleophile, a dienophile, a diene, a 1,3-dipole or a dipolarophile.
Although Applicant points to this excerpt as a suitable example as to what “configured” might encompass, the Examiner acknowledges that this only seems to be applicable to the extracellular/extravesicular structure recited in the claims.
As discussed in the previous Office Action at pages 5-6 (and reiterated above), the claims recite multiple phrases, such as “is configured to interact with” (claim 1, 17); “is configured to bind to” (claim 1, 17); “configured to facilitate” (claim 2); “configured for interacting” (claim 10); and “configured for intracellular or intravesicular biomolecular interaction” (claim 17) when referring to the receptor structure (claim 1, 17), intracellular/intravesicular receptor structure (claim 1), linker domain (claim 2), affinity tag (claim 10), and protein of interest (claim 17).
The ordinary and customary meaning of the term “configure” is to “set up or arrange to function in a particular way” and “to design or adapt to form a specific configuration for some specific purpose” (see for example, entries www.vocabulary.com/dictionary/configure and www.dictionary/com/browse/configure). However, as discussed in the previous Office Action, it is not clear what specific layout/arrangement, adaptations, elements, or components are included or excluded by the “configured” terminology in the instant claims. For example, how is a receptor structure arranged/configured/adapted to interact with an intracellular or intravesicular component? How is an affinity tag arranged/configured/adapted for interacting with membrane recognition elements? How is a protein of interest arranged/configured/adapted for intracellular or intravesicular biomolecular interaction? Are amino acid substitutions, deletions, insertions involved? Post-translational modifications? Or, something else altogether? Even Applicant’s arguments of 13 May 2026 discussing the clarity of “configured” in terms of a receptor configured to interact with a small molecule are confusing and vague. Applicant states that “while Grb2 is configured to interact with the Grb2-targeting protein within the cell, eYFP is not”. What does this mean? Has the Grb2 or the receptor structure been altered/adapted/re-arranged in some way to elicit this difference?
Applicant is reminded that the primary purpose of the requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent/protected subject matter (see MPEP §2173). Claim language may not be "ambiguous, vague, incoherent, opaque, or otherwise unclear in describing and defining the claimed invention." In re Packard, 751 F.3d 1307, 1311, 110 USPQ2d 1785, 1787 (Fed. Cir. 2014) (MPEP §2173.05(a)(I)). Although Applicant need not confine themselves to the terminology used in the prior art, Applicant is required to make clear and precise the terms that are used to define the invention whereby the metes and bounds of the claimed invention can be ascertained (MPEP §2173.05(a)(I)). In the instant application, the phrases “is configured to interact with”; “is configured to bind to”; “configured to facilitate”; “configured for interacting”); and “configured for intracellular or intravesicular biomolecular interaction” are not clear and concise and one skilled in the art would not reasonably be apprised of the scope of the invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
MAINTAINED
Mackall et al.
11. Claim 17 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Mackall et al. (US 2022/0041686 and WO 2020/118076; priority to 06 December 2018). For purposes of brevity, citations below are provided from US 2022/0041686. The basis for this rejection is set forth at page 8 of the previous Office Action of 12 February 2026.
Mackall et al. teach engineered cell surface receptors that comprise an extracellular binding domain, a transmembrane domain, an intracellular signaling domain, and a protease cleavage site, meeting the limitations of instant claim 17 (page 1, [0004]; pages 3-4, [0043]; page 5, [0053, 0056]; page 8, [0071]; page 9, [0075]; page 12, [0097]). Mackall et al. indicate that the cell surface receptor comprises a short linker that links the transmembrane domain and the intracellular signaling domain (page 8, [0072]; Table 1, page 12; Table 1, bottom of page 13 through entire page 14).
Mackall et al. disclose nucleic acids encoding the cell surface receptors, expression vectors, cells that express the cell surface receptor, and a method of making the cells, meeting the limitations of instant claim 17 (page 12, [0096]; pages 13-16, [0098-0099]; page 16, [0105-0108] through page 18, [0122]). Lastly, Mackall et al. teach kits comprising the nucleic acids and/or expression vectors, meeting the limitations of instant claim 17 (page 20, [0146]).
(i) At page 13 of the Response of 13 May 2026, Applicant argues that Mackall is entirely silent as the cAMP pathway and the ERK signaling pathway as recited in the amended claims. Applicant contends that the document is directed to a chimeric antigen receptor engineered for therapeutic CAR-T cell immunotherapy against cancer and has nothing to do with an artificial transmembrane protein for use in a biomolecular detection device as claimed.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is noted that only independent claim 1 has been amended to add limitations regarding cAMP and ERK signaling pathways. Independent claim 17 has not been amended to recite such limitations. Therefore, claim 17 is still anticipated by the teachings of Mackall et al.
Eyckerman et al.
12. Claim 17 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Eyckerman et al. (US 2003/0100021 or WO 01/090188). For purposes of brevity, citations below are provided from US 2003/0100021. The basis for this rejection is set forth at pages 8-9 of the previous Office Action of 12 February 2026.
Eyckerman et al. teach a recombinant transmembrane receptor comprising an extracellular ligand binding domain, transmembrane domain, and a cytoplasmic domain that includes a heterologous bait polypeptide, meeting the limitations of instant claim 17 (page 1, [0011]; page 2, [0020]; entirety of page 8). Eyckerman et al. indicate that the recombinant receptor is activated by the binding of a ligand to the ligand binding domain and by the binding of a prey polypeptide to the heterologous bait peptide (page 1, [0002, 0011]). Eyckerman et al. disclose that the extracellular domain is at the N-terminus of the recombinant receptor and the cytoplasmic domain is at the C-terminus of the recombinant receptor (Figure 1). Eyckerman et al. teach a vector encoding the recombinant receptor, a eukaryotic cell comprising the recombinant receptor, and a kit comprising the vector, meeting the limitations of instant claim 17 (page 3, [0028-0030]; Examples 1-8).
(i) At the bottom of page 12 through the top of page 13 of the Response of 13 May 2026, Applicant argues that Eyckerman discloses a fundamentally different system that what is claimed. Applicant asserts that Eyckerman is entirely directed to the JAK/STAT signaling cascade and that an ERK pathway protein or cAMP protein is never incorporated into the intracellular domain.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is noted that only independent claim 1 has been amended to add limitations regarding cAMP and ERK signaling pathways. Independent claim 17 has not been amended to recite such limitations. Therefore, claim 17 is still anticipated by the teachings of Eyckerman et al.
Moss et al.
13. Claims 1, 3, 4, 6, 8, and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Moss et al. (ACS Med Chem Lett 5: 1043-1048, 2014), as evidenced by de Lera Ruiz et al. (J Med Chem 57: 3623-3560, 2014). The basis for this rejection is set forth at pages 9-10 of the previous Office Action of 13 February 2026 and is reiterated herein below for convenience.
Moss et al. teach that adenosine receptors (ARs), including the receptor subtype A2aAR, are members of the G protein-coupled receptor (GPCR) superfamily (abstract). It is well known in the art that GPCRs (and A2aAR) comprise 7 transmembrane domains, linked by three intracellular and three extracellular loops, as evidenced by de Lera Ruiz et al., meeting the limitations of instant claim 1 (page 3629, column 1, last paragraph; Figure 4A).
Moss et al. disclose that in A2aAR, the second extracellular loop (EL2) makes contact with bound ligands and plays an important role in ligand recognition (page 1043, column 2). Moss et al. disclose that EL2 comprises nucleophilic amino acids and that chemically reactive agonists are designed to target such nucleophiles, meeting the limitations of instant claims 3 and 4 (page 1043, column 2; page 1044, column 2; page 1045, column 1; Figure in abstract). Moss et al. disclose transfecting COS-7, HEK-293, and CHO cells with A2aAR constructs, meeting the limitations of instant claims 1, 12-15 (see page 1045, Table 1; page 1046, Figure 2 and Table 2;; see also supplemental pharmacological procedures (under transfections, membrane binding assays, whole cell preincubation, and cyclic AMP accumulation assay)).
(i) At the bottom of page 13 of the Response of 13 May 2026, Applicant argues that Moss discloses structure-based, chemically reactive nucleoside agonists for site-specific covalent modification of the A2A adenosine receptor. Applicant asserts that this subject matter has nothing to do with monitoring the cAMP or ERK pathway with a biomolecule detection device as claimed.
Applicant’s arguments have been fully considered but are not found to be persuasive. Specifically, Moss et al. disclose transfecting COS-7, HEK-293, and CHO cells with artificial A2A adenosine receptor constructs (see page 1045, Table 1; page 1046, Figure 2 and Table 2;; see also supplemental pharmacological procedures at pages S10 (under transfections, membrane binding assays, whole cell preincubation). Moss et al. teach that CHO cells expressing the artificial A2AAR construct are cultured with nucleoside agonists and then cAMP production is determined (page S10, last paragraph, “Cyclic AMP accumulation assay”; see also page S11, Figure “S1”). Thus, contrary to Applicant’s arguments, the artificial A2A adenosine receptor construct of Moss et al. mediates the cAMP pathway and anticipates the claims of the instant application.
NEW
Rohrs et al.
14. Claims 1-3, 6, 8-10, 12-15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rohrs et al. (bioRxiv, doi.org/10.1101/718767; 30 July 2019).
Rohrs et al. teach an anti-CD19 chimeric antigen receptor (CAR) comprising a codon-optimized CD19 single-chain scFv; a human CD8 hinge region; a CD28 transmembrane domain; and CD28 and CD3ζ intracellular domains, meeting the limitations of instant claims 1-3, 6, 8, and 17 (page 4, column 1, 2nd full paragraph). Rohrs et al. disclose that a CD8 leader sequence and HA tag are upstream of the CD19 scFv, meeting the limitations of instant claims 9 and 10 (page 4, column 1, 2nd paragraph). Rohrs et al. teach a lentiviral vector comprising a nucleic acid molecule encoding the CAR, meeting the limitations of instant claims 13, 14, and 17 (page 4, column 1; 2nd-4th full paragraphs). Rohrs et al. indicate that Jurkat T cells are transduced to express the CAR, meeting the limitations of instant claims 12, 15, and 17 (page 4, column 1, 4th-5th full paragraphs). Rohrs et al. teach that CAR-expressing Jurkat T cells are stimulated with either HA antibody or CD19-expressing cells and then phosphorylated ERK is measured, which demonstrates that the CAR and its intracellular domain mediate the ERK signaling pathway, meeting the limitations of instant claim 1 (page 4, column 1, last paragraph through entire column 2).
Taylor et al.
15. Claims 1, 3, 5, 6, 8, 10, 12-15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Taylor et al. (Cell 169: 108-119, 2017).
Taylor et al. teach a synthetic DNA-CARζ that consists of a single-stranded DNA (ssDNA) covalently reacted to an extracellular SNAP tag protein that is fused to a transmembrane domain of CD86 and the intracellular human CD3ζ chain, meeting the limitations of instant claims 1, 3, 5, 6, and 8 (page 109, column 2, last paragraph; Figure 1A; page e2, 2nd-4th full paragraphs). Taylor et al. teach a lentivirus that expresses the construct, meeting the limitations of instant claims 13 and 14 (entire page e2). Taylor et al. disclose that JRT3 Jurkat cells expressing DNA-CARζ-GFP are functionalized with BG-DNA receptor and then phosphoERK signaling is evaluated, meeting the limitations of instant claims 1, 12, and 15 (page 110, column 2; page 116, column 2, 1st full paragraph; Figure 2; page e5, 1st-3rd full paragraphs; bottom of page e7; Figure S2). It is noted that the DNA-CARζ-GFP construct comprises a C-terminal cytoplasmic eGFP (but not a transmembrane domain eGFP) (page e2, 2nd full paragraph). Taylor et al. also teach a synthetic DNA-CARζ that comprises a N-terminal HA epitope tag, meeting the limitations of instant claim 10 (page e2, 2nd full paragraph).
Watson et al.
16. Claims 1, 3, 6-8, 12-15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Watson et al. (J Exp Med 212(7): 1021-1041, 2015).
Watson et al. teach that CD99 is a membrane protein that comprises an extracellular domain, transmembrane domain, and cytoplasmic tail (or, intracellular domain), meeting the limitations of instant claims 1, 3, and 6 (page 1032, Figure 8a). Watson et al. teach the generation of CD99-GFP (green fluorescent protein) constructs, meeting the limitations of instant claims 6, 8, and 17 (Figure 8a). Specifically, Watson et al. disclose that full-length CD99-GFP and CD99-GFP cytoplasmic tail mutant constructs are cloned into vectors, recombined with adenovirus, and then introduced to human umbilical vein endothelial cells (HUVECs), meeting the limitations of instant claims 12-15 and 17 (page 1037, column 1, last paragraph through column 2, 3rd full paragraph). Watson et al. indicate that the cytoplasmic tail of CD99 mediates leukocyte transendothelial migration (TEM) through a positively charged juxtamembrane region, meeting the limitations of instant claim 7 (page 1029, column 2, 3rd full paragraph). Watson et al. also disclose that CD99 mediates signaling through the cAMP pathway, meeting the limitations of instant claim 1 (Figure 10(e); page 1036, column 1, 1st full paragraph).
Conclusion
No claims are allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Fussenegger et al. (US 2020/0216514; priority to 09 January 2019, same Applicant; teach a chimeric ligand receptor comprising a receptor subunit, wherein the receptor subunit comprises an extracellular domain, transmembrane domain, and an intracellular signaling domain (page 1, [0005]; disclose that the intracellular signaling domain induces downstream signaling via a MAPK signaling pathway (page 2, [0016]); teach a schematic of an extracellular molecule sensor platform and indicate that at the end of the MAPK signaling cascade, ERK phosphorylates a TetR-Elk1 fusion protein that activates transcription from a reporter plasmid (pages 5-6, [0050]; Figure 2)).
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.
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BEBArt Unit 1647
16 July 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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