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 09 October 2025 has been entered in full. Claim 1 is amended. Claim 11 is cancelled.
Claims 1-10 and 12-18 are pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-15 and 17, drawn to an artificial membrane protein, in the reply filed on 09 October 2025 is acknowledged. The traversal is on the ground(s) that Bastiaens et al. (US 2015/0064713; the reference utilized by the Examiner to demonstrate lack of unity of invention) teach that their transmembrane protein comprises a fluorescent label attached to the transmembrane domain (Figures 2-3; [0043]). At pages 10-11 of the Response of 09 October 2025, Applicant argues that Bastiaens et a. relies on fluorescence microscopy for measurement (bait-prey) while amended claim 1 specifies an artificial transmembrane protein which is fluorescent label-free. At pages 12-13 of the Response, Applicant also contends that Bastiaens et al. also discloses FRET-based sensors (page 6), that employs fluorescent labels. Applicant asserts at page 13 that one of ordinary skill in the art learns from Bastiaens et al. that fluorescent labels on the transmembrane domain simplify measurement results.
Applicant’s arguments have been fully considered and are found to be persuasive in view of the amended claims. However, Groups I-III still lack unity of invention after consideration of the prior art. Please see the rejections under 35 U.S.C. 102, below.
The requirement is still deemed proper and is therefore made FINAL.
Claims 16 and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. 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.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08 September 2022; 07 March 2024; 20 May 2024; 05 November 2024; and 15 April 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
It is noted that on the IDS of 07 March 2024, citation #5 (WO 2010052337) has been crossed off because it was cited in duplicate (see IDS of 08 September 2022).
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description (pages 34-35):
From Figure 5a: 10’ and 86’
From Figure 6b: 7”
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
1. The disclosure is objected to because of the following informalities:
1a. At page 10, line 4, there is a square instead of a symbol.
1b. At page 29, the Brief Description of the Drawings does not refer to Figure 4d.
Appropriate correction is required.
Claim Objections
2. Claims 9, 10, and 17 are objected to because of the following informalities:
2a. In claim 9, line 2, a word is missing after the phrase “signal peptide adjacent”. This issue could be overcome by inserting the word, “to” (i.e., “signal peptide adjacent to the…”).
2b. In claim 10, the word “extravesicullar” should be spelled “extravesicular”.
2c. Claim 17, subpart (b) depends from claim 16, which is currently withdrawn.
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.
3. 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.
3a. 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?
3b. Claims 6 and 7 are rejected as being indefinite because claim 6, lines 3-4 and 6-7 recites that the intracellular or intravesicular domain is arranged either adjacent to the C-terminus (subpart (a)) or the N-terminus (subpart (b)). What is the intracellular or intravesicular domain adjacent to? Claim 1 recites three components that comprise the artificial transmembrane protein. Therefore, the location of the intracellular or intravesicular domain cannot be determined. For instance, in claim 6 subpart (a), the intracellular or intravesicular domain is arranged adjacent to the C-terminus of what domain, region, binder structure? Furthermore, for subpart (b), the intracellular or intravesicular domain is arranged adjacent to the N-terminus of what domain, region, binder structure?
There is a similar issue regarding the extravesicular domain location. Claim 6, lines 4-5, 7-8 recites that the extracellular or extravesicular domain is arranged either adjacent to the N-terminus (subpart (a)) or the C-terminus (subpart (b)). What is the extracellular or extravesicular domain adjacent to? Claim 1 recites three components that comprise the artificial transmembrane protein. Therefore, the location of the extracellular or extravesicular domain cannot be determined.
3c. Claim 17 is rejected as being indefinite because in subpart (a), there are two lines that are missing a word(s). Therefore, it is unclear what word or phrase is encompassed or whether open or closed term language (such as, “comprising”, consisting of”) is intended. Please see after the phrase, “a recombinant nucleic acid molecule comprising at least one nucleic acid sequence encoding an artificial transmembrane protein XX”. See also after the phrase, “ a vector comprising a recombinant nucleic acid molecule comprising at least one nucleic acid sequence encoding an artificial transmembrane protein XX”.
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.
4. Claims 1, 2, 3, 6, 8, 12-15, and 17 are 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.
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 claims 1, 3, 6, and 8 (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, meeting the limitations of instant claim 2 (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 claims 12-15 (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]).
5. Claims 1, 3, 6, 8, 12-15, and 17 are 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.
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 claims 1 and 8 (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, meeting the limitations of instant claim 6 (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 claims 12-15 (page 3, [0028-0030]; Examples 1-8).
6. 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).
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)).
7. Claims 1, 3, 5, 6, 8, 10, 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Juillerat et al. (WO 2017/032777).
Juillerat et al. teach a chimeric antigen receptor comprising: (a) at least one ectodomain which comprises (i) an extracellular antigen binding domain; and (ii) a switch domain comprising at least a first and second multimerizing ligand-binding domain; (b) at least one transmembrane domain; and (c) at least one endodomain comprising a signal transducing domain and optionally, a co-stimulatory domain, meeting the limitations of instant claims 1, 3, 6, and 8 (page 2, lines 24-29; page 3, lines 1-8; Figures 1A-1B; page 39, lines 28-30). Juillerat et al. disclose polynucleotides and vectors comprising one or more nucleic acid sequences encoding a chimeric antigen receptor of the invention, meeting the limitations of instant claims 13 and 14 (page 3, lines 9-11). Juillerat et al. indicate that the invention also provides an immune cell comprising one chimeric antigen receptor of the invention, as well as methods of engineering such cell, meeting the limitations of instant claims 12 and 15 (page 3, lines 12-18).
Juillerat et al. disclose that the first multimerizing ligand-binding domain is a SNAP tag and that the second multimerizing ligand-binding domain is Halo-tag or CLIP tag, meeting the limitations of instants claim 5 and 10 (Table 1, page 9; page 11, line 8).
8. Claims 1, 3, 6, 7, 10, and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kiefer et al. (Biochem 35: 16077-16084, 1996).
Kiefer et al. teach an olfactory receptor (OR 5) fusion protein comprising GST fused to various regions of OR 5 that are extramembraneous (that is, the N-terminus or loops connecting the transmembrane regions), meeting the limitations of instant claims 1, 6, and 10 (page 16078, column 1, 3rd full paragraph; abstract; page 16083, column 1, 3rd full paragraph). Kiefer et al. disclose that intracellular domain of one fusion protein mutant comprises a higher amount of positively charged amino acid residues than the extracellular domain, meeting the limitations of instant claim 7 (entire page 16080; Figure 1; abstract; page 16083, column 1, 3rd paragraph). Kiefer et al. also teach nucleic acid molecules, vectors, cells, and methods of expressing the fusion protein, meeting the limitations of instant claims 12-15 (page 16078, column 1, 3rd and 4th full paragraphs).
9. Claims 1, 3, 6, 8, 9, and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schonfeld et al. (EP 3115373; 01 November 2017).
Schonfeld et al. teach a multi-functional or multi-domain protein comprising a signal peptide, a target specific recognition domain, a linker region, and an effector domain comprising a transmembrane region and one or more intracellular signaling domains, meeting the limitations of instant claim 1 (pages 2-3, [0010]; page 3, [0020]; page 6, [0047]). Schonfeld et al. indicate that the proteins are preferably cell surface receptor proteins, and thus, comprise an extracellular portion, a transmembrane portion, and a cytoplasmic portion, meeting the limitations of instant claims 1, 3, 6, and 8 (page 3, [0022]; Figure 2, 6). Schonfeld et al. state that the functionality of the proteins of the invention within a host cell is detectable in an assay suitable for demonstrating the signaling potential of said protein upon binding of a particular ligand (page 3, [0022-0023]). Schonfeld et al. teach a nucleic acid encoding the multi-functional protein, an expression construct for expressing such, a host cell, and a method of generating the multi-functional protein, meeting the limitations of instant claims 12-15 (page 3, [0012-0015]; pages 9-10). Schonfeld et al. disclose that a cleavable signal peptide is N-terminal to the transmembrane portion, meeting the limitations of instant claim 9 (page 4, [0026-0027]).
Conclusion
No claims are allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Von Heijne, G. J Mol Biol 225: 487-494, 1992 (teaches the “positive-inside rule” of transmembrane proteins)
Von Nickisch-Rosenegk et al. J Nanobiotechnol 10: 1, 2012 (fusion of SNAP-tag and membrane protein, DARC)
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BEB
Art Unit 1647
02 February 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647