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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/01/2025 has been entered.
Response to Amendment
Claims 1, 2, 4, 7, 8, 10, 12-20 are pending in the application. The Amendment filed on 10/01/2025 in which claims 1, 4 and 7 were amended, and claim 11 was canceled, has been entered. Claims 3, 5-6 and 9 were previously canceled. Claims 12-20 were previously withdrawn.
It is noted that amended claim 1 as submitted on 10/01/2025 recites “introducing the RBD-LgBiT DNA vector and the SmBiT-hACE2 DNA vector obtained in step (a) into prokaryotic cells, transfecting the RBD-LgBiT DNA vector and the SmBiT-hACE2 DNA vector obtained in step (a) into mammalian cells”. The species of prokaryotic cells and mammalian cells were previously recited in canceled claim 3 (see claim 3 as submitted on 10/19/2021). As indicated in the Restriction Action issued 09/24/2024, the species are independent or distinct because cell types in the instant case, are separate products having distinct functions, distinct structures, and distinct physical, chemical and functional properties requiring separate searches of the prior art. In addition, these species are not obvious variants of each other based on the current record. These cell types are thus deemed to constitute independent and distinct inventions within the meaning of 35 U.S.C. § 121. Absent evidence to the contrary, each such cell type is presumed to represent an independent and distinct invention, subject to a restriction requirement pursuant to 35 U.S.C. § 121 and 37 CFR 1.141 et seq. (MPEP § 803.04). It is noted that Applicant elected the species of “mammalian cells” in the response to the Election/Restriction requirement submitted on 10/11/2024. Accordingly, only the recitation concerning mammalian cells is herein being considered amended claim 1 as submitted on 10/01/2025.
Claims 1, 2, 4, 7, 8, and 10 are under examination on the merits.
Priority
Applicant’s claim for foreign priority of prior-filed Taiwanese application No. 110122937 filed on 06/23/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 10/19/2021. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
(Previous objection, withdrawn) Applicant’s amendments to the Specification submitted on 10/01/2025 have overcome the objection previously set forth in the Final Office Action mailed 05/01/2025.
Claim Objections
(Previous objections, withdrawn as to claims 1 and 7). Applicant’s amendments submitted on 10/01/2025 to claims 1 and 7 have overcome previous objections to claims 1 and 7.
Claims 1, 2, 7, 10 are objected to because of the following informalities:
Claims 1, 7 recite the term “the human angiotensin-converting enzyme II”, after the term was previously defined in claim 1 line 3 as “hACE2”. It is recommended that any consequent mentions of a term that was already defined use the abbreviation and not the full term.
Claims 1 part (a) is objected to because it contains a sequence disclosure that is encompassed by the definitions for amino acid sequences set forth in 37 CFR § 1.821(a)(1) and (a)(2) (i.e., “330-521 peptide sequence”) and it fails to make reference to the amino acid sequence by use of sequence identifiers (“SEQ ID NO:” or the like) in accordance to 37 CFR § 1.823(a)(5). See MPEP 2422. Appropriate correction is required.
The recitation in claim 1 part (b) of “into mammalian cells for establishing SmBiT-hACE2 expressing cells” should read “into mammalian cells to establish SmBiT-hACE2 expressing cells.” Appropriate correction is required.
The recitation in claim 2 of “SARS-CoV2” should read “SARS-CoV-2”. Appropriate correction is required.
The recitation in claim 10 of “screen a drug”, should read “screen for a drug” . Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1, 2, 4, 7, 8, and 10 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.
See claims 1, 2, 4, 7, 8, and 10 as submitted on 10/01/2025.
Claims 1 and 7 contain the trademark/trade name “LgBit” and/or “SmBit”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe biosensor proteins and, accordingly, the identification/description is indefinite.
Amended claim 1, part (a) recites the following wherein clause: “wherein E.coli optimized Spike-RBD domain sequence obtained from the 330-521 peptide sequence in complete sequence of E. coli optimized S is cloned into pET28a expression vector through NcoI and XhoI, Ala-Gly-LgBiT coding sequence is then incorporated through XhoI, wherein full-length hACE2 gene is subcloned into a EF-1a promoter-driven mammalian expression vector.” First, this recitation appears to have at least two independent clauses without proper punctuation or appropriate conjunctions. The absence of proper punctuation or appropriate conjunctions renders the indicated recitation unascertainable. The dependent claims do not add additional clarity and, therefore, are also indefinite. Second, it is unclear what the term “optimized” means because 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. Third, it is not clear if Applicant intended to recite “comprising”, “consisting essentially of” or “consisting of” to define the scope of a claim in relation to the “330-521 peptide sequence”. Fourth, the indicated recitation is unclear because it is missing indefinite articles (“a” or “an”) and/or a definite article (“the”) that clearly indicate the scope of the claim. For example, the recitation of “into pET28a expression vector” should read “into a pET28a expression vector”. Other instances of missing articles should be identified by Applicant and properly addressed. For purposes of compact prosecution and applying prior art, claim 1 part (a) was herein interpreted as referring to: “constructing a receptor-binding domain (RBD)-large BiT (LgBiT) DNA vector comprising a first DNA fragment encoding a large BiT (LgBiT) of a cleavable luciferase and a second DNA fragment encoding the spike protein receptor binding domain of the coronavirus from the specimen, and a small BiT (SmBiT)-hACE2 DNA vector comprising a second DNA fragment encoding a small BiT (SmBiT) of the cleavable luciferase and a DNA fragment encoding the human angiotensin-converting enzyme II”.
Claim 1, part (b) recites “transfecting the RBD-LgBiT DNA vector and the SmBiT-hACE2 DNA vector obtained in step (a) into mammalian cells for establishing SmBiT-hACE2 expressing cells”. This recitation is unclear because it seemingly indicates introducing two vectors into mammalian cells; the “RBD-LgBiT DNA vector” and the “SmBiT-hACE2 DNA vector” and establishing expression of only one of said vectors, the “SmBiT-hACE2 expressing cells”. For purposes of compact prosecution and applying prior art, claim 1 part (b) was herein interpreted as referring to: transfecting the RBD-LgBiT DNA vector and the SmBiT-hACE2 DNA vector obtained in step (a) into mammalian cells to establish RBD-LgBiT and/or SmBiT-hACE2 expressing cells”.
Regarding claim 1, part (c), the recitation of “the SmBiT forms a recombinant amino acid sequence with alanine (Ala)-glycine (Gly)-Ala, wherein the recombinant amino acid sequence is used with site-directed insertion between hACE2 amino acid 17th and 18th residues, wherein the mammalian cells are cells not expressing endogenous hACE2, wherein the SmBiT-hACE2 DNA vector enables the hACE2 expressed at cell surface” appears to have at least two independent clauses without proper punctuation or appropriate conjunctions. Additionally, this recitation appears to be missing definite and indefinite articles. The absence of proper punctuation or appropriate articles/conjunctions renders the indicated recitation confusing and unascertainable. For instance, it is not clear if the recitation of “SmBiT forms a recombinant amino acid sequence with alanine (Ala)-glycine (Gly)-Ala” refers to a GS linker between the SmBiT and the hACE2 sequence or not. Further, it is not clear what “the recombinant amino acid sequence is used with site-directed insertion” means. Further, it is not clear if the first DNA vector comprises a linker because the claim recites “without a linker” on line 6 and “LgBiT is linked to” on line 9. Further, the recitation above refers to amino acid sequences while the DNA vectors or plasmids are defined in terms of nucleic acids. For purposes of compact prosecution and applying prior art, claim 1 part (c) was herein interpreted as referring to: detecting the interaction between the spike protein receptor binding domain of the coronavirus and the human angiotensin-converting enzyme II by detecting a luminescence signal using fluorescence staining; wherein the first DNA vector comprises a LgBiT® subunit; wherein the second DNA vector comprises a SmBiT® subunit and the SmBiT® subunit is attached the N-terminus of the hACE2 gene and there’s a GS linker in the between the SmBiT® subunit and the hACE2 gene; and wherein detection time is 10 minutes.
The dependent claims do not add additional clarity and, therefore, are also indefinite.
Claim 8 recites “the luminescence signal are varied based on amounts of the ligand for detection and expression amounts of the cell expressing the human angiotensin- converting enzyme II in a dose-dependent manner”. This recitation appears to be grammatically incorrect and lack proper punctuation or appropriate articles/conjunctions. The absence of proper punctuation or appropriate articles/conjunctions renders the indicated recitation confusing and unascertainable. For purposes of compact prosecution and applying prior art, claim 8 was interpreted herein as referring to the biosensor activity showing a dose-dependent effect as measured in RLUs.
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this Office Action. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office Action.
Claim Rejections - 35 USC § 103
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 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.
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.
Claims 1, 2, 7-8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (prior art of record).
See claims 1, 2, 7-8, and 10 as submitted on 10/01/2025.
Regarding claim 1, as previously explained, Yang et al. teach a method of detection of protein-protein interactions both in vitro and in vivo between a spike protein receptor binding domain (RBD) of SARS-CoV-2 from a human specimen and the human angiotensin-converting enzyme II (hACE2) using NanoLuc® binary (NanoBiT®) technology, (Abstract; page 2, ¶ ¶ 3-6; Fig. 1B). The method of Yang et al. comprises the following steps:
Constructing a first DNA vector comprising a fragment of the Spike RBD of SARS-CoV-2, and the LgBiT® fragment of the cleavable NanoLuc® luciferase enzyme (page 2, ¶ 8; page 3, ¶ 1, Fig. 1A, B); and constructing a second DNA vector comprising a fragment of the hACE2 receptor, and the SmBiT® fragment of the cleavable NanoLuc® luciferase enzyme (page 2, ¶ 8; page 3, ¶ 1, Fig. 1A, B).
As indicated previously, Yang et al. teach transfecting mammalian HEK293T (human embryonic kidney) cells the two vectors described above, the first DNA vector comprising a fragment of the Spike RBD of SARS-CoV-2, and the LgBiT® fragment and the second vector comprising a fragment of the hACE2 receptor, and the SmBiT® fragment to establish expression of RBD-LgBiT and/or SmBiT-hACE2 (Abstract; page 3, ¶ 2; Fig. 1D).
As indicated previously, Yang et al. teach detecting the interaction between the spike protein receptor binding domain of the coronavirus and the human angiotensin-converting enzyme II by detecting a luminescence signal using fluorescence staining; wherein the first DNA vector comprises a LgBiT® subunit; wherein the second DNA vector comprises a SmBiT® subunit and the SmBiT® subunit is attached the N-terminus of the hACE2 gene and there’s a GS linker in the between the SmBiT® subunit and the hACE2 gene (page 4, ¶ 6, Fig. 1).
As indicated previously, Yang et al. teach an incubation time of 30 minutes followed by detection of biosensor activity (page 4, ¶ 6, Fig. 1). Further, as noted previously both, instant application and Yang et al., use a commercially available luciferase assay comprising the Nano-Glo® reagent (Promega, Madison, WI, USA) (Yang et al. page 4, ¶ 4; Specification, page 15), which supplies instructions for incubation periods and detection times, as well as optimization suggestions.
It would have been a matter of routine experimentation using standard laboratory techniques available before the effective filing date to determine the optimal detection time with a reasonable expectation of success, given that incubation instructions are supplied by the manufacturer of the Nano-Glo® reagent. Accordingly, the “detection time” recited in claim 1 of 10 minutes is considered to be one determined by routine optimization according to one of ordinary skill in the art in view of the teachings of Yang et al. It is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II.
Regarding claim 2, as described above, Yang et al. teach a spike protein receptor binding domain (RBD) of SARS-CoV-2 (Abstract; page 2, ¶ ¶ 3-6; Fig. 1B).
Regarding claim 7, as described above, Yang et al. teach a plasmid comprising a fragment of the Spike RBD of SARS-CoV-2 attached to the LgBiT fragment of the cleavable NanoLuc® luciferase enzyme (page 2, ¶ 8; page 3, ¶ 1, Fig. 1A, B). Yang et al. further teach the expression of this plasmid in cells wherein the recombinant RDB-LgBiT protein is used as a ligand for detection (page 4, ¶ 4; Fig. 1C, D).
Regarding claim 8, as previously explained, Yang et al. teach to the biosensor activity showing a dose-dependent effect as measured in RLUs (page 7, ¶ 1; Figs. 1E, 3A-C)
Regarding claim 10, as previously explained, Yang et al. teach the method described above for validation of small molecules, antibodies, and peptides with potential for treatment of SARS-CoV-2 infection (to screen a drug for treating coronavirus infection, as recited in claim 10) (page 5, ¶ ¶ 1, 2).
Accordingly, the limitations of claims 1, 2, 7, 8, 10 were prima facie obvious to one of ordinary skill in the art before the effective filing date especially in the absence of evidence to the contrary.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. as applied to claims 1, 2, 7, 8, 10 above, further in view of Khan (prior art of record).
See claim 4 as submitted on 10/01/2025.
Regarding claim 4, as indicated above, Yang et al. teach HEK293T cells (Abstract; page 3, ¶ 2; Fig. 1D).
Yang et al. do not teach a HeLa cell.
However, Khan teaches both HeLa cells and HEK293 cells are widely used for optimal mammalian gene expression (page 2, Table 3). Khan further teaches HeLa cells and HEK293 cells are functional equivalents for the application of the claimed method (mammalian gene expression) and one can be substituted for the other.
It would have been prima facie obvious to a person of ordinary skill in the art, at the time of filing, to include a HeLa cells as taught by Khan in the method of detection taught by Yang et al. for the benefit of using a second mammalian cell expression system with signals for synthesis, processing and secretion of eukaryotic proteins properly and efficiently recognized by the HeLa cells as taught by Khan. See MPEP 2144.06. Substituting Equivalents Known For The Same Purpose.
One of ordinary skill in the art would have had a reasonable expectation of success for introducing HeLa cells in the method of detection as taught by Yang et al. given that the methods of detection of protein-protein interactions with biosensors in many mammalian cells are known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Accordingly, the limitations of claim 4 were prima facie obvious to one of ordinary skill in the art before the effective filing date especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 10/01/2025 have been fully considered but they are not persuasive.
Applicant contends on page 19 of the Remarks submitted on 10/01/2025:
Applicant respectfully submits that the claims have been amended in accordance with Office suggestions (mainly derived from the interview conducted on 9/11/2025), with corresponding passages of the specification cited for express support. Distinctions from the prior art are further emphasized below, specifically, in step (b) of amended claim 1 which recites the establishment of SmBiT-hACE2 expressing cells, where hACE2 is displayed on the cell surface. As a result, the detection in amended step (c) can be completed within 10 minutes, and does not require a cell lysis step prior to detecting Nano-Luc luminescence, opposite the express requirements of Yang.
In response:
The Examiner acknowledges the amendment concerning the previous recitation of “recombinant plasmid”. It is also noted by the Examiner that no claim language was agreed upon in the Interview conducted on 09/11/2025. As explained above in detail the instant claims as written are rendered prima facie obvious by the teachings of Yang et al. and Khan. In response to Applicant’s remark about the recitation of establishment of SmBiT-hACE2 expressing cells, where hACE2 is displayed on the cell surface and does not require a cell lysis step prior to detecting Nano-Luc luminescence, it is noted that the claim as written requires establishment of SmBiT-hACE2 expression, which is already taught by Yang et al as explained above. The claim does not require stable expression which constitutes a different limitation. And even if the claim required such stable expression, the cited prior art already teaches stable expression (see Khan). Further, in response to Applicant’s Remarks with respect to the ACE2 receptor expressed on the cell surface. It is noted that the hACE2 gene is intrinsically expressed on the surface of cells and thus it serves as a receptor for the SARS-CoV-2 spike protein (see Yang et al., see Wells). Yang et al. specifically teach expression of the hACE2 gene at the surface of cells with the pFUSE_hIgG1 mammalian expression vector (Invivogen, San Diego, CA, USA) which contains a secretion signal (Yang et al., page 3). Further, Applicant’s remark that the claimed method does not require a cell lysis step prior to detecting Nano-Luc luminescence in pages 20, 24-27 of the Remarks as submitted on 10/01/2025, this remark is unpersuasive for the following reasons. First, instant claims do not explicitly exclude a lysis step nor does the Specification make any reference to the omission of a lysis step. Second, the lysis step in the protocol of the Nano-Glo® reagent (Promega, Madison, WI, USA) used by Yang et al. and by instant application (Yang et al. page 4, ¶ 4; Specification, page 15) is required for detection of luciferase-based luminescence with biosensors which are required to make contact (see Yang et al.). In fact, the lysis buffer is contained within the Nano-Glo® Luciferase Assay Buffer as evidence by the Nano-Glo® Luciferase Technical Manual (page 3) (See PTO-892: Notice of References Cited). Given that instant Specification (page 15) explicitly indicates the use of the Nano-Glo® reagent according to manufacturers instructions and such reagent already includes a lysis buffer, it is herein submitted that Applicant’s remark that the claimed method does not require a cell lysis step is unpersuasive.
Applicant contends on page 20 of the Remarks submitted on 10/01/2025:
Applicant respectfully submits that claims 1-4, 7-8, and 10 are fully enabled, fully descriptive, and are definite and particularly points out the subject matter which Applicant regards as the invention as required under 35 U.S.C. §112 and 37 C.F.R. §1.75.
In response:
The instant claims as written fail to particularly point out and distinctly claim the subject matter which the inventors regard as the invention. The specific reasons are explained above in detail. The instant claims require extensive revision to comply with 35 U.S.C. §112 (b).
Applicant contends on page 24 of the Remarks submitted on 10/01/2025:
Independent claim 1 has been amended by reciting the limitations of "the mammalian cells are cells not expressing endogenous hACE2", "the SmBiT-hACE2 DNA vector enables the hACE2 expressed at cell surface", and "E.coli optimized Spike-RBD domain sequence obtained from the 330-521 peptide sequence in complete sequence of E. coli optimized S is cloned into pET28a expression vector through NcoI and XhoI, Ala-Gly-LgBiT coding sequence is then incorporated through XhoI, wherein full-length hACE2 gene is subcloned into a EF-la promoter-driven mammalian expression vector". The Applicant respectfully submits that the cited references do NOT disclose or teach such limitations.
In response:
First, the combination of Yang et al. and Khan teach the same exact cells HeLa cells as required by instant claims. Therefore, the recitation of “the mammalian cells are cells not expressing endogenous hACE2" does not distinguish the claim invention from the cited prior art. Further, as indicated previously, claim 1 broadly encompasses any mammalian cell. Second, as indicated above, the hACE2 gene is intrinsically expressed on the surface of cells and thus it serves as a receptor for the SARS-CoV-2 spike protein (see Yang et al., see Wells). Further, Yang et al. specifically teach expression of the hACE2 gene at the surface of cells with the pFUSE_hIgG1 mammalian expression vector (Invivogen, San Diego, CA, USA) which contains a secretion signal (Yang et al., page 3). Further, with respect to the wherein clause of claim 1 (a): “wherein E.coli optimized Spike-RBD domain sequence obtained from the 330-521 peptide sequence in complete sequence of E. coli optimized S is cloned into pET28a expression vector through NcoI and XhoI, Ala-Gly-LgBiT coding sequence is then incorporated through XhoI, wherein full-length hACE2 gene is subcloned into a EF-1a promoter-driven mammalian expression vector”, a complete explanation of the rejection under 35 U.S.C. §112 and objection to this recitation is provided above. Further, the NanoLuc Binary Technology (NanoBiT®) was developed in 2016 and is widely used in binding assays (see Yang et al. and Wells et al.), the combination of the cited prior art teaches the exact embodiment of the claimed invention.
Applicant contends on page 27 of the Remarks submitted on 10/01/2025:
[T]he features of amended claim 1 in the present application are that "the spike protein receptor binding domain of the coronavirus from the specimen is attached to the LgBiT subunit without a linker" (see, e.g., FIG. 1C), not that there is a linker between RBD and LgBiT as disclosed in FIG. 1A of Yang. Furthermore, in the present application, RBD-LgBiT and SmBiT-ACE2 do not require a linker. In particular, the specification in Paragraph [0049], FIG. 1C, and the lower right panel of FIG. 1D clearly demonstrate that "The addition of an extra linker (SEQ ID NO: 4) between RBD and LgBiT did not increase the luciferase activity." On the contrary, Yang indeed reveals in FIG. lA the presence of a GS linker between RBD and LgBiT. This feature is clearly demonstrated in Paragraph [0049] of the present specification, FIGS. 1C and 1D.
In response:
First it is noted that Fig. 1C of instant Drawings show both, a construct comprising LgBiT® and RBD with a linker and one without a linker. In response to Applicant’s remark that “in the present application, RBD-LgBiT and SmBiT-ACE2 do not require a linker”. This assertion contradicts the limitations of the instant claims as submitted on 10/01/2025 which require a GS linker between the SmBiT® fragment and the hACE2 gene. With respect to the claimed RBD-LgBiT, it is noted that the instant claim language in claim 1 (c) contains seemingly contradicting terms, first the recitation of “without a linker” on line 6 and later “LgBiT is linked to the spike protein” on line 9. Further, it is noted that the use of linkers specifically for constructs comprising biosensors is considered to be subject of routine optimization (see Wells, see Yang et al.). Even in instant application the use of linkers has been tested in many configurations to optimize signal (see instant Drawings, Fig. 1C). Incorporation and/or omission of linkers in constructs are part of routinely optimization widely practiced in the art (see Yang et al., see Wells). Accordingly, it is herein maintained that it would have been prima facie obvious to one of ordinary skill in the art to change the configuration of the construct by switching attachment sites, adding or removing sequence linkers, and optimizing the length of a linker as shown in the cited prior art such that a luciferase activity can be optimized. Therefore, Applicant’s arguments with respect to a linker are unpersuasive. Again, the NanoLuc Binary Technology (NanoBiT®) was developed in 2016 and is widely used in binding assays (see Yang et al. and Wells et al.), the combination of the cited prior art teaches the exact embodiment of the claimed invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARLENE V BUCKMASTER whose telephone number is (703)756-5371. The examiner can normally be reached M-R 8:00 AM - 5:00 PM.
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/MARLENE V BUCKMASTER/
Examiner, Art Unit 1671
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672