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 .
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.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-16 in the reply filed on 3/11/2026 is acknowledged.
Claims 17-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II-III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/11/2026.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2021/031871, filed 5/11/2021, which claims benefit under 35 U.S.C. 119(e) to provisional application Nos. 63/067,273 filed 08/18/2020; 63/058,379 filed 07/29/2020; 63/056,509 filed 7/24/2020; and 63/022,789 filed 5/11/2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement filed 1/18/2023 and the information disclosure statement filed 3/15/2023 are being considered by the examiner.
Claim Objections
Claims 1 and 5 are objected to because of the following informalities:
In claim 1 line 1, Applicant uses the abbreviation “SARS-CoV-2”, it is recommended that abbreviations be accompanied by their full meaning at least at first instance that the abbreviation is being used in order to improve clarity of the record and avoid confusion.
In claim 5 line 2, "...is a Spike Protein wherein the first..." appears to be a typographical error, namely it is suggested that "...is a Spike Protein wherein the first..." read as "...is a Spike Protein, wherein the first..." (adding a comma between "Protein" and "wherein").
In claim 5 line 3, Applicant uses the abbreviation “RBD”, it is recommended that abbreviations be accompanied by their full meaning at least at first instance that the abbreviation is being used in order to improve clarity of the record and avoid confusion.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-8 and 10-16 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 written description rejection.
Claim 1 and its dependent claims (claims 2-8 and 10-16) require a first fusion protein that comprises a first peptide fragment of a split reporter protein, and a second fusion protein that comprises a second peptide fragment of the split reporter protein that associate to produce an enzymatically active reporter protein.
The specification does not describe which amino acid residues, nucleic acid residues, or other molecular components are present in the genus of agents encompassed by claims 1-8 and 10-16. The specification fails to disclose the structures common to all members of the genus and fails to provide sufficient specific examples of agents to be used. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described. Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement.
Although the specification discloses that “[i]n some approaches, the split reporter is a split-luciferase” (para. 80), “Other Split Reporter Systems…horseradish peroxidase… ascorbate peroxides…β-lactamase… β-galactosidase… dihydrofolate reductase…GFP… infrared fluorescent protein IFP1.4… spilt protein complementation… or biomolecular fluorescence complementation” (para. 85); these are not considered enough examples to show possession of the genus of agents claimed. A person having ordinary skill in the art would question whether Applicant was in possession of the whole genus of agents claimed, i.e. any two peptide fragments that associate to produce an enzymatically active reporter protein .
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of each genus of claimed agents, i.e., a first peptide fragment and a second peptide fragment that associate to produce an enzymatically active reporter protein. Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
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 3 and 9-10 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.
Claim 3 recites “The method of claim 1, wherein the SARS-CoV-2 viral protein is a SARS-CoV-2 N protein first fusion protein comprises a first SARS-CoV-2 N protein domain and the first peptide fragment of a split reporter protein, and the second fusion protein comprises a second SARS-CoV-2 N protein domain and the second peptide fragment of the split reporter protein; and wherein each of the first SARS-CoV-2 N protein domain and the second SARS-CoV-2 N protein domain comprises a sequence that is at least 90% identical to SEQ ID NO: 5”. However, the limitation “wherein the SARS-CoV-2 viral protein is a SARS-CoV-2 N protein first fusion protein comprises” is unclear. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 9 contains the trademark/trade name "LgBiT" and "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 a split luciferase system by "NanoBiT® from Promega (Madison, WI)" (specification para. 80) and, accordingly, the identification/description is indefinite.
Claim 10 recites the limitation "the SARS-CoV-2 N protein domain" in line 2. There is insufficient antecedent basis for this limitation in the claim. It is not clear what SARS-CoV-2 N protein domain is being claimed because “the SARS-CoV-2 N protein domain” could be referring to the “first SARS-CoV-2 N protein domain” or the “second SARS-CoV-2 N protein domain” recited in claim 3 lines 2-4.
For these reasons, the claims are indefinite.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 7-9, 11-12 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (CN 111024954 A)-Cite No. 4 of IDS 1/18/2023 ("Chen") in view of Dixon et al. al. (US 20160282340 A1)-Cite No. 2 of IDS filed 1/18/2023 ("Dixon").
Although Chen is cited on the IDS 1/18/2023, there is no English translation on record. Therefore, Chen is being cited on a PTO 892 form and an English translation is included.
Regarding claims 1-2 and 7-9, Chen teaches a method for detecting antibodies against a SARS-CoV-2 viral protein in a biological sample, wherein the antibodies detected are neutralizing antibodies (“The principle of the COVID-19 antibody detection test strip of the present invention to detect whether the sample contains COVID-19 antibody” page 8 para. 12, “the immunological reaction state of the body can be accurately judged” page 3 para. 3) comprising i) combining a) the biological sample; b) a fusion protein that comprises a first SARS-CoV-2 viral protein domain and a reporter agent; ii) maintaining the mixture under conditions in which, only if the biological sample comprises individual antibodies, at least one of which binds the SARS-CoV-2 viral protein domain, the reporter agent becomes detectable; and iii) detecting the reporter agent if the biological sample comprises antibodies against the SARS-CoV-2 viral protein (“after dropping the sample on the sample pad of the test strip… When the sample contains the new coronavirus COVID-19 antibody, the new coronavirus COVID-19 antibody will bind to the gold label antigen to form the gold label antigen-antibody complex, and the reaction complex moves to the detection line of the reaction pad due to chromatography ; When the new coronavirus COVID-19 antibody contained in the sample is an IgM antibody, a gold-labeled antigen-antibody-anti-human IgM antibody complex is formed on the second detection line 15, the gold-labeled antibody is fixed and detected in the second detection A red line is shown on line 15; when the new coronavirus COVID-19 antibody contained in the sample is an IgG antibody, a gold label antigen-antibody-anti-human IgG antibody complex is formed on the third detection line 16, and the gold label antibody is fixed Next, a red line is displayed on the third detection line 16” page 8 para. 12 “The COVID-19 antibody detection test strip includes…Gold-labeled new coronavirus NP protein and S protein” page 4 last paragraph and page 5 para. 1,“ The preparation of recombinant SARS NP protein is carried out according to the conventional method ” page 7 paras. 3). Chen teaches that in December 2019, a new coronavirus disease was discovered, i.e. COVID-19 (“ 2019In mid-December, atypical pneumonia (atypical pneumonia) of unknown etiology was first discovered in Wuhan, China. Scientific research has shown that it is caused by a new coronavirus COVID-19” page 1 para. 3).
Chen fails to teach a first peptide fragment comprising SEQ ID NO: 4 (LgBiT) of a split reporter protein, wherein the split reporter protein is a split-luciferase, and a second fusion protein that comprising a second SARS-CoV-2 viral protein domain, wherein the first and the second viral proteins domains are the same, and a second peptide fragment comprising SEQ ID NO: 3 (SmBiT) of the split reporter protein; ii) maintaining the mixture under conditions in which the first peptide fragment and the second peptide fragment associate to produce an enzymatically active reporter protein; and iii) detecting the association of the first peptide fragment and the second peptide fragment.
Dixon teaches “activation of bioluminescence by structural complementation” (Title). Dixon suggests mixing a sample with a first fusion protein that comprises a first viral protein domain and a first peptide fragment comprising SEQ ID NO: 4 (LgBiT) of a split reporter protein, wherein the split reporter protein is a split-luciferase, and a second fusion protein that comprises a second viral protein domain and a second peptide fragment comprising SEQ ID NO: 3 (SmBiT) of the split reporter protein, maintaining the mixture under conditions in which the first peptide fragment and the second peptide fragment associate to produce an enzymatically active reporter protein; and detecting the association of the first peptide fragment and the second peptide fragment (“(c) providing first and second fragments of a protein…wherein the fragments are individually substantially non-luminescent but exhibit luminescence upon interaction of the fragment” para. 15, “Interaction elements may facilitate formation of the bioluminescent complex by any suitable mechanism (e.g., bringing non-luminescent pair/group into close proximity” para. 219, “a first fusion protein comprising a first non-luminescent element and first interaction element as well as a second fusion protein comprising a second non-luminescent element and second interaction element are… combined…for signal detection” para. 243, “A protein of interest…is tagged with the non-luminescent peptide through binding of the reactive group to the protein of interest. Because the peptide is small, it does not affect the functionality of the protein of interest. Complimentary non-luminescent polypeptide is added to the system, and a luminescent complex is produced upon binding to the polypeptide to the peptide” para. 277, “enabling measurement of viral titers” para. 559, “In some embodiments, substantially non-luminescent peptides and polypeptides are provided with less than 100% sequence identity and/or similarity to any portion of an existing luciferase” para. 249, “Although not limited to such sequences, the polypeptide amino acid sequence may be selected from one of the amino acid sequences of SEQ ID NOS: 441-2156” para. 9). Note that SEQ ID NO: 2513 of Dixon is 100% matched to claimed SEQ ID NO: 3. Also, SEQ ID NO: 2150 of Dixon is 100% matched to claimed SEQ ID NO: 4. Dixon further teaches wherein the first and the second viral proteins domains are the same (“An interaction pair may be made of two of the same interaction elements (i.e. homopair)” para. 219). Dixon further teaches that “[s]uch assays are useful for monitoring molecular interactions under any suitable conditions (e.g., in vitro, in vivo, in situ, whole animal, etc.), and find use in, for example, drug discovery, elucidating molecular pathways, studying equilibrium or kinetic aspects of complex assembly, high throughput screening, proximity sensor, etc.” (para. 259).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Chen to rely on the technique of Dixon for SARS-CoV-2 antibody detection, i.e. to use a first peptide fragment comprising SEQ ID NO: 4 of a split reporter protein, wherein the split reporter protein is a split-luciferase, and a second fusion protein comprising a second SARS-CoV-2 viral protein domain, wherein the first and the second viral proteins domains are the same, and a second peptide fragment comprising SEQ ID NO: 3 of the split reporter protein, maintaining the mixture under conditions in which the first peptide fragment and the second peptide fragment associate to produce an enzymatically active reporter protein; and detecting the association of the first peptide fragment and the second peptide fragment taught by Dixon because Dixon teaches that this enables the monitoring of molecular interactions under any suitable condition, drug discovery, molecular pathway elucidation, high throughput screening, etc. and Chen is interested in the new COVID-19 disease. Therefore, one would have been motivated to make such a modification in order address the new coronavirus pneumonia (COVID-19), and to better diagnose, screen and study COVID-19. A person having ordinary skill in the art would have had a reasonable expectation of success given that Chen and Dixon are both concerned with methods to detect viral antibodies from a sample.
Regarding claims 11-12, Chen in view of Dixon teach the method of claim 1 as discussed above.
Chen fails to teach wherein the first peptide fragment of the split reporter protein is fused to the first SARS-CoV-2 viral protein domain via a first flexible linker and/or the second peptide fragment of the split reporter protein is fused to the second SARS-CoV-2 viral protein domain via a second flexible linker, wherein each of the first and second flexible linkers has a length in the range of one to 50 amino acids.
Dixon suggests wherein the first peptide fragment of the split reporter protein is fused to the first SARS-CoV-2 viral protein domain via a first flexible linker and/or the second peptide fragment of the split reporter protein is fused to the second SARS-CoV-2 viral protein domain via a second flexible linker, wherein each of the first and second flexible linkers has a length in the range of one to 50 amino acids (“In some embodiments, a linker provides a desired amount of distance ( e.g., 1, 2, 3, 4, 5, 6 ... 10 ... 20, or more monomer units) between signal and interaction elements… In some embodiments, a linker is any suitable chemical moiety capable of linking, connecting, or tethering a non-luminescent element to an interaction element. In some embodiments, a linker is a polymer of one or more repeating or non-repeating monomer units (e.g., nucleic acid, amino acid, carbon-containing polymer, carbon chain, etc.). When a non-luminescent element and interaction element are part of a fusion protein, a linker (when present) is typically an amino acid chain” paras. 245-246, “All fusions constructs contained a l0aa Gly-Ser flexible linker” para. 554). Dixon suggests that the linker assists the association between the peptide fragments (“linker assists the interaction element in facilitating the formation of a non-luminescent pair interaction” para. 245).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Chen in view of Dixon to rely wherein the first peptide fragment of the split reporter protein is fused to the first SARS-CoV-2 viral protein domain via a first flexible linker and/or the second peptide fragment of the split reporter protein is fused to the second SARS-CoV-2 viral protein domain via a second flexible linker, wherein each of the first and second flexible linkers has a length in the range of one to 50 amino acids taught by Dixon because Dixon suggests that this assists the association between the peptide fragments. A person having ordinary skill in the art would have had a reasonable expectation of success given that Chen and Dixon are both concerned with methods to detect viral antibodies from a sample.
Regarding claim 15, Chen in view of Dixon teach the method of claim 1 as discussed above.
Chen fails to teach wherein the first fusion protein is present in the mixture at a concentration in the range from 0.3 nM to 10 nM, and/or the second fusion protein is present in the mixture at a concentration in the range from 0.3 nM to 10 nM.
Dixon suggests wherein the first fusion protein is present in the mixture at a concentration in the range from 0.3 nM to 10 nM, and/or the second fusion protein is present in the mixture at a concentration in the range from 0.3 nM to 10 nM (“Peptides were diluted to 12.66 uM (4x) in PBS+0.1 % Prionex and then diluted serially 7 times (8 concentrations total) in 0.5 log steps (3.162 fold dilution)” para. 438 of Dixon). Note that Dixon teaches a concentration of 12.66 uM diluted 7 times by a factor of 3.612, i.e. 12.66/3.162 = 4/3.162 = 1.27/3.162 = .4/3.162 = .127/3.162 = .04/3.162 = .0127/3.162 = .004 = 4 nM, therefore, Dixon teaches a concentration down to 4 nM.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Chen in view of Dixon to rely on the first fusion protein is present in the mixture at a concentration in the range from 0.3 nM to 10 nM, and/or the second fusion protein is present in the mixture at a concentration in the range from 0.3 nM to 10 nM taught by Dixon because it would have been a simple matter of applying a known technique to a known method. In this case, both Chen and Dixon teach a fusion protein in a mixture. Dixon simply applies the art-recognized technique of the fusion protein being at a concentration in the range from 0.3 nM to 10 nM. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique taught by Dixon to the base method taught by both Chen and Dixon. A person having ordinary skill in the art would have had a reasonable expectation of success given that Chen and Dixon are both concerned with methods to detect viral antibodies from a sample.
Claims 3-4, 10 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Chen in view of Dixon as applied to claim 1 above, and further in view of Saha et al. bioRxiv preprint doi: https://doi.org/10.1101/2020.04.07.029132; this version posted April 11, 2020 as evidenced by the National Library of Medicine GenBank: QIA98590.1 (retrieved online https://www.ncbi.nlm.nih.gov/protein/QIA98590.1 on 4/2/2026).
Regarding claim 3, although the claim is indefinite (see112b rejection above), in the interest of compact prosecution, the limitation “wherein the SARS-CoV-2 viral protein is a SARS-CoV-2 N protein first fusion protein comprises” is interpreted as “wherein the SARS-CoV-2 viral protein is a SARS-CoV-2 N protein, wherein the first fusion protein comprises” (annotation added). Chen in view of Dixon teach the method of claim 1 as discussed above.
Chen in view of Dixon further suggest wherein the SARS-CoV-2 viral protein is a SARS-CoV-2 N protein (“the new coronavirus NP protein and S protein coated with colloidal gold” page 7 para. 34 of Chen, “nucleocapsid Nucleocapsidprotein (NP)” page 6 para. 9 of Chen), wherein the first fusion protein comprises a first SARS-CoV-2 N protein domain and the first peptide fragment of a split reporter protein, and the second fusion protein comprises a second SARS-CoV-2 N protein domain and the second peptide fragment of the split reporter protein; (page 7 para. 34 of Chen and paras. 15, 219, 243, 259, 277 and 559 of Dixon).
Chen in view of Dixon fail to teach wherein each of the first SARS-CoV-2 N protein domain and the second SARS-CoV-2 N protein domain comprises a sequence that is at least 90% identical to SEQ ID NO: 5
Saha teaches “A virus that has gone viral: Amino acid mutation in S protein of Indian isolate of Coronavirus COVID-19 might impact receptor binding and thus infectivity” (Title). Saha further teaches that “SARS-CoV-2 sequence data is expanding rapidly…From India, there are only two full genome sequences submitted from the state of Kerela (GenBank accession…MT050493” (page 3 paras. 2-3). Note that as evidenced by the National Library of Medicine, the sequence of accession number MT050493, which corresponds to GenBank: QIA98590, has a 100% match to SEQ ID NO: 5 claimed. Saha further suggests that wherein each of the first SARS-CoV-2 N protein domain and the second SARS-CoV-2 N protein domain comprises a sequence that is at least 90% identical to SEQ ID NO: 5, enables the biological study and understanding of the virus (“of now, compared to many countries, the rate of transmission is comparatively controlled in India. Although this might be influenced by many factors like general immunity, point of entry of this virus in the country, measures taken to contain the spread, diagnosis, data management etc, we have used the available sequence data of Indian isolates to understand the biology of this virus” page 3 para. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Chen in view of Dixon to rely on the wherein each of the first SARS-CoV-2 N protein domain and the second SARS-CoV-2 N protein domain comprises a sequence that is at least 90% identical to SEQ ID NO: 5 taught by Saha because Saha teaches that this enables the biological study and understanding of the SARS-CoV-2 virus and Chen in view of Dixon are interested in the COVID-19 disease. A person having ordinary skill in the art would have had a reasonable expectation of success given that Saha teaches the sequence is deposited on the GenBank database.
Regarding claim 4, Chen in view of Dixon and Saha teach the method of claim 3 as discussed above.
Chen in view of Dixon and Saha further suggest wherein the first and second SARS-Cov-2 N protein domains are the same (para. 219 of Dixon).
Regarding claim 10, Chen in view of Dixon and Saha teach the method of claim 3 as discussed above.
Chen in view of Dixon and Saha further suggest wherein the first peptide fragment of the split reporter protein is fused to the C-terminus of the SARS-CoV-2 N protein domain, and wherein the second peptide fragment of the split reporter protein is fused to the C- terminus of the second SARS-CoV-2 N protein domain (“In some embodiments, a single amino acid chain comprises, consists of, or consists essentially of a non-luminescent element, an interaction element, and… a C-terminal sequence” para. 242, “All of the peptides were fused to a HALOTAG protein (Promega Corporation). Peptides identified as "HT-NLpep" indicate that the peptide is located at the C-terminus of the HALOTAG protein” para. 297 of Dixon).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Chen in view of Dixon and Saha to rely on the wherein the first peptide fragment of the split reporter protein is fused to the C-terminus of the SARS-CoV-2 N protein domain, and wherein the second peptide fragment of the split reporter protein is fused to the C- terminus of the second SARS-CoV-2 N protein domain taught by Dixon because it would have been a simple matter of applying a known technique to a known method. In this case, both Chen in view of Dixon and Saha and Dixon teach a first peptide fragment of the split reporter protein fused to the SARS-CoV-2 N protein domain. Dixon simply applies the art-recognized technique of the split reporter protein being fused to the C-terminus of the SARS-CoV-2 N protein domain. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique taught by Dixon to the base method taught by both Chen in view of Dixon and Saha and Dixon. A person having ordinary skill in the art would have had a reasonable expectation of success given the cumulative disclosures of these prior art references.
Regarding claim 14, Chen in view of Dixon and Saha teach the method of claim 3 as discussed above.
Chen in view of Dixon and Saha further suggest wherein the first peptide fragment of the split reporter protein is fused to the first SARS-CoV-2 N protein domain via a first flexible linker and/or the second peptide fragment of the split reporter protein is fused to the second SARS-CoV-2 N protein domain via a second flexible linker, and wherein the first flexible linker and the second flexible linker each have a length of 10 amino acids (paras. 245-246 and 554 of Dixon).
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Chen in view of Dixon as applied to claim 1 above, and further in view of Wrapp et al. bioRxiv preprint doi: https://doi.org/10.1101/2020.02.11.944462; this version posted February 15, 2020 (“Wrapp”).
Regarding claim 5, Chen in view of Dixon teach the metho of claim 1 as discussed above.
Chen in view of Dixon suggest wherein the SARS-CoV-2 viral protein is a Spike protein (“the new coronavirus NP protein and S protein coated with colloidal gold” page 7 para. 34 of Chen, “spikeglycoprotein (S),” page 6 para. 9 of Chen), wherein the first fusion protein comprises a first SARS-CoV-2 SpikeRBD protein domain and the first peptide fragment of a split reporter protein, and the second fusion protein comprises a second SARS-CoV-2 SpikeRBD protein domain and the second peptide fragment of the split reporter protein; (page 7 para. 34 of Chen and paras. 15, 219, 243, 259, 277 and 559 of Dixon).
Chen in view of Dixon fail to teach wherein each of the first SARS-CoV-2 SpikeRBD domain and the second SARSCoV-2 SpikeRBD domain comprises a sequence that is at least 90% identical to SEQ ID NO: 1.
Wrapp teaches “Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation” (Title). Wrapp further teaches that “[t]he outbreak of a novel betacoronavirus (2019-nCov) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for urgently needed vaccines, therapeutic antibodies, and diagnostics” (Abstract). Wrapp further teaches the amino acid sequence of the SARSCoV-2 SpikeRBD domain (“Supplementary Figure 5. Sequence alignment of 2019-nCoV S, SARS-CoV S and RaTG13 S” page 25). Note that the sequence taught by Wrapp is 100% matched to claimed SEQ ID NO: 1. Wrapp further teaches that “[d]ue to the indispensable function of the S protein it represents a vulnerable target for antibody-mediated neutralization” (page 3 lines 33-34). Wrapp further teaches that “[w]e also analyzed the 61 available 2019-nCoV S sequences in GISAID and found that there were only 9 amino acid substitutions among all deposited sequences. Most of these substitutions are relatively conservative and they are not expected to have a dramatic effect on the structure or function of the 2019-nCoV S protein (Supplementary Figure 6)” (page 6 lines 88-92). Wrapp further teaches that “2019-nCoV S shares roughly 96% sequence identity with the S protein from the bat coronavirus RaTG13” (page 5 lines 80-81).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Chen in view of Dixon to rely on the first SARS-CoV-2 SpikeRBD domain and the second SARSCoV-2 SpikeRBD domain comprising a sequence that is at least 90% identical to SEQ ID NO: 1 taught by Wrapp because Wrapp suggests this sequence is associated with antibody-mediated neutralization of SARS-CoV-2 and diagnostics and Chen in view of Dixon are interested in a method of detecting antibodies against SARS-CoV-2. A person having ordinary skill in the art would have had a reasonable expectation of success given that Wrapp teaches that there are 61 available sequences of the SARS-CoV-2 SpikeRBD domain in GISAID.
Regarding claim 6, Chen in view of Dixon and Wrapp teach the method of claim 5 as discussed above.
Chen in view of Dixon and Wrapp further suggest wherein the first and second SARS-Cov-2 SpikeRBD domains are the same (para. 219 of Dixon).
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Chen in view of Dixon and Wrapp as applied to claim 5 above, and further in view of Chichili et al. Protein Sci. 2012 Dec 6;22(2):153–167. doi: 10.1002/pro.2206 (“Chichili”).
Regarding claim 13, Chen in view of Dixon and Wrapp teach the method of claim 5 as discussed above.
Chen in view of Dixon and Wrapp further suggest wherein the first peptide fragment of the split reporter protein is fused to the first SARS-CoV-2 SpikeRBD domain via a first flexible linker and/or the second peptide fragment of the split reporter protein is fused to the second SARS-CoV-2 SpikeRBD domain via a second flexible linker (paras. 245-246 and 554 of Dixon).
Wrapp further teaches that “[t]he outbreak of a novel betacoronavirus (2019-nCov) represents a pandemic threat that has been declared a public health emergency of international concern” (Abstract).
Dixon teaches that “a linker provides a desired amount of distance ( e.g., 1, 2, 3, 4, 5, 6 ... 10 ... 20, or more monomer units)… typically an amino acid chain.” (paras. 245-246).
Although Chen in view of Dixon and Wrapp suggest an amino acid flexible linker between 1 to “20, or more monomer units” (para. 245 Dixon), Chen in view of Dixon and Wrapp fail to explicitly teach wherein the first flexible linker has a length of 15 amino acids and the second flexible linker each have a length of 25 amino acids.
Chichili teaches “Linkers in the structural biology of protein–protein interactions” (Title). Chichili further teaches that “The lengths of linkers vary from 2 to 31 amino acids, optimized for each condition so that the linker does not impose any constraints on the conformation or interactions of the linked partners. Various structures of covalently linked protein complexes have been described” (Abstract). Chichili further teaches that “In general, the minimum and maximum lengths of linkers used in the studies reviewed here were between 2 and 31 amino acids (Table I)” (page 163 col. 2 para. 2).
With regards to the claimed length of 15 amino acids for the first linker and 25 amino acids for the second linker, the prior art teaches a range of linkers from 2 to 31 amino acids (Chichili Abstract). In such a case, since there is a substantial overlap of the prior art range of lengths and the claimed lengths, a prima facie case of obviousness exists because it would have been obvious to a person having ordinary skill in the art to arrive at the claimed lengths of 15 and 25 amino acids by selecting values disclosed within the prior art range. See MPEP 2144.05.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Chen in view of Dixon and Wrapp to rely on the first flexible linker having a length of 15 amino acids and the second flexible linker each having a length of 25 amino acids taught by Chichili because it would have been obvious to try picking a first flexible linker of 15 amino acids and a second flexible linker of 25 amino acids from the finite list of linker lengths disclosed by Chichili. In this case, given that Wrapp teaches that there is an ongoing pandemic emergency (COVD-19), and that Chichili suggest a finite list of possible predictable solutions to the amino acid length of flexible linkers to be used for fusion proteins, a person having ordinary skill in the art would have been motivated to try picking the 15 and 25 amino acid linker taught by Chichili in order to optimize the method for detecting antibodies against SARS-CoV-2 and address COVID-19. A person having ordinary skill in the art would have had a reasonable expectation of success given that both Chen in view of Dixon and Wrapp and Chichili teach flexible amino acid linkers for fusion proteins.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Chen in view of Dixon as applied to claim 15 above, and further in view of Lindholm A BiT or BRET, Which is Better? POSTED ON FEBRUARY 27, 2019 (retrieved online https://www.promegaconnections.com/a-bit-or-bret-which-is-better/ on 4/2/2026).
Regarding claim 16, Chen in view of Dixon teach the method of claim 15 as discussed above.
Chen in view of Dixon fail to teach wherein the first fusion protein and the second fusion protein are present in the mixture at about equal molar concentrations.
Lindholm teaches “A BiT or BRET, Which is Better?” (Title). Lindholm further teaches “The NanoLuc® Binary Technology (NanoBiT®)…composed of … Large BiT (LgBiT; 18kDa) … and Small BiT (SmBiT;1.3kDA)” (page 1 para. 2). Lindholm further teaches that “In general, a 1:1 ratio of SmBiT and LgBiT vectors is appropriate for PPI assays” (page 4 col. 2 row 2). Note that Lindholm inherently provides wherein the first fusion protein and the second fusion protein are present in the mixture at about equal molar concentrations when teaching that the SmBiT and LgBiT are present at equal concentrations because the SmBiT and LgBiT are fused to the fusion proteins, i.e. are the first and second peptide fragment of the split reporter protein.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Chen in view of Dixon to rely on the first fusion protein and the second fusion protein being present in the mixture at about equal molar concentrations taught by Lindholm because Lindholm teaches this is appropriate for protein-protein interaction assays and Chen in view of Dixon are interested in detecting antibodies using fusion proteins, i.e. protein-protein interactions. A person having ordinary skill in the art would have had a reasonable expectation of success given that both Chen in view of Dixon and Lindholm teach the Promega split reporter protein.
Conclusion
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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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