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 .
DETAILED ACTION
The instant application is in response to the papers filed on January 6, 2026. Claims 1, 2, 4, 6, 7, 10, 15-17, 19, 21, 23, 27, 32-36, 38, 40, 44 are currently pending as per claims filed on January 6, 2026. Claims 3, 5, 8, 9, 11-14, 18, 20, 22, 24-26, 28-31, 37, 39, 41-43, 45-64, have been cancelled, and claims 4, 6, 7, 10, 17, 19, 21, 23, 27, 32, 35, 36, 38, 40, 44 have been amended in Applicant’s amendment filed May 2, 2023. The most recent claims filed on January 6, 2026 have no new claims, recently cancelled claims, and amended claims.
Applicant’s election without traverse of the invention of Group I, e.g., claims 1, 2, 4, 6, 7, and 10, drawn to a nucleic acid construct encoding a modular reporter polypeptide, in the reply filed on January 6, 2026 in response to the restriction requirement filed on November 6, 2025 is acknowledged.
Claims 15-17, 19, 21, 23, 27, 32-36, 38, 40, 44 are withdrawn from further consideration by the Examiner, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Reinstatement of claims drawn to non-elected inventions will be withdrawn during prosecution. The requirement for restriction between Groups I-II is maintained for reasons of record, and hereby made FINAL. Applicant timely responded to the restriction (election) requirement in the Paper filed on January 6, 2026.
Therefore, claims 1, 2, 4, 6, 7, and 10 are currently under examination to which the following grounds of rejection are applicable.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US2021/057723, filed November 2, 2021. Applicant’s claim for the benefit of a prior-filed parent provisional application 63/108,611 November 2, 2020 filed under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is November 2, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 3, 2023 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because the Sequence Listing filed on May 2, 2023 describes SEQ ID NO: 25 and 27 as being 969 a.a. and 970 a.a. in length, yet Figures 3A and 4A which illustrate these respective sequences, reveal different lengths, specifically, 973 a.a. for both. It appears that Applicant unintentionally copied portions of the tables for Fig. 2A, based on this figure representing SEQ ID NO: 23 which is 973 a.a.. Therefore, corrected drawings are required wherein the residue numbers are appropriately corrected for Fig. 3A and 4A.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) 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. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. 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.
Claim Objections
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. Claim 6 recites “wherein the Tat sequence comprises amino acids 1 to 72 of HIV-I Tat.”, but there is no mention of a related SEQ ID NO for this sequence of amino acids. Where the description or claims of a patent application discuss a sequence that is set forth in the "Sequence Listing," in accordance with paragraph (c) of this section, reference must be made to the sequence by use of the sequence identifier (§ 1.823(a)(5) ), preceded by "SEQ ID NO:" or the like, in the text of the description or claims, even if the sequence is also embedded in the text of the description or claims of the patent application.
The proper amendment is to include a SEQ ID NO in claim 6, and to point to locations in the Drawings and/or Specification for support.
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.
Claim 10 is 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 10 recites the limitation “the fluorescent reporter polypeptide” in lines 4-5. There is insufficient antecedent basis for this limitation in the claim. Claim 1 introduces “a reporter polypeptide”, but there is no further limitation and introduction of the reporter being a fluorescent reporter, and therefore “the fluorescent reporter polypeptide” in claim 10 lacks antecedent basis. It appears that claim is intended to depend from claim 7 wherein such introduction is made.
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, 2, 4, 6, 7 and 10 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP § 2163. The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
The instant claims are drawn to a nucleic acid construct encoding a modular reporter polypeptide, wherein the modular reporter polypeptide comprises, in order from N-terminus to C-terminus: a myristoylation motif, a protease polypeptide, a transactivator of transcription (Tat) sequence, and a reporter polypeptide. Therefore, the claims are drawn to a vast genus of modular reporter polypeptides comprising any protease polypeptides and reporter polypeptide, and in combination with the remaining elements acts as a modular reporter polypeptide.
Teachings within the Specification:
The Specification describes the Instant Application is based on the development of a gain-of-function reporter for the MPpro that is used to determine potential inhibitors via drug screening (par 0005, 0025). The protease can be a viral protease with select examples recited , e.g. SARS-CoV-2 Mpro polypeptide, a MERS Mpro polypeptide, a SARS Mpro polypeptide, a hepatitis C virus (HCV) NS3/4a protease polypeptide, a picornavirus 3C protease polypeptide, a HCoV-229E Mpro polypeptide, or a HCoV-NL63 Mpro polypeptide, and further requires at a minimum a portion of a full-length protease protein, provided that it includes protease activity (par 0006,0030). In relation to using the modular reporter polypeptide in identifying protease inhibitors, the inhibitors are identified based on the level of reporter activity being higher than that of the control level of activity, i.e. gain-of-function, wherein the control level of reporter activity can be a level of reporter activity in a corresponding cell transfected with and expressing the nucleic acid construct but not contacted with the agent (par 0007, 0056). Further, “If the level of reporter activity in the test cell is not increased as compared to the control level of reporter activity, then the agent may not be identified as an inhibitor of the protease.”
In reference to reporter element, the Specification describes the reporter can be a fluorescent polypeptide, e.g. green fluorescent polypeptide (GFP), a red fluorescent polypeptide (RFP), or a yellow fluorescent polypeptide (YFP), and enhanced green fluorescent polypeptide (eGFP); or a luminescent polypeptide, e.g. .luciferase, and variants thereof (par 0006, 0032).
Figures 1-4A shows the sequences of several reporter polypeptides. Fig 1A is directed to the amino acid sequence for a Src-Mpro -Tat-eGFP polypeptide (SEQ ID NO:1). Fig 2A shows the amino acid sequence for a Src-SARS2-Mpro-Tat-fLuc polypeptide (SEQ ID NO:23). Fig 3A shows the amino acid sequence for a Src-HCoV229E-Mpro-Tat-fLuc polypeptide (SEQ ID NO:25). Fig 4A shows the amino acid sequence for a Src-HCoV-NL63-Mpro-Tat-fLuc polypeptide (SEQ ID NO:27). These figures represent using different viral coronavirus main proteases with either a fluorescent or luminescent reporter.
Altogether, the modular reporter polypeptide taught does not report unless interacted with a respective inhibitor, and the control cell/group will show little to no reporting, e.g. fluorescence or luminescence.
Working Examples:
The Specification lists four examples that are further represented in the Figures, particularly Fig. 5A-10B. Example 1 describes the generation of the construct listed in Fig 1A,B, (SEQ ID NO: 1, 2) wherein the modular reporter polypeptide employs Mpro, and eGFP.
Example 2 describes a gain of function assay for Mpro inhibition for the vector taught in Example 1, further describing the identification of this construct, stating “During this work, an apparently non-functional chimeric protein was constructed that consisted of an N-terminal myristoylation domain from Src kinase, the full Mpro amino acid sequence with cognate N- and C-terminal self-cleavage sites, the HIV-1 transactivator of transcription (Tat), and eGFP (FIG. 5A). Transfection into 293T cells failed to yield green fluorescence by flow cytometry or microscopy (FIGS. 5A and 5B).” The mutants of this constructs wherein the first mutant with a catalytic site mutation in Mpro (C145A) resulted in high levels of fluorescence, and a cleavage site double mutant construct (CSM), in which the conserved glutamines required for Mpro auto-proteolysis were changed to alanines (corresponding to Nsp4-Q500A and Mpro /Nsp5-Q306A), resulted in less fluorescence than the C145A mutant, and was undetectable by eGFP immunoblotting. Figure 5 A depicts all three constructs, and the specific mutations, Figure 5B depicts the fluorescence of these vectors in 293T cells, and Figure 5C depicting immunoblotting of the GFP proteins of these vectors.
Example 2 then tested two different known small molecule inhibitors of Mpro,, e.g. GC376 and boceprevir, to determine whether a high dosage could mimic the genetic mutants described previously, and restore fluorescence activity of the wild type construct. The findings were similar to these mutants in that fluorescence was restored, and were determined to be dose dependent (Par 0069; Fig 6A-E). It is then described “The system is modular and is likely to be equally effective …, with sequences from other proteases (e.g., closely related coronavirus proteases such as MERS and SARS Mpro, more distantly related viral proteases such as HCV NS3/4a and picornavirus 3C), and with the full color spectrum of fluorescent proteins or luminescent proteins.” (par 0070).
However, then further stating in relation to this finding of the construct, “The molecular explanation for the instability of the wild type chimeric construct is not clear. Without being bound by a particular mechanism, however, the instability might be due to protease-dependent exposure of an otherwise protected protein degradation motif (degron). Regardless of the full mechanism, the gain-of-function system described herein for protease inhibitor characterization and development in living cells is likely to have immediate and broad utility in academic and pharmaceutical research.”
Example 3 describes similar outcomes in using a luciferase reporter as opposed to the previously employed GFP reporter, and finding the luciferase reporter yielded higher relative levels of signal/activity with both inhibitors described previously compared to the GFP vector.
Example 4 describes using different Coronavirus Mpro Enzyme proteases, specifically, constructs encoding reporters containing SARS-CoV-2 Mpro, HCoV-229E Mpro, or HCoV-NL63 Mpro (reporter amino acid sequences set forth in SEQ ID NOS:23, 25, and 27, respectively). These findings revealed SARS-CoV-2 Mpro yielded higher relative levels of signal/activity in response to both GC376 and boceprevir, followed by HCoV-229E Mpro and then HCoV-NL63 Mpro.
In summary the Specification and Working Examples describe identifying a gain-of-function reporter polypeptide with Mpro , yet the molecular reasoning in relation to structure and/or function for having this characteristic are not yet known. Therefore, there is no certainty that such outcome would be observed with any protease due to the chemical, structural, and functional diversity that is found in this genus that is known in the art as the examples only teach this outcome in relation to coronavirus Mpro, and therefore be considered to act as a modular reporter polypeptide. Example 4 does provide examples with other proteases, but these remain to be coronavirus proteases, which are expected to be similar in both structure and function, in relation to the vast scope encompassed by claim 1 for any protease polypeptide. Lastly, it is not clear that the structure or function of the reporter is related to the gain-of-function characteristic, and therefore the reporter polypeptide should be limited to only fluorescent and luminescent reporters for which there is support.
Prior Art:
As described in the Specification, there are existing assays for SARS-CoV-2 Mpro activity in cells. Resnick et al. (of record IDS) described measuring cell death with Mpro overexpression that results in toxicity, and can then be rescued with inhibitors. This assay utilized Mpro and YFP, but they were not part of the same reporter construct as recited in claim 1.
Froggatt et al. (of record IDS) teaches the “FlipGFP” employing the Mpro activity to “flip-on” GFP fluorescence during expression of the protease, wherein the lack of fluorescence would suggest the identity of a Mpro inhibitor (abstract, Fig. 1). Furthermore, Froggatt identifies the conservation of coronavirus 3CLpro activity enables CoV protease reporter compatibility with many coronaviruses, specifically across three coronavirus groups: Alphacoronavirus, Betacoronavirus, and Gammacoronavirus, stating, “FlipGFP 3CLpro reporter is generally compatible with many CoV 3CLpro
proteins across coronavirus groups and host species” (p 4). The distinction with the prior art is the instant application teaches an assay that provides a gain-of-function fluorescent signal, wherein the prior art teaches the opposite approach in which an inhibitor reduces reporter activity, e.g. fluorescence, luminescence.
The diversity of proteases is extensive, with Lopez-Otín et al. stating, “Based on the mechanism of catalysis, proteases are classified into six distinct classes, aspartic, glutamic, and metalloproteases, cysteine, serine, and threonine proteases, although glutamic proteases have not been found in mammals so far.”, and “The complexity of proteases is further increased through posttranscriptional events such as alternative splicing and differential polyadenylation of genes encoding proteases (32, 33), by the occurrence of gene copy number variations or polymorphic variants that may contribute to the modification of protease functions or alter their regulatory mechanisms (34, 35), or by post-translational modifications such as glycosylation and phosphorylation”, and in reference to size “the architectural design of proteases ranges from small enzymes made up of simple catalytic units (~20 kDa) to sophisticated protein-processing and degradation machines, like the proteasome and meprin metalloproteinaseisoforms (0.7–6MDa) (p 2-3). In summary, there is much diversity in the genus of proteases in relation to function, structure, and size. The instant claim 1 is directed to this full genus, yet the Specification only supports viral proteases, more specifically coronavirus main proteases. This species of proteases is not considered to teach the entirety of the genus as it is not clear if any proteases would operate in the modular reporter construct in a similar fashion as Mpro has been shown to.
Conclusion:
Altogether, the instant application is directed to a reporter construct that was unexpectedly found to not provide reporter activity unless in the presence of a respective inhibitor. The Applicant has stated the reasoning for this finding remains unknown as the structure and/or function of the designed modular reporter polypeptide has not elucidated in view of this finding. Therefore, there is no indication this similar outcome would be observed with any other proteases that are not structurally and functionally similar to the Mpro used herein. Additionally, the working examples are only limited to the fluorescent and luminescent reporters as described in the examples.
Conclusion
Claims 1, 2, 4, 6, 7, and 10 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634