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 .
Information Disclosure Statement
The information disclosure statements (IDS’s) submitted on 12/26/2023 and 12/24/2024 have been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The specification is objected to for failing to adhere to the requirements of the sequence rules, see Figures 3B, 4A, and 4B in instant published disclosure, USPgPub 2024/0376558. Applicant must append SEQ ID NOs. to all mentions of specific sequences comprising four or more amino acids and ten or more nucleic acids in the specification. When a sequence is presented in a drawing, the sequence must still be included in the sequence listing if the sequence falls within the definition set forth in 37 CFR 1.821(a), and the sequence identifier ("SEQ ID NO:X") must be used, either on the drawing itself or in the Brief Description of the Drawings. Applicant is required to append a SEQ ID NO. to any sequence applicable to the rule. See 37 CFR § 1.821 (a)-(d) and MPEP § 2422. Appropriate correction is required.
The use of the terms “NCBI”, “Addgene”, and “ATCC” exemplified in paragraphs [0144, 0156, and 0157], respectively, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Applicant is required to properly annotate all trade names and/or marks present in the instant specification, if any additional trade names and/or marks are discovered.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in paragraphs [0188 and 0194] of the instant published disclosure. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Applicant' s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites “an” (singular) “R203K/G204R” mutation. The slash appears to imply that the mutations can be one or the other or both, consistent with the abstract and paragraphs [0069, 0070, 0084, and 0139] of the instant published disclosure, USPgPub 2024/0376558. It is suggested that the slash be substituted for language iterated in the listed paragraphs for consistency. Appropriate correction is required.
Claim Objections
Claim 27 is objected to because of the following informalities: While there is insufficient antecedent basis for “the quantitating” in claim 25, from which claim 27 depends, there is ample antecedent basis for this phrase in claim 26. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 recites “R203K/G204R” in line 3. Claim 3, ultimately depending on claim 1 recites, “the nucleocapsid protein has a lysine (K) at the amino acid position 203, or an arginine (R) at the amino acid position 204, or both”, encompassed by claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-12, 18-28, 30, 32-34, and 36 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 1 requires “a nucleocapsid (N) protein derived from SARS-CoV-2 virus, or a functional fragment or variant thereof”. Regarding the “functional fragment”, Schiavina et al. (Biomolecular NMR Assignments. 2021 Apr;15 (1): 219-227) teach SARS-CoV-2 N has a myriad of functions, such as stabilizing viral RNA, homo-dimerization, formation of the ribonucleoprotein complex (RNP), and transcription and virus assembly in infected host cells, see the paragraph bridging pages 219-220. Due to the quantity of functions SARS-CoV-2 N conducts, it is not clear which function the instant fragment is referring to. Regarding the “variant thereof”, it is unclear whether the claimed variant is drawn to structural or functional variations. The structural requirements correlating to divergent, uncharacterized functions attributed to the instant fragment and variant is vague and indefinite. This rejection affects all dependent claims.
Claim 5 requires a variant comprising “at least…100% sequence identity to SEQ ID NOs: 1-4 in the alternative. It is not evident how a sequence can have “at least”, i.e., more than, 100% sequence identity or how a variant would possess 100% sequence identity.
Regarding claim 21, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It cannot be determined if the limitations following the word are required or not.
Claim 30 is incomplete because it depends from cancelled claim 29.
Regarding claim 33, recitation of "e.g." and parenthetical language renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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, 3-12, 18-28, 30, 32-34, and 36 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 requires “a nucleocapsid (N) protein derived from SARS-CoV-2 virus, or a functional fragment or variant thereof”. Regarding the “functional fragment”, Schiavina et al. (Biomolecular NMR Assignments. 2021 Apr;15 (1): 219-227) teach SARS-CoV-2 N has a myriad of functions, such as stabilizing viral RNA, homo-dimerization, formation of the ribonucleoprotein complex (RNP), and transcription and virus assembly in infected host cells, see the paragraph bridging pages 219-220. Due to the quantity of functions SARS-CoV-2 N conducts, it is not clear which function the instant fragment is referring to. Regarding the “variant thereof”, it is unclear whether the claimed variant is drawn to structural or functional variations.
The structural requirements correlating to divergent, uncharacterized functions attributed to the instant fragment and variant are not adequately described and the instant disclosure does not convey possession of the genus of fragments and variants thereof, claimed. Each of SEQ ID NOs: 1-4, recited in instant claim 2, are 419 residues in length. Claim 4 is drawn to any fragment comprising between “about 50 to about 419 contiguous residues”, sufficient to maintain the biological function of binding to viral RNA. A SARS-CoV-2 N protein comprising “about 419” contiguous residues encompasses N proteins greater than 419 residues since “about” is only an approximate term. There is no support provided for a SARS-CoV-2 N protein greater than 419 residues in length encompassed by the claim. There is also no structural correlation between any approximate quantity of 50 contiguous residues of SARS-CoV-2 N and the requisite function of maintaining the biological function of binding to viral RNA. A definition by function alone “does not suffice, to sufficiently describe a coding sequence “because it is only an indication of what the gene does, rather than what it is.” Eli Lily, 119 F.3 at 1568, 43 USPQ2d at 1406. Claim 5 is drawn to a variant of a SARS-CoV-2 N functional fragment comprising at least 65% identity to SEQ ID NOs: 1-4, each 419 residues in length. A 35% variation of a SARS-CoV-2 N protein is approximately 147 residues. Kannan et al. (Journal of Pure Applied Microbiology. May 2020; 14 (suppl 1): 757-763) teach MERS-CoV and SARS-CoV-2 nucleocapsid sequence alignment indicates 65% identity, see the first paragraph under “Results and Discussion” and Figure 1. Therefore, claim encompasses proteins with no structural identity to SARS-CoV-2 N, as required. The specification does not reasonably convey possession of these undefined N proteins.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the claim is a partial structure in the form of a recitation of percent identity. There is not even identification of any particular portion of the structure that must be conserved. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). As discussed above, the skilled artisan cannot envision the detailed structure of the encompassed genus of polypeptides, given that the specification has only described SEQ ID NOs: 1-4. Therefore, only isolated polypeptides comprising the amino acid sequence set forth in SEQ ID NOs: 1-4, but not the full breadth of the claims meets the written description provision of 35 U.S.C. §112, first paragraph.
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, 3, 4, 6-9, 11, 12, 18-28, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al. (Journal of Visualized Experiments: Jove. 2017 Jan 16 (119): 54391) and Leary et al. (bioRxiv. 2020 Jan 1; 10 (2020.04): 10-029454).
Singh et al teach isolating RNA-protein complexes (ribonucleoprotein particles (RNPs)), as required in instant claim 11, from cells using RNA-immunoprecipitation to simultaneously co-precipitate proteins and specific cognate RNA for downstream identification using immunoblot and RT-qPCR, respectively, see the “Abstract” and “Introduction”. In the paragraph above, “Protocol”, and Figure 2a, cognate MS2-tagged PCEgag retroviral RNA is captured by magnetic-bead-immobilized FLAG (capture)-tagged MS2 coat protein and immunoprecipitated from the cell extract, as required by instant claims 1, 7-9, 12, 19 and 20. The protocol described by Singh et al. requires enriching the RNA by contacting RNP complexes by adding a low-salt binding buffer having a pH of about 7 and an RNase inhibitor, see “Low-salt Buffer” and section 2, recited in instant claims 18 and 21, after the supernatant is removed, recited in instant claim 22. Section 3 of Singh et al. require several washing steps to remove non-specific binding, as required by instant claim 23. Section 4 isolates cognate RNA-protein complexes and eluting associated proteins and RNA isolation in appropriate buffers, required in claims 24 and 25, and quantifying the RNA by RT-qPCR, recited in claims 26-28.
In the Introduction, Singh et al. teach the methodology is applicable to viruses and detects and enriches an MS2 stem-loop containing retroviral PCEgag retroviral RNA in “Representative Results”, Singh et al. do not mention the instant SARS-CoV-2 nucleocapsid (N) protein comprising R203K/G204R mutations or detecting cognate SARS-CoV-2 RNA, as required in instant claims 1, 3, 4, and 30.
Leary et al. teach polymorphisms in the SARS-CoV-2 nucleocapsid resulting in R203K and G204R substitutions, see the abstract. These nucleocapsid substitutions meet the limitations recited in instant claims 1 and 3. Paragraphs [0038 and 0039] of the instant published application, USPgPub 2024/0376558, recite:
[0038] The term “polypeptides” includes proteins and functional fragments thereof.
[0039] The term “functional fragment” or “functional variant” means a fragment or variant of a polypeptide, such as a full-length or native polypeptide, that retains one or more functional properties of the full-length or native polypeptide.
Therefore, the full-length nucleoprotein of Leary et al. depicted in Figure S5, retains one or more functional properties, such as RNA binding and dimerization, as required in instant claim 4.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have substituted the MS2 coat protein of Singh et al. with the R203K/G204R-substituted-SARS-CoV-2-nucleocapsid of Leary et al. to detect and enrich cognate viral RNAs, as taught by Singh et al. One of ordinary skill in the art prior to the instant effective filing date would have been inspired to have applied a FLAG (capture)-tag of Singh et al. to the R203K/G204R-substituted-nucleocapsid of Leary et al. in the protocol of Singh et al. with a reasonable expectation of success to independently immunoprecipitated the nucleocapsid protein, as taught in section 1 of Singh et al. One of ordinary skill in the art prior to the instant effective filing date would have been inspired to have immobilized the FLAG-tagged R203K/G204R-substituted-nucleocapsid of Leary et al. in the protocol of Singh et al. to magnetic beads for with a reasonable expectation of success for facile capture of the RNP complex, see the paragraph above “Protocol” and section 1 of Singh et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have substituted the MS2 coat protein of Singh et al. with the R203K/G204R-substituted-SARS-CoV-2-nucleocapsid of Leary et al. to detect and enrich cognate viral RNAs, as taught by Singh et al. because Leary et al. teach the nucleocapsid R203K/G204R substitutions resulted in increased viral fitness that has resulted in European rapid spread during March 2020, see the Abstract, Background, “Newly emerging strain from Europe…”, Figure S1 and Leary et al. depict predicted viral RNA corresponding to the R203K/G204R nucleocapsid in Figure S4.
Claims 2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al. and Leary et al. as applied to claims 1, 3, 4, 6-9, 11, 12, 18-28, and 30 above, and further in view of SEQ ID NO: 1 alignment with Geneseq db access no BHU92023 Jul 2020 by Wang et al. CN11220803.
See the teachings of Singh et al. and Leary et al. above. Neither teach a nucleocapsid amino acid sequence corresponding to SEQ ID NO: 1.
Geneseq db access no BHU92023 shares 100% identity to SEQ ID NO: 1, see the alignment provided.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have used the nucleocapsid sequence of Geneseq db access no BHU92023 comprising the R203K/G204R, taught by Leary et al., in the protocol of Singh e al. to detect viral RNA specific to the R203K/G204R nucleocapsid. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have used the nucleocapsid sequence of Geneseq db access no BHU92023 comprising the R203K/G204R, taught by Leary et al., in the protocol of Singh e al. to detect viral RNA specific to the R203K/G204R nucleocapsid because the sequence of Geneseq db access no BHU92023 is a nucleocapsid used in methods of detection and early diagnosis, see the description provided with the alignment.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Singh et al. and Leary et al. as applied to claims 1, 3, 4, 6-9, 11, 12, 18-28, and 30 above, and further in view of The Protein Man. (“Advantages of Magnetic Beads for Protein Immunoprecipitation”, Posted 11 July 2017 in The Protein Man's Blog | A Discussion of Protein Research: G-Biosciences).
See the teachings of Singh et al. and Leary et al. above. Neither references mentions the diameter of magnetic beads, as required.
The Protein Man teaches magnetic beads used for protein immunoprecipitation have a diameter between 1-4µm, see the first section and “Magnetic beads provide optimal binding capacity”.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have used conventional sized magnetic beads in the method of Singh et al. and Leary et al.
Claims 32-34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al. and Leary et al. as applied to claims 1, 3, 4, 6-9, 11, 12, 18-28, and 30 above, and further in view of Wozniak et al. (Nature Scientific Reports. 2020 Oct 6; 10 (1): 16608).
See the teachings of Singh et al. and Leary et al. above. Neither Singh et al. nor Leary et al. teach evaluating a biological sample from a subject with one or more symptoms, required in instant claims 32-34 and 36.
Wozniak et al. teach evaluating 50 nasal clinical samples, predetermined as positive, undetermined, and negative, see the last paragraph bridging the pages before: “Materials and methods”, and saliva samples from two asymptomatic subjects in “Biological Samples.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have tested clinical samples, as taught by Wozniak et al. in the combined method of Singh et al. and Leary et al., to determine and/or diagnose SARS-CoV-2 infection. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have tested clinical samples, as taught by Wozniak et al. in the combined method of Singh et al. and Leary et al. because both Wozniak et al. and Singh et al. require RT-qPCR, see the abstract and “RT‑qPCR analysis” of Wozniak et al. and the “Abstract” and “Introduction” of Singh et al.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Ahn et al. (Analyst. 2009;134(9):1896-901) detect the presence of the SARS coronavirus nucleocapsid protein with RNA aptamers, see sections 2.6 and 3.2, Figures 1-3, and Table 1.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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/Shanon A. Foley/Primary Examiner, Art Unit 1671
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