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 .
Applicant’s amendments and reply have overcome the objections to the instant specification and claims and most of the rejections under 35 USC 112(b).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 11, 2026 was filed after the mailing date of the non-final rejection on March 17, 2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Double Patenting
Applicant is advised that should claim 1 be found allowable, the “SARS-CoV-2 genome” recited in claim 2 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. Claim 1 is drawn to a SARS-CoV-2 (virus) or a SARS-CoV-2 nucleic acid genome. Claim 2 is drawn to a SARS-CoV-2 nucleic acid genome or a region thereof. Therefore, the SARS-CoV-2 genomes of claims 1 and 2 are substantial duplicates. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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 1-5, 8, 11-13, 15, 16, 19, 20, 22, 24, and 25 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.
Claims 1, 2, 8, and 11 are drawn to a partly codon deoptimized nucleotide sequence as shown in SEQ ID NO: 60 or a nucleotide sequence with up to 10% fewer or up to 10% more codon changes than shown. It is noted that these limitations were previously presented in claim 21. It is still not readily apparent from the nucleic acid sequence of SEQ ID NO: 60 which codon changes are encompassed therein. Therefore, 10% fewer or 10% more codon changes from SEQ D NO: 60 remains indeterminable. This rejection affects all dependent claims. Deletion of “up to 10% fewer or up to 10% more” in each of claims 1, 2, 8, and 11 is encouraged.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-5, 15, 16, 19, 20, 22, 24, and 25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature, without significantly more.
In reply to the rejection of record, applicant highlights that the amended claims require a deoptimized nucleic acid of SEQ ID NO: 60 with up to 10% fewer or up to 10% more codon changes. Applicant explains that the GenEmbl access no: MT534332 differs with SEQ ID NO: 60 by more than 2% and since SEQ ID NO: 60 includes codon deoptimized nucleotides, SEQ ID NO: 60 is not a product of nature, incorporating engineered changes described in Example 6. Applicant argues that sequences that include up to or at least 10% deoptimized codon changes are not products of nature.
Applicant’s arguments have been fully considered, but are found unpersuasive. Instant SEQ ID NO: 60 is 7059 nucleotides and corresponds to 2353 total codons (7059/ 3). A 10% less than or up to of 2353 codons is approximately 235. Therefore, the claims encompass any nucleic acid sequence that possesses up to 235 or fewer than 235 codon changes. Approximately 235 codon changes within 7059 total nucleotides of SEQ ID NO: 60 is 0.03329…, multiplied by 100 (for percentage) = 3.329 %, or 3%, rounding to the most significant figure. GenEmbl database accession no: MT534332 on 29 May 2020, which shares 97.6% (rounds to 98%) sequence identity with instant SEQ ID NO: 60, which is less than the 3% difference in codon changes to SEQ ID NO: 60 encompassed by the instant claims. As evidenced by GenEmbl database accession no: MT534332, the instant claims encompass products of nature. See Association for Molecular Pathology v. Myriad Genetics Inc., 569 U.S. 576, 589-90 (2013) (naturally occurring things are “products of nature” which cannot be patented).
An amendment to the claims requiring SEQ ID NO: 60, which is not a natural product, would ameliorate this rejection.
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 1-5, 8, 11-13, 15, 16, 19, 20, 22, 24, and 25 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.
In reply to the written description, applicant states that the specification provides extensive directions regarding the optimization strategy to generate the SARS-CoV-2-7N-1 clone (SEQ ID NO: 6) in Examples 10-23. Applicant asserts that the skilled person can produce a suitable deoptimized genome from Tables 1a, 1b, and 11, and evaluate whether the clone is sufficiently attenuated.
Applicant’s arguments have been fully considered, but are found unpersuasive. (Note: the SARS-CoV-2-7N-1 clone is identified as SEQ ID NO: 60 in the sequence listing and paragraph [0299] of the instant published disclosure, USPgPub 2024/025616, of record.) An invitation for further research does not constitute written disclosure of a sufficiently attenuated, codon deoptimized SARS-CoV-2 clone. See Eli Lilly, 119 F.3d at 1566 (holding that written description requires more than a “mere wish or plan for obtaining the claimed chemical invention”); see also id. at 1567(“[A]description which renders obvious a claimed invention is not sufficient to satisfy the written description requirement of that invention.”).
The instant materials claimed are indistinguishable from naturally-occurring SARS-CoV-2 nucleic acid genomes as evidenced by the sequence alignment of instant SEQ ID NO: 60 with GenEmbl database accession no: MT534332 on 29 May 2020, which shares 97.6% (rounds to 98%) sequence identity. GenEmbl database accession no: MT534332 is a complete genome of SARS-CoV-2/human/USA/CA-CZB-1262/2020 that possesses 106 mismatched nucleic acids in ORF1a, see the alignment provided, which is encompassed by the instantly claimed nucleic acid having up to 10% fewer or up to 10% more codon changes than SEQ ID NO: 60.
There is no teaching for which structural elements of a SARS-CoV-2 genome could be modified by the skilled artisan to provide a nexus to desired attenuating attributes, as required. Posani et al. (Front. Biosci. (Landmark Ed) 2022; 27 (1): 013, of record) compare 320,338 SARS-CoV-2 genomes isolated from all over the world to the first sequenced genome in Wuhan, China. Posani et al. conclude that all SARS-CoV-2 genes show a deoptimization of codon usage with respect to the human host as it evolves towards sub-optimal codon usage to favor host survival and ensure virus spread. In contrast, Błażej et al. (bioRxiv. 2025 Jun 2: 2025-05, of record) compare 94,571 SARS-CoV-2 genomes collected between January 2020 to October 2024. Błażej et al. find that non-structural ORF1a and ORF1ab codon preference evolves to favor human codon pair bias while genes coding for structural proteins trend toward deoptimized human codon usage. Błażej et al. opines the more optimal codon optimization adapted by ORF1a and ORF1ab increases translation efficiency of coded polyproteins and virus proliferation while adaptations of structural genes using deoptimized codons leads to a gained advantage of evading the host immune response resulting from divergent translation altering protein folding patterns.
The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). 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 sufficiently attenuated SARS-CoV-2 comprising a partly codon deoptimized genome in ORF1a is SEQ ID NO: 60. There is no disclosure of sufficient characteristics of the claimed genus of partially codon-deoptimized SARS-CoV-2 to allow persons of ordinary skill in the art to recognize that applicants were in possession of the broad genus of SARS-CoV-2 comprising a partly codon-deoptimized genome that is live and attenuated. There is no teaching or working example describing codon deoptimization of any region within the SARS-CoV-2 genome, encompassed by the instant claims and depicted in Figure 13, besides ORF1a. Of the 68 clones generated, listed under “Description of Sequences” in the instant disclosure, only SEQ ID NO: 60 is characterized as highly attenuated, with a very low replication rate in mammalian cells and exhibits a ‘small plaque phenotype’ indicative of a high level of attenuation, depicted as “LAV” in Figure 33. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. A definition by function alone is not sufficient because it is only an indication of what a thing does, rather than what it is. Eli Lily, 119 F.3 at 1568, 43 USPQ2d at 1406.
The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, 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 the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the distinguishing, identifying characteristics of the encompassed genus of codon deoptimized SARS-CoV-2 attenuated viruses claimed. Given that the specification has only described SEQ ID NO: 60, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claims 1-5, 8, 11-13, 15, 16, 19, 20, 22, 24, and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an attenuated, codon deoptimized SARSCoV-2 genome “SARS-CoV-2-7N-1” comprising SEQ ID NO: 60, does not reasonably provide enablement for any codon deoptimized SARSCoV-2 genome that is sufficiently attenuated. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
In reply to the rejection of record, applicant points to the instant claim amendments, drawn to SEQ ID NO: 60 and deoptimized sequences comprising 10% fewer or up to 10% more codon changes thereto.
Applicant’s arguments and the instant claim amendments have been fully considered, but are found unpersuasive. The instant materials claimed are still indistinguishable from naturally-occurring SARS-CoV-2 nucleic acid genomes as evidenced by the sequence alignment of instant SEQ ID NO: 60 with GenEmbl database accession no: MT534332 on 29 May 2020, which shares 97.6% (rounds to 98%) sequence identity.
There is no teaching or working example describing codon deoptimization of any region within the SARS-CoV-2 genome, encompassed by the instant claims and depicted in Figure 13, besides ORF1a. Of the 68 clones generated, listed under “Description of Sequences” in the instant disclosure, only SEQ ID NO: 60 is characterized as highly attenuated, with a very low replication rate in mammalian cells and exhibits a ‘small plaque phenotype’ indicative of a high level of attenuation, depicted as “LAV” in Figure 33.
The skilled artisan would not predict codon deoptimization of SARS-CoV-2 would result in a sufficiently attenuated virus. Working Examples 5-6 describe four different strategies for codon deoptimization of four different fragment segments of ORF1a, depicted in Figure 14. All clones demonstrated cytopathic effect (CPE), clear evidence of tissue damage, distribution of inflammatory cells, vascular lesions, and hyperplasia of alveolar epithelial cells in Examples 7-14, except for clone SARS-CoV-2-7N-1 (SEQ ID NO: 60), identified in paragraph [0402]. Only SEQ ID NO: 60 is characterized as highly attenuated, with a very low replication rate in mammalian cells and exhibits a ‘small plaque phenotype’ indicative of a high level of attenuation, depicted as “LAV” in Figure 33. Therefore, the scope of codon deoptimized SARS-CoV-2 genomes claimed are either not sufficiently attenuated or are so severely attenuated, the clones are non-viable, dead clones, described in paragraph [0312 and 0381-0402].
There is no teaching or guidance provided in the instant published describing genomic codon deoptimization of SARS-CoV-2 resulting in sufficiently attenuated virus, as asserted by the instant claims. There is no teaching for which structural elements could be modified to provide a nexus to desired attenuating attributes. Posani et al. (Front. Biosci. (Landmark Ed) 2022; 27 (1): 013, of record) compare 320,338 SARS-CoV-2 genomes isolated from all over the world to the first sequenced genome in Wuhan, China. Posani et al. conclude that all SARS-CoV-2 genes show a deoptimization of codon usage with respect to the human host as it evolves towards sub-optimal codon usage to favor host survival and ensure virus spread. In contrast, Błażej et al. (bioRxiv. 2025 Jun 2: 2025-05, of record) compare 94,571 SARS-CoV-2 genomes collected between January 2020 to October 2024. Błażej et al. find that non-structural ORF1a and ORF1ab codon preference evolves to favor human codon pair bias while genes coding for structural proteins trend toward deoptimized human codon usage. . Błażej et al. opines the more optimal codon optimization adapted by ORF1a and ORF1ab increases translation efficiency of coded polyproteins and virus proliferation while adaptations of structural genes using deoptimized codons leads to a gained advantage of evading the host immune response resulting from divergent translation altering protein folding patterns.
For these reasons, it is determined that an undue quantity of experimentation would be required of the skilled artisan to make the instant invention in its full scope.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 15, 16, 19, 20, 22, 24, and 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by GenEmbl database accession no: MT534332 on 29 May 2020 sequence alignment with instant SEQ ID NO: 60, of record.
Claims 1-5, 15, 16, 19, 20, 22, 24, and 25 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Mueller et al. (WO 2021/154828), of record.
In reply to the anticipatory rejections, applicant points to the instant claims, amended to require SEQ ID NO: 60, which is indicated as clear of the prior art.
Applicant’s amendment to the instant claims have been fully considered, but are found unpersuasive because the claims are not limited to SEQ ID NO: 60. The claims also encompass nucleic acids with up to 10% fewer or up to 10% more codon changes in EQ ID NO: 60.
Instant SEQ ID NO: 60 is 7059 nucleotides and corresponds to 2353 total codons (7059/ 3). A 10% less than or up to of 2353 codons is approximately 235. Therefore, the claims encompass any nucleic acid sequence that possesses up to 235 or fewer than 235 codon changes. Approximately 235 codon changes within 7059 total nucleotides of SEQ ID NO: 60 is 0.03329…, multiplied by 100 (for percentage) = 3.329 %, or 3%, rounding to the most significant figure. GenEmbl database accession no: MT534332 on 29 May 2020, which shares 97.6% (rounds to 98%) sequence identity with instant SEQ ID NO: 60, which is less than the 3% difference in codon changes to SEQ ID NO: 60 encompassed by the instant claims, which also corresponds to less than 0.3 codon pair bias in the codon pair bias (CPB) deoptimized SARS-CoV-2 genome sequences of Mueller et al., discussed in at least paragraphs [0008-0009+].
Therefore, GenEmbl database accession no: MT534332 SARS-CoV-2 genome isolate and the CPB deoptimized SARS-CoV-2 genome sequences of Mueller et al., in the alternative, anticipate instant claims 1-5, 15, 16, 19, 20, 22, 24, and 25.
An amendment to the claims requiring SEQ ID NO: 60, which is not anticipated or obvious to GenEmbl database accession no: MT534332 or Mueller et al., would ameliorate this rejection.
Allowable Subject Matter
The prior art does not teach or suggest SEQ ID NO: 60.
Applicant points to the data presented in working Examples 10-16, pertinent to SEQ ID NO: 60.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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