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 .
Election/Restrictions
Applicant’s election without traverse of Group I, species 2, drawn to a partly codon deoptimized SARS-CoV-2 genome comprises or consists of codon changes within the ORFla region of SARS-CoV-2 corresponding to between about nucleotide position 1534 and about nucleotide position 8586 of the wild-type Wuhan SARS-CoV-2 genome (recited in instant claim 15), and species 4k, drawn to a deoptimized nucleotide sequence as shown in SEQ ID NO: 60 but with up to 10% fewer or up to 10% more codon changes than shown, in the reply filed on January 29, 2026 is acknowledged.
Claims 1-5, 8, and 11-25 are pending;
Claims 8, 11-13, 15 (in part), 16, 21 (in part) and species 1, 3a-3f, 4g-4j, species corresponding to SEQ ID NOs: 39-59 and SEQ ID NOs: 61-68 of species 4k, and 4l-4o are withdrawn from consideration; and
Claims 1-5, 14, 15 (corresponding to elected species 2, wherein the partly codon deoptimized SARS-CoV-2 genome comprises or consists of codon changes within the ORFla region of SARS-CoV-2 corresponding to between about nucleotide position 1534 and about nucleotide position 8586 of the wild- type Wuhan SARS-CoV-2 genome), 17-20, 21(corresponding to elected SEQ ID NO: 60 with up to a 10% fewer or up to 10% more codon changes than shown), and 22-25 are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/13/2023 and 9/4/2024 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 title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in paragraph [0098, 0119] and Table 1a in USPgPub 2024/0252616. 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 is reminded that the incorporation of essential material in the specification by reference to a foreign application or patent, or to a publication is improper, i.e., Indian Provisional Patent Application No. 202041030397, filed 16 Jul. 2020, and Indian Provisional Patent Application No. 202041056151, filed 23 Dec. 2020, in paragraph [0001] and GenBank as entry NCBI Reference Sequences in paragraphs [0121 and 0122] and non-patent literature references listed in paragraphs [0177 and 0194]. Applicant is required to amend the disclosure to include the material incorporated by reference. The amendment must be accompanied by an affidavit or declaration executed by the applicant, or a practitioner representing the applicant, stating that the amendatory material consists of the same material incorporated by reference in the referencing application. See In re Hawkins, 486 F.2d 569, 179 USPQ 157 (CCPA 1973); In re Hawkins, 486 F.2d 579, 179 USPQ 163 (CCPA 1973); and In re Hawkins, 486 F.2d 577, 179 USPQ 167 (CCPA 1973). Furthermore, if a required sequence was not set forth in the specification as filed, and was not publicly available from Genbank® at the time the application was filed, the amendment will be treated as an attempt to introduce new matter (similar to attempts to incorporate essential material by reference to unpublished material). In addition, note that the amendment will probably require a replacement Sequence Listing, to add the sequences which are added to the disclosure.
The use of the term GenBank®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term 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 lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 19 is objected to because of the following informalities: “one or more Phe codons are changed” is recited twice. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 14, 15, and 17-25 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, 4, 5, 14, 15, and 17-25 recite, “SARS-CoV-2, SARS-CoV-2, SARS-CoV-2 particle or SARS-CoV-2 nucleic acid”. There is no distinction between twice recited: “SARS-CoV-2, SARS-CoV-2”. A distinction also cannot be made between “SARS-CoV-2, SARS-CoV-2,” and a SARS-CoV-2 particle since “SARS- CoV-2” is a virus particle. Designation that the partly codon deoptimized SARS-CoV-2 nucleic acid genome as “live” and “attenuated” is not distinguishing since a virus genome that is codon deoptimized is inherently “live” and “attenuated” compared to a virus genome that is not codon deoptimized and a virus genome that is codon deoptimized cannot express deoptimized codons without being live. Codon deoptimization necessarily occurs in the virus nucleic acid genome. Therefore, recitation of a SARS-CoV-2 nucleic acid comprising a genome that is partly codon deoptimized is redundant. For these reasons, it cannot be determined whether the claims intend to encompass different aspects of a SARS-CoV-2 virus and/or genome. This rejection affects all dependent claims. In the interest of compact prosecution, the claims are interpreted as a live, attenuated severe acute respiratory coronavirus 2 (SARS-CoV-2) comprising a partly codon-deoptimized genome. A clarifying amendment is required.
Claims 2 and 15 recite a “substantially purified” nucleic acid comprising a partly codon deoptimized SARS-CoV-2 genome or region thereof. The instant published disclosure (USPgPub 2024/0252616) recites “substantially purified nucleic acid” sixty times, but does not provide a definition for what requisite degree of purified is considered substantial. This phrase is indeterminable and affects all dependent claims.
Claim 15 recites nucleotide positions between “about” 1534 and “about” 8586 of the wild-type Wuhan SARS-CoV-2 genome. There is no discussion provided in the instant disclosure for how many nucleic acid positions are encompassed before and after residues 1534 and 8586 to clarify which and how many nucleotides are encompassed by “about”. In addition, a SARS-CoV-2 genome that “consists of” codon changes between “about 1534” and “about 8586” nucleotide positions, within the ORF la region contradicts the transitional phrase “consisting of”, which excludes any codon change not specified in the claim, see MPEP § 2111.03 II.
Claim 17 requires “the partly codon deoptimized SARS-CoV-2 genome comprises or consists of between about 10 and about 1850 codon changes within the ORF la region; or wherein the partly codon deoptimized SARS-CoV-2 genome comprises or consists of between about 24 and about 546 codon changes within the ORF la region.”. There is no discussion provided in the instant disclosure for how many codon changes are encompassed by “about” to determine the requisite quantity of encompassed by “about 10”, “about 24”, “about 546”, and “about 1850”. In addition, a SARS-CoV-2 genome that “consists of” “about 10”, “about 24”, “about 546”, and “about 1850” codon changes within the ORF la region contradicts the transitional phrase “consisting of”, which excludes any codon change not specified in the claim, see MPEP § 2111.03 II.
Claim 18 requires, “the partly codon deoptimized SARS-CoV-2 genome comprises or consists of codon changes to synonymous codons that are used less frequently, moderately, less rarely, and/or rarely in the genome of Homo sapiens; or wherein the partly codon deoptimized SARS-CoV-2 genome comprises or consists of codon changes to one or more rare codons, one or more less rare codons, one or more moderate codons, one or more codons containing CG (CpG) dinucleotides, one or more codons containing UA (UpA) dinucleotides, or any combination thereof.” Table 11 of the instant published disclosure lists some of the following columns: amino acids/ rare codon for amino acid/ and % of codon frequency in humans/ number of amino acids in deoptimized (DO) region/ number of rare amino acids in (DO) region. However, there is no teaching in the instant disclosure characterizing synonymous codons as less frequently, moderately, less rarely, and/or rarely in the genome of Homo sapiens, as recited in the claim. The skilled artisan would not determine the metes and bounds of “less frequently, moderately, less rarely, and/or rarely in the genome of Homo sapiens” without guidance provided in the specification. In addition, a SARS-CoV-2 genome that “consists of” one or more synonymous codon changes recited in claim 18 contradicts the transitional phrase “consisting of”, which excludes any codon change not specified in the claim, see MPEP § 2111.03 II. These same issues are also applicable to instant claims 19 and 20.
Claim 21 is drawn to a deoptimized nucleotide sequence as shown or “substantially as shown” in SEQ ID NO: 60 with up to a 10% fewer or up to 10% more codon changes than shown. It is not clear how a sequence can be shown substantially or what is intended by this phrase. In addition, it is 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 is indeterminable.
Claim 22 recites Table 1b and Table 11. “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.’ Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)).
Claims cannot refer back to tables in the specification because claims must be complete in themselves. Applicant is required to copy the table contents into the claim itself. There is no limit to the length of a claim. If the subject matter can be listed in the specification, that list can be copied and pasted into a claim.
Claim 23 is drawn to a partly codon deoptimized SARS-CoV-2 genome comprising the nucleotide sequence or “substantially the same nucleotide sequence as clone…or any variant thereof, such as…”. It is not clear how a sequence can be shown substantially or what is intended by this phrase, especially in view of any variant sequence also recited. None of the clones recited correspond to specific sequences. Therefore, it is unclear which requisite nucleotide sequence corresponds to each clone or what would be substantially the same sequence or a variant or a substantial variant sequence thereof, as encompassed by the instant claim. The presence of "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The issues of a substantial nucleotide sequence or any variant thereof such as, is also applicable to claims 24 and 25.
In addition, Claim 25 requires a “nucleic acid sequence of clone SARS-CoV-2-7N-1 or the sequence of SEQ ID NO: 60”. Paragraph [0402] of the instant published disclosure identifies SARS-CoV-2-7N-1 as SEQ ID NO: 60. Therefore, any difference in sequence intended by “or” between the clone name and the clone sequence is not apparent.
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, 14, 15, and 17-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature, without significantly more. Claims 1, 2, 4, 5, 14, 15, and 17-25 are drawn to a live, attenuated severe acute respiratory coronavirus 2 (SARS-CoV-2) comprising a partly codon-deoptimized genome or within a region thereof or within the ORF1a region corresponding to between about nucleotide position 1534 and about nucleotide position 8586 of the wild-type Wuhan SARS-CoV-2 genome. Claims 4 and 5 state that the nucleic acid is in a vector and a cell. Claim 17 states that the partly codon deoptimized SARS-CoV-2 genome comprises or consists of between about 10 and about 1850 codon changes within the ORF la region; or wherein the partly codon deoptimized SARS-CoV-2 genome comprises or consists of between about 24 and about 546 codon changes within the ORF la region. Claims 18-20 and 22 state that the codon changes comprise or consist of codon changes to synonymous codons that are used less frequently, moderately, less rarely, and/or rarely in the genome of Homo sapiens; or wherein the partly codon deoptimized SARS-CoV-2 genome comprises or consists of codon changes to one or more rare codons, one or more less rare codons, one or more moderate codons, one or more codons containing CG (CpG) dinucleotides, one or more codons containing UA (UpA) dinucleotides, or any combination thereof. Claim 21 is drawn to a deoptimized nucleotide sequence as shown in SEQ ID NO: 60 but with up to 10% fewer or up to 10% more codon changes than shown. Claims 23-25 are drawn to a partly codon deoptimized SARS-CoV-2 genome comprising the nucleotide sequence or “substantially the same nucleotide sequence as clone SARS-CoV-2-7N-1 or SEQ ID NO: 60…or any variant thereof, such as…”.
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. Visual analysis of the mismatched nucleic acid sequences between instant SEQ ID NO: 60 with GenEmbl database accession no: MT534332 shows altered codon expression between nucleotide positions ranging between about 1534 to about 8586 of ORF1a to those listed in “Column #2 Rare codon for amino acid (target codon)” in Table 11, see the sequence alignments and the following exemplative excerpts depicting 100% sequence alignments incorporating substituted codons and mismatched alignments further altering codon expression provided below (“Qy” designates instant SEQ ID NO: 60):
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592
682
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Similar to the fact pattern described in Myriad, the genetic information or genetic structure of the instant SARS-CoV-2 genome comprising deoptimized codons are not created or altered upon isolation from its native environment. Finding or discovering an important structure does not satisfy the §101 inquiry. Isolation by severing chemical bonds naturally linking the ASFV peptide subunits from the remainder of the naturally-occurring virus components or vector (recited in instant claims 3) or the host cell infected with said virus (recited in instant claim 4) does not in itself provide a markedly different characteristic from any SARS-CoV-2 genome encoding deoptimized codons found in nature since there are no chemical changes resulting from the isolation. Since an assumption cannot be made that a vector comprises heterologous sequences, a vector comprising a naturally-occurring gene linked to its naturally-occurring promoter reads on the gene and the promoter as they exist in nature. Therefore, the instant claims recite a natural phenomenon according to Step 2A in MPEP § 2106.04(II).
The comparison between the material claimed and the material of the GenEmbl database sequence indicates that there are no differences in structure, function, or other characteristics. Therefore, the claimed SARS-CoV-2 genome comprising deoptimized codons is a natural exception product. 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). Accordingly, analysis must therefore proceed to Step 2A Prong Two.
Step 2A Prong Two requires eligibility analysis to evaluate whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. The instant claims recite no additional element that distinguishes the instantly claimed SARS-CoV-2 genome comprising deoptimized codons from the naturally-occurring SARS-CoV-2 genome comprising deoptimized codons. Instant claims 5 and 25 further require that the SARS-CoV-2 materials are encompassed in a “vaccine”. However, recitation of “vaccine” fails to meaningfully limit the claim because it is at best the equivalent of merely adding the words “apply it” to the judicial exception. The presence of a possible pharmaceutical carrier, vehicle, and/or excipient does not change the nature or properties of the naturally-occurring SARS-CoV-2 genome. Accordingly, recitation of a “vaccine” does not integrate the recited judicial exception into a practical application that is patent eligible pursuant to the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics, Inc. -U.S.—(June 13, 2013).
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, 14, 15, and 17-25 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.
Claims 1, 2, 4, 5, 14, 15, and 17-25 are drawn to a live, attenuated severe acute respiratory coronavirus 2 (SARS-CoV-2) comprising a partly codon-deoptimized genome or within a region thereof or within the ORF1a region corresponding to between about nucleotide position 1534 and about nucleotide position 8586 of the wild-type Wuhan SARS-CoV-2 genome. Claims 4 and 5 state that the nucleic acid is in a vector and a cell. Claim 17 states that the partly codon deoptimized SARS-CoV-2 genome comprises or consists of between about 10 and about 1850 codon changes within the ORF la region; or wherein the partly codon deoptimized SARS-CoV-2 genome comprises or consists of between about 24 and about 546 codon changes within the ORF la region. Claims 18-20 and 22 state that the codon changes comprise or consist of codon changes to synonymous codons that are used less frequently, moderately, less rarely, and/or rarely in the genome of Homo sapiens; or wherein the partly codon deoptimized SARS-CoV-2 genome comprises or consists of codon changes to one or more rare codons, one or more less rare codons, one or more moderate codons, one or more codons containing CG (CpG) dinucleotides, one or more codons containing UA (UpA) dinucleotides, or any combination thereof. Claim 21 is drawn to a deoptimized nucleotide sequence as shown in SEQ ID NO: 60 but with up to 10% fewer or up to 10% more codon changes than shown. Claims 23-25 are drawn to a partly codon deoptimized SARS-CoV-2 genome comprising the nucleotide sequence or “substantially the same nucleotide sequence as clone SARS-CoV-2-7N-1 or SEQ ID NO: 60…or any variant thereof, such as…”.
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. Visual analysis of the mismatched nucleic acid sequences between instant SEQ ID NO: 60 with GenEmbl database accession no: MT534332 shows altered codon expression between nucleotide positions ranging between about 1534 to about 8586 of ORF1a to those listed in “Column #2 Rare codon for amino acid (target codon)” in Table 11, see the sequence alignment provided, depicting 100% sequence alignments incorporating substituted codons and mismatched alignments further altering codon expression. Therefore, the instant claims encompass SARS-CoV-2 wild-type isolates that are structurally and biologically different from those encoding 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) 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) 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, 14, 15, and 17-25 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.
Claims 1, 2, 4, 5, 14, 15, and 17-25 are drawn to a live, attenuated severe acute respiratory coronavirus 2 (SARS-CoV-2) comprising a partly codon-deoptimized genome or within a region thereof or within the ORF1a region corresponding to between about nucleotide position 1534 and about nucleotide position 8586 of the wild-type Wuhan SARS-CoV-2 genome. Claims 4 and 5 state that the nucleic acid is in a vector and a cell. Claim 17 states that the partly codon deoptimized SARS-CoV-2 genome comprises or consists of between about 10 and about 1850 codon changes within the ORF la region; or wherein the partly codon deoptimized SARS-CoV-2 genome comprises or consists of between about 24 and about 546 codon changes within the ORF la region. Claims 18-20 and 22 state that the codon changes comprise or consist of codon changes to synonymous codons that are used less frequently, moderately, less rarely, and/or rarely in the genome of Homo sapiens; or wherein the partly codon deoptimized SARS-CoV-2 genome comprises or consists of codon changes to one or more rare codons, one or more less rare codons, one or more moderate codons, one or more codons containing CG (CpG) dinucleotides, one or more codons containing UA (UpA) dinucleotides, or any combination thereof. Claim 21 is drawn to a deoptimized nucleotide sequence as shown in SEQ ID NO: 60 but with up to 10% fewer or up to 10% more codon changes than shown. Claims 23-25 are drawn to a partly codon deoptimized SARS-CoV-2 genome comprising the nucleotide sequence or “substantially the same nucleotide sequence as clone SARS-CoV-2-7N-1 or SEQ ID NO: 60…or any variant thereof, such as…”.
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. Visual analysis of the mismatched nucleic acid sequences between instant SEQ ID NO: 60 with GenEmbl database accession no: MT534332 shows altered codon expression between nucleotide positions ranging between about 1534 to about 8586 of ORF1a to those listed in “Column #2 Rare codon for amino acid (target codon)” in Table 11, see the sequence alignment provided, depicting 100% sequence alignments incorporating substituted codons and mismatched alignments further altering codon expression. Therefore, the instant claims encompass SARS-CoV-2 wild-type isolates that are structurally and biologically different from those encoding SEQ ID NO: 60.
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. Paragraph [0312] of the instant published disclose cautions against deoptimizing 35% of a virus genome since the result is a “severely 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) 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) 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, 14, 15, and 17-25 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.
GenEmbl database accession no: MT534332 shares 97.6% (rounds to 98%) sequence identity with instant SEQ ID NO: 60. 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. Visual analysis of the mismatched nucleic acid sequences between instant SEQ ID NO: 60 with GenEmbl database accession no: MT534332 shows altered codon expression between nucleotide positions ranging between about 1534 to about 8586 of ORF1a to those listed in “Column #2 Rare codon for amino acid (target codon)” in Table 11, see the sequence alignments and the following exemplative excerpts depicting 100% sequence alignment incorporating substituted codons and mismatched alignments further altering codon expression provided below (“Qy” designates instant SEQ ID NO: 60).
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592
682
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581
655
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Therefore, GenEmbl database accession no: MT534332 SARS-CoV-2 genome isolate anticipates the deoptimized codons required for attenuation as required by instant claims 1-5, 14, 15, and 17-25.
Claims 1-5, 14, 15, and 17-25 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Mueller et al. (WO 2021/154828).
Mueller et al. anticipate a live, attenuated severe acute respiratory coronavirus 2 (SARS-CoV-2) comprising a partly codon-deoptimized genome or within a region thereof of the wild-type Wuhan SARS-CoV-2 genome, see Figures 1, 2; paragraphs [0069, 0070, 0081, 0145, 0179, 0185, and 0291+]; and claims 1-3, 5, 8, 11-16, and 28-30, anticipating instant claims 1 and 2. The codon pair bias (CPB) deoptimized genome sequences of claims 18 and 20 of Mueller et al. reasonably anticipate the deoptimized nucleotide sequence “substantially as shown” in instant SEQ ID NO: 60, anticipating instant claim 21 and “any variant thereof such as” recited in instant claims 23-25. Instant claims 3 and 4 state that the nucleic acid is in a vector and a cell, anticipated by claims 24-26 of Mueller et al. Claims 34-37 of Mueller et al. anticipate an immunogenic composition and vaccine comprising the codon deoptimized SARS-CoV-2, recited in instant claim 5. Claim 31 of Mueller et al. requires that the SARS-CoV-2 is codon deoptimized, resulting in a reduction in expression of RNA-dependent RNA polymerase (RdRp), produced from ORF1a and ORF1ab, anticipating instant claims 14 and 15. Paragraphs [0082-0084] of Mueller et al. anticipate at least 5 to 500 less frequently human synonymous codon substitutions in RdRp, required in instant claim 17. Paragraphs [0091-0099] describe the use of rare codons to reduce translation rate and/or accuracy and claim 9 requires that the SARS-CoV-2 polynucleotide is recoded by increasing CpG or UpA dinucleotides, anticipating claim 18. Paragraph [0092] and Table 2 discuss synonymous codon changes and frequency of usage in Homo sapiens, including serine, arginine, threonine, proline, valine, leucine, alanine, isoleucine, cysteine, glycine, histidine, glutamine, tryptophan, asparagine, phenylalanine, lysine, and glutamic acid, encoded by TCG, CCG, ACG, ATA, GCG, GCT, CGA, anticipating instant claims 19, 20, and 22.
Allowable Subject Matter
The prior art does not teach or suggest SEQ ID NO: 60.
Conclusion
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/Shanon A. Foley/Primary Examiner, Art Unit 1671