DETAILED ACTION
Disposition of Claims
Claims 1-13, 18-19, 21, and 23-26 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250295756A1, Published 09/25/2025.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/25/2025, 08/16/2024, and 07/19/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being 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 disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. See ¶[0004] “https://coronavirus.jhu.edu/map.html”; ¶[0023] “https://www.ncbi.nlm.nih.gov/genbank/”; ¶[0064] and the links listed in Table 4; ¶[0226] “https://www.jnj.com/johnson-johnson-covid-19-vaccine-authorized-by-u-s-fda-for-emergency-usefirst-single-shot-vaccine-in-fight-against-global-pandemic #_edn2”; and “https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines”.
Claim Objections
Claims 11-13 and 19 are objected to because of the following informalities: only one period can be present per claim (See MPEP § 608.01(m)). Also, as per MPEP §2412.04, reference must be made to the sequence by use of the sequence identifier, preceded by “SEQ ID NO:” For instance, “SEQ ID NO.2” and “SEQ ID NO.4” in claim 11 should be amended to “SEQ ID NO:2” and “SEQ ID NO:4”, respectively. Appropriate correction is required.
Claims 12-13 and 19 are objected to because of the following informalities: for clarity and consistency with the sequence identity alternative, it is highly suggested the claims be amended from “a nucleic acid sequence as defined by SEQ ID NO: X” to instead recite “the nucleotide sequence of SEQ ID NO:X” or “a nucleotide sequence comprising SEQ ID NO:X” or “a nucleotide sequence consisting of SEQ ID NO: X”. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: “fulfils least one” should be “fulfils at least one”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 and dependent claims 2-13, 18-19, 21, and 23-26 thereof 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 recites a “polynucleotide encoding
a) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein; and/or
b) at least one non-structural SARS-CoV-2 protein selected from the group consisting of non-structural protein 7, non-structural protein 8, non-structural protein 9, non-structural protein 10, non-structural protein 11, non-structural protein 12, an endoribonuclease, and a 2′-O-methyltransferase,
wherein the polynucleotide comprises or consists of at least one sequence part comprising codon-pair deoptimizations in comparison to the SARS-CoV-2 genome.” The use of “and/or” renders the scope of the claim unclear because it does not distinctly identify whether the polynucleotide must encode the spike protein, at least one of the listed non-structural proteins (nsps), or both the spike protein and at least one listed nsp. Although these alternatives may have been intended, the claim does not recite them as separate and definitive alternatives.
The ambiguity is further compounded by the subsequent requirement that “the polynucleotide contains at least one sequence part having codon-pair deoptimizations relative to the SARS-CoV-2 genome”. It is unclear whether, when the polynucleotide encodes both the spike protein and one or more nsps, the recoded sequence part must occur in the portion encoding the spike protein, the portion encoding a nsp, either portion, or both portions.
Additionally, the term “codon-pair deoptimizations” in claim 1 is a relative term which renders the claim indefinite. The term “codon-pair deoptimizations” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While the term has a definition in the specification at ¶[0014], the definition does not provide clear and objective boundaries. The specification does not provide a sufficiently precise definition that would allow one of skill in the art to determine, with reasonable certainty, when a given codon pair is “deoptimized” relative to the SARS-CoV-2 genome. The term appears to depend on comparative assessments of codon-pair usage, codon context, and organism-specific or reference-dependent optimization criteria, none of which are consistently or objectively defined in the claims or specification. For instance, one issue with this term is that no reference “base” genome sequence of SARS-CoV-2 has been provided as to compare whether or not a resulting codon pair has, or has not, been “deoptimized”. Claiming the limitation of a genome as in claim 1, specific positions of a genome as in claim 3, or a percent identity to a genome as in claim 5 is unclear because nucleotide positions or sequences are being claimed without providing an appropriate frame of reference for said sequence. No “base” sequence of comparison for the “SARS-CoV-2 genome” is provided through reference to a specific isolate, SEQ ID NO:, or otherwise appropriate reference deposit to allow one to compare whether or not the codon-pair deoptimizations within the independent and dependent claims are naturally occurring or not. As a result, it is unclear what specific nucleotide changes are required to meet the limitations of these claims, or how many or what degree of changes constitute “codon-pair deoptimizations”.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 1 is rejected on the grounds of being indefinite. Claim(s) 2-13, 18-19, 21, and 23-26 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1 and, as noted supra, provide further indefiniteness issues to the claimed subject matter.
Claim 3 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 3 recites that “the SARS-CoV-2 genome section extending from position 11,000 to position 27,000.” This limitation is unclear because a SARS-CoV-2 genome is not the same thing as a section of that genome. The recitation appears to redefine the entire SARS-CoV-2 genome as a partial genomic region extending from position 11,000 to position 27,000, even though the remainder of the claim depends from claim 1, which refers to codon-pair deoptimizations relative to the “SARS-CoV-2 genome”. It is therefore unclear whether claim 3 is intended to require that the claimed polynucleotide comprise only the genomic section extending from position 11,000 to position 27,000, that the codon-pair deoptimized sequence part be located within that genomic section, or that the recited genomic section merely serve as the reference sequence for determining codon-pair deoptimization. These interpretations impose materially different structural requirements on the claimed polynucleotide.
For at least these reasons, the metes and bounds of claim 3 are unclear.
Claim 13 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 13 recites alternatives with “at least one of the following criteria” but uses the conjunction “and” to join the alternatives. It is unclear if the last two criteria are meant to be “joined” together since “and” is used, or if every criteria is meant to be an alternate option (meaning the “and” should be replaced with “or”). Due to this grammatical usage, it is unclear what combinations of criteria must be met in order to satisfy the metes and bounds of the claim.
For at least these reasons, claim 13 is rejected on the grounds of being indefinite.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to an isolated polynucleotide encoding
a) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein; and/or
b) at least one non-structural SARS-CoV-2 protein selected from the group consisting of non-structural protein 7, non-structural protein 8, non-structural protein 9, non-structural protein 10, non-structural protein 11, non-structural protein 12, an endoribonuclease, and a 2′-O-methyltransferase,
wherein the polynucleotide comprises or consists of at least one sequence part comprising codon-pair deoptimizations in comparison to the SARS-CoV-2 genome.
Further limitations on the polynucleotide of claim 1 are wherein the polynucleotide encodes at least two of the non-structural proteins (claim 2); wherein the SARS-CoV-2 genome is the SARS-CoV-2 genome section extending from position 11,000 to position 27,000 (claim 3); wherein the at least one sequence part comprising codon-pair deoptimizations has a length in a range of from 750 nucleotides to 2500 nucleotides (claim 4); wherein between 15% and 40% of the nucleotides of the at least one sequence part comprising codon-pair deoptimizations are different from the nucleotides of a corresponding SARS-CoV-2 genome (claim 5); wherein the at least one sequence part comprising codon-pair deoptimizations comprises between 200 and 500 nucleotides that are different from the nucleotides of a corresponding SARS-CoV-2 genome (claim 6); wherein between 40% and 70% of the codons of the at least one sequence part comprising codon-pair deoptimizations are different from the codons of a corresponding SARS-CoV-2 genome (claim 7); wherein the at least one sequence part comprising codon-pair deoptimizations comprises between 150 and 400 codons that are different from the codons of a corresponding SARS-CoV-2 genome (claim 8); wherein the at least one sequence part comprising codon-pair deoptimizations comprises a first deoptimized sequence part and a second deoptimized sequence part, wherein the first deoptimized sequence part and the second deoptimized sequence part are separated from each other by a non-deoptimized sequence section comprising at least 300 nucleotides (claim 9), wherein the first deoptimized sequence part has a length lying in a range of from 1300 nucleotides to 1600 nucleotides and the second deoptimized sequence part has a length lying in a range of from 100 nucleotides to 400 nucleotides (claim 10), wherein the first deoptimized sequence part has at least 95% sequence identity to SEQ ID NO: 2 and the second deoptimized sequence part has at least 95% sequence identity to SEQ ID NO: 4 (claim 11); wherein the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 6 or a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 6 (claim 12); wherein at the polynucleotide fulfils least one of the following criteria:
the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 8 or a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8,
the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 10 or a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10,
the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 15 or a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 15,
the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 16 or a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 16, or
the polynucleotide comprises the nucleic acid sequence of SEQ ID NO: 17 or a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 17 (claim 13);
Claim 18 is drawn to a live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) comprising the polynucleotide according to claim 1.
Further limitations on the live attenuated SARS-CoV-2 according to claim 18 are wherein:
the SARS-CoV-2 has the nucleic acid sequence of SEQ ID NO: 18 or a nucleic acid sequence having at least 98% sequence identity to SEQ ID NO: 18, or
the SARS-CoV-2 has the nucleic acid sequence of SEQ ID NO: 19 or a nucleic acid sequence having at least 98% sequence identity to SEQ ID NO: 19 (claim 19).
Claim 21 is drawn to a pharmaceutical composition comprising the live attenuated SARS-CoV-2 according to claim 18.
Claim 23 is drawn to a method of vaccinating a human or animal patient, comprising the step of administering the pharmaceutical composition according to claim 21 to the patient.
Further limitations on the method according to claim 23 are wherein the pharmaceutical composition is administered by an intranasal application, an oral application, or by parenteral administration (claim 24); wherein a single dose of the pharmaceutical preparation comprises between 1*10^3 and 1*10^8 focus forming units of the live attenuated SARS-CoV-2 (claim 25); and wherein the pharmaceutical preparation is administered to the patient at least two times, wherein a second administration is separated from a first administration by a first time period lying in range of from 2 weeks to 36 months (claim 26).
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 1-3, 18-19, and 21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to naturally-occurring SARS-CoV-2 viruses and amino acid/nucleic acid sequences without significantly more. In light of the 35 USC 112b rejection supra, at least one interpretation is that the claims recite a polynucleotide encoding a SARS-CoV-2 S protein and/or other non-structural proteins that have been “deoptimized” with respect to their codon usage. Using the subject-matter eligibility analysis to determine the claim scope, under step 1 of the analysis, claims 1-3, 18-19, and 21 are directed to polynucleotides, viruses encoding said polynucleotides, and compositions thereof. The claims are therefore drawn to compositions of matter. Under step 2A, prong one, the claims recite nature-based products that, under their broadest reasonable interpretation, encompass naturally occurring SARS-CoV-2 polynucleotides and naturally occurring SARS-CoV-2 viruses. A nature based product that does not exhibit markedly different characteristics from its naturally-occurring counterpart is a product-of-nature exception (MPEP §2106.04(c)).
The specification defines codon-pair deoptimization as recoding codons such that the encoded protein remains the same while suboptimal codon pairs and/or CpG dinucleotides emerge (¶[0014]). The specification further states that a polynucleotide is considered codon-pair deoptimized when “at least one codon pair is deoptimized with respect to the corresponding natural sequence.” The definition therefore does not require deliberate engineering or other intervention by a person. It encompasses a naturally occurring viral polynucleotide in which mutation and natural selection have produced at least one synonymous codon-pair change that is less optimal relative to another SARS-CoV-2 genome sequence. Naturally evolving SARS-CoV-2 genomes undergo synonymous nucleotide substitutions and changes in codon usage. Wu et. al. (Wu X, et. al. Adv Sci (Weinh). 2023 Aug;10(23):e2205445. Epub 2023 Jun 2.) reports that SARS-CoV-2 displayed use of nonoptimal human codons and a decreasing codon adaptation index during viral evolution. Wu therefore provides evidence that codon deoptimization can arise through natural SARS-CoV-2 evolution rather than only through deliberate laboratory engineering. The mere characterization of a naturally evolved codon pair as “deoptimized” does not convert the naturally occurring polynucleotide into a “hand-of-man” product.
Accordingly, the broadest reasonable interpretation of claim 1 encompasses a naturally occurring SARS-CoV-2 polynucleotide having at least one naturally acquired synonymous codon-pair substitution that is considered suboptimal relative to a corresponding sequence in another SARS-CoV-2 genome. Such an encompassed polynucleotide had the nucleotide sequence, encoded protein, and biological properties produced through natural viral evolution, and claim 1 does not require any structural or functional characteristic that distinguishes this polynucleotide from its naturally occurring counterpart.
Claims 2 and 3 identify that the nucleotide encodes at least two non-structural proteins and identifies a region of the SARS-CoV-2 genome, and neither claim does anything to distinguish the polynucleotide sequence from its naturally occurring counterpart. Claims 18 and 19 identify the polynucleotide as being within a live, attenuated SARS-CoV-2 without defining how said virus is “attenuated” compared to other viruses. A reasonable interpretation is that such virus results in milder infections in the host, which again has been shown within natural viral isolates. Claim 18 does not require that the virus possess any structural, genetic, phenotypic, or functional characteristic that is markedly different from naturally occurring virus. Describing the virus as “attenuated” does not alter its structure or function relative to what occurs in nature. Claim 19 further requires that the virus comprise SEQ ID NO: 18 or 19, or a nucleotide sequence having 98% identity thereto. As the ABSS results show, naturally-occurring viral isolates fall well within this percent identity. The percentage-identity alternative encompasses sequences differing from the reference sequence by as much as approximately 2% across the full SARS-CoV-2 genome. For a genome of approximately 30,000 nucleotides, the limitation permits approximately 600 nucleotide differences. The claim does not require retention of any particular engineered substitutions of SEQ ID NO: 18 or SEQ ID NO: 19, nor does it require that the sequence differences from a naturally occurring genome be introduced or engineered artificially. Because SEQ ID NOs: 18 and 19 retain the substantial majority of the naturally occurring SARS-CoV-2 genome, the genus defined by at least 98% identity is sufficiently broad to encompass naturally-occurring SARS-CoV-2 genomic sequences that also satisfy the broad codon-pair optimization of claim 1. Claim 19 does not require that every claimed sequence exhibit a structural or functional characteristic markedly different from a naturally occurring SARS-CoV-2 genome or virus.
Claim 21 requires that the virus is within a “pharmaceutical composition”, but the recitation of a “pharmaceutical composition” does not require any particular pharmaceutically acceptable carrier, excipient, adjuvant, diluent, dosage form, concentration, formulation, or other component that alters the structure or function of the claimed virus in a markedly distinct manner.
Under Step 2A, prong Two, claims 1-3, 18-19, and 21 do not recite additional elements that integrate the product-of-nature exception into a practical application. Claims 1-3 merely define the naturally occurring polynucleotide by the protein it encodes, its genomic location, and the presence of naturally attainable codon usage. These limitations describe the product of nature itself rather than applying it in a treatment, manufacturing process, laboratory method, or other meaningful use. Claims 18 and 19 similarly claim the virus itself. The requirement that the virus be live and attenuated describes biological characteristics of an encompassed naturally occurring virus. It does not require administration of the virus, preparation of a vaccine, controlled production, deliberate genetic modification, or another use that applies the judicial exception in a meaningful manner. Claim 21 requires that the virus be within a pharmaceutical composition, but does not add anything to the virus to markedly change said virus from its naturally occurring counterpart.
Under step 2B, the claims do not recite additional elements that are sufficient to amount to significantly more than the judicial exception because the protein-encoding limitations, the specified genomic region, the “live attenuated” designation, and the percentage identity limitation merely identify or describe the naturally occurring polynucleotide or virus. They do not add a non-conventional structure, treatment step, manufacturing operation, or other element that transforms the claimed natural product into a patent-eligible product. Applicant’s disclosure of particularly deliberately recoded vaccine constructs does not cure the breadth of the claims, as the claims do not require that the codon-pair deoptimization be engineered or otherwise intentionally introduced through the “hand-of-man”.
For at least these reasons, the claims are rejected for being directed to products of nature without additional elements to integrate the exception into a practical application or amount to significantly more than the exception. One suggestion is to incorporate limitations into the independent claims which were not included in this rejection. Another suggestion is to require that the polynucleotide is a non-naturally occurring, synthetically engineered construct comprising codon-pair deoptimized sequences designed to reduce viral replication or pathogenicity in a host cell, and optionally further specifying its use in a recombinant vector, vaccine composition, or therapeutic application, thereby integrating the claimed subject matter into a practical application and providing significantly more than a product of nature.
Claim Rejections - 35 USC § 112(a); First Paragraph
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 1-13 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 isolated polynucleotides encoding the claimed SARS-CoV-2 proteins, does not reasonably provide enablement for any polynucleotide system which may comprise said SARS-CoV-2 protein coding regions. 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 and/or use the invention commensurate in scope with these claims.
The claim is directed broadly to “a polynucleotide” without limitation as to form, environment, or method of use. As such, the claim encompasses the nucleic acid in a wide range of contexts, including incorporation into vectors, plasmids, artificial chromosomes (e.g. bacterial or yeast artificial chromosomes (BACs or YACs)), cosmids, prokaryotic and eukaryotic cells, and organismal systems (e.g. Bacteria and Archaea, Eukaryotes (including vertebrate and invertebrate animals, plants, and fungi), and viruses).
The specification does not provide guidance sufficient to enable the use of the claimed nucleic acid across this full scope, including in complex biological systems where expression, stability, and functionality may vary depending on the host environment and delivery method.
Accordingly, undue experimentation would be required to determine how to make and use the claimed nucleic acid across the full scope of the claim. It is suggested that the claims be amended to read upon “an isolated polynucleotide” [emphasis added] in order to overcome this rejection.
Claims 1-13, 18-19, 21, and 23-26 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 the disclosed CPD6, sCPD9, and sCPD10 viruses under the particular cell-culture and animal model (hamster) conditions tested, does not reasonably provide enablement for the full genus of polynucleotides that can be deoptimized or the live, attenuates SARS-CoV-2 viruses, pharmaceutical compositions containing those viruses with deoptimized codon pairs, or vaccination methods encompassed by the claims. 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 and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims. The claimed invention is directed to polynucleotides comprising SARS-CoV-2 coding regions for such SARS-CoV-2 proteins as spike and non-structural proteins (e.g. nsp7-12), wherein the polynucleotide comprises codon-pair deoptimizations in comparison to a SARS-CoV-2 genome. The claims are further drawn to live, attenuates SARS-CoV-2 viruses comprising said polynucleotides, pharmaceutical compositions comprising said viruses, and methods of using said pharmaceutical compositions to vaccinate an animal or human patient. Under the definition provided for in the specification, one deoptimized codon pair is sufficient to meet the limitation (¶[0013-0014][0018]). “Polynucleotides” include both DNA and RNA.
The specification describes specific recoded viruses designated CPD6, sCPD3, sCPD4, sCPD9, an sCPD10. The CPD6 virus contains two recoded regions involving nsp7 through nsp12, and the sCPD9 virus contains a recoded region involving nsp15 and nsp16, while sCPD10 contains a recoded spike protein region sequence (¶[0099-0108]; Tables 1-2). The attenuation amongst these resulting viruses was very different. CPD6, sCPD9, and sCPD10 showed attenuation in Syrian hamsters, but sCPD3 and sCPD4 caused clinical and histological signs resembling those cause by pathogenic wild-type SARS-CoV-2. The vaccination trials for sCPD3 and sCPD4 were therefore discontinued (¶[0119-0131]).
However, the scope of the claims, including the scope of the deoptimized regions of the claimed polypeptide and the scope of the live, attenuated SARS-CoV-2 viruses, is not limited to the disclosed embodiments. The claims also encompass SARS-CoV-2 viruses with any polynucleotide according to claim 1, including later-arising SARS-CoV-2 variants and recoding designs which involve substantially different SARS-CoV-2 genes and sequence contexts. The claims also encompass viruses only having one deoptimized codon pair up to viruses having many hundreds of changes, and such range of polypeptides and resulting viruses were not generated or tested. Further claims add sequence-identity genus of polynucleotides and viruses having a percent identity to a given sequence, and a range or percentage of total codon pairs which may be deoptimized, as well as different regions of deoptimization separated by conserved regions. The pharmaceutical compositions are not limited to only those compositions with only the reagents within tested, nor are the method claims only limited to the particular animal model tested in the vaccination regimen tested (e.g. route, timing, and dosage of administration.) The claimed scope therefore extends beyond the embodiments described in the specification.
State of the prior art and predictability of the art. At the time the application was filed, codon-pair deoptimization was known as a method for producing attenuated viral candidates. Osterrieder et. al. (Osterrieder N, et. al. Curr Clin Microbiol Rep. 2018;5(1):66-72. Epub 2018 Jan 19.) teaches that codon and codon-pair deoptimization had been used to attenuate viruses, but also stated that “the exact mechanisms that lead to viral attenuation by recoding are yet to be determined.” Osterrieder further discusses that synonymous recoding may affect translation, dinucleotide frequencies, RNA stability, and host antiviral responses rather than operating through a single predictable mechanism.
Tulloch et. al. (Tulloch F, et. al. Elife. 2014 Dec 9;3:e04531.) investigated the effect of RNA-virus attenuation attributed to codon-pair deoptimization and found that replication was primarily influenced by CpG and UpA frequencies rather than codon-pair usage or translation efficiency alone. Tulloch concluded that increasing CpG and UpA frequencies could strongly attenuate viral replication even when codon-pair usage was considered separately. This teaching shows that a recoded sequence cannot be evaluated solely from the number of nominally unfavorable codon pairs because dinucleotide content and sequence context materially affect the resulting phenotype.
Trimpert et. al. (Trimpert J, et. al. Cell Rep. 2021 Aug 3;36(5):109493. Epub 2021 Jul 20.) reported the SARS-CoV-2 recoding work which is in the underlying present disclosure. Trimpert constructed multiple recoded genomes, but recovery and phenotype differed materially according to the region and the extend of recoding. The publication identifies sCPD9 as the lead candidate after comparative cell culture and hamster testing, rather than suggesting that SARS-CoV-2 attenuation or vaccine performance could be predicted for any recoded region or sequence.
Mueller et. al. (WO2021154828A1) likewise describes recoded SARS-CoV-2 viruses in which codon usage, codon pair bias, CpG, or UpA content may be altered in selected genomic regions. Mueller provides particular recoded sequences and teaches that modified viruses are evaluated for viral growth, attenuation, immunogenicity, and suitability as vaccines. The need to design and test particular constructs is consistent with the conclusion that the effect of recoding depends on the selected region, the specific synonymous mutations/substitutions, and the resulting viral phenotype rather than following automatically from the generic presence of codon-pair deoptimization.
The prior art therefore established both the availability of recoding techniques and the biological uncertainty that remained after a sequence was designed. It was possible to make candidate recoded polynucleotides of viral genomic regions, and to thus make viral recoded genomes. It was not predictable, however, whether a given candidate would be recoverable as infectious virus, replicate sufficiently for manufacture, remain attenuated in vivo, or provoke protective immunity without unacceptable disease. The art was not sufficiently predictable to support extrapolation from CPD6, sCPD9, and sCPD10 to every polynucleotide or every virus within the scope of the claims. Accordingly, the results obtained using the disclosed constructs would not have reasonably established that the broader claimed scope could be practiced without further experimentation.
Level of skill in the art. One skilled in the art would have been familiar with SARS-CoV-2 reverse genetics systems, viral genome synthesis, cell culture recovery, focus forming assays, sequencing, animal infection models (especially with respect to SARS-CoV-2 infection), and measurements of viral load, pathology, and neutralizing antibodies. However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further experimentation, which additional deoptimized polynucleotides within which SARS-CoV-2 backbones would satisfy the claimed limitations. The selection of codon pairs is not governed by a predictable rule set that allows a skilled artisan to identify successful designs without iterative construction and biological screening.
Working examples. The specification provides working examples directed to the attempted construction of nine separate SARS-CoV-2 genomes carrying recoded fragments. Infectious virus was initially recovered only from constructs containing recoded fragments 2 and 6 (¶[0057-0059][0063-0064][0104-0108]; Tables 1, 4). The inventors suspected that some constructs were not recoverable because the extent of recoding was too great (¶[0108]). Six additional constructs were then prepared with shorter, approximately 1,000 nucleotide recoded sequences, but infectious viruses were recovered from only four of the six constructs (¶[0108]). This was not a minor optimization issue, as some recoded viruses did not produce infectious virus at all. Among the recovered viruses, replication in Vero E6 cells was “highly variable” and sCPD9 and sCPD10 replicated at substantially lower levels than the parental virus (¶[0109]). The animal results were also construct dependent, as CPD6, sCPD9, and sCPD10 were attenuated in Syrian hamsters, but sCPD3 and sCPD4 produced disease resembling pathogenic wild-type infection (¶[0119-0131]). The application itself therefore demonstrates that successful recovery of a recoded virus dis not establish that the virus would be attenuated. The more detailed vaccination examples focus primarily on sCPD9 administered intranasally to Syrian and Roborovski dwarf hamsters. The specification reports protection after challenge with ancestral, Alpha, and Beta SARS-CoV-2 variants (¶[0135-0153][0194-0210]).
The specification does not provide working examples directed to the breadth of polynucleotides claimed in instant claims 1-13, as in the specification fails to provide working examples recoding the different claimed potential combinations of non-structural proteins with or without spike protein. It does not test the large number of sequences having the percent identity claimed to the claimed SEQ ID NOs, nor are there any human vaccination examples, no working oral or parenteral vaccination example, and no example using the outer portions of the claimed dose or booster-interval ranges. The disclosed examples therefore do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides guidance regarding the sequences and genomic locations of CPD6, sCPD9, and sCPD10. It describes reverse genetics recovery, cell culture characterization of the viruses, hamster infection and pathology, and subsequent wild-type virus challenge experiments. It also provides broad ranges for the length of a recoded region and the percentages or numbers of altered nucleotides and codons. However, the specification does not provide sufficient guidance regarding for selecting other recoding designs in other polynucleotides, especially ones that will produce a live attenuated virus. The disclosure expressly states that “[s]ince the effect of CPD strongly depends on the genome sequence to be deoptimized, no general measure of codons to be deoptimized can be indicated”(¶[0017]). That statement identifies the central technical deficiency, as the specification does not explain how wone should select a genomic region and determine an appropriate degree of recoding before constructing the virus. It does not identify a threshold codon pair score, a permissible CpG or UpA range, or a predictable relationship between the selected viral gene and attenuation. The specification also fails to explain which positions in the 98% identity viruses or the 95% identity polynucleotides may be changed while still resulting in a working coding sequence, especially in the context of the entire SARS-CoV-2 viral genome. With respect to the full genomic sequences claimed, hundreds of differences are permitted, but no general rule identifies whether those differences may restore favorable codon pairs, alter RNA structures, change viral proteins, impair genome replication, or eliminate the attenuated phenotype.
The specification also fails to provide a reliable in vitro endpoint that predicts safe and effective vaccination. The results show that weaker replication in Vero E6 cells did not directly establish the degree of attenuation in animals. The application reports that sCPD9 and sCPD10 replicated efficiently in the upper respiratory tract of hamsters despite weaker replication in Vero E6 cells (¶[0127][0167][0197]).
The disclosure therefore provides examples and testing methods, but not a general quality or selection rule that permits the full claimed scope to be practiced without empirical construction and screening of the sequences and any resulting virus.
Quantity of experimentation necessary. To practice the full scope of the claims, one skilled in the art would need to select one or more SARS-CoV-2 genes from the alternatives incorporated through claim 1. The skilled person would then need to choose a sequence region, design a synonymous recoding pattern (including deoptimized codon pairs), synthesize or assemble the genome, attempt virus recovery, and determine whether the resulting virus is viable. A recoverable virus would still require further testing. Its replication would have to be measured in appropriate cell systems, genetic stability assessed, and attenuation examined in a susceptible animal model. Candidates that remained pathogenic would be discarded, while candidates that were over-attenuated or grew poorly might also require redesign because they could be unsuitable for manufacture or fail to induce adequate immunity.
For claims 1-13 in particular, the experimentation burden is exacerbated by the lack of predictive rules governing codon-pair selection. The specification does not provide a deterministic or even semi-empirical framework for selecting deoptimized codon pairs that reliably yield attenuation. As a result, the skilled artisan would be required to explore a large combinatorial space of synonymous substitutions and codon pair arrangements, with no assurance of success prior to empirical testing. The process would have to be repeated for other sequence backgrounds and SARS-CoV-2 variants covered by the claims. Claim 19 would additionally require evaluation of a very large number of whole genome variants differing at potentially hundreds of positions. Sequence identity alone would not predict which variants retained the required phenotype.
To practice the full scope of claims 23-26, a skilled person would also need to determine whether each candidate was safe and immunogenic in the claimed human or animal subject. Route, dose, and administration schedule would require further study because a live respiratory virus administered intranasally does not necessarily behave in the same manner when given orally, intramuscularly, intravenously, or by another parenteral route.
Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test the additional embodiments noted supra to determine whether they result in virus, especially virus that is live-attenuated and suitable for vaccination. Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays. The relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, one skilled in the art would need to prepare and test additional deoptimized sequences to determine which embodiments are live, attenuated, manufacturable, and effective as vaccines.
Amgen. The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610-13 (2023).
In the instantly claimed invention, the specification describes the exact CPD6, sCPD9, and sCPD10 constructs and demonstrates attenuation and immunogenicity under selected hamster-study conditions. The claims also encompass viruses using many other recoded polynucleotides, recoded genomic regions, any SARS-CoV-2 variant, and whole genome sequences having hundreds of permissible differences. The dependent claims extend still further to broad patient groups, routes of delivery, dosage ranges, and vaccination schedules. The specification does not identify a general quality or provide sufficient guidance linking codon-pair deoptimized sequence structure to a live-attenuated phenotype that would allow one skilled in the art to practice that broader scope without undue experimentation.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and/or use the full scope of the invention recited in the claims without undue experimentation.
Claims 1-13, 18-19, 21, and 23-26 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement, the specification must reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention as of the filing date. Possession may be shown by a description of the complete structure of the claimed invention, a representative number of species falling within the scope of a claimed genus, or relevant identifying characteristics sufficient to show that the inventor had possession of the claimed subject matter.
Claim(s) 1-13 recite polynucleotides encoding SARS-CoV-2 spike protein and/or one or more listed non-structural proteins (nsps), wherein at least one sequence part comprises codon-pair deoptimizations in comparison to a SARS-CoV-2 genome. Depending on the claim, the polynucleotide may be further defined by the location or length of the recoded part, the number or percentage of changed nucleotides or codons, the presence of two separated deoptimized parts, or sequence identity to one of the disclosed sequences. The specification defines “SARS-CoV-2” as “any variant that is classified as SARS-CoV-2” and states that the SARS-CoV-2 protein and genome may be those of a SARS-CoV-2 variant (¶[0009-0011]). The specification also states that a polynucleotide is considered codon-pair deoptimized “if at least one codon pair is deoptimized with respect to the corresponding natural sequence” (¶[0018]). Claim 1 therefore encompasses a very large group of polynucleotides from any SARS-CoV-2 variant, involving any one or more of the listed coding regions, in which as little as one codon pair is considered deoptimized relative to a corresponding genome sequence.
The specification describes particular recoded sequences designated CPD6A, CPD6B, sCPD9, and sCPD10. CPD6A corresponds to a 1,482-nucleotide region extending from positions 11,969 to 13,450 and encoding portions of nsp7 through nsp12. CPD6B corresponds to a 354-nucleotide region extending from positions 13,954 to 14,307 and encoding a portion of nsp12. The disclosed sCPD9 sequence is a 1,146 nucleotide sequence extending from positions 20,359 to 21,504 and encoding portions of nsp15 and nsp16, while sCPD10 is a 999-nucleotide spike-region sequence extending from positions 24,335 to 25,333 (Table 1; ¶[0143-0148]). The specification further describes that CPD6A contains 338 altered codons, CPD6B contains 84 altered nucleotides and 70 altered codons, sCPD9 contains 239 altered nucleotides and 205 altered codons, and sCPD10 contains 241 altered nucleotides and 201 altered codons (Table 2; ¶[0165]). These sequences provide examples of particular recoding designs at three genomic locations, but they do not represent the substantially larger genus recited in claim 1.
The scope of claims 1-10 is not limited to these embodiments described in the specification. The claims broadly encompass deoptimization anywhere within the coding sequence for spike, nsp7, nsp8, nsp9, nsp10, nsp11, nsp12, nsp15, or nsp16. They also encompass different SARS-CoV-2 lineages and later arising variants, different selections of synonymous codons, different codon-pair scores, and different distributions of CpG dinucleotides. Claim 1 reaches an embodiment having one altered codon pair, while claims 4-10 recite broad length and numerical ranges that may be applied to numerous coding regions and sequence backgrounds not structurally described in the specification.
The specification does not describe a sufficient number of species representative of the claimed scope. The specification also does not describe structural features common to the claimed genus which would allow one skilled in the art to recognize which additional recoded sequences are members of the genus possessed by the inventors. The disclosure identifies the proteins that may be encoded and supplies broad ranges for the amount of recoding, but those features do not identify which codons should be rearranged, which codon-pair combinations are suitable, or which sequence contexts will produce the intended result. The specification states that “[s]ince the effect of CPD strongly depends on the genome sequence to be deoptimized, no general measure of codons to be deoptimized can be indicated”(¶[0017]). The specification states that the inventors provide examples of codon pairs to recode and that the skilled person could arrive at other polynucleotides (¶[0018-0019]). A statement that additional sequences may be made does not describe the structures of those additional sequences or identify common structural characteristics demonstrating that the inventors possessed them.
The experimental disclosure confirms that recoding outcome depends materially on the sequence selected and the extent of recoding. The inventors recoded nine SARS-CoV-2 genomic fragments, but infectious virus was initially recovered from only constructs carrying recoded fragments 2 and 6 (¶[0108-0118][0181-0184]). The inventors then produced six constructs having shorter recoded regions, but recovered infectious viruses from only four of these six constructs (¶[0108][0185-0186]). The specification explains that extensive codon-pair deoptimization can produce a lethal phenotype (¶[0108]). These results show that being within the scope of the claimed genus cannot be identified merely from the fact that a sequence encodes one of the listed proteins and contains one or more codon-pair changes.
Claims 9 and 10 are narrower because they require two deoptimized sequence parts separated by at least 300 non-deoptimized nucleotides and assign length ranges to those parts. The specification describes one relevant arrangement, CPD6, in which the recoded CPD6A and CPD6B sequences flank a conserved 503-nucleotide region containing the frameshift stimulation element (¶[0179-0180]; Table 1). Claims 9 and 10 are not limited to CPD6, the disclosed genomic coordinates, the frameshift stimulation element (FSE), or SEQ ID NOs: 2 and 4, as they encompass other pairs of deoptimized regions placed elsewhere in any claimed SARS-CoV-2 coding region, separated by any non-deoptimized section of at least 300 nucleotides.
The specification does not describe representative two-part arrangements across that scope. Nor does it identify structural criteria showing when two recoded regions separated by an arbitrary non-deoptimized section will preserve replication, maintain the required RNA elements for viral replication and/or packaging, or otherwise possess the properties attributed to CPD6. The description of the single CPD6 arrangement does not reasonably convey possession of the broader genus recited in claims 9 and 10.
Claims 11-13 recite sequences having at least 95% sequence identity to SEQ ID NOs: 2, 4, 6, 8, 10, and 15-17. The specification describes the identified sequences and states that the claimed polynucleotides may have at least 95%, 96%, 97%, 98%, 99%, or 100% identity to those sequences (¶[0031-0037]). The recitation of percentage identity values, standing alone, does not describe the structures of the variants falling within those genera. A sequence having 95% identity to one of those disclosed regions may contain many nucleotide substitutions, insertions, and/or deletions. Those differences may occur at codons deliberately rearranged in the disclosed sequence, at CpG dinucleotides, at RNA structures, or at other positions affecting replication and attenuation. The claims do not require that the variants preserve the particular synonymous substitutions, codon-pair score, CpG distribution, amino acid sequence, or attenuation characteristics of the disclosed sequence. The specification does not identify which positions within SEQ ID NOs: 2, 4, 6, 8, 10, and 15-17 may be altered while retaining the relevant recoding characteristics. It does not describe representative 95% identity variants, and it does not identify a conserved sequence motif or other structural feature sufficient to distinguish variants belonging to the claimed genus from sequences that merely satisfy the numerical identity threshold. Accordingly, the disclosure of the identified sequences and a series of percent identity values does not demonstrate possession of the broader claimed group of sequences recited in claims 11-13.
Claim 18 recites a live attenuated SARS-CoV-2 comprising the polynucleotide of claim 1. The claimed virus is defined, at least in part, by the functional requirement that it be “live attenuated”. The specification explains that a live attenuated virus provokes fewer, less severe, or no symptoms while inducing an immune response that is at least partially protective (¶[0016]). The specification also states that codon-pair deoptimization may result in increased mRNA decay, reduced translation efficiency, less virus, reduced virulence, or a live-attenuated virus (¶[0014]). The specification describes recovered viruses CPD6, sCPD3, sCPD4, sCPD9, and sCPD10; these five viruses failed to behave uniformly. CPD6, sCPD9, and sCPD10 were attenuated in Syrian hamsters, while sCPD3 and sCPD4 caused clinical and histological signs resembling those caused by pathogenic wild-type SARS-CoV-2 (¶[0119-0134]; Figs. 3-6). The inventors identified sCPD9 as providing the best balance of attenuation, safety, immunogenicity, and protective efficacy (¶[0171]).
However, claim 18 is not limited to only this virus, and broadly encompass additional live attenuated viruses containing any recoded sequence within the broad genus described above, including a sequence with only one deoptimized codon pair. The specification does not describe a structural correlation between the location, number, or identity of codon-pair substitutions and the recited live-attenuated phenotype sufficient to identify other viruses falling within the claim. Instead, the disclosed results show that some recoding designs were nonviable, while others remained pathogenic or differed substantially in replication and attenuation. The disclosure of the desired attenuation function, together with a few specific structurally distinct viruses, does not reasonably convey possession of the substantially broader scope recited in the claim(s). One skilled in the art would be required to create additional recoded genomes not described in the specification, recover virus where possible, and then determine experimentally whether each virus remained viable and was sufficiently attenuated.
Claim 19 recites viruses having the sequence of SEQ ID NO: 18 or 19, or at least 98% sequence identity to either sequence. The specification describes SEQ ID NOs: 18 and 19 and states that the live attenuated SARS-CoV-2 may be at least 98%, 99%, or 100% identical to those sequences (¶[0065-0066]). The specification does not describe representative whole-genome variants across the claimed 98% identity scope. A SARS-CoV-2 genome is approximately 30kb long, and a 98% identity limitation therefore permits variation at hundreds of nucleotide positions. The claims do not require that those variants retain the disclosed recoded segment, preserve the particular codon-pair substitutions, or maintain attenuation, replication competence, immunogenicity, and genetic stability. The specification does not identify which genomic positions may vary while retaining the claimed live-attenuated phenotype. Nor does it provide structural characteristics sufficient to recognize the full group of whole-virus genomes encompassed by claim 19.
Claim 21 recites a pharmaceutical composition comprising the live attenuated virus of claim 18. The specification describes a composition containing such a virus and states that the composition may further contain an adjuvant (¶[0067-0077]). Claim 21 does not cure the written description deficiency of claim 18 because it continues to encompass a composition containing any virus within the unsupported genus incorporated from claim 18. Describing optional pharmaceutical ingredients does not demonstrate possession of the broader group of live attenuated viruses placed in those compositions.
Claims 23-26 recite methods of vaccinating a human or animal patient by administering the pharmaceutical composition, including intranasal, oral, or parenteral administration, doses from 10^3 to 10^8 FFU, and repeated administration separated by two weeks to 36 months. The specification generally describes these subjects, routes, dose ranges, and intervals (¶[0070-0077]). The working examples, however, concern intranasal administration to Syrian or Roborovski hamsters. The tested doses were principally 10^4 or 10^5 FFU, and the challenge studies generally occurred 21 days after vaccination (¶[0109-0153]). The specification does not describe vaccination of humans. It does not provide working examples of oral, subcutaneous, intramuscular, intravenous, or intraperitoneal administration, and it does not demonstrate repeated vaccination at intervals extending to 36 months. More importantly, claims 23-26 continue to require a pharmaceutical composition containing any live attenuated virus within the unsupported genus of claim 18. The specification itself states that the safety, immunogenicity, and vaccine efficacy of the lead sCPD9 candidate should be investigated in other animals, nonhuman primates, and ultimately humans (¶[0215][0171]). This statement confirms that the disclosed animal results were ties to particular constructs and particular rodent models rather than demonstrating possession of vaccination methods using the full genus of claimed viruses in every claimed subject and route.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventor had possession of the full scope of the subject matter recited in the claims at the time the application was filed.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-8, 18-19, 21, 23-24, and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mueller et. al. (WO2021154828A1; Pub. 08/05/2021; CITED ART OF RECORD IN IDS 07/19/2024; hereafter “Mueller”.)
The Prior Art
Mueller teaches modified SARS-CoV-2 coronaviruses, wherein these viruses have been recoded, for example, codon deoptimized or codon pair bias deoptimized, and are useful in compositions and methods for reducing the likelihood or severity of a SARS-CoV-2 coronavirus infection, preventing a SARS-CoV-2 coronavirus infection, eliciting and immune response, or treating a SARS-CoV-2 coronavirus infection (entire document; see abstract.) Mueller teaches an isolated polynucleotide encoding one or more viral proteins or one or more fragments thereof of a parent SARS-CoV-2 coronavirus wherein the polynucleotide is recoded compared to its parent SARS-CoV-2 coronavirus polynucleotide (reference claim 1). Mueller teaches said polynucleotide could be the SARS-CoV-2 genome (¶[0037][0080]; reference claim 46) and would comprise at least one codon-pair bias (CPB) deoptimized region selected from bp 11294-12709, bp 14641-15903 (nsp12), bp 21656-22306 (spike beginning), bp 22505-23905 (spike middle), and bp 24110-25381 (spike end) of SEQ ID NO:1 or SEQ ID NO:2, such as a comprising a recoded spike protein or a fragment of spike protein wherein the furin cleavage site is eliminated (reference claims 18-19; instant claims 1-5). Mueller teaches that anywhere from 10 to 500 codons are substituted with synonymous codons less frequently used in the host (¶[0082-0085]; instant claims 6-8). Mueller teaches that these deoptimized sequences can generate live attenuated SARS-CoV-2 virus vaccine candidates (¶[0073-0074][00179]; instant claim 18), and SEQ ID NOs: 1 and 4 of Mueller align with instant SEQ ID NOs: 18 and 19 with 98.7% and 98.9% identity, respectively (see ABSS sequence search results, namely alignment with 17/794,862 in .rnpbm ABSS file; instant claim 19). Mueller teaches that these viruses can be within pharmaceutical compositions (¶[00188]; reference claims 34-37; instant claim 21). Mueller teaches methods of vaccinating using said pharmaceutical compositions to induce a protective immune response in a subject (reference claims 34-45; instant claim 23), wherein the composition is administered intranasally (reference claims 38 and 42; instant claim 24). Mueller teaches the dose is about 104-106 PFU, or the prime dose is about 104-106 PFU and the one or more boost dose is about 104-106 PFU (reference claim 45), and can be delivered in a prime/boost dosing regimen (reference claim 45; ¶[0028]), wherein the first administration and the second administration are delivered about 2-12 weeks apart (¶[0204]; instant claim 26).
For at least these reasons, Mueller teaches the limitations of instant claims 1-8, 18-19, 21, 23-24, and 26, and anticipates the invention encompassed by said claims.
Claims 1-8, 18-19, 21, 23-24, and 26 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Mueller et. al. (US20230117167A1; Priority 01/28/2020; hereafter “Mueller-167”.)
The Prior Art
Mueller-167 teaches modified SARS-CoV-2 coronaviruses, wherein these viruses have been recoded, for example, codon deoptimized or codon pair bias deoptimized, and are useful in compositions and methods for reducing the likelihood or severity of a SARS-CoV-2 coronavirus infection, preventing a SARS-CoV-2 coronavirus infection, eliciting and immune response, or treating a SARS-CoV-2 coronavirus infection (entire document; see abstract.) Mueller-167 teaches an isolated polynucleotide encoding one or more viral proteins or one or more fragments thereof of a parent SARS-CoV-2 coronavirus wherein the polynucleotide is recoded compared to its parent SARS-CoV-2 coronavirus polynucleotide (reference claim 1). Mueller-167 teaches said polynucleotide could be the SARS-CoV-2 genome (¶[0037][0304]; reference claim 46) and would comprise at least one codon-pair bias (CPB) deoptimized region selected from bp 11294-12709, bp 14641-15903 (nsp12), bp 21656-22306 (spike beginning), bp 22505-23905 (spike middle), and bp 24110-25381 (spike end) of SEQ ID NO:1 or SEQ ID NO:2, such as a comprising a recoded spike protein or a fragment of spike protein wherein the furin cleavage site is eliminated (reference claims 18-19; instant claims 1-5). Mueller-167 teaches that anywhere from 10 to 500 codons are substituted with synonymous codons less frequently used in the host (¶[0082]; instant claims 6-8). Mueller-167 teaches that these deoptimized sequences can generate live attenuated SARS-CoV-2 virus vaccine candidates (¶[0073-0074]; instant claim 18), and SEQ ID NOs: 1 and 4 of Mueller-167 align with instant SEQ ID NOs: 18 and 19 with 98.7% and 98.9% identity, respectively (see ABSS sequence search results, namely alignment with 17/794,862 in .rnpbm ABSS file; instant claim 19). Mueller-167 teaches that these viruses can be within pharmaceutical compositions (¶[0200]; reference claims 34-37; instant claim 21). Mueller-167 teaches methods of vaccinating using said pharmaceutical compositions to induce a protective immune response in a subject (reference claims 34-43; instant claim 23), wherein the composition is administered intranasally (reference claims 38 and 42; instant claim 24). Mueller-167 teaches the dose is about 104-106 PFU, or the prime dose is about 104-106 PFU and the one or more boost dose is about 104-106 PFU (reference claim 45), and can be delivered in a prime/boost dosing regimen (reference claim 45; ¶[0028]), wherein the first administration and the second administration are delivered about 2-12 weeks apart (¶[0216]; instant claim 26).
For at least these reasons, Mueller-167 teaches the limitations of instant claims 1-8, 18-19, 21, 23-24, and 26, and anticipates the invention encompassed by said claims.
Claims 1-13, 18-19, 21, and 23-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Trimpert et. al. (Trimpert J, et. al. Cell Rep. 2021 Aug 3;36(5):109493. Epub 2021 Jul 20.; CITED ART OF RECORD IN 07/19/2024 IDS; hereafter “Trimpert”.)
The Prior Art
Trimpert teaches generation of live attenuated SARS-CoV-2 vaccine candidates by large-scale recoding of the SARS-CoV-2 genome and assess their safety and efficacy in Syrian hamsters (entire document; see abstract.) Trimpert teaches recoding of the SARS-CoV-2 genome and generation of different SARS-CoV-2 mutants with deoptimized codon pairs in the spike protein and non-structural proteins, such as nsp7-10 (Fig. 1; p. 2, left col., ¶2; instant claims 1-2, 15). Trimpert teaches rescue of 4 recoded SARS-CoV-2 viruses, CPD2, CPD6, sCPD3, sCPD4, sCPD9, and sCPD10 (which appear to be the same viruses of the instant disclosure; see 35 USC 112a rejections supra), wherein certain viruses had gaps in the recoded segments, as Fragments 1 and 12, which are relatively short, 591 and 1,812bp, respectively, and fragment 11, which contains many short ORFs, were excluded from the recoding. (p. 2, rt. Col., ¶3; p. 3, left col., ¶1; instant claims 3-13, 18-19). Trimpert teaches generation of vaccine compositions comprising the viruses and the intranasal vaccination of Syrian hamsters with said compositions (“Vaccination of Syrian hamsters and challenge infection setup” starting at p. 3; instant claims 21, 23-24). The hamsters received 1x10^4 or 1x10^5 FFU dosages of virus (p. 4, left col., ¶1; instant claim 25).
Trimpert teaches the limitations of instant claims 1-13, 18-19, 21, and 23-25, and anticipates the invention encompassed by said claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Muller, or, in the alternative, Mueller-167, as applied to claims 1-8, 18-19, 21, 23-24, and 26 above, and further in view of Amarilla et. al. (Amarilla AA, et. al. Front Microbiol. 2021 Feb 12;12:625136.; hereafter “Amarilla”.)
The Prior Art
The teachings of Mueller and Mueller-167 have been set forth supra. While both teach methods of delivering live, attenuated SARS-CoV-2 deoptimized codon pair viruses to a subject to elicit a prophylactic or therapeutic immune response, Mueller and Mueller-167 teach the delivery of the viral dose in plaque forming units (PFUs) as opposed to foci forming units (FFUs). However, the use of one measurement over the other was known in the art, as shown by Amarilla.
Amarilla teaches an immuno-plaque assay as a focus-forming assay for SARS-CoV-2 and reports the results of their assay in FFU/mL (entire document; see e.g. Fig. 9, p. 13, rt. Col., ¶1). Amarilla teaches that the assay is an alternative to the standard plaque assay and state that it provides a “comparable and reliable assay for SARS-CoV-2 quantification” (p. 13, rt. Col., ¶1). Amarilla further explains that both methods determine infectious virus titer through infection of a cell monolayer under a semisolid overlay, with the focus-forming method using virus-specific antibodies to confirm infected areas (p. 13, rt. Col., ¶2; p. 15, ¶ bridging cols.)
Given the teachings of Mueller or Mueller-167, one of skill in the art would be apprised as to how to measure the viral titer of a dosage of virus-based vaccine given PFUs. Given the teachings of Amarilla, one of skill in the art would have a more advanced methodology of measuring active virus and plaques which are actually formed by viral infection by using the immuno-plaque assay that measures the virus in each focus with an antibody. Therefore, one of skill in the art would find it obvious to optimize the dosage from PFU to FFU in the methods of Mueller or Mueller-167, given the teachings of Amarilla, rendering the limitations of instant claim 25 obvious.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Mueller or Mueller-167 in order to measure the viral titer via FFU instead of PFU, thereby generating a more accurate reading of active virus in the tested sample. One would have been motivated to do so, given the suggestion by Amarilla that the use of immunoassays to measure active virus in foci was a more accurate means to determine viral titer. There would have been a reasonable expectation of success, given the knowledge that the PFU method could easily be adapted to determine FFU in SARS-CoV-2 virus samples, as taught by Amarilla. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-13, 18-19, 21, and 23-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 16-19 of copending Application No. 19/109,030 (reference application) in view of Johnson et. al. (Johnson BA, et. al. Nature. 2021 Mar;591(7849):293-299. Epub 2021 Jan 25.; hereafter “Johnson”.)
Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming polynucleotides encoding SARS-CoV-2 spike proteins and non-structural proteins, including endoribonuclease and a 2'-O-methyltransferase. Both claim SEQ ID NOs: 6, 8, 10, and 15-17, which are 100% identical to each other, instant SEQ ID NO: 18 is 99.8% identical to reference SEQ ID NO: 19, and instant SEQ ID NO: 19 is 99.8% identical to reference SEQ ID NO: 20 (See ABSS .rnpn result files). Both claim methods of using the polynucleotide to vaccinate a subject comprising administration of a pharmaceutical composition comprising the polypeptide, such as through intranasal, oral, or parenteral administration. Both claim live, attenuated SARS-CoV-2 that comprise the nucleic acid sequences that are deoptimized. Both claim the delivery of the same dosage of live, attenuated SARS-CoV-2 comprising the polynucleotide mutations. Both claim the pharmaceutical preparation is administered to the patient at least two times, wherein a second administration is separated from a first administration by a first time period lying in range of from 2 weeks to 36 months. The main difference is that the reference ‘030 claims require a furin cleavage site modification, wherein the furin cleavage site modification results in a loss of a furin cleavage site being naturally present in the SARS-CoV-2 genome. However, mutation of the furin cleavage site in SARS-CoV-2, namely the S protein, was suggested in the art to generate attenuated SARS-CoV-2 variants, as taught by Johnson. Johnson teaches the generation of mutant SARS-CoV-2 wherein the furin cleavage site was deleted (ΔPRRA), and the ΔPRRA mutant showed reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis (entire document; see abstract.) Therefore, as both the instant and the reference claims are drawn to the production of live, attenuates SARS-CoV-2 viruses, this would be an additional obvious modification to make to the claimed polynucleotides in order to further attenuate the resulting viruses. Therefore, the instant claims and the ‘030 claims are not patentably distinct, especially in light of the teachings of Johnson.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Saphire et. al. (US20230398204A1; Priority 10/21/2020). Teaches mutation of furin cleavage sites in spike protein with flexible linkers to generate spike proteins with greater trimeric stability. Not utilized as rejection would be redundant to those set forth supra.
US20200268865A1. Teaches deoptimization of coronavirus codons to reduce replicative fitness. Not utilized as rejection would be redundant to those set forth supra.
US20240252616A1. Teaches deoptimization of SARS-CoV-2 codons to reduce replicative fitness. Not utilized as rejection would be redundant to those set forth supra.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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