Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Disposition of Claims
Claims 1-14 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250249088A1, Published 08/07/2025.
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.
Of note, there is not an attorney of record on file due to a lack of an official power of attorney of record. While a customer number has been provided on the ADS submitted 04/17/2024, this is not the equivalent of a power of attorney or an authorization to act in a representative capacity. In order to expedite prosecution in the instant application, it is suggested that a power of attorney be filed as per MPEP §402 or MPEP §1807, or an Authorization to Act in a Representative Capacity be filed as per MPEP §403 in order for the Office to freely and openly discuss the merits of the case with the applicant's representative(s). Please refer to https://www.uspto.gov/about-us/contact-us if you have questions regarding the proper filing of a power of attorney.
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 statement (IDS) submitted on 04/17/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of implied phraseology (See e.g. “Also disclosed herein…”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because of the following informalities: in the figure legends, the numbering goes from Fig. 6 to Fig. 8. There is no Fig. 8, and the legend for Fig. 7 is missing. It appears as though the figure legend at ¶[0030] is misnumbered.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities: the definition of the abbreviations “SARS-CoV-2” and “ACE2” are not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)...).
Appropriate correction is required.
Claim 2 is objected to because of the following informalities: the definition of the abbreviations “RBD” and “RBM” are not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … receptor binding domain (RBD)...).
Appropriate correction is required.
Claim 3 is objected to because of the following informalities: “SAR-CoV-2” should be “SARS-CoV-2”. Appropriate correction is required.
Claim 11 is objected to because of the following informalities: the infection is caused by the virus SARS-CoV-2, while “COVID” is a disease state caused by the viral infection. The claim should either be amended to recite “SARS-CoV-2 infection” or “COVID disease”. 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 2-12 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 is drawn to an immunogenic composition comprising a nucleotide sequence encoding a C-A Complex antigen comprising an antigenic domain spanning a spike protein of SARS-CoV-2 and an ACE2 receptor of an intermediate structure formed between SARS-CoV-2 and ACE2 receptor. The term “intermediate structure” in claim 1 is a relative term which renders the claim indefinite. The term “intermediate structure” 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. At ¶[0039] it is noted the “C-A Complex” is the “the sequence representing antigenic domains spanning the spike protein and the ACE2 receptor that form during the intermediate structure or complex formed between SARS-CoV-2 and ACE2 receptor” and at ¶[0064] it states “SARS-CoV-2 infection of host cells is orchestrated by the interactions between spike glycoprotein S1 subunit and ACE2 receptor on the cell surface followed by S2 mediating the fusion of viral and cell membranes for virus entry. This interaction leads to intermediate structures that are short-lived during natural viral infection. The present invention relates to compositions and methods useful for targeting this interaction in order to induce an immune response.” The specification refers to supposed multiple “intermediate structures” that may be formed during natural infection, but it is unclear as to the number and breadth of said potential structures. The specification does not identify an objective structural characteristic, conformational requirement, binding relationship, or test by which a person of ordinary skill could determine whether an antigen is “of an intermediate structure”. It is therefore unclear whether this language requires the antigen to adopt a particular receptor-bound conformation or merely describes the intended theory or purpose of the antigen.
Further, the structural scope of “an antigenic domain spanning” in relation to “a spike protein of SARS-CoV-2 and an ACE2 receptor of an intermediate structure formed between SARS-CoV-2 and ACE2 receptor” is unclear. The claim does not date whether the antigenic domain is a covalent fusion of Spike RBD and ACE2 sequences, a noncovalent RBD-ACE2 complex, a molecule containing unspecified portions of both proteins, or another structure intended to represent the interaction between spike and ACE2.
Accordingly, a person of ordinary skill in the art would not be able to ascertain the metes and bounds of the claimed C-A complex antigen. One suggestion is to amend the claim along the lines of the following:
“1. An immunogenic composition comprising an isolated nucleotide sequence encoding a chimeric antigen comprising a severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) spike protein or immunogenic fragment thereof covalently linked to a human angiotensin converting enzyme 2 (ACE2) polypeptide.”
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. Claims 2-12 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claim 2 and dependent claims 4-6 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 2 provides that “ wherein the spike protein component of the antigenic domain is an RBD/RBM domain of S1 protein of SARS-CoV-2.” With the limitation of “RBD/RBM”, it is unclear if the domain must include only the RBD or RBM domain, or if the domain must include all of the RBD domain, which inherently comprises the smaller RBM domain, or if another structural composition is encompassed, such as a full-length RBD fused to another RBM domain. It is suggested this limitation be amended to read upon “receptor binding domain (RBD) or receptor binding motif (RBM)” to clarify the metes and bounds of the claim.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant claim 2 is rejected on the grounds of being indefinite. Claims 4-6 are also rejected since they depend from claim 2, but do not remedy these deficiencies of claim 2.
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.
The term “evolved strains” in claim 3 is a relative term which renders the claim indefinite. The term “evolved strains” 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. The term does not provide an express temporal, genetic, or nomenclature boundary. It is unclear whether the claim includes every strain arising after the priority date of the instant application, or if it relies upon a specific “base” sequence of SARS-CoV-2 and every mutant beyond that base sequence, or some other grouping of strains, sequences, or variants.
For at least these reasons, the metes and bounds of claim 3 are unclear.
Claims 5 and 6 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 5 recites the limitation "the nucleic acid molecule" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 6 is rejected as it depends upon claim 5 and recites “the nucleotide sequence” instead of “the nucleic acid molecule”, making it unclear as to which item the claim depends upon. It is suggested claim 5 be recited to read upon “the nucleotide sequence” to provide proper antecedence to claims 1 and 6.
For at least these reasons, claims 5 and 6 are rejected on the grounds of being indefinite.
Claim 6 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 6 is drawn to “wherein the nucleotide sequence comprises one or more plasmids.” The wording of this claim is unclear, as nucleotide sequences are usually comprised within a plasmid, not vice versa as claimed. Furthermore, it is unclear how the singular sequence would comprise multiple plasmids in one sequence. One suggestion is to amend claim 6 to read along the lines of the following:
“6. The composition of claim 5, wherein the immunogenic composition comprises a plasmid comprising the nucleotide sequence.”
For at least these reasons, claim 6 is rejected on the ground of being indefinite.
Claim 8 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 8 is drawn to the composition of claim 1, wherein a nucleotide sequence encoding region is operably linked to at least one regulatory sequence selected from the group consisting of a start codon, an IgE leader sequence and a stop codon. The phrase “a nucleotide sequence encoding region” is grammatically unclear and lacks clear antecedent basis back to claim 1. Claim 1 recites a nucleotide sequence encoding a C-A complex antigen, but does not include a separate “nucleotide sequence encoding region”. It is therefore unclear whether claim 8 refers to the nucleotide sequence of claim 1, a coding region within that nucleotide sequence, or an additional nucleotide sequence.
The recited relationship between the encoding region and the start codon, IgE leader sequence, or stop codon is also unclear. The term “operably linked” ordinarily indicates that two nucleic acid elements are positioned so that one element regulates or otherwise affects the function or expression of the other. A start codon and a stop codon, however, ordinarily define the beginning and end of a coding sequence, rather than being regulatory elements operably linked to that sequence. An IgE leader sequence ordinarily forms part of the encoded open reading frame (ORF) and is positioned in frame with the sequence encoding the antigen. The claim does not make clear whether these elements are optional alternatives, whether all three may be present, or what structural relationship is required between each element and the sequence encoding the C-A complex antigen.
One suggestion is to amend the claim along the lines of the following:
“8. The immunogenic composition of claim 1, wherein the nucleotide sequence comprises an open reading frame (ORF) comprising, in a 5’ to 3’ direction, a start codon, an optional nucleotide sequence encoding an IgE leader peptide, the nucleotide sequence encoding the C-A Complex antigen, and a stop codon.”
For at least these reasons, the metes and bounds of claim 8 are unclear.
Claim 9 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 9 recites the limitation "the nucleic acid molecule" in line 1. There is insufficient antecedent basis for this limitation in the claim. It is suggested the claim be amended to read on “the nucleic acid sequence” to provide proper antecedence.
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 immunogenic composition comprising an isolated nucleotide sequence encoding a chimeric antigen comprising a severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) spike protein or immunogenic fragment thereof covalently linked to a human angiotensin converting enzyme 2 (ACE2) polypeptide.
Further limitations of the immunogenic composition of claim 1 are wherein the spike protein component of the chimeric antigen is an RBD or RBM domain of S1 protein of SARS-CoV-2 (claim 2), wherein the C-A Complex antigen comprises an amino acid sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, and an amino acid sequence that is at least 90% identical to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:12 (claim 4), wherein the nucleotide sequence is selected from the group consisting of a DNA sequence and an RNA sequence (claim 5), wherein the immunogenic composition comprises a plasmid comprising the nucleotide sequence (claim 6); wherein the spike protein component includes point mutations identified in evolved strains of SARS-CoV-2 (claim 3); further comprising a nucleotide sequence encoding an adjuvant (claim 7); wherein the nucleotide sequence comprises an open reading frame (ORF) wherein the nucleotide sequence comprises an open reading frame (ORF) comprising, in a 5’ to 3’ direction, a start codon, an optional nucleotide sequence encoding an IgE leader peptide, the nucleotide sequence encoding the C-A Complex antigen, and a stop codon (claim 8); wherein the nucleic acid sequence is incorporated into a viral particle (claim 9); and wherein the composition is further comprising a pharmaceutically acceptable excipient (claim 10).
Claim 11 is drawn to a method of treating or preventing COVID disease in a subject in need thereof, the method comprising administering the composition of claim 1 to the subject.
Further limitations on the method of claim 11 are wherein the administering step comprises electroporation (claim 12).
Claim 13 is drawn to an isolated nucleic acid molecule comprising one or more nucleotide sequences selected from the group consisting of: SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, and a nucleotide sequence that is at least 90% identical to SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, or SEQ ID NO:11.
Claim 14 is drawn to a protein comprising one or more amino acid sequences selected from the group consisting of: SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, and an amino acid sequence that is at least 90% identical to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:12.
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 1-10 and 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 nucleic acids encoding the C-A complex antigen, does not reasonably provide enablement for any nucleic acid system encoding the C-A complex antigen. 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 nucleic acid” 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 nucleic acid” [emphasis added] in order to overcome this rejection.
Claims 1-14 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 specifically disclosed Pan-C1, Pan-C2, and Pan-C3 plasmid DNA constructs comprising SEQ ID NOs: 1, 3, and 5 encoding the proteins of SEQ ID NOs: 2, 4, and 6, and for the reported mouse immunization and in vitro testing of those constructs, does not reasonably provide enablement for the full scope of the C-A Complex antigens, nucleic acid molecules, proteins, immunogenic compositions, and 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 / USE / MAKE AND 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 nucleic acid molecules encoding a C-A Complex antigen, immunogenic compositions containing such nucleic acids, proteins and nucleic acids defined by sequence identity, and methods of treating or preventing COVID infection using the compositions. The intended antigen is based on an association between a SARS-CoV-2 spike region, namely the receptor binding domain (RBD) or the shorter receptor binding motif (RBM) found within said RBD, and an ACE2 receptor that is said to mimic an intermediate structure formed during viral entry.
The specification describes three principal DNA constructs: Pan-C1, Pan-C2, and Pan-C3. Pan-C1 comprises a wild-type SARS-CoV-2 RBD tethered to human ACE2 by a short linker, Pan-C2 comprises the alpha-, beta-, and gamma-variant RBDs tethered in series and then tethered to human ACE2, while Pan-C3 comprises the wild-type RBD tethered to human ACE2 and further tether to nucleocapsid epitopes (¶[0159-0164]). The three DNA constructs were expressed in mammalian cells of unidentified type, and expression of RBD and ACE2 components was evaluated by immunoblotting (¶[0164]). The specification further describes immunizing BALB/c mice with the DNA constructs of SEQ ID NOs: 1, 3, and 5, and evaluation of antibody binding, IgG subclasses, inhibition of RBD binding to ACE2, and neutralization of “wild-type” SARS-CoV-2 (it is unclear what was considered “wild-type” from the specification) in cultured Vero cells (¶[0165-0172]). The live virus experiment used sera from mice immunized with the Pan-C1 and Pan-C3 constructs, but the reported conclusion identifies strong neutralization by the Pan-C1 serum against an unidentified wild-type isolate (¶[0171-0172]). The specification appears to use “wild type RBD” and “wild type SARS-CoV-2” to refer generally to an ancestral or initial pandemic SARS-CoV-2 strain/sequence/variant, but it is unclear which particular isolate, lineage, accession number, or reference sequence said viral items were derived.
However, claims 1-14 are not limited to the disclosed embodiments. Claim 1 does not require a particular RBD or RBM, does not limit the ACE2 receptor to human ACE2, and does not define the amino acid boundaries of either component. The claim also does not require the disclosed orientation, a particular peptide linker, retention of ACE2 binding, or any identified conformation. Claim 2 limits the spike component to an RBD/RBM domain, but still does not identify which RBD or RBM sequence, which portion of that sequence must be present, or which ACE2 receptor is used. Claim 3 further encompasses point mutations associated with an open class of “evolved” SARS-CoV-2 strains. Claims 4 and 14 encompass amino acid sequences having at least 90% identity to any of six long, multidomain, chimeric proteins. Claim 13 similarly encompasses nucleotide sequences having at least 90% identity to any of six referenced nucleotide sequences. Even under the narrower construction, that identity is measured across the entire referenced sequence, and the claims permit extensive variation within the RBD or RBM, ACE2, peptide linker, domain junction, and nucleocapsid portions of the molecules. Claims 13 and 14 also permit a molecule or protein to comprise “one or more” of the recited sequences without limiting the number, arrangement, or relationship of those sequences.
The specification itself states that the specifically describe full-length nucleotide and amino acid variants may have about 96%, 97%, 98%, 99%, or 100% identity over the entire length of the disclosed sequences (¶[0073-0074]). The lower 90% threshold appearing in the claims is not accompanied by representative 90% identity molecules or functional data showing that such molecules retain the properties attributed to the C-A complex. The generic definitions of “substantially identical” and “variant” provide numerical ranges and general statements concerning conservative substitutions, but do not identify which positions in these particular multidomain proteins tolerate substitution, deletion, or insertion (¶[0056-0060]).
Claims 5-12 do not cure the underlying breadth. The claims continue to encompass the structurally undefined C-A Complex genus while adding DNA or RNA formats, plasmids, an encoded adjuvant of unknown type, regulatory elements, viral particle delivery using an unknown virus or virus-like particle, excipients, electroporation for delivery, and therapeutic or prophylactic administration. The specification discusses many of these features at a general platform level, but the working examples use plasmid DNA encoding the three disclosed human-ACE2 constructs. Claims 11 and 12 further encompass treatment of an established COVID infection, even though the examples do not report administration to an infected subject or therapeutic improvement after onset of disease.
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, it was known that amino acid substitutions within the SARS-CoV-2 RBD did not have uniform or readily predictable effects. Starr et. al. (Starr TN, et. al. Cell. 2020 Sep 3;182(5):1295-1310.e20. Epub 2020 Aug 11.) experimentally measured the effects of substantially all single amino acid substitutions in the RBD on expression of folded protein and ACE2 binding and reported that “[m]ost mutations are deleterious for RBD expression and ACE2 binding”. Starr also found that some substitutions were tolerated, while others increased ACE2 binding, demonstrating that the result depended on the position and identity of the substitution rather than on overall sequence identity alone. Shang et. al. (Shang J, et. al. Nature. 2020 May;581(7807):221-224. Epub 2020 Mar 30.) determined the crystal structure of a SARS-CoV-2 RBD bound to human ACE2. The authors reported that “several residue changes in SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD/hACE2 interface” and that these structural features increased ACE2-binding activity. Shang further identified matching structural features and specific contact residues in the viral RBM and human ACE2, indicating that the interaction depends on the particular residues and conformation present at both sides of the interface.
With respect to the breadth of ACE2 receptors claimed, Liu et. al. (Liu Y, et. al. Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):e2025373118.) functionally evaluated a broad collection of animal ACE2 orthologs for spike binding and support of SARS-CoV-2 entry. The authors found that ACE2 orthologs from several New World monkey species did not support entry despite having greater sequence identity to human ACE2 than orthologs from rabbit, dog, or cattle, and concluded that “high sequence identity does not necessarily correlate with its function to support virus entry”. The study also traced loss of receptor activity to particular interface residues, showing that an unqualified reference to an “ACE2 receptor” does not identify receptors expected to interact with a selected SARS-CoV-2 RBD in the same manner as human ACE2. Chan et. al. (Chan KK, et. al. Science. 2020 Sep 4;369(6508):1261-1265. Epub 2020 Aug 4.) used deep mutagenesis to examine 2,340 coding mutations in human ACE2 and identified ACE2 substitutions that increased binding to the SARS-CoV-2 spike protein. The authors combined selected substitutions to obtain additional increases in binding affinity and observed that ACE2 residues at different portions of the interface had different degrees of mutational tolerance. These results further show that changes within the ACE2 component can alter its relationship with the RBD and that the functional result cannot be determined from a global identity percentage alone.
Post-filing art has indicated that a SARS-CoV-2 infection could possibly trigger an autoimmune response where the body's immune system mistakenly attacks its own Angiotensin-Converting Enzyme 2 (ACE2) receptors. In the study by Arthur et. al. (Arthur JM, et. al. PLoS One. 2021 Sep 3;16(9):e0257016.), it was suggested that because the S protein and the ACE2 receptor physically interact so closely, the immune response against the viral S protein can result in a cross-reactive or anti-idiotypic response, leading lymphocytes to produce antibodies against ACE2 itself. As ACE2 is widely distributed throughout the human body (found in the lungs, heart, kidneys, and blood vessels), this autoimmune attack is suggested to be a contributing factor to the severe tissue damage, systemic inflammation, and multiple organ injuries seen in severe COVID-19, but has yet to be proven.
As these findings show, the art was not sufficiently predictable to support extrapolation from the three disclosed human-ACE2 constructs to any antigenic domain containing an unspecified spike region and an unspecified ACE2 receptor, much less to every protein and nucleic acid sequence within the 90% identity genera. Accordingly, the results obtained using Pan-C1, Pan-C2, and Pan-C3 would not have reasonably established that the broader claimed scope of RBD or RBM, ACE2 orthologs, domain arrangements, linkers, sequence substitutions, and additional pharmaceutical components in the composition could be expressed properly and elicit a safe and therapeutically effective response in the host without further experimentation.
Level of skill in the art. One skilled in the art would have been familiar with gene synthesis, codon optimization, plasmid construction, and expression of recombinant proteins in mammalian cells. A skilled artisan would be familiar with immunoblotting and ELISA techniques to evaluate antibody expression and binding, as well as inhibition or neutralization assays. The specification acknowledges that methods for introducing and expressing genes in host cells were known and identifies transfection methods. 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 RBD or RBM sequences, ACE2 receptors, 90% identity variants, multidomain arrangements, pharmaceutically acceptable adjuvants and excipients, and nucleic acid delivery constructs would satisfy the claimed limitations.
Working examples. The specification provides two working examples directed to the DNA plasmid embodiments. Example 1 is directed to the design and mammalian cell expression of Pan-C1, Pan-C2, and Pan-C3 plasmid DNA constructs. Example 2 is directed to immunization of mice with the three DNA constructs and the testing of the resulting sera (¶[0159-0171]).
The specification does not provide working examples directed to testing any protein or nucleotide sequence having only 90% identity to a referenced sequence. They do not test a nonhuman ACE2 receptor, a different ACE2 domain, an independently selected RBD or RBM, a reversed domain orientation, or any alternative linkers. SEQ ID NOs: 7-12 are identified as “trimmed” sequences, but the examples do not separately establish their expression, conformation, immunogenicity, or neutralizing activity. No working example uses an RNA vaccine or viral particle containing the claimed nucleic acid. Claim 7 recites a nucleotide sequence encoding an adjuvant, while the specification broadly defines an adjuvant as “any molecule” added to enhance immunogenicity (¶[0037]). To the extent claim 7 is construed as limited to an encoded protein adjuvant, the specification still does not identify or test a particular encoded adjuvant with a C-A complex construct. The examples also do not demonstrate treatment of an existing SARS-CoV-2 infection in an animal model (e.g. mouse engineered to express human ACE2) or human.
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 nucleotide and amino acid sequences of the disclosed Pan-C1, Pan-C2, and Pan-C3 plasmid DNA constructs, identifies the basic domain arrangements, and explains that the RBD is tethered to human ACE2 through a short peptide linker (¶[0160-0164]). It also provides generic definitions of sequence identity and variants and discusses DNA, RNA, plasmid, viral vector, pharmaceutical formulations, and delivery technologies (¶[0046][0056][0058-0060][0095-0108][0117-0149]).
However, the specification does not provide sufficient guidance regarding selection of additional members of the claimed genera. In particular, the specification does not explain how to identify which spike residues or RBD/RBM boundaries are required to form the proposed intermediate structure. It does not identify the ACE2 residues, species, or domain boundaries that may be changed while retaining the intended interaction, nor does it provide a structural assay that distinguishes a C-A Complex adopting the asserted intermediate conformation from a fusion protein that merely contains both components. The specification also fails to identify permissible changes at the peptide-linker and domain junction regions of the claimed 90% identity proteins. It does not provide a sequence-function map, a set of conserved residues, or a rule by which one could select variants expected to remain expressed, folded, immunogenic, and capable of producing the asserted neutralizing response. The generic discussion of hydrophobicity, hydrophilicity, and conservative amino acid substitution in ¶[0058-0060] does not address the specific structural requirements of the RBD-ACE2 interface or the behavior of the disclosed multidomain fusion proteins.
With respect to claims 11 and 12, the specification does not explain which members of the broad antigen genus would be therapeutically effective after infection has occurred, what disease stages would be treated, or how administration of a vaccine construct would suppress an established infection. As noted supra, there were no safety trials in humans or animal models to ensure the construct did not generate an autoimmune response to native ACE2 and exacerbate the disease state. The general definition of treatment includes administration after clinical appearance of disease, but the working examples are limited to immunization of uninfected mice and testing of collected sera (¶[0057][0123-0130][0165-0171]).
Quantity of experimentation necessary. To practice the full scope of claims 1-14, one skilled in the art would need to select candidate spike regions and ACE2 receptors and decide which domain boundaries, orientations, and linkers to use. For the 90% identity genera, the skilled artisan would then need to prepare numerous nucleoside and protein variants containing different substitutions or other sequence changes throughout the RBD, ACE2, linker, junction, and optional nucleocapsid regions. Each candidate would need to be expressed and evaluated for stability and proper folding. The artisan would then need to determine whether the components interact tin the intended manner or adopt a structure corresponding to the asserted transient intermediate. Candidates passing those preliminary tests would still require immunization studies, antibody binding assays, inhibition testing, and neutralization testing to determine whether they function as the disclosed C-A complex antigens. Members intended for therapeutic treatment would require additional testing in subjects for safety and therapeutic efficacy. The skilled artisan would also have to develop and test RNA formulations, encoded adjuvant combinations, and viral particle delivery systems.
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 additional embodiments to determine which combinations retain expression, structural interaction, immunogenicity, neutralization, and are safely therapeutic/prophylactic in vivo. 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 nucleic acid constructs of the RBD or RBM tethered to ACE2 to determine which embodiments satisfy the claimed functional limitations.
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 three principal RBD-human ACE2 fusion constructs and reports testing of the corresponding plasmid DNA vaccines, but the claims also encompass unspecified spike antigenic domains, unspecified ACE2 receptors, open-ended viral variants, extensive 90% identity protein and nucleotide genera, multiple delivery formats, and both prophylactic and therapeutic methods. The specification does not identify a general structural quality or sequence rule that would allow one skilled in the art to determine which additional members will express, assume the intended intermediate conformation, and produce the asserted immune response without undue experimentation. The disclosure instead provides a starting point and the assays by which additional candidates could be evaluated. Requiring the skilled artisan to generate and test candidates through the claimed scope to determine which ones would work is not enablement of the claimed genus.
Conclusion. For the reasons discussed above, the specification does not enable one skilled in the art to make and use the full scope of the invention recited in claims 1-14 without undue experimentation.
Claims 1-14 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.
Claims 1-12 recite immunogenic compositions comprising nucleic acids encoding a C-A complex antigen and methods of administering those compositions to treat or prevent COVID infection. Claims 13 and 14 separately recited broad nucleic acid and protein genera that include the specifically disclosed sequences and any sequences having at least 90% identity to the referenced sequences.
The specification describes three principal DNA constructs: Pan-C1, Pan-C2, and Pan-C3. Pan-C1 comprises a wild-type SARS-CoV-2 RBD tethered to human ACE2 by a short linker, Pan-C2 comprises the alpha-, beta-, and gamma-variant RBDs tethered in series and then tethered to human ACE2, while Pan-C3 comprises the wild-type RBD tethered to human ACE2 and further tether to nucleocapsid epitopes (¶[0159-0164]). The three DNA constructs were expressed in mammalian cells of unidentified type, and expression of RBD and ACE2 components was evaluated by immunoblotting (¶[0164]). The specification further describes immunizing BALB/c mice with the DNA constructs of SEQ ID NOs: 1, 3, and 5, and evaluation of antibody binding, IgG subclasses, inhibition of RBD binding to ACE2, and neutralization of “wild-type” SARS-CoV-2 (it is unclear what was considered “wild-type” from the specification) in cultured Vero cells (¶[0165-0172]). The live virus experiment used sera from mice immunized with the Pan-C1 and Pan-C3 constructs, but the reported conclusion identifies strong neutralization by the Pan-C1 serum against an unidentified wild-type isolate (¶[0171-0172]). The specification appears to use “wild type RBD” and “wild type SARS-CoV-2” to refer generally to an ancestral or initial pandemic SARS-CoV-2 strain/sequence/variant, but it is unclear which particular isolate, lineage, accession number, or reference sequence said viral items were derived.
However, the scope of the claims is not limited to the embodiments described in the specification. For instance, claim 1 broadly encompasses a C-A complex antigen comprising an antigenic domain spanning a SARS-CoV-2 spike protein and an ACE2 receptor of an intermediate structure formed between SARS-CoV-2 and an ACE2 receptor. The claim does not limit the spike component to the particular RBD sequences used in Pan-C1, Pan-C2, or Pan-C3. Nor does claim 1 limit the ACE2 component to human ACE2 or to the particular aCE2 sequence and boundaries present in the disclosed constructs.
The specification defines the C-A complex as comprising an RBD or RBM domain of the spike protein S1 domain fused to ACE2 (¶[0039]). However, the specification does not describe a representative number of RBD or RBM domains, ACE2 receptors, or RBD-ACE2 combinations falling within the scope of claim 1. The working disclosure is confined to the particular wild type and variant RBD sequences used in Pan-C1, Pan-C2, and Pan-C3, each joined to a disclosed human ACE2 sequence (¶[0157-0171]). The claimed antigen is defined, at least in part, by its asserted relationship to an “intermediate structure” formed between SARS-CoV-2 and an ACE2 receptor. The specification describes tethering an RBD to aCE2 to mimic a transient structure or complex formed during receptor engagement. It does not identify structural features that establish when another RBD-ACE2 construct represents that intermediate structure. The specification does not identify required contact residues, necessary domain boundaries, a required orientation, or a conformation common to the full claimed genus. Accordingly, the disclosure of the desired intermediate structure does not establish possession of every antigenic domain containing an unspecified spike region and an unspecified ACE2 receptor. One skilled in the art would be required to select additional spike domains, RBD or RBM sequences, ACE2 receptors, and domain arrangements not described in the specification and then determine whether those additional constructs possess the asserted structural and antigenic properties.
Claim 2 limits the spike component to an RBD or RBM domain, but it does not cure the deficiency. The claim continues to encompass any SARS-CoV-2 RBD or RBM sequence joined to any ACE2 receptor. The specification does not describe representative species across that scope or identify structural features common to the broader genus. Claim 3 further encompasses point mutations identified in “evolved strains” of SARS-CoV-2, while the specification only refers to certain strains, including alpha, beta, and gamma, and Pan-C2 contains the corresponding RBDs (¶[0162][0166-0169]). Claim 3 is not limited to those strains or to the disclosed mutations, as it encompasses mutations from an open group of “evolved” strains without identifying which mutations may be incorporated, where they may be incorporated, or which combinations remain a part of the C-A Complex antigen. The disclosure of selected RBD sequences from several variants does not reasonably convey possession of every C-A Complex antigen containing point mutations associated with past or future evolved SARS-CoV-2 strains. 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 species fall within the scope of the claimed invention.
The specification describes the nucleotide sequences of SEQ ID NOs: 1, 3, 5, 7, 9, and 11 and the protein sequences of SEQ ID NOs: 2, 4, 6, 8, 10, and 12. The rejection is not based on a lack of written description support for those specifically identified sequences. However, claims 4 and 14 also encompass additional sequences having at least 90% sequence identity to any of the six referenced protein sequences, and claim 13 similarly encompasses every nucleotide sequence having at least 90% identity to the claimed nucleotide SEQ ID NOs. Claims 13 and 14 also permit a nucleic acid or protein to comprise “one or more” of the recited sequences without limiting their arrangement or relationship. The specification does not identify which positions may be altered while retaining the recited function, describe representative variants across the claimed scope, or identify structural features sufficient to distinguish operative variants from other sequences. These reference sequences are long, multidomain constructs containing an RBD or multiple RBDs, an ACE2 component, peptide linker or junction regions, and, in Pan-C3, nucleocapsid epitopes. A sequence having 90% identity to one of these constructs may contain numerous changes, including insertions, deletions, and substitutions, distributed throughout those different regions. The claims do not limit the changes to conservative substitutions or to positions outside the RBD-ACE2 interface. They do not require preservation of the disclosed linkers, domain boundaries, or junction sequences.
The specification provides general definitions of sequence identity and sequence variants (¶[0056][0058-0060]). It also states that certain full-length sequences may have about 90%, 97%, 98%, 99%, or 100% identity to the disclosed sequences (¶[0073-0074]). These generic statements do not identify particular variants of the claimed Pan-C sequences, much less representative variants approaching the 90% boundary recited in claims 4, 13, and 14. The specification does not identify which positions in the RBD, ACE2, linker, or nucleocapsid regions may be altered while preserving the asserted C-A Complex antigen. It does not identify a conserved sequence pattern shared by the claimed variants or describe a structure-function relationship that would allow one skilled in the art to recognize which additional protein sequences belong to the claimed antigen genus. No 90% identity protein variant is described or tested. The nucleotide genus of claim 13 is broader still. The claim does not require that a 90%-identity nucleotide sequence encode a C-A complex antigen, preserve the reading frame, or encode any protein having any specified activity. The specification does not describe representative nucleotide variants across that scope or identify common structural feature sufficient to show possession of every nucleotide sequence satisfying the numerical identity threshold. A numerical percentage identity limitation, by itself, does not describe the claimed genus when the specification does not identify the changes that are permitted or the structural features that distinguish the members of that genus. The disclosure of twelve specific sequences and generic statements that variants may be used does not reasonably convey possession of the substantially broader groups recited in claims 4, 13, and 14.
Claims 5, 6, and 8-10 add limitations concerning DNA or RNA, plasmids, expression elements, viral particles, and pharmaceutically acceptable excipients. The specification describes plasmid DNA encoding the Pan-C1-3 constructs and provides general disclosure concerning nucleic acid expression and delivery (¶[0095-0108][0117-0149][0159-0164]). The disclosure may support the use of known expression and delivery components with the specifically described constructs, but it does not provide written description support for the materially broader antigen and sequence genera incorporated into these dependent claims. Claim 9, for example, adds incorporation of the nucleic acid molecule into a viral particle. The specification generally refers to viral delivery methods, but does not identify or describe a viral particle containing any of the disclosed Pan-C sequences. More importantly, claim 9 continues to encompass viral particles containing nucleic acids encoding any member of the unsupported claim 1 genus. The addition of a broadly identified delivery vehicle does not show possession of the underlying antigen genus.
Claim 7 further requires a nucleotide sequence encoding an adjuvant. The specification describes an adjuvant as “any molecule” added to enhance the immunogenicity of an antigen and identifies several conventional adjuvant materials (¶[0037]). Those materials are not described as proteins or other adjuvanting material encoded by a nucleotide sequence. The specification refers generally to gene constructs encoding an immunomodulating protein (¶[0045][0051]). It does not identify a particular encoded adjuvant for use with the claimed C-A Complex antigen, provide a nucleotide sequence encoding such an adjuvant, or describe a construct containing both the C-A Complex coding sequence and an encoded adjuvant. The specification therefore does not describe a representative composition falling within claim 7 or identify the encoded adjuvants that were regarded as part of the invention. The generic possibility that an expression construct may encode an immunomodulating protein or other adjuvanting material does not reasonably convey position of an immunogenic composition containing a nucleotide sequence encoding any adjuvant.
Claims 11-12 are drawn to methods for treating or preventing COVID disease in a subject in need thereof, especially through administration of the composition of claim 1 through electroporation. The specification describes immunization of uninfected mice with the three disclosed Pan-C DNA plasmid constructs and subsequently testing the resulting immune sera from these mice (¶[0165-0171]). However, claims 11-12 broadly encompass administration of compositions containing any member of the unsupported C-A Complex genus of claim 1. The specification does not describe representative embodiments of treatment or prevention methods across that broader scope or otherwise demonstrate possession of the broader claimed method by delivery of additional spike domains, ACE2 receptors, sequence variants, and domain arrangements encompassed by claim 1. The specification also fails to describe administration of a C-A complex composition to a subject having an established COVID disease. The working disclosure concerns immunization before the resulting sera was collected and tested. The general statement that the compositions may be used for treatment, without a described therapeutic embodiment or identifying characteristics of a composition suitable for post-infection treatment, does not reasonably convey possession of the full treatment scope recited in claims 11 and 12.
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 claims 1-14 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 1-2, 5-6, 8, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bauer et. al. (Bauer MS, et. al. bioRxiv 2020.09.27.315796; doi: https://doi.org/10.1101/2020.09.27.315796. 09/28/2020.; hereafter “Bauer”.)
The Prior Art
Bauer teaches a flexible peptide linker connects the C-terminus of the SARS-CoV-2 receptor binding domain (RBD) to the N-terminus of the ACE2 ectodomain (Supplementary Figure S2). Bauer teaches DNA plasmids generated in DH5-alpha E. coli cells, and the protein was expressed from the isolated plasmid in HeLa cells (p. 8, “MATERIALS AND METHODS: Cloning and Protein Construct Design” and “In Vitro Protein Expression”; instant claims 1-2, 5-6, 8). Bauer teaches protein purification into TRIS buffered saline (p. 9, “Protein Purification”) and also teaches the DNA plasmid in transfection-facilitating reagents, which meets the limitations per the specification of a “pharmaceutically acceptable excipient”(¶[0142]; pp. 8-9, “In Vitro Protein Expression”; instant claim 10).
For at least these reasons, Bauer teaches the limitations of instant claims 1-2, 5-6, 8, and 10, and anticipates the invention encompassed by said claims.
Claims 1-2, 5-6, 8, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Deshpande et. al. (Deshpande A, et. al. Front Immunol. 2021 Jun 4;12:691715.; hereafter “Deshpande”.)
The Prior Art
Deshpande teaches the analysis of different sequences RBD from SARS-CoV-2 binding to the ACE2 receptor (entire document; see abstract.) Deshpande teaches RBD-ACE2 fusion protein (RBD-ACE2FP) DNAs were inserted into the DNA plasmid pMTV5/His and expressed in S2 insect cells as C-terminal his-tagged proteins (p. 5, left col., ¶1; instant claims 1-2, 5-6, 8). This fusion protein complex was tested against neutralizing antibodies (NAbs) for their ability to bind to and recognize the overlap of NAb epitopes with the RBD-ACE2 binding site (p. 11, left col., ¶1). These proteins were expressed, isolated, and purified into buffering agents (p. 5, left col., ¶1; instant claim 10).
For at least these reasons, Deshpande teaches the limitations of instant claims 1-2, 5-6, 8, and 10, 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.
Claims 3, 7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Bauer as applied to claims 1-2, 5-6, 8, and 10 above, and further in view of Smith et. al. (US20210228709A1; Pub. 07/29/2021; hereafter “Smith”) and Deshpande (supra.)
The Prior Art
The teachings of Bauer and Deshpande have been set forth supra. While Bauer only teaches one RBD-ACE2 fusion protein, Bauer teaches that their tools could provide a tool to characterize emerging mutations of the viral S protein that alter binding or interfere with antibody recognition (p. 7, ¶3). While Deshpande teaches a RBD-ACE2 fusion protein, Deshpande does not teach generation of mutations directly into said RBD. However, Deshpande does teach different point mutations in RBD of the alpha, beta, gamma, and other variants of concern, and how these mutations affect binding to ACE2 (See Abstract; Table 2; Figs. 2, 5-6; pp. 5-7, “RBD Variant Analysis”.) Therefore, given the combined teachings of Bauer and Deshpande, it would be obvious to substitute in variants to determine how this affects the RBD-ACE2 complex formation and overall epitope formation, thus rendering obvious the limitations of instant claim 3. While both Bauer and Deshpande teach that the RBD-ACE2 fusion protein is expressed from a DNA plasmid, neither Bauer nor Deshpande teach that said fusion protein-encoding nucleic acid is incorporated into a viral particle, nor do either teach about the nucleotide sequence further encoding an adjuvant. However, such a difference would be obvious given the prior art, as shown by the teachings of Smith.
Smith teaches SARS-CoV-2 spike (S)-based vaccines and binding molecules, as well as preparations and methods of their use in the treatment and/or prevention of disease, such as COVID-19 (entire document; see abstract.) Smith teaches the spike protein may comprise variants or mutants (¶[0076-0096][0198]). Smith teaches that nucleic acid, such as DNA, encoding a coronavirus RBD, an RBD fragment, a variant of said RBD, or a fusion protein comprising said RBD may be used as a vaccine and can be incorporated into a plasmid for expression in vivo (reference claims 1-27; ¶[0009-0013][0076-0096][0131-0133][0146][0158][0197-0202]). Smith teaches the nucleic acid that encodes the S protein may be a viral vector (¶[0197][0199]; reference claims 26-27) and that there may be an adjuvant within the composition (¶[0162-0183]). As Smith teaches a viral vector encoding the protein, the presence of the additional viral components may reasonably be read as “adjuvanting” material, as many viral proteins are immunogenic (¶[0199-0200]).
It would have been obvious to substitute point-mutated RBD sequences from emerging SARS-CoV-2 variants, as taught by Deshpande, for the ancestral RBD sequence in the tethered construct of Bauer, as Bauer expressly suggested using the tethered construct to characterize emerging spike mutations, and Deshpande identified specific variant RBD mutations that retained or altered ACE2 binding. In view of Smith, one would have also recognized that RBD-encoding plasmid or viral DNA as a known immunogenic format capable of eliciting antibodies that inhibit RBD-ACE2 binding, and would have found it to be further obvious to use adjuvants to enhance the immunogenic response, as taught by Smith. Therefore, the limitations of instant claims 3, 7, and 9 would be obvious modifications to the teachings of Bauer, given the teachings of Deshpande and Smith.
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Bauer in order to use RBD variants, thereby generating mutants with different RBD/ACE2 antigenic interfaces. One would have been motivated to do so, given the suggestion by Deshpande that RBD mutants bound differently to ACE2 and could be detected immunogenically, and given the motivation to test RBD mutants in the RBD-ACE2 fusion provided by Bauer. There would have been a reasonable expectation of success, given the knowledge that both Bauer and Deshpande expressed their fusion proteins from DNA plasmids, and also given the knowledge that said fusion proteins could be expressed from further formats, such as viral vectors, as taught by Smith, and could further include adjuvanting materials, as taught by Smith. 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.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: SEQ ID NOs: 1-12 appear to be novel and nonobvious.
Conclusion
Claims 1-14 are rejected. SEQ ID NOs: 1-12 appear to be novel and nonobvious.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Bauer MS, et. al. Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2114397119. Epub 2022 Mar 21. Post-filing art related to the BioRx art utilized in the 102 rejection.
Ferrareze PAG, Zimerman RA, Franceschi VB, Caldana GD, Netz PA, Thompson CE. Molecular evolution and structural analyses of the spike glycoprotein from Brazilian SARS-CoV-2 genomes: the impact of the fixation of selected mutations. bioRxiv 2021.07.16.452571; doi: https://doi.org/10.1101/2021.07.16.452571. Teaches mutations in Spike protein and how they affect ACE2 binding. Not utilized as would be redundant to those rejections set forth supra.
Padhi AK, et. al. High Throughput Designing and Mutational Mapping of RBD-ACE2 Interface Guide Non-Conventional Therapeutic Strategies for COVID-19. bioRxiv (2020) 1-27, 2020. doi: https://doi.org/10.1101/2020.05.19.104042. Teaches mapping of RBD-ACE2 interface. 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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