DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Restriction/Election of Species
The previous Examiner required a restriction in the Office Action mailed out on 24 March 2026.
In their Response filed on 22 May 2026, Applicant elected Group I, claims 1-3 and 5-12, without traverse.
The previous Examiner also required an election of species in the Office Action mailed out on 24 March 2026.
In their Response filed on 22 May 2026, Applicant elected a nucleic acid, specifically an mRNA encoded by a nucleic acid of SEQ ID NO: 38; a retrovirus as the expression vector; and SEQ ID NO: 34 as the peptide to be examined.
Applicant’s election without traverse of Group 1 and the relevant species in the reply filed on 22 May 2026 is acknowledged.
Response to Amendment/Disposition of Claims
Applicant’s Amendment filed on 22 May 2026 has been received and entered. Claims 1-3 and 5-19 were pending. Claims 8 and 14-19 have been amended. Claim 4 has been cancelled. No new claims have been added. Claims 13-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 24 March 2026. It should be noted for the record that the withdrawn claims do not have the proper claim status identifiers in the most recent claim set. Claims 13-19 should all say “(Withdrawn – Currently Amended)”.
Accordingly, Claims 1-3 and 5-12 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2024/0226280 A1, Published 11 July 2024. Applicant’s amended Specifications as presented on 22 May 2026 and 06 November 2023 are acknowledged and entered.
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.
Information Disclosure Statement
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.
The information disclosure statements (IDSes) submitted on 27 December 2023 and 23 December 2024 have been considered by the examiner.
Drawings
The Drawings are objected to for containing color and referring to colors (red, orange, blue, green, etc.) in either the figures themselves or the figure legends within the Specification. Specifically, Figures 1, 2A, 2C, 2D, 2F, 2G, 4B, 4D, 7B, and 7C all refer to colors. Note: references to black, white, and/or grey/gray are acceptable. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The objection to the drawings will not be held in abeyance.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Specifically, Table 2 contains at least one sequence which requires a sequence identifier. The sequence in question is “AAGCCACAACA”. This sequence has at least 10 specifically defined and enumerated nucleotides and therefore it is required to have a SEQ ID NO.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Specifically, Figures 2B, 3A, and 3F all comprise sequences which have at least 4 specifically defined and enumerated residues or at least 10 specifically defined and enumerated nucleotides and are therefore required to have their own unique SEQ ID NOs.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in Paragraph 0045 of the PGPub of the instant application (Page 15, Lines 1-5 of the most recent Specification filed on 22 May 20206). The sequence in question is SEQ ID NO: 39, which corresponds to the amino acid sequence for the claimed mutant N protein. The Sequence Listing filed on 22 May 2026, however, only has 38 sequences. There is no SEQ ID NO: 39.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. Specifically, the size of the Sequence Listing file is incomplete. The file size should be given in bytes, but the units are missing. The statement reads in part “…and having a file size of 15,359 is hereby…”.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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 it contains language which can be implied, specifically in the form of the word “disclosed” (i.e., disclosed compositions) [emphasis added]. 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 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://, www., or other browser-executable code. The hyperlinks in question are https://github.com/evogytis/baltic (Paragraph 0083); http://n2t.net/addgene:141391 (Paragraph 0092); https://covid19.moh.gov.sa (Paragraph 0101); https://covid19.cdc.gov.sa/ (Paragraph 0101); https://www.spa.gov.sa/search.php?lang=en&search=COVID (Paragraph 0101); https://www.moi.gov.sa/ (Paragraph 0101); and http://broadinstitute.github.io/picard/ (Paragraph 0102); See MPEP § 608.01.
The disclosure is objected to because, in Paragraph 0006, at least, and Table 3, sequences are described by reference to GenBank Accession Nos., which are subject to change, rather than to sequences set forth in the specification. This is an improper incorporation by reference, since the information required to describe and enable the required sequences is found in the NCBI database, extraneous to the application. Furthermore, since the NCBI sequences are not irrevocably fixed but are corrected and updated as additional sequence information becomes available, the NCBI accession numbers may refer to sequences which change after the application filing date. Thus, the disclosure is objected to for this improper incorporation by reference.
Furthermore, essential material such as that which provides written description or enablement should not come from NPLs. See 37 CFR 1.57d.
Appropriate correction is required.
The disclosure is objected to because of the following informalities: there appear to be typographical errors present. In Paragraph 0130, it says “…some of which are shown in FIG. 4 (see also, see Table 7)”.
Additionally, as noted above, the disclosure is objected to containing color and referring to colors (red, orange, blue, green, etc.) in either the figures themselves or the figure legends within the Specification. Specifically, Figures 1, 2A, 2C, 2D, 2F, 2G, 4B, 4D, 7B, and 7C all refer to colors. Note: references to black, white, and/or grey/gray are acceptable.
Appropriate correction is required.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1-3 and 5-12 are objected to because of the following informalities: In Claim 1, it is suggested that it say “a SARS-CoV-2 N protein or peptide” instead of “a SARS-CoV-2 N protein/peptide”.
In Claims 2-3 and 5-12, it is suggested that they say “The pharmaceutical composition of…” instead of “The composition of…”.
In Line 3 of Claim 3, there is a space between “and” and “/or”. It should be removed so the claims recites “and/or”.
In Claim 7, it is suggested that it say “…a plasmid, a minicircle DNA (mcDNA) and a viral vector” instead of “…plasmid, minicircle DNA (mcDNA) and viral vector”.
In Claim 8, it is suggested that it say “wherein the viral vector is selected from” instead of “wherein the vector is selected from”.
In Claim 10, it is suggested that it say “SEQ ID NOs:” instead of “SEQ ID Nos.”.
In Claim 12, it is suggested that it say “…comprising an mRNA encoded by…” instead of “…comprising mRNA encoded by…”.
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.
Claims 1, and dependent claims 2-3 and 5-12 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.
Regarding Claim 1, it recites the limitation “a nucleic acid, preferably, an mRNA encoding a SARS-CoV-2 N protein/peptide comprising an R203K/G204R mutation relative to SEQ ID NO:1”. As the claim is currently written, it is unclear if both mutations must be present or if only one is required, especially since the claim recites “an…mutation” which implies that only a single mutation is present. This lack of clarity renders the claim indefinite. It is suggested that the claim be amended to recite “an mRNA encoding a SARS-CoV-2 N protein/peptide comprising an R203K/G204R double mutation relative to SEQ ID NO:1”, if both mutations must be present, but Applicant is free to amend the claim as they deem necessary.
Additionally, the use of the word “preferably” also renders the claim indefinite as it is unclear if the recited element following “preferably” is a required element of the claim. It is suggested that the claim be amended by removing “preferably”, but Applicant is free to amend the claim as they deem necessary.
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 2-3 and 5-12 are also rejected, since they depend upon Claim 1 but do not remedy the deficiencies of Claim 1.
Claim 5 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.
Regarding Claim 5, it recites the limitation “wherein the nanoparticle is a lipid nanoparticle optionally comprising an ionizable cationic lipid, a neutral lipid, a sterol, and a PEG-modified lipid”. Due to the use of the word “optionally, all of the lipid components of the lipid nanoparticle (LNP) are optional. This makes it unclear as to what then exactly is in the claimed LNP. This lack of clarity renders the claim indefinite as it is unclear what is and what is not encompassed by the claimed LNP since it does not positively recite the required presence of a lipid. It is suggested that the claim be amended by removing the word “optionally”, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 5 is rejected on the grounds of being indefinite.
Claims 7, and dependent claim 8 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 7 recites the limitation "the expression vector" in Line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1, which Claim 7 depends upon, does not introduce the limitation of an expression vector. As such, it is unclear what expression vector is being referenced in Claim 7. It is suggested that Claim 7 be amended to be dependent on Claim 3, which would provide proper antecedence, but Applicant is free to amend the claim as they deem necessary.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 7 is rejected on the grounds of being indefinite. Claim 8 is also rejected, since it depends on Claim 7 but does not remedy the deficiencies of Claim 7.
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 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.
Claim 12 is 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 a composition comprising an mRNA encoded by a nucleic acid with 100% sequence identity to instant SEQ ID NO: 38, does not reasonably provide enablement for a composition comprising an mRNA encoded by a nucleic acid having less than 100% sequence identity to instant SEQ ID NO: 38 . 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 clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a pharmaceutical composition comprising: (a) a polypeptide fragment of a SARS-CoV-2 N protein/peptide comprising a R203K/G204R mutation relative to SEQ ID NO:1 or (b) a nucleic acid, preferably, an mRNA encoding a SARS-CoV-2 N protein/peptide comprising an R203K/G204R mutation relative to SEQ ID NO:1 and a composition of claim 1 comprising mRNA encoded by a nucleic acid molecule up to 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% identical to SEQ ID NO:38.
State of the prior art/Predictability of the art. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Working examples. No working examples of the claimed variants are disclosed in the specification.
Guidance in the specification. The specification provides guidance towards the various roles the N protein plays in viral replication (see Paragraph 0044) and describes that conservative substitutions can be made (see Paragraph 0048), but provides no clarity regarding which regions of the N gene and encoded protein can tolerate such changes while still maintaining the desired functions, aside from the claimed mutations.
Amount of experimentation necessary. Since the art teaches that it is unpredictable whether or not peptide variants of known proteins will function as expected, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of instant claims as broadly as they are currently claimed.
Claim 12 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant application attempts to tie function to sequence identity in the context of a pharmaceutical composition comprising: (a) a polypeptide fragment of a SARS-CoV-2 N protein/peptide comprising a R203K/G204R mutation relative to SEQ ID NO:1 or (b) a nucleic acid, preferably, an mRNA encoding a SARS-CoV-2 N protein/peptide comprising an R203K/G204R mutation relative to SEQ ID NO:1 and the composition of claim 1 comprising mRNA encoded by a nucleic acid molecule up to 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% identical to SEQ ID NO:38. While a percent identity threshold is provided in the claims, the instant Specification fails to specify the critical or essential nucleotides which must be present and cannot be changed, aside from the claimed mutations. While the instant Specification states the various roles the N protein plays in viral replication (see Paragraph 0044) and describes that conservative substitutions can be made (see Paragraph 0048), no clarity is provided regarding which regions of the N gene and encoded protein can tolerate such changes while still maintaining the desired functions. As such, it would be unclear to a person having ordinary skill in the art what to change and what not to change.
Furthermore, while it is not explicitly stated, it is assumed that the constructs shown in the data provided are 100% identical to the claimed sequence. Even if that is not the case, the data do not explicitly include any claimed variants having as little as 50% sequence identity, or even 51-99% sequence identity, relative to the claimed sequence, raising questions about how effective these claimed variants would be in the data provided. Thus, it is not clear what was tested, it does not appear that any claimed variants were tested, and the essential characteristics of the genus being claimed by Applicant have not been identified or disclosed.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contributions to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle and Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient details that one skilled in the art can reasonably conclude that the invention had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the nucleotide variants can have any sequences which vary from instant SEQ ID NO: 18 by as much as 50%, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any nucleotide variants with the required sequence identity other than the few species provided by Applicant and the prior art. Therefore, since only a few species are provided to represent the genera, the claims encompassing the same clearly fail the written description requirement.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014).
Overall, at the time the invention was made, the level of skill for preparing nucleotide variants and then selecting those nucleic acids which meet the desired percent identity cutoff was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identity nucleotide variants with the recited percent identity cutoff, the written description provision of 35 U.S.C. 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010). Absent the conserved structure provided by a nucleotide sequence, the skilled artisan would not be able to visualize or otherwise predict, a priori, what any nucleotide which meets the recited percent identity cutoff would look like structurally.
While applicant has described a few species within the genera recited, and the art may provide more, each genus is very large and would encompass nucleotide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the nucleotide structures encompassed by the claimed/recited genera only defined by sequence identity. Any future nucleotide variants may or may not be encompassed, as if they are, they would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genera of nucleotide variants. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Therefore, the claims are rejected here.
As such, it does not appear Applicant was in possession of the full scope of the claimed invention at the time of filing and thus Claim 12 does not meet the written description requirement.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding Claim 6, it recites the limitation “The composition of claim 1, wherein the nucleic acid is mRNA”. This claim is redundant and is already encompassed by Claim 1 due to Applicant’s species election of “an mRNA encoded by a nucleic acid of SEQ ID NO: 38”. As such, Claim 6 does not further limit Claim 1.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim 12 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding Claim 12, it recites the limitation “The composition of claim 1 comprising mRNA encoded by a nucleic acid molecule up to 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% identical to SEQ ID NO:38”. Due to the large amount of sequence identity variation being claimed, Claim 12 encompasses embodiments that broaden the scope of Claim 1, in light of Applicant’s species election of “an mRNA encoded by a nucleic acid of SEQ ID NO: 38”. Additionally, a sequence that is only 50% identical to instant SEQ ID NO: 38, for example, would contain sequences of other coronaviruses unrelated to SARS-CoV-2, which also broadens the scope of Claim 1 as this claim is limited to SARS-CoV-2 as the coronavirus. As such, Claim 12 does not further limit Claim 1.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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, 5-7, 9-10, and 12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature/natural phenomenon without significantly more. The claims, particularly Claim 1, recite a pharmaceutical composition comprising: a nucleic acid, preferably, an mRNA encoding a SARS-CoV-2 N protein/peptide comprising an R203K/G204R mutation relative to SEQ ID NO:1. Claims 1, 9-10, and 12 are ineligible because they simply recite a composition comprising a nucleic acid, specifically an mRNA encoding a SARS-CoV-2 N protein/peptide comprising a R203K/G204R double mutation, such as the one disclosed by instant SEQ ID NO: 38, and a peptide fragment corresponding to said double mutation, such as that disclosed by instant SEQ ID NO: 34, without any additional elements to distinguish said molecules from their naturally-occurring counterparts. The claimed double mutation occurs naturally, as taught by Leary et al., 2021 (cited by Applicant on the IDS filed on 27 December 2023). Leary et al. teach “the adjacent amino acid polymorphisms in the nucleocapsid (R203K/G204R) of SARS-CoV-2 that arose on the background of the spike D614G change” (see Abstract, Background section) and “that the 3 adjacent nucleotide changes that result in the K203/R204 variant have arisen by homologous recombination from the core sequence of the leader transcription-regulating sequence (TRS) rather than by stepwise mutation” (see Abstract, Methods section). The teachings of Leary et al. demonstrate that the claimed mutations occur naturally in the virus. While Claim 1 recites a “pharmaceutical composition”, the term “pharmaceutical” alone does not prevent the claims from reading on a natural phenomenon. As defined by Applicant in Paragraphs 0064 and 0065 of the PGPub of the instant application, the “composition of the invention can be formulated in pharmaceutical compositions including a pharmaceutically acceptable excipient, carrier, buffer, stabilizer, or other materials well known to those skilled in the art”, that pharmaceutical “compositions for oral administration can be in tablet, capsule, power, or liquid form”, and that liquid “pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil”. As disclosed by Applicant, the claimed pharmaceutical composition encompasses a liquid composition comprising a carrier wherein water is the carrier. Water would not materially alter the claimed molecules or impart an characteristics which would markedly distinguish the claimed molecules from their naturally occurring counterparts. Claims 2-3 and 5-7 are ineligible because, under the broadest reasonable interpretation of the claims as currently written, the phrases “nanoparticle” and “lipid nanoparticle” in Claims 2 and 5, respectively, can be interpreted as reading upon a Coronavirus viral particle, as the particles themselves are measured on the nanometer scale (see Page 2, Last Paragraph of Fehr, A. R., & Perlman, S. (2015). Coronaviruses: an overview of their replication and pathogenesis. Methods in molecular biology (Clifton, N.J.), 1282, 1–23.) (see attached PTO-892 Form) and each virion possesses a viral envelope (see the Abstract and Page 1, Last Paragraph of Fehr and Perlman). While the limitation of “a PEG-modified lipid” in Claim 5 would not appear to read on the naturally-occurring virus, this limitation is optional and is therefore not a required element of the claim. As such, this claim encompasses patent-ineligible matter. As disclosed by Fehr and Perlman, “Coronaviruses contain a non-segmented, positive sense RNA genome” containing “a 5’ cap structure along with a 3’ poly(A) tail, allowing it to act as an mRNA for translation” (see Page 2, Paragraph 2), that the “5’ end of the genome contains a leader sequence and untranslated region (UTR)”, and that the “3’UTR also contains RNA structures required for replication and synthesis of viral RNA (see Page 2, Paragraph 2). They also disclose that the “organization of the Coronavirus genome is 5’-leader-UTR-replicase-S (Spike)-E (Envelope)-M (Membrane)-N (Nucleocapsid)-3’ UTR-poly(A) tail” (see Page 2, Paragraph 2; Figure 1). As such, the compositions recited in Claims 3 and 6 are ineligible because they simply read upon the naturally-occurring virus without additional elements to distinguish them from the virus as it is found in nature. Claim 7 is ineligible because the claimed expression vector can be a viral vector, which reads on the naturally-occurring virus expressing the mutated N protein from its genome.
This judicial exception is not integrated into a practical application because, as currently written, the claimed invention is not used to provide a particular treatment or prophylaxis for a disease or medical condition. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claimed invention, as currently written, simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception. It is suggested that the claims be amended to not read upon products of nature. With respect to the composition, it is suggested that the claims be amended to include required additional reagents which markedly change the composition (e.g., adjuvant, PEG-modified lipid). Another suggestion is to include elements with or within the claimed nucleic acid and/or peptide, such as tags or non-naturally occurring nucleotides or amino acids, which would markedly distinguish them from their naturally-occurring counterparts. Applicant is free to amend the claims as they deem necessary, as long as said amendments to not introduce new matter, or persuasively argue that they are patent eligible.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 5-7, and 10-11 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by BenMohamed (US 2024/0269266 A1, earliest Priority Date 14 April 2020).
BenMohamed teaches a pharmaceutical composition comprising a plurality of lipid nanoparticles wherein a first lipid nanoparticle comprises three mRNAs encapsulated therein, and each mRNA comprises an open reading frame encoding a Coronavirus protein selected from the group consisting of an NSP2 protein, an NSP14 protein, and a Nucleoprotein (see Paragraph 0024), wherein each mRNA further comprises a 5’ UTR, a 3’UTR, a 3’ poly(A) tail, and/or a 5’ cap or cap analog (see Paragraph 0025), which reads on instant Claims 1-3 and 5-6. BenMohamed also teaches SEQ ID NO: 9, an amino acid sequence which corresponds to the Nucleoprotein and comprises instant SEQ ID NO: 34 which comprises the instantly claimed mutations (see Sequence Listing), which reads on instant Claims 1 and 10. Additionally, BenMohamed teaches a pharmaceutical composition comprising a plurality of lipid nanoparticles wherein said nanoparticles comprise an ionizable cationic lipid, a neutral lipid, a sterol, and a PEG-modified lipid (see Paragraph 0167), which reads on instant Claim 5. Furthermore, BenMohamed teaches delivery of said pharmaceutical compositions using viral vectors (see Paragraphs 0120-0121), which reads on instant Claim 7. Finally, BenMohamed teaches that said pharmaceutical compositions can further comprises adjuvants (see Paragraphs 0110-0114), which reads on instant Claim 11.
For at least these reasons, BenMohamed teaches the limitations of instant Claims 1-3, 5-7, and 10-11 and anticipates the invention encompassed by said claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3 and 5-12 are rejected under 35 U.S.C. 103 as being unpatentable over BenMohamed (US 2024/0269266 A1, earliest Priority Date 14 April 2020), Hanson (U.S. Patent No. 11,640,851 B2, earliest Priority Date 28 June 2020), and Marcusson et al. (US 2024/0307522 A1, earliest Priority Date 09 October 2020).
BenMohamed teaches a pharmaceutical composition comprising a plurality of lipid nanoparticles wherein a first lipid nanoparticle comprises three mRNAs encapsulated therein, and each mRNA comprises an open reading frame encoding a Coronavirus protein selected from the group consisting of an NSP2 protein, an NSP14 protein, and a Nucleoprotein (see Paragraph 0024), wherein each mRNA further comprises a 5’ UTR, a 3’UTR, a 3’ poly(A) tail, and/or a 5’ cap or cap analog (see Paragraph 0025), which reads on instant Claims 1-3 and 5-6. BenMohamed also teaches SEQ ID NO: 9, an amino acid sequence which corresponds to the Nucleoprotein and comprises instant SEQ ID NO: 34 which comprises the instantly claimed mutations (see Sequence Listing), which reads on instant Claims 1 and 10. Additionally, BenMohamed teaches a pharmaceutical composition comprising a plurality of lipid nanoparticles wherein said nanoparticles comprise an ionizable cationic lipid, a neutral lipid, a sterol, and a PEG-modified lipid (see Paragraph 0167), which reads on instant Claim 5. Furthermore, BenMohamed teaches delivery of said pharmaceutical compositions using viral vectors (see Paragraphs 0120-0121), which reads on instant Claim 7. Finally, BenMohamed teaches that said pharmaceutical compositions can further comprises adjuvants (see Paragraphs 0110-0114), which reads on instant Claim 11.
BenMohamed does not teach an mRNA encoded by instant SEQ ID NO: 38 or a composition comprising a nucleic acid expressed by a retroviral vector.
Hanson teaches SEQ ID NO: 1, which is a DNA fragment corresponding to the SARS-CoV-2 genome and is 100% identical to instant SEQ ID NO: 38 (see Sequence Listing; Claim 1), which reads on instant Claims 9 and 12. Hanson also teaches a composition comprising said DNA fragment encapsulated in an appropriate delivery system as well as a composition comprising mRNA fragments, corresponding to said DNA fragments, also encapsulated in an appropriate delivery system (see Abstract; Claims 1-2).
Marcusson et al. teach compositions comprising nucleic acids, such as DNA or mRNA, encoding one or more proteins, peptides, fragments or variants thereof of SARS-CoV-2 (see Abstract), wherein said nucleic acids encode one or more polypeptides, such as the N protein, comprising one or more mutations, such as the R203K and G204R mutations (see Paragraphs 0123 and 0139) and wherein said nucleic acids may be cloned into a retroviral replicating vector (see Paragraph 0408), which reads on instant Claim 8.
A person having ordinary skill in the art would have been motivated to combine the teachings of BenMohamed, Hanson, and Marcusson et al. in order to develop a composition comprising a nucleic acid encoding a specific SARS-CoV-2 protein. While BenMohamed teaches an amino acid sequence corresponding to the N protein comprising the R203K/G204R double mutation, it would have been obvious to and routine for a skilled artisan to generate the nucleic acid, such as mRNA and/or DNA which encoded said amino acid sequence, as disclosed by Hanson. The expression vectors taught by Marcusson, such as the retroviral replicating vector, would have been obvious to use depending on factors, such as the expression system(s) being used and whether or not the final peptide or protein was being expressed in vitro or in vivo in order to maximize expression of the desired peptide or protein. The combination of these teachings renders obvious the invention encompassed by the instant claims.
Such modifications, combining the teachings of the prior art according to known methods, would have had a reasonable expectation of success and arrived at the claimed invention prior to the effective filing date of the instant application. For at least these reasons, instant Claims 1-3 and 5-12 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Meinke et al. (US 2024/0293531 A1, earliest Priority Date 06 April 2020)
Meinke et al. teach SEQ ID NO: 15, which comprises a sequence that is 100% identical to instant SEQ ID NO: 38. This reference has not been utilized, as rejection would have been redundant to those set forth above.
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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671
/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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