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 .
Claim Status
Claims 1-7 are pending under examination and are currently amended.
Priority
The instant application is the 371 national stage entry of PCT/CN2022/071356, filed 1/11/2022, which claims priority to CN202110466103.7, filed 4/28/2021. The priority date of 4/28/2021 is acknowledge although it is noted that there is no translation of record.
Information Disclosure Statement
The IDS submitted on 12/20/2022 is under consideration.
Drawings
The drawings are objected to because 1) Figure 1 depicts a sequence without a SEQ ID NO, 2) Figure 2 is illegible, and 3) Figures 5-7 depict various types of staining in color but the image is in black and white, making it difficult to interpret. 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. The objection to the drawings will not be held in abeyance.
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 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.
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.
Figure 1 recites a sequence without a SEQ ID NO. Include the relevant SEQ ID NO in either the Figure itself or its corresponding legend in the Brief Description of the Drawings.
Claim Objections
Claims 3, 5, and 6 are objected to because of the following informalities: The claims list amino acid sequences with 4 or more specifically defined and enumerated residues and therefore require SEQ ID NOs. However, no SEQ ID NOs are listed in the claims. See MPEP 2422 and 37 C.F.R. 1.821. Appropriate correction is required.
Claim Interpretation
Claim 1 recites “(c) modifying the interfering peptide segment fused with HIV-TAT into a reverse isomer to obtain an amino acid sequence of a final interfering peptide NIP-V” (emphasis added). This claim is being interpreted as a peptide comprising NIP-V, wherein a peptide or protein encompassing or containing the entirety of NIP-V meets the limitation of the claim. Conversely, smaller fragments encompassed by NIP-V (i.e., dipeptides) are being interpreted as not meeting the limitations of the claim. This same interpretation is also being applied to claims 2-6.
Claim 1 also recites modifying the interfering peptide segment fused with HIV-TAT into a reverse isomer. A “reverse isomer” is being interpreted as a retro-D or retro-inverso peptide.
Claim 6 recites a molecular weight, which is being interpreted as an inherent characteristic of the recited peptide sequence SEQ ID NO: 3.
Claim 7 recites a method comprising applying an interfering peptide targeting SARS-CoV-2 N protein in anti-SARS-CoV-2 infection. The claim is being interpreted as a method of treating a SARS-CoV-2 infection comprising using or administering (applying) a peptide targeting SARS-CoV-2 N protein. Further, it is noted that there are no defining structural characteristics (i.e., amino acid sequences) for the limitation “an interfering peptide targeting SARS-CoV-2 N protein”; as such, this limitation has been interpreted to be met any peptide sequence that interferes, disrupts, or treats, SARS-CoV-2.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
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 recites that the amino acid sequence of the final interfering peptide NIP-V is (SEQ ID NO: 3) and a molecular weight thereof is 3040.69. It is unclear what the molecular weight represents as there are no units indicated. Thus, the scope of this claim is indefinite. For purposes of examination, the claim is being interpreted as a molecular weight thereof of 3040.69 Daltons.
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.
Claims 3, 4, and 6 are 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.
Claim 3 recites that the amino acid sequence of the amino acids 346-357 is FKDQVILLNKHI (SEQ ID NO: 2). This does not further limit claim 2, which recites that the amino acid are amino acids 346-357. Although the sequence is not listed, the amino acid range is the same, and both claims read on the N protein of SARS-CoV-2. Therefore, both claims 2 and 3 recite the same peptide sequence, and, thus, claim 3 is not further limiting.
Claim 4 recites that the amino acids are L-type natural amino acids, wherein the amino acids are located in a dimerization domain of the SARS-CoV-2 N protein. As evidenced by Genchi (An overview on d-amino acids. Amino Acids 49, 1521–1533 (2017).), viruses do not have peptides consisting of D-amino acids. Therefore, the sequence of the dimerization domain of the SARS-CoV-2 N protein must consist of L-type natural amino acids, so claim 4 does not further limit claim 2.
Claim 6 recites in step (c) an amino acid sequence of the final interfering peptide NIP-V is SEQ ID NO: 3 and a molecular weight thereof is 3040.69. Per the claim interpretation above, NIP-V and SEQ ID NO: 3 are the same peptide, and the molecular weight recited is a characteristic of NIP-V/SEQ ID NO: 3. Thus, claim 6 does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 7 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.
Claim 7 recites a method comprising applying an interfering peptide targeting SARS-CoV-2 N protein in an anti-SARS-CoV-2 infection. The rejection is based on the limitation “an interfering peptide targeting SARS-CoV-2 N protein”, which recites a feature by functional rather than structural language. There is nothing further in the claim to indicate the structural feature(s) (i.e., amino acid sequence(s)) required to meet this functional limitation, and describing an invention by function is insufficient to meet the written description requirement.
Per MPEP 2163(II)(3)(a), for some biomolecules, examples of identifying characteristics include a sequence, structure, binding affinity, binding specificity, molecular weight, and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics or combinations of characteristics may demonstrate the requisite possession. As explained by the Federal Circuit, "(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met … even where actual reduction to practice of an invention is absent; and (3) there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure." Falkner v. Inglis, 448 F.3d 1357, 1366, 79 USPQ2d 1001, 1007 (Fed. Cir. 2006); see also Capon v. Eshhar, 418 F.3d at 1358, 76 USPQ2d at 1084 ("The Board erred in holding that the specifications do not meet the written description requirement because they do not reiterate the structure or formula or chemical name for the nucleotide sequences of the claimed chimeric genes" where the genes were novel combinations of known DNA segments.). However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
Essa et al. (Antiviral peptides against SARS-CoV-2: therapeutic targets, mechanistic antiviral activity, and efficient delivery. Pharmacol Rep. 2022 Dec;74(6):1166-1181; published October 2022, after Applicant’s effective filing date) describes the process of identifying and validating antiviral peptides (AVPs) for SARS-CoV-2. AVPs can inhibit viral infection or replication, such as by targeting processes like viral attachment, entry, uncoating, synthesis, and assembly. The mechanism of each AVP is dependent on the process it interferes with and the viral proteins with which it interacts (Pg 1171-1172, “Viral target identification and validation of antiviral peptides”). Table 1 of Essa lists a number of peptides with defined structural characteristics (amino acid sequences), each of which targets SARS-CoV-2 via a distinct mechanism. Per the claim interpretation described above and based on the lack of structural limitations recited, any of these would meet the limitations of the instant claim 7.
Applicants have disclosed SEQ ID NO: 3 as an interfering peptide that can target the SARS-CoV-2 N protein but it is not recited in the present claim. No other peptide sequences are disclosed within the instant specification, and the claims listed above are written such that they contemplate or include additional compounds that retain the same functional characteristics beyond these limited examples. Thus, the instant specification does not provide adequate written description to possess the broad genus described above.
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 1-6 are rejected under 35 U.S.C. 101 because they are directed to a judicial exception.
The Supreme Court has given a three-part test for patent eligibility (see flowchart of MPEP 2106(III)):
Are the claims drawn to a process, machine, manufacture, or composition of matter?
2a) If the claims pass the first test, are the claims drawn to a judicial exception (a law of nature, a natural phenomenon (product of nature), or an abstract idea)?
2b) If a judicial exception applies, do the claims recite additional elements that amount to significantly more than the judicial exception?
Applying the three-part test to the instant claims:
Regarding 1), the claims are drawn to a process, a method of preparing an interfering peptide.
Regarding 2a), the process claimed recites abstract ideas, specifically mental processes.
Claim 1 recites a preparation method of an interfering peptide targeting SARS-CoV-2 N protein, comprising the following steps: (a) designing an interfering peptide segment targeting amino acids located in a dimerization domain of the SARS-CoV-2 N protein; (b) fusing the interfering peptide segment with HIV-TAT; (c) modifying the interfering peptide segment fused with HIV-TAT into a reverse isomer to obtain an amino acid sequence of a final interfering peptide NIP-V; and (d) synthesizing the interfering peptide NIP-V using D-amino acids as raw materials. Steps (a)-(c) recite mental processes, which are a type of abstract idea (MPEP 2106.04(a)(2)(III)). Dependent claims 2-6 provide further limitations regarding steps (a)-(c) that still constitute mental processes.
Regarding 2b), the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The only additional step recited in claim 1 is step (d), which is not a mental process itself but is routine and conventional in the art of protein synthesis. As such, it does not constitute significantly more. Thus, the claims are drawn to patent ineligible subject matter and are rejected here.
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.
Claim(s) 7 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Outlaw et al. (Inhibition of Coronavirus Entry In Vitro and Ex Vivo by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain. mBio. 2020 Oct 20;11(5):e01935-20.).
Outlaw describes a lipopeptide derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S protein that inhibits infection of SARS-CoV-2 (“an interfering peptide targeting SARS-CoV-2 N protein”, see claim interpretation section above; Abstract). Introducing (applying) the lipopeptide to SARS-CoV-2 infected human airway epithelium (HAE) models prevented the spread of the virus as compared to untreated controls (Pg 6-9, “SARS-CoV-2 HRC peptide inhibits infectious SARS-CoV-2 viral spread in a human airway epithelial ex vivo model”; Figure 4). Thus, Outlaw anticipates claim 7.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (Crystal structure of the severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein dimerization domain reveals evolutionary linkage between corona- and arteriviridae. J Biol Chem. 2006 Jun 23;281(25):17134-17139.), Chang et al. (The dimer interface of the SARS coronavirus nucleocapsid protein adapts a porcine respiratory and reproductive syndrome virus-like structure. FEBS Lett. 2005 Oct 24;579(25):5663-8.), Zinzula et al. (High-resolution structure and biophysical characterization of the nucleocapsid phosphoprotein dimerization domain from the Covid-19 severe acute respiratory syndrome coronavirus 2. Biochem Biophys Res Commun. 2021 Jan 29;538:54-62.), Kenneth (WO 2021211784 A2, filed 4/15/2021), and Arranz-Givert et al. (Immunosilencing peptides by stereochemical inversion and sequence reversal: retro-D-peptides. Sci Rep 8, 6446 (2018).).
Yu teaches that the nucleocapsid (N) protein of SARS-CoV plays an essential role in genome packing and viral assembly (Abstract; Pg 17137, left column, Discussion first paragraph). The N protein of SARS-CoV dimerizes through the C-terminal domain (CTD; Abstract), and the CTD comprises helix E, which consists of residues 346-357 (Pg 17136, right column, second paragraph; Figure 2A).
Yu does not teach a method of preparing a SARS-CoV-2 interfering peptide that targets the dimerization domain of the N protein.
Chang teaches that helix E helps to stabilize the dimer interface of the N protein of SARS-CoV (Pg 5666, “3.2 The dimer interface is composed of a β-sheet stabilized by helix E”).
Zinzula teaches the crystal structure of SARS-CoV-2 N protein CTD (Abstract). Like SARS-CoV, SARS-CoV-2 also dimerizes through its CTD (Pg 59, “3.2. SARS-CoV-2 N CTD oligomerization profile and thermal stability” and “3.3. Crystal structure of the SARS-CoV-2 N CTD”). Residues 346-357 of the SARS-CoV-2 N (the instant SEQ ID NO: 1) protein only differ from the SARS-CoV N protein at one amino acid, which is a conservative substitution (Figure 1D). Zinzula teaches that the CTD is a very attractive target for designing antiviral drugs (Pg 60, right column, first paragraph under Discussion).
Kenneth teaches methods of treating infectious diseases such as coronavirus infections, including SARS-CoV-2 through administration of apelin receptor agonists ([0003, 0019]). Kenneth teaches making fusion proteins of the invention by attaching a peptide receptor agonist to a penetrating agent, which is an agent that enhances translocation of any of the attached peptides across a cell membrane. The penetrating agent can be a cell penetrating peptide (CPP). One such CPP taught is SEQ ID NO: 67, which consists of YGRKKRRQRRR and is identical to the instant SEQ ID NO: 2 ([0121]). Further, the permeability-enhancing moiety is preferably connected to the amino terminus of the peptide moiety ([0119]).
Arranz-Givert teaches modifying existing peptide sequences by creating retro-D-peptides, which are peptides derived from a parent peptide in which the sequence is reversed and made by D-amino acids (reverse isomer). This rearrangement is advantageous in that it produces protease-resistant peptides with topology that overlaps with that of the parent peptide for good mimicry (Pg 1, third paragraph; Pg 5, “Solid-Phase Peptide Synthesis, Cleavage, and Work-Up”).
Thus, regarding claims 1, Yu teaches that the N protein of SARS-CoV, which is involved in genome packaging and viral assembly, dimerizes through its CTD, which comprises helix E that consists of residues 346-357. Chang teaches that helix E stabilizes the N protein dimer interface of SARS-CoV. Further, Zinzula teaches that residues 346-357 of the SARS-CoV-2 N protein are nearly identical in sequence and structure to those of SARS-CoV. Therefore, it would be prima facie obvious to design a peptide that targets the SARS-CoV-2 N protein dimerization interface in order to effectively disrupt the viral life cycle. Further, it would be obvious to select SEQ ID NO: 1 as the sequence to disrupt dimerization because dimerization of the SARS-CoV N protein depends on this segment and SARS-CoV and SARS-CoV-2 exhibit substantial sequence and structural homology to each other. One skilled in the art would have a reasonable expectation of success as Chang established that these residues contribute to dimer stabilization, so disrupting them would destabilize the dimer.
Further, Kenneth, as a part of a method for treating coronaviruses such as SARS-CoV-2, teaches fusing peptide therapeutics of interest to CPPs from HIV-TAT, such as the instant SEQ ID NO: 2. Thus, it would be prima facie obvious to fuse SEQ ID NO: 2, as taught by Kenneth, to the peptide derived from helix E, as taught by Yu, Chang, and Zinzula, in order to enhance the ability of the peptide to penetrate target cells. One skilled in the art would have a reasonable expectation of success as Kenneth demonstrated previously that the instant SEQ ID NO: 2 could be fused to other therapeutic peptides in order to effectively treat SARS-CoV-2.
Finally, Arranz-Givert teaches creating retro-D-peptides is advantageous because it produces protease-resistant peptides with good mimicry. Thus, it would be prima facie obvious to modify and synthesize a reverse isomer of the SEQ ID NO: 2-SEQ ID NO: 1 fusion protein consisting of D-amino acids, thereby arriving at the instant SEQ ID NO: 3, in order to make the peptide more protease-resistant. One skilled in the art would have a reasonable expectation of success as Arranz-Givert demonstrated that this approach increases the protease-resistance of other peptide therapeutics.
Regarding claims 2 and 3, as described above, Zinzula teaches the residues of 346-357 in SARS-CoV-2 N protein consist of the sequence FKDQVILLNKHI (Figure 1).
Regarding claim 4, Arranz-Givert teaches the parent peptide, from which retro-D-peptides are derived, is made of L-amino acids (Pg 1, third paragraph).
Regarding claim 5, as stated above, Kenneth teaches the instant SEQ ID NO: 2 ([0121]).
Claim(s) 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (Crystal structure of the severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein dimerization domain reveals evolutionary linkage between corona- and arteriviridae. J Biol Chem. 2006 Jun 23;281(25):17134-17139.), Chang et al. (The dimer interface of the SARS coronavirus nucleocapsid protein adapts a porcine respiratory and reproductive syndrome virus-like structure. FEBS Lett. 2005 Oct 24;579(25):5663-8.), Zinzula et al. (High-resolution structure and biophysical characterization of the nucleocapsid phosphoprotein dimerization domain from the Covid-19 severe acute respiratory syndrome coronavirus 2. Biochem Biophys Res Commun. 2021 Jan 29;538:54-62.), Kenneth (WO 2021211784 A2, filed 4/15/2021), and Arranz-Givert et al. (Immunosilencing peptides by stereochemical inversion and sequence reversal: retro-D-peptides. Sci Rep 8, 6446 (2018).), as applied to claims 1-5 above, and further in view of Strieker et al. (WO 2014086835 A1, published 6/12/2024).
The teachings of Yu, Chang, Zinzula, Kenneth, and Arranz-Givert have been set forth above. Yu, Chang, Zinzula, Kenneth, and Arranz-Givert do not explicitly teach SEQ ID NO: 3 as recited in claim 6. Specifically, the difference between what is taught by Yu, Chang, Zinzula, Kenneth, and Arranz-Givert and the instant claim 6 is the HIV-TAT sequence that is N-terminally conjugated to SEQ ID NO: 1 in the retro-inverso peptide SEQ ID NO: 3; Zinzula establishes that residues 346-357 of SARS-CoV-2 constitute the sequence FKDQVILLNKHI in Figure 1, which is encompassed in the retro-inverso sequence of SEQ ID NO: 3.
Strieker teaches conjugates comprising peptides and multivalent CPPs as well as methods of diagnosing, preventing, and treating disease (Abstract). Strieker teaches both HIV-TAT CPPs SEQ ID NO: 459 with the sequence YGRKKRRQRRR (the instant SEQ ID NO: 2, recited in claim 5) and SEQ ID NO: 759 with the sequence GRKKRRQRRRPP (Table 1, starting on Pg 28). The retro-inverso sequence of SEQ ID NO: 759 is encompassed in the instant SEQ ID NO: 3 as recited in claim 6.
Thus, regarding claim 6, it would have been prima facie obvious to substitute a known element for another to obtain predictable results. Yu, Chang, Zinzula, Kenneth, and Arranz-Givert teach attaching the CPP SEQ ID NO: 2, derived from HIV-TAT, to the N-terminus of a peptide therapeutic, such as SEQ ID NO: 1, in order to enhance its ability to penetrate cells. The peptide taught by Yu, Chang, Zinzula, Kenneth, and Arranz-Givert only differs from the instant SEQ ID NO: 3 of claim 6 in that the CPP is a different variant of HIV-TAT. However, Strieker indicates that multiple variants of HIV-TAT can be used as CPPs to enhance the penetration of peptide therapeutics. Therefore, one of ordinary skill in the art could have substituted the instant SEQ ID NO: 2 taught by Yu, Chang, Zinzula, Kenneth, and Arranz-Givert for SEQ ID NO: 759 of Strieker, leading to predictable results – enhanced penetration of the retro-inverso peptide SEQ ID NO: 3.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sara E Konopelski Snavely whose telephone number is (571)272-1841. The examiner can normally be reached Monday - Friday 9-6pm EST.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/FRED H REYNOLDS/Primary Examiner, Art Unit 1658