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 .
Information Disclosure Statement
The information disclosure statements (IDS’s) submitted on October 1, 2023 have been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The specification filed June 27, 2023 does not conform to 37 CFR 1.125(b) and (c) because: the specification does not comply with MPEP § 2414.02 (2):
(2) An amendment to the specification to incorporate by reference the material in the "Sequence Listing XML" by reciting in a separate paragraph of the specification the name of the file, the date of creation, and the size of the file in bytes (37 CFR 1.835(a)(2) and 37 CFR 1.835(c))
The specification is objected to for failing to adhere to the requirements of the sequence rules. Figures 1 and 10A of instant published disclosure, USPgPub 2024/0316174 depict sequences without a corresponding SEQ ID NO. Applicant must append SEQ ID NOs. to all mentions of specific sequences comprising four or more amino acids and ten or more nucleic acids in the specification. When a sequence is presented in a drawing, the sequence must still be included in the sequence listing if the sequence falls within the definition set forth in 37 CFR 1.821(a), and the sequence identifier ("SEQ ID NO:X") must be used, either on the drawing itself or in the Brief Description of the Drawings. Applicant is required to append a SEQ ID NO. to any sequence applicable to the rule. See 37 CFR § 1.821 (a)-(d) and MPEP § 2422. Appropriate correction is required.
The use of “ATCC” in paragraph [0228] of the instant published application is a trade name or mark used in commerce. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant is required to properly annotate all trade names and/or marks present in the instant specification, if any additional trade names and/or marks are discovered. Applicant' s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show colors, ‘red’, ‘blue’, ‘green’, and ‘yellow’, described as depicted in Figures 1, 3, 7, 9, 10, 12, and 13. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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.
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).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-11, 16, 20-23, 29, 36-40, and 45-48 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.
Instant claim 1 requires at least one immunogenic peptide between 5 and 17 contiguous amino acids “derived from a conserved or non-conserved region of NS1 peptide of dengue virus (DENV).” The quoted phrase does not particularly point out and distinctly claim the immunogenic peptides required because conserved and non-conserved regions are all that exist in a Dengue NS1 protein according to Figure 1. Therefore, the immunogenic peptides encompassed by claim 1 are indeterminate. In the instant case, the immunogenic peptides claimed encompass an exponential number of distinct alternative members since one skilled in the art cannot determine the metes and bounds due to an inability to envision all of the peptides encompassed, including the 5-17 contiguous residues of specific SEQ ID NOs recited. This rejection affects claims 2-11, 16, 20-23, 37-40, and 45-48.
Regarding recitation of Figure 10A in instant claim 29, where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." See MPEP 2173.05(s) and Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). Claims cannot refer back to tables in the specification. Figure 10A appears to depict 35 peptide sequences, already recited and identified in claim 29 as corresponding to SEQ ID NOs: 14-48. Therefore, recitation of Figure 10A is redundant. To overcome this rejection, it is suggested that applicant delete “of FIGURE 10A”.
Claim 36 recites the limitation, SEQ ID NOs: "or 23-48" in line 2. There is insufficient antecedent basis for this limitation in the claim. The lack of antecedent basis for these recited sequences makes the scope of the claim indeterminate. Also, why is there an “or” between “SEQ ID NOs: 14-22 or 23-48” since the sequence identifiers are linearly numbered?
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-11, 16, 20-23, 26, 31-40, and 45-48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Instant claim 1 requires at least one immunogenic peptide between 5 and 17 contiguous amino acids “derived from a conserved or non-conserved region of NS1 peptide of dengue virus (DENV).” The quoted phrase does not particularly point out and distinctly claim the immunogenic peptides required because conserved and non-conserved regions are all that exist in a Dengue NS1 protein according to Figure 1. Therefore, the immunogenic peptides encompassed by claims 1-11, 16, 20-23, 37-40, and 45-48 are indeterminate. In the instant case, the immunogenic peptides claimed encompass a massive number of distinct alternative members since one skilled in the art cannot envision all of the peptides encompassed, including the 5-17 contiguous residues of specific SEQ ID NOs recited. Claim 26 specifies that the immunogenic peptides comprise at least 5 contiguous amino acid residues of any one of SEQ ID NOs: 1-8 and claims 31-35 require that the immunogenic peptide is between 5 and 17 contiguous amino acids of amino acid sequences SEQ ID NOs: 1-10 and 14-22. Claim 36 additionally recites that the immunogenic peptide is between 5 and 17 contiguous amino acids of SEQ ID NOs: 23-48.
Figure 1 depicts NS1 sequences from all four Dengue virus serotypes, each having 352 amino acid residues. However, the disclosure fails to adequately describe the scope of immunogenic peptides claimed. Peptides encompassing at least 5 and up to 17 contiguous amino acids of Dengue NS1 (discussed in instant paragraph [0008] of the instant published disclosure) or at least 5 and up to 17 contiguous amino acids of SEQ ID NOs: 1-10 and 14-48, encompass an exponential quantity of peptide sequences. For example, SEQ ID NOs: 1-5 comprise 11, 16, 17, 9, and 12 amino acid residues respectively. The total quantity of five contiguous amino acid sequences that can be produced from a total of 11, 16, 17, 9, and 12 residues present in SEQ ID NOs: 1-5 is seven, twelve, thirteen, five, and eight different sequences encoding at least 5 contiguous amino acids of each sequence. Therefore, the scope of peptide sequences claimed, encoding at least 5 consecutive amino acids of SEQ ID NOs: 1-10 and 14-48 have not been adequately described in the instant disclosure.
The scope of nucleic acids claimed are not particular to Dengue NS1, as claimed and required. UniProt db access no K9Z1F9_CYAAP Mar 2013 is identified as a Cyanobacterium aponinum phytoene dehydrogenase and comprises 7 consecutive amino acid residues with instant SEQ ID NO: 10, see the alignment provided. Geneseq db access no BGI69222 Jun 2019 is identified as a Zika NS1 and comprises 6 consecutive amino acid residues with instant SEQ ID NO: 5, see the alignment provided. Therefore, the claims encompass peptides unrelated to Dengue NS1 and the specification does not reasonably convey possession of these peptides.
The applicable standard for the written description requirement can be found in MPEP 2163; University of California V. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. V. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. V. Mahurkar, 19 USPQ2d 1111; and University of Rochester V. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the specification are peptide sequences comprising 100% identity to SEQ ID NOs: 1-10 and 14-48.
Vas-Cath Inc. V. Mahurkar, 19USPQ2d 1111, clearly states "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116). Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers V. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
There is no disclosure of sufficient characteristics of the peptides claimed to allow persons of ordinary skill in the art to recognize that applicants were in possession of the exponential quantity of peptide sequences encompassed by claims. The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. The claims do not meet the written description provision of 35 U.S.C. 112, first paragraph.
Claims 39 and 45-48 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an immunogenic composition and a method of inducing an immune response with a composition comprising bacteriophage VLPs comprising dengue NS1 peptides conjugated phage coat proteins, does not reasonably provide enablement for a vaccine and a method of treating or inhibiting a dengue virus infection by administering bacteriophage VLP comprising dengue NS1 peptides conjugated phage coat proteins. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claim 39 is drawn to a vaccine comprising bacteriophage VLP comprising dengue NS1 peptides conjugated phage coat proteins. Paragraph [0172] of the instant published disclosure, USPgPub 2024/01316174, states:
There are currently no antiviral treatments for DENV and prevention efforts rely on local control of the vector Aedes aegypti mosquito populations. Although efforts to develop a DENV vaccine have been pursued for almost 90 years, a safe and effective vaccine remains elusive largely due to the unique pathogenic features of DENV infection.
The claimed dengue NS1 peptide conjugated to the bacteriophage comprises between 5 and 17 contiguous amino acids derived from a conserved or non-conserved region of NS1. The scope of peptide sequences claimed, encoding at least 5 consecutive amino acids of SEQ ID NOs: 1-10 and 14-48 have not been adequately described in the instant disclosure. However, none of the NS1 peptides comprising between 5 and 17 contiguous amino acids derived from NS1 or SEQ ID NOs: 1-10 and 14-48 are identified as possessing prophylactic and/or therapeutic efficacy requires by the asserted vaccine. Paragraph [0211] of the instant disclosure identifies peptide 112-122 as highly immunogenic against all four Dengue serotypes, which does not correspond to any SEQ ID NO claimed, as evidenced by paragraph [0022] (emphasis underlined):
KYSWSEWGAK (SEQ ID NO: 10) corresponding to a modification of amino acids 112-122 of NS1 protein with SE substituting for KS in the peptide
Paragraph [0232] and Figures 11-13 describe and depict murine immune responses and binding to dengue-infected cells, and hexameric forms of NS1 with 9, Qβ VLP vaccines conjugated with SEQ ID NOs: 14-22. Paragraph [0234] states:
Future experiments will assess the protective capacity of these VLPs in animal models of DENV infection.
Therefore, there is no evidence that the instant Qβ VLP formulations conjugated with NS1 peptides are efficacious as a vaccine or would be effective in a method of treating and preventing dengue virus infection, morbidity, or a symptom thereof in a patient or subject, as asserted in claims 39 and 45-48.
The skilled artisan would not predict success using the instant phage VLP formulations conjugated with NS1 peptides as a vaccine or in a method of treating and preventing dengue virus infection, morbidity, or a symptom thereof in a patient or subject. Chew et al. (Antiviral research. 2024; 227: 105915) review the complexity of NS1 conformations. Chew et al. teach NS1 forms a dimer and a hexametric, trimeric dimer upon secretion that binds to epithelial cell membranes, inducing dengue pathogenicity and vascular leakage. In Figure 1 and Table 1, Chew et al. depict several dynamic configurations of dimer-tetramer-hexamer NS1 states, with the tetramer being the predominant form. Given the various multiformities of NS1 during infection, NS1 peptide antigenicity and pathogenicity are not predictable.
Kraivong et al. (Current Opinion in Virology 2025, 73:101488) teach that while protective efficacy has been demonstrated in animal models, antibodies to NS1 can induce vascular pathology, cross-react with host proteins, and promote hepatic endothelial cell apoptosis and platelet dysfunction in vivo. See Table 1 and Figure 1. Kraivong et al. discuss a number of obstacles to dengue NS1 vaccine development including a lack of predictable epitope selection to achieve broad coverage across diverse HLA genetic presentations in the population and DENV strain variability. Kraivong et al. also consider the lack of an animal model mimicking human dengue infection.
The instant disclosure does not provide a nexus between gaps of knowledge in the art and the asserted vaccine efficacy of the instant bacteriophage VLP formulations conjugated with NS1 peptides. For these reasons, it is determined that an undue quantity of experimentation would be required to practice the invention in its full scope.
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 1-11, 16, 20-23, 26-38 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Bachmann et al. (USPgPub 2011/0262472) and Smith et al. (WO 2015/095735), as evidenced by Cui et al. (PNAS. 2017; 114 (44): 1697-11702).
(Examiner note: interpretation that the claimed NS1 peptide “comprises” between 5-17 contiguous amino acids of specific disclosed sequences is gleaned from: “the present invention comprise polypeptide subunits”, in the abstract and paragraph [0003]; “nucleic acids encoding the polypeptide(s) and oligopeptide having the same amino acid sequence as the sequences disclosed herein”, in paragraph [0099]; and “the term “polypeptide” refers broadly to a polymer of two or more amino acids joined together by peptide bonds”, in paragraph [0157] of the instant published disclosure USPgPub 2024/0316174.)
Bachmann et al. teach a Qbeta or AP05 bacteriophage VLP comprising coat proteins and at least one immunogenic dengue virus peptide conjugated onto the VLP, see claims 1, 10-12, 23, 34, and 36, as required by instant claims 1, 5, 7, 8, and 31. Paragraphs [0025, 0058, and 0094] teach that the attachment site of the immunogenic antigen is through a linker and a cross-linker group attached to the ε-amino (4-aminobutyl) group on the lysine on the surface of the Qbeta VLP, as required by instant claims 2-4 and 9-11. Paragraphs [0079-0086 and 0110-0124+] of Bachmann et al. state that the cross-linker is SMPH , required in instant claims 22 and 31, and that the antigen is attached to a C-terminal glycine linker comprising GGC or GGGGCG comprising cysteinyl and sulfhydryl groups, see claims 17, 18 and 23 of Bachmann et al., required in instant claims 16, 20, 21, and 31. Paragraphs [0033, 0042, and 0053] teach the Qbeta bacteriophage comprises 180 coat protein subunits, required in instant claim 31. Paragraphs [0013, 0034, and 0054+] describe plural (populations) of Qbeta phage with attached dengue antigens, as required by instant claim 37, and claim 28 of Bachmann et al. is drawn to pharmaceutical composition comprising dengue-linked Qbeta phage, as required by instant claim 38. Paragraphs [0020, 0106, 0107, and 0142] discuss the inclusion of an adjuvant, recited in instant claim 40.
Bachmann et al. do not mention that the coat protein of Qbeta is a dimer, recited in claim 6. However, Cui et al. teach natural assembly of Qbeta phage includes extra coat protein dimers sequestered in the interior of the virion, see the abstract, “Significance”, and Figures 1A and 1C. Therefore, the Qbeta bacteriophage of Bachmann et al. inherently possess dimer coat proteins, as evidenced by Cui et al.
Bachmann et al. do not teach a dengue peptide derived from NS1, recited in instant claim 1 or that the NS1 peptide comprises between 5-17 contiguous amino acids of SEQ ID NOs: 2, 3, 15, and 22, required in instant claims 1, 26-34, and 36.
See the following sequence alignments of disclosed by Smith et al.:
Geneseq database access no: BCB29898, sharing 100% identity with instant SEQ ID NO: 2;
Geneseq database access no: BCB29808, sharing 100% identity with instant SEQ ID NO: 3;
Geneseq database access no: BCB29935 sharing 100% identity with instant SEQ ID NO: 15;
and
Geneseq database access no: BCB29926, sharing 100% identity with instant SEQ ID NO: 22.
The sequences of Smith et al. comprise at least 5-17 contiguous amino acid residues of dengue NS1, as required by claim 1, SEQ ID NOs: 2 and 3, required in claims 26-29 and 31-34, and SEQ ID NOs: 15 and 22, encompassed by claims 29-31 and 36.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have attached the NS1 peptides of Smith et al. to the Qbeta phage of Bachmann et al. to induce an immune response against dengue, see lines 20-22 on page 9 and lines 16-30 on page 17 of Smith et al. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have attached the NS1 peptides of Smith et al. to the Qbeta phage of Bachmann et al. because Smith et al. contemplate various antigen carriers, such as NS-1-coated liposomes, microcapsules, microspheres, and inclusion complexes, in the pharmaceutical formulation, see Figure 3B, Figure 9, lines 31-33 on page 4, and lines 18-22 on page 24, and Bachmann et al. teach VLPs as antigen carriers, see paragraphs [0006 and 0144].
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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/Shanon A. Foley/ Primary Examiner, Art Unit 1671
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