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 statement (IDS) submitted on 1/24/2024; 5/30/2024, and 11/14/2025 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
Applicant is reminded that the incorporation of essential material (i.e., GenBank® Accession Nos. NC_006430.1, AF052755.1, KC852177.1, KP893891.1, KC237065.1, KC237064.1, KC237063.1 of PIV5 genomes; exemplary RSV F and G protein variants in WO/2008/114149; PIV5-based constructs in WO 2013/112690 and WO 2013/112720; and F. P. Polack, et al., J Exp Med 196, 859-865 (2002); B. Bagga, et al., J Infect Dis 212, 1719-1725 (2015, discussing Th2-biased immune response and potential risk factor for vaccine-associated enhanced RSV disease) in paragraphs [0065, 0067, 0151, 0255, and 0256] of the instant published disclosure, USPgPub 2024/0148857, by reference to a foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference. The amendment must be accompanied by an affidavit or declaration executed by the applicant, or a practitioner representing the applicant, stating that the amendatory material consists of the same material incorporated by reference in the referencing application. See In re Hawkins, 486 F.2d 569, 179 USPQ 157 (CCPA 1973); In re Hawkins, 486 F.2d 579, 179 USPQ 163 (CCPA 1973); and In re Hawkins, 486 F.2d 577, 179 USPQ 167 (CCPA 1973). Furthermore, if a required sequence was not set forth in the specification as filed, and was not publicly available from Genbank® at the time the application was filed, the amendment will be treated as an attempt to introduce new matter (similar to attempts to incorporate essential material by reference to unpublished material). In addition, note that the amendment will probably require a replacement Sequence Listing, to add the sequences which are added to the disclosure.
The use of the term “GenBank”, which is a trade name or a mark used in commerce, has been noted in paragraphs [0065, 0115, 0162, and 0256] of this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears 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.
The disclosure is objected to because of the following informalities: Paragraphs [0012 and 0013] recite “19, or 19” instead of SEQ ID NOs: 18, or 19, gleaned from Table 5.
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
Claim 1 is objected to because of the following informalities: the acronyms “RSV F” should be spelled out prior to first.
In addition, it is suggested that the limitations describing the “viral expression vector” of claim 1 is drafted more concisely by reciting something like:
“A viral expression vector comprising a parainfluenza virus 5 (PIV5) genome, wherein the viral expression vector is a live recombinant canine parainfluenza (CPI) vector backbone engineered to express a Respiratory Syncytial Virus Fusion protein (RSV F) comprising at least 95% sequence identity to SEQ ID NO: 1.”
Claims 5 and 11 are objected to because of the following informalities: “19” is recited twice. Appropriate correction is required to be in agreement with Table 5 of the instant published disclosure, USPgPub 2024/0148857.
Appropriate correction is required.
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 2, 5, 8, and 11 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.
Claims 2 and 8 require the RSV F encoded by a wild-type or mutated RSV F protein gene. Chen et al. (Scientific Reports. 2018 Mar 14; 8 (1): 4491) sequences the F gene from 183 RSV A and 69 RSV B isolates obtained from hospitalized children. F gene sequence identities among RSV A isolates ranged between 94.3% to 100%, resulting from 83 nucleotide changes and sequence identities among RSV B isolates ranged between 96.5%–100% , resulting from 59 nucleotide changes. See “The samples”, “Phylogenetic analysis”, and “Variation analysis”. Given the amount of sequence variation and nucleotide differences in wild-type RSV F genes taught by Chen et al., it is unclear how genes encoded by wild-type or (naturally) mutated RSV F protein genes are distinguished, as claimed. To ameliorate this rejection, “codon optimized for expression in a human”, recited in claims 3 and 9, is encouraged to replace the “mutated” limitations in claims 2 and 8.
Claims 5 and 11 state that antigenomic canine parainfluenza virus (CPI) cDNA is sequenced with primers listing SEQ ID NO: 2,…, or 19. It is not clear whether the claims intend for only one of the listed primers to be used in sequencing due to the presence of “or”. Chuang et al. (Biotechnology Letters. 2013; 35: 1541-1549) reviews primer design, including the standard necessity of using two primers for amplification, one forward and one reverse, see “Definition of primers” and Pf and Pr in Figure 2. The requisite designation of forward and reverse for any of the primers recited is indeterminable.
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 1-3, 5-9, and 11-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a PIV5 canine parainfluenza (CPI) vector backbone expressing a respiratory syncytial virus fusion protein (RSV F) between the SH and HN gene junction, does not reasonably provide enablement for a PIV5 canine parainfluenza (CPI) vector backbone expressing a respiratory syncytial virus fusion protein (RSV F) between any gene junction. 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 use the invention commensurate in scope with these claims.
The claims are drawn to a PIV5 canine parainfluenza (CPI) vector backbone expressing a heterologous respiratory syncytial virus fusion protein (RSV F), where RSV F is inserted anywhere within the PIV5 (CPI) vector. Paragraphs [0012, 0013, 0115, 0162, 0164, and 0167] of the instant published disclosure (USPgPub 2024/0148857) discuss the RSV F gene inserted between the SH and HN gene junctions of the PIV5 (CPI) vector. Paragraphs [0077 and 0083-0086] review prior art comparing CPI and W3A strains of PIV5 expressing RSV F in prefusion conformation or unmodified RSV F inserted between SH-HN and HN-L gene junctions. Paragraph [0077] concludes:
These studies led to the selection of CPI-RSV-F (CPI-RSV-F), containing the full length of RSV F-protein inserted between SH and HN gene (FIG. 1) for use in the initial human studies.
Paragraph [0086] concludes:
Following immunization, both humoral and cell mediated immune responses were observed. The highest neutralizing antibody responses were detected with vaccine construct using the wt F protein. Also, vaccine constructs containing the wt F inserted prior to the HN junction with ΔSH seemed to be most immunogenic. The level of cell-mediated immune responses (based on IFN-gamma using ELISPOT) was similar between the various vaccine constructs.
Li et al. (Journal of Virology. 2013; 87 (1): 354-362) teach PIV5 genomes with a heterologous insert between the promoter and the leader sequence did not result in viable virus. Heterologous insertion between the NP and V/phosphoprotein gene junction lead to disabled virus replication, but heterologous insertion between SH and HN genes produced protective efficacy upon virulent challenge. In section 2, Chen (Reviews in Medical Virology. 2018; 28 (2): e1965) teach PIV5 transcription is highest at the 3’ genome end, see Figure 1B. In section 3, Chen emphasizes criticality of the foreign gene insertion site within PIV5 due to impact on expression levels and viral replication efficiency (as observed by Li et al.).
There is no guidance provided in the instant published disclosure for inserting the RSV F gene within the PIV5 CPI genome other than the gene junction between SH and HN. As evidenced by the teachings in the prior art, the skilled artisan would not expect success with RSV F gene insertion at any other gene junction within the PIV5 CPI genome, as encompassed and asserted by the instant claims. For these reasons, it is determined that an undue quantity of experimentation would be required of the skilled artisan to make and use the invention commensurate in its full scope.
Claims 5 and 11 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.
Claims 5 and 11 require primers having a nucleic acid sequence with at least 95% identity to SEQ ID NOs: 2-19 (disregarding the inadvertent typo listing “19” twice). However, the instant disclosure only teaches primers with exact sequences of SEQ ID NOs: 2-19 in Table 5, each ranging between 22 residues (SEQ ID NO: 13) and 27 residues (SEQ ID NO: 5). A 5% difference in any of the primers is approximately one nucleotide. Since each primer is approximately 25 nucleotides in length, any single nucleotide of which can be changed/ unchanged to encompass a 5% difference within each specific sequence, the number of primer variants that can be generated from each primer is approximately 225 or 33,554,432 different primers. The instant disclosure only teaches primers with exact sequences of SEQ ID NOs: 2-19 and does not suggest possession of 18 primers with approximately 33,554,432 variations. Mismatches in primers cause a shift in amplification profiles, especially at the 3’ end, leading to reduced PCR yields and non-specific amplification, see Figure 1B, Figure 2, Table 1, and Table 2 of Boyle et al. (BMC Biotechnology. 2009; 9: 75). The skilled artisan would not recognize a primer having 5% sequence variation to instant SEQ ID NOs: 2-19 that sequences PIV5 canine parainfluenza (CPI) antigenomic cDNA. There is no teaching for which single nucleotide comprised by any of SEQ ID NOs: 2-19 can be changed and functionally sequence canine parainfluenza (CPI) antigenomic cDNA, as required.
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 exact primer sequences SEQ ID NOs: 2-19. There is no disclosure of sufficient characteristics of the claimed genus of primer sequences to allow persons of ordinary skill in the art to recognize that applicants were in possession of the claimed genus of primers encoded by a sequence that is at least 95% identical to SEQ ID NOs: 2-19. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. A definition by function alone is not sufficient because it is only an indication of what a thing does, rather than what it is. Eli Lily, 119 F.3 at 1568, 43 USPQ2d at 1406.
The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that “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 the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the quantity of primer variations encompassed by a 5% difference in sequence identity to instant SEQ ID NOs: 2-19 claimed. Given that the specification has only described SEQ ID NOs: 2-19, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claims 5 and 11 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 5 and 11 require primers having a nucleic acid sequence with at least 95% identity to SEQ ID NOs: 2-19, supported in instant Table 5. However, the instant disclosure only teaches primers with exact sequences of SEQ ID NOs: 2-19, each ranging between 22 residues (SEQ ID NO: 13) and 27 residues (SEQ ID NO: 5). A 5% difference in any of the primers is approximately one nucleotide. Since each primer is approximately 25 nucleotides in length, any one of which can be changed/ unchanged to encompass a 5% difference within each specific sequence, the number of primer variants that can be generated from each primer is approximately 225 or 33,554,432 different primers. The instant disclosure only teaches primers with exact sequences of SEQ ID NOs: 2-19 and does not suggest possession of 18 specific primers, each with approximately 33,554,432 variations. Mismatches in primers cause a shift in amplification profiles, especially at the 3’ end, leading to reduced PCR yields and non-specific amplification, see Figure 1B, Figure 2, Table 1, and Table 2 of Boyle et al. (BMC Biotechnology. 2009; 9: 75). The skilled artisan would not predict a primer having 5% sequence variation to instant SEQ ID NOs: 2-19 that sequences CPI antigenomic cDNA. There is no teaching for which single nucleotide comprised by any of SEQ ID NOs: 2-19 can be changed and functionally sequence canine parainfluenza (CPI) antigenomic cDNA, as required. There is no discussion or working example provided in the instant disclosure for sequencing an antigenomic CPI cDNA with any primer variant of SEQ ID NOs: 2-19.
Claims 5 and 11 additionally require antigenomic cDNA sequencing with primers having SEQ ID NO: 2,…, or 19. It is not clear whether the claims intend for only one of the listed primers to be used in sequencing due to the presence of “or”. Chuang et al. (Biotechnology Letters. 2013; 35: 1541-1549) reviews primer design, including the standard necessity of using two primers for amplification, one forward and one reverse, see “Definition of primers” and Pf and Pr in Figure 2. The requisite designation of forward and reverse for any of the primers recited is not provided in the specification and would be unpredictable to the skilled artisan. The skilled craftsman would not predict successful sequencing using one primer (if intended) or using primers going the same direction.
For these reasons, it is determined that an undue quantity of experimentation would be required of the skilled artisan to make and use the instant invention.
Allowable Subject Matter
A nucleic acid sequence with at least 95% identity to SEQ ID NO: 1 and primer sequences having 100% identity to SEQ ID NOs: 2-19 are free of the art.
Claims 4 and 10 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Wang et al. (Journal of virology. 2017; 91 (11): 10-128) demonstrate protection against RSV challenge in cotton rats and African green monkeys administered a PIV5 backbone with RSV F inserted between HN and L regions, see the paragraph prior to “Results”, “Protection of cotton rats from RSV challenge”, “Protection of African green monkeys from RSV challenge”, and cell-mediated immune responses depicted in Figure 7. A single intranasal dose of PIV5-RSV-F induced neutralizing antibody titers in previously infected monkeys, suggesting potential protective efficacy in pediatric and elderly populations, see Figure 9, “Importance”, and the first paragraph under the Discussion. Table 1 of Wang et al. show a significantly higher lung pathology score for peribronchiolitis, perivasculitis, interstitial pneumonitis, and alveolitis in formalin-inactivated RSV (FI-RSV) immunized animals compared to PIV5/F immunized animals.
Phan et al. (Journal of Virology. 2017; 91 (19): 10-128) demonstrate protective efficacy against RSV challenge with an RSV F inserted at the SH-HN gene junction in a PIV5 backbone when the construct was administered by intranasal or subcutaneous routes. Phan et al. show both humoral and cell-mediated immunity and reduced RSV loads in both the upper
and lower respiratory tracts. See “Generation and analysis of PIV5 expressing wild-type RSV F and a prefusion stabilized RSV F mutant” and Figures 1-9.
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