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 .
Applicant’s amendments to the claims and reply have overcome the objections to the instant disclosure, claim objections, and the rejections under 35 USC §§ 101 and 112, written description of record.
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 12, 17, 22, 33, 34, and 36-39 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 12, 17, 22, 33, 34, and 36-39 are drawn to a “vaccine for inducing an immune response against respiratory distress (RD) associated Erythroparvovirus RDAV in an equine. Claim 12 required the immune response to be induced by administering an immunogenically effective amount of at least one capsid protein selected from sequences encoding VP1, VP2, and/or VP3. Claim 17 combines the one or more capsid proteins of claim 12 with an RDAV NS1 amino acid sequence. Claim 33 states the at least one capsid of claim 12 is VP2. Claim 34 states that the vaccine comprises a vector encoding at least one capsid protein selected from sequences encoding VP1, VP2, and/or VP3. Claim 36 states that the one or more capsid proteins of claim 12 is assembled into a virus-like particle (VLP). Claims 37-39 is drawn to a method of inducing an immune response against RDAV in an equine by administering at least one capsid protein selected from sequences encoding VP1, VP2, and/or VP3 to raise antibodies in an equine, wherein infection of RDAV or equine recurrent laryngeal neuropathy is prevented. Claim 22 is drawn to a method of inducing an immune response against RD-associated Erythroparvovirus in equine by administering antibodies against the at least one capsid protein raised in an equine.
Instant paragraph [0047] of the instant published disclosure (USPgPub 2023/0340032) discussions for vaccination are provided:
…Combating RD is considered to comprise vaccination in order to prevent, ameliorate or cure an infection with the Erythroparvovirus, or any sign of the disease (RD) or another disorder that is associated with this infection. Vaccination may take place before the initial infection (prophylactic vaccination) or once the virus is diagnosed in an infected animal that is not yet suffering from the syndrome (therapeutic vaccination). In practice, vaccination in a herd of animals will often be a mix of prophylactic and therapeutic vaccination.
However, there is no evidence or data provided in the instant disclosure that the components of the claimed vaccine would be efficacious to prevent, ameliorate or cure a symptomatic or asymptomatic infection with the Erythroparvovirus, or any sign of the disease (RD) or another disorder that is associated with this infection, including equine recurrent laryngeal neuropathy, as required and asserted by the instant claims. There is also no evidence provided in the instant disclosure that antibodies raised in an equine against at least one capsid proteins would be efficacious in inducing an immune response against RDAV.
Paragraph [0081] and working Examples 4-6, teach isolation of serum samples and nasal swabs taken from horses at three different farms. A novel virus, isolated from the samples is designated “RD-associated virus” (RDAV) in paragraph [0017]. Examples 1-3 describe sequence analysis and phylogeny of the isolated virus sequences. Examples 4-6 detail clinical symptoms of horses diagnosed with RDAV and other same-housed horses in farms 1-3. Example 10 correlates an inoculated RDAV infection with spread to another stall-mate and laryngeal tissue histology analysis. While this evidence is indicative of infection and pathology with the novel etiologic agent, there is no evidence or data presented providing therapeutic and/or prophylactic efficacy of RDAV genomic and/or subunit components when administered. There is no guidance or working example describing administration of the claimed RDAV components.
The skilled artisan would not predict efficacious success if the instant RDAV materials are administered to horses to treat and/or prevent disease associated with infection. Jager et al. (Virology Journal. 2021; 18: 210, of record) review veterinary parvoviruses, including the genus, Erythroparvovirus on page 16, affecting a wide range of species, listed Table 1, and resulting in disparate clinical manifestations in Figure 2. No vaccine or therapeutic is discussed for Erythroparvovirus in contrast with Feline Panleukopenia Virus and Canine Parvovirus, see the corresponding sections.
Mazzei et al. (Animals. 2024; 14: 3347, of record) review respiratory pathogens in horses, including parvoviruses in Table 1. Yu et al. (Microbiology Resource Announcements. 2025 Mar 11; 14 (3): e00897-24, of record) identify equine Erythroparvovirus in the U.S. in January 2025. However, neither Mazzei et al. nor Yu et al. mention therapeutic or prophylactic materials effective for against equine Erythroparvovirus.
Paragraph [0037] and Figure 2 of the instant disclosure teaches that the novel parvovirus claimed is phylogenically related to human parvovirus B19. Suzuki et al. (Vaccine. 2022; 40: 6100-6106, of record) review a candidate B19 vaccine lacking phospholipase A2 function. In the abstract and Introduction, Suzuki et al. teach that no B19 vaccines are available. The challenges to be overcome are adequate culture methods and efficacious immune responses to vaccine candidates. Generation of neutralizing antibodies in a B19 VLP formulated with M59, resulted in development of rash, discussed in the Introduction and Discussion sections. Other challenges hindering the development of a B19 vaccine are identification of potent epitopes, discussed in section 3.3; and requisite mutations to VP1, resulting in balanced cytokine production, required for pathogen elimination, and reduced adverse inflammatory reactions observed in previous B19 vaccine candidates in Figures 1-4 and the Discussion section. There is no guidance or data provided in the instant disclosure indicating that the challenges of phylogenically-related human parvovirus B19 in paragraph [0037], are circumvented, solved, or irrelevant to the instant novel parvovirus claimed.
In reply to the rejection of record, applicant points to Example 9, where recombinantly produced VP2 proteins are exposed to serum collected from RDAV-infected horses. Table 8 and Figures 3A-3D demonstrate specific detection of antibodies directed against the VP2 in the horse serum. Applicant reasons that the skilled artisan would reasonably expect that the instant capsid proteins are immunogenic and can induce immune responses against RDAV, including antibody production.
Applicant’s arguments and a review of the data provided have been fully considered, but are found unpersuasive. Paragraph [0037] and Figure 2 of the instant disclosure teaches that the novel parvovirus claimed is phylogenically related to human parvovirus B19. Paragraph [0132] states the N-terminal part of B19 VP1, amino acids 5-80, contains neutralizing epitopes. No identification of neutralizing epitopes in any of the instant capsid proteins claimed have been identified. There is no evidence that one or more of the instant capsid proteins claimed, possessing at least 70% sequence identity, i.e., SEQ ID NO: 3, and/or amino acids possessing at least 70% identity encoded by SEQ ID NO: 4 and/or SEQ ID NO:5, any of which in combination with an amino acid sequence at least 70% to SEQ ID NO: 7, would possess the requisite neutralizing epitopes needed to induce neutralizing antibodies.
The skilled artisan would not predict inducing neutralizing antibodies against any one or more of the instant capsid proteins. Kajigaya et al. (PNAS. 1991; 88: 4646-4650) teach rabbits inoculated with B19 VP2 empty capsids produced antibodies, but that none of the antibodies in the sera contained neutralizing activity, see “Production of Neutralizing Antisera” and Figure 5A. In addition, Penkert et al. (Vaccines 2021, 9, 860) show non-neutralizing sera elicited by mouse immunizations with VP2 VLPs also recognized VP1uWT (VP1 unique region (VP1u), comprising an immunodominant peptide for neutralizing antibodies depicted in Figure 1A) and that the ability of sera to bind VP1uWT did not correlate with parvovirus B19 neutralization. See section 3.1. Therefore, while the instant VP2 is immunoreactive, there is no evidence or data presented indicating that antibodies induced are neutralizing or would be effective to prevent, ameliorate or cure a symptomatic or asymptomatic infection with the instant equine Erythroparvovirus, or any sign of the disease (RD) or another disorder that is associated with infection, including equine recurrent laryngeal neuropathy, as required and asserted by the instant claims.
Applicant asserts that the lack of discussion regarding equine erythroparvovirus by Jager et al., Mazzei et al., and Yu et al., does not suggest that the instant vaccine is infeasible or unpredictable.
Applicant’s arguments and a review of Jager et al., Mazzei et al., and Yu et al. have been fully considered, but are found unpersuasive. The teachings of Jager et al., Mazzei et al., and Yu et al. present a comprehensive review of veterinary parvoviruses in the current state of the art. No vaccine or therapeutic is discussed for Erythroparvovirus, including B19, the most studied of the Erythroparvoviruses and concluded to be the most related virus to the instant equine Erythroparvovirus claimed in paragraph [0037] and Figure 2. The teachings of Jager et al., Mazzei et al., and Yu et al. further support the lack of predictability of the skilled artisan to reasonably expect efficacious success with the vaccine and methods instantly claimed.
Regarding the teachings of Suzuki et al., applicant argues that the teachings support enablement of the instant claims by demonstrating B19 VLPs inducing strong virus-specific antibody responses in Figure 4. Applicant opines that the ordinary artisan would have reasonably expected that the instant proteins of the instant invention would induce an immune response against RDAV in an equine.
Applicant’s arguments and a review of the teachings of Suzuki et al. have been fully considered, but are found unpersuasive. In the abstract and Introduction, Suzuki et al. teach that no B19 vaccines are available. Instant claims 12, 17, 33, 34, and 36 all recite a vaccine. The immune response induced against RDAV in instant claim 37 requires inducing antibodies in an equine against one or more capsid proteins, where the administration results in infection of RDAV or equine recurrent laryngeal neuropathy being prevented in the equine. Claim 22 is drawn to a method of inducing an immune response against RD-associated Erythroparvovirus in equine and/or equine recurrent laryngeal neuropathy by administering antibodies against the at least one capsid protein raised in an equine. However, the skilled artisan would not predict inducing neutralizing antibodies against any one or more of the instant capsid proteins. Kajigaya et al. (PNAS. 1991; 88: 4646-4650) teach rabbits inoculated with B19 VP2 empty capsids produced antibodies, but that none of the antibodies in the sera contained neutralizing activity, see “Production of Neutralizing Antisera” and Figure 5A. In addition, Penkert et al. (Vaccines 2021, 9, 860) show non-neutralizing sera elicited by mouse immunizations with VP2 VLPs also recognized VP1uWT (VP1 unique region (VP1u), comprising an immunodominant peptide for neutralizing antibodies depicted in Figure 1A) and that the ability of sera to bind VP1uWT did not correlate with parvovirus B19 neutralization. See section 3.1. Therefore, while the instant VP2 is immunoreactive, there is no evidence or data presented indicating that antibodies induced are neutralizing or would be effective to prevent, ameliorate or cure a symptomatic or asymptomatic infection with the instant equine Erythroparvovirus, or any sign of the disease (RD) or another disorder that is associated with infection, including equine recurrent laryngeal neuropathy, as required and asserted by the instant claims.
There is no evidence provided in the instant disclosure that the materials claimed as a vaccine would be efficacious as a vaccine to prevent, ameliorate or cure an infection with equine Erythroparvovirus, or any sign of the disease (RD) or another disorder that is associated with this infection, including equine recurrent laryngeal neuropathy, as required and asserted by the instant claims. Without some guidance in the instant disclosure or the prior art to fill the gaps of knowledge of those skilled in the art regarding requisite vaccine components against Erythroparvovirus, the skilled artisan would be unable to predict how to induce an efficacious immune response against RDAV in horses, as instantly asserted. 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 claimed.
Allowable Subject Matter
Expression of a parvovirus capsid from a nucleotide sequence in a host cell not infected with the parvovirus is well known in the art, see claim 1 of US 6,204,044, for example. However, the prior art does not teach or suggest expressing an equine erythroparvovirus capsid protein comprising at least 70% sequence identity to instant SEQ ID NO: 3 and/or an amino acid sequence having at least 85% identity to the amino acid sequence encoded by SEQ ID NO: 4 and/or an amino acid sequence having at least 85% identity to the amino acid sequence encoded by instant SEQ ID NO: 5 from a host cell not infected with the parvovirus, as required in claims 5, 24, and 26. The prior art also does not teach or suggest a vector comprising a nucleic acid sequence operably linked to a heterologous regulatory element having at least 85% identity to the amino acid encoded by SEQ ID NO: 4; and/or a nucleic acid sequence having at least 70% identity to SEQ ID NO: 4 and/or a nucleic acid sequence having at least 85% identity to the amino acid encoded by SEQ ID NO: 5 and/or a nucleic acid comprising SEQ ID NO: 2 or SEQ ID NO: 4 or SEQ ID NO: 5, as required in claims 28-30.
Claims 5, 24-30, and 35 are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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