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
Foreign patent document numbers 1, 3, and 4 listed on the information disclosure statement filed 1/20/2023 fail to comply with 37 CFR 1.98(a)(3)(i) because there is no concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. A note next to each reference stating, “see abstract”, is noted. However, the abstracts of the cited documents are also not in the English language. It has been placed in the application file, but the information referred to therein has not been considered.
Specification
The use of the terms “Montanide GEL 01 PR”, “ISA 206 VG”, and “ISA 201 VG”, which are a trade names or marks used in commerce, has been noted in this application, see paragraph [0015] of the instant published disclosure, USPgPub 2023/0265129. The terms 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 provide proper annotation to each trade name or mark in the instant application.
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.
Claim 15 is rejected under 35 U.S.C. 101 because the claimed recitation of a use, i.e., application, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ 678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966).
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, 8, and 10-15 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 8 and 12 contain the trademark/trade name “ISA 201 VG”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an adjuvant and, accordingly, the identification/description is indefinite. This rejection also affects dependent claims 13 and 14.
Regarding claim 10, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Instant claim 11 requires a preservative, “thiomersalate”. Table 2 on page 4 of the instant published disclosure, USPgPub 2023/0265129, lists a “Thiomersal” heading. An art-recognized, widely used, vaccine preservative is “Thimerosal”. It is not clear if the art-recognized preservative, “Thimerosal”, is what is intended to be claimed or if a different preservative is intended. If a different preservative, other than Thimerosal, is what is intended to be claimed, it is unclear what ingredients or components the claimed “thiomersalate” contains.
Step 1 of claim 12 requires the p72 trimeric protein content of not less than 40% of the total amount of the exterior envelope subunit protein p72 derived from African swine fever virus (reflected in Table 2 of the instant published disclosure) and also recited in claim 2. It is presumed this limitation means that trimeric p72 is not less than 40% of the total content of the instant composition. Though, the phrase may mean that 40% of the total p72 is in trimeric form. This limitation recited in claims 2 and 12 is unclear. However, step 2 of claim 12, requires mixing p72 and CD2v to achieve a mass ratio of 1-8:8-1, which encompasses quantities of trimeric p72 less than 40% of the content, i.e., final volume, seemingly required in step 1, depending on the ratio chosen from the recited range. It is not clear how much of which protein is required.
MPEP 2173.05(q) "Use" Claims [R-10.2019] states:
Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. For example, a claim which read: "[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon" was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986).
Claim 15 is drawn to: "An application of the subunit vaccine…in preparation of a vaccine…”. However, there are no active steps recited for the intended initial application or the preparation. It is unclear if the claims are intended to be drawn to a product with an intended use or the claims are intended to be drawn to a method. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced. In the interest of compact prosecution, these claims are interpreted as products of intended use.
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 1-15 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.
Claim 1 is drawn to an African Swine Fever Virus (ASFV) subunit vaccine comprising a glycosylated CD2V expressed in a eukaryotic system, a trimeric p72, and pharmaceutically acceptable adjuvant. There is no guidance provided for these claimed components functioning as an effective vaccine. Tables 2 and 3 and paragraph [0041] of the instant published disclosure, USPgPub 2023/0265129, discuss efficacy of “vaccine 3” and “vaccine 4” formulations comprising CD2v and p72 trimer content of 40% and 71.79%, respectively. Therefore, the “vaccine 3” and “vaccine 4” formulations are beyond the scope of components recited in instant claims 1-15. While the efficacy data of “vaccine 3” and “vaccine 4” formulations is encouraging, it is not clear what is administered or whether protective efficacy would be predicted by the skilled artisan (discussed below).
Regarding the trimeric forms of p72 recited in the claims, Cui et al. (ACS Infectious Diseases. 2025 Jul 9;11(8):2104-15) discuss difficulty in forming trimeric forms of p72 due to susceptibility to misfolding and dependence on specific post-translational modifications. At the bottom of the page under “Main”, Cui et al. state “previous attempts to utilize recombinant P72 in subunit vaccine development have been hindered by its tendency to form monomers rather than the more immunogenic native trimers and the requirement for chaperone pB602L for folding.” Cui et al. also discusses poor immunogenicity due to improper folding in the Discussion section. In the paragraph above “Methods and Materials”, Cui et al. admits it is not known whether neutralizing antibodies are induced against membrane-bound, secreted, and intracellular forms of P72 and immunogenicity was not assessed.
The instant specification fails to describe how to make the requisite subunit components. Paragraph [0026] of the instant published disclosure, USPgPub 2023/0265129, states:
[0026] 1.1 Refer to the preparation method of African swine fever exterior envelope subunit protein CD2V of Application No. 201910004596.5 or 201910069838.9 of the applicant, or the preparation method of the exterior envelope subunit protein CD2V derived from African swine fever virus of other patents or documents (prokaryotic expression system expression, such as CHO, 293T cells, etc.).
Though the phrase, “incorporated by reference” is not stated in the paragraph, it is evident that the information provided in Application No. 201910004596.5 or 201910069838.9 is essential for the requisite glycosylation expressed in a eukaryotic system. Incorporation by reference to an unpublished U.S. application, foreign application (Application No. 201910004596.5 or 201910069838.9) or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
Paragraph [0027] of the instant published disclosure states:
[0027] 1.2 Reference document is Structure of the African swine fever virus major capsid protein written by Liu Q, Ma B, Qian N, et al., p72. Cell Res. 2019; 29 (11): 953-955. Or other protein expression modes (such as the eukaryotic expression system, the insect baculovirus expression system, the CHO cell expression system, etc). Or the preparation method of African swine fever virus subunit protein p72 of other patents or documents. The content of the trimer reaches more than 40%.
It is not evident how the content of the trimer reaches more than 40%, as recited in instant claims 2 and 12. In the first paragraph, Liu et al. (Cell Res. 2019; 29 (11): 953-955) teach the “major capsid protein (MCP) p72 is the most dominant structural component of the virion and constitutes about ~31%–33% of the total mass of the virion.” There is no teaching in the instant disclosure or the prior art for achieving a “content of the trimeric protein is not less than 40% of the total amount of the exterior envelope subunit protein p72 derived from African swine fever virus”, as claimed. It is presumed this limitation means that trimeric p72 is not less than 40% of the total content of the instant composition. Though, the phrase may mean that 40% of the total p72 is in trimeric form. This limitation recited in claims 2 and 12 is unclear. Step 2 of claim 12, requires mixing p72 and CD2v to achieve a mass ratio of 1-8:8-1, which encompasses quantities of trimeric p72 less than 40% of the content, i.e., final volume, seemingly required in step 1, depending on the ratio chosen from the recited range. It is not clear how much of which protein is required.
Paragraph [0027] further describes peaks depicted in Figure 1. Peak 4 is attributed to the p72 protein trimer because its molecular weight is between 158 kDa and 440 kDa. However, there is no data provided for p72 trimer configuration. Cui et al. supra teach SDS-PAGE analysis under non-reducing conditions revealed a band approximately 240 kDa (Fig. 1G), trimer formation. The range in molecular weight between 158 kDa and 440 kDa, attributed to Peak 4 in paragraph [0027] does not possess specificity for identifying the trimeric form of p72.
The skilled artisan would not predict a formulation comprising glycosylated CD2v expressed in a eukaryotic system, a trimeric p72, and pharmaceutically acceptable adjuvant would be effective as an ASFV vaccine, as asserted by claims 1-15.
Because the instant CD2v protein is glycosylated and expressed in a eukaryotic system, viral vectored-derived proteins combined in a cocktail formulation appear to be within the scope of the instant claims. Lopera-Madrid et al. (Veterinary Immunology and Immunopathology. 2017; 185: 20-33) teach priming with (eukaryotic) human embryonic kidney 293 (HEK)-purified antigens: p72, p54, and p12 and boosting with three MVA-vectored antigens: p72, EP153R, and CD2v in the abstract, section 2.6. Therefore, the formulation of Lopera-Madrid et al. exposes pigs to more p72 than any other antigen in the formulation, similar to the “content of the trimeric protein is not less than 40% of the total amount of the exterior envelope subunit protein p72 derived from African swine fever virus”, instantly claimed. However pigs that were administered MVA-ASFV construct cocktails failed to generate detectable ASFV antibody responses, but T-cell proliferative and IFN-γ T-cell responses were detected following HEK-ASFV antigen boost. While the cytotoxic immune response taught by Lopera-Madrid et al. is encouraging, immune determinants for ASFV protection have not been elucidated, see section 4 of Gaudreault et al. (Vaccines. 2019 Jun 25; 7 (2): 56).
In section 3.1, Gaudreault et al. teach CD2v is not a strong immunogenic antigen, and high doses of the protein would likely be required to induce good protection. It is unclear whether the quantity ranges recited in instant claims 4-6, 12, and 13 would be sufficient. In Table 1, Gaudreault et al. teach baculovirus-expressed proteins, including p72, combined with Freund’s adjuvant resulted in a slight delay of clinical disease and viremia, but no protection.
Neilan et al. (Virology. 2004; 319: 337– 342) teach neutralizing antibodies to ASFV p72 does not provide protection.
Cadenas-Fernández et al. (Pathogens. 2020 Feb 28; 9 (3): 171) teach an adenovirus-vectored ASFV cocktail of thirty-five ASFV antigens, including p72 and a modified CD2v (EP402R∆PRR), failed to elicit protective efficacy, required of a vaccine, see the abstract, sections 2.2, 3.2, and 3.3.
Lokhandwala et al. (Veterinary Microbiology. 2019; 235: 10-20) teach a nine-ASFV-antigen cocktail including p72 and a modified CD2v antigen, EP402RΔPRR administered prior to challenge, see section 2.4.2. When Lokhandwala et al. formulated the cocktail in BioMize adjuvant, strong IgG responses were induced, but when challenged, the vaccinees had more severe reaction relative to the controls. In the abstract, Lokhandwala et al. teach a “seven antigen cocktail-(II) was evaluated using two adjuvants: BioMize and ZTS-01. The BioMize formulation induced stronger antibody responses, but 8/10 vaccinees and 4/5 controls succumbed to the disease or reached experimental endpoint at 17 days post-challenge. In contrast, the ZTS-01 formulation induced weaker antibody responses, but 4/9 pigs succumbed to the disease while the 5 survivors exhibited low clinical scores and no viremia at 17 days post-challenge, whereas 4/5 controls succumbed to the disease or reached experimental endpoint. Overall, none
of the immunogens conferred statistically significant protection.” See sections 3.2 and 3.3. Therefore, the skilled artisan would not conclude that any adjuvant, encompassed by instant claims 1-7, 9-11, and 15, would be efficacious. Above “Author contributions”, Lokhandwala et al. conclude “evidence of disease enhancement in vaccinees was observed with both Ad-ASFV cocktail-I and cocktail-II when formulated with the BioMize adjuvant, but not with cocktail-II when formulated with the ZTS-01 adjuvant. The cocktail-II-ZTS vaccinees had better survival rate, but clinical disease was not prevented”.
Regarding the requisite adjuvant recited in claims 8 and 12, section 3.2.1 of Wu et al. (Pathogens. 2024; 13: 706) teach a recombinant adenovirus mixture containing 42 multiepitope ASFV 42 antigens combined with Montanide ISA-201™ adjuvant induced a humoral immune response, but no protective effect was observed after challenge. Another study combined an inactivated ASFV by gamma-irradiation combined with Montanide™ ISA 201 VG adjuvant. While all animals developed antibodies against ASFV p72, the immune response was insufficient to confer protection from ASFV strain attacks.
The state of the art indicates that African swine fever (ASF) is a viral disease of domestic and wild swine for which there is currently no vaccine or treatment available. 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.
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