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
Applicant’s amendment submitted on 5/4/2026 is acknowledged.
The indicated allowability of claims 1-7 is withdrawn in view of the newly discovered reference(s) to Meyer, et al. (Comp. Immun. Microbiol. Infect. Dis. 31 2008. 191–225) in view of Schlender (J. Virol. Sept. 2000, pp. 8234-8242, Vol 74, No. 18), Alkheraif, et al. (Virology 507 (2017) 123–134), Hatesuer (J Innate Immun 2017;9:145–161), Crawford (WO 2006116082 A1, published 11/2/2006), and Drew, et al. (PGPub US 20130129685 A1, published 5/23/2013). Rejections based on the newly cited reference(s) follow.
Amended Claims 1-7, 10, and 12-14 are under examination on the merits.
Claim Interpretation
The examiner is interpreting claim 2 require that at least one of IRF3 and IRF7 are knocked out, and both are functionally inactivated. The claims encompass both IRF3 and IRF7 being knocked out, but it is not required.
Objections and Rejections Withdrawn
The previous objections and rejections are hereby withdrawn due to Applicant’s amendment submitted 5/4/2026:
Specification: the objection to the specification.
35 U.S.C. §112(a): claims 10 and 12-13 for scope of enablement.
35 U.S.C. §112(b): claim 12 for indefiniteness.
New Objections
Claim 10 is objected to because of the following informalities: claim 10, on line 1, recites “a MDBK cell”, but should instead read “an MDBK cell”. Appropriate correction is required.
New Rejections
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 7 and 12-14 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.
Claim 7 recites “a cell culture comprising the MDBK cell of claim 1” on line 1. The specification indicates that “cell culture” encompasses the maintenance and/or propagation of cells and could be in vitro or ex vivo (p. 8). Thus, claim 7 reads on, in addition to a physical cell culture, a method of use, but does not include the requisite active steps. Essentially, claim 7 can interpreted as a method without a method step.
Claim 12 recites “the pharmaceutically acceptable carrier comprises a natural deep-eutectic solvent (NADES) having a water activity of less than 0.8” on lines 1-3. The specification indicates that “water activity is commonly measured by comparing (at the same temperature) the vapor pressure of a test composition, relative to that of pure water and to a number of saturated salt-solutions of known water activity (pp. 12-13).
“A claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite.” See, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008). MPEP §2173.05(b).
Applicant has provided multiple definitions, and thus there are multiple interpretations of “water activity”. Specifically, it is unclear regarding which salt is saturated, or pure water. The claims require a water activity of less than 0.8, but it is not clear how that is achieved.
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.
Claims 1-7, 10, and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Meyer, et al. (Comp. Immun. Microbiol. Infect. Dis. 31 2008. 191–225) in view of Schlender (J. Virol. Sept. 2000, pp. 8234-8242, Vol 74, No. 18), Alkheraif, et al. (Virology 507 (2017) 123–134), Hatesuer (J Innate Immun 2017;9:145–161), Crawford (WO 2006116082 A1, published 11/2/2006), and Drew, et al. (PGPub US 20130129685 A1, published 5/23/2013).
The Prior Art
Meyer teaches that bovine respiratory syncytial virus (BRSV) is the most important causative agent of respiratory tract infections of calves (Abstract). Meyer further discloses that BRSV vaccines have been available since the 1970s, and live attenuated vaccines are obtained by serial passage of the virus in cell culture (p. 205, para. 1). Additionally, Meyer teaches that BRSV is a member of the genus Pneumovirus in the family Paramyxoviridae, and that the virion is wrapped into a lipid envelope derived from the host plasma membrane (p. 193, para. 3).
However, Meyer does not teach a recombinant MDBK cell characterized in that the cell is genetically engineered by which the IRF3 and/or IRF7 encoding genes are functionally inactivated by knockout of said IRF3 and/or IRF7 genes.
Schlender teaches that recombinant BRSV carrying single and double gene deletions in BRSV NS1 and NS2 protein encoding genes exhibit a 5,000-10,000-fold reduction in MDBK cells, which is due to type I interferon secretion by the infected MDBK cells, as demonstrated by supernatant from MDBK-infected cells conferring resistance to NS1 and/or NS2 deletion mutant replication in Vero cells that is rescued by exogenous IFNAR2 monoclonal antibody neutralization of the inhibitory effect produced by BRSV-infected MDBK cells (Figs. 1 and 3-5; Abstract). Schlender also discloses that wild-type BRSV replicates to ~108 infectious virus particles/ml by 6 days post-infection of MDBK cells (Fig. 3).
Alkheraif teaches that BRSV-infected cells expressed significantly up-regulated IRF3 and IRF7 (Abstract). Alkheraif further discloses that BRSV titer and RNA levels significantly increased in cells co-infected with BRSV and bovine viral diarrhea virus (BVDV), which also abolished up-regulation of IRF3 and IRF7 in infected cells (Figs. 5 & 6; Abstract).
Accordingly, it would have been obvious to one of ordinary skill in the art to suppress IRF3 and/or IRF7 activity to increase BRSV viral yield, for applications including vaccines.
Hatesuer discloses that the IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and other IFN genes (Abstract), and generated irf3/irf7 double knockout mice to investigate the roles of IRF3 and IRF7 in for the host defense to influenza A virus infection (p. 146, col. 1, paras. 1-3).
Accordingly, it would have been obvious to one of ordinary skill in the art that genetic knockout of IRF3 and/or IRF7 is a method to suppress IRF3 and/or IRF7 activity to increase BRSV viral yield, for applications including vaccines.
It would have been obvious to one of ordinary skill in the art to modify the BRSV vaccines taught by Meyer to be propagated in MDBK cells because Schlender discloses that MDBK cells are permissive for growing BRSV. It would have been further obvious to inactivate IRF3 and IRF7 in the MDBK cells, because Alkheraif teaches that BRSV-infected cells induced IRF3 and IRF7, and BRSV titer and RNA levels significantly increased in cells where IRF3 and IRF7 induction was abolished. It also would have been obvious to one of ordinary skill in the art to knockout IRF3 and IRF7-encoding genes, as was known in the art, as demonstrated by Hatesuer generating an irf3/irf7 double knockout mouse. One of ordinary skill in the art would have been motivated to increase BRSV titer for applications such as vaccines.
Regarding claim 4, which requires the virus is an enveloped virus, BRSV is an enveloped virus, as taught by Meyer.
Although claim 7 is indefinite for the reasons described above in the rejection under 35 U.S.C. §112(b), one interpretation of the claim is that it is a composition, which is also rendered obvious by the claimed references because BRSV is propagated in cultures of MDBK cells in Meyer. There would be a reasonable expectation of success because BRSV vaccines have been available for decades, MDBK cells are permissive to BRSV infection, suppression of IRF3 and IRF7 activity was associated with higher BRSV titer and RNA levels in infected cells, and double knockout of IRF3 and IRF7 encoding genes was known in the art. Therefore, claims 1-7 were prima facie obvious before the priority date of the instant invention.
However, Meyer, Schlender, Alkheraif, and Hatesuer fail to teach a vaccine composition comprising an MDBK cell that is genetically engineered by which the IRF3 and/or IRF7 encoding genes are functionally inactivated by knockout of said IRF3 and/or IRF7 genes, and a pharmaceutically acceptable carrier, wherein the MDBK cell is infected with BRSV.
Crawford teaches compositions and methods for inducing an immune response against an influenza virus (Abstract), wherein the vaccine or immunogenic compositions may comprise virus-infected cells or virus-infected cell lines (p. 21, lines 9-14; claim 22). Crawford also teaches that its vaccine compositions and immunogens can be provided with a pharmaceutically-acceptable carrier or diluent (p. 22, lines 3-5).
It would have been obvious to one of ordinary skill in the art to modify the vaccines rendered obvious by Meyer, Schlender, Alkheraif, and Hatesuer to comprise the BRSV-infected irf3 and/or irf7 knockout MDBK cell, along with a pharmaceutically acceptable carrier or diluent. One of ordinary skill in the art would have been motivated to vaccinate against BRSV.. There would be a reasonable expectation of success because vaccines against other viruses, such as influenza A virus, are known to be formulated in such a manner as virus-infected cells or cell lines. Therefore, claims 1-7 and 10 were prima facie obvious before the priority date of the instant invention.
However, Meyer, Schlender, Alkheraif, Hatesuer, and Crawford fail to teach a vaccine characterized in that the pharmaceutically acceptable carrier comprises a natural deep-eutectic solvent (NADES) having a water activity of less than 0.8.
Drew teaches methods for preserving viral particles, and teaches aqueous vaccine solutions of virus particles comprising a preservation mixture comprising N,N,N-trimethylglycine (also known in the art as betaine), and sucrose (claims 1, 3, 16, 24, and 28; paras. [0173-0175]). These ingredients correlate to the instant organic salt and polyol components of the natural deep-eutectic solvent (NADES), as the instant specification indicates that the NADES consists of an organic salt, such as betaine, and a sugar, such as sucrose (spec., p. 13). Additionally, Drew teaches admixing virus particles with the preservation mixture (paras. [0130] & [0175]), and also discloses methods of vaccinating a subject against a viral pathogen by administering the liquid composition comprising the preservation mixture (paras. [0182] & [0198-0200]). Drew also teaches that a wide variety of particles may be preserved in its compositions as vaccines, which may be used to prevent or treat infection by veterinary viruses such as bovine viral diarrhea virus (BVDV; para. [0174]). The viral particles disclosed by Drew may be live viruses or live attenuated viruses (para. [0088]).
It would have been obvious to one of ordinary skill in the art to modify the vaccine compositions rendered obvious by Meyer, Schlender, Alkheraif, Hatesuer, and Crawford to incorporate use of pharmaceutically acceptable carrier that comprises a natural deep-eutectic solvent (NADES) having a water activity of less than 0.8, such as that disclosed by Drew. Regarding claims 13 and 14, it would have been obvious that the BRSV virus could be a live virus or a live attenuated virus, because Crawford discloses vaccines comprising virus-infected cells and Drew discloses that viruses preserved in its solutions can be live viruses or live attenuated viruses. One of ordinary skill in the art would have been motivated to preserve BRSV particles. There would be a reasonable expectation of success because Drew discloses that vaccines may be formulated with its compositions, and that a wide variety of particles may be preserved in its compositions. Therefore, claims 1-7, 10, and 12-14 were prima facie obvious before the priority date of the instant invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is (571)272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
