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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/15/2026 has been entered.
Claims 1, 2, 4-15 and 17-20 are pending and are examined on the merits. No claims are allowed.
Information Disclosure Statement
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.
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.
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.
(Prior Rejection Maintained) Claim(s) 1, 2, 4-15 and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Dhakal et al. (Frontiers in Immunology, 2018, Vol. 9, Article 934) and Jiang et al. (Biomaterials, 2008, Vol. 29, pages 1931-1939).
Dhakal et al. teach the formulation of a mucoadhesive chitosan nanoparticles, which encapsulates inactivated (killed) antigens from a swine influenza virus. [see abstract and page 3] The swine influenza virus that provided the inactivated antigens is A/Swine/OH/FAH10-1/10 (H1N2) and Dhakal et al. refer to this nanoparticle composition as CNPs-KAg. [see first section of Materials and Methods] The nanoparticles encapsulated 67% of the influenza antigens and the formulation of these encapsulated antigens also included the addition of tripolyphosphate. [see left hand column of page 6 and left column of page 3] Following the formulation of the nanoparticle composition, Dhakal et al. teach the intranasal administration to piglets at a dosage of 10^7 TCID50 equivalent of inactivated antigen. [see Experimental Design section] The chitosan particles with killed influenza antigen containing nanoparticles are structurally the same as those of applicant’s invention and had a diameter of about 500 nm. [see right column of page 11] The encapsulation rate is higher than applicant’s minimum amount of at least 60% and since the antigen is from an H1N2 virus, it is heterologous to other influenza viruses, such as H3N2. Dhakal et al. report increased IgA levels in piglets following vaccination [see figures 3 and 5] reduced viral levels in the lungs of piglets [see Figure 8]. The administration of these nanoparticles to the piglets involved formulating the nanoparticles in a pharmaceutically acceptable carrier and therefore meets the requirements of a vaccine. The administration of these nanoparticles to piglets achieved reducing transmission of influenza A and eliciting an immune response since Dhakal et al. teach administering the same composition presently claimed to pigs intranasally and immune responses were observed.
However, Dhakal et al. do not teach the use of mannose conjugated to chitosan.
Jiang et al. teach chitosan nanoparticles with conjugated mannose to encapsulate killed antigens of bacteria. They also teach that mannose can facilitate macrophage uptake. [see page 1-introduction] Jiang et al. teach that incorporating mannose improves delivery of the antigen to mice intranasally. [see section 2.4.1] Mice receiving the mannose chitosan containing killed antigen exhibited a survival rate of 70%. [see section 3.3.3]
It would have been obvious to one of ordinary skill in the art to modify the compositions and methods taught by Dhakal et al. in order to employ mannose conjugated to the chitosan nanoparticles. One would have been motivated to do so, given the suggestion by Dhakal et al. chitosan nanoparticles can facilitate delivery of inactivated influenza antigens and achieve immune responses capable of reducing influenza infections. There would have been a reasonable expectation of success, given the knowledge that including mannose conjugated to chitosan particles with encapsulated killed bacterial antigens improved immune responses through macrophage targeted uptake, as taught by Jiang et al. Furthermore, the claim limitations of: reduces transmission of influenza A virus, reduces the nasal shedding of influenza A virus, reduces the amount of influenza A virus in the upper respiratory tract of a subject by at least 1x10^1TCID50/mL compared to a control, reduces the amount of the influenza virus within 4 days of exposure to the influenza A virus, and an increased amount of IgA antibody in respiratory tract of the subject compared to a control is also elicited, are obvious features of the nanoparticles one of ordinary skill in the art would arrive at based on the teachings of Dhakal et al. and Jiang et al.
Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to arguments:
Applicant presents the following arguments in traversal of the rejection:
Applicants argue that administering their mannose-conjugated chitosan nanoparticle-based influenza vaccine (mCS NPs-KAg) intranasally has an unexpected superior effect on innate and adaptive immune responses. Applicants point to Figures 5A-5D and 7C and 7D (see below with description of this figure) that shows higher levels of IL-4 and IFNy expression in pigs that received a vaccine comprising mannose-conjugated chitosan nanoparticles with inactivated influenza virus of a H1N2 serotype (Group 5 in Figure 5), compared to chitosan nanoparticles with inactivated influenza virus of a H1N2 serotype (Group 4 in Figure 5). As summarized above and discussed by applicant, Group 4 is the same composition taught by Dhakal et al.
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Figure 5A establishes that lymphocyte proliferation stimulation is either statistically the similar between Groups 4 and 5 or Group 4 is slightly higher than Group 5. Additionally, Figure 5D shows IFNy mRNA from Groups 4 and 5 being statistically similar. Group 5 did result in a higher IL-4 and IL-10 mRNA presence in vaccinated pigs compared to Group 4. Therefore, Group 5 resulted in potentially higher T-helper cell type 2 (Th2) immune response. Figure 7C shows that Group 5 resulted in higher IFNy CTL responses and Figure 7D shows that Groups 4 and 5 are statistically similar with regard to IFNy T-helper/memory cell responses. Of note, the overall lymphocyte stimulation (Figure 5A) was higher for Group 4 and the IFNy mRNA levels were statistically similar (Figure 5D) between Groups 4 and 5.
However, as stated above, Jiang et al. teach that including mannose can improve antigen delivery when intranasal administration is employed. Therefore the teachings of Dhakal et la. in view of the Jiang et al. renders obvious the claimed compositions and methods. Furthermore, while Group 5 did result in a higher T-helper cell related cytokine mRNA levels and T-helper/memory cell responses compared to Group 4, applicant’s argument that the claimed invention achieved unexpected superior results is not convincing. As stated in the last Office action, the claimed invention at least does not specify what the influenza A antigen is, other than it being from an H1N1, H1N2 or H3N2 virus and it is inactivated, while applicant’s working example (see page 34 of specification) involves inactivated influenza virus of a specific H1N2 serotype. This specific inactivated antigen is what was employed in Groups 4 and 5. In addition, with regard to the other adaptive immune responses monitored by applicant a summary of the IgA and IgG responses to vaccines is provided in Figure 1, which shows similar cross-reactive IgA antibodies for H1N1-OH7 (panel B) and different cross-reactive IgA antibody titers relative to H3N2-OH4 (panel C). However, for cross-reactive IgG antibodies, whether mannose was included or not, the nanoparticle did not exhibit different antibody responses (see panels D-F). Therefore, applicant’s arguments related to unexpected results is not persuasive.
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Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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