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 .
Priority
The instant application is a national stage entry under 35 U.S.C. § 371 of PCT/JP2022/017328 (filed 04/08/2022). Acknowledgement is made of Applicants’ claim for priority to Japanese Application No. JP2021-066427 (filed 04/09/2021).
Response to Amendment
The amendment filed on 07/17/2026 has been received and entered into the application file.
Claims 1-2, 7-12, 14-15, and 19 are cancelled; new claims 20-29 have been added.
Claims 3-6, 13, 16-18, and 20-29 are pending in the instant application and examined on the merits herein.
Status of Prior Rejections/Response to Arguments
RE: Rejection of:
claims 1, 3, 6-7, 9, 11, 13, and 17 under 35 U.S.C. 102(a)(1) over Mu;
claim 5 under 35 U.S.C. 103 over Mu; and
claims 4 and 15 under 35 U.S.C. 103 over Mu in view of Kang, further in view of Salmon Facts:
The cancellation of claims 1, 7, 9, 11, and 15 renders the rejections thereof moot.
Claim 3 has been amended to recite the antigen protein as a porcine parvovirus antigen protein or a norovirus antigen protein; this is effective to obviate the rejections of record for claims 3-6, 13, 15, and 17.
Accordingly, the remaining rejections of record are withdrawn.
RE: Rejection of:
claims 2, 8, 10, 12, 14, and 18-19 under 35 U.S.C. 103 over Gallei in view of Cardosa; and
claim 16 under 35 U.S.C. 103 over Gallei in view of Cardosa, further in view of Murwitz:
The cancellation of claims 2, 8, 10, 12, 14, and 19 renders the rejections thereof moot.
Applicants assert the combination of the Gallei and Cardosa references do not teach all the features of amended claim 3; however, the Gallei reference does disclose an embodiment wherein the antigenic epitope of interest is porcine parvovirus (par. 0038). Thus, respectfully, this argument is not found persuasive.
Applicants further assert the Examples of the present application demonstrate excellent and unexpected results in terms of specific antibody production (bottom of pg. 3 of “Remarks”). However, a showing of unexpected results must be based on evidence, not argument or speculation; see In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed Cir. 1997) and MPEP 2145. Indeed, the evidence relied upon “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.”; see e.g. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992), MPEP 716.02(b).
The Examiner notes the Examples of the instant specification disclose the IgG and IgA response of mice fed baculovirus-infected pupae were analyzed via IgG and IgA levels in the intestinal lavage fluid (ILF) and serum from the mice after 22 days of being fed baculovirus-infected pupae (Example 2; pg. 16). For porcine parvovirus (PPV), IgG and IgA antibody production was observed in serum, but not ILF (Fig. 3). For norovirus (NV), high levels of IgG and IgA antibody production were observed in both serum and ILF; compared with injectable vaccine, antibody production was observed at a level comparable to that of the injectable vaccine without the combined administration of an adjuvant (par. 0064; Fig. 4). However, Fig. 4 shows a naïve (control) group, and two experimental groups: mice fed 2x/week, and mice fed 5x/week; for the IgG and IgA response (for both serum and ILF), it appears the 2x/week group have a response comparable to the naïve group. It also appears the IgG response of the injectable vaccine group is more than two-fold compared to the same in the ILF of the 5x/week group, and a stronger response as compared to the serum of the 5x/week group.
Therefore, respectfully, absent a clearer explanation of why these results are unexpected, unobvious, and of statistical and practical significance, the allegations of unexpected results are found unpersuasive in regards to the remaining rejections of record.
Accordingly, the rejections are modified as necessitated by amendment and set forth below.
RE: Provisional rejection on the ground of nonstatutory double patenting of:
claims 1-5, 7-15, and 17-19 over copending Application No. 18/870,285; and
claims 6 and 16 over copending Application No. 18/870,285 in view of Murwitz:
The cancellation of claims 1-2, 7-12, 14-15, and 19 renders the rejections thereof moot.
Claim 3 has been amended to recite the antigen protein as a porcine parvovirus antigen protein or a norovirus antigen protein; this is effective to obviate the rejections of record for claims 3-6, 13, and 16-18.
Accordingly, the remaining rejections of record are withdrawn.
Claim Objections
Applicant is advised that should claim 6 be found allowable, claim 16 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof; likewise, should claims 17 or 18 be found allowable, claims 20 or 21 will be objected to, respectively, as being a substantial duplicate thereof.
When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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.
Claims 3-4, 13, 18, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Gallei, et al. (US 2018/0080045) in view of Cardosa, et al. (US 2015/0056244).
Gallei, et al. (hereinafter Gallei) teaches recombinant canine adenoviruses, methods of making them, and uses for them, including vaccine compositions (Abstract).
Cardosa, et al. (hereinafter Cardosa) teaches materials and methods for producing immunologically active antigens (Abstract).
Regarding claims 3, 13, 18, 21: Gallei teaches a method of producing a vaccine composition comprising a recombinant vector, wherein the method comprises introducing the vector into a host cell, cultivating the infected cells, harvesting the infected cells, and admixing said harvest with a pharmaceutically acceptable carrier (par. 0042), wherein the vector comprises a heterologous DNA encoding an antigenic epitope (pars. 0034-0035); additionally disclosed is an embodiment wherein the composition is lyophilized (par. 0141). In an embodiment, the antigenic epitope of interest is porcine parvovirus (par. 0038). Gallei teaches an embodiment wherein the host cell is an Sf9 or Sf21 cell, i.e., cells derived from Spodoptera frugiperda (par. 0054). Lastly, Gallei teaches a method of immunizing an animal comprising administering the vaccine to induce an immune response (par. 0048), wherein the vaccine may be administered orally (par. 0041).
Gallei does not teach the vector as a recombinant baculovirus vector, teaching the vector as a recombinant canine adenovirus vector instead (par. 0042).
However, Cardosa teaches baculoviruses as suitable recombinant viruses for the transfection of host cells such as Sf9 cells (par. 0154).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Gallei by substituting the recombinant adenovirus for a recombinant baculovirus, as taught by Cardosa. This conclusion of obviousness is based on the ‘substitution rationale’. The use of a recombinant baculovirus in place of a recombinant adenovirus is a predictable use of prior art elements according to their established functions as viral vectors, leading to the predictable result of delivery of genetic material into a host cell. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results; see MPEP 2143(I)(B). Further, as Cardosa. teaches the use of recombinant baculoviruses to transfect the same cell type used in the method of Gallei, one skilled in the art would have more than a reasonable expectation of success.
Thus, the modified method of Gallei set forth above renders obvious:
the oral vaccine composition, comprising baculovirus-infected cells that have been free-dried, wherein the baculovirus comprises DNA encoding a porcine parvovirus antigen protein limitations recited in claim 3;
the method of inducing immunity to an antigenic protein in a subject by administering the oral vaccine composition according to claim 3 limitation recited in claim 13;
the which comprises said baculovirus-infected cells and wherein the cells are from Spodoptera frugiperda limitation recited in claim 18; and
the which comprises said baculovirus-infected cells limitation recited in claim 21.
Regarding claim 4: Following the above discussion, Gallei teaches an embodiment wherein the composition further comprises a solution comprising an adjuvant (pars. 0140-0142); this renders obvious the further comprising a solution containing an adjuvant limitation recited in claim 4.
Claims 3-6, 13, 16-18, 20-26, 28 are rejected under 35 U.S.C. 103 as being unpatentable over Sebastian, et al. (US 2015/0307899) in view of Rosales-Mendoza, et al. (Trends Biotechnol. 2016) and Feng, et al. (PLoS ONE. 2014).
Sebastian, et al. (hereinafter Sebastian) teaches the improved production of recombinant proteins in insect cells or insect larvae as biofactories by a novel expression cassette (Abstract).
Rosales-Mendoza, et al. (hereinafter Rosales-Mendoza) teaches the use of food-grade organisms as recombinant vaccine expression hosts and delivery vehicles (Abstract).
Feng, et al. (hereinafter Feng) teaches the oral administration of raw homogenates containing canine parvovirus virus-like particles to dogs results in a systemic immune response (Abstract).
Regarding claims 3, 13, 17, 20, 22-26, 28: Sebastian teaches the production of recombinant proteins using insect larvae as biofactories (par. 0001), wherein the recombinant protein is a vaccine protein (see e.g., par. 0172) used for vaccination (par. 0261); in an embodiment, the insect is a baculovirus-infected Bombyx mori pupa comprising an expression cassette (pars. 0248-0252). In embodiments, the expression cassette comprises DNA (par. 0120) encoding porcine parvovirus VP1 and VP2, and human norovirus capsid protein (par. 0131).
Sebastian is silent in regards to the route of administration.
However, Rosales-Mendoza teaches food-grade organisms, or food-grade vaccines (FGVs), can serve at the same time as biofactory and oral delivery for vaccines, avoiding costly purification processes; FGVs generate low-cost and easy to administer vaccines with the potential to facilitate universal coverage (pg. 125; par. 1). Rosales-Mendoza further teaches that not only do silkworm expression systems offer advantages such as high protein expression levels, low cost, and the capacity to produce large and multiple proteins in addition to performing co-translational and post-translational modifications, but the proteins produced thereby for oral consumption are stable in the stomach and intestines due to the presence of protease inhibitors and biocapsule-like fat in silkworms (pg. 130; par. 1). These silkworm-based oral vaccines are capable of inducing strong immunoprotective responses (pg. 130; par. 1).
Feng teaches silkworm pupae were infected with a recombinant baculovirus comprising DNA encoding canine parvovirus (CPV) VP2 protein, harvested 5 days post-infection and homogenized prior to administration to dogs via the oral route (pg. 2; cols. 1-2). Serum samples were collected from the dogs and subjected to the hemagglutination inhibition (HI) test to determine the antibody titer against CPV; HI titers gradually increased from the second week after vaccination, and all dogs orally immunized with VLPs developed serum IgG anti-CPV antibodies (pg. 4; col. 1, par. 1). Even without an adjuvant, all dogs developed a system immune response against the VLPs, demonstrating the VLPs are immunogenic when presented to the gut mucosal immune system (pg. 5; col. 2, par. 1).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have orally administered the B. mori pupae vaccine composition of Sebastian. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so for the benefits disclosed by Rosales-Mendoza; e.g., low-cost, easy administration, high protein expression, stability of the proteins in the stomach and intestines (pgs. 125, 130). Further, as Feng teaches baculovirus-infected silkworm pupae orally administered to dogs and effective to induce immunogenicity against CPV, the skilled artisan would have more than a reasonable expectation of success. This renders obvious:
the oral vaccine composition, comprising baculovirus-infected insect pupae, wherein the baculovirus comprises DNA encoding a porcine parvovirus antigen protein or a norovirus antigen protein limitations recited in claim 3;
the method of inducing immunity to an antigenic protein in a subject by administering the oral vaccine composition according to claim 3 limitation recited in claim 13;
the which comprises said baculovirus-infected insect pupae and wherein the insect is Bombyx mori limitation recited in claim 17;
the which comprises said baculovirus-infected insect pupae limitation recited in claim 20;
the wherein the baculovirus comprises DNA encoding a porcine parvovirus antigen protein limitation recited in claims 22 and 24;
the wherein the baculovirus comprises DNA encoding a norovirus antigen protein limitation recited in claims 23 and 25;
the wherein said porcine parvovirus antigen protein is VP2 of porcine parvovirus limitation recited in claim 26; and
the method of inducing immunity to an antigenic protein in a mammalian subject by administering the oral vaccine composition according to claim 26 to the subject limitation recited in claim 28.
Regarding claim 4: Following the above discussion, Rosales-Mendoza teaches the use of adjuvants can be applied to overcome tolerance and to improve the immunoprotective efficacy of oral vaccines (pg. 132; par. 5). Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the B. mori pupae vaccine composition of Sebastian by including a solution containing an adjuvant, as taught by Rosales-Mendoza. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so for overcoming any tolerance and improving the immunoprotective efficacy of oral vaccines (Rosales-Mendoza; pg. 132); further, as evidenced by the same, inclusion of an adjuvant in vaccine compositions is a well-known technique in the art. Thus, the skilled artisan would have more than a reasonable expectation of success. This renders obvious the further comprising a solution containing an adjuvant limitation recited in claim 4.
Regarding claim 5: Following the above discussion, Sebastian does not teach the limitation recited in the instant claim.
However, Rosales-Mendoza teaches immune tolerance is important for preventing allergic and autoimmune diseases or allograft rejection, but factors inducing tolerance (i.e., dose and frequency of administration) are also crucial for immunization; there’s a required balance between immunogenicity and tolerance (pg. 131; par. 7). To evoke antigen-specific mucosal immune responses, the ingested antigens that reach the mucosal surfaces must be transported across the epithelium into the mucosa-associated lymphoid tissue; oral tolerance is mediated by two main mechanisms depending on the dose and frequency of antigen administration (pg. 131; par. 8). High doses of antigen may induce clonal deletion and/or anergy of lymphocyte T cells associated with suppression of type 1 T helper (Th1) and Th2 responses, while repeated administration of low doses of antigen may induce active suppression characterized by the generation of regulatory T cells and a shift toward a Th2/Th3 response (pgs. 131-132). Thus, Rosales-Mendoza teaches the dose of oral vaccine should be optimized in order to achieve an effective immune response; i.e., dose is a result effective variable.
Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art. Furthermore, differences in dosage will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such a dose is critical. See MPEP 2144.05(II)(A). This renders obvious the wherein the pupa is contained in an amount of at least 20% by weight based on the total weight of the composition limitation recited in claim 5.
Regarding claims 6, 16: Following the above discussion, Rosales-Mendoza evidences silkworm pupae are a source of high-quality proteins and lipids, and are consumed as a food source in many countries (pg. 129; par. 1); thus, the modified B. mori pupae vaccine composition of Sebastian renders obvious the functional food limitation recited in claims 6 and 16.
Regarding claims 18, 21: Following the above discussion, Sebastian teaches an embodiment wherein insect cells are used as the biofactories for the production of the recombinant proteins (par. 0001); e.g., cells derived from Trichoplusia ni, Spodoptera frugiperda, Bombyx mori (par. 0247). This renders obvious the which comprises said baculovirus-infected cells limitation recited in claims 18 and 21, as well as the wherein the cells are from Bombyx mori, Spodoptera frugiperda, or Trichoplusia ni limitation recited in claim 18.
Claims 27 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Sebastian, et al. (US 2015/0307899) in view of Rosales-Mendoza, et al. (Trends Biotechnol. 2016) and Feng, et al. (PLoS ONE. 2014), further in view of Campillay-Véliz, et al. (Front Immunol. 2020).
The teachings of Sebastian, Rosales-Mendoza, and Feng are set forth above.
Campillay-Véliz, et al. (hereinafter Campillay-Véliz) teaches the functions of both structural and non-structural proteins of human norovirus (Abstract).
Regarding claims 27, 29: Following the above discussion, Sebastian does not specifically teach the human norovirus capsid protein as VP1 (par. 0131).
However, Campillay-Véliz teaches the recognition and bindings of human noroviruses (HuNoVs) to histo-blood group antigens (HBGAs) is the primordial step that precedes entry of the viral particle into the cell; in HuNoV, the HGBA binding sites are specifically located in the P2 subdomain of the P domain of VP1 (pg. 7; col. 1, par. 2).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the B. mori pupae vaccine composition of Sebastian by encoding the VP1 protein as the human norovirus capsid protein. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so because Campillay-Véliz teaches HuNoVs binding to the HGBA binding sites located in VP1 is the primordial step preceding viral entry into the cell (pg. 7); thus, it would have been obvious to the skilled artisan to target VP1 in order to prevent entry of the virus into the cell. Further, as evidenced by Sebastian, encoding specific capsid proteins (e.g., porcine parvovirus VP1 and VP2; par. 0131) is well within the purview of the skilled artisan; thus, one would have more than a reasonable expectation of success. This renders obvious:
the wherein said norovirus antigen protein is VP1 protein of norovirus limitation recited in claim 27; and
the method of inducing immunity to an antigenic protein in a mammalian subject by administering the oral vaccine composition according to claim 27 to the subject limitation recited in claim 29.
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 GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at (571)272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
