DETAILED ACTION
Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of Group I: claims 1-7, 15-19, 21, 23-27, 43 and 46 in the reply filed on 03/10/2025 is acknowledged. Group II: claims 47-49 and Group III: claims 50-52 are withdrawn in response to restriction/election office action dated 01/10/2025.
Status of Claims
3. Claims 1-6, 15-19, 21, 23-27, 43, 46, 47-52 as amended/filed on 09/16/2025 are pending
4. Claims 47-52 are withdrawn from consideration due to restriction/election.
5. Claims 7, 8-14, 20, 22, 28-42, 44-45, 53-59 are cancelled by the applicant in the amended filing on 09/16/2025.
6. Claims 1-6, 15-19, 21, 23-27, 43, and 46 are under examination in this office action.
Information Disclosure Statement
7. The information disclosure statements (IDS) submitted on 02/07/2022, and 01/20/2023 are acknowledged. The submission is in-compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Rejections and / Objections
8. (A) Withdrawn rejection under 35 U.S.C. §§ 102(a)(l) and (a)(2). Applicant’s argument regarding rejection of claims 1-2, 15-19, 21, 43 and 46 under 35 U.S.C. §§ 102(a)(l) and (a)(2) were found persuasive because applicant amended claim 1 by introducing claim 7 limitation “a polypeptide induces a Type I interferon immune response” and therefore the rejection of claims 1-2, 15-19, 21, 43 and 46 under 35 U.S.C. §§ 102(a)(l) and (a)(2) is withdrawn.
(B) The 35 U.S.C. §§ 103 rejections of record have been modified to address the claim 1 and or other amendments.
(C). It is noted that amending claim 1 by incorporating the limitation from cancelled claim 7 resulted in a broader scope than that encompassed by the original claims, where claim 7 was dependent on claims 1 and 5 or 6. This increase in breadth resulted in the "New" 112(a) rejections as recited below.
Claim Interpretation (Amended)
9. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claims 1, and dependent claims 2-4, 15-16 are interpreted as drawn to a virus-like particle (VLP) comprising a surface protein, a matrix protein and an intra-VLP protein. A surface protein, a matrix protein and an intra-VLP are interpreted as derived from a virus. A polypeptide adjuvant is attached to an intra-VLP viral protein, and the polypeptide induces a type I interferon. The claims 17-19 are interpreted as the intra-VLP protein in a virus-like particle (VLP) is viral nucleoprotein (NP) or a NP fragment is a C-terminal fragment of a viral NP. Claims 21, 23-27 are interpreted as a VLP comprising viral protein from different viruses or strains. Claims 5-6, 23-27 are interpreted comprising limitation(s) a polypeptide adjuvant comprising signaling domain CARD domain from RIG-I like receptor (RIG-I) that induces a type I interferon immune response, RIG-I is a Melanoma Differentiation-Associated protein 5 (MDA5). Claim 43 is interpreted as a cell expressing and producing the VLP of claim 1. Claim 46 is interpreted as immunogenic composition or a vaccine formulation comprising the VLP of claim 1.
Claim Rejections - 35 USC § 112 (written description) - New
10. 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.
The instant claims 1-4, 15-19, 21, 43, and 46 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention and thus constitutes “new matter”.
It is noted that amending claim 1 by incorporating the limitation from cancelled claim 7 resulted in a broader scope than that encompassed by the original claims, where claim 7 was dependent on claims 1 and 5 or 6. There is no explicit support or implicit support from the original specification and/or original claims that places applicant in possession of this added scope. See e.g. MPEP 2163 and 2163.02.
Additionally, claim 1 is directed to a VLP comprising claim limitations (a), (b), and (c). The claim 1 limitations (a), (b), has full support in the specification, however, there is a partial support for limitation (c) a polypeptide, because the amended limitation (c) does not define the structure of claimed polypeptide for induction of type I interferon immune response (IFN-I).
The specification does not disclose even a single working example of a VLP that can induce type I interferon (IFN – I) without a polypeptide (polypeptide adjuvant) linked to intra-VLP protein and the polypeptide not comprising the two CARD domains of RIG-I (2CARD). It is important to note that a polypeptide with two CARD domains of RIG-I (2CARD) is capable of inducing IFN-I response and required as an added limitation for instant amended claim 1 to be fully enabled to induce IFN-I response (See, Specification, examples, pages 26-35).
Each of the dependent claims 2-4, 15-19, 21, 43, and 46 are drawn, inherently or explicitly, to a polypeptide that induce IFN-I.
Thus, the claims 1-4, 15-19, 21, 43, and 46 are drawn to a VLP compositions comprising a genus of a polypeptide that induce IFN-I.
The following quotation from section 2163 of the Manual of Patent Examination
Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirement for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice..., reduction to drawings..., or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 'A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the context of claimed invention, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) recently decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate enablement for claims drawn to antibodies (antibody is a protein with a function of binding that reads on instant claim 1 limitation a polypeptide with a function to induce IFN-I). The Federal Circuit encompassed factors relevant to Written Description by explaining Amgen that when an antibody (antibody is a protein with a function of binding that reads on instant claim 1 limitation a polypeptide with a function to induce IFN-I) is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself (See, Amgen, 872 F.3d at 1378-79). The Amgen court expressly stated that the so-called "newly characterized antigen" can be read as “instantly claimed claim 1 limitation “a polypeptide with a function to induce IFN-I” test should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen (instant claimed limitation e.g. “a polypeptide with a function to induce IFN-I”) alone is not considered adequate written description of a claimed antibody (reads on instant claim 1 limitation “a polypeptide with a function to induce IFN-I”) to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Id.
Thus, when a claim covers a genus of inventions, “a polypeptide with a function to induce IFN-I” the specification must provide written description support for the entire scope of the genus (in the instant case a working example of a VLP as claimed in instant claim 1). Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
In the present case, the specification teaches a VLP that can induce type I interferon (IFN-I) with a polypeptide (polypeptide adjuvant) linked to intra-VLP protein and the polypeptide comprise the two CARD domains of RIG-I (2CARD). (See, Specification, examples, pages 26-35).
The specification does not disclose even a single working example of a VLP that can induce type I interferon (IFN – I) without a polypeptide (polypeptide adjuvant) linked to intra-VLP protein and the polypeptide not comprising the two CARD domains of RIG-I (2CARD). It is important to note that a polypeptide with two CARD domains of RIG-I (2CARD) is capable of inducing IFN-I response and required as an added limitation for instant amended claim 1 to be fully enabled to induce IFN-I response (See, Specification, examples, pages 26-35).
Further, the claim 1 has identified a polypeptide (a genus) by only by function: the ability to induce IFN-1. Because there is no identification of structure of a polypeptide, nor sufficient representative examples of a polypeptide by which such a structure may be determined, the application fails to provide sufficient written description support for the identified genus of a polypeptide through identification of a structure and function of induction of IFN-I. A polypeptide as a genus is not alone sufficient structure to correlate with the function induction of IFN-I. This is because the mere presence of the claimed a genus of polypeptide does not correlate with a function of induction of IFN-I. The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004).
In this case, the only factor present in the claims is a genus of “a polypeptide” and a function of induction of IFN-I without claiming a single species of “a polypeptide” and disclosure of a specific complete or partial structure for a species of “a polypeptide” in the claimed VLP of claim 1. EliLily, 119 F.3 at 1568, 43 USPQ2d at 1406. The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. As discussed above, the skilled artisan cannot envision the detailed chemical structure encompassed by a genus “a polypeptide” capable of “a function of induction of IFN-I” as claimed in claim 1. Given that the specification has only described the function of a component, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph. The applicant/inventor needs to show that they have truly invented a genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of a genus. Otherwise, the applicant/inventor has only a research plan, leaving it to others to explore and figure out the unknown contours of the claimed genus." AbbVie Deutsch/and GmbH & Co. v. Janssen Biotech, 759 F.3d 1285, 1300 (Fed. Cir. 2014). "In other words, the test for sufficiency is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad, 598 F.3d at 1351.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim 1. In Regents of the University of California v. Eli Lilly & Co., the court stated: “A written description of an invention involving a chemical genus, like a description of a chemical species requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or sub-combinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representatives, the Courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618.
For the reasons above, and in view of the uncertainty, the applicant has not provided sufficient written description support for the genus of “a polypeptide” with a function “to induce IFN-I” identified in claim 1. The application therefore fails to provide adequate support for the claimed genus of “a polypeptide” with a function “to induce IFN-I”.
Therefore, the claims 1-4, 15-19, 21, 43, and 46 are rejected.
Claim Rejections - 35 USC § 103 (New Rejection)
11. 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.
12. Claims 1-3, 15-19, 21, 43 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Galarza (US20140286992A1, published 09/25/2014), and further in view of Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601), Terajima et al 2008 (published in Journal of Virology, 2008, vol 82 no.18, pages 9283-9287), Chen et al 2014 (published in Journal of Virology, 2014, vol 88, no. 20, pages 11760-11773) and Del Campo Ascarateil 2016 (US20150098958A1, published 04/09/2015).
Regarding claim 1, 15-19 and 21: Galarza (US20140286992A1) teaches instant claims 1, 15-19 and 21 limitation by disclosing a VLP comprising influenza proteins, the influenza proteins consisting essentially of an influenza matrix M1 protein, an influenza matrix M2 protein (US9387241B2 teaches instant claim 16 limitation, See, page 17; claim 1), a first influenza HA protein (surface protein) and a first influenza NA protein (surface protein) (US9387241B2 teaches instant claim 15 limitation, See, page 17; claim 1), and a polypeptide adjuvant that enhances an immune response is linked to an intra-VLP protein by disclosing the VLPs may further comprise additional influenza virus internal proteins (intra-VLP proteins) an influenza nucleoprotein (NP) (the NP comprise C-terminal fragment) (teaches instant claims 17-19 limitations) and/or one or two proteins of the polymerase complex (made up of PB1, PB2 and PA), For example, the VLP may include NP and/or PB1, PB2 and PA; NP and/or PB1 and PB2; NP and/or PB1 and PA; and/or NP and/or PB2 and PA (See, para [010]). The VLPs do not include NP in combination with all three proteins of the polymerase complex (PB2, PB1 and PA) (See, para [0063]). The matrix M1 protein underlines the membrane of the structure and chimeric glycoproteins HA (e.g., HA1, HA5 and/or HA7) and NA (e.g., NA1 and/or NA7) decorate the surface of the particle. The VLP comprise M1 and or M2, HA and NA from one influenza virus. The HA may be selected from H1 HA, H5 HA, H7 HA and NA may be selected from N1 NA and N7 NA, the VLP may comprise H7 HA and N7 NA or H5 HA and N1 NA; the VLP may comprise influenza virus NP (instant claim 21 limitation) (See, para [0009]). The M2 protein spans the membrane and may carry adjuvant molecule(s) linked to either the internal carboxyl terminus. The polypeptide adjuvant molecules are expressed as hybrid molecules and incorporated into the sub-viral structure (VLP). These hybrid molecules are generated by linking, at the DNA level. The sequences coding for the M1 or M2 genes with sequences coding for an adjuvant or immuno-regulatory moiety (polypeptide adjuvant). During sub-viral structure formation, these chimeric proteins are incorporated into the VLP depending on whether M1 or optionally included M2 carries the adjuvant molecule. One or more sequences encoding non-influenza proteins may be expressed and incorporated into the VLP, including, but not limited to, sequences comprising and/or encoding immunomodulatory molecules (adjuvants), for example, immunomodulating oligonucleotides (e.g., CpGs), and cytokines (See, Galarza US20140286992A1, para [0015]; [0028], Fig 11; [0067], [0077]).
Galarza (US20140286992A1) teaches all limitations of claim 1 and dependent claims 2, 15-19, 21, 43 and 46 except added partial limitation (c) a polypeptide induces a Type 1 interferon immune response.
Kobiyama et al 2009 is in the art and further teaches the added limitation of instant claim 1 and thereby dependent claims 2-3, 15-19, 21, 43 and 46, wherein the polypeptide adjuvant enhances a B-cell mediated immune response, a T cell-mediated immune response, or both a B-cell mediated immune response and a T cell-mediated immune response by disclosing administration of flu vax + N’-CARD-PTD polypeptide elicited production of type I IFNs, maturation of bone marrow-derived dendritic cells, and promotion of vaccine immunogenicity by enhancing Ag-specific Th1-type immune responses, thereby protecting mice from lethal influenza infection. In accordance with such adjuvant effects, immunization with flu vax plus N-CARD-PTD conferred superior protection against a lethal influenza challenge relative to that with flu vax alone (See, Kobiyama et al 2009, abstract, p. 1595 col 2 Immunization, Fig. 4, Fig 5 A, Flu vax Ag-specific IgG2a, Fig. 5, B and C, p.1600 col 1 para 2, entire article).
Kobiyama et al 2009 further teaches the polypeptide adjuvant comprises one or more signaling domains by disclosing that the N’-CARD-PTD polypeptide belongs to a new class of vaccine adjuvant that directly triggers intracellular signal transduction by a distinct mechanism from those engaged by conventional vaccine adjuvants (See, Kobiyama et al 2009, abstract last 3 lines, entire article).
Kobiyama et al 2009 further teaches the one or more signaling domains comprise caspase activation and recruitment domains (CARDs) (See, Kobiyama et al 2009, abstract, entire article).
Kobiyama et al 2009 further teaches the polypeptide induces a Type I interferon immune response (See, Kobiyama et al 2009, abstract, entire article).
Regarding claim 2: Galarza (US20140286992A1) teaches the added limitation of instant claim 2, wherein the surface protein induces a B-cell mediated immune response is disclosed by reciting the hemagglutinin (HA) protein of the influenza virus is the most abundant protein on the surface of the virus and is primarily responsible for the humoral immune response … ; HA is the leading candidate for inclusion in a subunit vaccine for influenza. The antibody responses directed against the surface protein, HA, is a key component in a protective immune response serum antibody response to VLP; humoral immune response refers to an immune response mediated by antibody molecules, the production of antibodies by B cells (See, Galarza (US20140286992A1), para [0009]; Fig 6 and legends; para [0040]). Galarza discloses serum antibody response to HA surface protein of on VLP of influenza virus.
Regarding claim 3: Kobiyama et al 2009 teaches the added limitation of instant claim 3, wherein the intra-VLP protein or a fragment thereof induces a T cell-mediated immune response (See, Kobiyama et al 2009, abstract, p. 1595 col 2 Immunization, Fig. 4, Fig 5 A, Flu vax Ag-specific IgG2a, Fig. 5, B and C, p.1600 col 1 para 2, entire article).
Additionally, regarding claim 3: Galarza (US20140286992A1), as recited supra, taught VLP of claim 1 comprising influenza virus matrix proteins M1, M2; NP protein; surface proteins HA and NA; and one or two proteins of the polymerase complex from PB1, PB2 and PA, when the VLP include NP, the VLP include one or two but not all three proteins of the polymerase complex, PB1, PB2 and PA (as recited supra). Galarza (US20140286992A1) disclosed that an immunogenic composition comprising the antigenic molecule (VLP) induces humoral and/or a cellular immune response to the antigenic molecule (VLP) in the subject (See, para [0039]- [0041]).
Terajima et al 2008 further teaches that influenza A virus Matrix Protein 1 (M1) specific human CD8+ T-cell response is induced in subjects that were vaccinated with trivalent inactivated influenza vaccine (TIV). The inactivated trivalent influenza vaccine comprises matrix 1 protein (M1). T-cell cytotoxicity assays showed that TIV is processed, and the epitope is presented by antigen-presenting cells to an M1 epitope-specific CD8+ T-cell line for specific lysis. Thus TIV, comprises surface glycoproteins to induce serotype-specific antibody responses, also contains M1, capable of inducing subtype cross-reactive CD8+ T-cell response in some vaccinees (See, abstract; page 9284, figure 1 A, B and associated legends, table 1 shows M1 peptides analyzed). CD8+ T-cell response.
Similarly, Chen et al 2014 further teaches by a systematic screening of immunodominant CD4+ T-cell responses to influenza A virus using PBMC from healthy donors and demonstrate that IAV-specific CD4+ T-cell responses focus on matrix 1-protein (M1) (See, abstract, figures 1-9 and table 1-2 and associated legends).
Del Campo Ascarateil 2016 (US20150098958A1) further teaches that nucleoprotein antigen from influenza virus in an immunogenic composition or a vaccine induces T cell mediated immune response in an animal or a human (See, para [0004]- [0008], [0010], [0018], [0020], [089], [0118], [0149], claim 35).
Regarding claim 43: An isolated host cell that expresses the VLP of claim 1. Galarza (US20140286992A1) teaches the added limitation of instant claim 43 an isolated host cell that expresses the VLP of claim 1 is anticipated by disclosing a host cell comprising a VLP, a packaging cell/mammalian cell for producing a VLP (See, US20140286992A1, claims 1 and 9-12; para [0012]- [0014], and [0016]).
Regarding claim 46: An immunogenic composition comprising the VLP of claim 1 and a pharmaceutically acceptable carrier. Galarza (US20140286992A1) anticipated the VLP of claim 1 as recited supra. Galarza further discloses the added limitation of instant claim 46 an immunogenic composition comprising the VLP of claim 1 and a pharmaceutically acceptable carrier (See, claim 13, para [0015], [0052]).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to modify prior art teachings of Galarza (US20140286992A1) and link influenza virus VLP intra-VLP protein NP to a polypeptide comprising two signaling N’-CARD as per additional teachings of Kobiyama et al 2009, and disclosures of Terajima et al 2008, Chen et al 2014 and Del Campo Ascarateil 2016 to arrive at the inventions of claims 1-3, 15-19, 21, 43 and 46. One of ordinary skills in the art would have been motivated to link two N’-CARD polypeptides or CARD domain from RIG-I-like receptor to intra-viral protein Nucleoprotein for improved obtaining enhanced immune response that is induction of type I interferon response and commercial success by developing the influenza VLP vaccine that induce IFN-1 for better efficacy against the viral infection. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claims 1-3, 15-19, 21, 43 and 46 given the combined prior teachings of Galarza (US20140286992A1), and Kobiyama et al 2009, and disclosures of Terajima et al 2008, Chen et al 2014 and Del Campo Ascarateil 2016 as applied and as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 1-3, 15-19, 21, 43 and 46. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Claim Rejections - 35 USC § 103 (Amended)
13. 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.
As recited supra, the instant claims 1-3, 15-19, 21, 43 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Galarza (US20140286992A1, published 09/25/2014), and further in view of Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601), Terajima et al 2008 (published in Journal of Virology, 2008, vol 82 no.18, pages 9283-9287), Chen et al 2014 (published in Journal of Virology, 2014, vol 88, no. 20, pages 11760-11773) and Del Campo Ascarateil 2016 (US20150098958A1, published 04/09/2015) and the teachings of the prior arts as recited supra are incorporated here in its entirety to render obvious the instant claims 1-3, 15-19, 21, 43 and 46.
14. Claims 4-6 and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Galarza (US20140286992A1, published 09/25/2014), and further in view of Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601), Terajima et al 2008 (published in Journal of Virology, 2008, vol 82 no.18, pages 9283-9287), Chen et al 2014 (published in Journal of Virology, 2014, vol 88, no. 20, pages 11760-11773) and Del Campo Ascarateil 2016 (US20150098958A1, published 04/09/2015) and further in view of Meylan et al 2006 (Molecular Cell 22, 561–569, June 9, 2006), and Xu et al 2018 (Protein Cell 2018, 9(3):246–253).
Claims 4-6 and 23-26: The combined prior art teachings of Galarza, Kobiyama et al 2009, Terajima et al 2008, Chen et al 2014 and Del Campo Ascarateil 2016 teaches claim 1 as recited supra.
Kobiyama et al 2009 further teaches the added limitation of instant claim 4, wherein the polypeptide adjuvant enhances a B-cell mediated immune response, a T cell-mediated immune response, or both a B-cell mediated immune response and a T cell-mediated immune response by disclosing administration of flu vax + N’-CARD-PTD polypeptide elicited production of type I IFNs, maturation of bone marrow-derived dendritic cells, and promotion of vaccine immunogenicity by enhancing Ag-specific Th1-type immune responses, thereby protecting mice from lethal influenza infection. In accordance with such adjuvant effects, immunization with flu vax plus N-CARD-PTD conferred superior protection against a lethal influenza challenge relative to that with flu vax alone (See, Kobiyama et al 2009, abstract, p. 1595 col 2 Immunization, Fig. 4, Fig 5 A, Flu vax Ag-specific IgG2a, Fig. 5, B and C, p.1600 col 1 para 2, entire article).
Kobiyama et al 2009 further teaches the added limitation of instant claim 5, wherein the polypeptide adjuvant comprises one or more signaling domains by disclosing that the N’-CARD-PTD polypeptide belongs to a new class of vaccine adjuvant that directly triggers intracellular signal transduction by a distinct mechanism from those engaged by conventional vaccine adjuvants (See, Kobiyama et al 2009, abstract last 3 lines, entire article).
Kobiyama et al 2009 further teaches the added limitation of instant claim 6, wherein the one or more signaling domains comprise caspase activation and recruitment domains (CARDs) (See, Kobiyama et al 2009, abstract, entire article). Kobiyama et al 2009 further teaches the polypeptide induces a Type I interferon immune response (See, Kobiyama et al 2009, abstract, entire article).
Xu et al 2018 reviewed and teaches retinoic acid inducible gene I (RIG-I) and CARD domains from RIG-I receptors (See, Xu et al 2018, abstract, introduction, Fig 1, entire review).
Meylan et al 2006 teaches a human RIG-I, RIG-I encoded protein of 925 amino acids that contains an N-terminal region characterized by the presence of two caspase recruitment domains (CARD) and a C-terminal region harboring potential ATP-dependent RNA helicase (See, page 562, col 2, para 3, Detection of …..).
Claims 23-26: The combined prior art teachings of Galarza (US20140286992A1), Kobiyama et al 2009, Xu et al 2018 and Meylan et al 2006 further teaches the added limitations of instant claims 23-26. Galarza (US20140286992A1) as recited supra teaches influenza virus VLP (eVLP) containing influenza virus surface protein(s) HA or NA, an influenza matrix M1 protein, an influenza matrix M2 protein and Nucleoprotein (NP) an intra-VLP protein.
Kobiyama et al 2009 teaches a polypeptide adjuvant comprises signaling domain by disclosing that the N’-CARD and RIG-I (RIG-I 2CARDs) (See, abstract, p.1596 col 2 para 2). Additionally, Xu et al 2018 reviewed and teaches retinoic acid inducible gene I (RIG-I) and CARD domains from RIG-I receptors (See, Xu et al 2018, abstract, introduction, Fig 1, entire review).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to modify prior art teachings as applied to render obvious claim 1 and incorporate additional teachings on linking influenza virus VLP intra-VLP protein NP to a polypeptide comprising two signaling N’-CARD as per teachings of Kobiyama et al 2009, Meylan et al 2006 and Xu et al 2018 regarding N’-CARD or CARD domain from RIG-I-like receptor to arrive at the inventions of claims 4-6 and 23-26. One of ordinary skills in the art would have been motivated to link two N’-CARD polypeptides or CARD domain from RIG-I-like receptor to intra-viral protein Nucleoprotein for improved and obtaining enhanced immune response that is induction of type I interferon response and commercial success by developing the claimed VLP vaccine that induce IFN-1 for better efficacy against the viral infection. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claims 4-6 and 23-26 given the combined prior teachings of Galarza, Kobiyama et al 2009, Terajima et al 2008, Chen et al 2014 and Del Campo Ascarateil 2016, Meylan et al 2006 and Xu et al 2018 as applied and as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claims 4-6 and 23-26. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Claim Rejections - 35 USC § 103 (Amended)
15. 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.
16. Claims 1, 15-17, 19 and 43 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Warfield et al 2007 (Journal of Infectious Diseases, published 2007, suppl 2, p. S430-S437) and further in view of Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601).
Claim 1: Warfield et al 2007 teaches claim 1 limitations by disclosing an Ebola virus VLP (eVLP) containing Ebola virus glycoprotein (GP), Nucleoprotein (NP), and matrix protein (VP40). Warfield et al 2007 further teaches vaccination of monkeys using the Ebola virus VLPs comprising adjuvant (See, abstract; page S431, col 1, materials and methods eVLPs).
Warfield et al 2007 teaches use of adjuvant in the Ebola VLP immunogenic composition, however, do not teach a polypeptide adjuvant linked to an intra-VLP protein (Nucleoprotein).
Kobiyama et al 2009 is in the viral vaccine and adjuvant art and teaches a polypeptide adjuvant comprising the caspase recruitment domain (CARD) or N’-CARD fused to a protein transduction domain (PTD) that promotes influenza vaccine immunogenicity in mice (See, abstract).
Kobiyama et al 2009 further teaches the polypeptide adjuvant enhances a T cell-mediated immune response by disclosing administration of flu vax + N’-CARD-PTD polypeptide elicited production of type I IFNs, maturation of bone marrow-derived dendritic cells, and promotion of vaccine immunogenicity by enhancing Ag-specific Th1-type immune responses, thereby protecting mice from lethal influenza infection. In accordance with such adjuvant effects, immunization with flu vax plus N-CARD-PTD conferred superior protection against a lethal influenza challenge relative to that with flu vax alone (See, Kobiyama et al 2009, abstract, entire article).
Kobiyama et al 2009 further teaches the polypeptide adjuvant comprises one or more signaling domains by disclosing that the N’-CARD-PTD polypeptide belongs to a new class of vaccine adjuvant that directly triggers intracellular signal transduction by a distinct mechanism from those engaged by conventional vaccine adjuvants (See, Kobiyama et al 2009, abstract last 3 lines, entire article).
Kobiyama et al 2009 further teaches the one or more signaling domains comprise caspase activation and recruitment domains (CARDs) (See, Kobiyama et al 2009, abstract, entire article).
Kobiyama et al 2009 further teaches the polypeptide induces a Type I interferon immune response (See, Kobiyama et al 2009, abstract, entire article).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to further modify the prior art teachings of Warfield et al 2007 on Ebola virus VLP as applied to claim 1 by incorporating teachings of Kobiyama et al 2009 on a polypeptide adjuvant comprising the caspase recruitment domain (CARD) or N’-CARD and link the CARD or N’-CARD polypeptide to intra-viral protein Nucleoprotein in the VLP of Ebola virus to induce type I interferon. One of ordinary skills in the art would have been motivated to link the CARD or N’-CARD polypeptide to intra-viral protein Nucleoprotein in the VLP of Ebola virus as the VLP design choice for improved and obtaining enhanced immune response that is induction of type I interferon response and commercial success by developing the claimed VLP vaccine that induce IFN-1 for better efficacy against the viral infection and is convenient for immunization delivery of the safer VLP composition comprising an inherently designed or self-adjuvanted VLPs. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 1 given the combined prior teachings of Warfield et al 2007 and Kobiyama et al 2009 as applied and as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claim 1. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Claims 15-17, and 19: Warfield et al 2007 further teaches an Ebola virus VLP (eVLP) wherein the surface protein is a Ebola virus glycoprotein (instant claim 15 limitation); wherein the matrix protein (VP40) is from an Ebola virus (instant claim 16 limitation); wherein the intra-VLP protein Nucleoprotein (NP) is from an Ebola virus (instant claim 17 limitation); and wherein the viral surface protein, the viral matrix protein and the viral NP or a fragment thereof are from the same Ebola virus (instant claim 19 limitation).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to comprise the VLP comprising an Ebola virus glycoprotein, matrix protein and nucleoprotein as per prior art teachings of Warfield et al 2007 by incorporating teachings of Kobiyama et al 2009 on a polypeptide adjuvant comprising the caspase recruitment domain (CARD) or N’-CARD and link the CARD or N’-CARD polypeptide to intra-viral protein Nucleoprotein in the VLP of Ebola virus. One of the ordinary skills in the art would have been motivated to produce the Ebola virus derived VLP to develop a vaccine against a specific antigenic group Ebola virus. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the inventions of claims 15-17 and 19 given the combined prior teachings of Warfield et al 2007 and Kobiyama et al 2009 as applied and as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claims 15-17 and 19. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Claim 43: Warfield et al 2007 further teaches a 293T cell-derived eVLPs containing Ebola virus surface glycoprotein (GP), nucleoprotein (NP), and matrix protein VP40.
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to develop a host cell or cell line that expresses the VLP of claim 1 wherein the VLP comprise an Ebola virus glycoprotein, matrix protein and nucleoprotein as per prior art teachings of Warfield et al 2007 and incorporates prior art teachings of Kobiyama et al 2009 on a polypeptide adjuvant comprising the caspase recruitment domain (CARD) or N’-CARD and link the CARD or N’-CARD polypeptide to intra-viral protein Nucleoprotein in the VLP of Ebola virus. One of the ordinary skills in the art would have been motivated to develop a host cell or cell line that expresses the VLP of claim 1 produce the VLPs to develop a vaccine against an Ebola virus for commercial success. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 43 given the combined prior teachings of Warfield et al 2007 and Kobiyama et al 2009 as applied and as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claim 43. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Claim 46: The combined teachings of Warfield et al 2007 and Kobiyama et al 2009 teaches the VLP of claim 1. Warfield et al 2007 further teaches intramuscular vaccination of Nonhuman Primates with an Ebola VLP comprising formulated in sterile saline and comprising adjuvant (See, Warfield et al 2007, p. S431, col 1, Materials and Methods).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to apply the combined prior art teachings of Warfield et al 2007 and Kobiyama et al 2009 to arrive at the invention of claim 46. One of the ordinary skills in the art would have been motivated to develop an immunogenic composition comprising the VLP of claim 1 and a pharmaceutically acceptable carrier to arrive at the invention of claim 46 for commercial success. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 46 given the combined prior teachings of Warfield et al 2007 and Kobiyama et al 2009 as applied and as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claim 46. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
17. Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Warfield et al 2007 (Journal of Infectious Diseases, published 2007, suppl 2, p. S430-S437) and Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601) and further in view of McElory et al 2015 (PNAS, vol. 112 (5) p.4719-4724).
Claim 3: The VLP of claim 1, wherein the intra-VLP protein or a fragment thereof induces a T cell-mediated immune response.
The combined teachings of Warfield et al 2007 and Kobiyama et al 2007 teaches claim 1 as recited supra. However, do not teach added limitation of instant claim 3, wherein the intra-VLP protein or a fragment thereof induces a T cell-mediated immune response.
McElory et al 2015 teaches Ebola virus-specific T-cell response with the NP being the major viral target of CD8 T cells-mediated immune response, suggesting the inclusion of this protein in future T cell-based vaccine designs (See, abstract, p. 4723, col 1, para 1; entire article).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings of Warfield et al 2007 and Kobiyama et al 2009 with the teachings of McElory et al 2015 to arrive at the invention of claim 3. One of the ordinary skills in the art would have been motivated to develop an Ebola virus VLP capable of inducing T cells-mediated immune response for better immune protection and for commercial success of the VLP vaccine. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 3 given the combined prior teachings of Warfield et al 2007, Kobiyama et al 2009 and McElory et al 2015 as applied to claim 3 as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claim 3. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
18. Claims 2 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Warfield et al 2007 (Journal of Infectious Diseases, published 2007, suppl 2, p. S430-S437) and Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601) further in view of Schweneker et al 2017 (Journal of Virology, vol 91 Issue 11 e00343-17).
The combined teachings of Warfield et al 2007 and Kobiyama et al 2009 teaches claim 1 as recited supra.
Claim 2: Warfield et al 2007 as recited supra teaches an Ebola virus VLP with surface glycoprotein and the VLP induces antibody response which is a B-cell mediated immune response (See, abstract). Schweneker et al 2017 provides evidence that an Ebola virus VLP comprising Ebola virus glycoprotein induces glycoprotein binding and neutralizing antibody response (See, abstract, p.10-11, Fig. 7).
Claim 21: Schweneker et al 2017 further teaches the VLP comprising VP40 (matrix protein) and glycoprotein (GP) of Zaire ebolavirus variant Mayinga and the nucleoprotein (NP) of Taï Forest virus (TAFV) and thus teaches added limitation of instant claim 21 wherein the viral surface protein, the viral matrix protein and the viral NP or a fragment thereof are from different strains of the same virus or different viruses. The TAFV version of NP was chosen to provide a broader representation of T cell antigens from different Ebola virus species in the vaccine construct (See, Schweneker et al 2017, p. 2, last para).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings of Warfield et al 2007 and Kobiyama et al 2009 with the teachings of Schweneker et al 2017 to arrive at the invention of claims 2 and 21. One of the ordinary skills in the art would have been motivated to develop the VLP of claim 21 comprising the proteins from different strains of the same virus or different viruses providing broader immune protection (See, Schweneker et al 2017, p. 2, last para, entire article) and for commercial success. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claims 2 and 21 given the combined prior teachings of Warfield et al 2007, Kobiyama et al 2009 and Schweneker et al 2017 as applied to claims 2 and 21 as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claims 2 and 21. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
19. Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Warfield et al 2007 (Journal of Infectious Diseases, published 2007, suppl 2, p. S430-S437) and Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601) further in view of Licata et al 2004 (Journal of Virology, vol 78 (14) p.7344–7351.2004).
Claim 18: The VLP of claim 17, wherein the viral NP fragment is a C-terminal fragment of a viral NP.
The combined teachings of Warfield et al 2007 and Kobiyama et al 2009 teaches claim 17 as recited supra.
Licata et al 2004 is in the Ebola virus VLP art and teaches NP appears to physically interact with VP40 as judged by detection of NP in VP40-containing VLPs. The C-terminal 50 amino acids of NP may be important for interacting with and enhancing release of VP40 VLPs (See, Licata et al 2004, abstract, entire article).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to modify the combined prior art teachings of Warfield et al 2007 and Kobiyama et al 2009 with the teachings of Licata et al 2004 on the NP protein C-terminal 50 amino acids importance for interacting with VP40 and enhance budding and release of VLPs to arrive at the invention of claim 18. One of the ordinary skills in the art would have been motivated to develop the VLP of claim 18 comprising minimum required NP protein fragment for budding and release of the VLP and to incorporate and accommodate the polypeptide adjuvant for linking to the intra-VLP NP protein fragment (See, Licata et al 2004, abstract, entire article) for commercial success. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 18 given the combined prior teachings of Warfield et al 2007, Kobiyama et al 2009 and Licata et al 2004 as applied to claim 18 as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claim 18. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
20. Claims 4-6 and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Warfield et al 2007 (Journal of Infectious Diseases, published 2007, suppl 2, p. S430-S437) and Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601) and further in view of Meylan et al 2006 (Molecular Cell 22, 561–569, June 9, 2006), and Xu et al 2018 (Protein Cell 2018, 9(3):246–253).
Claims 4-6 and 23-26: Warfield et al 2007 in view of Kobiyama et al 2009 teaches claim 1 as recited supra.
Claim 4: Kobiyama et al 2009 further teaches the added limitation of instant claim 4, wherein the polypeptide adjuvant enhances a B-cell mediated immune response, a T cell-mediated immune response, or both a B-cell mediated immune response and a T cell-mediated immune response by disclosing administration of flu vax + N’-CARD-PTD polypeptide elicited production of type I IFNs, maturation of bone marrow-derived dendritic cells, and promotion of vaccine immunogenicity by enhancing Ag-specific Th1-type immune responses, thereby protecting mice from lethal influenza infection. In accordance with such adjuvant effects, immunization with flu vax plus N-CARD-PTD conferred superior protection against a lethal influenza challenge relative to that with flu vax alone (See, Kobiyama et al 2009, abstract, p. 1595 col 2 Immunization, Fig. 4, Fig 5 A, Flu vax Ag-specific IgG2a, Fig. 5, B and C, p.1600 col 1 para 2, entire article).
Claim 5: Kobiyama et al 2009 further teaches the added limitation of instant claim 5, wherein the polypeptide adjuvant comprises one or more signaling domains by disclosing that the N’-CARD-PTD polypeptide belongs to a new class of vaccine adjuvant that directly triggers intracellular signal transduction by a distinct mechanism from those engaged by conventional vaccine adjuvants (See, Kobiyama et al 2009, abstract last 3 lines, entire article).
Claim 6: Kobiyama et al 2009 further teaches the added limitation of instant claim 6, wherein the one or more signaling domains comprise caspase activation and recruitment domains (CARDs) (See, Kobiyama et al 2009, abstract, entire article). Kobiyama et al 2009 further teaches that the polypeptide induces a Type I interferon immune response (See, Kobiyama et al 2009, abstract, entire article).
Claims 23-26: Xu et al 2018 reviewed and teaches retinoic acid inducible gene I (RIG-I) and CARD signaling domains from RIG-I receptors (See, Xu et al 2018, abstract, introduction, Fig 1, entire review).
Meylan et al 2006 teaches a human RIG-I, RIG-I encoded protein of 925 amino acids that contains an N-terminal region characterized by the presence of two caspase recruitment domains (CARD) that are signaling domains and a C-terminal region harboring potential ATP-dependent RNA helicase (See, page 562, col 2, para 3, Detection of ….., entire article).
The combined teachings of Warfield et al 2007, Kobiyama et al 2009, Xu et al 2018 and Meylan et al 2006 further teaches the added limitations of instant claims 23-26. Warfield et al 2007 teaches Ebola virus VLP (eVLP) containing Ebola virus glycoprotein (GP), Nucleoprotein (NP) an intra-VLP protein, and matrix protein (VP40). Kobiyama et al 2009 teaches a polypeptide adjuvant comprises signaling domain by disclosing that the N’-CARD and RIG-I (RIG-I 2 CARDs) (See, abstract, p.1596 col 2 para 2). Additionally, Xu et al 2018 reviewed and teaches retinoic acid inducible gene I (RIG-I) and CARD domains from RIG-I receptors (See, Xu et al 2018, abstract, introduction, Fig 1, entire review).
It would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to modify prior art teachings of Warfield et al 2007 and link Ebola virus VLP intra-VLP protein NP to a polypeptide comprising two signaling N’-CARD as per teachings of Kobiyama et al 2009, Meylan et al 2006 and Xu et al 2018 regarding N’-CARD or CARD domain from RIG-I-like receptor to arrive at the inventions of claims 4-6 and 23-26. One of ordinary skills in the art would have been motivated to link two N’-CARD polypeptides or CARD domain from RIG-I-like receptor to intra-viral protein Nucleoprotein for improved obtaining enhanced immune response and commercial success of the VLP vaccine. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claims 4-6 and 23-26 given the combined prior teachings of Warfield et al 2007, Kobiyama et al 2009, Meylan et al 2006 and Xu et al 2018 as applied and as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claims 4-6 and 23-26. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
21. Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Warfield et al 2007 (Journal of Infectious Diseases, published 2007, suppl 2, p. S430-S437), Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601), Meylan et al 2006 (Molecular Cell 22, 561–569, June 9, 2006), Xu et al 2018 (Protein Cell 2018, 9(3):246–253) and further in view of Rhee et al 2012 (Clin Exp Vaccine Res 2012;1:50-63), Gitlin et al 2010 (PLoS Pathogens, vol 6 (1) e1000734), Benitez et al 2015 (Cell Reports 11, 1714–1726) and Junior et al 2019 (Trends in Microbiology, January 2019, Vol. 27, No. 1).
Claim 27: The VLP of claim 25, wherein the RIG-I-like receptor is Melanoma Differentiation-Associated protein 5 (MDA5).
The combined teachings of Warfield et al 2007, Kobiyama et al 2009, Meylan et al 2006 and Xu et al 2018 teaches the VLP of claim 25 as recited supra. However, do not teach the added limitation of instant claim 27 wherein the RIG-I-like receptor is Melanoma Differentiation-Associated protein 5 (MDA5).
Rhee et al 2012 is in the virology and vaccine art and teaches an RNA helicase RIG-1 and melanoma differentiation-associated gene 5 (MDA5) are cytosolic sensor for viral infections. These two RNA helicases possess two N-terminal caspase-recruitment domains (CARDs) followed by an RNA helicase domain. They are activated viral infections and trigger cooperative activation of NF-kB and IFN regulatory factor 3 and 7 (IRF3/7) to induce antiviral type I IFNs (See, Rhee et al 2012, p.54 col 1 RLRs; Fig. 2B).
Benitez et al 2015 is in the virology and vaccine art and teaches MDA5 as a significant contributor to the cellular defense against Influenza A virus (See, abstract, entire article).
Gitlin et al 2010 is in the virology and vaccine art and teaches Melanoma Differentiation-Associated Gene 5 (MDA5) is involved in the innate immune response to Paramyxoviridae infection in vivo (See, abstract, entire article).
Junior et al 2019 is in the virology and vaccine art and teaches MDA5 in antiviral immunity (See, abstract, entire article). MDA5 is a pattern-recognition receptor for RNA and induces a type I interferon
response.
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the prior art teachings as applied to the claim 25 to incorporate the prior art teachings of Rhee et al 2012, Benitez et al 2015, Gitlin et al 2010, and Junior et al 2019 on MDA-5 to incorporate it in the VLP as an adjuvant linked to the intra-VLP protein NP to arrive at the invention of claims 27. One of ordinary skills in the art would have been motivated to link the MDA-5 to intra-viral protein Nucleoprotein for improved obtaining enhanced antiviral type I interferon immune response and commercial success of the VLP vaccine. One of the ordinary skills in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 27 given the combined prior teachings applied to the claim 27 as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention of claim 27. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Response to Arguments
22. Applicant's arguments filed 09/16/2025 have been fully considered but they are not persuasive. Amendment (dated 09/16/2025) to claim 1 by incorporating limitation from claim 7, “wherein the polypeptide induces a Type 1 interferon immune response” has substantially changed the scope of amended claim 1 for examination purpose and claim 1 and dependent claims scope of enablement and written description and introduction of a new matter situations.
(i) Applicants Arguments 1: 35 U.S.C. § 102: Novelty:
Claims 1-2, 15-19, 21, 43 and 46 Rejection Under 35 U.S.C. §§ 102(a)(I) and (a)(2)
Claims 1-2, 15-19, 21, 43 and 46 are rejected under 35 U.S.C. §§ 102(a)(l) and (a)(2) as allegedly anticipated by US 2014/0286992Al to Galarza ("Galarza"). Applicant respectfully traverses this rejection.
The Office alleges that Galarza anticipates the claims by disclosing a VLP comprising influenza proteins consisting essentially of an influenza matrix Ml protein, an influenza matrix M2 protein, a first influenza HA protein (surface protein), a first influenza NA protein (surface protein), and a polypeptide adjuvant that enhances an immune response linked to an intra-VLP protein by disclosing the VLPs may further comprise additional influenza virus internal proteins (intra-VLP proteins), an influenza nucleoprotein (NP), and/or one or two proteins of the polymerase complex (Office Action, p.4).
Without acquiescing to the merits of the rejection and solely to advance prosecution, Applicant has amended claim I to recite "wherein the polypeptide induces a Type I interferon immune response". The cited reference fails to disclose, either expressly or inherently, a VLP comprising a polypeptide adjuvant that is linked to an intra-VLP protein, wherein the polypeptide induces a Type I interferon immune response. Accordingly, Applicant submits that amended independent claim I (from which claims 2, 15-19, 21, 43, and 46 depend) address and overcome the grounds of rejection as previously set forth by the Office, rendering the rejection to claims 1, 2, 15-19, 21, 43, and 46 moot. Accordingly, Applicant respectfully requests withdrawal of the rejections to claims 1, 2, 15-19, 21, 43, and 46.
Claim 3 Rejection Under 35 USC.§§ 102(a)(J) and (a)(2)
Claim 3 is rejected under 35 U.S.C. §§ 102(a)(l) and (a)(2) as allegedly anticipated by Galarza and as evidenced by Terajima et al., Journal of Virology, 82(18): 9283-9287 (2008) ("Terajima"), Chen et al., Journal of Virology, 88(2): 11760-11773 (2014) ("Chen"), and US20150098958Al to Del Campo Ascarateil ("Del Campo Ascarateil"). Applicant respectfully traverses this rejection.
The Office alleges Galarza discloses that an immunogenic composition comprising the antigenic molecule (VLP) induces humoral and/or a cellular immune response to the antigenic molecule (VLP) in the subject (Office Action, p. 6). The Office alleges that Terajima provides evidence that influenza A virus Matrix Protein I (Ml) specific human CD8+ T-cell response is induced in subjects that were vaccinated with trivalent inactivated influenza vaccine (TIV) (Office Action, p. 7). The Office alleges that Chen provides evidence by a systematic screening of immunodominant CD4+ T-cell responses to influenza A virus using PBMC from healthy donors and demonstrates that IAV-specific CD4+ T-cell responses focus on matrix I-protein (Ml) (Office Action, p. 7). The Office alleges that Del Campo Ascarateil provides evidence that nucleoprotein antigen from influenza virus in an immunogenic composition or a vaccine induces T-cell mediated immune response in an animal or a human (Office Action, p. 7).
Without acquiescing to the merits of the rejection and solely to advance prosecution, Applicant has amended claim I to recite "wherein the polypeptide induces a Type I interferon immune response". The cited reference fails to disclose, either expressly or inherently, a VLP comprising a polypeptide adjuvant that is linked to an intra-VLP protein, wherein the polypeptide induces a Type I interferon immune response. Accordingly, Applicant submits that amended independent claim I (from which claim 3 depends) addresses and overcomes the grounds of rejection as previously set forth by the Office, rendering the rejection to claim 3 moot. Accordingly, Applicant respectfully requests withdrawal of the rejections to claim 3.
In Response 1: Applicants argument regarding rejection of claims 1-2, 15-19, 21, 43 and 46 under 35 U.S.C. §§ 102(a)(l) and (a)(2) were found persuasive because applicant amended claim 1 by introducing claim 7 limitation “a polypeptide induces a Type I interferon immune response” and therefore the rejection of claims 1-2, 15-19, 21, 43 and 46 under 35 U.S.C. §§ 102(a)(l) and (a)(2) is withdrawn.
(ii) Applicants Arguments 2: 35 U.S.C. § 103: Obviousness:
Claims 1-2, 15-19, 21, 43 and 46 Rejection Under 35 US. C. § 103
Claims 1-2, 15-19, 21, 43 and 46 are rejected under 35 U.S.C. § 103 as allegedly unpatentable over Galarza for the reasons recited in the 35 U.S.C. § 102 section (Office Action, p. 8). Applicant respectfully traverses this rejection.
Applicant respectfully submits that the Office's rejection in the Office Action does not meet the requirements for establishing a prima facie case of obviousness under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify the teachings of Galarza to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
A proper obviousness rejection must be supported by specific factual findings and a clear explanation of the reasoning, rather than a mere conclusory statement or incorporation by reference. The current Office Action lacks the necessary factual basis and articulated rationale to enable the Applicant to understand and meaningfully respond to the asserted grounds for rejection.
Notwithstanding this deficiency, Applicant submits that Galarza fails to disclose or suggest a virus-like particle (VLP) comprising: a surface protein, a matrix protein, and a polypeptide that enhances an immune response, wherein the polypeptide is a polypeptide adjuvant and wherein the polypeptide is linked to an intra-VLP protein, wherein the polypeptide induces a Type 1 interferon immune response, as recited in the present claims.
Accordingly, Applicant respectfully requests that the rejection to claims 1-2, 15-19, 21, 43 and 46 under 35 U.S.C. 103 be withdrawn. Alternatively, Applicant requests that the Office provide a detailed statement of the basis for the rejection, including a clear identification of the differences between the claims and the cited reference, the motivation to combine or modify, and any supporting rationale.
Claim 3 Rejection Under 35 USC.§ 103
Claim 3 is rejected under 35 U.S.C. § 103 as allegedly unpatentable over Galarza and further in view of Terajima, Chen, and Del Campo Ascarateil. Applicant respectfully traverses this rejection.
The Office alleges that the prior art teachings of Galarza in view of Terajima, Chen, and Del Campo Ascarateil render obvious claim 3 as recited in the 35 U.S.C. § 102 rejection (Office Action, p. 9).
Applicant respectfully submits that the Office's statement in the Office Action does not meet the requirements for establishing a prima facie case of obviousness under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Galarza, Terajima, Chen, and Del Campo Ascarateil to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed.
Cir. 2000).
A proper obviousness rejection must be supported by specific factual findings and a clear explanation of the reasoning, rather than a mere conclusory statement or incorporation by reference. The current Office Action lacks the necessary factual basis and articulated rationale to enable the Applicant to understand and meaningfully respond to the asserted grounds for rejection.
Notwithstanding this deficiency, Applicant submits that Galarza, Terajima, Chen, and Del Campo Ascarateil, in combination, fail to disclose or suggest a virus-like particle (VLP) comprising: a surface protein, a matrix protein, and a polypeptide that enhances an immune response, wherein the polypeptide is a polypeptide adjuvant and wherein the polypeptide is linked to an intra-VLP protein, wherein the polypeptide induces a Type 1 interferon immune response, as recited in the present claims.
Accordingly, Applicant respectfully requests that the rejection of claim 3 under 35 U.S.C.
§ 103 be withdrawn. Alternatively, Applicant requests that the Office provide a detailed statement of the basis for the rejection, including a clear identification of the differences between the claims and the cited reference, the motivation to combine or modify, and any supporting rationale.
Claims 4-7 and 23-26 Rejection Under 35 USC§ 103
Claims 4-7 and 23-26 are rejected under 35 U.S.C. § 103 as allegedly unpatentable over Galarza and further in view of Kobiyama, The Journal of lmmunology, 182: 1593-1601 (2009) ("Kobiyama"), Meylan et al., Molecular Cell 22, 561-569 (2006) ("Meylan") and Xu et al., Protein Cell, 9(3):246-253 (2018) ("Xu"). Claim 7 is cancelled herein; therefore, this rejection is moot. Applicant respectfully traverses the rejection of claims 4-7 and 23-26.
Regarding claims 4-7, the Office alleges that Galarza and Kobiyama teach the limitations of claims 4-7 (Office Action, p. 9-10). Applicant respectfully submits that the Office's statement in the Office Action does not meet the requirements for establishing a prima facie case of obviousness for claims 4-7 under 35 U.S.C. §103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Galarza and Kobiyama to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
A proper obviousness rejection must be supported by specific factual findings and a clear explanation of the reasoning, rather than a mere conclusory statement or incorporation by reference. The current Office Action lacks the necessary factual basis and articulated rationale to enable the Applicant to understand and meaningfully respond to the asserted grounds for rejection.
Regarding claims 23-26, the Office alleges that it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify prior art teachings of Galarza and link influenza virus VLP intra-VLP protein NP to a polypeptide comprising two signaling N'-CARD as per teachings of Kobiyama, Meylan and Xu regarding N'-CARD or CARD domain from RIG-I-like receptor to arrive at the inventions of claims 23-26.
The Office further alleges that one of ordinary skill in the art would have been motivated to link two N'-CARD polypeptides or CARD domain from RIG-I-like receptor to intra-viral protein Nucleoprotein for improved obtaining enhanced immune response and commercial success of the influenza VLP vaccine. The Office alleges that one of ordinary skill in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 23-26 (Office Action, p.10-11).
Applicant respectfully submits that the Office Action fails to establish a prima facie case of obviousness for claims 23-26 under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Galarza, Kobiyama, Meylan and Xu to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). In the absence of specific findings or a clearly stated rationale, the rejection does not allow the Applicant to meaningfully respond to the asserted grounds.
Moreover, setting aside this deficiency, Applicant respectfully submits that the cited references fail to teach or suggest the use of a polypeptide adjuvant in a virus-like particle (VLP) that specifically induces a Type I interferon immune response, as recited in amended claim 1 (from which claims 4-7 and 23-26 depend on). The induction of a Type I interferon response is a specific and non-obvious improvement of the claimed invention as amended.
Accordingly, Applicant respectfully requests withdrawal of the rejection of claims 4- 7 and 23-26 under 35 U.S.C. § 103. If the Office maintains the rejection, Applicant requests that the Office provide a detailed statement of the basis for the rejection, including a clear identification of the differences between the claims and the cited references, the motivation to combine or modify, and any supporting rationale as required by KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
In Response 2: Applicants argument regarding rejection of claims 1-2, 15-19, 21, 43 and 46 are rejected under 35 U.S.C. § 103 as allegedly unpatentable over Galarza for the reasons recited in the 35 U.S.C. § 102 section (Office Action, p. 8). Applicant respectfully traverses this rejection were not found persuasive because although the applicant amended claim 1 by introducing claim 7 limitation a polypeptide induces a Type I interferon immune response, the amended claim 1 and dependent claims 2-3, 15-19, 21, 43 and 46 are rendered obvious, as recited supra, by the prior art teachings of Galarza (US20140286992A1, published 09/25/2014), and further in view of Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601), Terajima et al 2008 (published in Journal of Virology, 2008, vol 82 no.18, pages 9283-9287), Chen et al 2014 (published in Journal of Virology, 2014, vol 88, no. 20, pages 11760-11773) and Del Campo Ascarateil 2016 (US20150098958A1, published 04/09/2015). Because Kobiyama et al 2009 teaches the added limitation in the amended claim 1 limitation (c) a polypeptide induces a Type I interferon immune response. This obviousness rejection comprises analogous prior arts and teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention claimed inventions. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Applicant's arguments filed 09/16/2025 have been fully considered but they are not persuasive, and the 35 USC 103 rejections as recited supra are maintained.
(iii) Applicant’s Argument 3: 35 U.S.C. § 103 (Second Rejection):
Claims 1, 15-17, 19, 43 and 46 Rejection Under 35 U.S.C.§ 103
Claims 1, 15-17, 19, 43 and 46 are rejected under 35 U.S.C. § 103 as allegedly unpatentable over Warfield et al., Journal of lnfectious Diseases, suppl 2, p. S430-S437 (2007) ("Warfield") and further in view ofKobiyama. Applicant respectfully traverses this rejection.
The Office alleges that one of ordinary skill in the art would have been motivated to link the CARD or N'-CARD polypeptide to intra-viral protein Nucleoprotein in the VLP of Ebola virus as the VLP design choice for commercial success for convenient immunization delivery of the VLP. The Office further alleges that one of ordinary skill in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 1 given the combined prior teachings of Warfield and Kobiyama as applied (Office Action, p. 12-15).
Applicant respectfully submits that the Office Action fails to establish a prima facie case of obviousness for Claims 1, 15-17, 19, 43 and 46 under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Warfield in view ofKobiyama, to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). In the absence of specific findings or a clearly stated rationale, the rejection does not allow the Applicant to meaningfully respond to the asserted grounds of rejection.
Notwithstanding this deficiency, Applicant submits that Warfield and Kobiyama, in combination, fail to disclose or suggest a virus-like particle (VLP) comprising a surface protein, a matrix protein, and a polypeptide that enhances an immune response, wherein the polypeptide is a polypeptide adjuvant and wherein the polypeptide is linked to an intra-VLP protein, wherein the polypeptide induces a Type 1 interferon immune response, as recited in the present claims.
Accordingly, Applicant respectfully requests withdrawal of the rejection of claims 1, 15-17, 19, 43 and 46 under 35 U.S.C. § 103. If the Office maintains the rejection, Applicant requests that the Office provide a detailed statement of the basis for the rejection, including a clear identification of the differences between the claims and the cited references, the motivation to combine or modify the cited references, and any supporting rationale as required by KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir.
2000).
Claim 3 Rejection Under 35 USC.§ 103
Claim 3 is rejected under 35 U.S.C. § 103 as allegedly unpatentable over Warfield and Kobiyama and further in view ofMcElory et al., PNAS, vol. 112(5) p.4719-4724 (2015) ("McElory"). Applicant respectfully traverses this rejection.
The Office alleges that one of ordinary skill in the art would have been motivated to develop an Ebola virus VLP capable of inducing T-cells-mediated immune response for better immune protection and for commercial success of the VLP vaccine. The Office alleges that one of ordinary skill in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 3 given the combined prior teachings of Warfield, Kobiyama, and McElory, as applied to claim 3 (Office Action, p. 15-16).
Applicant respectfully submits that the Office Action fails to establish a prima facie case of obviousness for claim 3 under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Warfield, Kobiyama, and McElory, to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). In the absence of specific findings or a clearly stated rationale, the rejection does not allow the Applicant to meaningfully respond to the asserted grounds ofrejection.
Notwithstanding this deficiency, Applicant submits that Warfield, Kobiyama, and McElory, in combination, fail to disclose or suggest a virus-like particle (VLP) comprising a surface protein, a matrix protein, and a polypeptide that enhances an immune response, wherein the polypeptide is a polypeptide adjuvant and wherein the polypeptide is linked to an intra-VLP protein, wherein the polypeptide induces a Type 1 interferon immune response, as recited in the present claims.
Accordingly, Applicant respectfully requests withdrawal of the rejection of claim 3 under 35 U.S.C. § 103. If the Office maintains the rejection, Applicant requests that the Office provide a detailed statement of the basis for the rejection, including a clear identification of the differences between the claims and the cited references, the motivation to combine or modify the cited references, and any supporting rationale as required by KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
Claims 2 and 21 Rejection Under 35 USC.§ 103
Claims 2 and 21 are rejected under 35 U.S.C. § 103 as allegedly unpatentable over Warfield and Kobiyama further in view of Schweneker et al., Journal of Virology, vol 91 Issue 11 e00343-l 7 (2017) ("Schweneker"). Applicant respectfully traverses this rejection.
The Office alleges that one of ordinary skill in the art would have been motivated to develop the VLP of claim 21 comprising the proteins from different strains of the same virus or different viruses providing broader immune protection and for commercial success. The Office alleges that one of ordinary skill in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claims 2 and 21 given the combined prior teachings of Warfield, Kobiyama, and Schweneker, as applied to claims 2 and 21 (Office Action, p. 16-17).
Applicant respectfully submits that the Office Action fails to establish a prima facie case of obviousness for claims 2 and 21 under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Warfield, Kobiyama, and Schweneker, to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). In the absence of specific findings or a clearly stated rationale, the rejection does not allow the Applicant to meaningfully respond to the asserted grounds ofrejection.
Notwithstanding this deficiency, Applicant submits that Warfield, Kobiyama, and Schweneker, in combination, fail to disclose or suggest a virus-like particle (VLP) comprising a surface protein, a matrix protein, and a polypeptide that enhances an immune response, wherein the polypeptide is a polypeptide adjuvant and wherein the polypeptide is linked to an intra-VLP protein, wherein the polypeptide induces a Type 1 interferon immune response, as recited in the present claims.
Accordingly, Applicant respectfully requests withdrawal of the rejection of claims 2 and 21 under 35 U.S.C. § 103. If the Office maintains the rejection, Applicant requests that the
Office provide a detailed statement of the basis for the rejection, including a clear identification of the differences between the claims and the cited references, the motivation to combine or modify the cited references, and any supporting rationale as required by KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
Claim 18 Rejection Under 35 USC.§ 103
Claim 18 is rejected under 35 U.S.C. § 103 as allegedly unpatentable over Warfield and Kobiyama further in view of Licata et al., Journal of Virology, vol 78(14):7344-7351 (2004) ("Licata"). Applicant respectfully traverses this rejection.
The Office alleges that Licata teaches that NP appear to physically interact with VP40 as judged by detection of NP in VP-40-containing VLPs (Office Action, p. 17). The Office further states that Licata discloses that the C-terminal 50 amino acids of NP may be important for interacting with an enhancing release of VP40 VLPs (Office Action, p. 18). The Office alleges that one of ordinary skill in the art would have been motivated to develop the VLP of claim 18 comprising minimum required NP protein fragment for budding and release of the VLP and to incorporate and accommodate the polypeptide adjuvant for linking to the intra-VLP NP protein fragment for commercial success. The Office further alleges that one of ordinary skill in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 18 given the combined prior teachings of Warfield, Kobiyama and Licata, as applied to claim 18 (Office Action, p. 18).
Applicant respectfully submits that the Office Action fails to establish a prima facie case of obviousness for claim 18 under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Warfield, Kobiyama and Licata, to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). The mere observation in Licata that the C-terminal 50 amino acids of NP may be important for interacting with and enhancing release of VP40 VLPs does not itself provide a sufficient reason or motivation for one of ordinary skill to select, isolate, and utilize an C-terminal fragment of NP for the specific purpose recited in amended claim 1 (from which claim 18 depends on). The Licata disclosure is at most, a speculative comment about protein-protein interaction, and does not teach or suggest the claimed invention of a VLP comprising a polypeptide that enhances an immune response, wherein the polypeptide is a polypeptide adjuvant and wherein the polypeptide is linked to an intra-VLP protein, wherein the polypeptide induces a Type 1 interferon immune response as claimed in amended claim 1.
It is well established that a proper obviousness rejection cannot rely on conclusory statements or general assertions about commercial success or reasonable expectation of success. See In re Kotzab, 217 F.3d at 1371. The Office Action's reliance on a general statement about the importance of the NP' s C-terminal region does not provide the necessary obviousness rationale. Accordingly, Applicant respectfully requests withdrawal of the rejection of claim 18 under 35 U.S.C. 103. If the Office maintains the rejection, Applicant requests that the Office provide a detailed statement of the basis for the rejection, including a clear identification of the differences between the claims and the cited references, the motivation to combine or modify the cited references, and any supporting rationale as required by KSR Int 'l Co. v. Teleflex Inc., 550
U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
Claims 4-7 and 23-26 Rejection Under 35 USC§ 103
Claims 4-7 and 23-26 are rejected under 35 U.S.C. § 103 as allegedly unpatentable over Warfield and Kobiyama and further in view ofMeylan. Claim 7 is cancelled herein; therefore, this rejection is moot with respect to claim 7. Applicant respectfully traverses this rejection with respect to claims 4-7 and 23-26.
Regarding claims 4-7, the Office alleges that Warfield and Kobiyama teach the limitations of claims 4-7 (Office Action, p. 18-19). Applicant respectfully submits that the Office's statement in the Office Action does not meet the requirements for establishing a prima facie case of obviousness for claims 4-7 under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Warfield and Kobiyama, to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
A proper obviousness rejection must be supported by specific factual findings and a clear explanation of the reasoning, rather than a mere conclusory statement or incorporation by reference. The current Office Action lacks the necessary factual basis and articulated rationale to enable the Applicant to understand and meaningfully respond to the asserted grounds for rejection.
In regard to claims 23-26, the Office alleges that it would have been obvious to one of ordinary skill to modify the prior art teachings of Warfield and link Ebola virus VLP intraVLP protein NP to a polypeptide comprising two signaling N'-CARD as per teachings ofKobiyama, Meylan, and Xu, regarding N'-CARD or CARD domain from RIG-I-like receptor to arrive at the inventions of claims 23-26. The Office alleges that one of ordinary skill in the art would have been motivated to link two N'-CARD polypeptides or CARD domain from RIG-I-like receptor to intra-viral protein Nucleoprotein for improved obtaining enhanced immune response and commercial success of the VLP vaccine. The Office alleges that one of ordinary skill in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 23-26 (Office Action, p. 19-20).
Applicant respectfully submits that the Office Action fails to establish a prima facie case of obviousness for claims 23-26 under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Galarza, Kobiyama, Meylan and Xu to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). In the absence of specific findings or a clearly stated rationale, the rejection does not allow the Applicant to meaningfully respond to the asserted grounds.
Moreover, setting aside this deficiency, Applicant respectfully submits that the cited references fail to teach or suggest the use of a polypeptide adjuvant in a virus-like particle (VLP) that specifically induces a Type I interferon immune response, as recited in amended claim 1 (from which claims 4-7 and 23-26 depend on). While the prior art may disclose polypeptides that generally enhance immune responses, the induction of a Type I interferon response is a specific and non-obvious improvement of the claimed invention as amended.
Accordingly, Applicant respectfully requests withdrawal of the rejection of claims 4- 7 and 23-26 under 35 U.S.C. § 103. If the Office maintains the rejection, Applicant requests that the Office provide a detailed statement of the basis for the rejection, including a clear identification of the differences between the claims and the cited references, the motivation to combine or modify, and any supporting rationale as required by KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
Claim 27 Rejection Under 35 U.S.C.§ 103
Claim 27 is rejected under 35 U.S.C. § 103 as allegedly unpatentable over Warfield, Kobiyama, Meylan, Xu and further in view of Rhee et al., Clin Exp Vaccine Res 1:50-63 (2012) ("Rhee"), Gitlin et al., PLoS Pathogens, vol 6 (1) el000734 (2010) ("Gitlin"), Benitez et al., Cell Reports, 11: 1714-1726 (2015) to ("Benitez") and Junior et al., Trends in Microbiology, Vol. 27, No. 1 (2019) ("Junior"). Applicant respectfully traverses this rejection.
The Office alleges that it would have been obvious to one of ordinary skill in the art to modify the prior art teachings as applied to claim 25 and incorporate the prior art teachings of Rhee, Benitez, Gitlin, and Junior on MDA-5 with the teachings on VLP as an adjuvant linked to the intra-VLP protein NP to arrive at claim 27. The Office alleges that one of ordinary skill in the art would have been motivated to link the MDA-5 with the intra-viral protein Nucleoprotein to obtain enhanced antiviral type I interferon immune response and commercial success of the VLP vaccine. The Office alleges that one of ordinary skill in the art would have been apprised of a reasonable expectation of success to arrive at the invention of claim 27 given the combined prior teachings applied to the claim 27 (Office Action, p. 20-22).
Applicant respectfully submits that the Office Action fails to establish a prima facie case of obviousness for claim 27 under 35 U.S.C. § 103. In particular, the Office Action fails to articulate how or why a person of ordinary skill in the art would have been motivated to modify or combine the teachings of Warfield, Kobiyama, Meylan, Xu, Rhee, Gitlin, Benitez and Junior to arrive at the claimed invention. There is no reasoned analysis or rational underpinning for the conclusion of obviousness, as required by precedent including KSR Int 'l Co. v. Teleflex Inc., 550
U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). In the absence of specific findings or a clearly stated rationale, the rejection does not allow the Applicant to meaningfully respond to the asserted grounds of rejection.
Notwithstanding this deficiency, Applicant submits that Warfield, Kobiyama, and Schweneker, in combination, fail to disclose or suggest a virus-like particle (VLP) comprising a surface protein, a matrix protein, and a polypeptide that enhances an immune response, wherein the polypeptide is a polypeptide adjuvant and wherein the polypeptide is linked to an intra-VLP protein, wherein the polypeptide induces a Type 1 interferon immune response, as recited in the present claims.
Accordingly, Applicant respectfully requests withdrawal of the rejection of claim 27 under 35 U.S.C. § 103. If the Office maintains the rejection, Applicant requests that the Office provide a detailed statement of the basis for the rejection, including a clear identification of the differences between the claims and the cited references, the motivation to combine or modify the cited references, and any supporting rationale as required by KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), and In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
In Response 3: Applicants argument regarding rejection of claims 1, 15-17, 19, 43 and 46 are rejected under 35 U.S.C. § 103 as allegedly unpatentable over Warfield et al., Journal of lnfectious Diseases, suppl 2, p. S430-S437 (2007) ("Warfield") and further in view of Kobiyama. Applicant respectfully traverses this rejection were not found persuasive because although the applicant amended claim 1 by introducing claim 7 limitation a polypeptide induces a Type I interferon immune response, the amended claim 1 and dependent claims 15-17, 19 and 43 and 46 are rendered obvious by prior arts Warfield et al 2007 (Journal of Infectious Diseases, published 2007, suppl 2, p. S430-S437), Kobiyama et al 2009 (The Journal of Immunology, 2009, 182: 1593–1601) as recited supra. Because Kobiyama et al 2009 teaches the added limitation in the amended claim 1 limitation (c) a polypeptide induces a Type I interferon immune response. This obviousness rejection comprises analogous prior arts and teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed inventions. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Applicant's arguments filed 09/16/2025 have been fully considered but they are not persuasive, and the 35 USC 103 rejections as recited supra are maintained.
Relevant Prior Arts:
Gack MU, Kirchhofer A, Shin YC, Inn KS, Liang C, Cui S, Myong S, Ha T, Hopfner KP, Jung JU. Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated antiviral signal transduction. Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16743-8.
Martinez O, Valmas C, Basler CF. Ebola virus-like particle-induced activation of NF-kappaB and Erk signaling in human dendritic cells requires the glycoprotein mucin domain. Virology. 2007 Aug 1;364(2):342-54.
Holm et al 2012. Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nat Immunol. 2012 Jun 17;13(8):737-43.
Conclusion
23. No claim is allowed.
24. 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).
25. 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.
26. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Quality Assurance Specialist, Art Unit 1600