Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-8, 10, and 12-21 are pending in the instant application.
Claims 3 and 5 were previously withdrawn from further consideration as being drawn to a nonelected species in the reply filed on 10/30/2025.
Claim status
Applicant’s previous election of:
1) Species A (the first structural unit/ interferon): SEQ ID NO: 22 reciting the sequence of Human IFNa2 (Q124R);
2) Species B (the third structural unit/ target antigen): SEQ ID NO: 26 reciting the sequence of HBV Pres1 (ay subtype); and
3) Species C (the second structural unit/Fe): SEQ ID NO: 2 in claim 12, reciting the sequence of human IgG1-Fc,
in the reply filed on 10/30/2025 was acknowledged in the Non-Final Office Action on 1/27/2026. Claims 1-2, 4, 6-8, 10, and 12-21 are under examination for the elected species
Claim Objections and Rejections Withdrawn
The objection to claims 1-2, 4, 6-8, 10, and 12-21 is withdrawn in view of claim amendment.
The rejection of claims 1-2, 4, 6-8, 10, and 12-21 under 35 U.S.C. 112(b) is withdrawn in view of claim amendment.
The rejection of claims 1-2, 4, 6-8, 10, and 12-21 under 35 U.S.C. 103 is withdrawn in view of claim amendment.
Claim Interpretation
In claim 1, the word “containing” will be interpreted as ---comprising--- in the claimed vaccine, which comprises a fusion protein containing, from N-terminal to C-terminal, a type I interferon (IFN), a target antigen, and an immunoglobulin Fc region.
Claim Rejections Necessitated by Amendment
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
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.
Claims 1-2, 4, 6-8, 10, and 12-21 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/225731 (Goh Y et al. reference of record), Glebe D et al. (World J Gastroenterol 2007; 13(1): 22-38 reference of record), Bian Y et al. (Hepatology 2017 66(4) 1067-1082 reference of record), Sikora AG et al. (J Immunol 2009 182(12) 7398-407), Nimal S et al. (Vaccine 2005 23(30) 3984-3990), CN 108727504A, WO 2001/007081 (Gillies SD et al. IDS reference), and Hong Y et al. (Vaccine 2011 29(22) 3909-3916 reference of record) as evidenced by the English Translation of CN108727504 (reference of record) and the English translation of WO 2018/225731 (reference of record).
‘731 taught using a composition comprising virus like particles to generate an immune response against HBV and as a vaccine for treating and/or preventing HBV (translated ‘731 page 2, [0001]). ‘731 taught the Pre-S1 region of HBV plays a role as a sensor that recognizes and binds to cells when HBV infects human hepatocytes (translated ‘731 page 3, [0004]). ‘731 taught anti-Pre-S1 antibodies have been known to have a protective effect on HBV infection (translated ‘731 page 4, [0012]). ‘731 taught a vaccination method of a subject comprising administering a pharmaceutical composition comprising Freund’s adjuvant and pre-S1 peptides for immunization, wherein the degree of binding to pre-S1 of genotype D of antiserum obtained by immunization with pre-S1 peptide of genotype D was high and effective (translated ‘731 page 16, [0111] and Fig 14D). ‘731 taught the amino acid sequence of SEQ ID NO:38 as an antigen for genotype D (translated ‘731 page 8 [0041]).
‘731 did not teach: 1) an IFN-a2a-HBV preS1 antigen-Fc vaccine in the N-terminal to C-terminal direction; 2) an IFNα interferon of instant SEQ ID NO:22; 3) an Fc of SEQ ID NO:2; 4) an HBV preS1 antigen of SEQ ID NO:26; 5) administration of the IFN-a2a-HBV preS1 antigen-Fc vaccine pharmaceutical composition to a subject with HBV, but this is obvious in view of Glebe, Bian, Sikora, Nimal, ‘504, ‘081, and Hong.
Glebe taught the discovery of a crucial domain within the preS1 part of the L-protein, the available HBV vaccines have to be improved (page 35, left column, last paragraph). Glebe taught inclusion of the preS1 sequences into vaccines should therefore directly protect against infection (page 35, left column, last paragraph). Glebe taught HBV preS1 genotype D is 108 amino acids (Figure 2 and Figure 2 legend).
Bian taught PreS1 domain presents more immunogenicity than HBsAg in clinical chronic hepatitis B patients (Fig. 1). Bian taught an effective method of vaccination wherein subjects were administered a vaccine of a pharmaceutical composition comprising a PreS1-polypeptide that effectively prevents HBV infection (Fig. 4). Bian taught PreS1-polypeptide serves as a therapeutic vaccine in HBV carrier mice (Fig. 5).
Sikora taught Type I interferons (IFNs), including IFN-α, can enhance antigen presentation and promote the expansion, survival and effector function of CD8+ cytotoxic T lymphocytes (CTL) during viral infection (abstract). Sikora taught Type I IFNs can act as adjuvants for a variety of experimental vaccines, wherein Type I IFN, when used in conjunction with an influenza vaccine, boosted Th1-type humoral immune responses, improved protection against viral challenge, and enhanced CTL induction after immunization with an influenza-derived peptide (page 7398, right column, last paragraph).
Nimal taught antigen–cytokine fusion proteins have been used successfully in enhancing immune responses against recombinant protein vaccines, wherein both tumor and viral antigens fused to cytokine adjuvants were more effective than a mixture of the two (page 3984, right column, second-third paragraph and page 3985, left column, first paragraph). Nimal taught an effective vaccine fusion composition of the cytokine interferon gamma and a viral antigen gp120 (abstract).
‘504 taught 293 human cells were transfected with an expression vector encoding a heterodimeric IFNα-Fc-antibody fusion protein comprising human IgG1Fc (SEQ ID NO:15) wherein IFNα was fused to the N-terminal of Fc (translated ‘504 page 6, under the heading of construction of IFN-anti-PD-L1 fusion protein, paragraph 1) wherein the fusion protein effectively protected L929 cells from vesicular stomatitis virus (VSV) infection, indicating that the antiviral activity of IFNα remained unchanged (Fig. 2d), wherein the heterodimeric fusion protein was effective in vivo (Fig. 2f-i). ‘504 taught the fusion proteins comprising IFNα-Fc mediate their anti-tumor effects through IFN signaling in subject host cells (translated ‘504 page 8, last line of Example 7). Thus, the fusion proteins comprising IFNα-Fc increased immune cell activation to kill cells. ‘504 taught the Interferon (IFN) as hIFN-alpha 2(Q124R) (SEQ ID NO. 35), wherein mutant IFNα avoids inducing IFNAR signaling pathway activation on other non-targeted cells to avoid IFNα side effects (page 9, Example 10 and page 9, lines 45-46).
‘081 taught a dimeric fusion protein, wherein either or both of the polypeptide chains comprise an adjuvant-antigen-Fc fusion protein from the N-terminal to C-terminal (Fig. 1G). ‘081 taught the antigen as a viral protein (page 8-9 bridging paragraph). ‘081 taught the adjuvant as a cytokine (page 22, second paragraph). ‘081 taught an effective method of immunization with a pharmaceutical composition comprising an antigen-Fc of EpCAM-Fc in combination with the Fc-adjuvant cytokine of Fc-GMCSF, wherein addition of the Fc-cytokine improved antibody titers by about 3-fold boosted the immune response (page 39, first paragraph and Fig. 8A-B), and wherein the administration of the pharmaceutical composition to a subject as a vaccine was effective against cancer cells that expressed the target in vivo (page 39-40, Table 1). Thus, antigens fused to the N terminus of Fc were known to generate effective immune responses. ‘081 taught expression of a combined EpCAM-Fc-GMCSF fusion protein from a DNA from an expression vector in human 293 cells, wherein the antigen EpCAM is fused to the immunoglobulin heavy chain constant region (Fc region) and the adjuvant cytokine GMCSF in a single fusion protein (page 13, lines 19-22; page 40, lines 6-25; Figure 9). ‘081 taught an effective immunization with a viral antigen-Fc in combination with Fc-adjuvant, wherein Fc-gp41pep626 in combination with Fc-GMCSF was effective (Fig. 14A-B). Thus, viral antigens fused to an Fc are effective.
Hong taught immunoglobin Fc fusions enhance the immunization effect (page 3911, left column, last paragraph). Hong taught a recombinant lentiviral vector that expressed a hepatitis B antigen fused to an immunoglobin Fc (Fig. 1), wherein the lentivector expressing HBsAg-Fc fusion was a potent immunization vehicle for stimulating HBsAg specific adaptive immune responses and can induce HBsAg specific immune responses in the presence of low level of HBsAg, implicating the potential of using lentivector for immunotherapy of chronic HBV infection (page 3910, left column, third paragraph). Hong taught administration of the Fc-HBsAg fusion lentivector for immunization stimulated potent CD8 T cell responses (Fig. 2), elicited CD4 T cell responses and humoral immune responses (Fig. 3), and could break immune tolerance in subjects expressing a low level of HBsAg (Fig. 5).
Regarding instant claims 1-2, 4, 6-8, 10, and 12-21, it would have been obvious for a person having ordinary skill in the art to take the effective vaccination method of a subject of ‘731 comprising administering a pharmaceutical composition comprising Freund’s adjuvant and pre-S1 peptides for immunization – and:
Use a PreS1 polypeptide of the first 108 amino acids of ‘731 SEQ ID NO:38 which is the HBV preS1 region for genotype D and administered the polypeptide to a subject with the HBV pathogen for immunization and as a therapeutic vaccine of HBV in view of ‘731, Glebe, and Bian;
Conjugate hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35 to the antigenic HBV preS1 peptide in view of Sikora, Nimal, and ‘504;
Conjugate a Fc domain of IgG1Fc of ‘504 SEQ ID NO:15 to the IFN-a- HBV preS1 vaccine in the order of from N-terminal to C-terminal, (a type I interferon of IFN-a2a)-(a target antigen of HBV preS1)-(an immunoglobulin Fc region) to both Fc regions in view of ‘504, ‘081, and Hong; and
Produce the fusion protein via transfection of an expression plasmid vector of nucleic acids encoding the fusion protein into human HEK293 host cells in view of ‘504
This is obvious because:
1a) Glebe taught: i) inclusion of the preS1 sequences into vaccines should directly protect against infection; and ii) HBV preS1 genotype D is 108 amino acids;
1b) ‘731 taught: i) a pre-S1 peptide of genotype D was effective; and ii) the amino acid sequence of ‘731 SEQ ID NO:38 as an antigen for genotype D;
1c) Bian taught: i) PreS1 domain presents more immunogenicity than HBsAg in clinical chronic hepatitis B patients; ii) an effective method of vaccination wherein subjects were administered a vaccine of a pharmaceutical composition comprising a PreS1-polypeptide that effectively prevents HBV infection; and iii)PreS1-polypeptide serves as a therapeutic vaccine in HBV carrier mice. Thus, an HBV preS1 peptide is known to be antigenic;
2a) Nimal taught antigen–cytokine fusion proteins have been used successfully in enhancing immune responses against recombinant protein vaccines, wherein both tumor and viral antigens fused to cytokine adjuvants were more effective than a mixture of the two;
2b) Sikora taught: i) Type I interferons (IFNs), including IFN-α, can enhance antigen presentation and promote the expansion, survival and effector function of CD8+ cytotoxic T lymphocytes (CTL) during viral infection; and ii) Type I IFNs can act as adjuvants for a variety of experimental vaccines, wherein Type I IFN, when used in conjunction with an influenza vaccine, boosted Th1-type humoral immune responses, improved protection against viral challenge, and enhanced CTL induction after immunization;
2c) ‘504 taught hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35 is a mutant IFNα that avoids inducing IFNAR signaling pathway activation on other non-targeted cells to avoid IFNα side effects;
2d) ‘504 taught a heterodimeric fusion comprising IFNα-IgG1Fc had antiviral activity of IFNα and was effective in vivo wherein IgG1Fc was ‘504 SEQ ID NO:15; Thus, an antigen-cytokine fusion is known to be more effective, IFN-α is effective in vaccines, and hIFN-alpha 2(Q124R) avoids inducing IFNAR signaling pathway activation on other non-targeted cells to avoid IFNα side effects;
3a) ‘081 taught a dimeric fusion protein, wherein either or both of the polypeptide chains comprise an adjuvant-antigen-Fc fusion protein from the N-terminal to C-terminal, wherein the antigen as a viral protein and the adjuvant as a cytokine;
3b) ‘081 taught an effective method of immunization with a pharmaceutical composition comprising an antigen-Fc of EpCAM-Fc in combination with the Fc-adjuvant cytokine of Fc-GMCSF, wherein addition of the Fc-cytokine improved antibody titers by about 3-fold boosted the immune response, and wherein the administration of the pharmaceutical composition to a subject as a vaccine was effective;
3c) Hong taught: i) immunoglobin Fc fusions enhance the immunization effect; ii) a recombinant lentiviral vector that expressed a hepatitis B antigen fused to an immunoglobin Fc, wherein the lentivector expressing HBsAg-Fc fusion was a potent immunization vehicle for stimulating HBsAg specific adaptive immune responses and can induce HBsAg specific immune responses in the presence of low level of HBsAg, implicating the potential of using lentivector for immunotherapy of chronic HBV infection; iii) administration of the Fc-HBsAg fusion lentivector for immunization stimulated potent CD8 T cell responses, elicited CD4 T cell responses and humoral immune responses, and could break immune tolerance in subjects expressing a low level of HBsAg;
3d) ‘504 taught a heterodimeric fusion comprising IFNα-IgG1Fc had antiviral activity of IFNα and was effective in vivo wherein IgG1Fc was ‘504 SEQ ID NO:15; Thus, Fc vaccine conjugates N-terminal to C-terminal of (a cytokine)-(a target antigen)-(an immunoglobulin Fc region) have been previously taught, HBV antigen-Fc vaccine fusions are known to be effective, and IFNα-IgG1Fc are known to be effective;
4a) ‘504 taught 293 human cells were effectively transfected with an expression vector encoding a heterodimeric IFNα-Fc-antibody fusion protein comprising human IgG1Fc (SEQ ID NO:15) wherein IFNα was fused to the N-terminal of Fc.
There is a reasonable expectation of success because:
1a) Glebe taught: i) inclusion of the preS1 sequences into vaccines should directly protect against infection; and ii) HBV preS1 genotype D is 108 amino acids;
1b) ‘731 taught: i) a pre-S1 peptide of genotype D was effective; and ii) the amino acid sequence of ‘731 SEQ ID NO:38 as an antigen for genotype D;
1c) Bian taught: i) PreS1 domain presents more immunogenicity than HBsAg in clinical chronic hepatitis B patients; ii) an effective method of vaccination wherein subjects were administered a vaccine of a pharmaceutical composition comprising a PreS1-polypeptide that effectively prevents HBV infection; and iii)PreS1-polypeptide serves as a therapeutic vaccine in HBV carrier mice. Thus, an HBV preS1 peptide is known to be antigenic;
2a) Nimal taught antigen–cytokine fusion proteins have been used successfully in enhancing immune responses against recombinant protein vaccines, wherein both tumor and viral antigens fused to cytokine adjuvants were more effective than a mixture of the two;
2b) Sikora taught: i) Type I interferons (IFNs), including IFN-α, can enhance antigen presentation and promote the expansion, survival and effector function of CD8+ cytotoxic T lymphocytes (CTL) during viral infection; and ii) Type I IFNs can act as adjuvants for a variety of experimental vaccines, wherein Type I IFN, when used in conjunction with an influenza vaccine, boosted Th1-type humoral immune responses, improved protection against viral challenge, and enhanced CTL induction after immunization;
2c) ‘504 taught hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35 is a mutant IFNα that avoids inducing IFNAR signaling pathway activation on other non-targeted cells to avoid IFNα side effects;
2d) ‘504 taught a heterodimeric fusion comprising IFNα-IgG1Fc had antiviral activity of IFNα and was effective in vivo wherein IgG1Fc was ‘504 SEQ ID NO:15. Thus, an antigen-cytokine fusion is known to be more effective, IFN-α is effective in vaccines, and hIFN-alpha 2(Q124R) avoids inducing IFNAR signaling pathway activation on other non-targeted cells to avoid IFNα side effects;
3a) ‘081 taught a dimeric fusion protein, wherein either or both of the polypeptide chains comprise an adjuvant-antigen-Fc fusion protein from the N-terminal to C-terminal, wherein the antigen as a viral protein and the adjuvant as a cytokine;
3b) ‘081 taught an effective method of immunization with a pharmaceutical composition comprising an antigen-Fc of EpCAM-Fc in combination with the Fc-adjuvant cytokine of Fc-GMCSF, wherein addition of the Fc-cytokine improved antibody titers by about 3-fold boosted the immune response, and wherein the administration of the pharmaceutical composition to a subject as a vaccine was effective;
3c) Hong taught: i) immunoglobin Fc fusions enhance the immunization effect; ii) a recombinant lentiviral vector that expressed a hepatitis B antigen fused to an immunoglobin Fc, wherein the lentivector expressing HBsAg-Fc fusion was a potent immunization vehicle for stimulating HBsAg specific adaptive immune responses and can induce HBsAg specific immune responses in the presence of low level of HBsAg, implicating the potential of using lentivector for immunotherapy of chronic HBV infection; iii) administration of the Fc-HBsAg fusion lentivector for immunization stimulated potent CD8 T cell responses, elicited CD4 T cell responses and humoral immune responses, and could break immune tolerance in subjects expressing a low level of HBsAg;
3d) ‘504 taught a heterodimeric fusion comprising IFNα-IgG1Fc had antiviral activity of IFNα and was effective in vivo wherein IgG1Fc was ‘504 SEQ ID NO:15; Thus, a pharmaceutical vaccine composition comprising a fusion protein containing from N-terminal to C-terminal of a (type I interferon of hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35)-(a target antigen of the first 108 amino acids of HBV preS1 genotype D ‘731 SEQ ID NO:38)-(an immunoglobulin Fc region of ‘504 SEQ ID NO:15) would be expected to be an effective pharmaceutical vaccine composition in combination with Freund adjuvant;
4a) ‘504 taught 293 human cells were effectively transfected with an expression vector encoding a heterodimeric IFNα-Fc-antibody fusion protein comprising human IgG1Fc (SEQ ID NO:15) wherein IFNα was fused to the N-terminal of Fc.
This would produce an effective vaccination method of a subject with the HBV pathogen for immunization and as a therapeutic vaccine of HBV (instant claims 7-8 and 10) comprising administering a pharmaceutical vaccine composition (instant claim 20) comprising Freund’s adjuvant (instant claims 19 and 21) and a homodimeric (instant claim 4) fusion protein wherein the first and second polypeptide chains are the identical (instant claim 13) of a N-terminal to C-terminal fusion protein of:
[hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35]-[the first 108 amino acids of the HBV pre-S1 peptide of genotype D of ‘731 SEQ ID NO:38 as an antigen (instant claim 2)]-[IgG1Fc of ‘504 SEQ ID NO:15] (instant claims 1 and 12), wherein the fusion protein is produced via transfection of an expression plasmid vector (instant claim 14) of nucleic acids (instant claim 6) encoding the fusion protein into human HEK293 host cells (instant claim 15-18). The homodimeric fusion protein is identical to the elected species of [IFN-alpha 2 instant SEQ ID NO:22]-[HBV Pres1 (ay subtype) instant SEQ ID NO:26]-[IgG1 Fc instant SEQ ID NO:2].
Response to Arguments
Applicant argues amended claim 1 recites a vaccine comprising a fusion protein comprising, from N-terminal to C-terminal, a type 1 interferon (IFN), a target antigen, and an immunoglobulin Fc region. Applicant submits that the cited references fail to teach or suggest Applicant's claimed fusion protein with the particularly claimed orientation of features.
Applicant argues the inventors have discovered that a fusion protein with three structural units as presently claimed unexpectedly exhibit a synergistic effect. Specifically, the present application provides ample data demonstrating that a fusion protein containing an interferon, a target antigen, and an immunoglobulin Fc region, in the claimed N-terminal to C-terminal orientation, unexpectedly produced superior effects compared to other fusion proteins tested and exhibited a synergistic effect in promoting antigenic immunizing activity. See, Examples 3-20 and Figs. 8-31. Applicant's data demonstrates that the claimed fusion protein significantly enhances the immunogenicity of the antigenic molecule and induces the production of broad-spectrum neutralizing antibodies as compared to, for example, a free antigen or an antigen-Fc fusion protein, See, Example 3 and Fig. 8. Further, the claimed fusion protein can be used as a prophylactic vaccine for effective prevention of pathogenic infections (see, Example 4 and Fig. 9) and can be used as a therapeutic vaccine (see, Examples 5 and 7, and Figs. 10 and 12). Moreover, the fusion protein can break immune tolerance against an antigen (see, Example 8, and Fig. 13), and can elicit a stronger antibody response (see, Example 9 and Fig. 15), and the like.
The Declaration of Hua Peng under 37 C.F.R. § 1.132 ("the Declaration") argues in #3 that the immunogenicity of the interferon-antigen-Fc (IFN-Ag-Fc) fusion protein form as recited in the present claims to different antigen fusion protein forms, including interferon-antigen (IFN-Ag), Ag-Fc, and the mixture of IFN-Ag and Ag-Fc, using the same methods described in the above-captioned application was compared. In the study below, we used the hepatitis B virus (HBV) antigen preSl or the SARS-CoV-2 RBD as the antigens and either interferon alpha 4 (IFNa4) or interferon gamma (IFNγ) as the IFN component in the fusion proteins. Our results show that the IFN-Ag-Fc fusion protein unexpectedly elicited a significantly stronger immune response compared to the other fusion proteins tested.
The Declaration argues in #6 that We first examined the immunogenicity of different fusion proteins using IFNa and the preSl polypeptide. The preSl polypeptide of HBV L-HBsAg is the functional domain which allows HBV virus to bind to host cells. Our study revealed that the immunogenicity of IFNa-Ag-Fc is significantly stronger than either IFNa-Ag, Ag-Fc, and the IFNa-Ag + Ag-Fc mixed vaccination group. See FIG. 1 (left) and Table 1 (top). In fact, immunogenicity of IFNa-Ag-Fc is significantly stronger than even the sum of both IFNa-Ag and Ag-Fc immune responses. See Table 1 (top). In addition, the antibody response induced by the IFNa-preSl-Fc fusion protein is significantly stronger than that of IFNa-preSl, preSl-Fc, and the IFNa-preSl + preSl-Fc mixture group. See FIG. 1 (right) and Table 1 (bottom). The antibody response induced by the IFNa-preSl-Fc fusion protein was also significantly greater than the sum of the IFNa-preSl and preSl-Fc antibody responses. See Table 1 (bottom). The results suggest that the IFNa-preSl-Fc fusion protein induces a more potent T cell response, and the fusion of IFN, Ag, and Fc together can synergistically improve the antigen specific immune response.
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The Declaration argues in #7 that we next examined the immunogenicity of different fusion proteins using the INFy or INFa with the RBD antigen. The effect of interferon in the IFN-Ag-Fc molecule on antibody response is shown in FIG. 2 and Table 2 below. Both the mIFNa-RBD-Fc and the mINFy-RBDFc fusion proteins elicited a significantly stronger response than any of the other fusion proteins tested.
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In response, Applicant's arguments filed 4/24/2026 have been fully considered but they are not persuasive. Regarding the amended claims, the updated 103 rejection is above.
Regarding an unexpectedly synergistic effect of a fusion protein containing an interferon, a target antigen, and an immunoglobulin Fc region, in the claimed N-terminal to C-terminal orientation and the Declaration filed 4/24/2026 – the Applicant elected species under review is a fusion protein containing, from N-terminal to C-terminal:
1) Species A (the first structural unit/ interferon): SEQ ID NO: 22 reciting the sequence of Human IFNa2 (Q124R);
2) Species B (the third structural unit/ target antigen): SEQ ID NO: 26 reciting the sequence of HBV Pres1 (ay subtype); and
3) Species C (the second structural unit/Fe): SEQ ID NO: 2 in claim 12, reciting the sequence of human IgG1-Fc.
The specification and Declaration do not show unexpected results regarding the elected species. The disclosure and the Declaration used the hepatitis B virus (HBV) antigen preSl or the SARS-CoV-2 RBD as the antigens and either interferon alpha 4 (IFNa4) or interferon gamma (IFNγ) as the IFN component in the fusion proteins. MPEP 716.02(d) states whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support."
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4, 6-8, 10, and 12-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 19/172,135 in view of WO2001/007081 (Gillies SD et al. IDS reference), CN 108727504A (reference of record), Bian Y et al. (Hepatology 2017 66(4) 1067-1082 reference of record), WO 2018/225731 (Goh Y et al. reference of record), Glebe D et al. (World J Gastroenterol 2007; 13(1): 22-38 reference of record), and Hong Y et al. (Vaccine 2011 29(22) 3909-3916 reference of record) as evidenced by the English Translation of CN 108727504 (reference of record) and the English translation of WO 2018/225731 (reference of record).
The claims of copending ‘135 taught a vaccine, production of a vaccine, and method of treatment with a vaccine wherein the vaccine comprises a fusion protein of an interferon, target antigen of a HBV Pres1 antigen, and immunoglobulin Fc region in copending claims 1-18, wherein a vaccine comprising a fusion protein of an interferon, target antigen of a HBV Pres1 antigen, and immunoglobulin Fc region in copending claim 1, wherein the fusion protein is a homodimer fusion protein comprising an identical first and second polypeptide chain comprising from N-terminal to C-terminal, the interferon, the target antigen, and the immunoglobulin Fc region in copending claim 2, wherein the immunoglobulin Fc region is IgG1 in copending claim 3, wherein the target antigen is HBV Pres1 antigen of SEQ ID NO.16 in copending claim 4, wherein the fusion protein contains a linking fragment between each structural unit in copending claim 6, wherein a nucleic acid molecule encoding the fusion protein is claimed in copending claim 7, wherein an expression vector comprising the nucleic acid of the fusion protein is claimed in copending claim 8, wherein a eukaryotic host cell comprises the nucleic acid molecule or expression vector encoding the fusion protein is claimed in copending claims 9-10. Copending ‘135 taught a method of preventing or treating HBV in a subject, comprising administering to the subject the fusion protein in the vaccine above in copending claim 11, wherein the vaccine is in a composition in copending claim 12, wherein the composition is used as a prophylactic or therapeutic vaccine for hepatitis B in copending claim 13, wherein the vaccine composition further comprises Freund's adjuvant in copending claims 14-15, wherein the vaccine can be used in combination with other prophylactic or therapeutic therapies in copending claims 16-17. Copending ‘135 taught a method of preventing or treating hepatitis B virus infection in a subject comprising administering to the subject the fusion protein above in copending claim 18.
Copending ‘135 does not teach: 1) an IFNα interferon of instant SEQ ID NO:22; 2) an Fc of SEQ ID NO:2; 3) an HBV preS1 antigen of SEQ ID NO:26 which has 108 amino acids; 4) administration of the IFN-a2a- HBV preS1 antigen-Fc in a vaccine pharmaceutical composition with Freund adjuvant to a subject with HBV; but this is obvious in view of ‘081, ‘504, Bian, ‘731, Glebe, and Hong.
‘081 taught a dimeric fusion protein, wherein either or both of the polypeptide chains comprise an adjuvant-antigen-Fc fusion protein from the N-terminal to C-terminal (Fig. 1G). ‘081 taught the antigen as a viral protein (page 8-9 bridging paragraph). ‘081 taught the adjuvant as a cytokine (page 22, second paragraph). ‘081 taught an effective method of immunization with a pharmaceutical composition comprising an antigen-Fc of EpCAM-Fc in combination with the Fc-adjuvant cytokine of Fc-GMCSF, wherein addition of the Fc-cytokine improved antibody titers by about 3-fold boosted the immune response (page 39, first paragraph and Fig. 8A-B), and wherein the administration of the pharmaceutical composition to a subject as a vaccine was effective against cancer cells that expressed the target in vivo (page 39-40, Table 1). Thus, antigens fused to the N terminus of Fc were known to generate effective immune responses. ‘081 taught expression of a combined EpCAM-Fc-GMCSF fusion protein from a DNA from an expression vector in human 293 cells, wherein the antigen EpCAM is fused to the immunoglobulin heavy chain constant region (Fc region) and the adjuvant cytokine GMCSF in a single fusion protein (page 13, lines 19-22; page 40, lines 6-25; Figure 9). ‘081 taught an effective immunization with a viral antigen-Fc in combination with Fc-adjuvant, wherein Fc-gp41pep626 in combination with Fc-GMCSF was effective (Fig. 14A-B). Thus, viral antigens fused to an Fc are effective.
‘504 taught 293 human cells were transfected with an expression vector encoding a heterodimeric IFNα-Fc-antibody fusion protein comprising human IgG1Fc (SEQ ID NO:15) wherein IFNα was fused to the N-terminal of Fc (translated ‘504 page 6, under the heading of construction of IFN-anti-PD-L1 fusion protein, paragraph 1) wherein the fusion protein effectively protected L929 cells from vesicular stomatitis virus (VSV) infection, indicating that the antiviral activity of IFNα remained unchanged (Fig. 2d), wherein the heterodimeric fusion protein was effective in vivo (Fig. 2f-i). ‘504 taught the fusion proteins comprising IFNα-Fc mediate their anti-tumor effects through IFN signaling in subject host cells (translated ‘504 page 8, last line of Example 7). Thus, the fusion proteins comprising IFNα-Fc increased immune cell activation to kill cells. ‘504 taught the Interferon (IFN) as hIFN-alpha 2(Q124R) (SEQ ID NO. 35), wherein mutant IFNα avoids inducing IFNAR signaling pathway activation on other non-targeted cells to avoid IFNα side effects (page 9, Example 10 and page 9, lines 45-46).
Bian taught PreS1 domain presents more immunogenicity than HBsAg in clinical chronic hepatitis B patients (Fig. 1). Bian taught PreS1-polypeptide vaccination effectively prevents HBV infection (Fig. 4). Bian taught PreS1-polypeptide serves as a therapeutic vaccine in HBV carrier mice (Fig. 5).
‘731 taught using a composition comprising virus like particles to generate an immune response against HBV and as a vaccine for treating and/or preventing HBV (translated ‘731 page 2, [0001]). ‘731 taught the Pre-S1 region of HBV plays a role as a sensor that recognizes and binds to cells when HBV infects human hepatocytes (translated ‘731 page 3, [0004]). ‘731 taught anti-Pre-S1 antibodies have been known to have a protective effect on HBV infection (translated ‘731 page 4, [0012]). ‘731 taught administration of a composition of Freund’s adjuvant and pre-S1 peptides for immunization, wherein the degree of binding to pre-S1 of genotype D of antiserum obtained by immunization with pre-S1 peptide of genotype D was high and effective (translated ‘731 page 16, [0111] and Fig 14D). ‘731 taught the amino acid sequence of SEQ ID NO:38 as an antigen for genotype D (translated ‘731 page 8 [0041]).
Glebe taught the discovery of a crucial domain within the preS1 part of the L-protein, the available HBV vaccines have to be improved (page 35, left column, last paragraph). Glebe taught inclusion of the preS1 sequences into vaccines should therefore directly protect against infection (page 35, left column, last paragraph). Glebe taught HBV preS1 genotype D is 108 amino acids (Figure 2 and Figure 2 legend).
Hong taught immunoglobin Fc fusions enhance the immunization effect (page 3911, left column, last paragraph). Hong taught a recombinant lentiviral vector that expressed a hepatitis B antigen fused to an immunoglobin Fc (Fig. 1), wherein the lentivector expressing HBsAg-Fc fusion was a potent immunization vehicle for stimulating HBsAg specific adaptive immune responses and can induce HBsAg specific immune responses in the presence of low level of HBsAg, implicating the potential of using lentivector for immunotherapy of chronic HBV infection (page 3910, left column, third paragraph). Hong taught administration of the Fc-HBsAg fusion lentivector for immunization stimulated potent CD8 T cell responses (Fig. 2), elicited CD4 T cell responses and humoral immune responses (Fig. 3), and could break immune tolerance in subjects expressing a low level of HBsAg (Fig. 5).
Regarding instant claims 1-2, 4, 6-8, 10, and 12-21, it would have been obvious for a person having ordinary skill in the art to take the method of copending ‘135 claims 1-4 and 7-18 of preventing or treating hepatitis B virus infection in a subject comprising administering to the subject a vaccine composition of Freund’s adjuvant and a homodimeric first polypeptide chain and the second polypeptide chain from N-terminal to C-terminal an interferon, target antigen of an HBV Pres1 antigen of ‘135 SEQ ID NO.16, and immunoglobulin IgG1 Fc fusion protein, wherein the fusion peptide was produced in an eukaryotic host cell comprising an expression vector comprising the nucleic acid molecule encoding the fusion protein: and –
exchange the IFN-α interferon for the hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35 in view of ‘504;
use the IgG1 Fc sequence of ‘504 SEQ ID NO:15 in view of ‘504;
use the first 108 amino acids of the HBV preS1 antigen of ‘135 SEQ ID NO.16 which is the HBV preS1 region for genotype D in view of Glebe;
administer the heterodimeric fusion IFN-a2a-HBV preS1 antigen- Fc in a pharmaceutical vaccine composition which further comprised the adjuvant of Freund’s adjuvant to a subject with HBV in view of ‘731, and Hong.
This is obvious because:
‘504 taught hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35 is a mutant IFNα that avoids inducing IFNAR signaling pathway activation on other non-targeted cells to avoid IFNα side effects;
‘504 taught a heterodimeric fusion comprising IFNα-IgG1Fc had antiviral activity of IFNα and was effective in vivo wherein IgG1Fc was ‘504 SEQ ID NO:15;
a) Glebe taught: i) inclusion of the preS1 sequences into vaccines should directly protect against infection; and ii) HBV preS1 genotype D is 108 amino acids;
b) ‘731 taught a pre-S1 peptide of genotype D was effective;
a) ‘504 taught heterodimeric IFNα fused to the N terminus of IgG1 Fc is effective;
‘731 taught: i) anti-Pre-S1 antibodies have been known to have a protective effect on HBV infection; and ii) administration of a composition of Freund’s adjuvant and pre-S1 peptides for immunization, wherein binding to pre-S1 of genotype D of antiserum obtained by immunization with pre-S1 peptide of genotype D was effective;
Hong taught administration of a Fc-HBV fusion lentivector for immunization stimulated potent CD8 T cell responses, elicited CD4 T cell responses and humoral immune responses, and could break immune tolerance in subjects expressing a low level of HBV antigens.
There is a reasonable expectation of success because:
hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35 is a mutant IFNα that avoids inducing IFNAR signaling pathway activation on other non-targeted cells to avoid systemic IFNα side effects;
a heterodimeric fusion comprising IFNα-IgG1Fc had antiviral activity of IFNα and was effective in vivo. Thus, IFNα-IgG1Fc constructs were known to be effective;
a) Glebe taught: i) inclusion of the preS1 sequences into vaccines should directly protect against infection; and ii) HBV preS1 genotype D is 108 amino acids;
b) ‘731 taught: i) a pre-S1 peptide of genotype D was effective; and ii) the amino acid sequence of ‘731 SEQ ID NO:38 as an antigen for genotype D. Thus, using the first 108 amino acids of the pre-S1 peptide of genotype D of ‘731 SEQ ID NO:38 would be expected to be an effective antigen;
a) ‘504 taught heterodimeric IFNα fused to the N terminus of IgG1 Fc is effective;
‘731 taught: i) anti-Pre-S1 antibodies have been known to have a protective effect on HBV infection; and ii) administration of a composition of Freund’s adjuvant and pre-S1 peptides for immunization, wherein binding to pre-S1 of genotype D of antiserum obtained by immunization with pre-S1 peptide of genotype D was effective;
Hong taught administration of a Fc-HBV fusion lentivector for immunization stimulated potent CD8 T cell responses, elicited CD4 T cell responses and humoral immune responses, and could break immune tolerance in subjects expressing a low level of HBV antigens.
Thus, the fusion protein of N-terminal to C-terminal of [hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35]-[the first 108 amino acids of the pre-S1 peptide of genotype D of ‘731 SEQ ID NO:38 as an antigen]- [IgG1Fc of ‘504 SEQ ID NO:15] would be expected to be an effective vaccine composition.
This would produce a method of preventing or treating hepatitis B virus infection, which would include the vaccine as a therapeutic vaccine (instant claim 10) in a subject comprising administering to the subject a pharmaceutical vaccine composition of Freund’s adjuvant and a homodimeric (instant claim 4) first polypeptide chain and the second polypeptide chain that are identical (instant claim 13) comprising from N-terminal to C-terminal:
[hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35]-[the first 108 amino acids of the pre-S1 peptide of genotype D of ‘135 SEQ ID NO.16 as an antigen (instant claim 2)]- [IgG1Fc of ‘504 SEQ ID NO:15] (instant claims 7-8) (instant claims 19-21), wherein the fusion peptide was produced in a eukaryotic host cell comprising an expression vector comprising the nucleic acid molecule encoding the fusion protein (instant claims 6 and 14-18) (instant claims 1 and 12). The heterodimeric fusion protein is identical to the elected species of [IFN-alpha 2 instant SEQ ID NO:22]-[IgG1 Fc instant SEQ ID NO:2]-[HBV Pres1 (ay subtype) instant SEQ ID NO:26].
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant argues amended claim 1 of the present application requires the order of the fusion protein units from the N-terminal to the C-terminal as interferon -
target antigen - Fc. Applicant submits that the units in the fusion protein of the' 135
Application are not recited in this specific order. Thus, the claimed vaccine of the present application and that of the '135 Application are patentably distinct.
As discussed above, nothing in the disclosures of Gillies, CN 108727504A, Bian,
Yasumasa, Glebe, and Hong disclose or suggest a fusion protein comprising the "interferon-target antigen-Fc" structural units as presently claimed. Therefore, these cited documents do not overcome the deficiencies of the '135 Application.
In response, Applicant's arguments filed 4/24/2026 have been fully considered but they are not persuasive. Regarding the amended claims, the updated 103 rejection is above. Regarding the units in the fusion protein of ‘135 are not recited as N-terminal to the C-terminal as interferon -target antigen-Fc –
copending ‘135 recited the fusion protein comprising from N-terminal to C-terminal, the interferon, the target antigen, and the immunoglobulin Fc region in copending claim 2 as described above. In claim 1, the word “containing” is interpreted as ---comprising--- in the claimed vaccine, which comprises a fusion protein containing, from N-terminal to C-terminal, a type I interferon (IFN), a target antigen, and an immunoglobulin Fc region. Thus, the order of ‘135 is identical. The elected species is obvious with a reasonable expectation of success as discussed in the obvious rational above.
Conclusion
Claims 1-2, 4, 6-8, 10, and 12-21 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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