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Claims 3 and 5 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/30/2025.
Restriction Response
Applicant’s 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 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-2, 4, 6-8, 10, and 12-21 are under examination for the elected species
Priority
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and
41.202(e).
Failure to provide a certified translation may result in no benefit being accorded
for the non-English application. The effective priority date is the filing date of
PCT/CN2021/103931 filed on 7/1/2021 in the absence of a certified translation of
CN202010623708.8 filed on 7/1/2020 or CN202110353488.6 filed on 3/31/2021.
Objections to the Claims
Claims 1-2, 4, 6-8, 10, and 12-21 are objected to because of the following informalities:
Regarding instant claim 1, the claim is grammatically incorrect, wherein the claim recites “as first structural” as opposed to ---as a first structural--- in line 3. Claims 2, 4, 6-8, 10, and 12-21 are dependent on claim 1 and further contain the incorrect wording. Thus, claims 2, 4, 6-8, 10, and 12-21 are also objected to.
Regarding instant claim 8, hepatitis B and HBV are both recited in 4). Appropriate correction is required.
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4, 6-8, 10, and 12-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding instant claim 1, the claim recites a fusion protein containing, from N-terminal to C-terminal, an interferon, a target antigen, and an immunoglobulin Fc region, as first structural unit, third structural unit, and second structural unit, respectively. It is unclear: 1) if the structure of the fusion protein is from N-terminal to C-terminal, an interferon, a target antigen, and an immunoglobulin Fc region wherein the components are identified as the first structural unit, third structural unit, and second structural unit, respectively; or 2) if the structure of the fusion protein is from N-terminal to C-terminal, an interferon, an immunoglobulin Fc region, a target antigen. Thus, the meets and bounds are indefinite. It is recommended to write the fusion protein in the order from N-terminal to C-terminal for clarity. Claims 2, 4, 6-8, 10, and 12-21 are dependent on claim 1 and further contain the indefinite claimed matter and thus are also rejected.
To promote compact prosecution the structure of the fusion protein will be interpreted as a fusion protein containing, from N-terminal to C-terminal, an interferon, an immunoglobulin Fc region, a target antigen.
Regarding instant claim 8, the claim recites preventing or treating: 1) a virus or a bacterium; 2) a virus selected from HBV…; 3) SARS-COV…; 4) hepatitis B…, but the meets and bounds are indefinite for treating or preventing “an infection in the subject” rather than treating or preventing the virus or bacterium.
To promote compact prosecution ---the subject from or with an infection of--- will be inserted before the first virus species of 1)-4).
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 2012/146630 A1(Stefan J et al. IDS reference), WO2001/007081 (Gillies SD et al. IDS reference), CN 108727504A, Bian Y et al. (Hepatology 2017 66(4) 1067-1082), WO2018/225731 and, Glebe D et al. (World J Gastroenterol 2007; 13(1): 22-38), and Hong Y et al. (Vaccine 2011 29(22) 3909-3916) as evidenced by the English Translation of CN108727504 and the English translation of WO2018/225751.
Stefan taught an HBV preS1-Fc-IFN-a2a fusion protein which comprises a heterodimeric first polypeptide chain and the second polypeptide chain fusion protein, wherein the N-terminal to C-terminal the fusion protein is HBV preS1-Fc-IFN-a2a (page 31, IV, Fig 1 description and Fig. 1).
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Stefan taught a method of treating an individual having a hepatitis-B- virus infection comprising administering to the individual an effective amount of the fusion protein (page 6, lines 27-29). Stefan taught generation of an HBV preS1-Fc-IFN-a2a fusion protein via transfection of an expression plasmid encoding the fusion protein into human HEK293 cells (page 36, Example 2, lines 17-33). Stephan taught fusion proteins of the invention can be used in combination with other agents such as an adjuvant in a therapy (page 27 last paragraph to page 28 first paragraph).
Stefan did not teach: 1) an IFN-a2a-Fc-HBV preS1 antigen 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-Fc-HBV preS1 antigen 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 generation of effective immune responses for fusion proteins of Fc-antigen with the Fc as the N-terminus fused to the antigen on the C-terminus, wherein mice injected with Fc-EPCAM antigen generated immune responses and produced antibodies directed against the antigen (pages 38-39, Example 6, Fig. 7-8). Thus, antigens fused to the N terminus of Fc were known to generate effective immune responses. ‘081 taught co-administration of Fc-antigen with a Fc-adjuvant of a Fc-cytokine boosted the immune response (pages 38-39, Example 6, Fig. 7-8). ‘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).
‘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 Stefan for generating a first polypeptide chain and the second polypeptide chain heterodimeric N-terminal to C-terminal HBV preS1-Fc-IFN-a2a fusion protein via transfection of an expression plasmid of nucleic acids encoding the fusion protein into human HEK293 cells: and –
reverse the order of the fusion protein to produce a fusion protein of N-terminal to C-terminal of IFN-a2a-Fc-HBV preS1 antigen in view of ‘081;
exchange the IFN-α interferon for the hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35 in view of ‘504;
exchange the Fc for an IgG1Fc of ‘504 SEQ ID NO:15 in view of ‘504;
exchange the HBV preS1 antigen for the first 108 amino acids of ‘731 SEQ ID NO:38 which is the HBV preS1 region for genotype D in view of ‘731 and Glebe;
administer the heterodimeric fusion IFN-a2a-Fc-HBV preS1 antigen in a pharmaceutical vaccine composition which further comprised the adjuvant of Freund’s adjuvant to a subject with HBV as a therapeutic treatment in view of ‘731, Hong, and Stefan.
This is obvious because:
‘081 taught generation of effective immune responses for fusion proteins of: i) Fc-antigen with the Fc as the N-terminus fused to the antigen on the C-terminus, wherein mice injected with Fc-EPCAM antigen generated effective immune responses and produced antibodies directed against the antigen Thus, antigens fused to the C terminus of Fc were known to generate effective immune responses;
‘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: 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.
a) ‘801 taught antigens fused to the C terminus of Fc were known to generate effective immune responses;
‘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; and
Stefan taught a method of treating an individual having a hepatitis-B- virus infection comprising administering to the individual an effective amount of the fusion protein.
There is a reasonable expectation of success because:
Antigens fused to the C terminus of Fc were known to generate effective immune responses;
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) ‘801 taught antigens fused to the C terminus of Fc were known to generate effective immune responses;
‘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]-[IgG1Fc of ‘504 SEQ ID NO:15]-[the first 108 amino acids of the pre-S1 peptide of genotype D of ‘731 SEQ ID NO:38 as an antigen] would be expected to be an effective vaccine composition.
This would produce a method of generating a heterodimeric (instant claim 4) fusion protein wherein the first and second polypeptide chains are different (instant claim 13) N-terminal to C-terminal fusion protein of:
[hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35]-[IgG1Fc of ‘504 SEQ ID NO:15]-[the first 108 amino acids of the pre-S1 peptide of genotype D of ‘731 SEQ ID NO:38 as an antigen (instant claim 2)], wherein
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), which can be used in a vaccine composition,
wherein the vaccine composition is further comprised of the fusion protein of [hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35]-[IgG1Fc of ‘504 SEQ ID NO:15]-[the first 108 amino acids of the pre-S1 peptide of genotype D of ‘731 SEQ ID NO:38 as an antigen]
and Freund’s adjuvant (instant claims 19 and 21) and is a pharmaceutical vaccine composition (instant claim 20) and is administered to a subject with the HBV pathogen for immunization and as a therapeutic vaccine of HBV (instant claims 7-8, 10) (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].
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, Bian Y et al. (Hepatology 2017 66(4) 1067-1082), WO2018/225731 and, Glebe D et al. (World J Gastroenterol 2007; 13(1): 22-38), and Hong Y et al. (Vaccine 2011 29(22) 3909-3916) as evidenced by the English Translation of CN108727504 and the English translation of WO2018/225751.
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 IFN-a2a-Fc-HBV preS1 antigen 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 which has 108 amino acids; 5) administration of the IFN-a2a-Fc-HBV preS1 antigen 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 generation of effective immune responses for fusion proteins of Fc-antigen with the Fc as the N-terminus fused to the antigen on the C-terminus, wherein mice injected with Fc-EPCAM antigen generated immune responses and produced antibodies directed against the antigen (pages 38-39, Example 6, Fig. 7-8). Thus, antigens fused to the N terminus of Fc were known to generate effective immune responses. ‘081 taught co-administration of Fc-antigen with a Fc-adjuvant of a Fc-cytokine boosted the immune response (pages 38-39, Example 6, Fig. 7-8). ‘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).
‘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 –
change the order of the fusion protein to produce a fusion protein of N-terminal to C-terminal of IFN-a2a-Fc-HBV preS1 antigen in view of ‘081;
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-Fc-HBV preS1 antigen 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:
‘081 taught generation of effective immune responses for fusion proteins of: i) Fc-antigen with the Fc as the N-terminus fused to the antigen on the C-terminus, wherein mice injected with Fc-EPCAM antigen generated effective immune responses and produced antibodies directed against the antigen Thus, antigens fused to the C terminus of Fc were known to generate effective immune responses.
‘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) ‘801 taught antigens fused to the C terminus of Fc were known to generate effective immune responses;
‘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:
Antigens fused to the N and C terminus of Fc were known to generate effective immune responses.
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) ‘801 taught antigens fused to the C terminus of Fc were known to generate effective immune responses;
‘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]-[IgG1Fc of ‘504 SEQ ID NO:15]-[the first 108 amino acids of the pre-S1 peptide of genotype D of ‘731 SEQ ID NO:38 as an antigen] 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) from N-terminal to C-terminal:
[hIFN-alpha 2(Q124R) of ‘504 SEQ ID NO. 35]-[IgG1Fc of ‘504 SEQ ID NO:15]-[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)] (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.
Conclusion
Claims 1-2, 4, 6-8, 10, and 12-21 are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643