DETAILED ACTION
Non-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 .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/07/2026 has been entered.
Election/Restrictions (Finalized)
3. As indicated in the non-final rejection office action dated 05/15/2025 the election of species was extended to anti-HBV siRNA to include amended claim limitation to an anti-HBV siRNA. Applicant’s election of Group III claims 27 and 72-80 with traverse between Group III and IV. Applicant’s argument on traverse between Groups III and IV were found persuasive on the ground that claims 27 and 34 have overlapping subject matter. Restriction for Group IV was withdrawn, and the Group III were rejoined with claims 34 and 81-84 and the claims 27, 34 and 72-84 read on the elected species anti-HBV siRNA.
The requirement for election of invention of the Group and a species anti-HBV siRNA was made FINAL in the office action dated 05/15/2025.
The election of species to the extent of interferon α (IFN α), pegylated interferon α (PEG- IFN α) is withdrawn in view of the prior art search results. The species anti-HBV siRNA, interferon α (IFN α), and pegylated interferon α (PEG- IFN α) are under examination in this office action.
Status of Claims
4. Claims 27, 34, 72-73, 75-78, 80-81 and 83-84 are pending as per claim listing filed on 12/17/2025.
5. Applicant cancelled withdrawn claims 74 and 82 without prejudice or disclaimer.
6. Claims 27, 34, 72-73, 75-78, 80-81 and 83-84 are under examination in this office action.
Priority
7. This application claims the benefit under 35 U.S.C. § 119(e) of the United States Provisional Application Serial No. 63/522,851, filed June 23, 2023.
Information Disclosure Statement
8. The information disclosure statement (IDS) submitted on 04/24/2025 is in compliance with the provisions of 37 CFR 1.97, accordingly, the information disclosure statement is being considered by the examiner.
Claim Interpretation
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.
Claim 27. A method for treating a hepatitis B viral (HBV) infection in a subject with chronic hepatitis B (CHB), the method comprising:
a) determining a baseline HBV antibody concentration in a subject with CHB prior to administering an HBV surface antigen (HBsAg) to the subject;
b) administering the HBsAg to the subject;
c) determining a post-baseline HBV antibody concentration in the subject after being administered the HBsAg, and identifying the subject as a responder subject if the post-baseline HBV antibody concentration is greater than the baseline HBV antibody concentration; and
d) administering an HBV therapy to the responder subject while the responder subject is not administered the HBsAg,
wherein the HBsAg comprises virus-like particles (VLPs) comprising HBV surface envelope proteins Pre-S1, Pre-S2 and S, and the HBV therapy comprises an anti-HBV siRNA.
The instant claim 27 is interpreted to be directed to a method of treatment of chronic hepatitis B virus infection in a subject that involves steps (i) determining baseline anti-HBs antigen antibody level (titer), (ii) administration of HBs Ag in the for of VLP derived from HBV envelope proteins Pre-S1, Pre-S2 and S (iii) identification of responders based on rise in anti-HBs antigen antibody level (titer) referred as post-baseline level, and (iv) treatment with anti-HBV therapy siRNA against HBV.
The instant claim 27 preamble recites a transitional phrase “comprising” which is open ended to include additional elements that are not the recited elements.
The claim 27 amendment introduced a “wherein” contingent clause and also include transitional phrase “comprise” multiple tiles, for reciting an additional claim limitation, “wherein the HBsAg comprises virus-like particles (VLPs) comprising HBV surface envelope proteins Pre-S1, Pre-S2 and S, and the HBV therapy comprises an anti-HBV siRNA”.
It is interpreted that the HBsAg and VLPs may include additional elements (e.g. adjuvant, other proteins of HBV).
The “wherein” clause also recites, and “the HBV therapy”, however further introduces a transitional phrase “comprises” which is open ended to comprise additional elements directed to HBV therapy.
Claim 34. A method for treating an HBV infection in a subject with chronic hepatitis B, the method comprising:
a) administering an HBV therapy, without administering an HBV surface antigen (HBsAg), to the subject wherein the subject has been determined to have a post-baseline HBV antibody concentration after being administered the HBsAg that is greater than a baseline HBV antibody concentration prior to being administered the HBsAg,
wherein the HBsAg comprises virus-like particles (VLPs) comprising HBV surface envelope proteins Pre-S1, Pre-S2 and S, and the HBV therapy comprises an anti-HBV siRNA.
The instant claim 34 preamble recites a transitional phrase “comprising” which is open ended to include additional elements that are not the recited elements.
The instant claim 34 amendment introduced a “wherein” contingent clause and also include transitional phrase “comprise” multiple tiles, for reciting an additional claim limitation, “wherein the HBsAg comprises virus-like particles (VLPs) comprising HBV surface envelope proteins Pre-S1, Pre-S2 and S, and the HBV therapy comprises an anti-HBV siRNA”.
It is interpreted that the HBsAg and VLPs may include additional elements (e.g. adjuvant, other proteins of HBV).
The “wherein” clause also recites, and “the HBV therapy”, however further introduces a transitional phrase “comprises” which is open ended to comprise additional elements directed to anti-HBV therapy.
Claim 76. The method of claim 27, wherein the HBV therapy further comprises an interferon alfa (IFNα) or pegylated interferon alfa (PEG-IFNα).
Claim 83. The method of claim 81, wherein the HBV therapy further comprises an interferon alfa (IFNα) or pegylated interferon alfa (PEG-IFNα).
The instant claims 76, and 83 as above, recites a “wherein” clause to include “the HBV therapy”, however further introduces a transitional phrase “comprises” which is open ended to comprise additional or alternative elements directed to anti-HBV therapy.
Claim Rejections - 35 USC § 112
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 27, 34, 72-73, 75-78, 80-81 and 83-84 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.
New matter situation arises because applicant fails to provide where the support is found in the specification in commensurate with the full scope of amended claim limitations of instant claims 27 and 34 and upon review of the specification, it was not readily apparent, that applicant possessed the instantly amended scope. See MPEP 2163 section 1B (“… “While there is no in haec verba requirement, newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure.”; section II (“… With respect to newly added or amended claims, applicant should show support in the original disclosure for the new or amended claims. See, e.g., Hyatt v. Dudas, 492 F.3d 1365, 1370, n.4, 83 USPQ2d 1373, 1376, n.4 (Fed. Cir. 2007) (citing MPEP § 2163.04) …”)
Claim Rejections - 35 USC § 112
11. 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.
The instant claims 27, 34, 72-73, 75-78, 80-81 and 83-84 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.
Amendments to the claims 27 and 34 introduced a claim limitation with “wherein” contingent clause and also include transitional phrase “comprise” multiple times, for reciting an additional claim limitation:
“Wherein the HBsAg comprises virus-like particles (VLPs) comprising HBV surface envelope proteins Pre-S1, Pre-S2 and S, and the HBV therapy comprises an anti-HBV siRNA”.
The limitation recites “the HBV therapy” and further incorporate an open-ended phrase “comprise” that is followed by “an anti-HBV siRNA”, therefore the claim limitation is indefinite.
Claim Rejections - 35 USC § 102
12. 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 27 and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen 2021 (Clinical Trial NCT04749368 first posted 02/11/2021, see PDF printout, BRII Biosciences Limited, Vir Biotechnology, Inc, and VBI Vaccines Inc) as evidenced by Ma et al 2021 (JHEP Reports 2021 (3) p. 1-11), Ji et al 2025 (Gastroenterology 2025;169:136–149).
Chen 2021 (Clinical Trial NCT04749368) anticipated instant claims 27 and 34 by disclosing a Phase-2 clinical trial to investigate the safety and efficacy of BRII-835 and BRII-179 combination therapy treating adult participants with chronic Hepatitis B Virus (HBV) infection. Chen 2021 (Clinical Trial NCT04749368) further disclosed that the experimental Cohort A were treated via subcutaneous injection with BRII-835 (VIR-2218), experimental Cohort B were treated with BRII-835 (VIR-2218) for 32 weeks, BRII-179 (VBI-2601) with IFN-α up to Week 40, and experimental Cohort C received BRII-835 (VIR-2218) and BRII-179 (VBI-2601) up to Week 40 (See, Clinical Trial NCT04749368, attached PDF printout).
Ma et al 2021 provides evidence BRII-179 is an HBV VLP comprising large (L), middle (M), and small (S) envelope proteins (VLP reads on comprising Pre-S1, Pre-S2, and S envelope proteins of HBV) (See, Ma et al 2021, page 2, col 1 para 3). A recently initiated clinical study (NCT04749368) is evaluating the combination of HBV-specific small-interfering RNA and BRII-179, with the aim of reducing immunosuppressive viral antigen levels via gene silencing before stimulating HBV-specific immunity with multi-doses of BRII-179 (See, Ma et al 2021, page 10 col 2 last para). Ji et al 2025 provides evidence an HBV-targeting siRNA (elebsiran) (BRII-835) (See, page 137, col 1 para 3).
In the clinical trial NCT04749368 determining a bassline HBV antibody concentration in a subject prior to administering the VLP (HBs Ag), identification of responders following administration of the VLP based on increase in antibody titers to HBs Ag and subsequent administration of anti-HBV siRNA are inherent to the study protocol.
Claim Rejections - 35 USC § 103
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.
14. Claims 27, 34, 76, 78, and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al 2021 (JHEP Reports 2021 (3) p. 1-11), and further in view of Hoa et al 2009 (Antimicrob Agents Chemother. 2009 Dec;53(12):5134-40), Chen 2021 (Clinical Trial NCT04749368 first posted 02/11/2021, see PDF printout, BRII Biosciences Limited, Vir Biotechnology, Inc, and VBI Vaccines Inc), Sepp-Lorenzino et al 2018 (WO2018195165A1 published 10/15/2018), Hui et al 2022 (Clin Mol Hepatol. 2022 Feb 17;28(3):408–424), and as evidenced by Ji et al 2025 (Gastroenterology 2025;169:136–149).
Claim 27: Ma et al 2021 is in the art and teaches instant claim 27 by disclosing a clinical trial directed to a therapeutic vaccine BRI-179 restores HBV-specific immune responses in responder patients with chronic HBV (See, See, Ma et al 2021, abstract). Ma et al 2021 discloses a method for treating a hepatitis B viral (HBV) infection in a responder subject with chronic hepatitis B (CHB). Ma et al 2021 teaches therapeutic vaccine BRII-179 restores HBV-specific B cell (antibody/humoral) and T cell (cellular immune response) immune responses in patients with chronic HBV in a phase Ib/IIa study. Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB. Ma et al 2021 indicated further clinical evaluation of BRII-179 in combination with other therapies (See, Ma et al 2021, abstract, p.2, col 1, col 2 Patients and methods), the method comprising:
(a) determining a baseline HBV antibody concentration in a subject with CHB prior to administering an HBV surface antigen (HBsAg) to the subject requiring a visit for clinical evaluation, full laboratory evaluation (See, p.2 col 2, para 1);
( b) administering the HBsAg to the subject, the HBsAg in the form of BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S) (See, p.2 col 1, para 3; abstract)
(c) determining a post-baseline HBV antibody concentration in the subject after being administered the HBsAg, by disclosing positive anti-HBs response was defined at any post-baseline visit with either (i) post-baseline anti-HBs ≥ 2 IU/L if anti-HBs antibody was undetectable at baseline or (ii) post-baseline anti-HBs ≥ 5 times the baseline anti-HBs if baseline anti-HBs was ≥ 2 IU/L. Antibodies to Pre-S1 (anti-Pre-S1) and Pre-S2 (anti-Pre-S2) were measured at baseline and all subsequent visits using a customized ELISA protocol (See, p.2 col 2, para 3; abstract) and identifying the subject as a responder subject if the post-baseline HBV antibody concentration is greater than the baseline HBV antibody concentration. Ma et al 2021 teaches BRII-179, also known as VBI-2601, is a virus-like particle (VLP)-based immunotherapeutic derived from the prophylactic Sci-B-Vac® vaccine …… was used previously in a therapeutic setting in patients with CHB and showed signs of efficacy, i.e., restoration of anti-HBs to >10 mIU/ml in the vaccinated groups, a higher HBeAg seroconversion frequency, and suppression of HBV DNA to <4 log copies/ml in the anti-HBs responders compared to non-responder. The anti-HBs responders had a significantly higher HBeAg seroconversion rate and more frequent HBV DNA suppression than anti-HBs non-responders, demonstrating the functional relevance of anti-HBs seroconversion. However, the peak antibody titers in most antibody responders were observed after 3 or 4 doses of vaccination (at weeks 12 or 16), indicating that the antibody response was attenuated in the highly tolerant patients compared to healthy individuals in whom the protective titer (≥10 mIU/ml) was generally reached after the second dose. (See, page 2 col 1 para 3 and page 9 col 1 discussion para 2, and col 2 para 1 for “responders” and “non-responders”; abstract, p. 7, table 3-columns on antibody response, T-cell response can also be considered a response to identify responders); and
(d) Ma et al 2021 teaches administering anti-HBV therapy IFN-α to the responder subject by disclosing study design treatment group and responders BRII-179 20 ug+ IFN-α +NA (See, p.2 col 2, para 2 on Study design; abstract; p. 7, table 3-columns on Treatment and associated legends). Ma et al 2021 further shows express motivation by disclosing that a recently initiated clinical study (NCT04749368) is evaluating the combination of HBV-specific small-interfering RNA and BRII-179, with the aim of reducing immunosuppressive viral antigen levels via gene silencing before stimulating HBV-specific immunity with multi-doses of BRII-179 (See, Ma et al 2021, page 10, col 2 last para on conclusion).
Hoa et al 2009 is in the art and discloses a randomized controlled study investigating viral suppression and serological response following pre-S1/pre-S2/S vaccine therapy combined with lamivudine treatment in HBeAg-positive patients with chronic hepatitis B and teaches identification of responders by disclosing anti-HBs responders showed significantly higher HBeAg seroconversion rates, greater suppression of HBV DNA levels, and a lower median reduction in HBV DNA levels than those of anti-HBs non-responders. Thus the concept of identification of responders and non-responders for combination treatment comprising the vaccine and antiviral (anti-HBV) for CHB patients is taught by Hoa et al 2009 (See, abstract, see methods, results, discussion , figures, entire article).
Chen 2021 (Clinical Trial NCT04749368) further discloses the Phase-2 clinical trial NCT04749368 to investigate the safety and efficacy of BRII-835 and BRII-179 combination therapy treating adult participants with chronic Hepatitis B Virus (HBV) infection. Chen 2021 disclosed that the experimental Cohort A were treated via subcutaneous injection with BRII-835 (VIR-2218), experimental Cohort B were treated with BRII-835 (VIR-2218) for 32 weeks, BRII-179 (VBI-2601) with IFN-α up to Week 40, and experimental Cohort C received BRII-835 (VIR-2218) and BRII-179 (VBI-2601) up to Week 40 (See, Clinical Trial NCT04749368, attached PDF printout).
Sepp-Lorenzino et al 2018 (WO2018195165A1) is in the art and discloses methods for the treatment of a subject having a Hepatitis B virus (HBV) infection, e.g., a chronic HBV infection, using a combination of an RNAi agent that targets HBV and an HBV vaccine. It is disclosed a RNAi agent and an HBV vaccine for use in treatment of HBV infection, comprising sequentially administering to the subject having an HBV infection: a) an RNAi agent that inhibits expression of at least three HBV transcripts, wherein the RNAi agent forms a double stranded region; b) a protein-based vaccine comprising a first HBV core antigen (HBcAg) polypeptide, and a first HBV surface antigen (HBsAg) polypeptide; and c) a nucleic acid-based vaccine comprising an expression vector construct encoding a second HBcAg polypeptide, and/or a second HBsAg polypeptide, wherein the second HBcAg polypeptide, and/or the second HBsAg polypeptide, shares at least one epitope with at least one of the first HBcAg polypeptide, and/or the first HBsAg polypeptide (See, abstract, entire WO2018195165A1).
Hui et al 2022 is in the art and teaches RNA interference as a novel treatment strategy for chronic hepatitis B infection. RNA interference (RNAi) by small-interfering RNA (siRNA) and anti-sense oligonucleotide (ASO) has been studied as a novel treatment strategy for CHB. RNAi targets post-transcriptional messenger RNAs and pregenomic RNAs to reduce hepatitis B virus (HBV) antigen production and viral replication. By reducing viral antigens, host immune reconstitution against HBV may also be attained. Phase I/II trials on siRNAs have demonstrated them to be safe and well-tolerated. siRNA is effective when given in monthly doses with different total number of doses according to different trial design, and can lead to sustainable dose-dependent mean HBsAg reduction by 2–2.5 log (See, abstract, entire article).
It would have been obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior teachings of Ma et al 2021 with the teachings of Hoa et al 2009, Chen et al 2021, Sepp-Lorenzino et al 2018 and Hui et al 2022 on anti-HBV siRNA to arrive at the invention of claim 27. Based on the combined teachings applied to render obvious the claim 27, as recited supra, it is obvious that CHB subjects/patients are immunologically exhausted and requires restimulation or awakening of the immune system to HBV antigens. Having identified the immune responders to HBs Ag it would be obvious to not repeatedly stimulate the subjects only with HBs Ag (VLP), however additionally comprise the anti-HBV si RNA therapy to target the HBV replication by targeting HBV mRNA transcription and lower the HBV production. Combination therapies known in the art would be obvious to practice e.g. anti-HBV siRNA. The motivation based on the applied prior art teachings for the combination therapy would be to comprise anti-HBV therapy siRNA to target a HBV mRNA translation by targeting the HBV mRNAs by administering specific siRNA therapy targeting the HBV to mitigate exhaustion of the subject’s or patients’ immune system to overcome HBV replication engaging immune system and better allow engagement of already exhausted (CHB patients) immune system to better respond to the administered HBs Ag (VLP) vaccination or immunization for better outcome of treatment in CHB patients and for commercial success. One of the ordinary skills in the art would have a reasonable expectation of success given the disclosures of the prior art teachings as applied to claim 27 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 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).
Claim 34. Ma et al 2021 teaches instant claim 34 by disclosing a clinical trial directed to a therapeutic vaccine BRI-179 restores HBV-specific immune responses in responder patients with chronic HBV (See, Ma et al 2021, abstract, entire research paper) by disclosing the limitations of claim 34 a method for treating an HBV infection in a subject with chronic hepatitis B, the method comprising: a) administering an HBV therapy to the subject wherein it has been determined that a post-baseline HBV antibody concentration in the subject after being administered an HBsAg is greater than a baseline HBV antibody concentration in the subject prior to being administered the HBsAg (See, Ma et al 2021, abstract, entire research paper, and applied anticipatory teachings to claim 27 as recited above). The additional teachings of Ma et al 2021 with the teachings of Chen et al 2021, Sepp-Lorenzino et al 2018 and Hui et al 2022 on anti-HBV siRNA as applied to claim 27 are incorporated here in entirety to render obvious instant claim 34. The claim 34 does not explicitly recite identification of a responder subject, however, the claim limitation requires the subject to have a higher post-baseline HBV Ab concentration after HBs Ag administration as compared to a baseline HBV Ab concentration prior to HBs Ag administration.
It would have been obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior teachings of Ma et al 2021 with the teachings of Hoa et al 2009, Chen et al 2021, Sepp-Lorenzino et al 2018 and Hui et al 2022 on anti-HBV siRNA to arrive at the invention of claim 34. Based on the combined teachings applied to render obvious the claim 34, as recited supra, it is obvious that CHB subjects/patients are immunologically exhausted and requires restimulation or awakening of the immune system to HBV antigens. Having identified the immune responders to HBs Ag it would be obvious to not repeatedly stimulate the subjects only with HBs Ag (VLP), however additionally comprise the anti-HBV si RNA therapy to target the HBV replication by targeting HBV mRNA transcription and lower the HBV production. Combination therapies known in the art would be obvious to practice e.g. anti-HBV siRNA. The motivation based on the applied prior art teachings for the combination therapy would be to comprise anti-HBV therapy siRNA to target a HBV mRNA translation by targeting the HBV mRNAs by administering specific siRNA therapy targeting the HBV to mitigate exhaustion of the subject’s or patients’ immune system to overcome HBV replication engaging immune system and better allow engagement of already exhausted (CHB patients) immune system to better respond to the administered HBs Ag (VLP) vaccination or immunization for better outcome of treatment in CHB patients and for commercial success. One of the ordinary skills in the art would have a reasonable expectation of success given the disclosures of the prior art teachings as applied to claim 34 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 claim 34. 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).
15. Claims 76, 78, and 80 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Ma et al 2021 (JHEP Reports 2021 (3) p. 1-11), Hoa et al 2009 (Antimicrob Agents Chemother. 2009 Dec;53(12):5134-40), Chen 2021 (Clinical Trial NCT04749368 first posted 02/11/2021, see PDF printout, BRII Biosciences Limited, Vir Biotechnology, Inc, and VBI Vaccines Inc), Sepp-Lorenzino et al 2018 (WO2018195165A1 published 10/15/2018), Hui et al 2022 (Clin Mol Hepatol. 2022 Feb 17;28(3):408–424), and as evidenced by Ji et al 2025 (Gastroenterology 2025;169:136–149) as applied to claims 27 and 34 above, and further in view of Vasconcelos et al 2022 (Case Reports in Infectious Diseases, vol 2022, Article ID 3890309), Wang et al 2016 (Scientific Reports volume 6, Article number: 29605), and Anderson et al 2020 (WO2020254878A1, 03/11/2021).
Claims: 76, 78 and 80 (dependent on claim 27): The combined teachings of Ma et al 2021, Hoa et al 2009, Chen 2021, Sepp-Lorenzino et al 2018, Hui et al 2022, and as evidenced by Ji et al 2025 teaches claim 27 as recited supra. The combined teachings do not recite pegylated interferon alfa (IFNα).
Claim 76: Both Ma et al 2021, and Chen et al 2021 (Cohort B treatment) teaches added limitation of instant claim 76 (dependent on claim 27), wherein the HBV therapy further comprises an interferon alfa (IFNα) by disclosing a recently initiated clinical study (NCT04749368) is evaluating the combination of HBV-specific small-interfering RNA and BRII-179, with the aim of reducing immunosuppressive viral antigen levels via gene silencing before stimulating HBV-specific immunity with multidoses of BRII-179 (See, p.10, col 2, last para); a randomized phase Ib/IIa study in CHB subjects, NA plus BRII-179 with co-adjuvant IFN-α (See, Ma et al 2021 abstract, p.7 Table 3; p.10, col 2, last para, Chen et al 2021 Cohort B treatment).
Sepp-Lorenzino et al 2018 is in the art and is directed to a method for the treatment of a subject having a Hepatitis B virus (HBV) infection, e.g., a chronic HBV infection, using a combination of an RNAi agent that targets HBV and an HBV vaccine (combinatorial approach of treatment). The methods further comprise administration of an immune stimulator to the subject. In certain embodiments, the immune stimulator is selected from the group pegylated interferon alfa 2a (PEG-IFN-alpha-2a), Interferon alfa-2b, PEG-IFN-alpha-2b (See, claim 69).
Vasconcelos et al 2022 is in the art and teaches a case of PEG-INFα-treated CHB patients that attained sustained off-treatment virological response with only 16 weeks of treatment, with loss of both HBeAg and HBsAg (this latter the optimal treatment endpoint) (See, abstract, entire article). We report a singular CHB case with a surprising response to PEG-IFNα; with only 16 weeks of treatment, our patient attained loss of HBsAg and sustained off-treatment virological response (See, pages 1-3, discussion and conclusion sections).
Wang et al 2016 is in the art and teaches predictors of response to pegylated interferon in chronic hepatitis B: a real-world hospital-based analysis. Pre-treatment HBsAg level is an important predictor of virological response in CHB patients undergoing PEG-IFN alpha treatment (See, abstract, entire article).
Anderson et al 2020 (WO2020254878A1) is in the art and discloses methods useful for inducing an immune response and overcoming immune tolerance in a subject suffering from chronic Hepatitis B virus infection. The compositions of the disclosure comprise HBsAg having S, Pre-S1 and Pre- S2 proteins, an aluminum phosphate adjuvant and interferon-α. The addition of a low dose of interferon- mg (3 MIU) to a prophylactic Hepatitis B vaccine improved antibody titers in immunocompromised or non-responder populations but not in healthy subjects (See, para [0038], abstract, and entire prior art WO2020254878A1).
Claim 78: Ma et al 2021 teaches added limitation of instant claim 78 (dependent on claim 27), wherein the HBV antibody concentration is a serum anti-HBs concentration by disclosing antibody response to HBs, Pre-S1 and Pre-S2 antigens (See, abstract; p.2, col 2, para 3).
Claim 80. Ma et al 2021 teaches added limitation of instant claim 80 (dependent on claim 27), wherein the subject is identified as a responder subject if the post-baseline HBV antibody concentration is 5 times greater than the baseline HBV antibody concentration by disclosing antibody response to HBs, post-baseline anti-HBs ≥ 5 times the baseline anti-HBs if baseline anti-HBs was ≥2 IU/L (See, p.2, col 2, para 3; p.6 Fig 3 A-B and legends).
It would have been obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior teachings of Ma et al 2021, Chen et al 2021, Sepp-Lorenzino et al 2018 and Hui et al 2022 as applied to render obvious claims 27 and 34 with additional teachings of Vasconcelos et al 2022, Wang et al 2016, and Anderson et al 2020 to arrive at the invention of claims 76, 78 and 80 as recited supra. Based on the combined prior art teachings as recited supra, it is obvious that CHB subjects/patients are immunologically exhausted and requires restimulation or awakening of the immune system to HBV antigens. Having identified the immune responders to HBs Ag it would be obvious to not repeatedly stimulate the subjects only with HBs Ag (VLP), however additionally comprise the anti-viral anti-HBV interferon alfa (IFNα) or pegylated interferon alfa (IFNα) to target the HBV replication, to lower the HBV production, and also as an immune stimulator. Combination therapies known in the art would be obvious to practice e.g. anti-HBV siRNA and interferon alfa (IFNα) or pegylated interferon alfa (IFNα). The motivation based on the applied prior art teachings for the combination therapy would be to comprise an additional anti-HBV therapy to reduce replication/production of HBV to mitigate exhaustion of the subject’s or patients’ immune system to overcome HBV replication engaging immune system and better allow engagement of already exhausted (CHB patients) immune system to better respond to the administered HBs Ag (VLP) vaccination or immunization for better outcome of treatment in CHB patients and for commercial success. The motivation to select subjects with post-baseline HBV Ab concentration >5 times than baseline would be the CHB subjects would be good responders and would help for superior HBV therapy outcome (instant claims 78, and 80). One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the inventions of claims 76, 78 and 80 given the disclosures of the prior art teachings as applied to claims 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 76, 78 and 80. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), MPEP § 2143, example of rationales, A-G).
16. Claims 72-73, 75 and 81, 83-84 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Ma et al 2021 (JHEP Reports 2021 (3) p. 1-11), Hoa et al 2009 (Antimicrob Agents Chemother. 2009 Dec;53(12):5134-40), Chen 2021 (Clinical Trial NCT04749368 first posted 02/11/2021, see PDF printout, BRII Biosciences Limited, Vir Biotechnology, Inc, and VBI Vaccines Inc), Sepp-Lorenzino et al 2018 (WO2018195165A1 published 10/15/2018), Hui et al 2022 (Clin Mol Hepatol. 2022 Feb 17;28(3):408–424), and as evidenced by Ji et al 2025 (Gastroenterology 2025;169:136–149) as applied to claims 27 and 34 above, and further in view of Gupta et al 2021 (Clinical Trial NCT03672188 by Vir Biotechnology, Inc conducted during 09/14/2018 to 12/13/2021 and related publication in Drugs in R&D (2021) 21:455–465), Ma et al 2019 (Front Immunol. 2019 Sep 24;10: 2308), Vasconcelos et al 2022 (Case Reports in Infectious Diseases, vol 2022, Article ID 3890309), Wang et al 2016 (Scientific Reports volume 6, Article number: 29605) and Anderson et al 2020 (WO2020254878A1, 03/11/2021).
Claims 72-73, 75 and 81, 83-84: The combined teachings of Ma et al 2021, Hoa et al 2009, Chen 2021, Sepp-Lorenzino et al 2018, Hui et al 2022, and as evidenced by Ji et al 2025 teaches claims 27 and 34 as recited supra and the teachings are incorporated here in its entirety.
Ma et al 2021 provides additional teaching: a recently initiated clinical study (NCT04749368) is evaluating the combination of HBV-specific small-interfering RNA and BRII-179, with the aim of reducing immunosuppressive viral antigen levels via gene silencing before stimulating HBV-specific immunity with multi-doses (See, Ma et al 2021, p. 10, col 2 last para conclusion).
Ma et al 2021 does not teach the added limitations of steps of the methods of claims
72-73, 75, 81, and 83-84.
Vir Biotechnology, Inc 2021 (Clinical Trial NCT03672188) teaches by disclosing doses of siRNA VIR-2218 that are applicable to the instant claims 72-75, 81, and 83-84 reciting limitations for HBV therapy, or elected species anti-HBV siRNA therapy. A phase 1/2, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of VIR-2218 in subjects with chronic HBV. VIR-2218, also known as Elebsiran, is an investigational small interfering RNA (siRNA) that targets hepatitis B virus (HBV) transcripts administering to chronic HBV (CHB) patents different doses ranging from Chronic HBV (CHB), Chronic HBV, HBeAg negative, subjects received 2 SC doses of 20 mg VIR-2218 administered 4 weeks apart, HBeAg negative, subjects received 2 SC doses of 100 mg VIR-2218 administered 4 weeks apart to Chronic HBV, HBeAg positive, subjects received 2 SC doses of 200 mg VIR-2218 administered 4 weeks apart (See, Clinical Trial NCT03672188, study design).
Chen 2021 (Clinical Trial Number NCT04749368) as evidenced by Ji et al 2025 teaches the added limitations of steps of the methods of claims 72-73, 75, 81, and 83-84 by disclosing: a phase 2a open-label study was conducted from March 11, 2021, to July 4, 2023, at 25 investigational sites in 7 countries/ regions across the Asia and Pacific Region. Eligible participants were randomly assigned to an elebsiran monotherapy cohort or 2 elebsiran + BRII-179 combination therapy cohorts. All cohorts received nine 4-weekly doses of 100 mgelebsiran via subcutaneous injection from day 1 through week 32 (cohorts A, B, and C). Two combination therapy cohorts received additional nine 4-weekly doses of admixture of 40 mg BRII-179 and 3 million IU IFN-a coadministration (cohort B) or 40 mg BRII-179 (cohort C) via intramuscular injection from week 8 through week 40, respectively (See, Chen 2021 (Clinical Trial Number NCT04749368; Ji et al 2025 p.3 col 1 para 2 Study design).
Accordingly, the “Vir Biotechnology, Inc 2021” and “Chen” references, taken separately or in combination, suggest that the timing of the “initial dose of the HBV therapy” (e.g. “at least 4 doses of the HBsAg: claims 72, 75, 81); the HBsAg amount and weekly protocol (claim 73: 20ug-100ug/dose every 2-4 weeks). All three references (“Ma”; “Vir Biotechnology”; and “Chen”) teach “serum” concentrations of anti-HBV as in instant claim 84. Additionally, it is noted that the HBV therapy as being anti-HBV siRNA or interferon α (instant claim 83 limitation) is taught/suggested by Ma et al 2021, interferon α taught by Anderson et al 2020, pegylated interferon α (instant claim 83 limitation) is taught/suggested by Sepp-Lorenzino et al 2018, Vasconcelos et al 2022, Wang et al 2016 as recited supra.
Further, it is noted that the above dependent claim method parameters (e.g. bioactive amounts/timing) are art-recognized result effective-variables, which a medical practitioner or researcher, would alter and optimize. See MPEP 2144; 2144.05 and In re Aller, 220 F.2d 454,456 (CCPA 1955).
Still further, Ma et al 2019 reviews approaches toward a functional cure for Hepatitis B: The Rationale and Challenges for Therapeutic Targeting of the B Cell Immune Response teaches: Long-term antiviral treatment by nucleoside analogs, by targeting viral translation by siRNA, by inhibiting HBsAg release via nucleic acid polymers, or by neutralizing HBsAg via specific antibodies could potentially reduce the HBsAg load in CHB patients. A combined strategy including a reduction of the HBsAg load via the above treatments and the therapeutic targeting of B cells by vaccination may induce the appearance of anti-HBs antibodies and lead to a functional cure of CHB.
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to modify the prior arts teachings of Ma et al 2021 as applied to claims 27, and 34, as recited supra, by incorporating the teachings of Chen 2021 on clinical trial number NCT04749368, Gupta et al 2021 teachings on Clinical Trial NCT03672188 and related publication in Drugs in R&D (2021) 21:455–465) and Ma et al 2019 as evidenced by Ji et al 2025 (Gastroenterology. 2025 Mar 3: S0016-5085(25)00466-4) to arrive at the invention of claims 72-73, 75, 81, and 83-84. One of the ordinary skills would have been motivated to modify the prior arts teachings as applied to claims 27 and 34 with the additional prior art teachings as recited supra to arrive at the methods of combination therapy against Chronic Hepatitis B virus infection in subjects with CHB as claimed in claims 72-73, 75, 81, and 83-84 for developing an effective anti-HBV treatment for the CHB responder subjects and would have a motivation for commercial success. There would have been a reasonable expectation of success given the combined prior art teachings in the same field of subjects with CHB and combination therapy approach as applied to claims 72-73, 75, 81, and 83-84. It is similar to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skills to modify the primary prior art reference to combine secondary prior art references teachings to arrive at the claimed inventions of claims 72-73, 75, 81, and 83-84. 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 72-73, 75, 81, and 83-84. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), MPEP § 2143, example of rationales, A-G).
Response to Applicant’s Arguments
17. Applicant's arguments filed 12/17/2025 have been fully considered but they are not persuasive. Additional prior art was included in this office action to the extent necessary to address the amended claims and arguments relying on the amended language are thereby moot.
------APPLICANT’S ARGUMENTS FOLLOW:
Claim Rejections - 35 USC §103
Claims 27,34, 76, 78, and 80 are rejected under 35 U.S.C. 103 as allegedly being unpatentable over Ma 2021 (JHEP Reports 2021), and further in view of Sepp-Lorenzino (W02018195165A), Anderson (W02020254878Al), Hui (Clin Mal Hepatol.2022), Vasconcelos (Case Reports in Infectious Diseases, 2022), and Wang (Scientific Reports 2016). Claims 72-75 and 81-84 are rejected under 35 U.S.C. 103 as allegedly being unpatentable over combined teachings of Vasconcelos, and Wang and further in view of Chen (Clinical Trial Number NCT04749368 2021). Gupta (Clinical Trial NCT03672188, 2021), Ma 2019 (Front Immunol. 2019) as evidenced by Ji (Gastroenterology 2025). Application respectfully submits that these Section 103 rejections should be withdrawn at least in view of the claim amendments, for the reasons that follow.
(A) The Amended Claims:
Both independent claims, claims 27 and 34, as currently amended, recite the administration of an HBV therapy to treat hepatitis B viral (HBV) infection in a subject with chronic hepatitis B (CHB) that has been identified as a responder to an HBsAg. Importantly, the HBV therapy comprises an anti-HBV siRNA and does not-include the HBsAg which comprises virus-like particles (VLPs) comprising HBV surface envelope proteins Pre-S 1, Pre-S2 and S.
B) The Cited Art Fails to Support a Prima Facie Case of Obviousness:
As acknowledged by the Office, while the primary reference, Ma 2021, discloses the administration of an HBsAg (BRII-179), it fails to disclose a subsequent administration, to a responder of the HBsAg of an HBV therapy that does not include the HBsAg. To remedy this deficiency, the Office cites a large number of secondary references. Nevertheless, despite the long listing of citations, the cited references, even in combination, fail to establish a prima facie case of obviousness.
Briefly, with respect to the secondary references, the Office reads Sepp-Lorenzino to
disclose the use of an RNAi agent before the use an HBV vaccine to treat HBV infection, reads Anderson to disclose the use of an HBsAg for overcoming immune tolerance in an HBV patient, reads Hui to disclose the use of an siRNA to treat HV infection, reads Vasconcelos to disclose the use of PEG-INFα to treat HBV infection, reads Wang to disclose pre-treatment HBsAg level as a predictor of response to a pegylated interferon treatment, reads Chen, Gupta and Ji to disclose certain initial doses of HBV therapy and reads Ma 2019 to disclose siRNA targeting HBsAg as a potential long-term treatment.
First, all of these references, except Sepp-Lorenzino, only relate to non-HBsAg HBV treatments alone. They do not teach or suggest that a prior HBsAg administration can serve as predictor for the likely response to these treatments, and thus cannot remedy the deficiency of Ma, Sepp-Lorenzino, on the other hand, teaches to use an siRNA before an HBV vaccine. In any event, Sepp-Lorenzino fails to teach or suggest the use of a patient's response to either treatment as a predictor for the other, and thus also fails to remedy the deficiency of Ma.
Second, central to the rejection is Office's allegation that "[h]aving identified the responders to HBs Ag it would be obvious to not repeatedly stimulate the subjects with HBs Ag therapy" apparently "to avoid exhaustion of the subject's or patient's immune system with HBs Ag therapy."
Office Action at page 10, second paragraph (emphasis in original). There is nothing in any cited prior art to support such a critical but unsubstantiated assertion, i.e. repeated administration of an HBsAg therapy would lead to exhaustion of a patient's immune system with the HBsAg therapy and hence require the use of an alternative therapy.
As noted above, all of the secondary references focus on non-HBsAg therapies. The Office fails to point to any one of them, much less a particular location within the references, to support such an allegation. At least for this reason, the Office fails to establish a prima facie case of obviousness.
------EXAMER’S RESPONSE TO APPLICANT’S ARGUMENTS FOLLOW:
In Response: The rejection of claims 27, 34, 72-73, 75-78, 80-81 and 83-84 under 35 U.S.C. 103 obviousness is modified in this office action as recited below because of applicant’s amendment of the claims 27, 34, 76, 77 and 83.
Applicant’s argument that the applied prior art does not teach or suggest that a prior HBsAg administration can serve as predictor for the likely response (reads on responders and non-responders) to these treatments is not persuasive. Ma et al 2021 (the prior art that was recited in the prior office action and in this office action), and Hoa et al 2009 in this office action teaches the inventive concept of anti-HBs antigen responders and non-responders in CHB patients (See, Ma et al 2021, page 2 col 1 para 3 and page 9 col 1 discussion para 2, and col 2 para 1 for “responders” and “non-responders”, see, abstract, figures, Fig 3, see entire article; See, Ho et al 2009 entire article). Both Ma et al 2021 and Sepp-Lorenzino taught /suggested combination therapy HBs Ag vaccine (VLP) and anti-HBV therapy that comprise IFN alpha or siRNA. The instant methods claim 27 and 34 and dependent claims comprise the steps of HBs Ag administration and siRNA administration and could comprise the steps in different order as suggested by Ma et al 2021 “A recently initiated clinical study (NCT04749368) is evaluating the combination of HBV-specific small-interfering RNA and BRII-179, with the aim of reducing immunosuppressive viral antigen levels via gene silencing before stimulating HBV-specific immunity with multi-doses of BRII-179 (See, Ma et al 2021, page 10 col 2 last para).
Applicant’s argument that, “There is nothing in any cited prior art to support such a critical but unsubstantiated assertion” is not persuasive because Ma et al 2021 (See, page 2 col 1 para 2) recites that, “The main obstacle to HBV clearance is the profound state of immune exhaustion which is thought to be driven by the combination of decades of high-dose antigenic stimulation and the tolerogenic environment in the liver”.
(C) The Primary Reference Actually Contradicts the Office's Rejection
The primary reference, Ma 2021, not only does not support the Office's allegation, but actually teaches away from it.
First, as noted in the Office Action, Ma 2021 makes note of "further clinical evaluation of BRII-179 in combination with other therapies." Id. at paragraph bridging pages 7 and 8 (emphasis added) because "BRII-179 treatment alone had minimal effect on patient's virological status." Ma 2021 at Lay Summary. Clearly, instead of discontinuing the use of a HBsAg as the Office alleges, Ma 2021 actually teaches to continue its use, only to combine it with additional therapies to enhance its efficacy. The "combination" therapy suggested by Ma 2021, therefore, belies the Office's allegation that there was suggestion in the art to discontinue the use of the HBsAg.
Second, Ma 2021 teaches that CHB patients are already immune-exhausted. "The main obstacle to HBV clearance is the profound state of immune exhaustion which is thought to be driven by the combination of decades of high-dose antigenic stimulation and the tolerogenic environment in the liver." Id. at page 2, left col., second paragraph (emphasis added). Unless such immune exhaustion has been reversed by the HBsAg treatment, then there is nothing to exhaust again. On the other hand, if the HBsAg treatment is able to reverse the immune exhaustion, then the skilled artisan would have had no motivation to discontinue such a beneficial treatment. In either case, the Office fails to provide any reasonable basis on why the skilled artisan would have any motivation to discontinue the use of an HBsAg.
Also because of the teach-away by the primary reference, Applicant respectfully submits that the Section 103 rejections should be withdrawn.
In Response: Applicant has mis-interpreted the prior office action in context to “immune exhaustion”. More clarity is added in this office action. The HBs Ag (VLP) when administered as a vaccine function via immunological arm of the body to induce immune response (humoral and cellular immunity) in responders. In CHB patients there is an immune exhaustion. In addition to HBs Ag (VLP) vaccination, alternate anti-HBV therapy (anti-viral therapy) e.g. IFNα, siRNA, and nucleoside analogues are directed to the HBV and HBV replication that would reduce the HBV replication in CHB providing an opportunity for the immune system to develop immune response to HBs Ag (VLP). It would have been obvious to the ordinary skills in the art that the dual approach of treatment that comprise stimulation of immune system by HBs Ag (VLP) vaccination and administration of an anti-HBV therapy (e.g. siRNA) would result in better treatment outcome in CHB patients.
(D) The Claimed Invention Exhibited Unexpected Results
In addition to the data already present in the specification, Applicant respectfully requests that the Office consider a recently published article co-authored by the instant inventors. Wong, G. ILi., et al. Nat Med (2025) https://doi.org/10.1038/s41591-025-04049-z (Exhibit A). This article, published in the highly prestigious, peer-reviewed journal of Nature Medicine, demonstrates unexpected results exhibited by the claimed invention.
Like what has been disclosed in Ma 2021. Exhibit A also notes that "[o]ne of the core
features of chronic HHBV infection is the interplay between the HBV and the immune system, with chronic viral infection leading to immune tolerance and immune exhaustion. "Page 7, second to last paragraph (emphasis added). H BRII-179 was able to "immunologically prime" such patients. Id. In addition, treatment with BRII-179 can "aid[] in the identification and selection of patients with chronic HBV infection with more intact intrinsic immunity. who are able to mount an anti-HBs response." Id.
Both the priming and the identification functions of the BRII-179 treatment, Applicant respectfully submits, were not taught or suggested in the cited art, and therefore amounted to unexpected results achieved by the instant claims. Such unexpected results, Applicant notes, further underscores the non-obviousness of the claims. For all of the above reasons. Applicant believes that the Section 103 rejections should be withdrawn.
In Response: The instant claims 27, 34, 72-73, 75-78, 80-81 and 83-84 are rejected under 35 U.S.C. 103 obviousness in this office action as recited below including applicant’s amendment of the claims 27, 34, 76, 77 and 83. Therefore, the combined prior art as applied to the claim rejections render obvious the results of the invention. Wong et al. Nat Med (2025) https://doi.org/10.1038/s41591-025-04049-z (Exhibit A) is published after the priority date of the instant application. The specification does not recite “unexpected results”, or “superior results” on the effective priority date of the provisional application.
Applicant's arguments filed on 12/17/2025 have been fully considered but they are not persuasive, and the amended claims rejections are maintained.
18. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
(i) Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol. 2016 Apr;64(1 Suppl): S71-S83.
(ii) Yuen et al 2022. Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection. N Engl J Med. 2022 Nov 24;387(21):1957-1968. Yuen et al 2022 teaches New therapies are being developed for the treatment of chronic HBV infection, including small interfering RNAs (siRNAs).
(iii) Gane E, Lim YS, Cloutier D, et al. Safety and antiviral activity of VIR-2218, an X-targeting RNAi therapeutic, in participants with chronic hepatitis B infection: week 48 follow-up results. J Hepatol 2021;75: Suppl 2: S287-S288.
(iv) Luangsay et al 2023 (WO2023083906A2) discloses pharmaceutical combinations for treating hepatitis B virus (HBV) infection comprising administering at least two, preferably two or three, different HBV therapeutics. In particular, the present invention relates to pharmaceutical combinations comprising an RNAi oligonucleotide targeting HBV and an anti-PDL1 antisense oligonucleotide.
(v) Fisicaro et al 2020. Pathogenetic Mechanisms of T Cell Dysfunction in Chronic HBV Infection and Related Therapeutic Approaches. Front Immunol. 2020 May 12; 11:849.
Conclusion
19. No claim is allowed.
20. 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/Primary Examiner, Art Unit 1600