DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. Claims 1-16 are pending and being examined.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
2. Claims 12-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim(s) are directed to a pharmaceutical composition comprising: (1) an antibody that binds to SARS-CoV-2 RBD-HBsAg conjugate or to a virus-like particle comprising the conjugate, or (2) blood or serum isolated from a subject to which the conjugate or virus-like particle comprising the conjugate was administered. The claims encompass naturally occurring anti-RBD antibody in human blood or serum and naturally occurring human blood or serum. This judicial exception is not integrated into a practical application and does not include additional elements that are sufficient to amount to significantly more than the naturally occurring antibodies and blood/serum sample. Ju et al (Nature, May 2020, 584:115-119) and Xiaojie et al (Stem Cell Research, January 2021, 50:102125) demonstrate that antibodies binding to SARS-CoV-2 RBD protein occur naturally in patient blood after SARS-CoV-2 infection (see prior art rejections below). The antibody in human blood or serum is not markedly different from what occurs in nature, and the claims recite that the serum/blood composition is taken directly from nature unaltered.
Claim Rejections - 35 USC § 102
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.
3. Claim(s) 12-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ju et al (Nature, May 2020, 584:115-119).
Claims 12-14 are drawn to a product-by-process. MPEP 2113 states: “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.”
Ju teaches a composition comprising neutralizing monoclonal antibodies binding to SARS-CoV-2 RBD protein and teaches pharmaceutical use of the antibodies (abstract; Figure 3 and 4; Methods). Ju teaches these antibodies were isolated from the blood of human subjects who suffered infection with SARS-CoV-2 (Methods; p. 115, col. 2; Figures 1 and 2).
The antibodies taught by Ju bind to the same SARS-CoV-2 RBD antigen comprised by the claimed conjugate, therefore are expected to function the same as instantly claimed.
4. Claim(s) 12-14 and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xiaojie et al (Stem Cell Research, January 2021, 50:102125).
Claims 12-14 are drawn to a product-by-process. MPEP 2113 states: “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.”
Xiaojie teaches identifying and isolating antibodies that bind to SARS-CoV-2 RBD and neutralize SARS-CoV-2 virus, for the purpose of producing a therapeutic antibody pharmaceutical composition to administer for the treatment of SARS-CoV-2 infection. The antibodies are isolated from patients previously infected with SARS-CoV-2, from animals immunized against RBD, from phage-display libraries, or by single-domain antibody screening (abstract; sections 2-3 and 5; Figure 2). Xiaojie teaches numerous SARS-CoV-2 RBD antibodies clinically administered to treat SARS-CoV-2 infection in human patients (Table 1).
The antibodies taught by Xiaojie bind to the same SARS-CoV-2 RBD antigen comprised by the instantly claimed conjugate, therefore are expected to function the same as instantly claimed.
Claim Interpretation
5. Claims 2 and 3 recite the RBD or HBsAg “comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:…”
These claims are interpreted to encompass any amino acid sequence selected from the listed SEQ ID NOs, as small as two consecutive amino acids long. Therefore claim 2 and 3 encompass a vast genus of sequences comprising as few as two consecutive amino acids found in any of the claimed SEQ ID NOs.
To limit the claimed RBD and HBsAg sequences to the actual SEQ ID NOs claimed, Examiner suggests amending the claims to recite: “comprises the amino acid sequence selected from the group consisting of SEQ ID NOs:…”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
6. Claim(s) 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0416309, Zhu et al, claiming priority to October 23, 2020; in view of Cruz et al (International Immunopharmacology, 2009, 9:1452-1459); CN 111303255, published June 19, 2020 (English translation provided); Mohsen et al (Seminars in Immunology, 2017, 34:123-132).
Zhu teaches a pharmaceutical composition comprising a SARS-CoV-2 spike protein receptor binding domain (RBD) conjugated to HBsAg, “RBD-HBsAg” ([6]; [34]; [153]; [173-174]; [199-204]; [208]; [238-242]; [289]; [321-323]; Tables 7 10, and 11; Example 18; claims 1, 14);
wherein the RBD comprises SEQ ID NO:83 (claim 8; [13]; [70]; [117]; [128]; [174]; [248]; [289]; claim 8) that is 100% identical to instant SEQ ID NO:3 (see sequence alignment below);
wherein the HBsAg comprises GenBank CAA24234 sequence ([157]; [199]; [278]) that is 99.5% identical to instant SEQ ID NO:12 (see sequence alignment below), therefore comprises a sequence of SEQ ID NO:12;
wherein the composition further comprises adjuvant, such as an aluminum ion-containing adjuvant, lipid-containing adjuvant, nucleic acid-containing adjuvant, oil-based emulsion adjuvant (MF59 or AS03), or peptide-containing adjuvant ([134]; [159]; [288]; [293]; [303-314]; [333]; Examples 12-18 and 21; Tables 10 and 11).
Zhu teaches a method of administering the pharmaceutical composition comprising RBD-HBsAg conjugate to mammals; and isolating neutralizing antibodies produced against the conjugate (Example 18; Tables 10 and 11; [137]; [336]). The neutralizing antibodies of Zhu are expected to function the same as the instantly claimed antibodies of claims 12-14 regardless of process made.
Zhu teaches a method for treating coronavirus infection or COVID-19 disease in a subject comprising administering the conjugate ([140]; [324-332]; [339]; claim 45).
Zhu teaches: The-receptor-binding domain (RBD) of the spike protein (S protein) of SARS-CoV-2 is considered the most important antigen target region to induce the production of neutralizing antibodies. RBD as a vaccine can stimulate the body to produce neutralizing antibodies that can be more efficiently directed to the virus receptor binding, which can improve the immunogenicity and immunization efficiency of the vaccine ([3]).
Zhu teaches the conjugated protein is more immunogenic and can induce more neutralizing antibodies than the RBD antigen alone ([5]; Examples).
Zhu does not teach the conjugate comprises a bifunctional chemical crosslinking agent that is SMPH and is linked to a virus-like particle.
Cruz explains and demonstrates that conjugating HBsAg to a viral antigen increases immunogenicity of that antigen. Cruz teaches that conjugation led to “huge immuno-potentiation” (Table 2; section 4, Discussion). Cruz concludes that conjugate-based immunogens are more prompt to elicit immunogenicity and cross reactivity than antigen alone, and HBsAg conjugation was one of the most effective conjugations in enhancing antigen immunogenicity (abstract). Therefore, Cruz enforces the teaching of Zhu that conjugating HBsAg to a viral antigen enhances immunogenicity of the antigen.
CN 111303255 teaches linking “COVID-19-S-RBD” (SARS-CoV-2 spike-RBD) antigen to a virus like particle (VLP) utilizing bifunctional linker SMPH to serve as a vaccine for COVID-19 (Figure 1; Example 2). CN 111303255 teaches the SMPH linker provides high connection efficiency, and high yield, and the process is easy, and convenient for industrial application (p. 2, “Background”; p. 2-4, “Disclosure of the Invention”). CN 111303255 teaches linking the RBD antigen to a VLP enhances immune response to the antigen. In Example 3, mice are immunized with the COVID-19-S-RBD-VLP, serum is collected, and neutralizing antibodies to COVID-19-S-RBD are detected (Table 1). CN 111303255 teaches mice immunized with COVID-19-S-RBD-VLP resulted in high specific antibody titers (section 1.6). In Figure 5, CN 111303255 demonstrates the antibodies produced against COVID-19-S-RBD-VLP effectively neutralized an infectious pseudovirus expressing COVID-19-S-RBD.
Mohsen also teaches chemically linking immunogenic antigens to VLPs as a vaccine strategy utilizing SMPH linker, demonstrating the chemical reaction to accomplish the linkage (Figure 3). Mohsen teaches the SMPH bifunctional linker for attaching antigens to VLPs is known and can result in the VLP displaying multiple copies of the antigen (section 2.2.1). Mohsen teaches advantages of using VLPs to carry immunogenic antigens including: VLPs are highly immunogenic vaccine templates, VLPs can be rapidly and efficiently produces in vast quantities, and VLPs have effective opsonization and uptake by antigen presenting cells, which subsequently augment the adaptive arm of the immune system (section 1, Introduction). Mohsen summarizes numerous VLP-based vaccines in clinical trials (p. 129).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to link the RBD-HBsAg conjugate of Zhu to a VLP using an SMPH linker. One would have been motivated to, and have a reasonable expectation of success to, because: (1) all of the cited references teach the same goal of enhancing immune response to the conjugated viral antigen and increasing neutralizing antibody titers in order to effectively neutralize the virus for treatment, and teach or successfully demonstrate that the addition of either HBsAg or VLP to the RBD viral antigen enhances immune response to the antigen; (2) CN 111303255 suggests linking the viral RBD antigen to a VLP using an SMPH linker in order to enhance immune response to the antigen, (3) Mohsen teaches advantages of using VLPs to carry immunogenic antigens including: VLPs are highly immunogenic vaccine templates, VLPs can be rapidly and efficiently produces in vast quantities, and VLPs have effective opsonization and uptake by antigen presenting cells, which subsequently augment the adaptive arm of the immune system; (4) Mohsen teaches the process of chemically linking antigen to VLP using a bifunctional SMPH linker is known and established; (5) CN 111303255 teaches the process of linking the antigen to the VLP using a SMPH linker provides high connection efficiency and high yield, and the process is easy, and convenient for industrial application; (6) CN 111303255 successfully demonstrates chemically linking RBD antigen to VLP using SMPH bifunctional linker; and (7) CN 111303255 successfully demonstrates immunization with RBD antigen linked to a VLP results in production of high neutralizing antibody titers that effectively neutralize RBD-expressing virus.
Instant RBD SEQ ID NO:3 aligned with Zhu RBD SEQ ID NO:83:
(Qy) = instant SEQ ID NO:3
(Db) = Zhu SEQ ID NO:83
RESULT 1
AASEQ2_03042026_162415
Query Match 100.0%; Score 1212; DB 1; Length 223;
Best Local Similarity 100.0%;
Matches 223; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 RVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFK 60
Qy 61 CYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGTIADYNYKLPDDFTGCVIAWNS120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 CYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGTIADYNYKLPDDFTGCVIAWNS120
Qy 121 NNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVKGFNCYFPLQSYGFQ180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 NNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVKGFNCYFPLQSYGFQ180
Qy 181 PTYGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNF 223
|||||||||||||||||||||||||||||||||||||||||||
Db 181 PTYGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNF 223
Instant HBsAg SEQ ID NO:12 aligned with Zhu HBsAg GenBank CAA24234 (printed March 2026):
(QY) = instant SEQ ID NO:12
(Db) = Zhu SEQ GenBank CAA24234
RESULT 1
AASEQ2_03042026_164044
Query Match 99.5%; Score 1268; DB 1; Length 226;
Best Local Similarity 99.1%;
Matches 224; Conservative 1; Mismatches 1; Indels 0; Gaps 0;
Qy 1 MESTTSGFLGPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGAPTCPGQNSQSPTSNH 60
||:|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MENTTSGFLGPLLVLQAGFFLLTRILTIPQSLDSWWTSLNFLGGAPTCPGQNSQSPTSNH 60
Qy 61 SPTSCPPICPGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLLPGTSTTSTGP120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SPTSCPPICPGYRWMCLRRFIIFLFILLLCLIFLLVLLDYQGMLPVCPLLPGTSTTSTGP120
Qy 121 CKTCTIPAQGTSMFPSCCCTKPSDGNCTCIPIPSSWAFARFLWEWASVRFSWLSLLVPFV180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 CKTCTIPAQGTSMFPSCCCTKPSDGNCTCIPIPSSWAFARFLWEWASVRFSWLSLLVPFV180
Qy 181 QWFAGLSPTVWLSVIWMMWYWGPSLYNILSPFLPLLPIFFCLWVYI 226
||| ||||||||||||||||||||||||||||||||||||||||||
Db 181 QWFVGLSPTVWLSVIWMMWYWGPSLYNILSPFLPLLPIFFCLWVYI 226
7. Conclusion: No claim is allowed.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642