DETAILED ACTION
Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Examiner’s Note: Allowable subject matter is indicated below in the office action.
Election/Restrictions
3. Applicant's election with traverse of Group I claims 3, 9, 13-16, 18, 23, 30-31 and 33-54 in the reply filed on 10/28/2025 is acknowledged. The traversal is on the ground that unity of the invention apply at the national stage and restriction between compositions and methods of their use is an improper ground for lack of unity. This is not found persuasive because the unity of invention is overcome by obviousness of the claimed special feature as recited in the prior office action for Election/Restriction.
Species election: Applicant elected species without traverse as recited in response filed on 10/28/2025.
(i). a VH of SEQ ID NO.: 38, comprising HCDRs of SEQ ID NOs.: 34, 35, and 37, and a VL of SEQ ID NO.: 62, comprising LCDRs of SEQ ID NOs.: 41, 49, and 55.
Applicant’s election of species (ii) A polynucleotide sequence, (iii) A polymerase inhibitor, and (iv) RNAi agent, reads on claims belonging to Group of inventions (other than elected Group I) that lack with group I inventions and the species therefore are not examined.
The applicant’s election of claims 3, 9, 13-16, 18, 23, 30-31 and 33-54 (Group I) is made final. Applicant’s elected species and indication of the claims in Group I on which the elected species read on for examination purpose is acceptable to the examiner and is made final. The requirement is still deemed proper and is therefore made FINAL.
For compact prosecution, in view of applicants claim amendment and the Markush limitations of the claimed sequence, the search was extended to non-elected species of antibody CDR or VH and VL sequences and results were considered.
Priority
4. This application is 371 of PCT/US2021/038667 filed on 06/23/2021 and claims priority to US provisional application 63/043,692 filed on 06/24/2020.
Information Disclosure Statement
5. The information disclosure statements (IDSs) submitted on 11/13/2023, 01/09/2024, 01/09/2024, 04/15/2024, and 10/28/2025, 05/08/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
6. Amendment to the specification filed on 05/08/2026 are entered.
Withdrawn Objections to Specification
7. Withdrawn objection to the specification about embedded hyperlink in view of the amendment to the specification filed on 05/08/2026.
8. Withdrawn objection to the specification about trade name, or a mark used in commerce in view of the amendment to the specification filed on 05/08/2026.
Withdrawn Non-Statutory Double Patenting Rejection
9. Withdrawn the non-statutory double patenting rejection of Application No. 19/318,167 because the inventor and assignee search on DAV file indicates that the application is abandoned on 07/10/2026.
Status of Claims
10. Claims 3, 9 ,13-16, 18, 23, 30-31, 33-54, 60-72, 74, 76, 83, 118, 125, 130, 133, 135, 137, 139, 143, 151-152, 166-167, 170, 174 and 187-193 are pending.
11. Claims 60-72,74,76,83,118,125,130,133,135,137,139,143,151-152,166-167,170,174 and 187-193 are withdrawn from consideration being in non-elected Group of invention due to Restriction/Election.
12. Claims 3, 9, 13-16, 18, 23, 30-31 and 33-54 are under examination in this office action.
Claim Objections
13. Claims 14, 47, 49, 51, and 53 (05/08/2026) are objected to because of the following informalities:
The claims recite a limitation “comprising or consisting of” that introduces ambiguity affecting clarity of the claim.
The applicant can overcome the rejection by deleting “consisting of” and retain the limitation “comprising of”.
Appropriate correction is required.
Examiner’s note: The unelected group of claims 188, 189, 190 although are not under examination in this office action has similar issues.
Claim Interpretation (modified)
14. 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.
The elected Group I claims 3, 9, 13-16, 18, 23, 30-31 and 33-54 and inventions in this application are directed to an antibody or engineered antibody or antigen-binding fragment thereof that binds HBV S antigen and neutralize HBV, and the antibody is administered or used for treatment of HBV infection in a subject. The antibodies or CDRs comprise engineered variations for broadly reactive binding activity to HBV S antigen or for broadly neutralizing activity against different genotypes of HBV, and also bind or neutralize to HDV for therapeutic applications.
Claim 3 (amended): An antibody, or an antigen-binding fragment thereof, comprising:
a heavy chain variable region (VH) comprising a CDRH1 amino acid sequence, a CDRH2 amino acid sequence, and a CDRH3 amino acid sequence, wherein the CDRH1, CDRH2, and CDRH3 amino acid sequences comprise SEQ ID NOs: 34, 35, and 37, respectively; and
a light chain variable region (VL) comprising a CDRL1 amino acid sequence, a CDRL2 amino acid sequence, and a CDRL3 amino acid sequence, wherein the CDRL1, CDRL2, and CDRL3 amino acid sequences are according comprise SEQ ID NOs.:
41, 49, and 55, respectively;
41, 46, and 55, respectively;
41, 47, and 55, respectively;
41, 48, and 55, respectively;
41, 45, and 55, respectively;
41, 50, and 55, respectively;
41, 51, and 55, respectively;
41, 52, and 55, respectively; or
41, 53, and 55, respectively
The instant claim 3 is interpreted to be directed to comprise a recombinant or engineered antibody comprising VH chain or VH CDRs 1-3 from one antibody species whereas VL chain or VL CDRs 1-3 arising from different species of antibodies as combination or from a single antibody to develop broadly reactive and neutralizing antibody for treatment of HBV and HDV.
Claim 9: The instant claim 9 is interpreted to comprise the variant antibody or antigen-binding fragments comprised in VH (SEQ ID NO: 38) and VL (SEQ ID NO: 62) with the variant species comprising amino acid sequence identity (e.g. 90%, 99%).
The instant elected claims 3, 9, 13-16, 18, 23, 30-31 and 33-54 are interpreted to be directed to comprise an antibody, monoclonal antibody (e.g. monoclonal antibody HBC34 variant(s), recited in the instant specification) in view of the instant specification (page 21 para 2, page 22, para 2) that recites, the term "antibody" refers to an intact antibody is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments thereof.
Withdrawn Claim Rejections - 35 USC § 112 (b)
15. Withdrawn rejection of claims 3, 9, 13, 15-16, 18, 23, 30-31, and 33-54 under 35 U.S.C. 112(b) in view of the amendment of claim 3 filed on 05/08/2026.
Claim Rejections - 35 USC § 112 (a)
16. Withdrawn rejection of claims 3, 9, 13, 15-16, 18, 23, 30-31, and 33-54 under 35 U.S.C. 112(a) in view of the amendment of claim 3 and arguments filed on 05/08/2026.
Claim Rejections - 35 USC § 103 (modified)
17. 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.
18. Claims 3 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Corti 2020 (US10683344B2, 06/16/2020 with an earlier priority of 01/17/2019 to the published application US20190016785A1 that claims priority to US15/766,703 filed on 10/07/2016), and further in view of Corti 2025 (US12304946B2, 05/20/2025 or WO2020132091A2, 06/25/2020 with an earlier priority to US 62/782,274 filed on 12/19/2018).
Claims 3 and 15: Corti 2020 (US10683344B2) is directed antibodies, and antigen binding fragments thereof that bind to the antigenic loop region of hepatitis B surface antigen (HBsAg) and neutralize infection of both hepatitis B virus (HBV) and hepatitis delta virus (HDV). FIG. 4 shows for Example 2 the neutralization activity of different concentrations of HBC34 (antibody) on infectious HDV. At a concentration of 0.12 μg/ml HBC34 no HDV-positive cells were detectable, indicating potent neutralization of HDV. HBIG, in contrast, did not neutralize HDV (tested in 1:1000 dilution, i.e. 50 μg/ml). Table 2 shows the amino acid sequences of the CDR's and the heavy chain variable region (VH) and the light chain variable region (VL) of an exemplary antibody according to the present invention (“HBC34”).
Corti 2020 (US10683344B2) disclosed SEQ ID NO: 41 that shows 100% amino acid sequence identity with instant CDRH1, CDRH2, and CDRH3 amino acid sequences comprising instant SEQ ID NOs: 34, 35, and 37 as recited below:
Query Match 87.4%; Score 171.4; Length 119;
Best Local Similarity 44.6%;
Matches 37; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GRIFRSFYMS--------------TINQDGSEKLYVDSVKG------------------- 27
|||||||||| |||||||||||||||||
Db 26 GRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLYVDSVKGRFTISRDNAKNSLFLQMNN 85
Qy 28 -------------WSGNSGGMDV 37
||||||||||
Db 86 LRVEDTAVYYCAAWSGNSGGMDV 108
Corti 2020 (US10683344B2) do not teach instant VL light chain CDRs sequences SEQ ID NOs: 41, 52, and 55.
Corti 2025 (US12304946B2) is directed to antibodies, and antigen binding fragments thereof, that can bind to the antigenic loop region of hepatitis B surface antigen (HBsAg) and can neutralize infection of both hepatitis B virus (HBV) and hepatitis delta virus (HDV). See, FIG. 4 shows neutralization (EC50 value), by HBC34-V35-MLNS-GAALIE, of individual HBV genotypes using an HDV pseudotyping system. See, Examples 3 In Vitro Neutralization Activity of Antibodies, Example 4: Pan-Genotype Neutralization Capacity of HBC34-V35 MLNS-GAALIE Assessed in an HDV Pseudosystem.
Corti 2025 (US12304946B2) disclosed is SEQ ID NO: 89 that has 100% sequence identity (one conservative amino acid substitution) with instant CDRL1, CDRL2, and CDRL3 amino acid sequences comprising SEQ ID NOs: 41, 52, and 55 (instant SEQ ID NOs: 41, 52, and 55 are comprised in instant SEQ ID NO: 65) as recited below:
Query Match 79.8%; Score 109.3; Length 106;
Best Local Similarity 35.1%;
Matches 26; Conservative 1; Mismatches 0; Indels 47; Gaps 2;
Qy 1 SGDKLGNKNVA---------------QVKYRPS--------------------------- 18
||||||||||| :||||||
Db 23 SGDKLGNKNVAWFQHKPGQSPVLVIYEVKYRPSGIPERFSGSNSGNTATLTISGTQAMDE 82
Qy 19 -----QTFDSTTVV 27
|||||||||
Db 83 AAYFCQTFDSTTVV 96
The SEQ ID NO: 89 of Corti 2025 (US12304946B2) has a single conservative amino acid substitution Q : E as recited supra in the sequence alignment comparison to the instant specification. The instant specification page number 15 para 1 (date 12/21/2022) allowable substitutions Q : E (Gln : Glu) for preserving the function of binding or neutralizing of the claimed antibody to HBV or HDV.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teachings of Corti 2020 (US10683344B2) on the claimed antibody VH CDR sequences with additional teachings of Corti 2025 (US12304946B2) on the antibody VL CDR sequences and combine the teachings to arrive at the invention of claims 3 and 15. The motivation would be that both Corti 2020 (US10683344B2) and Corti 2025 (US12304946B2) are directed to anti-HBV and anti-HDV binding and neutralizing antibody and therefore it would have been obvious to one of the ordinary skills to combine the prior art teachings to engineer to develop a broadly neutralizing antibody that neutralize the claimed HBV genotypes and HDV to develop therapeutics as recited in the applied prior arts and for commercial success.
The applied prior arts (by Corti, as recited supra) are suggestive and provide motivation to combine the prior art teachings because both prior arts are known individually for the antibody that binds and neutralize HBV and HDV therefore it would have been obvious to combine the teachings to engineer VH and VL chain CDRs to develop a third antibody that has VH CDR from fisrt antibody and VL CDRs from a second antibody and arrive at a third recombinant/engineered antibody to be used for the same purpose with a reasonable expectation for improved binding and neutralizing therapeutic effect. See MPEP 2144.06 Art Recognized Equivalence for the Same Purpose [R-01.2024]. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claims 3 and 15 given the applied prior art teachings 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 3 and 15. There would have been a reasonable expectation of success to arrive at the inventions of claims 3 and 15 given the applied prior arts. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), see MPEP § 2143, example of rationales A-G.
18. Claims 9, 23, 30-31, 33-36, and 37-54 are rejected under 35 U.S.C. 103 as being unpatentable over the combined prior art teachings of Corti 2020 (US10683344B2, 06/16/2020 with an earlier priority of 01/17/2019 to the published application US20190016785A1 that claims priority to US15/766,703 filed on 10/07/2016) and Corti 2025 (US12304946B2, 05/20/2025 or WO2020132091A2, 06/25/2020 with an earlier priority to US 62/782,274 filed on 12/19/2018) as applied to claim 3 and 15 and further additional teachings of Corti 2020 (US10683344B2) and Corti 2025 (US12304946B2, 05/20/2025 or WO2020132091A2).
Claim 9: The combined prior art teachings of Corti 2020 and Corti 2025 taught claim 3 as recited supra.
The additional teachings of Corti 2020 (US10683344B2) teaches amino acid sequence represented in SEQ ID NO: 41 that has 100% amino acid sequence identity with amino acid sequence of instant SEQ ID NO: 38 of instant claim 9.
Query Match 100.0%; Score 630; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
Qy 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSS 119
Corti 2025 (US12304946B2, 05/20/2025 with an earlier priority to US 62/782,274 filed on 12/19/2018) teaches amino acid sequence represented in SEQ ID NO: 92 that has 100% amino acid sequence identity with amino acid sequence of instant SEQ ID NO: 38 of instant claim 9.
FEATURE:
OTHER INFORMATION: Synthetic sequence HC of HBC34-V35-MLNS and
HBC34-V34-MLNS (g1M17, 1)
Query Match 100.0%; Score 630; Length 449;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
Qy 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSS 119
Corti 2020 (US10683344B2) do not teach instant SEQ ID NO: 62 of instant claim 9.
Corti 2025 (US12304946B2, 05/20/2025 with an earlier priority to US 62/782,274 filed on 12/19/2018) teaches SEQ ID NO: 89 (Db) that has 97.2% amino acid sequence identity with amino acid sequence of instant SEQ ID NO: 62 (Qy) of instant claim 9.
FEATURE:
OTHER INFORMATION: Synthetic sequence HBC34-V35 VL
Query Match 97.1%; Score 541; Length 106;
Best Local Similarity 97.2%;
Matches 103; Conservative 1; Mismatches 2; Indels 0; Gaps 0;
Qy 1 SYELTQPPSVSVSPGQTVSIPCSGDKLGNKNVAWFQHKPGQSPVLVIYQDSYRPSGIPER 60
||||||||||||||||||||||||||||||||||||||||||||||||: |||||||||
Db 1 SYELTQPPSVSVSPGQTVSIPCSGDKLGNKNVAWFQHKPGQSPVLVIYEVKYRPSGIPER 60
Qy 61 FSGSNSGNTATLTISGTQAMDEAAYFCQTFDSTTVVFGGGTRLTVL 106
||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSNSGNTATLTISGTQAMDEAAYFCQTFDSTTVVFGGGTRLTVL 106
Corti 2025 (US12304946B2, 05/20/2025 with an earlier priority to US 62/782,274 filed on 12/19/2018) teaches SEQ ID NO: 89 (Db) that has 99.5% amino acid sequence identity with amino acid sequence of instant SEQ ID NO: 65 (Qy) of instant claim 9.
Query Match 99.5%; Score 553; Length 106;
Best Local Similarity 99.1%;
Matches 105; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SYELTQPPSVSVSPGQTVSIPCSGDKLGNKNVAWFQHKPGQSPVLVIYQVKYRPSGIPER 60
||||||||||||||||||||||||||||||||||||||||||||||||:|||||||||||
Db 1 SYELTQPPSVSVSPGQTVSIPCSGDKLGNKNVAWFQHKPGQSPVLVIYEVKYRPSGIPER 60
Qy 61 FSGSNSGNTATLTISGTQAMDEAAYFCQTFDSTTVVFGGGTRLTVL 106
||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSNSGNTATLTISGTQAMDEAAYFCQTFDSTTVVFGGGTRLTVL 106
Therefore, as recited supra, the claimed SEQ ID NOs: 38 and 62 or SEQ ID NOs: 38 and 65 requiring at least 90% amino acid sequence identity of VH and VL are rendered obvious by combined teachings of Corti 2020 and Corti 2025.
Claim 23: Corti 2025 (US12304946B2) teaches added limitations of instant claim 23, wherein the antibody or antigen-binding fragment is capable of binding to a HBsAg (adw) with an EC50 (ng/ml) of about 3.2 or less, less than 3.0, less than 2.5, less than 2.0, less than 1.5, or less than 1.0, by disclosing is capable of neutralizing (a) an HBV of genotype A with an EC50 of about 2.34 ng/mL; (b) an HBV of genotype B with an EC50 of about 2.22 ng/mL; (c) an HBV of genotype C with an EC50 of about 0.92 ng/mL; (d) an HBV of genotype D with an EC50 of about 1.10 ng/mL; (e) an HBV of genotype E with an EC50 of about 1.12 ng/mL; (f) an HBV of genotype F with an EC50 of about 1.93 ng/mL; (g) an HBV of genotype G with an EC50 of about 1.43 ng/mL; and/or (h) an HBV of genotype H with an EC50 of about 1.93 ng/mL, wherein the EC50 is optionally determined using a recombinant HDV engineered to express an HBsAg of the HBV genotype (See, col 50 line 28-39).
Claim 30: Corti 2025 (US12304946B2) teaches added limitations of instant claim 30, wherein antibody or antigen-binding fragment thereof and a scFv, Fab, or F(ab′)2 fragment (See, col 13 last para, col 14 para 1-2).
Claim 31: Corti 2025 (US12304946B2) teaches added limitations of instant claim 31, wherein antibodies and antigen binding fragments of the present disclosure may, in embodiments, be multispecific (e.g., bispecific, trispecific, tetraspecific, or the like), (See, col 13 last para, col 14 para 1-2).
Claims 33, 36: Corti 2025 (US12304946B2) teaches added limitations of instant claim 33 and 36, wherein a binding protein (e.g., antibody or an antigen binding fragment thereof) of the present disclosure comprises an Fc moiety. In certain embodiments, the Fc moiety may be derived from human origin, e.g., from human IgG1, IgG2, IgG3, and/or IgG4, or from another Ig class or isotype. In specific embodiments, an antibody or antigen binding fragments can comprise an Fc moiety derived from human IgG1 (See, Section on Fc moiety, col 42 lines 1-62).
Claims 34: Corti 2025 (US12304946B2) teaches added limitations of instant claim 34, the Fc moiety may comprise or consist of at least a portion of an Fc moiety that is involved in binding to FcRn binding. In certain embodiments, the Fc moiety comprises one or more amino acid modifications that improve binding affinity for (e.g., enhance binding to) FcRn (See, col 42 lines 1-62).
Claims 35: Corti 2025 (US12304946B2) teaches added limitations of instant claim 35, wherein, it is possible to engineer the Fc moiety to enhance FcγRIIB binding by introducing the mutations (See, col 44 lines 1-23).
Claims 36-37: Corti 2025 (US12304946B2) teaches added limitations of instant claim 36, wherein, antibodies were produced as IgG1 (g1m17, 1 allotype), an antibody, antigen-binding fragment, or Fc region or moiety of the present disclosure comprises a IgG1 allotype g1m17, k1 (See, FIG 1, Example 1, legends for Fig 1 col 2 lines 57-62, col 52 para 2 lines 16-29).
Claims 38-45: Corti 2025 (US12304946B2) teaches added limitations of instant claims 38-45, wherein, in certain embodiments, the Fc moiety comprises or is derived from a IgG Fc and a half-life-extending mutation comprises any one or more of: M428L; N434S; N434H; N434A; N434S; M252Y; S254T; T256E; T250Q; P257I Q311I; D376V; T307A; E380A (EU numbering), (See, col 45, lines 5-63).
Claim 46: Corti 2025 (US12304946B2) teaches added limitations of instant claim 46, wherein, in certain embodiments, a complete Fc moiety comprises a hinge domain, a CH2 domain, and a CH3 domain (e.g., EU amino acid positions 216-446). An additional lysine residue (K) is sometimes present at the extreme C-terminus of the Fc moiety but is often cleaved from a mature antibody (See, col 42, para 2 lines 9-24).
Claims 47-54: Based on the election of the antibody species, claims 47-54 are interpreted to comprise a VH of SEQ ID NO.: 38, comprising HCDRs of SEQ ID NOs.: 34, 35, and 37, and a VL of SEQ ID NO.: 62, comprising LCDRs of SEQ ID NOs.: 41, 49, and 55. The combined prior art teachings as applied to the claims 3, 9 and 45 as recited supra teachings claims 47-54 (See, prior art teachings of Corti 2020 (US10683344B2, and Corti 2025 US12304946B2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teachings of Corti 2020 (US10683344B2) with additional teachings of Corti 2020 (US10683344B2) and Corti 2025 (US12304946B2) to arrive at the invention of claims 9, 23, 30-31, and 33-54. The motivation would be to develop a broadly neutralizing antibody that neutralize the claimed HBV genotypes and HDV for therapeutics as recited in the applied prior arts and for commercial success. 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 9, 23, 30-31, and 33-54. There would have been a reasonable expectation of success to arrive at the inventions of claims 9, 23, 30-31, and 33-54 given the applied prior arts.
The applied prior arts (by Corti, as recited supra) are suggestive and provide motivation to combine the prior art teachings because both prior arts are known individually for the antibody that binds and neutralize HBV and HDV therefore it would have been obvious to combine the teachings to engineer VH and VL chains to develop a third antibody that has VH chain from first antibody and VL chain from a second antibody and arrive at a third recombinant/engineered antibody to be used for the same purpose with a reasonable expectation for improved binding and neutralizing therapeutic effect. See MPEP 2144.06 Art Recognized Equivalence for the Same Purpose [R-01.2024]. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), see MPEP § 2143, example of rationales A-G.
19. Claims 13, 16 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over
combined prior art teachings of Corti 2020 (US10683344B2, 06/16/2020 with an earlier priority of 01/17/2019 to the published application US20190016785A1 that claims priority to US15/766,703 filed on 10/07/2016) and Corti 2025 (US12304946B2, 05/20/2025 or WO2020132091A2, 06/25/2020 with an earlier priority to US 62/782,274 filed on 12/19/2018) as applied to claim 3 and 15 and further additional teachings of Corti 2020 (US10683344B2) and Corti 2025 (US12304946B2, 05/20/2025 or WO2020132091A2).
Claim 13: The antibody or antigen-binding fragment of claim 3, wherein the VH and the VL comprise or consist of the amino acid sequences set forth in SEQ ID NOs.: (i) 38 and 65, respectively (non-elected species is examined).
The combined teachings of Corti 2020 (US10683344B2), and Corti 2025 (US12304946B2, 05/20/2025 or WO2020132091A2) teaches claims 3 and 15 as recited supra.
The additional teachings of Corti 2020 (US10683344B2), and Corti 2025 (US12304946B2 or WO2020132091A2) teaches the added claim limitations of instant claim 13 as recited below.
Corti 2020 (US10683344B2) teaches amino acid sequence represented in SEQ ID NO: 41 that has 100% amino acid sequence identity with amino acid sequence of instant SEQ ID NO: 38 of instant claim 13.
Query Match 100.0%; Score 630; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
Qy 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSS 119
Corti 2025 (Corti 2025 (US12304946B2, 05/20/2025 or WO2020132091A2) teaches amino acid sequence represented in SEQ ID NO: 92 that has 100% amino acid sequence identity with amino acid sequence of instant SEQ ID NO: 38 of instant claim 13.
FEATURE:
OTHER INFORMATION: Synthetic sequence HC of HBC34-V35-MLNS and
HBC34-V34-MLNS (g1M17, 1)
Query Match 100.0%; Score 630; Length 449;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ELQLVESGGGWVQPGGSQRLSCAASGRIFRSFYMSWVRQAPGKGLEWVATINQDGSEKLY 60
Qy 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VDSVKGRFTISRDNAKNSLFLQMNNLRVEDTAVYYCAAWSGNSGGMDVWGQGTTVSVSS 119
Corti 2025 (US12304946B2, 05/20/2025 with an earlier priority to US 62/782,274 filed on 12/19/2018) teaches SEQ ID NO: 89 (Db) that has 99.5% amino acid sequence identity with amino acid sequence of instant SEQ ID NO: 65 (Qy) of instant claim 13.
The E (database) to Q (instant SEQ ID NO; 65) amino acid substitution is synonymous.
Qy 1 SYELTQPPSVSVSPGQTVSIPCSGDKLGNKNVAWFQHKPGQSPVLVIYQVKYRPSGIPER 60
||||||||||||||||||||||||||||||||||||||||||||||||:|||||||||||
Db 1 SYELTQPPSVSVSPGQTVSIPCSGDKLGNKNVAWFQHKPGQSPVLVIYEVKYRPSGIPER 60
Qy 61 FSGSNSGNTATLTISGTQAMDEAAYFCQTFDSTTVVFGGGTRLTVL 106
||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSNSGNTATLTISGTQAMDEAAYFCQTFDSTTVVFGGGTRLTVL 106
Therefore, as recited supra, the claimed SEQ ID NOs: 38 and 65 requiring 100% amino acid sequence identity of VH and VL are rendered obvious by combined teachings of Corti 2020 and Corti 2025.
Claims 16 and 18 (dependent on claim 3): The added limitations of claims 16 and 18 on the characteristic of an antibody or antigen-binding fragments thereof comprising the claimed VH and VL SEQ ID NO: 38 and 62 comprising the mutations recited in instant claim 3 and reduced dimer formation are obvious in view of the prior arts as applied to render obvious the instant claim 3 as recited supra, and additionally comprising antibody with reduced dimer formation is a design choice for the composition and the antibody therapeutic against HBV and HDV.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teachings of Corti 2020 (US10683344B2) and Corti 2025 (US12304946B2, 05/20/2025 or WO2020132091A2) with additional teachings of Corti 2020 (US10683344B2) and Corti 2025 (US12304946B2) to arrive at the invention of claims 13, 16 and 18. The motivation would be to develop a broadly neutralizing antibody that neutralize the claimed HBV genotypes and HDV for therapeutics as recited in the applied prior arts and for commercial success.
The applied prior arts (by Corti, as recited supra) are suggestive and provide motivation to combine the prior art teachings because both prior arts are known individually for the antibody that binds and neutralize HBV and HDV therefore it would have been obvious to combine the teachings to engineer VH and VL chains to develop a third antibody that has VH chain from first antibody and VL chain from a second antibody and arrive at a third recombinant/engineered antibody to be used for the same purpose with a reasonable expectation for improved binding and neutralizing therapeutic effect. See MPEP 2144.06 Art Recognized Equivalence for the Same Purpose [R-01.2024]. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
There would have been a reasonable expectation of success to arrive at the inventions of claims 13, 16 and 18 given the applied prior arts. 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 13, 16 and 18. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. 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.
Allowable Subject Matter
20. Claim 3: The elected species of antibody comprising: the CDRH1, CDRH2, and CDRH3 amino acid sequences SEQ ID NOs: 34, 35, and 37, respectively and CDRL1, CDRL2, and CDRL3 amino acid sequences SEQ ID NOs: 41, 49, and 55, respectively is free of prior art.
Claims 9, and 13: SEQ ID NO: 38 and 62 is free of prior art.
21. An independent Claim 14 is allowable because the claimed SEQ ID NO: 38 and 62 or SEQ ID NO: 38 and 66 is free of prior art because the claim limitation requires 100% sequence identity of the claimed sequences.
Response to Arguments
22. Applicant’s arguments with respect to amended claims 3, 9, 13-16, 18, 23, 30-31 and 33-54 have been considered but are moot because the new ground of rejection relies on additional teachings of the reference applied in the prior rejection of record for teaching or matter specifically challenged in the argument or the amended claim limitations.
Applicant’s arguments:
Rejections under 35 U.S.C. § 103: Claims 3 and 15 - Corti + Paul + Thomas (see, Remarks - 05/08/2026 - Applicant Arguments/Remarks Made in an Amendment).
In Response:
The applicant has amended claim 3 that is directed to an antibody, or an antigen-binding fragment thereof, comprising: a heavy chain variable region (VH) comprising a CDRH1 amino acid sequence, a CDRH2 amino acid sequence, and a CDRH3 amino acid sequence, wherein the CDRH1, CDRH2, and CDRH3 amino acid sequences comprise SEQ ID NOs: 34, 35, and 37, respectively and a light chain variable region (VL) comprising a CDRL1 amino acid sequence, a CDRL2 amino acid sequence, and a CDRL3 amino acid sequence from different species of antibodies (see, instant claim 3).
In response to the claim amendment, additional search and consideration the amended claims 3 and 15 and dependent claims 9, 13, 15-16, 18, 23, 30-31 and 33-54 were rendered obvious by combined teachings of Corti 2020 (US10683344B2) and Corti 2025 (US12304946B2, 05/20/2025 or WO2020132091A2, 06/25/2020) wherein both prior arts are directed to engineered or recombinant antibody that bind or neutralize HBV and HDV as recited in the office action above.
Secondary Considerations
Applicant’s argument: As explained in Examples 1-4 of the present application, the antibodies according to the present claims address potentially problematic dimerization issues without a loss of binding affinity. The inventors identified a tendency for the antibody referred to as "HBC34-v35" to form dimers, which can lower binding capacity. Corti 2020 is silent on the issue of dimerization for the antibodies disclosed therein. It does not provide any motivation to substitute amino acids near or within the light chain CDR2, or any teachings to arrive specifically at the sequences recited in the present claims. Corti 2020 itself does not teach, suggest, or motivate modifying the antibody sequences disclosed therein; thus, the motivation to do so appears to be based merely on the notion that it is generally desirable to generate additional antibodies that could be used as therapeutics.
In Response:
The combined prior art teachings of Corti 2020 and Corti 2025 as applied has rendered obvious instant claims 3 and 15 because the prior art teaches the claimed VH SEQ ID NOs: 34, 35, and 37 and VL SEQ ID NOs: 41, 52, and 55 as recited supra. The claimed antibody structure of the engineered or recombinant antibody that bind or neutralize HBV and HDV is rendered obviousas recited supra. Therefore, it is reasonably expected that the prior art teachings inherently teach and prevent Fab-Fab dimerization and aggregation of a claimed antibody without a loss of binding affinity, unless availability of contrary evidence if any.
Perchiacca et al 2012 (see below relevant prior art) is in the art and addressed engineering aggregation resistant antibodies.
Kanai et al 2008 (see below relevant prior art) addressed Reversible Self-Association of a Concentrated Monoclonal Antibody Solution Mediated by Fab–Fab Interaction That Impacts Solution Viscosity that can provide motivation for engineering antibody Fab-Fab interaction in view of Courtois et al 2016 and Perchiacca et al 2012.
The USPTO do not have the laboratory facilities to confirm the results of the prior art teachings or inexplicit teachings that rendered obvious the structure of the claimed antibody and thereby resolution of or mitigation of potentially problematic dimerization issues of the claimed antibody without a loss of binding affinity.
Applicant's arguments filed have been fully considered but they are not persuasive.
23. Relevant Prior Arts:
Perchiacca et al 2012. Engineering Aggregation-Resistant Antibodies. Annual Review Chemical and Biomolecular Engineering. 3:263-286.
Courtois et al 2016. Rational design of therapeutic mAbs against aggregation through protein engineering and incorporation of glycosylation motifs applied to bevacizumab. In MAbs (Vol. 8, No. 1, pp. 99-112). Taylor & Francis.
Kanai et al 2008. Reversible self-association of a concentrated monoclonal antibody solution mediated by Fab–Fab interaction that impacts solution viscosity. Journal of pharmaceutical sciences, 97(10), 4219-4227.
Conclusion
24. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
25. A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J Visone can be reached at 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMADHAN JAISING JADHAO/ Examiner, Art Unit 1672
/BENNETT M CELSA/ Primary Examiner , Art Unit 1600
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