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 .
Claim Status
Applicant’s amendment filed 2/5/2025 has been entered. Claims 3, 4, 21, and 26-44 are cancelled. Claims 1, 2, 5-20, and 22-25 are pending. Claims 13-14, 17-18, 20, and 22-25 are withdrawn. Claims 1 and 5 are amended. Claims 1, 2, 5-12, 15, and 19 are examined herein.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1, 2, 5-12, 15, and 19 in the reply filed on 2/5/2026 is acknowledged. The traversal is on the ground(s) that Groups II and III require the isolated nucleic sequence of Group I. This is not found persuasive because as detailed in the Requirement for Restriction mailed 12/5/2025, the shared technical feature of an HBV genome variant comprising C-ORF, S-ORF and P-ORF, where the C-ORF comprises an exogenous insertion sequence between precore and core genes, and the exogenous insertion sequence comprises a nucleotide sequence encoding a first fragment of luciferase, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Guangzhou City No8 People's Hospital ("Guangzhou" CN110669735A; cited in the IDS filed 3/25/2025). Guangzhou teaches HBV cccDNA variants comprising N-terminal luciferase fragments in the C-ORF (entire document; claims 1-10; Figure 4). Therefore, the groups do not relate to a single general inventive concept under PCT Rule 13.1 because the shared technical feature does not make a contribution over the prior art..
The requirement is still deemed proper and is therefore made FINAL.
Claims 13-14, 17-18, 20, and 22-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 2/5/2026.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings at Figures 2 and 5 are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms PIGGYBAC™ at pages 6, 8, 11, 13, 18, 21, and 22, TET-ON® at pages 3-5 and 21, and NANO-GLO® at page 2, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5-6, 8-11, and 19 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 5-6, 9 and 10, the abbreviation “e.g.” or the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 11 depends from claim 9, and is therefore included in this rejection.
Regarding claims 5, 8-10, and 19, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claims 6 and 11 depend from claims 5 and 9, respectively, are therefore included in this rejection.
Regarding claims 8 and 19, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 2, 8-10, 12, 15, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Guangzhou (CN110669735A; published 1/10/2020 with priority to 6/18/2019; cited in the IDS filed 3/25/2025), in view of Sasaki et al. (Development of a rapid and quantitative method for the analysis of viral entry and release using a NanoLuc luciferase complementation assay. Virus research 243 (2018): 69-74); published 1/2/2018) and Gao et al. (US20170327797A1; published 11/16/2017). Note: Gao et al. is not required for the 103 rejection of claims 1 or 8. However, in view of compact prosecution, the third reference is added to this 103 rejection because it teaches 100% of the nucleic acid sequence recited in claim 8.
Regarding claim 1, Guangzhou teaches HBV cccDNA variants comprising exogenous luciferase fragments in the C-ORF inserted between the precore and core genes (entire document; claims 1-10; Figure 4 – see below). Guangzhou further teaches that the luciferase fragment Glu-N and the luciferase fragment Glu-C are connected to the 5’ and 3’ ends of the linear HBV gen and Phic31 recombinase recognition sites, such that when Phic31 recombinase is expressed by HepG2 liver cancer cells, the recombinase induces the linear genome to form cccDNA, which can then be transcribed to express the luciferase gene (pp. 3-4).
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Guangzhou (Fig. 4)
However, Guangzhou does not specifically teach that the first fragment of luciferase is HiBiT and the second fragment of luciferase is LgBiT.
Gao‘s disclosure is directed to recombinant HBV cccDNA comprising HBV genome or the fragment or variant thereof and a site-hybrid insert, a method to generate said recombinant HBV cccDNA, a method for establishment of an in vitro or in vivo cccDNA based model for persistently hepatitis B virus replication by using the recombinant HBV cccDNA of the present invention, and a method for anti-HBV drug evaluation (abstract).
Regarding claim 1, Gao teaches recombinant HBV cccDNA comprising HBV genome or the fragment or variant thereof and a site-hybrid insert (abstract).
Sasaki’s disclosure is directed to quantitative methods for the detection of cellular entry and release of subviral particles (SVPs) and flavivirus-like particles (VLPs) by applying a luciferase complementation assay based on the high affinity interaction between the split NanoLuc luciferase protein, LgBiT and the small peptide, HiBiT (abstract; entire document).
Regarding claim 1, Sasaki teaches that the split luciferase fragments are HiBiT and LgBit (entire document). Sasaki further teaches nucleic acid molecules comprising viral genome sequences comprising the luciferase fragments for a sensitive quantitative assay (entire document).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Guangzhou’s HBV cccDNA variants comprising a split luciferase assay with the HBV genome sequence of described by Gao and with the HiBiT and LgBit split luciferase assay comprising, as described by Sasaki because it would have amounted to a simple substitutions of known HBV genome sequences and luciferase fragments to obtain predictable results. Guangzhou teaches HBV cccDNA variants comprising exogenous luciferase fragments in the C-ORF inserted between the precore and core genes (entire document; claims 1-10; Figure 4 – see above). Gao teaches recombinant HBV genome sequences (see above).Sasaki teaches a viral quantitative method using HiBiT and LgBiT NanoLuc luciferase complementation assay (entire document). One would have had a reasonable expectation of success because Guangzhou, Gao, Sasaki are directed to viral genome detection and modifications. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 2, Guangzhou teaches the HBV genome fragment comprising X-ORF (Fig. 4).
Regarding claim 8, Guangzhou teaches full-length and overlength HBV genome up to double-length (p.1; Fig. 4). Note: The Office has rejected claim 8 “preferably, the HBV genome comprises the sequence set forth in SEQ ID NO: 1” under 112(b) above as being unclear whether the limitation is required for the claimed invention. However, in the interest of compact prosecution, Gao is used to reject the portion of the claim following the term “preferably”. Regarding claim 8, Gao teaches SEQ ID NO: 7, encoding HBV, having 100% sequence identity to Applicant’s claimed SEQ ID NO: 1 (See OA.Appendix for sequence alignment).
Regarding claim 9, Guangzhou teaches that the inducible promoter Tet (p. 1, last para).
Regarding claim 10, Guangzhou teaches the reporter gene is selected from the fluorescent protein gene EGFP and antibiotic resistance gene puromycin and that Puro-EGFP is linked by self-cleaving polypeptide 2A (p. 3, para 10; p. 7, para 13; Fig. 4).
Regarding claim 12, Guangzhou teaches recombinant HBV cccDNA and a method for inducing the formation of HBV cccDNA (p. 1, Technical field).
Regarding claims 15 and 19, Guangzhou teaches that vectors and host cells (liver cancer cell line HepG2 cells) comprising a recombinant HBV cccDNA (p. 1; last para; p. 3, para 3; p. 4, para 5).
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Guangzhou (CN110669735A; published 1/10/2020 with priority to 6/18/2019; cited in the IDS filed 3/25/2025), in view of Sasaki et al. "Development of a rapid and quantitative method for the analysis of viral entry and release using a NanoLuc luciferase complementation assay." Virus research 243 (2018): 69-74; published 1/2/2018) and Gao et al. (US20170327797A1; published 11/16/2017) as applied to claims 1, 2, 8-10, 12, 15, and 19 above, and further in view of Guo et al. (US20170240600A1; published 8/24/2017).
The teachings of Guangzhou and Sasaki are applied to claims 5 and 6 as they are applied to claims 1, 2, 8-10, 12, 15, and 19 above.
However, Guangzhou and Sasaki do not teach that the exogenous insertion sequence comprises multiple copies of luciferase fragment in tandem repeats.
Guo’s disclosure is directed to methods and uses for screening anti-hepadnaviral substances, wherein the substances are screened for the capacity to inhibit covalently closed circular (ccc) DNA of a hepadnavirus, like hepatitis B virus (abstract). Guo teaches taking advantage of cells comprising a nucleic sequence encoding a tagged hepadnavirus e antigen, like Hepatitis B virus e antigen (HBeAg) and teach nucleic acid sequences encoding a tagged hepadnavirus e antigen (abstract). Guo teaches HBV cccDNA variants comprising tags in HepG2 cells (Example 1).Regarding claim 5, Guo teaches improving the specificity and sensitivity of cccDNA HBV reporter detection with various tags (para 0025). Guo further teaches HBV tags that are luciferase reporter protein tags in tandem repeats and can also be in repeats separated by linkers (paras 0063-0074).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the HBV cccDNA variants of Guangzhou and Sasaki to include tandem repeats of the luciferase tag, as described in Guo because it would have amounted to a simple combination of prior art elements according to known methods to yield predictable results. Guangzhou and Sasaki teach HBV cccDNA variants with split luciferase components for detection (see 103 rejection above). Guo teaches improving the specificity and sensitivity of cccDNA HBV reporter detection with various tags and that tags can be used in tandem repeats (paras 0025 and 0063-0074). One would have had a reasonable expectation of success because Guangzhou, Sasaki, and Guo are directed to improving methods of detecting HBV cccDNA variants. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 6, Guangzhou further teaches the luciferase gene fragment connected to the 5’ end of the HBV gene linked by self-cleaving polypeptide 2A (p. 3, paras 5-13).
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Allowable Subject Matter
Claim 7 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
SEQ ID NO: 4 (recited in claim 7), a 117bp sequence encoding HiBiT16 insertion sequence, appears to be free of the prior art (see OA.Appendix). The closest prior art in Feng et al. (CN110592031A; published 12/20/2019) teaches a HiBiT sequence having 33.8% match with Applicant’s SEQ ID NO: 4 (see OA.Appendix for sequence alignment).
SEQ ID NO: 8 (recited in claim 11), a 3488bp sequence encoding a nucleic acid molecule of the invention, appears to be free of the prior art. The closest prior art in Gao teaches Hepatitis B virus circle-HBVl.3 construct DNA SEQ ID NO: 11 having 93.7% sequence identity to the 4180 bp of Applicant’s claimed SEQ ID NO: 8 (Example 5 and see OA.Appendix for sequence alignment).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 7:30am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KHALEDA B HASAN/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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