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 .
Application Status and Election
Claims 1-25 are pending.
Applicant’s election of Group III (claims 11-15) and the species (See listing below) in the reply filed March 13 2025 remains acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 1-10 and 16-20 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Applicants elect without traverse the species as follows:
1) Species A: Hepatitis B Virus protein: HBs antigen protein.
2) Species B: RNA-binding protein inhibitor: Inhibition of expression of the RNA binding protein which corresponds to Enhancer II region, SEQ ID NO: 2. “Regarding ‘speciify the target as enhancer I of the viral genome DNA or enhancer II of the viral RNA sequence’, Applicants elect ‘ehnancer II of the viral RNA sequence.”
3) Species C: Expression level: “the expression level of the hepatitis B virus gnome DNA”.
4) Species D: RNA binding protein: “YTHDC1”.
Examiner notes that in the response to election filed 3/13/25 Applicants elected without traverse between the species of RNA binding protein enhancer target, Applicants elected “enhancer II of the viral RNA sequence” and not “enhancer I”.
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Examiner further notes that the amendments to claim 11 to change “and/or” to “and” does not alter the Markush groups designated by “at least one sequence selected from…” thus “enhancer I” is not a necessary limitation of claim 11. Furthermore, “enhancer I” is the non-elected species and continues to be withdrawn from consideration.
Claim 26 was canceled with limitations incorporated into amended claim 11.
No new claims were added.
Examination on the merits commences on claims 11-15, and 21-24.
35 USC §103 rejections of record are maintained.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103 – Modified Maintained
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 11-15, and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Li of record (Li, Yuan, et al. "LUC7L3/CROP inhibits replication of hepatitis B virus via suppressing enhancer II/basal core promoter activity." Scientific reports 6.1 (2016): 36741.) in view of Yuh of record (Yuh CH, Ting LP. The genome of hepatitis B virus contains a second enhancer: cooperation of two elements within this enhancer is required for its function. J Virol. 1990 Sep;64(9):4281-7. doi: 10.1128/JVI.64.9.4281-4287.1990.) and GenBank1 of record (GenBank1, AB246345.1, Hepatitis B virus DNA, complete genome, clone: C_JPNAT, retrieved June 19 2025, Revision Oct 28 2006, https://www.ncbi.nlm.nih.gov/nuccore/116812287?sat=3&satkey=6039361, printed as pages 1 of 2 to pages 2 of 2) and Cook of record (Cook, Kate B., et al. "RBPDB: a database of RNA-binding specificities." Nucleic acids research 39.suppl_1 (2010): D301-D308) and Kretschmer of record (Kretschmer, Jens. Interactions and functions of RNA-binding proteins. Diss. Georg-August-Universität Göttingen, 2016.)
Examiner notes that Applicants have elected inhibiting HBV viral antigen production (HBsAg) expression through inhibiting (via dsRNA RNAi) an RNA-binding protein which binds to Enhancer II region of the HBV viral genome.
Regarding claim 11 (a), Li teaches inhibiting HBV viral replication and HBV viral protein production including HBs antigen protein by the method of detecting and inhibiting LUC7L3 (LUC7 like 3 pre-mRNA splicing factor), a novel interacting partner of HBV enhancer II and basal core promoter (ENII/BCP) where LUC7L3 functions as a negative regulator of ENII/BCP (abstract and Figure 2). Li teaches gene silencing of LUC7L3 significantly increased expression of the viral genes and antigens as well as the activities of ENII/BCP and core promoter where as in contrast, overexpression of LUC7L3 inhibited their activities and HBV replication (abstract). Li teaches two HBV enhancers regions, ENI and ENII, are involved in upregulating the activities of HBV promotors (page 1, paragraph [0001]); that the 1627-1817 nt sequence of HBV ENII/BCP was used to identify a regulator of the HBV 3.5 kb pregenome/precore RNA (pgRNA) (page 2, paragraph [0003]); and that a 1666-1700 nt region of ENII/BCP is important for negative regulation (page 3, last paragraph; figure 4). Li teaches inhibition of HBV replication mediated by LUC7L3 may provide a new antiviral strategy (page 8, paragraphs [0003], [0004]).
Although Li teaches a method of inhibiting Hepatitis B virus protein production by influencing a substance that promotes the Enhancer II (ENII) region of the HBV genome and identifies a method of determining important binding regions within the Enhancer II region (Fig 4), Li does not teach a method of inhibiting an RNA binding protein which binds to RNA corresponding to that Enhancer II region.
Yuh teaches identification of the second enhancer (enhancer II) region in the HBV genome located at nt 1636 to 1741, downstream of enhancer I and immediately upstream of the core gene (abstract).
GenBank1 teaches the known HBV genome with 100% identity to nucleotides 1638 and 1771 which is where Yuh identified the Enhancer 2 region of the HBV genome (GenBank1).
Cook teaches a method of screening a substance (RNA binding proteins) that binds to and influences RNA and is critical for mapping and understanding transcriptional and post-transcriptional networks and regulatory mechanisms (pg D301, col1 para 3). Cook teaches RNA-binding proteins (RBPs) have a fundamental role in a wide variety of cellular processes including transcription, RNA splicing and processing, localization, stability and translation (pg D301, col1 para 2). Cook teaches the RNA-Binding Protein DataBase (RBPDB), a database of RNA-binding experiments with a total of 1453 in vitro and in vivo experiments on 272 proteins are included, as well as 71 binding profiles in the form of position weight matrices (PWMs) and sequence logos, and 36 sets of sequences bound in vivo in immunoprecipitation experiments (pg D301, col1 para 2). Cook teaches the RBPDB allows users to scan RNA sequences for matches to RBP binding preferences stored in RBPDB where the collected motifs should prove invaluable for genome-wide scans to identify cis -regulatory elements involved in post-transcriptional regulation via RBPs (pg D301, col2, para 2). Cook teaches the inclusion of in vivo bound transcripts provides a snapshot of enriched RNA-binding protein specific mRNA targets (pg D301, col2, para 2).
Kretschmer also teaches a bioinformatic pipeline for the mapping of CRAC data onto the human genome and verified that this could be used to identify RNA substrates of RNA modifying enzymes, such as the RNA-binding protein YTHDC1 identified in humans to interact with the YTH domain (pg 47 para 2) and which functions in alternative splicing by interacting with splicing enhancer-binding SR proteins to control inclusion vs skipping of targeted exons (pg 21 para 3).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the known Enhancer II region within Cook’s RNA binding protein screening method incorporating the RBPDB database to screen for and identify RNA binding proteins such as YTHDC1 identified by Kretschmer’s database method and inhibit that target RNA binding protein to facilitate a decrease in HBV promotion, thus decreasing viral replication and HBV antigen protein production. It would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation of identifying an RNA-binding protein which targets the Enhancer II region of the HBV viral genome because Li teaches the method of identifying important targets within that Enhancer II region, GenBank1 teaches the known Enhancer II region, and Cook teaches the method of identifying RNA-binding proteins which can influence viral activity. It would have been predictable that inhibiting target RNA-binding proteins that target ENII would inhibit HBV viral protein production because Cook demonstrates the significant role of RNA binding proteins in transcriptional and post-transcriptional networks and regulatory mechanisms and Li demonstrates that inhibiting substances which enhance the Enhancer II region disclosed by Yuh is capable of inhibiting HBV viral protein production. The skilled artisan would therefore be motivated to screen for, identify, and inhibit an RNA-binding protein which promotes viral production so as to inhibit HBV viral production and enhance the method of treating HBV.
Regarding claim 11(b), Examiner interprets this step as contacting HBV infected cells with a substance that reduces expression levels of an RNA binding protein.
Li does not teach contacting HBV cells with a substance which reduces expression levels of an RNA binding protein. However, Li teaches use of siRNA RNAi to decrease expression of a protein which binds to a region corresponding to Enhancer II which decreases HBV production in HBV infected cells (Figure 2). Similarly, Kretschmer teaches RNAi siRNA inhibition of the RNA-binding protein YTHDC1 in the method of targeting exon skipping by inhibiting the RNA-binding protein (Table 1 pg 25). It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used this known RNAi nucleic acid interference to inhibit expression of the target RNA-binding protein, as screened for and identified given the §103 rationale applied for claim 11(a).
Regarding claim 11(c), Li teaches measuring decrease in Hepatitis B virus protein after RNAi inhibition of the target protein which binds to a region corresponding to the Enhancer II (Figure 2).
Similarly, regarding newly amended claim 11(d), Li teaches selecting an siRNA RNAi agent capable of inhibiting production of the hepatitis B virus protein production (Figure 2). Furthermore, as described above, Kretschmer teaches a bioinformatic pipeline for the mapping of CRAC data onto the human genome and verified that this could be used to identify RNA substrates of RNA modifying enzymes, such as the RNA-binding protein YTHDC1 identified in humans to interact with the YTH domain (pg 47 para 2) and which functions in alternative splicing by interacting with splicing enhancer-binding SR proteins to control inclusion vs skipping of targeted exons (pg 21 para 3). It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have employed the known RNA-binding protein database screening tools taught by Cook and Kretschmer to identify RNA binding proteins such as YTHDC1 and screened against the known Enhancer II region taught by GenBank1 and Yuh to decipher binding patterns for the Enhancer II region and then incorporate the disclosed RNAi interference method to inhibit the expression of that RNA binding protein so as to decrease the enhancement of the HBV viral genome, as described in the §103 rationale applied above for claim 11(a).
Regarding claim 12, Cook teaches includes a step of using an RNA-binding protein sequence database (abstract).
Regarding claims 13 and 15, Li and Kretschmer teach antisense nucleic acid RNAi as the test substance which inhibits expression of the target protein which causes a decrease in hepatitis B virus protein production (Figure 2).
Regarding claim 14, Li teaches measuring a hepatitis B virus protein in a culture supernatant of the cells (Figure 2).
Regarding claims 21 and 22, GenBank1 teaches 100% identity to instant SEQ ID NO: 2 between nucleotides 1638 and 1771 which is where Yuh identified the Enhancer 2 region of the HBV genome.
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Regarding claims 23 and 24, Li teaches measuring decrease in Hepatitis B virus genome DNA and HBs antigen after RNAi inhibition of the target protein which binds to a region corresponding to the Enhancer II (Figure 2).
Response to Arguments
Applicants submit (Remarks pg 14) that the §103 rejection of record should be withdrawn because Li, Yuh, GenBank1, Cook and Kretschmer do not disclose or render obvious the presently amended method of screening a substance that inhibits production of a hepatitis B virus protein. Applicant’s arguments have been thoroughly reviewed and found unpersuasive. The newly amended claim 11 merely incorporates the limitations of canceled claim 26 into claim 11(d) and which was thoroughly addressed in the §103 rejection of record of former claim 26 pertaining to the elected RNA-binding protein YTHDC1. The modified §103 rejection detailed above reflects the incorporation of claim 26 limitations into claim 11(d).
Applicants further argue (Remarks pg 1) that Li of record does not address the newly amended claims because Li does not teach a binding protein which targets enhancer I but rather enhancer II. Specifically, Applicants argue that Li reports the identification of LU7L3 as a novel factor interacting with the HBV DNA Enhancer (Enh) II region and that LU7L3 acts on the Enh II region sequence of HBV DNA to regulate pgRNA transcription. Applicants argue that in contrast, the present invention of the amended claims focuses on a protein that acts (binds) to an HBV RNA sequence corresponding to the EnhI or EnhII region of HBV DNA. Applicant’s arguments have been thoroughly reviewed and found unpersuasive because the Enhancer I region of the HBV DNA is not the elected species. Applicants clearly elected without traverse the species of Enhancer II region of target HBV DNA, therefore Applicants arguments regarding the inapplicability of Li to the enhancer I region of HBV DNA is moot. Furthermore, the Markush groupings as disclosed in claim 11(a) do not require Enhancer I region target as a necessary limitation.
Applicants continue to argue (Remarks pg 16) the deficiencies of Li, however examiner notes that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The above detailed §103 rejection is based on the combination teachings of the references of record, their predictable success in the therapeutic method, and motivation to combine said teachings for enhanced therapeutic efficacy. As noted above, Applicants arguments relate mostly to the deficiencies of Li regarding Enhancer I target region of HBV DNA which is the non-elected species.
In support of the teachings of Li, the secondary references establish the following:
Yuh teaches identification of the second enhancer (enhancer II) region in the HBV genome located at nt 1636 to 1741, downstream of enhancer I and immediately upstream of the core gene (abstract).
GenBank1 teaches the known HBV genome with 100% identity to nucleotides 1638 and 1771 which is where Yuh identified the Enhancer 2 region of the HBV genome (GenBank1).
Cook teaches a method of screening a substance (RNA binding proteins) that binds to and influences RNA and is critical for mapping and understanding transcriptional and post-transcriptional networks and regulatory mechanisms (pg D301, col1 para 3).
Kretschmer teaches a bioinformatic pipeline for the mapping of CRAC data onto the human genome and verified that this could be used to identify RNA substrates of RNA modifying enzymes, such as the RNA-binding protein YTHDC1 identified in humans to interact with the YTH domain (pg 47 para 2) and which functions in alternative splicing by interacting with splicing enhancer-binding SR proteins to control inclusion vs skipping of targeted exons (pg 21 para 3).
Therefore, as described in the §103 rejection above, it would have been predictable that inhibiting target RNA-binding proteins that target ENII region would inhibit HBV viral protein production because Cook demonstrates the significant role of RNA binding proteins in transcriptional and post-transcriptional networks and regulatory mechanisms and Li demonstrates that inhibiting substances which enhance the Enhancer II region disclosed by Yuh is capable of inhibiting HBV viral protein production. The skilled artisan would be motivated to screen for, identify, and inhibit an RNA-binding protein which promotes viral production so as to inhibit HBV viral production and enhance the method of treating HBV.
Conclusion
No claims are allowable.
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).
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN CHARLES MCKILLOP whose telephone number is (703)756-1089. The examiner can normally be reached Mon-Fri 8:30-5:30.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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