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 .
Priority
This application is a DIV of l 7 /369,589 dated 07/07/2021. US Pat. 11957667
17/369,589 has PRO 63/049,140 dated 07/08/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/28/2023, and 02/16/2024
were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information
disclosure statements are being considered by the examiner.
Status of claims
Claims 1 and 6-17 are currently pending in this application and under examination. Claims 1, 11 and 15-16 have been amended. Claims 2-5, and 18-20 have been cancelled by applicant without prejudice or disclaimer.
Applicant’s arguments, filed 06/30/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application.
The obviousness rejection below is repeated from the 04/01/2026 Office Action and modified in order to address the most recent amendments.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1 and 6-17 are rejected under 35 U.S.C. 103 as being unpatentable over Lee (US Pat. US 8,440,649 B2) in view of Su et al. (Design, synthesis, antiviral activity, and SARs of 13a-substituted phenanthroindolizidine alkaloid derivatives) and further in view of Wang et al. (Tylophorine Analogs Allosterically Regulates Heat Shock Cognate Protein 70 And Inhibits Hepatitis C Virus Replication).
The instant claims are directed to a method of inhibiting a positive strand RNA virus by identifying a subject infected with a positive strand RNA virus and administering to the subject an effective amount of a compound of Formula I, wherein the positive strand RNA virus is a Zika or Dengue virus.
Lee teaches Coronavirus (CoV) is a family of enveloped viruses that have a positive-sense single-stranded RNA genome. (background, lines 14-15) Lee also teaches phenanthroindolizidine analogues which exhibit anti-CoV activity, i.e., reducing CoV-induced cytopathic effects or inhibiting viral protein production and viral replication which is used as a method of treating infection by CoV (e.g., SARS-associated virus and transmissible gastroenteritis virus) with a compound of Formula I, wherein the derivative of compound 1 anticipates the structural limitations of Formula I of the instant claims 1 and 6-17 wherein the X-Y ring comprises single bonds, Y is N, R1, R4, RS, R8-R15 are H, R2, R3, R6, and R7 are alkoxy (OMe), Rl6 and R17 are bond, a X is CR'R" wherein R' and R" are H and n is 1 (Summary, table 1).
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Lee's compound 1 (Left) Applicants Formula I (Right)
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Compound 1, instant claim 17 (Left)
However, Lee et al. fail to disclose Tylophorine analogs for inhibiting specific single-stranded positive RNA ((+) ssRNA) viruses of Zika (ZIKV) or Dengue (DENV).
In addition to the disclosures of Lee above, Su et al. teach the phenanthroindolizidine alkaloid compound of (R)-tylophorine (Below), registry number 25908-92-3 which meets the structural limitations of the compound of formula I (Above) of the instant claims wherein the X-Y ring comprises single bonds, Y is N, R1, R4, RS, R8-R15 are H, R2, R3, R6, and R7 are alkoxy (OMe), Rl6 and R17 are bond, a X is CR'R" wherein R' and R" are Hand n is 1 (fig. 1).
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Su discloses Table I and 2 wherein the In vivo antiviral activity of tylophorine targeting the positive strand RNA virus of tobacco mosaic virus (TMV) RNA.
However, Su et al. fail to explicitly disclose administering the compound of (R)tylophorine for the treatment of the positive strand RNA viruses of Zika, and Dengue.
Wang et al. teach tylophorine analogs which exhibit potent inhibitory activity against hepatitis C virus (HCV) replication in genotype lb Con 1 isolate wherein the HCV replication is partially mediated through cellular heat shock cognate protein 70 (Hsc70) (Abstract). Wang also teaches Hsc70 is associated with the HCV replication complex. Host chaperones and co-chaperones play important functions in the assembly of the viral replication complex and the replication of the viral genome. Hsc70 participated in the RNA-dependent replication of sindbis virus, influenza virus, rotavirus, and dengue virus (Discussion, page 7, 2nd paragraph). Wang also discloses the tylophorine analogues (Below) of DCB-3503 and RAC-cryptopleurine which satisfies the structural limitations of Formula I of the instant claims. (Abstract).
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Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer Lee’s compound of formula I (Su’s (R)-tylophorine) as a tylophorine for the treatment of a positive strand RNA virus to a subject in need thereof by combining the anti-TMV teachings of Su with the anti-HCV activity and Hsc-70 participation in the RNA dependent replication of dengue (Flaviviridae family) virus as disclosed by Wang because each of the viruses are positive stranded RNA viruses and Lee teaches compound of tylophorine is useful in treating an infected subject with a positive strand RNA virus. See MPEP 2144.06 and MPEP 2143.
A person of ordinary skill in the art would have been motivated to administer an effective amount of a compound of tylophorine to treat a disease caused by a positive strand RNA virus in a subject because the teachings of Lee, Su and Wang in treating TMV, SARs, Dengue (DENV) and other positive strand diseases with tylophorines. A skilled artisan would have had a reasonable expectation of success in treating other positive stranded RNA viruses including the Zika and Dengue virus based on the results disclosed by Lee, Su and Wang of tylophorines ability to treat the positive stranded RNA viruses of TMV and dengue. See MPEP 2112 and MPEP 2144.05(11).
Response to Arguments
Applicant's arguments filed 06/30/2026 have been fully considered but they are not persuasive.
Applicant argues exhibit A, Fernandes et al. (Reporter Replicons for Antiviral Drug Discovery against Positive Single-Stranded RNA Viruses), teaches that none of the antiviral drugs identified for inhibiting Sars CoV also inhibit Dengue virus (DENV) or Zika virus (ZIKV), and also teaches that none of the Dengue virus inhibitors also inhibit Zika virus. See Exhibit A, Table 1 at pages 14 and 15. Therefore, an ordinary artisan would not have had a reasonable expectation of success in inhibiting a Zika virus or a Dengue virus using a compound of Formula I described in Lee as effective for treating Sars CoV, in view of the general knowledge in the art exemplified by Exhibit A, that these three viruses are inhibited by distinct compounds and that a skilled artisan, even with the teachings of Su and Wang in mind, would not have been led to use a compound of Formula I described in Lee as a Sars CoV inhibitor to inhibit Zika virus and Dengue virus, as required by amended claim 1.
Examiner agrees with applicant that Fernandes teaches different compounds for inhibiting Sars CoV, DENV and ZIKV as is shown in table 1 (Reproduced in part, Below).
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However, Fernandes also discloses in the introduction that single-stranded positive RNA ((+) ssRNA) viruses include a group of human pathogens with significant socioeconomic impacts, such as Dengue virus (DENY), Zika virus (ZIKV), Hepatitis C virus (HCV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). The examiner notes that the compounds in Fernandes Table 1 are compounds tested in replicon-based assays whereas Lee discloses the tylophorine compound 1 in a method used to treat single-stranded positive RNA ((+) ssRNA) infection by CoV (e.g., SARS-associated virus and transmissible gastroenteritis virus), Su discloses R-tylophorine to treat the single-stranded positive RNA ((+) ssRNA) virus of tobacco mosaic virus (TMV) and Wang who discloses tylophorine analogs of DCB-3503 and RAC-cryptopleurine which exhibit potent inhibitory activity against the single-stranded positive RNA ((+) ssRNA) hepatitis C virus (HCV). A skilled artisan would have had a greater expectation of success in inhibiting the single-stranded positive RNA ((+) ssRNA) viruses of DENV and ZIKV following the disclosures of Fernandes who disclosed DENV, ZIKV, HCV, and SARS-CoV are related as single-stranded positive RNA ((+) ssRNA) viruses and since Lee, Su and Wang teach tylophorine analogues useful in inhibiting single-stranded positive RNA ((+) ssRNA). Therefore, one of ordinary skill could reasonably expect that a tylophorine analogue compound disclosed in Lee, Su or Wang successful in treating one single-stranded positive RNA ((+) ssRNA) virus, would also produce beneficial results in treating the single-stranded positive RNA ((+) ssRNA) viruses of ZIKV and DENV.
Conclusion
All claims are rejected, no claims are allowed.
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 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623
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