DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 04/09/2025, in which claims 1, 11-12, 22, 26, and 28 are amended and claims 13-21 and 27 are canceled.
Claims 1-12, 22-26, and 28 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/US2020/048463, filed on 08/28/2020, which claims domestic benefit to 62/894,032 filed on 08/30/2019.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 112(a) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/894,032, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The provisional application No. 62/894,032 fails to provide support for treating a viral infection wherein the infection is an infection by a SARS-CoV-1, SARS-CoV-2, or MERS-CoV virus.
Accordingly, claims 1, 8-12, 22-25 and 28 are not entitled to the benefit of the prior application and receive the filing date of 08/28/2020, which is the filing date of PCT/US2020/048463 which provides support for these claims.
Objections and Rejections Withdrawn
Applicant’s Amendment, filed 04/09/2025, with respect that claim 11 is objected to because of informalities has been fully considered and is persuasive, as claim has been amended to remove the first period. This rejection has been withdrawn.
Applicant’s Amendment, filed 04/09/2025, with respect that claims 1-12, 22-25, and 27-28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a viral infection, does not reasonably provide enablement for preventing a viral infection has been fully considered and is persuasive, as claims 1-12, 22-25, and 28 have been amended to change the scope of the claim and claim 27 has been canceled. This rejection has been withdrawn.
Applicant’s Amendment, filed 04/09/2025, with respect that claims 1 and 6-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lindstrom et al. (Chem Med Chem, 2018) has been fully considered and is persuasive, as claims 1 and 6-7 have been amended to change the scope of the claim to exclude Formula II. This rejection has been withdrawn.
Applicant’s Amendment, filed 04/09/2025, with respect that claims 1-3, 11-12, and 26-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al. (Antiviral Research, 2013) has been fully considered and is persuasive, as claims 1-3, 11-12, and 26 have been amended to change the scope of the claim to exclude Formula II and claim 27 has been canceled. This rejection has been withdrawn.
Applicant’s Amendment, filed 04/09/2025, with respect that claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Antiviral Research, 2013) as applied to claim 1, further in view of Heinz et al. (Virology, 1994) has been fully considered and is persuasive, as claims 4-5 have been amended to change the scope of the claim to exclude Formula II. This rejection has been withdrawn.
Applicant’s Amendment, filed 04/09/2025, with respect that claims 8-9 and 28, are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Antiviral Research, 2013) as applied to claim 1, further in view of Pawar (International Journal of Antimicrobial Agents, April 2020) has been fully considered and is persuasive, as claims 8-9 and 28 have been amended to change the scope of the claim to exclude Formula II. This rejection has been withdrawn.
Applicant’s Amendment, filed 04/09/2025, with respect that claims 10 and 28, are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Antiviral Research, 2013) as applied to claim 1, further in view of Millet et al. (PNAS, 2014) has been fully considered and is persuasive, as claims 10 and 28 have been amended to change the scope of the claim to exclude Formula II. This rejection has been withdrawn.
Applicant’s Amendment, filed 04/09/2025, with respect that claims 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Antiviral Research, 2013) has been fully considered and is persuasive, as claims 22-25 have been amended to change the scope of the claim to exclude Formula II. This rejection has been withdrawn.
The following are new objections and modified grounds of rejection necessitated by Applicant’s amendment.
Claim Objections
Claim 12 is objected to because of the following informalities: as amended, claim 12 recites “comprising a or salt of Formula I.” This is a clear typographical error. For purposes of compact prosecution, under broadest reasonable interpretation, the claims will be interpreted as reciting “comprising a compound or salt of Formula I.” Appropriate correction is required.
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.
Claim 3 is 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.
Claim 3 recites “wherein the mosquito transmitted flavivirus” in line 1. There is insufficient antecedent basis for this limitation in the claim. For purposes of compact prosecution, under broadest reasonable interpretation, the claim will be interpreted as depending from claim 2, in which proper antecedent basis can be found.
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.
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.
Claims 1, 8-12, 22-25, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US 11,638,713 B2; PTO-892).
Zhang teaches the preparation of aryl-naphthalene glycoside derivatives, in particular Patentiflorin A analogs, and their use as antiviral agents (col. 1, lines 14-22). Viral infections treated by these analogues include HIV, CoV, EBOV and AIV (col. 3, lines 23-26). The coronaviruses treated by this method include SARS-CoV-2, SARS-CoV, and MERS-CoV (col. 166 and lines 14-18). The Patentiflorin A analogues taught by Zhang include compound 26b (col. 129, lines 64-66), which has the structure shown below (col. 8, line 50), and corresponds to Formula I in the instant claims. Zhang discloses that a number of compounds including compound 26b were tested in a cell assay to show inhibitory effects against SARS-CoV-2 and had lower EC50 values than the positive control arbidol (col. 173, lines 35-39). Zhang discloses that compositions comprising the Patentiflorin analogues may further comprise a pharmaceutically expectable excipient (claim 9 and col. 127, lines 58-61).
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Zhang does not expressly disclose a single embodiment of treating a coronavirus infection in a subject comprising administering compound 26b (instant claim 1).
It would have been prima facie obvious before the effective filing date of the claimed invention to treat a SARS-CoV-2 infection by administering to a subject in need thereof the Patentiflorin A analogue 26b to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to treat a SARS-CoV-2 infection by administering 26b because Zhang teaches treatment of viral infections including a SARS-CoV-2 viral infection by administering Patentiflorin A analogues and teaches that 26b is Patentiflorin A analogue. One of ordinary skill in the art would have a reasonable expectation of success because Zhang discloses that compound 26b was tested in a cell assay to show inhibitory effects against SARS-CoV-2 and had lower EC50 values than the positive control arbidol.
Regarding claims 22-25, although Zhang does not expressly disclose an optimal dosage for compound 26b, Zhang describes a toxicity evaluation of the compounds in mice dosed with either 25 or 50 mg/kg (col. 169, lines 34-48). Thus, it would have been obvious for one of ordinary skill in the art to optimize the dosage of compound 26b for the treatment of viral infections starting with a dosage of 25 mg/kg because Zhang suggests this dosage for testing of the toxicity of the compound.
Regarding claim 28, Zhang teaches that coronaviruses, which include SARS-CoV-2, are single-stranded, positive-sense RNA viruses (col 2, lines 49-55). Thus Zhang suggests that inhibition of SARS-CoV-2 infection includes the inhibition of the synthesis of SARS-CoV-2 viral RNA, which is interpreted as inhibiting the synthesis of viral RNA in cells. Zhang further teaches that compounds including compound 26b were tested and showed inhibitory effects against SARS-CoV-2 (col. 173, lines 35-39). The test involved administration of ten microliters of samples of the test compounds in varying concentrations to a SARS-CoV-2 susceptible liver cell line. The cells were then administered 190 microliters of HIV/SARSP (col. 168, lines 7-19), which is a SARS-CoV-2 pseudovirion comprising a SARS-CoV-2 spike protein and the replication defective HIV vector pNL4-3.Luc.RE, which allows measurement in infection level through measuring luciferase activity (col 166, lines 19-65). Although Zhang does not disclose contacting the cell with a SARS-CoV virus itself, Zhang demonstrates inhibition of a viral infection in a cell in a test comprising contacting the cell with a SARS-CoV-2 pseudovirion, which would provide one of ordinary skill in the art with a reasonable expectation of success in inhibiting the synthesis of SARS-CoV-2 RNA in a method comprising contacting the cell with a SARS-CoV-2 virus, because a SARS-CoV-2 pseudovirion bearing a SARS-CoV-2 spike protein would be expected to serve as a model of a SARS-CoV-2 virus.
Claims 1-3 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US 11,638,713 B2; PTO-892), further in view of Chen et al. (Antiviral Research, 2013; PTO-892 10/09/2024).
Zhang teaches the preparation of aryl-naphthalene glycoside derivatives, in particular Patentiflorin A analogs, and their use as antiviral agents including as anti-influenza and anti-HIV antivirals (col. 1, lines 14-22). The Patentiflorin A analogues taught by Zhang include compound 26b (col. 129, lines 64-66), which has the structure shown below (col. 8, line 50) and corresponds to Formula II in the instant claims. Zhang discloses that compounds including compound 26b were tested in a cell assay to show inhibitory effects against the influenza virus H5N1 and had comparable EC50 values to the positive control AZT (col. 173, lines 18-23).
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Zhang further describes diphyllin as a structural scaffold for C-O derivatization at C-7 (col. 163, lines 47-50) and teaches that 26b was derived by glycosylation of diphyllin and is a diphyllin analogue (col. 164, lines 10-12). Thus Zhang teaches that there are structural similarities between diphyllin and 26b.
Zhang does not expressly disclose a treating a flavivirus infection in a subject comprising administering compound 26b (instant claim 1).
Chen characterizes the application of diphyllin as an antiviral for various influenza virus
strains (page 372, paragraph 2). Chen teaches that the mechanism of influenza viral infection has shown that endosomal acidification plays a major role in facilitating the fusion between viral and endosomal membranes (abstract). Chen teaches that other viruses also have a mechanism of infection that involves endosomal acidification, including flaviviruses, vaccina viruses, and coronaviruses (page 372, paragraph 1).
Chen further teaches that diphyllin inhibits endosomal acidification in MDCK cells and A549 cells (page 374, paragraph 2). Furthermore, Chen teaches that diphyllin could interfere with the low pH-dependent membrane fusion between virus and intracellular endosomes (paragraph bridging pages 379-380). Pretreatment of cells with diphyllin was effective in altering the cellular susceptibility to influenza virus infection (page 374, paragraph 3). To further investigate the spectrum of antiviral activities of diphyllin, Chen extended use of diphyllin to the context of dengue virus, another emerging human pathogen that shares a similar pH-dependent virus entry mechanism as influenza viruses (paragraph bridging pages 379-380). Chen states that the results of testing diphyllin against dengue viruses showed that diphyllin interfered with dengue virus replication in cells, supporting the notion that diphyllin possesses a host-targeting, strain-independent mechanism of inhibition (paragraph bridging pages 379-380).
It would have been prima facie obvious to combine the teachings of Zhang and Chen before the effective filing date of the claimed invention by treating a dengue virus infection in a subject by administering compound 26b to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to treat an infection by the flavivirus dengue virus by administering compound 26b because Zhang teaches that 26b is useful for the treatment of influenza virus infections and Chen teaches that influenza and dengue share a similar pH-dependent virus entry mechanism and suggests the administration of anti-influenza compositions for treatment of dengue virus infections. One of ordinary skill in the art would have a reasonable expectation of success because Zhang teaches that 26b is a diphyllin analogue and both diphyllin and 26b have anti-influenza activity and Chen teaches applying anti-influenza antivirals to the treatment of dengue virus infections. Thus, one of ordinary skill in the art would furthermore have a reasonable expectation that diphyllin and 26b have a similar biological mechanism and would be useful for the treatment of similar virus infections and that 26b also functions as an anti-viral by reducing acidification of endosomes in a cell.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US 11,638,713 B2; PTO-892), in view of Chen et al. (Antiviral Research, 2013; PTO-892 10/09/2024) as applied to claim 1, further in view of Heinz et al. (Virology, 1994; PTO-892 10/09/2024).
The combined teachings of Chen and Zhang are as above. Furthermore, Chen teaches diphyllin is a newly discovered vacuolar ATPase (v-ATPase) inhibitor with a similar mechanism to the classical v-ATPase inhibitor bafilomycin, which exhibits high toxicity and causes liver and spleen damage that limits its clinical suitability. However, diphyllin is known to be safely administered to mice at a dose of 20 mg/kg without significant signs of toxicity (paragraph bridging pages 377-378).
The combined teachings of Chen and Zhang does not teach the treatment of a tick-transmitted flavivirus (instant claims 4-5).
Heinz investigates the involvement of acidic vesicles during entry and exocytosis of the tick-borne encephalitis virus (page 110, paragraph 2). Tick-borne encephalitis is a pH-dependent virus (page 110, paragraph 2). Heniz discloses that treatment with bafilomycin strongly inhibited tick-borne encephalitis virus penetration both in the case of administration before and after infection (abstract and page 111, paragraph 6). Heinz teaches that bafilomycin is a vacuolar type H+-ATPase (abstract and page 115, paragraph 1).
It would have been prima facie obvious to combine the teachings of Zhang, Chen, and Heinz before the effective filing date of the claimed invention by treating the tick-transmitted flavivirus infection tick-borne encephalitis by administering the diphyllin analogue 26b to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to administer 26b to treat a tick-borne encephalitis infection because Heinz teaches the vacuolar type H+-ATPase inhibitor bafilomycin strongly inhibited tick-borne encephalitis virus penetration, Chen teaches that bafilomycin exhibits high toxicity that limits its clinical suitability, whereas diphyllin functions as a v-ATPase inhibitor and does not cause signs of toxicity, and Zhang teaches that 26b is a diphyllin analogue and can be used to treat similar viruses as diphyllin, such as influenza virus. One of ordinary skill in the art before the effective filing date of the invention would have a reasonable expectation of success in treating tick-borne encephalitis by administering the diphyllin analogue 26b taught by Zhang because Heinz teaches that tick-borne encephalitis is a pH-dependent viral infection and Zhang teaches the 26b us useful for treating influenza, which Chen teaches is also a pH-dependent viral infection.
Claims 1 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US 11,638,713 B2; PTO-892), further in view of Lindstrom et al. (Chem Med Chem, 2018; PTO-892 10/09/2024).
Zhang teaches the preparation of aryl-naphthalene glycoside derivatives, in particular Patentiflorin A analogs, and their use as antiviral agents including as anti-influenza and anti-HIV antivirals (col. 1, lines 14-22). The Patentiflorin A analogues taught by Zhang include compound 26b (col. 129, lines 64-66), which has the structure shown below (col. 8, line 50) and corresponds to Formula II in the instant claims. Zhang discloses that compounds including compound 26b were tested in a cell assay to show inhibitory effects against the influenza virus H5N1 and had comparable EC50 values to the positive control AZT (col. 173, lines 18-23).
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Zhang further describes diphyllin as a structural scaffold for C-O derivatization at C-7 (col. 163, lines 47-50) and teaches that 26b was derived by glycosylation of diphyllin and is a diphyllin analogue (col. 164, lines 10-12). Thus Zhang teaches that there are structural similarities between diphyllin and 26b.
Zhang does not expressly disclose a treating a filovirus infection in a subject comprising administering compound 26b (instant claim 1).
Lindstrom teaches that diphyllin is known in the art to inhibit pH-dependent virus infection and has anti-viral activity against influenza and dengue viruses. This activity has prompted a study of diphyllin as a scaffold to develop broad-spectrum antiviral agents (page 2665, paragraph 1). Lindstrom reports the identification of novel diphyllin derivatives that are potent inhibitors of ebolavirus (EBOV) infection (page 2665, paragraph 2). Lindstrom discusses several derivatization strategies, and teaches that phenol ether derivatives demonstrated the greatest potency against EBOV (page 2665, paragraph 1). Diphyllin and all phenol ether derivatives significantly inhibited the model viral infection (page 2665, paragraph 3).
It would have been prima facie obvious to combine the teachings of Zhang and Lindstrom before the effective filing date of the claimed invention by treating an ebolavirus infection by administering compound 26b to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to treat an infection by the flavivirus dengue virus by administering compound 26b because Zhang teaches that 26b is useful for the treatment viral infections and Lindstrom teaches that derivatization of the diphyllin scaffolds is a useful route to find new antivirals against ebolavirus, and that preferred derivatives are phenol ether derivatives. One of ordinary skill in the art would have a reasonable expectation of success because Zhang teaches that 26b is a diphyllin analogue and the structure of 26b is a phenol ether analogue of diphyllin.
Response to Arguments
Applicant's arguments filed 04/09/2025 have been fully considered but they are not persuasive.
Applicant argues that Chen and Lindstrom discuss only the use of diphyllin and do not teach or suggest the use of the compound Formula I. This is not persuasive. In the modified grounds of rejection necessitated by applicant’s amendment Zhang has been newly added to address the use of the compound Formula I. The current rejections are based on combinations of Chen, Lindstrom, and Zhang, which together render obvious the use of the compound of Formula I in accordance with the instant claims.
Applicant further argues that the broad-spectrum antiviral properties of Formula I are surprising because Formula I was originally identified as an anti-cancer agent. This is not persuasive. As demonstrated in the grounds of rejection, Formula I was suggested in the art prior to the effective filing date of the claimed invention as an anti-viral agent with a broad range of antiviral activity, including activity against HIV, CoV, EBOV and AIV viral infections.
Applicant further argues that the instant specification shows that the antiviral activity of Formula I is superior to diphyllin in several assays of viral infection. This is not persuasive. In an analysis of the instant specification, the instant data does not obviate the case of obviousness because these data are missing a demonstration of statistical significance comparing the treatment of cells with Formula I versus treatment using diphyllin. For example, Figure 9 does not clearly demonstrate a statically significant difference between the treatment of cells with Formula I versus treatment with diphyllin, nor is this data elsewhere presented. MPEP 716.02(b) states that the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and are of both statistical and practical significance.
Because Applicant’s arguments are not persuasive, the instant claims are rejected.
Conclusion
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 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.
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/S.G.S./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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