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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/30/2026 has been entered.
Status of the Application
Receipt is acknowledged of Applicants’ amendment, filed on 04/30/2026, in which claims 1 and 4-5 are amended, and claims 2-3, 7, and 19-20 are cancelled.
Claims 1, 4-6, 8-18, and 21-23 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/IN2021/050451, filed on 05/10/2021, which claims foreign priority to India 202021019866, filed on 05/11/2020.
Rejections Withdrawn
Applicant’s amendment and remarks, filed 04/30/2026, with respect that claims 1, 2-3, 6, 8-9, 11-13, 15-16, 18, and 22-23 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention has been fully considered, as claims 2-3 are canceled, and the rejection is withdrawn. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 04/30/2026, with respect that claims 1-2, 8, and 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomena without significantly more has been fully considered and is persuasive, as claim 1 has been amended to remove the scope of compounds in which R1 and R2 together form a substituted or unsubstituted 5- or 6-membered ring and claim 2 is canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 04/30/2026, with respect that claims 1, 5, 11-17, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Chen in view of Yadav and Zhang has been fully considered and is persuasive, as claims 1 and 5 have been amended to recite “wherein the compound is administered to a subject in need at a dosage range of about 200 mg/kg to about 2000 mg/kg.” This rejection has been withdrawn.
The following are maintained or modified grounds of rejection and new grounds of objection.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 as amended in the claim set filed 10/01/2025 has been amended to recite “R4, R5 and R6 as shown in Formula I, R4, R5 and R6 are each independently is selected from -H, -OH” on line 8 of page 3. The variables R4, R5, and R6 are not previously recited as occurring in Formula I-III. These variables are inconsistent in this recitation. For purposes of compact prosecution, the claim will be interpreted as further limiting the structures of R4, R5, and R6. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6, 8-9, 11-13, 15-16, 18, and 22-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 1, as amended beginning with the amended claim set of 10/01/2025, recites wherein in the presence of
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R4, R5, and R6 are each independently selected from -H and -OH. Thus the scope of claims 1, 6, 8-9, 11-13, 15-16, 18, and 22-23 now excludes the sub-genus of compounds of Formula I which contain a morpholino functional group and an alkoxy group on any of R4, R5, or R6. However, this sub-genus has not been previously disclosed and thus there is no support for a claim excluding the recited sub-genus. MPEP 2163(I)(B) states that newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure. MPEP 2173.05(i) states that any negative limitations or exclusionary proviso must have basis in the original disclosure and that the mere absence of a positive recitation is not basis for an exclusion.
Response to Arguments
Applicant's arguments filed 04/30/2026 have been fully considered but they are not persuasive.
Applicant argues that the amended claims do not rely on an unsupported negative limitation phrased as "morpholino plus alkoxy is excluded" because the claims recite a positive restriction: R4/R5/R6 are limited to -H or -OH (Remarks, paragraph bridging pages 12-13). Applicant further argues that the limitation is supported because it is specifically tied to the inventorship' s described embodiments for morpholino-containing compounds (Remarks, page 13, paragraph 1), and that for morpholino-containing embodiments, the specification supports R4/R5/R6 = -H/-OH (Remarks, page 13, paragraph 3). This is not persuasive.
Applicant does not point to any examples in the instant specification or indicate where in the instant specification is located the support for the limitation of R4, R5, and R6 to hydrogen or hydroxyl or point to specific embodiments comprising a morpholino moiety and a hydrogen and hydroxyl. For example, although Applicant provides morpholino containing examples in which R4, R5, and R6 are each hydrogen, there are no morpholino containing examples in which hydroxyl is present. Furthermore, although the instant claim does not include the language of “excluded” or similar negative phrasing, the amended claims nonetheless introduces a proviso that excludes a subset of compounds and results in an unsupported genus.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4-6, 8-10, 18, and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yadav et al. (WO 2018/193476 A2; IDS 11/10/2020).
Yadav discloses compounds for the treatment of cancer, in particular cancer stem cells (page 1, line 22 to page 2, line 2). Yadav discloses specific compounds of instant claim 4. These compounds include Formula V (page 4, line 11) which corresponds to formula E of instant claims 4 and 5, Formula VI (page 5, line 1) which corresponds to formula D of instant claim 4, Formula XII (page 7, line 1) which corresponds to formula G of instant claim 4, and Formula XIII (page 7, line 4) which is a salt of formula H of instant claim 4. Thus Yadav anticipates instant claims 1, 4-5, 8-10 and 18. Yadav further describes the synthesis of Formula V, and teaches Formula V in a composition consisting of Formula V, ethanol, and ethyl acetate (page 38, lines 17-18) which are pharmaceutically acceptable excipients.
It is noted that Yadav does not provide an embodiment of the composition used in the manner instantly claimed, administered to a subject in need at a dosage range of about 200 mg/kg to about 2000 mg/kg as recited in instant claims 1 and 4-5, for inhibition of v-ATPase activity in a cell as recited in instant claims 8-9, or for inhibition of SARS-CoV-2 virus as recited in instant claim 10, or for preparing a medicament to inhibit V-ATPase activity as recited in instant claim 18. However, these cited recitations are considered an “intended use” of the claimed composition. The “intended use” of the claimed composition does not patentably distinguish the composition, per se, since such disclosed use is inherent in the reference composition. In order to be limiting, the intended use must create a structural difference between the claimed composition and the prior art composition. In the instant case, the intended use does not create a structural difference, thus the intended use is not limiting.
Response to Arguments
Applicant's arguments filed 04/30/2026 have been fully considered but they are not persuasive.
Insofar as Applicant’s arguments are applicable to the current rejections, Applicant argues that the teachings of Yadav must establish that the taught compounds inhibit v-ATPase activity in a cell under Applicant’s claimed conditions in order to establish that v-ATPase properties are necessarily present, and Applicant argues that the teachings of Yadav are directed to a different therapeutic context, that of cancer stem cells, and thus cannot be used to establish inhibition of v-ATPase activity (Remarks, paragraph bridging page 18-19). This is not persuasive.
Although the instant claims characterize the claimed compounds as an “antiviral V-ATPase inhibitor compound”, the instant claims are nevertheless directed to the chemical compounds themselves. The characterization of “antiviral V-ATPase inhibitor compound” in the preamble does not confer any structural limitations or change the structure of the compounds. Rather it recites a property of the compounds. As the instant compounds have the same chemical structure as those disclosed by Yadav, they have the same properties and thus anticipated. MPEP 2112.01(II) states that products of identical chemical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present.
Applicant further argues that the compounds in Yadav do not fall within the scope of amended claims because Yadav does not disclose or necessarily entail the functional activity limitation “wherein the compound is administered to a subject in need at a dosage range of about 200 mg/kg to about 2000 mg/kg” of the amended claims (Remarks, page 18, paragraph 2). This is not persuasive.
Instant claims 1, 4-5, 8-10, and 18 are directed to chemical compounds, and are not directed to a method of administration. Thus the limitation “wherein the compound is administered to a subject in need at a dosage range of about 200 mg/kg to about 2000 mg/kg” does not change the structure of the compounds of the instant claims and is not a functional limitation, as it does not confer any structural limitations and rather recites an intended use of the composition.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 04/30/2026.
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 11-17 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Antiviral Research, 2013; PTO-892 07/21/2025) in view of Yadav et al. (WO 2018/193476 A2; IDS 11/10/2020), Zhang et al. (European Journal of Medicinal Chemistry, 2014; PTO-892 07/21/2025), and Davisson et al. (WO 2019/182947 A1; IDS 11/10/2020).
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 v-ATPase activity is a regulating factor on influenza virus replication and that diphyllin alters cellular susceptibility to influenza viruses through the inhibition of endosomal acidification, thus interfering with downstream virus replication (abstract). Blocking v-ATPase activity, therefore, presents an opportunity to impede influenza infection by preventing the low pH-dependent membrane fusion between endosomes and virions. 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 goes on to characterize the application of diphyllin as an antiviral for various influenza virus strains (page 372, paragraph 2). Chen teaches that diphyllin interferes 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). Chen teaches that broad-spectrum antiviral agents of high potency and low toxicity may be further developed through the existing compounds or derivatives of diphyllin (paragraph bridging pages 378-379).
Chen does not disclose a compound of formula I (instant claim 1).
Yadav discloses compounds for the treatment of cancer, in particular cancer stem cells (page 1, line 22 to page 2, line 2). The compounds may be in the form of pharmaceutically acceptable salts (page 24, lines 3-7). In particular, Yadav discloses specific compounds of instant claim 4, including Formula V (page 4, line 11 and claim 3), which corresponds to instant formula E and is shown below. Formula V is taught as having activity against breast cancer cells (page 74, lines 17-18) and prostate cancer cells (page 75, lines 2-3).
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Yadav teaches that the compound of Formula V may be formulated as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient (page 8, lines 8-9), and that the compounds of the invention may be formulated in a composition along with other active agents (page 25, lines 5-7). Formula V is taught as belonging to general formula IV (claim 2), which is shown below.
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The scope of general formula IV includes compounds such as Formula VII (page 5, line 1), which corresponds to instant formula D. Compounds of general formula IV are described as diphyllin esters (page 51, line 19) and diphyllin derivatives (page 29, line 21).
Zhang discusses the anticancer activity of v-ATPases. In particular, Zhao discloses the synthesis and anti-proliferative activities of two natural diphyllin glycosides, Cleistanthin-A and Cleistanthoside-A, against cancer cells including MCF-7 breast cancer cells (abstract). The structure of Cleistanthoside-A is disclosed in figure 1 and shown below.
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Zhang teaches that the acidic tumor microenvironment is critical to managing cancer development, progression and metastasis; v-ATPases are responsible for microenvironment acidification and play a major role in tumor invasion and metastasis development (page 466, paragraph 1). Diphyllin potently inhibits v-ATPase and cancer cell proliferation development (page 466, paragraph 2). Similarly, the diphyllin glycosides Cleistanthin-A and Cleistanthoside-A exert their antiproliferative activities mainly through inhibiting v-ATPase (page 466, paragraph 3).
Davisson discloses compounds that are vacuolar-ATPase inhibitors (abstract) and teaches that the compounds are diphyllin derivatives [0097]. The compounds are useful for the treatment of influenza virus (claim 22 and [0017]). Davisson discloses a test of the A549 cell line activity of compounds including 2g to predict utility of an antiviral effect of compounds based on the fact that this tumor derived cell line requires high activity of v-ATPase for growth and survival [0103]. Furthermore, in describing a test of inhibition of EBOV cell entry [0099], Davisson states that the relative potencies of the EBOV cell entry effects track with the endosome acidification [0101]. Davisson teaches that therapeutically effective amounts of these compounds typically range from about 5 mg/kg to about 500 mg/kg of compound per patient body weight and that effective doses vary depending on the route of administration, optional excipient usage, and the possibility of co-usage of the compound with other conventional and non-conventional therapeutic treatments [0069].
It would have been prima facie obvious to combine the teachings of Yadav, Zhang and Chen before the effective filing date of the claimed invention by administering the v-ATPase compound Formula V of Yadav for the treatment of viral infections, including influenza viral infections, to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to administer Formula V for the treatment of influenza viral infections because Yadav teaches Formula V is a compound of general formula IV, which are taught as diphyllin derivatives and Chen teaches that derivatives of diphyllin are v-ATPase inhibitors useful for the treatment of viruses that rely on endosomal acidification. One of ordinary skill in the art would have a reasonable expectation of success because Zhang teaches that diphyllin and its derivatives exert their antiproliferative activities mainly through inhibiting v-ATPase and Chen teaches that broad-spectrum antiviral agents of high potency and low toxicity may be further developed through existing compounds or derivatives of diphyllin.
Furthermore, it would have been prima facie obvious to expect that the compound of Formula V – taught by Yadav as an anti-cancer compound derived from the same general formula that includes compounds described as diphyllin derivatives and bearing the same sugar and a similar structural core to Cleistanthin-A – has anti-cancer activity through inhibiting v-ATPase, which is taught by Zhang as the mechanism of action for diphyllin glycosides including Cleistanthin-A.
Furthermore, it would have been prima facie obvious for one of ordinary skill in the art to optimize the dosage of the v-ATPase inhibitor compound Formula V of Yadav for the treatment of viral infections in a given formulation and route of administration because Davisson teaches that diphyllin derivatives that are vacuolar-ATPase inhibitors may be administered range from about 5 mg/kg to about 500 mg/kg and that the dosage of the vacuolar-ATPase inhibitors is a result effective variable for therapeutic efficacy depending on, among other factors, excipients and route of administration.
Claims 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Antiviral Research, 2013; PTO-892 07/21/2025) in view of Yadav et al. (WO 2018/193476 A2; IDS 11/10/2020), Zhang et al. (European Journal of Medicinal Chemistry, 2014; PTO-892 07/21/2025), and Davisson et al. (WO 2019/182947 A1; IDS 11/10/2020). as applied to claim 12, further in view of Yang et al. (International Journal of Biological Sciences, 2020; PTO-892 01/30/2026).
The combined teachings of Chen, Yadav, Zhang, and Davisson are as above.
The combined teachings of Chen, Yadav, Zhang and Davisson differ from that of the instantly claimed invention in that they do not teach the treatment of SARS CoV-2.
Yang teaches that a key element in viral infection by COVID-19 is the process of viral entry into the host cells. As a result, the endocytic pathway, including endosomes and lysosomes, has become an important target for the development of therapeutic strategies in combating diseases caused by coronaviruses (abstract). Yang teaches that autophagy by lysosomes requires an acidic internal pH which is generated by the action of a V-ATPase, a proton-pumping membrane protein complex (page 1725, paragraph 2). Yang concludes that targeting autophagy is a novel therapeutic strategy against coronaviruses, including both SARS-CoV and SARS-CoV-2 (page 1728, paragraphs 4-5 and page 1729, paragraph 5).
It would have been prima facie obvious to administer the antiviral treatment suggested by the combined teachings of Chen, Yadav, Zhang, and Davisson for the treatment of SARS-CoV-2, because Chen teaches and suggests that broad-spectrum antiviral agents – including those for treatment of coronaviruses – of high potency and low toxicity may be developed from existing compounds or derivatives of diphyllin because diphyllin interferes with the low pH-dependent membrane fusion between virus and intracellular endosomes by v-ATPase, Yadav teaches derivatives of diphyllin, and Yang teaches that inhibition of the endocytic pathway and autophagy through inhibition of v-ATPase is a strategy for treating infections by SARS-CoV-2. One of ordinary skill in the art would have had a reasonable expectation of success because Zhang teaches that the mechanism of action for diphyllin glycosides including Cleistanthin-A is inhibition of v-ATPase.
Response to Arguments
Applicant's arguments filed 04/30/2026 have been fully considered but they are not persuasive.
Applicant argues that there is no evidence that Yadav' s particular diphyllin-derived compound, which is merely described as having anti-cancer activity, would inhibit viral replication in cells through v-ATPase modulation in the same way as diphyllin described in the teachings of Chen, which concern diphyllin and influenza-specific utility and that mechanistic relevance to endosomal acidification does not automatically translate to SARS-Co V-2 efficacy for Yadav' s compounds (Remarks, paragraph bridging pages 23-24 to page 24 paragraph 2). Applicant argues that Zhang's v-ATPase inhibition is discussed in an anticancer setting and does not establish that the same compound will be effective against viruses (Remarks, page 24, paragraph 3).
As indicated in the above grounds of rejection, it would have been prima facie obvious for one of ordinary skill in the art to administer Formula V of Yadav for the treatment of influenza viral infections because Formula V is taught as a glycosidic diphyllin derivative and Zhang teaches that the mechanism of action for anti-cancer diphyllin glycosides is through inhibiting v-ATPase. Thus one of ordinary skill in the art would have expected that the administration of Formula V results in the inhibition of v-ATPase. Chen teaches that derivatives of diphyllin that are v-ATPase inhibitors are useful for the treatment of viruses that rely on endosomal acidification, which includes influenza infections. Thus the combined teachings of the prior art would have suggested to one of ordinary skill in the art that the compounds of Yadav would be effective for the treatment of viral infections because they are derivatives of diphyllin having the same biological activity of v-ATPase inhibition as the mode of action, and derivatives of diphyllin that are v-ATPase inhibitors are effective for treating viral infections. Although the combined teachings of the prior art do not specifically demonstrate SARS-CoV2 efficacy for Yadav’s compounds, the teachings of the prior art suggest anti-SARS-CoV2-efficacy based on the mechanistic activity of glycosidic diphyllin derivatives. MPEP 2144.08(A)(4)I states that “obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties.”
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 04/30/2026.
Conclusion
No claims are allowed.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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