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
The instant application is a 371 National Stage Entry of PCT/US2021/061847 filed on December 3, 2021 which claims benefit to domestic application No. 18/265,030 filed on December 3, 2020.
Status of Claims
Acknowledgement is made of original (1-4, 6-15), amended (5, 16-20, 22-24), cancelled (21), and new (25-31) claims filed on December 8, 2023. Claims 1-20, 22-31 are pending in instant application.
Information Disclosure Statement
The information disclosure statements filed on June 2, 2023 and August 28, 2023 have been considered except where lined through.
Claim Interpretation
Regarding claim 1 and “subject”, the instant specification defines "subject” as:
“a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.” (see instant spec. at p. [0031]).
Accordingly “subject” may refer to cells.
Regarding claims 2 and 3, a compound of Formula I (claim 3) is understood to fulfill the limitation of an inhibitor of folate or one-carbon metabolism (claim 2) even if not specified in the prior art.
Regarding claim 5, the term “bivalent ring” is understood to be any ring system capable of bonding to the phenyl and methylene of Formula II. The specification does not provide a definition of bivalent ring, only exemplary rings are listed (see instant specification at p. 35 ¶[0082]).
Regarding “SARS-CoV-2”, COVID-19 is understood to be interchangeable with SARS-CoV-2 in the prior art (see instant spec. at p. 1 ¶[0005]).
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The Examiner suggests the title should reflect the claimed compound(s) core structure and their utility.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see instant specification at p.68 ¶[0150]). 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 disclosure is objected to because of the following informalities:
The structural limitations of the compounds listed in Tables 2 and 3 are not discernable. For example:
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It is unclear the identity of substituents (OH, Cl, CH3, etc) and atom identities (N, C, S, etc). It is also unclear if the species are numbered in Table 2, for example (see arrow below):
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Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 2, 4, 6 are 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 claim 2, the phrase "(SHMT1 and SHMT2, respectively)" 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).
Regarding claims 4 and 6, Claim 4 recites “…Table 2” and claim 6 recites “…Table 3”. There is insufficient antecedent basis for this limitation in the claim. For purposes of applying prior art, claim 4 is presumed to be an attempt to incorporate by reference Table 2 and claim 6 is presumed to be an attempt to incorporate by reference Table 3; however, this is improper (see MPEP § 2173.05(s), which states that where possible, claims are to be complete in themselves).
Moreover, the above objection to the specification highlights the difficultly ascertaining the species of the Tables, so if incorporated as-is would also be indefinite since the metes and bounds of the structural limitations are unclear.
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.
Claim(s) 1, 7, 13, 16, 19, 22, 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stegmann et. al.1
Regarding claims 1, 7, 13, 16, 19, Stegmann teaches methotrexate acts as an antiviral against SARS-Cov-2 when administered to infected Vero and Calu-3 cells (see Stegmann at p. 5 lines 124-125, p. 6 lines 155-158) (reading on claim 1 inhibiting viral replication in a subject and claims 16 and 19 wherein the virus is an RNA virus such as SARS-CoV-2). Stegmann teaches methotrexate is a folate antagonist, or antifolate (reading on claim 1 an inhibitor of folate metabolism and claim 7 an antifolate), a class of agents that disrupt purine synthesis (reading on claim 13) (see Stegmann at p. 4 lines 99-103 and 108-109).
Regarding claims 22, 26, Stegmann teaches methotrexate and remdesivir exhibit synergy against SARS-CoV-2 (see Stegmann at p. 15 lines 416-417).
Claim(s) 9-11, 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Takatsuki et. al.2 as evidenced by Yan et. al.3
Regarding claims 9, 10, 11, Takatsuki teaches inhibitors of electron transfer in mitochondrial respiration, including Piericidin A (reading on claims 10, 11), exhibit antiviral activity against Newcastle disease virus in chick embryo fibroblast cells (reading on claim 9 administering to a subject) (see Takatsuki at p. 826 Table 1).
Regarding claim 18, as evidenced by Yan, Newcastle disease virus is an RNA virus (see Yan at Abstract).
Claim(s) 14, 20, 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yamaya et. al.4
Regarding claims 14, 20, 31, and administering a serine synthesis inhibitor to inhibit viral replication, Yamaya teaches nafamostat is a serine protease inhibitor known to inhibit influenza (reading on an RNA virus, see Yamaya at Abstract) replication (see Yamaya at Title at at p. 3488 "3.2 Effects of nafamostat on the RNA replication of influenza viruses"). Nafamostat has been suggested to inhibit SARS‐CoV‐2 (reading on an RNA virus, instant claim 20) replication by inhibiting TMPRSS2‐mediated viral entry and to be a candidate drug to treat COVID‐19 patients (see Yamaya at p. 3493 right col par 3). Yamaya teaches administering nafamostat to a cells and mice reduced lung viral titers (reading on administering to a subject) (see Yamaya at p. 3493 left col. ¶7 and p.3486 left col. ¶2-3).
Regarding claim 31 and prophylaxis, Yamaya teaches pre-treating cells with nafamostat prior to infection (reading on prophylactically administering) (see Yamaya at Abstract).
Claim(s) 14-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et. al.5
Regarding claims 14-15, Wang 2019 teaches administering PHGDH inhibitors CBR-5884 and NCT-503 for treating Epstein-Barr virus in infected cells (see Wang 2019 at p. 544 right col. ¶4).
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, 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 24, 30 are rejected under 35 U.S.C. 103 as being unpatentable over Stegmann as applied to claims 1, 7, 13, 16, 19, 22, 26 above in further view of Mitja et. al.6
The prior art differs from the instant claims as follows: While Stegmann teaches administering a folate inhibitor to inhibit reproduction of a virus, Stegmann does not specify prophylactic administration.
However,
Regarding prophylactic administration, Mitja teaches preexposure prophylaxis and postexposure prophylaxis with antimicrobial drugs are effective in preventing illness before potential exposure or after documented exposure to a variety of microbial pathogens, and in reducing the risk of secondary spread of infection (see Mitja at p. e639 col. 1 par 3).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
It would have been obvious to prophylactically administer a known antimicrobial treatment (e.g. methotrexate or methotrexate and remdesivir as taught by Stegmann) for inhibiting a viral infection (e.g. SARS-CoV-2 as taught by Stegmann) because the prior art teaches prophylactic administration prevents the undesirable effect of illness (as taught by Mitja).
Furthermore, it is well-within the ordinary skill in art to administer a known drug prophylactically to prevent a known illness.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim 27 is are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yamaya as applied to claims 14, 20, 31 above in further view of Jefferson et. al.7
The prior art differs from the instant claims as follows: While Yamaya teaches administering a serine synthesis inhibitor for inhibiting viral replication, Yamaya does not specify administering with an additional antiviral.
However,
Jefferson teaches known antivirals for prophylaxis or treatment of influenza (see Jefferson at p.305 Table 1).
Therefore it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding a combination, per MPEP § 2144.06(I), "[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would be obvious to combine one antiviral for treating influenza such as nafamostat (as taught by Yamaya) with another antiviral known for treating influenza (as taught by Jefferson) in order to inhibit replication of an influenza virus because each component would be performing its art-recognized function separately as they would be together (inhibiting a virus).
Furthermore, it is well-within the ordinary skill in the art to administer two antivirals for treating a virus.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim(s) 1-3, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et. al.8
Regarding claims 1-3, Wang 2015 teaches anti-influenza agent AK-777/37076029, aka CAS# 1899835-62-1, which reads on instant Formula I when R0 is hydroxyl, R1 is OR11 and R11 is alkyl specifically methyl, R2 is nitro, R3 is H, R4 is alkyl specifically propyl, R5 is H, R6 is H, R7 is H (see Wang 2015 at p. 131 Figure 6).
Instant Formula I
CAS# 1899835-62-1
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Regarding claim 16, Wang 2015 teaches influenza is an RNA virus (see Wang 2015 at p. 123 right col. par 1).
The prior art differs from the instant claims as follows, While Wang 2015 teaches a compound of Formula I for inhibiting a virus, Wang 2015 does not specify administering to a subject.
However,
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
An artisan would readily recognize that because Wang 2015 identifies CAS# 1899835-62-1 as an anti-influenza agent, that administering CAS# 1899835-62-1 to a subject with influenza would inhibit the viral infection.
Furthermore, it is well-within the ordinary skill in art to administer a known antiviral to treat a viral infection.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim(s) 1, 2, 4, 7, 16 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180072751 A1 to Rabinowitz et. al.9 in view of Desbarats10.
Regarding claim 4 and compounds of Table 2, Rabinowitz teaches compounds of instant Formula I and Table 2 as SHMT inhibitors (see Rabinowitz at p. 23 – 45 Table 1).
The prior art differs from the instant claims as follows: While Rabinowitz teaches the instantly claimed structures, Rabinowitz does not teach administering to a subject for inhibiting viral replication.
However,
Regarding claims 1-2, 7 and the utility of inhibiting viral replication, Desbarats states:
“PLP regulates serine hydroxymethyltransferase 2 (SHMT2), an enzyme best known
for its role in folate metabolism…SHMT2 also regulates type I interferon production. Type I interferons are critical in the early host response to viral infections and may underlie successful host control of viral replication” (see Desbarats at p. 6).
Desbarats teaches PLP becomes depleted in COVID-19 infections (reading on an RNA virus) (see Desbarats at Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
One skilled in the art would recognize that due to SHMT2’s role in viral replication, that inhibitors of SHMT2 i) would be also be antifolate agents and ii) inhibit viral replication (as taught by Desbarats). An artisan would thus appreciate administering a known SHMT inhibitor (as taught by Rabinowitz) would inhibit viral replication in a subject (as taught by Desbarats), and in particular SARS-CoV-2 due to SHMT2’s role in its pathology (as taught by Desbarats).
Furthermore, it is well-within the ordinary skill in art to use an SHMT inhibitor for inhibiting SHMT. Furthermore, it is well-within the ordinary skill in art to understand viral pathology when developing treatment options.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim(s) 1, 5, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Gopinath et. al.11
Regarding claims 1, 5, 16, Gopinath teaches compounds that target S-protein to block SARS-CoV-2 entry, and suggest safe and effective treatment of SARS-CoV-2 (reading on claim 16, an RNA virus) (see Gopinath at p. 11 “Conclusion”). Gopinath teaches ZINC000002114285, also known as CAS Registry No. 956705-38-7 (see Gopinath at p. 7 Table 3) which reads on instant Formula II when R1 is a halogen specifically chlorine, A is
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, Rx and Rx’ are H, Ry is a substituted C1 specifically methylene phenyl, and Ry’ is H.
Instant Formula I
CAS# 956705-38-7
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The prior art differs from the instant claims as follows, While Gopinath teaches a compound of Formula II for inhibiting a virus, Gopinath does not specify administering to a subject.
However,
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
An artisan would readily recognize that because Gopinath identifies CAS# 956705-38-7 as an anti-SARS-CoV-2 agent, that administering CAS# 956705-38-7 to a subject with SARS-CoV-2 would inhibit the viral replication in the subject.
Furthermore, it is well-within the ordinary skill in art to administer a known antiviral to treat a viral infection.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim(s) 1, 5-6, 7, 16 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018106636 A1 to Mainolfi12 in view of Desbarats.
Regarding claims 5-6 and compounds of Table 3, Mainolfi teaches compounds of instant Formula II and Table 3 as SHMT inhibitors (see Maiolfi at pp. 19-29).
The prior art differs from the instant claims as follows: While Mainolfi teaches the instantly claimed structures, Mainolfi does not teach administering to a subject for inhibiting viral replication.
However,
Regarding claims 1-2, 7 and the utility of inhibiting viral replication, Desbarats states:
“PLP regulates serine hydroxymethyltransferase 2 (SHMT2), an enzyme best known
for its role in folate metabolism…SHMT2 also regulates type I interferon production. Type I interferons are critical in the early host response to viral infections and may underlie successful host control of viral replication” (see Desbarats at p. 6).
Desbarats teaches PLP becomes depleted in COVID-19 infections (reading on an RNA virus) (see Desbarats at Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
One skilled in the art would recognize that due to SHMT2’s role in viral replication, that inhibitors of SHMT2 i) would be also be antifolate agents and ii) inhibit viral replication (as taught by Desbarats). An artisan would thus appreciate administering a known SHMT inhibitor (as taught by Mainfoli) would inhibit viral replication in a subject (as taught by Desbarats), and in particular SARS-CoV-2 due to SHMT2’s role in its pathology (as taught by Desbarats).
Furthermore, it is well-within the ordinary skill in art to use an SHMT inhibitor for inhibiting SHMT. Furthermore, it is well-within the ordinary skill in art to understand viral pathology when developing treatment options.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim(s) 8, 9, 12, 17, 25 are rejected under 35 U.S.C. 103 as being unpatentable over Scheen et. al.13 as evidenced by Salani et. al.14
Regarding claims 9, 12, and an inhibitor of oxidative phosphorylation such as metformin, Scheen teaches a reduction in mortality in metformin (reading on instant claim 12) users compared with non-users among patients with type 2 diabetes hospitalized for COVID-19 (reading on an RNA virus, instant claim 18) (see Scheen at p. 425 left col. par 3).
Regarding claims 8, 17, and an inhibitor of glucose metabolism, as evidenced by Salani, metformin is an inhibitor of glucose metabolism in cancer cells (see Salani at p. 466 left col. par 3).
The prior art differs from the instant claims as follows, While Scheen and Salani teach metformin patients have better SARS-CoV-2 mortality, they do not specify administering to a subject.
However, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding administering to a subject, an artisan would readily appreciate that metformin is beneficial to patients with SARS-CoV-2 infections (as taught by Scheen), and thus administering metformin to a subject would inhibit a SARS-Cov-2 virus (see also MPEP § 2143(I)(G)).
Furthermore, it is well-within the ordinary skill in the art administer a known antiviral to a subject with a known virus.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim(s) 18, 23 are rejected under 35 U.S.C. 103 as being unpatentable over Scheen as evidenced by Salani as applied to claims 8, 9, 12, 17, 25 above and in further view of Yavuz et. al.15
The prior art differs from the instant claims as follows, While Scheen and Salani teach administering a an inhibitor of oxidative phosphorylation or an inhibitor of glucose metabolism for treating a virus such as SARS-CoV-2, they do not specify a combination with another antiviral.
However,
Regarding claims 18 and 23 and a combination, Yavuz teaches antivirals for treating SARS-CoV-2 such as remdesivir, favipiravir, hydroxychloroquine, lopinavir/ritonavir, and ivermectin (see Yavuz at p, 613 Table).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2144.06(I), "[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). It would be obvious to combine one antiviral such as metformin known to treat SARS-CoV-2 (as taught by Scheen and Salani) with another antiviral known to treat SARS-CoV-2 (as taught by Yavuz) in order to inhibit replication of a virus because each component would be performing its art-recognized function separately as they would be together (inhibiting a virus).
Furthermore, it is well-within the ordinary skill in the art to administer two antivirals for treating a virus.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim(s) 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Scheen as evidenced by Salani as applied to claims 8, 9, 12, 17, 18, 23, 25 above and in further view of Mitja.
The prior art differs from the instant claims as follows: While Scheen and Salani teach administering metformin to inhibit reproduction of a virus, Scheen and Salani do not specify prophylactic administration.
However,
Regarding prophylactic administration, Mitja teaches preexposure prophylaxis and postexposure prophylaxis with antimicrobial drugs are effective in preventing illness before potential exposure or after documented exposure to a variety of microbial pathogens, and in reducing the risk of secondary spread of infection (see Mitja at p. e639 col. 1 par 3).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
It would have been obvious to prophylactically administer a known antimicrobial treatment (e.g. metformin as taught by Scheen) for inhibiting a viral infection (e.g. SARS-CoV-2 as taught by Scheen) because the prior art teaches prophylactic administration prevents the undesirable effect of illness (as taught by Mitja).
Furthermore, it is well-within the ordinary skill in art to administer a known drug prophylactically to prevent a known illness.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Conclusion
The specification is objected to.
Claims 1-20, 22-31 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SOPHIA J REILLY whose telephone number is (703)756-5669. The examiner can normally be reached 9:00 am - 5:00 pm EST M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, KORTNEY KLINKEL can be reached at 571-270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/S.R./Examiner, Art Unit 1627
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
1 Stegmann et. al. "The folate antagonist methotrexate diminishes replication of the coronavirus SARS-CoV-2 and enhances the antiviral efficacy of remdesivir in cell culture models" bioRxiV 2020, 1-36. DOI: 10.1101/2020.07.18.210013. Published Online July 20, 2020. Corresponding with an earlier version of Cite No. 138 in the IDS filed 8/28/23. Hereinafter Stegmann.
2 Takatsuki et. al. "Antiviral and Antitumor Antibiotics XIV. Effects of Ascochlorin and Other Respiration Inhibitors on Multiplication of Newcastle Disease Virus in Cultured Cells" Applied Microbiology 1969, 17, 6, 825-829. DOI: 10.1128/am.17.6.825-829.1969 Hereinafter Takatsuki.
3 Yan et. al. "Role of Intergenic Sequences in Newcastle Disease Virus RNA Transcription and Pathogenesis" Journal of Virology 2008, 82, 3, 1323-1331. DOI: 10.1128/JVI.01989-07 Hereinafter Yan.
4 Yamaya et. al. "The clinically used serine protease inhibitor nafamostat reduces influenza virus replication and cytokine production in human airway epithelial cells and viral replication in mice" Journal of Medical Virology 2021, 93, 6, 3484-3495. DOI: 10.1002/jmv.26700. Published Online November 28, 2020. Hereinafter Yamaya.
5 Wang et. al. "Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation" Cell Metabolism 2019, 30, 539-555. DOI: 10.1016/j.cmet.2019.06.003 Hereinafter Wang 2019.
6 Mitja et. al. "Use of antiviral drugs to reduce COVID-19 transmission" The Lancet Global Health, 8, 5, e639-e640. DOI: 10.1016/S2214-109X(20)30114-5. Published Online March 19, 2020. Hereinafter Mitja.
7 Jefferson et. al. "Antivirals for influenza in healthy adults: systematic review" Lancet 2006, 367, 303-313. DOI: 10.1016/S0140-6736(06)67970-1
8 Wang et. al. "Predicting dual-targeting anti-influenza agents using multi-models" Molecular Diversity 2015, 19, 1, 123-134. DOI: 10.1007/s11030-014-9552-4. Hereinafter Wang 2015.
9 Published March 15, 2018. Hereinafter Rabinowitz.
10 Desbarats, J. "Pyridoxal 5'-phosphate to mitigate immune dysregulation and coagulopathy in COVID-19" Preprints 20202, 2020050144. DOI: 10.20944/preprints202005.0144.v1 Published Online May 8, 2020. Hereinafter Desbarats.
11 Gopinath et. al. "Screening of Natural Products Targeting SARS-CoV-2–ACE2 Receptor Interface – A MixMD Based HTVS Pipeline" Front. Chem. 2020, 8, 589769, 1-13. DOI: 10.3389/fchem.2020.589769 Published Online November 18, 2020. Hereinafter Gopinath.
12 Published June 14, 2018. Hereinafter Mainolfi.
13 Scheen et. al. "Metformin and COVID-19: From cellular mechanisms to reduced
Mortality" Diabetes & Metabolism 2020, 46, 423-426. DOI: 10.1016/j.diabet.2020.07.006. Published Online August 1, 2020. Hereinafter Scheen.
14 Salani et. al. "Metformin, cancer and glucose metabolism" Endocrine-Related Cancer 2014, 21, 6, r461-r471. DOI: 10.1530/ERC-14-0284. Hereinafter Salani.
15 Yavuz et. al. "Antiviral treatment of COVID-19" Turkish Journal of Medical Sciences 2020, 50, 611-619. DOI: :10.3906/sag-2004-145. Published Online April 15, 2020. Hereinafter Yavuz.