DETAILED ACTION
A non-final Office action was mailed 6 August 2025 (“Office Action”).
Applicant’s reply was received 24 October 2025 (“Reply”).
Status of the Claims
The listing of claims filed with the Reply has been examined.
Claim 1 is pending. Claims 2–20 are canceled.
Status of Rejections and Objections
The text of those sections of Title 35, U.S. Code and/or text providing the basis for non-statutory double patenting rejections not included herein can be found in the Office Action.
Unless repeated herein, any objection or rejection set forth in the Office Action is withdrawn.
Claim Rejections - 35 U.S.C. § 103
Claim 1 is rejected under 35 U.S.C. § 103 as being unpatentable over Wang et al., Cell Research (Feb. 2020), 30, 369–271 (“Wang”) in view of US 8,759,354 (“Maekawa”); Chou, Ting-Chao, Pharmacological Reviews (2006), 58(3), 621–681 (“Chou”); Harrison, Charlotte, Nature Biotech. (2020), 38(4), 379–381 (“Harrison”) [IDS]; De Clercq et al., Clinical Microbiology Reviews (2016), 29(3), 695–747 (“De Clercq”); Furuta et al., Antiviral Research (2013), 100, 446–454 (“Furuta”); and Ianevski et al., Drug Discovery Today (2019), 24(5), 1224–1228 (“Ianevski”).
The Graham factors are addressed in turn below.
Determining the scope and contents of the prior art
Wang discloses a study of FDA-approved antiviral drugs for the treatment of coronavirus. (Wang, p.269). Seven drugs were studied, including remdesivir (GS-5734) and favipiravir (T-705). (Id.). Both drugs exhibited an ability to reduce the viral infection. (Id.).
Maekawa discloses a pharmaceutical composition comprising a compound according to formula (I) in combination with another drug (i.e., a neuraminidase inhibitor). (Maekawa, Abstract; 2:13–32). The genus of compounds according to formula (I) in Maekawa is identical to or overlaps with the compounds of formula (1) in the instant claim.
Maekawa discloses the compound 6-fluoro-3-hydroxy-2-pyrazinecarboxamid, referred to as T-705 (also known as favipiravir). (Id., 4:60–62). T-705 has broad antiviral effects. Maekawa discloses using T-705 to treat influenza virus and “viral diseases” generally.
Maekawa discloses the pharmaceutical composition is “useful in the treatment (e.g., therapy or prevention) of viral diseases.” (Id., 1:15–19).
Maekawa discloses an improved antiviral effect for a combination comprising a compound according to formula (I) and the neuraminidase inhibitor. (Id., 5:1–8:59).
Maekawa discloses a combination drug therapy specifically comprising T-705 was known at the time of filing the instant application. (Id., Abstract; 2:13–32).
Combination drug therapy was generally known at the time of filing the instant application and such combinations had been used to treat viral infections. For example, Chou states: “Ever since the earliest days of recorded history, drug combinations have been used for treating diseases and reducing suffering.” (Chou, p.623). For example, De Clercq lists numerous examples of drug combinations approved for use. (De Clercq, pp.700–705, Table 2).
De Clerq discloses T-705 “shows broad-spectrum inhibitory activities against the RNA polymerases of influenza A viruses (including the highly pathogenic H5N1 viruses) and many other positive-sense RNA and negative-sense RNA viruses.” (De Clerq, p.726). For example, De Clerq discloses T-705 “has been proposed to treat patients infected with Ebola virus (EBOV)” and “can inhibit the replication of human norovirus and human arenaviruses.” (Id.).
Furuta discloses favipiravir has broad activity against a variety of viruses:
Favipiravir . . . has been found to inhibit all serotypes and strains of influenza A, B and C viruses against which it has been tested, including those resistant to currently approved neuraminidase inhibitors. It is also active against a number of arena-, bunya- and flaviviruses, both in vitro and in rodent models, and it has shown potent in vitro activity against members of the alphavirus, paramyxovirus and norovirus families.
(Furuta, p.447).
Furuta discloses favipiravir can be combined with other drugs that together result in a synergistic effect:
The effect of combining favipiravir and oseltamivir was investigated in mice infected with A/Victoria/3/75(H3N2). The combination of 25 mg/kg of each drug provided significant protection against a lethal challenge dose (Table 4). Synergistic improvements in survival were also achieved with the 20 mg/kg/day dose of favipiravir combined with 0.1 and 0.3 mg/kg/day of oseltamivir against the A/NWS/33(H1N1) virus. In mice infected with A/Duck/MN/1525/81(H5N1), combining doses of both drugs, which were ineffective as monotherapies, significantly improved survival and body weights. An increase in the numbers of survivors was also shown using a synergistic combination of 20 mg/kg/day of favipiravir with ineffective low doses of peramivir against the A/California/04/ 2009(H1N1)pdm infection. These results underline the value of combining favipiravir with NA inhibitors to improve the outcome of severe influenza virus infections, augmenting therapeutic options for outbreak management.
(Id., pp.447–48) (citations omitted).
Ianevski states: “Favipiravir is an anti-influenza drug that has shown antiviral effects against many different (-) and (+)ssRNA viruses.” (Ianevski, p.1224).
Ianevski suggests combining favipiravir with other drugs for the treatment of viral infections:
Another option would be to combine BSAs to obtain even broader antiviral effects. For example, a cocktail of nitazoxanide, favipiravir, and niclosamide could be developed for the treatment of infections of viruses belonging to 11 families. Such combinations could also have synergistic or additive effects on a particular viral disease and thereby increase the effectiveness and/or reduce the dosage of antiviral therapeutics.
(Id., p.1227).
Repurposing existing drugs for novel diseases or infections was known and ongoing for coronavirus at the time of filing the instant application. Harrison states: “From the start of the COVID-19 outbreak, medical practitioners have followed China’s guidelines set up in January and treated hospitalized patients with a-interferon combined with the repurposed drug Kaletra.” (Harrison, p.379). And Table 1 shows a list of ten studies of drugs and combinations of drugs that had been repurposed to treat COVID-19. (Id., p.380).
Ascertaining the differences between the prior art and the claims at issue
The cited references do not disclose a composition comprising remdesivir (GS-5734) and favipiravir (T-705).
Resolving the level of ordinary skill in the pertinent art
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The instant application includes a study comparing the cytopathic effect for a single use of favipiravir (T-705) and a combination use of favipiravir (T-705) and remdesivir, showing an improved effect for the combination in a model. (Spec., ¶¶67–73).
The question of obviousness
Based on the above factors, it would have been obvious for a person having ordinary skill in the art prior to the filing of the instant application to combine or modify the disclosures of Wang in view of Maekawa, Chou, Harrison, De Clercq, Furuta, and Ianevski to arrive at the claimed invention.
Wang discloses, at the time the instant application was filed, remdesivir (GS-5734) and favipiravir (T-705) were each being investigated for the treatment of coronavirus.
The other cited references establish favipiravir was known as a broad-spectrum antiviral drug effective against various virus infections.
The other cited references establish combination therapy for the treatment of viral infections was known in the art at the time of filing of the instant application, and favipiravir specifically was used in combination therapy for the treatment of viral infections.
The cited references establish repurposing existing drugs for novel diseases or infections was known and ongoing for coronavirus at the time of filing the instant application, and repurposing favipiravir specifically was suggested for treating various viral infections.
Although the cited references do not disclose the specific combination recited in the claim, the cited references disclose favipiravir and remdesivir are effective against the coronavirus, and favipiravir has been used in combination therapy; and the cited references suggest repurposing existing drugs, including favipiravir, for the treatment of coronavirus.
When considered as a whole, the cited references establish it would have been obvious for one of ordinary skill in the art to combine remdesivir and favipiravir. See, e.g., In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980) (“It 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 which is to be used for the very same purpose.”). There would have been a reasonable expectation of success at arriving at the claimed invention because the use of a pharmaceutical composition comprising a compound of formula (I) and another antiviral drug to treat viral infections was known at the time of filing of the instant application.
The evidence provided in the instant specification shows an improved effect for a combination of favipiravir and remdesivir, but that data is not sufficient to rebut the above prima facie case of obvious because it would not have been unexpected to observe an additive or synergistic effect for the combination compared to the single drug because it was known, based on Furuta and Ianevski, that favipiravir improves the effect of other antivirals.
Response to Arguments
Applicant first argues the drugs in the claimed invention have an identical target, whereas the drugs in Maekawa discloses a combination of drugs having different targets. Applicant’s argument is not persuasive because the claims are directed to a product comprising drugs (not a method of treatment), and the biological target for a drug is an inherent property of the drug. Moreover, the argument is moot because a new ground of rejection is presented and based on a primary reference not previously applied in the Office Action. Applicant further argues the combination of favipiravir and remdesivir resulted in an almost 100% of CPE inhibition effect. That argument is not persuasive because the result naturally flows from an obvious combination.
Double Patenting
(i) Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1–14 of copending App. No. 18/559,873 (reference claims).
17/997,422
18/559,873
A pharmaceutical composition for treating coronavirus infection, comprising a pyrazine derivative represented by the following formula:
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104
194
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,
wherein R1 and R2, which are identical or different, each represent a hydrogen atom or a halogen atom; and
R3 represents a hydrogen atom or an amino protecting group,
wherein the amino protective group is selected from the group consists of an acyl group, alkyloxycarbonyl group, arylalkyloxycarbonyl group, aryloxycarbonyl group, arylalkyl group, alkoxyalkyl group, arylalkyloxyalkyl group, arvlthio group, alkylsulfonyl group, arvlsulfonyl group, dialkylaminoalkylidene group, arylalkylidene group, nitrogen-containing heterocyclic alkylidene group, cycloalkylidene group, diarylphosphorvl group, diarylalkylphosphorvl group, oxygen-containing heterocyclic alkyl group, and substituted silyl group, or a salt thereof, and
a therapeutic agent for coronavirus infection, wherein the therapeutic agent is remdesivir.
1. A therapeutic agent for coronavirus infection caused by a variant of SARS-CoV-2, comprising 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an active ingredient.
[6-fluoro-3-hydroxy-2-pyrazinecarboxamide is favipiravir (instant formula (I) wherein R1=H; R2=F; R3=H).]
Although the claims at issue are not identical, they are not patentably distinct from each other because they cover compositions comprising the same compound (favipiravir) for use in treating the same disease. The reference claims are not specifically directed to a combination therapy (i.e., two or more drugs), but the claims encompass (using “comprising”) a composition having two or more drugs. Therapy comprising a combination of active agents are known and routinely used in the art. As such, it would have been prima facie obvious to modify the composition in the reference claims to include an additional agent to treat coronavirus. Further, an infringer of a patent granted based on the claims of one of the applications may also be an infringer of the other.
This is a provisional double patenting rejection because no claims have been patented.
(ii) Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1–6 of copending App. No. 17/907,722 (reference claims).
17/997,422
17/907,722
1. A pharmaceutical composition for treating coronavirus infection, comprising a pyrazine derivative represented by the following formula:
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104
194
media_image1.png
Greyscale
,
wherein R1 and R2, which are identical or different, each represent a hydrogen atom or a halogen atom; and
R3 represents a hydrogen atom or an amino protecting group,
wherein the amino protective group is selected from the group consists of an acyl group, alkyloxycarbonyl group, arylalkyloxycarbonyl group, aryloxycarbonyl group, arylalkyl group, alkoxyalkyl group, arylalkyloxyalkyl group, arvlthio group, alkylsulfonyl group, arvlsulfonyl group, dialkylaminoalkylidene group, arylalkylidene group, nitrogen-containing heterocyclic alkylidene group, cycloalkylidene group, diarylphosphorvl group, diarylalkylphosphorvl group, oxygen-containing heterocyclic alkyl group, and substituted silyl group, or a salt thereof, and
a therapeutic agent for coronavirus infection, wherein the therapeutic agent is remdesivir.
1 A therapeutic agent for coronavirus infection comprising 6- fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an active ingredient, which is administered to patients with non-serious pneumonia.
[6-fluoro-3-hydroxy-2-pyrazinecarboxamide is favipiravir (instant formula (I) wherein R1=H; R2=F; R3=H).]
Although the claims at issue are not identical, they are not patentably distinct from each other because they cover compositions comprising the same compound (favipiravir) for use in treating the same disease. The reference claims are not specifically directed to a combination therapy (i.e., two or more drugs) but the claims encompass (using “comprising”) a composition having two or more drugs. Therapy comprising a combination of active agents are known and routinely used in the art. As such, it would have been prima facie obvious to modify the composition in the reference claims to include an additional agent to treat coronavirus. Further, an infringer of a patent granted based on the claims of one of the applications may also be an infringer of the other.
This is a provisional double patenting rejection because no claims have been patented.
(iii) Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1–18 of copending App. No. 18/554,291 (reference claims).
17/997,422
18/554,291
A pharmaceutical composition for treating coronavirus infection, comprising a pyrazine derivative represented by the following formula:
PNG
media_image1.png
104
194
media_image1.png
Greyscale
,
wherein R1 and R2, which are identical or different, each represent a hydrogen atom or a halogen atom; and
R3 represents a hydrogen atom or an amino protecting group,
wherein the amino protective group is selected from the group consists of an acyl group, alkyloxycarbonyl group, arylalkyloxycarbonyl group, aryloxycarbonyl group, arylalkyl group, alkoxyalkyl group, arylalkyloxyalkyl group, arvlthio group, alkylsulfonyl group, arvlsulfonyl group, dialkylaminoalkylidene group, arylalkylidene group, nitrogen-containing heterocyclic alkylidene group, cycloalkylidene group, diarylphosphorvl group, diarylalkylphosphorvl group, oxygen-containing heterocyclic alkyl group, and substituted silyl group, or a salt thereof, and
a therapeutic agent for coronavirus infection, wherein the therapeutic agent is remdesivir.
1. A therapeutic agent for coronavirus infection comprising 6- fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof as an active ingredient, which is administered to patients with one or more risk factors for disease progression who are at an early stage after onset.
[6-fluoro-3-hydroxy-2-pyrazinecarboxamide is favipiravir (instant formula (I) wherein R1=H; R2=F; R3=H).]
10. A method of treating a subject with a coronavirus infection comprising administering a composition comprising 6-fluoro-3-hydroxy-2- pyrazinecarboxamide or a salt thereof as an active ingredient, to a subject with one or more risk factors for disease progression who are at an early stage after onset.
Although the claims at issue are not identical, they are not patentably distinct from each other because they cover compositions comprising the same compound (favipiravir) for use in treating the same disease. The reference claims are not specifically directed to a combination therapy (i.e., two or more drugs) but the claims encompass (using “comprising”) a composition having two or more drugs. Therapy comprising a combination of active agents are known and routinely used in the art. As such, it would have been prima facie obvious to modify the composition in the reference claims to include an additional agent to treat coronavirus. Further, an infringer of a patent granted based on the claims of one of the applications may also be an infringer of the other.
This is a provisional double patenting rejection because no claims have been patented.
Response to Arguments
Applicant requests that rejections (i) and (iii) be held in abeyance. (Remarks, pp. 9–12).
Rejections (i) and (iii) are maintained.
Applicant’s arguments regarding rejection (ii) have been considered. Applicant argues the reference claims do not recite a combination and an allegation the claimed combination of the instant claims would have been obvious over the reference claims are mere speculation. (Id.). Applicant further argues the claimed components have a similar mechanism of action that results in an almost 100% of CPE inhibition effect. (Id.).
The arguments are not persuasive. It was acknowledged in the rejection that the reference claims do not recite a combination. But the reference claims are open-ended and broad enough to encompass the combination recited in the instant claim. Accordingly, an infringer of a patent granted based on the instant claim would also be an infringer of the reference claims. Further, the mechanism of action for the two components of the combination is not relevant because the claims are directed to a product claim and patentability will be primarily based on the claimed structure of the product as opposed to an inherent function of a component.
Rejection (ii) is maintained.
Conclusion
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 C.F.R. § 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 C.F.R. § 1.17(a)) pursuant to 37 C.F.R. § 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.
Communication
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/JASON M. NOLAN/Patent Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623