NON-FINAL REJECTION
Receipt is acknowledged of Applicants' Amendments and Remarks, filed Mar. 3, 2026.
Claim 7 has been amended and incorporates no new matter.
Claims 1 and 3-5 have been canceled.
No new claims have been added.
Thus, claims 2, 6, and 7 now represent all claims currently pending and under consideration.
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The rejections and/or objections set forth below are either maintained or newly applied, and constitute the complete set presently applied to the instant claims.
REQUEST FOR CONTINUED EXAMINATION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Mar. 3, 2026 has been entered.
INFORMATION DISCLOSURE STATEMENT
No new Information Disclosure Statements (IDS) have been submitted.
RESPONSE TO ARGUMENTS
Applicant's arguments filed Mar. 3, 2026 have been fully considered but they are not persuasive.
First, Applicant argues that Chen does not disclose inclusion/exclusion criteria regarding fever (at least 37.5°C) or oxygen saturation (SpO2 of at least 95% without supplemental oxygen). Chen merely suggests treatments for "ordinary COVID-19" or a "broad patient group including moderate cases." Therefore, Chen does not disclose or suggest the specific sub-population recited by amended claim 7 (Remarks, p. 4).
It is acknowledged that the patients of Chen et al. are not explicitly disclosed to have a fever of at least 37.5°C or SpO2 of at least 95% without supplemental oxygen.
However, as evidenced by, e.g., the WHO Pulse Oximetry Training Manual (cited on PTO-892), "a healthy individual with normal lungs, breathing air at sea level, will have an arterial oxygen saturation of 95% – 100%" (p. 8). Thus, it is implicit in Chen et al. that patients not receiving supplemental oxygen are not hypoxemic and thus have an SpO2 in the normal range of at least 95%.
In addition, these limitations are addressed by Guan et al., as discussed in detail in the new rejection under 35 U.S.C. § 103 set forth below.
Second, Applicant argues that the selection of the patient population meeting criteria (1) to (4) of amended claim 7 is not a simple adjustment of numerical values which can be characterized as "routine optimization." Madelain et al. provide no suggestion to limit the patient population to the claimed patient population, and also do not provide a basis for defining the correct dosage for this specific group (Remarks, p. 4-5).
It is acknowledged that Madelain et al. and Cai et al. do not explicitly disclose the patient population meeting criteria (1)-(4) as recited by amended claim 7. However, Madelain et al. disclose wide variability in effective dosages of favipiravir depending on the viral infection being treated; and show that the critical factor determining the antiviral efficacy of favipiravir is the blood plasma concentration, not the dose orally administered. Thus, Madelain et al. provides an objective basis for modifying the dosage of oral favipiravir disclosed by Chen and Cai et al.
Further, the instant specification itself recognizes that the dose of favipiravir can be adjusted within the broad range of 10-5,000 mg, depending on various factors; and further specifies that the dose of "1,600 mg BID on Day 1 and at 600 mg BID on Day 2 and thereafter" –
the identical dose disclosed by Chen et al. and Cai et al. – is preferable (para. [0023]):
For example, Compound A can be administered to adults at 10 to 5,000 mg or preferably 200 to 2,400 mg once or divided into several doses a day. In the present invention, Compound A can be administered to adults at 1,000 to 2,400 mg BID on Day 1 and at 400 to 1,200 mg BID on Day 2 and thereafter. Compound A can be administered to adults preferable at 1,600 mg BID on Day 1 and at 600 mg BID on Day 2 and thereafter and Compound A can be administered to adults at 1,800 mg BID on Day 1 and at 800 mg BID on Day 2 and thereafter (emphasis added).
Third, Applicant argues that the patient population of Cai et al. was administered favipiravir in combination with IFN-a, in contrast, to amended claim 7, which explicitly excludes concomitant administration. Thus, Cai would in fact have led a person of ordinary skill in the art away from the claimed methods (Remarks, p. 5).
However, Cai et al. report the results of an open-label control study which investigated the effects of favipiravir (FPV) versus lopinavir (LPV)/ritonavir (RTV) for the treatment of COVID-19 (abstract). All participants received IFN-α1b twice daily by aerosol inhalation, as well as standard care including oxygen, rehydration, electrolytes, antipyretics, analgesics, and antiemetic drugs (p. 1193, right col.).
One of ordinary skill in the art would understand that Cai et al. sought to compare the efficacy of favipiravir to lopinavir + ritonavir in the treatment of COVID-19, which required all other parameters to be held constant for both groups. Nowhere does Cai et al. suggest that favipiravir would have been ineffective without concomitant administration of IFN-α1b or other therapies, nor would a skilled clinician interpret this as teaching away from the claimed methods.
In addition, the instant specification itself recognizes that the claimed methods "can include administration of a concomitant drug and/or performing a concomitant therapy. Specifically, the standard of care for pneumonia can be included. . . . Additionally, oxygen therapy can be included. Further, interferon-alpha formulations, ribavirin, or drugs having an antiviral effect against coronavirus can also be included" (para. [0024]; emphasis added).
Finally, Applicant argues that the Office has not met its burden to support an obviousness rejection with facts and by establishing prima facie obviousness. MPEP § 2144.II.B. requires the Office provides both 1) "an explanation of why it would have been routine optimization to arrive at the claimed invention" and 2) an explanation of "why a person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range." Applicant asserts that the Final Office Action satisfies neither of these requirements by merely asserting that "multiple variables were known to influence the plasma concentration and therapeutic effect of favipiravir" (Remarks, pp. 6-7).
However, Madelain et al. is cited as evidence that it would have been predictable to a skilled clinician to modify the oral dosage of favipiravir by routine experimentation.
In addition, the instant specification itself is evidence that multiple variables were known to influence the plasma concentration and therapeutic effect of favipiravir (para. [0023]):
The method of administering Compound A [favipiravir] is not particularly limited but is suitably determined depending on the form of the formulations, the patient's age, sex, and other conditions, and the severity of the patient's symptoms. . . . The dose of Compound A is suitably selected depending on the dosing regimen, the patient's age and sex, disease form, and other conditions.
Finally, in response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejection is based on a combination of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant's amendments are further addressed by the new rejection under 35 U.S.C. § 103 set forth below.
NEW REJECTIONS
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 2, 6, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (medRxiv, 3/20/2020), as evidenced by the CAS Registry Record for favipiravir, in view of Madelain et al. (CPT Pharmacometrics Syst. Pharmacol. 9, 258–271, 3/20/2020), Cai et al. (Engineering 6, 1192–1198 (2020)), and Guan et al. (N Engl J Med 382;18 (2/28/2020), cited on PTO-892).
Chen et al. disclose a clinical trial wherein patients diagnosed with COVID-19 were treated with orally administered favipiravir (a.k.a. 6-fluoro-3-hydroxy-2-pyrazinecarboxamide).
As evidenced by CAS Registry Record for 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (of record), the claimed compound is also known as favipiravir.
The trial excluded critical patients with an expected survival time of less than 48 hours (p. 8); i.e., patients with serious pneumonia were excluded. The results showed that “[f]avipiravir can be considered as a preferred treatment approach to ordinary COVID-19 pneumonia” (p. 3).
Thus, Chen et al. disclose a method for treating a patient with novel coronavirus infection and non-serious pneumonia, comprising administering the claimed compound, favipiravir (a.k.a. 6-fluoro-3-hydroxy-2-pyrazinecarboxamide), as recited by claims 2 and 7.
Chen et al. further disclose that the treatment group was administered favipiravir oral tablets as follows: 1600 mg/time on the first day, twice a day (BID), and 600 mg/time from the second day to the end of the experiment, twice a day (BID), for up to 10 days (p. 9; p. 29).
Chen et al. differs from the instant claims in that the favipiravir dosage is 1600 mg BID on the first day of treatment, and 600 mg BID on the second and subsequent days, rather than 1800 mg BID on the first day of treatment, and 800 mg BID on the second and subsequent days of treatment, as recited by claim 7.
However, it would have been predictable to an ordinarily skilled clinician to modify the dosage amounts taught by Chen et al. to treat the same disease in the same patient population with a reasonable expectation of success, for the reasons detailed below.
For example, Madelain et al. report the use of mathematical modeling to evaluate the efficacy of favipiravir against Ebola virus and other emerging RNA viruses. The model integrated viral dynamics, immune responses, and pharmacokinetics, finding wide variability in effective dosages across different viral species.
Madelain et al. report that the approved dosing regimen of favipiravir for influenza is the same as that disclosed by Chen et al.: 1600 mg twice daily (BID) on the first day followed by 600 mg (BID) on days 2-5. However, Madelain et al. disclose that even a much higher dosage of 6000 mg BID on the first day, followed by 1200 mg BID on days 2-5, resulted in subtherapeutic plasma concentrations against Ebola virus disease (EVD) which did not significantly improve the survival rate (p. 259, right col. to p. 260, left col.).
In non-human primate animal models, dosages of 200/100, 250/150, and 250/180 mg/kg BID were tested, which achieved therapeutic plasma concentrations and increased the survival rate, supporting the use of higher doses of favipiravir (Fig. 2).
Thus, Madelain et al. establish that the key metric to optimize to achieve therapeutic efficacy of favipiravir is the blood plasma concentration, which may require adjustment of the dose orally administered. Madelain et al. show that the therapeutic response also depends on the viral species as well as the timing of treatment initiation.
Further, the ordinarily skilled clinician understands that the optimal dose of a given drug to achieve a therapeutic dose while also minimizing the risk of toxicity also turns on a host of variables unique to the individual patient, such as age, weight, and lifestyle and genetic factors.
Notably, this is also recognized by the instant specification (para. [0023]):
The method of administering Compound A is not particularly limited but is suitably determined depending on the form of the formulations, the patient's age, sex, and other conditions, and the severity of the patient's symptoms. . . . The dose of Compound A is suitably selected depending on the dosing regimen, the patient's age and sex, disease form, and other conditions. For example, Compound A can be administered to adults at 10 to 5,000 mg or preferably 200 to 2,400 mg once or divided into several doses a day. In the present invention, Compound A can be administered to adults at 1,000 to 2,400 mg BID on Day 1 and at 400 to 1,200 mg BID on Day 2 and thereafter. Compound A can be administered to adults preferable at 1,600 mg BID on Day 1 and at 600 mg BID on Day 2 and thereafter and Compound A can be administered to adults at 1,800 mg BID on Day 1 and at 800 mg BID on Day 2 and thereafter.
As recognized by MPEP § 2144.05,
Generally, differences in concentration or tempera-ture will not support the patentability of subject mat-ter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to dis-cover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to modify the favipiravir dosages of Chen et al. as taught by Madelain et al. to arrive at the claimed dosages with a reasonable expectation of success, because Madelaine et al. teach that multiple variables were known to influence the plasma concentration and therapeutic effect of orally administered favipiravir, requiring adjustments to the oral dosage to achieve a therapeutic plasma concentration.
Chen et al. differs from the claims in that favipiravir was administered for up to 10 days, rather than 14 days as recited by claim 6.
Cai et al. report the effects of favipiravir versus lopinavir/ritonavir for the treatment of COVID-19, finding that patients administered favipiravir experienced a shorter time to viral clearance, a significantly higher improvement rate in chest CT (computed tomography) imaging, and fewer adverse events. Overall, Cai et al. demonstrate that favipiravir showed better therapeutic response in the treatment of COVID-19 than lopinavir/ritonavir (abstract).
Cai et al. disclose that the clinical characteristics of COVID-19 include respiratory symptoms, fever, cough, dyspnea, and pneumonia (p. 1192, right col.). The inclusion criteria for the favipiravir treatment group included patients whose nasopharyngeal swab samples tested positive for the novel coronavirus RNA (Sec. 2.2); whose CT scans showed chest lesions (Fig. 1); and with a fever (Table 1).
Thus, the COVID-19 patient population of Cai et al. (1) tested positive for coronavirus; and at least some patients (2) had a pulmonary lesion on a chest image, and (3) a fever of at least 37.5°C, as recited by claim 7.
Cai et al. disclose that favipiravir administration was continued until the viral clearance was confirmed or until 14 days had passed (p. 1193, right col.), as recited by claim 6.
Regarding the claimed patient population recited by claim 7, the COVID-19 patients of Chen et al. are explicitly disclosed to have (1) tested positive for coronavirus and (2) to have a pulmonary lesion on a chest image (p. 4), as recited by claim 7.
The patient population of Chen et al. is also disclosed to have a fever (pp. 3-5). Cough and fever were reported as the most typical symptoms of COVID-19 (p. 7). However, Chen et al. do not explicitly specify a fever of at least 37.5°C, as recited by claim 7.
Chen et al. also differs from the instant claims in that the reference does not explicitly specify COVID-19 patients having an SpO2 (oxygen saturation) of at least 95% without oxygen therapy, i.e., normal SpO2 on room air, as recited by claim 7.
Guan et al. compiled data for patients with laboratory-confirmed Covid-19, as reported to the National Health Commission of China between Dec. 11, 2019, and Jan. 29, 2020. Covid-19 was diagnosed on the basis of the WHO interim guidance. A confirmed case of Covid-19 was defined as a positive result on high-throughput sequencing or real-time RT-PCR assay of nasal and pharyngeal swab specimens. Only laboratory-confirmed cases were included in the analysis (p. 1709, left col.). The data included clinical symptoms and outcomes for 1099 patients, with Covid-19 categorized as nonsevere in 926 patients and severe in 173 patients (p. 1710, right col).
Guan et al. disclose that, during hospital admission, 89.5% of patients with non-severe disease received a diagnosis of pneumonia from a physician (p. 1717, right col.).
Guan et al. further disclose that 84.4% of patients with non-severe disease had abnormal results on CT scans performed at the time of admission (Table 1). Guan et al. exemplify COVID-19 patients with non-severe pneumonia having a pulmonary lesion on a chest image (Fig. S1).
In addition, Guan et al. disclose that 57% of patients with non-severe disease had a fever of 37.5°C or higher upon admission (Table 1), as recited by claim 7.
Thus, the patient population of Guan et al., like Chen et al. and/or Cai et al., discloses COVID-19 patients with non-serious pneumonia, a positive test for coronavirus, a pulmonary lesion on a chest image, and a fever of at least 37.5°C, as recited by claim 7.
Guan et al. report that 35.7% of patients with non-severe (mild) disease received oxygen therapy (Table 3). By implication, 64.3% of patients with non-severe (mild) disease did not receive oxygen therapy, from which a skilled clinician would reasonably infer that most or all of these patients, not receiving supplemental oxygen in a hospital setting, had a normal oxygen saturation (SpO2) of at least 95% on room air, as recited by claim 7.
Thus, Guan et al. establish additional characteristics of COVID-19 patients not explicitly disclosed by Chen et al. and Cai et al., thereby disclosing the claimed patient population: patients with novel coronavirus infection and non-serious pneumonia who also (1) test positive for coronavirus, (2) have a pulmonary lesion on a chest image, (3) have a fever of at least 37.5 °C, and (4) have SpO2 of at least 95% without oxygen therapy, as recited by claim 7.
Therefore, it would have been predictable to one of ordinary skill in the art as of the filing date to modify the favipiravir dosage regimen disclosed by Chen et al. and combine the cited references to arrive at the claimed methods with a reasonable expectation of success, because Madelaine et al. and Cai et al. provide the rationale to modify the favipiravir dosage regimen of Chen et al., and Guan et al. disclose detailed characteristics of COVID-19 patients that were intrinsically present in the COVID-19 patient populations of Chen et al. and Cai et al.
As recognized by MPEP §2143, combining prior art elements according to known methods to yield predictable results would motivate the skilled artisan to modify the references with a reasonable expectation of success. The rationale to support a conclusion of prima facie obviousness is that all the claimed elements were known in the prior art, and a skilled artisan could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. See KSR Int'l Co. v. Teleflex Inc. (550 U.S. 398, 409).
CONCLUSION
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 9:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA ELIZABETH TOWNSLEY/Examiner, Art Unit 1629
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