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 .
Claim Interpretation
Regarding the clause “wherein the administration results in…deuterated compound thereof” in claims 21 and 25 and “the administration results in… deuterated compound thereof” in claim 30, claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. A “wherein” clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited. See MPEP 2111.04. In the instant case, the clause simply expresses the intended result of a process step positively recited.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-22 of U.S. Patent No. 11,814,406 B2 in view of Xie et al. EP 4141007 A1 (Xie); Burns et al. US 11,638,715 B2 (Burns); and Humeniuk, Rita, et al. "Pharmacokinetic, pharmacodynamic, and drug-interaction profile of remdesivir, a SARS-CoV-2 replication inhibitor." Clinical pharmacokinetics 60 (2021): 569-583 (Humeniuk) in combination, as applied to claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 herein below. Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 differ from claims 16-22 of the ‘406 patent in that claims 16-22 do not explicitly recite administering the instantly claimed dose(s) or dosage regimen (e.g., administered twice daily, administered orally, etc.) and do not explicitly recite a method wherein the patient has an eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 or wherein the patient has normal or impaired renal function; however, these deficiencies would have been obvious in view of the teachings of Burns and Humeniuk in combination for the reasons set forth herein below.
Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54-65 of U.S. Patent No. 11,926,645 B2 in view of Xie et al. EP 4141007 A1 (Xie); Burns et al. US 11,638,715 B2 (Burns); and Humeniuk, Rita, et al. "Pharmacokinetic, pharmacodynamic, and drug-interaction profile of remdesivir, a SARS-CoV-2 replication inhibitor." Clinical pharmacokinetics 60 (2021): 569-583 (Humeniuk) in combination, as applied to claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 herein below. Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 differ from claims 54-65 of the ‘715 patent in that claims 54-65 do not explicitly recite administering the instantly claimed dose(s) or dosage regimen (e.g., administered twice daily, administered orally, etc.) and do not explicitly recite a method wherein the patient has an eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 or wherein the patient has normal renal function; however, these deficiencies would have been obvious in view of the teachings of Burns and Humeniuk in combination for the reasons set forth herein below.
Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-10, 13-18, 211-214, 219-222, 230, 255-256, 259, 267, and 269 of copending Application No. 18/205,745 in view of Xie et al. EP 4141007 A1 (Xie); Burns et al. US 11,638,715 B2 (Burns); and Humeniuk, Rita, et al. "Pharmacokinetic, pharmacodynamic, and drug-interaction profile of remdesivir, a SARS-CoV-2 replication inhibitor." Clinical pharmacokinetics 60 (2021): 569-583 (Humeniuk) in combination, as applied to claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 herein below. Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 differ from claims 1, 8-10, 13-18, 211-214, 219-222, 230, 255-256, 259, 267, and 269 of the reference application in that claims 1, 8-10, 13-18, 211-214, 219-222, 230, 255-256, 259, 267, and 269 do not explicitly recite administering the instantly claimed dose(s) or dosage regimen (e.g., administered twice daily, administered orally, etc.) and do not explicitly recite a method wherein the patient has an eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 or wherein the patient has normal renal function; however, these deficiencies would have been obvious in view of the teachings of Burns and Humeniuk in combination for the reasons set forth herein below.
This is a provisional nonstatutory double patenting rejection.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xie et al. EP 4141007 A1 (Xie); Burns et al. US 11,638,715 B2 (Burns); and Humeniuk, Rita, et al. "Pharmacokinetic, pharmacodynamic, and drug-interaction profile of remdesivir, a SARS-CoV-2 replication inhibitor." Clinical pharmacokinetics 60 (2021): 569-583 (Humeniuk) in combination.
Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 are drawn to a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound 16:
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(compound 16),
a deuterated compound thereof, or a pharmaceutically acceptable salt thereof; wherein the compound 16, the deuterated compound thereof, or the pharmaceutically acceptable salt thereof, is administered in a dosage of less than 1,600 mg/dose.
Xie provides a use of the nucleoside analogs having Formula (I) and compositions thereof in fighting viruses (e.g., coronavirus, influenza virus, respiratory syncytial virus, flaviviridae virus, filoviridae virus, and/or porcine epidemic diarrhea virus), in particular novel coronavirus (SARS-CoV-2) [0010].
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Xie provides a method for (a) inhibiting viral replication and/or (b) treating and/or preventing, alleviating related diseases caused by viral infection, comprising the steps of administrating safe and effective amount of a compound of formula (I), or the pharmaceutically acceptable salts thereof or the crystalline hydrate thereof or the solvate thereof or the prodrug thereof to the subject in need thereof [0059]. Xie teaches various dosage forms of the pharmaceutical compositions can be prepared according to the conventional preparation methods in the pharmaceutical field [0132]. The unit dose of the formulation generally contains 0.05-1000 mg of the active compounds of the present invention. Xie teaches that preferably, the unit dose of the formulation contains 1-500 mg of the active compounds. Xie teaches most preferred daily dose is of 0.01-400 mg/kg body weight, one-time administration, or 0.01-200 mg/kg body weight in divided doses [0133]. Xie teaches, regardless of any method of administration, the optimal dosage for an individual should be determined based on the specific treatment [0133]. Normally, start with a small dose and gradually increase the dose until the most suitable dose is found. Xie teaches that the formulation (or pharmaceutical composition) includes oral formulation and non-oral formulation [0039 – 0040].
Xie teaches, in a preferred embodiment, the compound of formula (I) may be Compound A50 [0034].
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The EC50 values and the inhibition rates of some preferred compounds on the replication of the 2019 novel coronavirus (SARS-CoV-2) are listed in Table 1.
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Xie differs from the instantly claimed invention in that 1) Xie does not explicitly teach or exemplify all of the instantly claimed elements in a singular embodiment; 2) Xie does not explicitly teach the administering the instantly claimed dose(s) or dosage regimen (e.g., administered twice daily, administered orally, etc.); and 3) Xie does not explicitly teach a method wherein the patient has an eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 or wherein the patient has normal or impaired renal function; however, these deficiencies would have been obvious in view of the teachings of Burns and Humeniuk in combination.
In the instant case, the references may be combined to show obviousness because Xie, Burns, and Humeniuk are each drawn to a method of treating a coronavirus infection in a patient in need thereof comprising administering a derivative or analog of GS-441524 or GS-443902. They are from the same field of endeavor, and/or are reasonably pertinent to a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof.
Burns is drawn to orally-bioavailable nucleoside analogs and pharmaceutical compositions comprising said compounds (Abstract). The subject compounds and compositions are useful for the treatment of coronavirus infections, including SARS-CoV-2 infection. Burns provides a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (III), (IV), (V), (VIa), (VIb), and (VIc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to treat viral infections (column 17, lines 14-51). Exemplary compounds include compound 14 (Table 1, column 89).
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Burns teaches small-molecule compounds that block coronavirus replication with the potential to be used as a monotherapy or in combination with additional antivirals and/or other agents that are useful for the treatment of coronavirus infection (column 2, lines 7-11). Burns teaches that in some embodiments, the infection is caused by the SARS-CoV or SARS-CoV-2 virus (column 16, lines 56-59). In some embodiments, the infection is COVID or COVID-19.
For any compound described therein, Burns teaches that the therapeutically effective amount can be initially determined from cell culture assays (column 42, lines 18-46). Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described therein, as measured using the methods described therein or known in the art. Burns teaches that therapeutically effective amounts for use in humans can also be determined from animal models (column 42, lines 24-46). For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. Adjusting the dose to achieve maximal therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. Burns teaches that the to prepare a pharmaceutical composition for oral delivery, 400 mg of compound described therein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and excipients are mixed intimately and pressed into single scored tablets (Example 1).
Humeniuk summarizes the clinical and pre-clinical pharmacology of remdesivir (RDV) with a focus on clinical pharmacokinetics (PK), pharmacodynamics/concentration-QT (C-QT) analysis, rationale for dose selection for clinical studies in patients with COVID-19, and drug interaction potential (page 570). Humeniuk teaches that remdesivir undergoes intracellular activation to form GS-443902 (an analog of adenosine triphosphate) that selectively inhibits viral RNA polymerases and has broad-spectrum activity against members of the CoV. The intracellular metabolic pathway of RDV is presented in Fig. 2 (page 571)
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Humeniuk teaches, in vivo, RDV showed therapeutic efficacy in SARS-CoV2-infected rhesus monkeys and prophylactic and therapeutic efficacy in MERS-CoV-infected rhesus monkeys (page 572). Briefly, 12 h after inoculation with SARS-CoV-2, rhesus monkeys received an RDV 10-mg/kg IV loading dose followed by maintenance doses of RDV 5 mg/kg at 24 h post-inoculation and once daily thereafter for a total of 6 days of treatment. The aim of the loading dose was to rapidly generate high GS-443902 concentrations following the first dose. Humeniuk teaches that treatment with this regimen resulted in a significant reduction in clinical signs of respiratory disease, lung pathology and gross lung lesions, and viral RNA levels compared with vehicle-treated animals.
Humeniuk teaches that kidney involvement is frequent in COVID-19; from mild proteinuria to acute kidney injury affecting the critically ill patients (~20 to 40% of patients admitted to intensive care) (page 579). Moreover, around 20% of patients admitted to an intensive care unit with COVID-19 require renal replacement therapy. The PK of RDV has not been evaluated in patients with renal impairment. However, as the acute reduction in renal function was commonly observed in patients with COVID19 at hospital admission, patients with an eGFR ≥30 mL/ min (mild-to-moderate renal disease) were included in the phase III clinical development program and received RDV for the treatment of COVID-19 with no dose adjustment. Remdesivir may be administered to patients with an eGFR ≥30 mL/min. The safety and efficacy of RDV have not been assessed in patients with an eGFR ≤30 ml/min, precluding RDV use in this patient population.
In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983).
In the instant case, it would have been prima facie obvious to one of ordinary skill to treat a SARS-CoV-2 infection in a patient in need thereof comprising orally administering to the patient a therapeutically effective amount of compound A50 of Xie (e.g., instant compound 16) as such a method is reasonably suggested by Xie. See [0039 – 0040], [0059], and Table 1. Regarding the instantly claimed dose (e.g., 350 mg/dose), Xie teaches, preferably, the unit dose of the formulation contains 1-500 mg of the active compounds. The instantly claimed dose (e.g., 350 mg/dose) is inside the range disclosed by Xie. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. See MPEP 2144.05.
Regarding the instantly claimed dosage regimen, generally differences in dosage regimen will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such dosage regimen is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In the instant case, the instantly claimed dosage regimen could have been obtained by routine experimentation using the dosage regimen of Xie, Burns, and/or Humeniuk as a starting point for further optimization. Xie, Burns, and/or Humeniuk teach oral administration, administration via divided doses, administration for five consecutive days, and wherein the first day of administration is within 5 days of commencement of symptoms of the viral infection. Burns teaches adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. Burns further teaches adjusting the dose to achieve maximal therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
Regarding instant limitations directed to the instant patient (e.g., the patient has mild renal impairment; wherein the patient has an eGFR of 60 to 89 mL/min/1.73 m2) or to determining the patient’s eGFR, Humeniuk teaches that kidney involvement is frequent in COVID-19, from mild proteinuria to acute kidney injury affecting the critically ill patients. Humeniuk teaches that the PK of RDV has not been evaluated in patients with renal impairment. However, as the acute reduction in renal function was commonly observed in patients with COVID19 at hospital admission, patients with an eGFR ≥30 mL/ min (mild-to-moderate renal disease) were included in the phase III clinical development program and received RDV for the treatment of COVID-19 with no dose adjustment. Thus, it would have been obvious to one of ordinary skill to treat a patient in need thereof, wherein the patient has an eGFR of 60 to 89 mL/min/1.73 m2 (e.g., patient has normal renal function) as the safety and efficacy of RDV, a structurally similar analog, have not been assessed in patients with an eGFR ≤30 ml/min, precluding RDV use in this patient population. A patient having an eGFR of 60 to 89 mL/min/1.73 m2 (e.g., a patient having normal renal function) is within the patient population described by Humeniuk rendering the limitation prima facie obvious. It would have also been obvious to determine that the patient has an eGFR of at least 30 mL/min/1.73 m2 prior to administration as Humeniuk teaches that the safety and efficacy of RDV have not been assessed in patients with an eGFR ≤30 ml/min. Humeniuk teaches that kidney involvement is frequent in COVID-19. Thus, assessment of a patient’s renal function prior to administration would have been obvious.
All of the instant limitations are taught by the combination of Xie, Burns, and Humeniuk. A person of ordinary skill in the art would have had a reason to combine the teachings of Xie, Burns, and Humeniuk. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Xie, Burns, and Humeniuk. Thus, claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 would have been obvious based on the preponderance of the evidence.
Claim(s) 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wei, Daibao, et al. "Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2." Bioorganic & Medicinal Chemistry 46 (2021): 116364 (Wei) and Choe, Pyoeng Gyun, et al. "Exploration for the effect of renal function and renal replacement therapy on pharmacokinetics of remdesivir and GS‐441524 in patients with COVID‐19: a limited case series." Clinical and translational science 15.3 (2022): 732-740 (Choe) in combination.
Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 are drawn to a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound 16:
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(compound 16),
a deuterated compound thereof, or a pharmaceutically acceptable salt thereof; wherein the compound 16, the deuterated compound thereof, or the pharmaceutically acceptable salt thereof, is administered in a dosage of less than 1,600 mg/dose.
Wei teaches that the nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19 (Abstract). However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Therein, Wei reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two L-valine esters, and one carbamate. Wei teaches that the 5′-isobutyryl ester 5c (e.g., instant compound 16) showed excellent oral bioavailability in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.
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Wei teaches that compound 5c was found to exhibit stronger anti-SARS-CoV-2 activities than GS-441524 (Table 2), which likely resulted from their improved cellular permeability (page 3).
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Wei teaches that an acute toxicity study of compound 5c was conducted with ICR mice (pages 5-6). The animals were fasted for 16 h, and then administered a single oral gavage dose of the test compound at 50 mg/kg, 100 mg/kg, 200 mg/kg, 500 mg/kg and 1000 mg/kg (formulated with 5% DMSO, 5% Solution Hs15 and 90% saline). No mortality occurred during the 7-day observation period. No significant changes in body weight, organ weight, or tissue histology were observed after animal sacrifice. This acute toxicity study indicated that compound 5c was well tolerated in ICR mice at an oral dosage of up to 1000 mg/kg. Wei further teaches single-dose PK parameters for GS441524 following oral (50 mg/Kg) and intravenous (25 mg/Kg) administration of the ester prodrugs (5a, 5b, 5c and 5g⋅HBr) in CD-1 mice (N = 3 per group). See Table 3.
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Thus, Wei discloses the antiviral activity of GS-441524 prodrugs (e.g., compound 5c) against SARS-CoV-2 in Vero E6 cells. Wei teaches that the 5′-isobutyryl ester 5c (e.g., instant compound 16) showed excellent oral bioavailability in mice. Wei indicated that compound 5c was well tolerated in ICR mice at an oral dosage of up to 1000 mg/kg.
Wei differs from the instantly claimed invention in that Wei does not explicitly teach administering compound 5c to an instant patient in need thereof (e.g., limited to in vitro data). Wei further differs from the instantly claimed invention in that Wei does not explicitly teach administration to an instant patient in need thereof (e.g., wherein the patient has an eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 and/or wherein the patient has mild renal impairment) and does not explicitly teach the instantly claimed dosage regimen (e.g., administered in a dose of 350 mg/dose and/or administered twice daily). However, these deficiencies would have been obvious in view of the teachings of Choe.
In the instant case, the references may be combined to show obviousness because Wei and Choe are each drawn to a nucleoside metabolite of remdesivir (e.g., GS-441524) or derivative thereof used for treating a viral infection (e.g., SARS-CoV-2). They are from the same field of endeavor, and/or are reasonably pertinent to a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound 16, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof.
Choe teaches that remdesivir, an antiviral agent for the treatment of coronavirus disease 2019 (COVID-19), is metabolized intracellularly, with these metabolites eliminated predominantly in urine (Abstract). Because of a lack of safety and pharmacokinetic (PK) data, remdesivir is not currently recommended for patients with estimated glomerular filtration rate less than 30 ml/min/1.73 m2 and those on hemodialysis. This study evaluated the PKs of remdesivir and its metabolite, GS-441524, in patients with COVID-19 who were and were not receiving renal replacement therapy (RRT). This study enrolled two patients with normal renal function, two with impaired renal function not receiving RRT, two receiving continuous RRT (CRRT), and three undergoing intermittent hemodialysis (IHD). Patients were administered 200 mg remdesivir on the first day, followed by 100 mg/day for 5–10 days. Serial blood samples were collected for PK analysis, and PK parameters were assessed by a noncompartmental method. Systemic exposure to remdesivir was higher in patients with impaired renal function and those receiving CRRT than in patients with normal renal function, but was similar in patients undergoing IHD and those with normal renal function. By contrast, systemic exposure to GS-441524 was highest in patients undergoing IHD, followed by patients with impaired renal function and those receiving CRRT, and lowest in patients with normal renal function. The PK profiles of remdesivir and GS-441524 varied according to renal function and RRT. The impact of PK changes of remdesivir and its metabolite on safety and efficacy should be considered when administering remdesivir to patients with COVID-19 with renal impairment.
In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983).
It would have been prima facie obvious to treat a SARS-CoV-2 infection in a patient comprising administering compound 16 in a dosage of less than 1,600 mg/dose as such a method is reasonably suggested by Wei. In considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom. As set forth above, Wei discloses the antiviral activity of GS-441524 prodrugs (e.g., compound 5c) against SARS-CoV-2 in Vero E6 cells. Wei teaches that the 5′-isobutyryl ester 5c (e.g., instant compound 16) showed excellent oral bioavailability in mice. Wei indicated that compound 5c was well tolerated in ICR mice at an oral dosage of up to 1000 mg/kg.
Regarding the instant dosage regimen, the claimed dosage regimen could have been obtained via routine experimentation using the dosage regimen for remdesivir (e.g., a close structurally related compound) disclosed by Choe as a starting point for further optimization. One would have had a reasonable expectation of success as Wei teaches that compound 5c was well tolerated in ICR mice at an oral dosage of up to 1000 mg/kg. Generally differences in dosage regimen will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such dosage regimen is critical. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Regarding the instant patient in need thereof, it would have been obvious to substitute remdesivir in the method(s) of Choe with instant compound 16 based upon their close chemical structure and common utility (e.g., antiviral agent against SARS-CoV-2). As set forth above, Choe teaches a method wherein the patient has mild renal impairment and/or eGFR of 30 mL/min/1.73 m2. In the case where the claimed ranges overlap, lie inside, or are sufficiently close to ranges disclosed by the prior art a prima facie case of obviousness exists.
All of the instant limitations are taught by the combination of Wei and Choe. A person of ordinary skill in the art would have had a reason to combine the teachings of Wei and Choe. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Wei and Choe. Thus, claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 would have been obvious based on the preponderance of the evidence.
Conclusion
Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 are pending. Claims 1, 8-9, 14, 17-18, 21, 25, 29-31, 34, 37, 40-41, 52, 54, 57, 60-61, 63, 81-83, 88-90, 94, 98, and 113-116 are rejected. No claims are allowed.
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/PATRICK T LEWIS/Primary Examiner, Art Unit 1691
/PL/