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 .
Claims 1, 2, 10, 13, and 30 have undergone amendments. Claims 15, 17, and 19-20 have been cancelled. Claim 32 is newly added. Thus, Claims 1-3, 5-6, 8, 10, 13, 18, 22, and 26-32, submitted on 10 February 2026, represent all claims currently under consideration.
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.
Response to Amendment
The objection to Claim 30 is withdrawn. Applicant has amended the claim to replace the “of” with “is”, overcoming the objection.
The 35 U.S.C. § 112(a) rejection of Claim 2 is withdrawn. Applicant has amended the claim to recite treating or ameliorating long COVID, or a symptom or complication thereof.
The 35 U.S.C. § 112(b) rejection of Claim 10 is withdrawn. Applicant has amended Claim 10 to correct the indefiniteness.
Response to Arguments
The 35 U.S.C. § 103 rejection of Claims 1-3, 5, 6, 8, 10, 13, 15, 17-20, 22, and 26-31 over Cihlar in view of Hoffmann and Uno is withdrawn. Cihlar does not describe or suggest any dosage or dosing regimen for camostat or its salts.
The 35 U.S.C. § 103 rejection of Claims 1-3, 5, 6, 8, 10, 13, 15, 17-20, 22, and 26-31 over Clinical Trial ID NCT04321096 in view of Uno is withdrawn. The clinical trial explicitly states that this method did not affect time to clinical improvement and thus the artisan would have no motivation to utilize this compound in further therapeutic methods to treat SARS-CoV-2.
The 35 U.S.C. § 103 rejection of Claims 1-3, 5, 6, 8, 10, 13, 15, 17-20, 22, and 26-31 over Clinical Trial NCT04374019 in view of Uno is withdrawn. The clinical trial demonstrates that this method did not affect time to clinical improvement and thus the artisan would have no motivation to utilize this compound in further therapeutic methods to treat SARS-CoV-2.
The 35 U.S.C. § 103 rejection of Claims 1-3, 5, 6, 8, 10, 13, 15, 17-20, 22, and 26-31 over Vaananen in view of Hoffmann and Uno is withdrawn as applicant has amended the dosages to be 800 mg, which is not disclosed by Uno. However, a new grounds of rejection is made in view of Vaanane, Hoffmann, Uno and Loftsson as Applicant has amended Claim 1 to incorporate a new limitation. Applicant states that Uno provides no clinical data on the use of the drug in blocking or at least reducing viral spread and pathogenesis of coronaviruses. Applicant further argues that Uno does not disclose orally administering to a subject 800 mg of camostat or an equimolar amount of a salt or solvate thereof in four equal doses, and applicant further states that the motivation to increase the daily from 600 mg to 800 mg in order to prevent total elimination of the drug from the body and keep therapeutic concentrations is without merit and is not supported in the cited art. The prior art shows that camostat has a 100 minute plasma half-life and is completely eliminated in 4-5 hours, and the divided doses are given to maintain plasma concentration at therapeutic levels, which is why Uno advises administration of 200 mg three times daily. Applicant argues that Uno already provides a dosage regimen to deal with the drawbacks of the pharmacokinetics of camostat. Applicant argues that the Office’s position is that “taking 200 mg three times daily of camostat is expected to reduce the SARS-CoV-2 infection”, there is no actual problem in the protocol of Uno when combined with the other prior art, and hence there is no motivation to use the dosing regimen claimed in the examined application. Thus, there is no credible rationale to increase the administered dosage of camostat to more than 600 mg daily when the prior art already provides a working protocol, and applicant argues that the altering an allegedly working therapeutic protocol should be tinkered with to meet the limitations of the examined claims is based on impermissible hindsight reasoning. The Examiner respectfully disagrees. The conditions are generally known in the prior art, and through routine experimentation, a new dosing regimen can be arrived at by the artisan. As applicant states, 200 mg is eliminated in 4-5 hours. 600 mg may be sufficient to cover an entire day; however, the artisan would also recognize that an additional 200 mg dosage (4 dosages daily, averaging one dosage every 6 hours) would provide greater coverage of the therapeutic window due to the stated pharmacokinetics of camostat. Thus, it flows from the art of Uno, as well as the known pharmacokinetics of camostat, that one additional dosage (for a total of 800 mg, once every 4-6 hours) would result in the maintenance of the drug within the plasma given the known plasma half-life of the drug. The addition of this dosage is prima facie obvious optimization within prior art conditions (See MPEP § 2144.05 II (A)). Uno teaches three doses of 200 mg camostat daily for the treatment of SARS-CoV-2 given the 4-5 hour elimination time of camostat. However, the artisan would recognize through their training of pharmacokinetics that an additional dosage could be added to ensure that there is drug within the plasma throughout the day.
Claim Rejections - 35 USC § 103- NEW GROUNDS OF REJECTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3, 5-6, 8, 10, 13, 18, 22, and 26-32 are rejected under 35 U.S.C. 103 as being unpatentable over Vaananen (US 11,007,187; Patent Date: 18 May 2021; Priority to 24 April 2020 and 25 March 2020) in view of Hoffmann (Cell, 2020 April 16, 181 (2): 271-280), Uno (Internal and Emergency Medicine, Published online 29 April 2020), and Loftsson (Essential Pharmacokinetics, Chapter 5-Pharmacologic Response and Drug Dosage Adjustments, Pages 119-130, Volume 1, 2015).
Vaananen (See IDS, 21 March 2023) discloses a medicine and a prophylactic medicine for COVID-19 disease. The inventive medicine targets the endosomic, non-endosomic, and/or intracellular viral pathways and inhibits them. The best mode of the invention is considered to be the medicine that blocks all three viral pathways. In the best mode of the individual dose of a constituent component of the medicine is arranged to a dosage size sufficient to inhibit its designated SARS-CoV-2 viral pathway (Abstract). The inventive medicine uses the aforementioned compounds in any permutation or combination in local administration by any of the following: nasal drops, nasal sprays or aerosols targeted into lower respiratory pathways, either alone or in the following combinations. The inventive medicine presents the viral infection and/or treats the infection in its early phase by decreasing viral entry into epithelial cells by any of the following exemplary compositions, and these embodiments include the use of camostat alone (Column 16, Lines 42-68).
Hoffmann teaches the involvement of TMPRSS2 in SARS-CoV-2 infections. Through a series of experiments, Hoffman demonstrated that SARS-CoV-2 can use TMPRSS2 for S protein priming and for cellular entry, and camostat mesylate, an inhibitor of TMPRSS2, blocks SARS-CoV-2 infection of lung cells (Figure 4).
Vaananen and Hoffmann do not teach the dosage schedules or doses of camostat or camostat mesylate claimed, or the oral administration of camostat.
Uno (See IDS, 21 March 2023) teaches that TMPRSS2 is a serine protease that primes the spike protein of highly pathogenic human coronaviruses, such as SARS-CoV, MERS-CoV, and facilitates its entry into the host cell. Camostat mesylate (CM), an inhibitor of TMPRSS2, blocked the spread and pathogenesis of SARS-CoV in a pathogenic mouse model and would be expected to show similar effect in MERS-CoV. Hoffman determined that SARS-CoV-2 requires TMPRSS2. Furthermore, using a sample of the SARS-CoV-2 virus isolated from a patient, they found that CM blocks the entry of the virus into the lung cells. CM therapy has been used for acute symptoms of chronic pancreatitis and postoperative reflux esophagitis since 1994; the oral doses in these cases are 600 and 300 mg/day, respectively. In a multicenter double-blind study on 189 subjects, 3% of the subjects in the group administered 900 mg CM daily for 8 weeks showed side effects (oedema and urticaria); however, there were no side effects over the 8 week period in groups that received a daily CM dose less than 600 mg. In an experiment on a mouse model, CM was effective in protecting the mice against death following a lethal SARS-CoV infection. The weights of the mice were not described, but the average weight was estimated to be approximately 20g considering the fact that 6- to 8-week-old female BALB/c mice were used. Assuming the weights of a mouse an adult human to be 20g and 60 kg, respectively, the equivalent CM dose for humans would be approximately 2.14 mg/kg. CM has a plasma half-life of 100 minutes and is almost completely eliminated in 4-5 hours.
Uno does not disclose an 800 mg daily dosage of camostat.
Loftsson teaches dosing of pharmaceuticals and that drugs are administered on the basis of their average pharmacokinetic parameters in normal patient populations (Page 119). Many drugs have a wide therapeutic window and can easily remain within their therapeutic window (Page 119). Pharmacodynamics describes the relationship between drug concentration at the receptor and the drug effect, with the receptor being a well-defined place within the body, or on or within the surface of a microorganism within the body (Section 5.3, Pharmacodynamics). The relationship between drug concentration and drug effect is shown in Figure 5.2A; at high drug concentrations, the drug effect approaches a maximum value where 100% drug response is obtained. At this concentration, virtually all receptors have formed a drug-receptor complex. This relationship is sigmoidal (Section 5.3, Pharmacodynamics).
Vaananen, Hoffmann, Uno, and Loftsson are considered analogous to the claimed invention as all are involved in the delivery of therapeutics for the treatment of disease. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to utilize camostat mesylate for the treatment of SARS-CoV-2 infections, as taught by Vaannanen, as Hoffman provides a reasonable expectation of success by demonstrating the mechanism by which this compound inhibits viral entry into the cell, and to further modify the dosage and treatment schedule in view of the teachings of Uno and Loftsson. Uno describes the pharmacokinetics of camostat mesylate in mice, and extrapolates this dosage to humans, stating that CM has a plasma half-life of 100 minutes and is almost completely eliminated in 4-5 hours, and recommends a total daily dose of 600 mg (200 mg, three times daily) to reduce the SARS-CoV-2 infection. It flows from this teaching to increase the total dosage to 800 mg (200 mg, four times daily) in order to prevent a total elimination of the drug from the body, and keep therapeutic concentrations within the body, allowing for greater elimination of the virus. The combination of these teachings to arrive at the claimed invention is prima facie obvious combination of prior art elements according to known methods to yield predictable results (See MPEP § 2143 I (A)); the use of camostat mesylate for the inhibition of TMPRSS2 and subsequent treatment of COVID-19 infections is known in the art, and Uno discloses a suggested dosage regimen which the artisan would recognize could be modified to lead constant therapeutic levels of the drug with the addition of a fourth 200 mg dosage, and Uno states that dosages these high have a low risk of side effects, providing a reasonable expectation of success for this modification. Dosage adjustments are routine in the field of medicine, and the artisan, who would have experience and training in pharmacokinetics, would recognize this, and would weigh the risks versus benefits of one additional dosage to further ensure that the plasma levels of camostat and its metabolite remain within its appropriate therapeutic window. The addition of this dosage is prima facie obvious optimization within prior art conditions (See MPEP § 2144.05 II (A)). Uno teaches three doses of 200 mg camostat daily for the treatment of SARS-CoV-2 given the 4-5 hour elimination time of camostat. However, the artisan would recognize through their training of pharmacokinetics that an additional dosage could be added to ensure that there is drug within the plasma throughout the day.
Regarding Claim 5, Long COVID is a symptom of a SARS-CoV-2 infection. It flows from this art that using an inhibitor of viral entry of COVID-19 can be useful for ameliorating the symptoms of Long COVID by preventing the virus from entering the cell and reducing viral load, thus ameliorating the symptoms of Long COVID.
Regarding Claims 6, 8, and 10, camostat mesylate has been shown to inhibit viral entry of COVID-19 into cells, and it flows from this art that by administering this compound to a patient in need thereof, the viral load would be reduced, and as such, the symptoms and progression of the coronavirus infection would be reversed or reduced.
Regarding Claim 18, the exact dosing regimen of daily treatment for a period of 7 days is not disclosed by the cited references. However, it would be obvious to one of ordinary skill in the art to perform this treatment daily, and for up to one week in order to ensure complete elimination of the virus and to prevent a refractory infection from incomplete elimination of the virus.
Regarding Claims 26-31, GBPA is the active metabolite which forms following administration of camostat. The concentrations which arise would be expected to be found following the modified dosage schedule of Uno, which results in therapeutically effective concentrations of the drug being found in plasma.
Conclusion
Claims 1-3, 5-6, 8, 10, 13, 18, 22, and 26-32 are rejected.
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 CFR 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 CFR 1.17(a)) pursuant to 37 CFR 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.
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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625