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 .
Request for Continued Examination (RCE)
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/27/26 has been entered.
Priority
This application is a CON of PCT/US2021/029375 (04/27/2021) and has PRO 63/016,886 (04/28/2020).
Status
Any rejection not reiterated in this action is withdrawn.
Claims 1, 24, 26, 32, 39, 43-45, 48, 50-56, 70 are currently pending.
Claim Rejections - 35 USC § 103
Claims 1, 24, 26, 32, 39, 43-45, 48, 50-56, 70 are rejected under 35 U.S.C. 103 as being unpatentable over Changeux et al. ("A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications", QEIOS, 22 April 2020 (2020-04-22), 12 pages, https://doi.org/10.32388/FXGQSB.2 ) in view of Ackermann et al. (US20190201397) and Ishida (World Scientific News 99 (2018) p. 125-145).
Regarding claim 1, Changeux teaches “the nicotinic acetylcholine receptor (nAChR) plays a key role in the pathophysiology of Covid-19infection and might represent a target for the prevention and control of Covid-19 infection” (Abstract). Changeux teaches nAChR orthosteric and allosteric agents as therapies with examples including ivermectin on page 6:
nAChRs play a critical role in the pathophysiology of SARS-CoV-2 infection and as a consequence propose nicotine and nicotinic orthosteric and/or allosteric agents as a possible therapy for SARS-CoV-2 infection. Interestingly, ivermectin, which has been recently shown to inhibit the replication of SARS-CoV-2 in cells in vitro[53], is a positive allosteric modulator of a7 nAChR [54].
Changeux teaches that other nAChR agonists have been shown to inhibit SARS-CoV-2 in vitro (p. 6: “ivermectin, which has been recently shown to inhibit the replication of SARS-CoV-2 in cells in vitro[53], is a positive allosteric modulator of a7 nAChR”) and propose use of other nAChR agonists as therapeutic agents for treating SARS-CoV-2 (p. 6-7).
Changeux does not teach a combination of nAChR agonist varenicline, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, and copper administered to the respiratory tract.
Ackermann teaches pharmaceutical use of nAChR agonists and teaches both varenicline or (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine ([0915]: nAChR agonists include “compound 1” ((R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) and Varenicline) including the in vivo studies of the intranasal route of administration ([0944], [0959]-[1060]).
Ishida teaches that copper is an antiviral, including specifically with coronavirus (Abstract, p. 135, 139). Ishida teaches copper ions, including copper chloride salt was antiviral (p. 138, Table 2; p. 131: “Copper(II) chloride dihydrate antiviral compound was tested for inhibitory effect on the replication during infection of dengue virus (DENV-2) in cell culture that the ratio of cytotoxic concentration 50 (CC50 = 5.03 μg/ml) to maximal inhibitory concentration 50(IC50 = 0.13 μg/ml) was measured”).
One of ordinary skill in the art following the teaching of Changeux would have considered using known nAChR agonist including those taught by Ackermann. One of ordinary skill in the art would have also considered a combination with the known coronavirus antiviral of copper as taught by Ishida. “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 to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In reKerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980); MPEP 2144.06. In this case, one of ordinary skill in the art would have had a a reasonable expectation of success in substituting the known agonists from the same class of compounds to have the same therapeutic effect taught by Changeux. In addition, the combination with copper known for the same purpose is prima facie obvious. Thus, one of ordinary skill in the art would have readily considered the combination of Changeux with Ackermann and Ishida and arrive at the claimed invention. Ackermann also teaches formulation with known preservatives and in liquid form ([0018]) which one of ordinary skill in the art would consider routine as part of forming a pharmaceutical formulation. Ackerman also teaches administration to the respiratory tract via a nasal spray. Therefore, the claim is rejected as obvious.
Regarding claim 24 and 26, Ackerman teaches administration for at least 30 days and multiple administrations daily ([0225]).
Regarding claim 32, one of ordinary skill in the art routinely optimizes the dosing schedule to optimize efficacy and given the mechanisms of action one of ordinary skill in the art would have considered multiple dosing during periods of likely exposure and arrive at the claimed invention.
Regarding claims 39, 43-45, 50, 56-57, 62, and 64-67 specifying the amounts of the active agents, one of ordinary skill in the art routinely optimizes the dosing amounts to optimize efficacy which is well-known in the art as a results-effective variable. Given the mechanisms of action one of ordinary skill in the art would have considered optimizing the amounts administered and arrive at the claimed invention with a reasonable expectation of success.
Regarding claim 48, the combination of Changeux with Ackermann and Ishida teach the formulation and is silent regarding preservative-free. Almirall, LLC v. Amneal Pharm., 28 F.4th 265, 273 (Fed. Cir. 2022) (“"[A] reference need not state a feature's absence in order to disclose a negative limitation." AC Techs., S.A. v. Amazon.com, Inc. , 912 F.3d 1358, 1367 (Fed. Cir. 2019).”).
Regarding claims 51-55, 58-61, 63, 68, and 69, Ackerman teaches intranasal route of administration including a nasal spray ([0018], [0944], [0959]-[1060]) which as defined in the specification ([0017]) would include both the upper and lower respiratory tract.
Regarding claim 70 specifying the copper salt, Ishida teaches copper chloride was antiviral (p. 131: “Copper(II) chloride dihydrate antiviral compound was tested for inhibitory effect on the replication during infection of dengue virus (DENV-2) in cell culture that the ratio of cytotoxic concentration 50 (CC50 = 5.03 μg/ml) to maximal inhibitory concentration 50(IC50 = 0.13 μg/ml) was measured”).
With each of the claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed before the effective filing date with a reasonable expectation of success.
Response to Remarks - 35 USC § 103
Applicant argues that the claimed invention exhibits an unexpected result of “better inhibition of cell infection than the same amount of varenicline by itself (without copper)” as supported by Example 7, a combination of copper chloride salt and varenicline tartrate on SARS-CoV-2 infection of Caco-2 cells.
The data and alleged unexpected result was fully considered and not found persuasive as to the nonobviousness of the claims. The data of Example 7 and reported in Figs. 3-5 show somewhat confusing results with very large error bars indicating the alleged unexpected result may not be statistically significant. In particular, Applicant argues that the results showed that lower concentrations of varenicline (0.1 mM and 0.5 mM) when combined with 0.3 mM copper chloride achieved the same “infection rate” as varenicline alone at 1 mM. According to Fig. 4, 0.3 mM copper chloride would be expected to show ~30% infection. According to Fig. 3, 0.1 mM varenicline would be expected to have a statistically significant % infection range of ~75 to 175% and ~0.5 mM varenicline a range of ~60 to 120% (based on estimates from the smallest data points on the figure). According to Fig. 5, the combination of those same amounts shows ~7 to ~34% and ~0 to 45% for varenicline at ~0.1 and 0.5 mM, respectively. Taking these results into account and the fact that both were known as antivirals, one of ordinary skill in the art would have had an expectation that their combined effect would be additive, which is what an analysis of the statistically significant results shows. Thus, the alleged unexpected result is actually the expected result and the argument is not persuasive.
Conclusion
No claims allowed.
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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626