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 .
Priority
The instant application, filed 01/09/2023, is a national stage entry of PCT/US2021/041163 filed on July 9, 2021 which claims priority to U.S. Provisional Application No. 63/049,905 filed on July 9, 2020.
Amendments and Claim Status
The following amendment filed on 02/09/2026 is acknowledged and entered.
Claim 1 is amended;
Claims 5-7 and 21-32 are cancelled;
Claims 15 remains withdrawn according to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species;
Claims 1-4 and 8-20 are pending and are under prosecution.
Response to arguments
Applicant’s arguments filed 02/09/2026 with respect to the objection to the drawings and claims, as well as the claim rejections under 35 U.S.C. §§ 112 (a), 112(b), and 103 have been fully considered.
With respect to the objection to the drawings, the amended figures, filed on 02/09/2026, are sufficient to overcome the objection. As such, the objection is withdrawn.
With respect to the objection to claim 11, the expansion of the acronym CNS to central nervous system is sufficient to overcome the objection. As such, the objection is withdrawn.
With respect to the rejection of claim 7 under 35 U.S.C. § 112 (a) the cancellation of the claim is sufficient to overcome the rejection. As such, the rejection is withdrawn.
With respect to the rejection of claims 1-14 and 16-20 under U.S.C. § 112(b), the cancellation of claims 5-7 is sufficient render the rejection against said claims moot. Furthermore, the removal of the relative terms “a disease or disorder associated with coronavirus infection” is sufficient to overcome the rejection. As such, the rejection is withdrawn.
With respect to the rejection of claims 1-6, 8, and 18-20 under 35 U.S.C. § 103 as being unpatentable over Spadavecchia et al. (WO 2021205083 A2, published October 14, 2021, effectively filed April 11, 2020, for the purpose of 102 (a)(2)), hereinafter Spadavecchia, the cancellation of claims 5-7 is sufficient render the rejection against said claims moot. Furthermore, the claim amendments made by applicant have necessitated the inclusion of a new reference to address the limitations now included in the independent claim. The arguments made by Applicant are herein addressed as follows.
Applicant argues that Spadavecchia does not disclose the method recited by the amended claims. Applicant invokes the obviousness standard from In re Stepan, 868 F.3d 1342, 1346, 123 USPQ2d 1838, 1841 (Fed. Cir. 2017), requiring both motivation to combine and reasonable expectation of success.
Applicant’s argument is found unpersuasive because the rejection relies on the teachings of Spadavecchia alone, and not a combination of references, rendering the case law citation inapplicable. Spadavecchia explicitly discloses intranasal administration of NAC for the treatment or prevention of SARS-CoV-2 (paragraph [0384]).
Applicant argues that the disclosure by Spadavecchia is directed primarily to BHT and its derivatives as the active antiviral compounds, and that NAC is treated as a secondary or ancillary component. As such, applicant contends that a person of ordinary skill in the art would understand that at least one of BHT or its derivatives must be used, and that Spadavecchia provides no motivation to modify the route of NAC administration, or to select a dose of NAC for any particular therapeutic effect.
Applicant’s argument is found in persuasive because Spadavecchia expressly recites NAC as an antioxidant active agent (paragraph [0379]), details its administration both symptomatic and symptomatic SARS-CoV-2 patients (paragraph [0382]), and teaches NAC in combination with other agents for the presentment and treatment of COVID-19 (paragraphs [0148], [0150], [0161- 0169]). NAC is not taught to be merely an ancillary component in the prior art. A person of ordinary skill in the art would have recognized it as a meaningful therapeutic agent with the explicitly disclosed routes of administration.
Applicant argues that the office action relies only on limited disclosure within Spadavecchia regarding intranasal administration, while Spadavecchia as a whole emphasizes and prefers oral administration as evidenced by numerous paragraphs throughout the reference.
Applicant’s argument is found unpersuasive because the references preference for one disclosed embodiment does not negate other explicitly disclosed embodiments. Intranasal administration is expressly enumerated as a viable route within the disclosure by Spadavecchia (paragraph [0384]), and a person having ordinary skill in the art would have had a reasonable expectation of success in selecting it for the same therapeutic purpose.
Applicant argues that amended claim 1 now requires administering NAC at a dose “effective to elevate GSH level in the brain of the human subject.” And that Spadavecchia neither discloses nor suggests the specific functional outcome, as Spadavecchia nor Reyes teach intranasal NAC administration at a dose selected for any particular effect.
Applicant’s argument is found unpersuasive because it was well-established in the prior art, prior to the effective filing date of the instant claims, that NAC elevates brain GSH levels, according to Reyes et al. (Neurotherapeutics, Volume 13, Issue 1, pages 217-225, published November 16, 2015), hereinafter Reyes. Reyes teaches that oxidative stress contributes to the pathogenesis conditions which affect the central nervous system, and GSH is depleted in these conditions (page 223). Reyes teaches that NAC supports neuronal GSH synthesis by supplying cysteine, the rate limiting substrate for GSH production (page 223). Reyes teaches that NAC administration normalizes neuronal GDH content and antioxidant capacity in the brain (Figure 2, pages 223-234). Accordingly, the functional outcome of elevating brain GSH levels is a well-known, and predictable consequence of NAC administration. Furthermore, the dosages taught by Spadavecchia overlap with those which elicit the intended elevation of GSH levels as outlined in the instant specification (see paragraphs [0385] of Spadavecchia and [0050] of the instant specification. Thus, the methods already taught and practiced by Spadavecchia would necessarily result in the elevating of GSH levels as instantly claimed, although not expressly recited by the prior art. Therefore, the GSH-elevating properties of NAC are well-established, and elevation of brain GSH by intranasal administration is a predictable consequence of administering a known compound by a disclosed route.
Applicant argues that Example 2 of the specification presented in Table 2, demonstrates that intranasal NAC administration leads to statistically significant increases in brain GSH levels as measured by MR spectroscopy in human subjects, necessary for secondary consideration, and sufficient to overcome the prima facie case of obviousness set forth in the office action filed on 10/07/2025.
The burden of demonstrating a secondary consideration such as unexpected results belongs to Applicant. The following factors are considered in determining whether the burden to establish unexpected results worthy of secondary considerations has been met:
(1) Evidence must show unexpected results MPEP §716.02 (a);
(2) Results are of statistical and practical significance MPEP §716.02 (b) (I);
(3) Applicant explains evidence presented MPEP §716.02 (b) (II);
(4) Evidence is appropriately comparative MPEP §716.02 (b) (III);
(5) Evidence is weighed against prima facie case of obviousness MPEP §716.02 (c) (I);
(6) Results are commensurate in scope within the instant claims MPEP §716.02 (d);
In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986)
In re Waymouth, 499 F.2d 1273, 1276, 182 USPQ 290, 293 (CCPA 1974)
In re Wagner, 371 F.2d 877, 884, 152 USPQ 552, 560 (CCPA 1967)
Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)
UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023)
Upon consideration of the Applicant arguments, the evidence in the instant specification, as well as the amendments filed on 02/09/2026, the Examiner has determined that Applicant has not met their burden for the reasons and stated hereinafter.
Applicant has not met their burden because according to MPEP § 716.02 (a), in order to overcome a prima facie case of obviousness Applicant must submit evidence which shows results which are greater than expected. According to MPEP § 716.02 (a) (III),
III. PRESENCE OF AN UNEXPECTED PROPERTY IS EVIDENCE OF NONOBVIOUS
Presence of a property not possessed by the prior art is evidence of nonobviousness. In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (rejection of claims to compound structurally similar to the prior art compound was reversed because claimed compound unexpectedly possessed anti-inflammatory properties not possessed by the prior art compound); Ex parte Thumm, 132 USPQ 66 (Bd. App. 1961) (Appellant showed that the claimed range of ethylene diamine was effective for the purpose of producing "‘regenerated cellulose consisting substantially entirely of skin’" whereas the prior art warned "this compound has ‘practically no effect.’ "). The submission of evidence that a new product possesses unexpected properties does not necessarily require a conclusion that the claimed invention is nonobvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979).
According to Applicant arguments filed on 02/09/2026, in reference to the evidence presented in the specification specifically regarding Example 2, Applicant argues that the results are significant. The Examiner disagrees with the assessment for the following reasons: Applicant’s data presented in Examples 1 and 2 are not comparative. Specifically, Example 2 focuses on the administration of NAC intranasally to healthy control subjects, and not patients diagnosed with COVID-19, as an Example 1. Furthermore, the studies employ different nasal delivery devices across two study periods, further undermining the reliability and conclusiveness of the presented results. Accordingly, Applicant has not demonstrated that intranasal administration of NAC is effective in COVID-19 patients. According to MPEP § 716.02 (b) (I),
I. BURDEN ON APPLICANT TO ESTABLISH RESULTS ARE UNEXPECTED AND SIGNIFICANT
The evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength “are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.”); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).
The practical significance of the data is not demonstrated by the comparative examples, nor by the arguments of Applicant’s counsel. According to the instant specification Applicant’s elected comparative compositions are not comparative to the closest prior art, as Example 2 evaluates intranasal NAC administration only in healthy control subjects at doses far lower than those of the oral administration disclosed in Example 1. Additionally, the comparative composition is not comparative to the closest prior art, Spadavecchia, as example 2 compares intranasal NAC only to a pre-administration baseline, without any direct comparison to any other administration method. The combined effect of different nasal delivery devices employed across study periods (mucosal atomizer in Study Period 1 vs. multi-dose pump in Study Period 2), different subject populations, and different measurement time points, means that there are at least 3 variables which could contribute to the alleged unexpected result.
Furthermore, Applicant has failed to meet their burden because according to MPEP § 716.02 (b) (II), Applicant must offer an explanation of all submitted data, and explain why the results are unexpected.
II. APPLICANTS HAVE BURDEN OF EXPLAINING PROFFERED DATA
“[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness.” Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992).
Applicants have provided data within the instant specification which Applicants allege to contain unexpected results. The Examiner disagrees that these results are sufficient to meet Applicant’s burden because Applicants have not explained why the results are unexpected. Applicants have not provided conclusive explanation as to which altered parameter such as the use of nasal delivery devices, subject populations, and measurement time points across as to study periods within the experiments led to the presented results. According to the analysis above, not only are the results not directly comparative, whatsoever, the results are not unexpected in any way, as it is widely known that if NAC is administered, GSH levels will increase in brain tissue, according to Reyes.
Furthermore, Applicant has failed to meet their burden according to MPEP § 716.02 (b) (III), which states that Applicant must identify the property directly attributable to the presented results by way of comparison to the closest prior art.
III. DIRECT AND INDIRECT COMPARATIVE TESTS ARE PROBATIVE OF NONOBVIOUSNESS
Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness.
“In order to establish that the claimed intermediate is a ‘contributing cause’ of the unexpectedly superior activity or property of an end product, an applicant must identify the cause of the unexpectedly superior activity or property (compared to the prior art) in the end product and establish a nexus for that cause between the intermediate and the end product.” Id. At 479.
Because the patients of Example 2 are healthy patients, this may directly contribute to the alleged unexpected results, more than any factors such as intranasal administration route of NAC. Thus, the examples of the specification are not comparative to the closest prior art, nor are the results presented unexpected in any way.
Furthermore, according to MPEP § 716.02 (c), Applicant has the burden of weighing the strength of the alleged unexpected results against the strength of the prima facie case of obviousness set forth by the Examiner,
I. EVIDENCE OF UNEXPECTED AND EXPECTED PROPERTIES MUST BE WEIGHED
Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) The court held the evidence of nonobviousness was not sufficient to rebut the evidence of obviousness.); See MPEP § 716.01(d) for guidance on weighing evidence submitted to traverse a rejection.
Applicant has not submitted newly presented arguments which discuss the results presented in the instant specification in light of the teachings of the prior art detailed in the prima facie case of obviousness set forth in the office action filed on 10/07/2025.
Finally, according to MPEP § 716.02 (d), Applicant has failed to demonstrate that the results are commensurate in scope with the instant claims. According to MPEP § 716.02 (d),
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.
The compositions have only been tested against a limited number (3) of healthy patients. Furthermore, independent claim 1 recites no specific critical range of NAC, or a specific metric of GSH to be achieved. The results presented in the instant specification test simply a single data point of concentration administered. Thus, no trend in the data can be reasonably be established which correlates to the vast scope of the instant claims. Furthermore, the independent claim 1 contains the word “comprising”, meaning that any un-recited additional variable can contribute to the alleged results. As such, the data is not commensurate in scope with the instant claims at least because of the use of the terminology “comprising”.
Thus, applicant has failed to meet the burden to: (1) demonstrate that any asserted unexpected results are significant and unexpected; (2) adequately explain the results presented; (3) weigh against the strength of the prima facie case of obviousness; (4) demonstrate the results are commensurate in scope with the instant claims. Applicant has failed to establish that the results presented are directly attributable to the instantly claimed composition and not on a parameter such as the GSH levels of healthy patients instead of patients affected by COVID-19, as well as a variety of other altered factors, which may be the greatest contributing factor and is therefore, obvious.
According to MPEP § 716.02 (e), Applicant may rebut a case of prima facie case of obviousness by direct comparison of their claimed composition with the closest prior art. The teachings of Spadavecchia according to the nonfinal rejection filed 10/07/2025, appear to be closer prior art than the comparative examples provided within the instant specification. Namely the treatment of patients affected with coronavirus is more closely related to the instant claims than that used in Applicant’s comparison. According to MPEP § 716.02 (e),
An affidavit or declaration under 37 CFR § 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential).
However, Applicant is entitled to submit a comparison of the results with prior art that is closer than that applied by the Examiner. According to MPEP § 716.02 (e) (I),
I. THE CLAIMED INVENTION MAY BE COMPARED WITH PRIOR ART THAT IS CLOSER THAN THAT APPLIED BY THE EXAMINER
Applicants may compare the claimed invention with prior art that is more closely related to the invention than the prior art relied upon by the examiner. In re Holladay, 584 F.2d 384, 199 USPQ 516 (CCPA 1978); Ex parte Humber, 217 USPQ 265 (Bd. App. 1961) (Claims to a 13-chloro substituted compound were rejected as obvious over nonchlorinated analogs of the claimed compound. Evidence showing unexpected results for the claimed compound as compared with the 9-, 12-, and 14- chloro derivatives of the compound rebutted the prima facie case of obviousness because the compounds compared against were closer to the claimed invention than the prior art relied upon.).
However, no such comparison with the prior art of record, or with any other prior art that is closer than that applied by the Examiner has been set forth. For the reasons outlined above, the comparisons set forth in the instant specification are not direct and do not isolate variables.
Applicants are reminded that “attorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965).
Accordingly, the rejection remains unsupported by the evidence herein presented, and the rejection is thus, maintained.
Regarding the rejections of Claim 9 rejected under 35 U.S.C. § 103 as being unpatentable over Spadavecchia and further in view of Pinna (Authorea, Hypothesis Paper, published May 11, 2020); ii) Claims 10 and 11 rejected under 35 U.S.C. § 103 as being unpatentable over Spadavecchia, and further in view of Deeks et al. (Cochrane Database of Systematic Reviews 2020, Issue 4. Article No.: CD013596, published April 24, 2020), hereinafter Deeks; iii) Claims 12-14 rejected under 35 U.S.C. § 103 as being unpatentable over Spadavecchia, and further in view of Merkus et al. (Adv Drug Deliv Rev, Volume 36, Issue 1, pages 41-57 published March 1, 1999), hereinafter Merkus; and iv) Claims 16 and 17 rejected under 35 U.S.C. § 103 as being unpatentable over Spadavecchia, and further in view of Herzenberg (The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine. Adis, Singapore, published September 21, 2018), and Goldstein (US 20090234011 A1, published September 17, 2009), no additional arguments have been presented in Applicant to address the rejections. The rejections are hereby amended to include the teachings of Reyes to address the amendments to the independent claim. As such, the rejections are hereby maintained.
Status of Claims
Claims 1-4 and 8-20 are pending in the instant application. Claim 15 is withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected species. Therefore, claims 1-4, 8-14, and 16-20 are being examined as they read on the elected species.
Drawings
The drawings filed on 02/09/2026 are found to be in compliance with 37 CFR §§ 1.121 and 1.84, and are hereby accepted.
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of pre-AIA 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.
Claims 1-4, 8, and 18-20 are rejected under 35 U.S.C. § 103 as being unpatentable over Spadavecchia et al. (WO 2021205083 A2, published October 14, 2021, effectively filed April 11, 2020, for the purpose of 102 (a)(2)), hereinafter Spadavecchia in view of Reyes et al. (Neurotherapeutics, Volume 13, Issue 1, pages 217-225, published November 16, 2015), hereinafter Reyes. Citations are directed to the Espacenet English translation of the French document by Spadavecchia.
The instant claims are drawn to a method of treating a disease or disorder associated with a coronavirus infection comprising intranasally administering to a human subject infected with a coronavirus an effective amount of at least one antioxidant compound or a pharmaceutically acceptable salt thereof, such as N-acetyl cysteine (NAC) in a total daily dose of from about 0.001 to about 900 mg/kg, which is about 0.06 mg to about 54 g per day for a 60 kg subject.
Spadavecchia teaches the treatment/prevention of SARS-CoV-2 infection using an antioxidant active agent, N-acetyl cysteine (NAC) (claim 1, paragraph [0379]), and expressly includes intranasal administration among the selectable routes (claim 2). Spadavecchia specifically teaches N-acetylcysteine combined with glutathione or other anti-inflammatory agents for the prevention and treatment of COVID-19 ([0148] [0150] [0161]-[0169]). Spadavecchia specifically teaches administration of BHT alone or in combination with NAC and GSH which can be administered orally, intranasally (in) or intravenously for the treatment or prevention of SARS-CoV-2 [0384].
The disclosure specifically details that the administration of NAC in patients infected with SARS-CoV-2, both symptomatic and asymptomatic (paragraph [0382]). Spadavecchia teaches wherein the dose of NAC is administered in a dose of 200 mg or 300 mg (paragraph [0385]), wherein dose (x) can be per kg body weight (paragraph [0054]) per day. In a 60 kg person, this dosage is equivalent to 3.33 mg/kg per day or 5 mg/kg/day of NAC (which is within the range taught in the instant specification). The disclosure further teaches that the composition may further comprise an anti-inflammatory agent (paragraph [0016], see instant claim 8). The doses provided in the disclosure may be administered for a duration of at least 7-30 days, and the duration of time can be multiplied by 2-12 times (paragraph [0175], see instant claim 18). The disclosure specifically highlights the need for new prophylactic and/or therapeutic solutions against coronavirus infections, particularly COVID-19 (paragraph [0014], see instant claim 19). Finally, the disclosure provides protocols for the treatment of mild forms of COVID-19 (paragraph [0736], see instant claim 20).
Spadavecchia does not specifically teach NAC administration by intranasal administration.
However, throughout the disclosure, it is stated that the antioxidants—including NAC—may be administered orally, intranasally (in), or intravenously for the treatment or prevention of SARS-CoV-2 (paragraph [0384]).
Furthermore, Spadavecchia does not specifically teach a dose which is specifically effective to elevate GSH levels in the brain.
The deficiencies of Spadavecchia are remedied by Reyes, who teaches that oxidative stress contributes to the pathogenesis conditions which affect the central nervous system, and GSH is depleted in these conditions (page 223). Reyes teaches that NAC supports neuronal GSH synthesis by supplying cysteine, the rate limiting substrate for GSH production (page 223). Reyes further discloses that specific concentrations of NAC are capable of normalizing neuronal GDH content and antioxidant capacity in the brain (Figure 2, pages 223-234). Accordingly, the functional outcome of elevating brain GSH levels is a well-known, and predictable consequence of NAC administration. As such, Reyes teaches that elevation of GSH is a predictable and well known consequence and outcome of NAC administration. Accordingly, the functional limitation of a dose effective at increasing GSH levels in the brain does not confer patentability over the prior art.
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art based on the teachings of Spadavecchia to administer the antioxidant NAC by intranasal administration with a reasonable expectation of predictable results in increasing GSH in the brain. An ordinary skilled artisan would have been motivated to select intranasal administration with a reasonable expectation of similar success as compared to the other routes of administrations disclosed therein, in order to achieve the functional effect of increasing GSH levels in the brain, to modulate the oxidative stress caused by coronavirus infection, which affects the central nervous system. Thus the administration of NAC by intranasal administration to increase GSH is rendered obvious in view of the cited prior art teachings.
Regarding claim 1, Spadavecchia teaches dosages of NAC which are within the range as claimed, i.e. 200 or 300 mg per day (equivalent to 3.33 mg/kg or 5 mg/kg (paragraph [0385]), which overlaps with the ranges taught within the instant specification to increase GSH in the brain (200mg/ml, see paragraph [0050] in the instant specification). Thus, the prior art teachings of Spadavecchia would inherently result in the increase GSH levels in the brain as the ranges taught by the prior art overlap with those demonstrated within the instant specification. It is noted that the courts have stated,
where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01).
The courts have also found that,
“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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II.
Therefore, the claimed dosage effective to elevate GSH levels in the brain merely represents an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 4, wherein the claim is drawn to administration of doses effective to loosen sputum in the lungs—Spadavecchia teaches administration of dosages of NAC that are within the range as taught by the instant specification, and therefore said dosages taught in the prior art will necessarily have the same effects as claimed—to loosen sputum in the lungs.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Claim 9 is rejected under 35 U.S.C. § 103 as being unpatentable over Spadavecchia (see earlier citation), in view of Reyes (see earlier citation), as applied to claims 1-4, 8, and 18-20 above, and further in view of Pinna (Authorea, Hypothesis Paper, published May 11, 2020).
Claim 9 of the instant application is drawn to treating a disease or disorder associated with the coronavirus infection comprising the intranasal administration of an antioxidant compound, N-acetyl cysteine (NAC), and further comprising the administration of the elected species, progesterone.
The teachings of Spadavecchia and Reyes are as set forth above.
Spadavecchia nor Reyes teach administration of progesterone.
Pinna teaches wherein reproductive steroids, specifically progesterone, exert anti-inflammatory actions and influence the immune system. The teachings suggests that reproductive steroids’ anti-inflammatory effects and their role in reshaping competence of immune cells (Abstract). Progesterone it is taught by Pinna to play significant role in suppression of cellular cytotoxicity (page 2). Pinna further discloses that progesterone binds to receptors in immune cells (page 2). Pina teaches that these and other actions of progesterone may be significant in protecting against COVID-19 and suggest that these steroids may offer a treatment to improve COVID-19 symptoms (page 4).
Accordingly, prior to the effective filing date of the claimed invention, a person of ordinary skill in the art would have been motivated to co-administer NAC with progesterone, to adjust to the well-recognized drivers of coronavirus morbidity—oxidative stress (addressed by the anti-inflammatory properties of NAC as taught as by Spadavecchia), and this regulated inflammation/immune signaling (addressed by progesterone, as taught by Pinna)—in the same population, with a reasonable expectation of additive, predictive benefit. Selecting adjunct agents with complementary mechanisms for the common purpose, i.e., treating coronavirus in diseases or disorders associated with the infection, is considered obvious. According to MPEP 2144.06 (I), combining compositions known for the same purpose is rendered obvious. The courts have said,
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 re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.).
Because NAC and progesterone are each taught as treating COVID-19 related pathology, a person of ordinary skill in the art would find it obvious to administer them to the same patients to obtain predictable, complementary effects, rendering the combination obvious.
Claims 10 and 11 are rejected under 35 U.S.C. § 103 as being unpatentable over Spadavecchia (see earlier citation), in view of Reyes (see earlier citation), as applied to claims 1-4, 8, and 18-20 above, and further in view of Deeks et al. (Cochrane Database of Systematic Reviews 2020, Issue 4. Article No.: CD013596, published April 24, 2020), hereinafter Deeks.
Claims 10 and 11 are drawn to a method of treating a disease or disorder associated with the coronavirus infection wherein the disease or disorder associated with coronavirus infection is a central nervous system disease, elected to be confusion, comprising the intranasal administration of NAC.
The teachings of Spadavecchia and Reyes are as set forth above.
Spadavecchia nor Reyes specifically teach treating confusion associated with coronavirus infection. However, regarding central nervous system symptoms associated with COVID-19, Spadavecchia does teach treating headache, dizziness, and anosmia within the disclosure (see for example [0184] and [0442]).
Regarding claims 10 and 11, the deficiencies of Spadavecchia in teaching confusion as being associated with SARS-CoV-2 infection are remedied by Deeks, who teaches a number of signs and symptoms in the initial diagnosis of suspected SARS-Cov-2 infection (page 3). Deeks specifically teaches confusion as one of the key symptoms associated with mild to moderate COVID-19 infection, i.e. a specific species of the genus of central nervous system disease.
In view of Deeks, a person of ordinary skill in the art would be motivated to apply the teachings of Spadavecchia intranasal antioxidant regimen administered to COVID patients presenting with confusion—a central nervous system manifestation of the same disease—to reduce oxidative stress/neural inflammation, and thereby ameliorate that symptom with a reasonable expectation of predictable success. A person of ordinary skill in the art prior to the effective filing date of the instant claims would have found it obvious to treat confusion related to coronavirus infection because Deeks establishes confusion as a common COVID-19 related CNS manifestation.
Moreover, since Spadavecchia specifically teaches treating COVID-19 infection including treating the symptoms of COVID-19 infection comprising the administration of the same NAC antioxidant as claimed, and confusion is a symptom of COVID-19 infection as taught by Deeks, the method of Spadavecchia will necessarily treat the confusion associated with COVID-19 infection. Thus, administration of the same compound for the treatment of the same disorder will necessarily treat the same symptoms as claimed.
Thus claims 10 and 11 are rendered obvious in view of the cited prior art teachings.
Claims 12-14 are rejected under 35 U.S.C. § 103 as being unpatentable over Spadavecchia (see earlier citation), in view of Reyes (see earlier citation), as applied to claims 1-4, 8, and 18-20 above, and further in view of Merkus et al. (Adv Drug Deliv Rev, Volume 36, Issue 1, pages 41-57 published March 1, 1999), hereinafter Merkus.
Claims 12-14 are drawn to a method of treating a disease or disorder associated with the coronavirus infection comprising the intranasal administration of an antioxidant, further comprising the administration of an agent for enhancing the delivery of the antioxidant compound, elected in this case to be 2-hydroxypropyl-beta-cyclodextrin (HPBCD), a cyclodextrin.
The teachings of Spadavecchia and Reyes are as set forth above.
Spadavecchia nor Reyes teach further administering the elected species, HPBCD.
The deficiencies of Spadavecchia and Reyes are remedied by Merkus, who teaches cyclodextrins used to improve the nasal absorption of drugs, through increased absorption, aqueous solubility, and enhanced nasal absorption resulting in greater transport across the nasal mucosa (Abstract). Specifically, the elected species HPBCD has been used as a solubilizer in combination with antiviral drugs (page 43). Furthermore, Merkus teaches that amino acid-containing drugs have seen success in absorption enhancement in combination with cyclodextrins (page 44-46, Table 1).
Therefore, a person of ordinary skill in the art prior to the effective filing date of the instant claims would have found it obvious to incorporate HBPCD into the intranasal use of NAC, because cyclodextrins are routinely employed to enhance dissolution, permeability, and uptake of comparable drug molecules across the nasal mucosa. Given the disclosure that HPBCD improves absorption of amino acid-based therapeutics, it would’ve been predictable refinement of the method outlined by Spadavecchia to treat coronavirus.
Claims 16 and 17 are rejected under 35 U.S.C. § 103 as being unpatentable over Spadavecchia (see earlier citation), in view of Reyes (see earlier citation), as applied to claims 1-4, 8, and 18-20 above, and further in view of Herzenberg (The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine. Adis, Singapore, published September 21, 2018), and Goldstein (US 20090234011 A1, published September 17, 2009).
The instant claims are drawn to a method of treating a disease or disorder associated with coronavirus infection comprising the intranasal administration of NAC and further comprising the administration of an agent for alleviating odor comprising one or more sweetening, flavoring, or perfuming agents, or an additive that prevents or slows oxidation of the antioxidant, elected to be NAC.
The teachings of Spadavecchia and Reyes are as set forth above.
Spadavecchia nor Reyes teach further including an agent for odor alleviation, sweetening, flavoring, perfuming, or an agent that slows or minimizes the oxidation of the antioxidant.
The deficiencies of Spadavecchia and Reyes are remedied by the teachings of Herzenberg. Herzenberg discloses wherein NAC is readily oxidized to foul-tasting products, developing a foul smell that patients commonly find repulsive (page 3). It is further disclosed that manufacturers have succeeded in producing and packaging NAC under conditions that minimize its oxidation to decrease the foul tasting contaminants in the product (page 3).
Herzenberg does not disclose a specific agent to prevent the oxidation of NAC.
The deficiencies of Herzenberg are further remedied by the teachings of Goldstein, who explicitly teaches use of food additives that can be added in combination with NAC as preservatives, antioxidants, and flavor enhancers. Specifically, Goldstein teaches the use of citric acid, lactic acid, vitamin C, vitamin D, starch, agar, or pectin for the purposes of jointly reducing oxidation and improving the flavor of NAC-containing compositions.
Therefore, a person of ordinary skill in the art, prior to the filing date of the instant claims, following the teachings of Spadavecchia would have been directly motivated to include an agent which would slow the oxidation of NAC, according to the teachings of Herzenberg. In light of specific agents taught by Goldstein to reduce NAC oxidation and improve flavor, it would have been an obvious and routine step to incorporate such agents to stabilize and improve the taste of the composition.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new grounds 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.
Correspondence
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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