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 Status
Claims 13-16, 19, 23, 25-40 and 42-61 are cancelled.
Claims 1-12, 17, 18, 20-22, 24 and 41 are pending. Applicants’ amendment has necessitated new ground of rejection. Accordingly, this Action is FINAL.
Withdrawn rejections
Applicants’ amendments and arguments filed 7/16/26 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn. Claim 22 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph; Claim(s) 1-2 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Arnold et al. (Nitric Oxide 2002;7:103-108); and claim(s) 1-6 , 9, 12, 17, 22 and 24 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Weichsel et al. (PNAS 2005;volume 102(3):594-599). Applicants’ amendments and arguments are persuasive.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-12, 17-22, 24 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Doxey et al. (US20190290681) and Doxey et al. (US20160256484; hereinafter Doxey2016; IDS filed 6/12/24) and Lulla et al. (US6962691) and Gonzalez et al. (US10413926).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims, for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a nitric oxide delivery research scientist who possesses interdisciplinary knowledge combining chemistry, materials science, and biology. That includes developing strategies to deliver nitric oxide in a controlled, sustained, and targeted manner to treat pathological conditions. Such an artisan has thorough knowledge of conventional compounds/materials that store and release nitric oxide as well as delivery vehicles for formulation with the NO donors. One can assume comfortably that such an educated artisan will draw conventional ideas from these areas— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1-7, 12 and 24, Doxey et al. teach compositions of a nitric oxide releasing active pharmaceutical agent and about 0.1-30% buffering agent buffer (Claims 1-2 and 11 and 35) where a pH range of a pH of about 3 to about 8 or any range and/or individual value therein, such as, but not limited to, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 7, about 5 to about 7, or about 6 to about 7 [0066-0067], which would read on at least an initial pH of about 4.5 to about 6, with one or more buffering agents including a citrate such as sodium citrate or calcium citrate and citric acid [0064] in amount of about 0.01% to about 20% by weight of the composition including about 1%, 1.5%, 2.5%, and 4% [0065]. It is the Examiner’s position that sodium citrate is understood by the artisan to encompass sodium citrate tribasic Na3C6H5O7 as well as the dihydrate thus rendering obvious about 1 to about 2.5% w/w sodium citrate tribasic and/or trisodium citrate dihydrate in an amount of about 1.5% to about 4% by weight. Doxey et al. teach a NO-releasing co-condensed silica particle (Claim 11; [0030, 0103, 0108-0113]). Regarding the limitation of “wherein the composition is configured to be sprayed and/or is a sprayable composition”, Doxey et al. teach a topical composition [0037] and expressly teach: “the admixture may be administered to the nail and/or skin of a subject…and/or configured for application to the nail and/or skin of a subject.” [0011] Doxey et al. teach that in some embodiments, the composition can be a film-forming composition [0007, 0053, 0127] with a thickening film forming agent [0056]. Doxey et al. teach that the composition in admixture or kits can comprise a hydrogel with water in an amount of about 50% to about 99% by weight of the composition and a second composition of claim 1 (Claims 20, 35 and 43) and can be stored in a dual pump container or a dual dispensing container in a kit [0131, 0135]. Thus, in certain embodiments of Doxey et al. the composition of Doxey et al. is purposefully designed, hence configured to, for a dual dispensing pump device. The kits of Doxey et al. are configured to mix the first and second compositions to provide an admixture [0054, 0133-0136].
Regarding claim 9, the composition of Doxey et al. implicitly has particles of the NO-releasing active pharmaceutical ingredient suspended in the buffer. See also [0128]: “An admixture of the present invention may provide a structure suitable for suspending an API, such as, but not limited to, a particulate API and/or an insoluble API” And [0226].
Regarding claim 10, Doxey et al. teach compositions with about 0.1% to about 50% including 3% [0119] where 3% is equivalent to 30 mg/ml.
Regarding claim 11, Doxey et al. teach: “the particle size of a NO releasing API may be in a range of about 20 nm to about 20 μm or any range therein, such as, but not limited to, about 100 nm to about 20 μm or about 1 μm to about 20 μm.” [0118].
Regarding claim 18, Doxey et al. teach that a NO-releasing compound may store and/or release NO in an amount of about 0.15% to 10% to 20% by weight of the composition using real time in vitro release testing or nitric oxide release may be determined using a chemiluminescent nitric oxide analyzer. [0120].
Regarding claims 20-21, Doxey et al. teach tetraethyl orthosilicate (TEOS) [0111] and the aminosilanes MAPS and EAiB3 [0112] where the amino group is substituted by a diazeniumdiolate moiety as in: R"-N(NONO-X+ )-R'-Si(OR)3 [0114]. See also [0117]: “a co-condensed silica network comprising diazeniumdiolated methylaminopropyl trimethoxysilane (MAPS) and tetraethyl orthosilicate (TEOS).” Doxey et al. teach Nitricil™ which is formed from the co-condensation of N-methylaminopropyltimethoxysilane (MAP3), tetraethoyxysilane (TEOS) and N,N-methylaminopropyldiazeniumdiolate-trimethoxysilane sodium salt (MAP3-NONOate) via a sol-gel process. (Example 4; [0220]).
Regarding claim 22, since Doxey et al. claim treating/preventing viral, bacterial, protozoan and/or fungal infection in and/or on a subject by administration of a nitric oxide releasing macromolecule (Claims 52 and 67), then that amount is sufficient to induce apoptosis in virally infected cells and/or in an amount sufficient to reduce or eliminate viral replication. Especially when no degree of reduction is claimed.
Regarding claim 24, Doxey et al. teach kits comprising first and second compositions where the buffering agent is in one composition and the nitric oxide releasing API is separately in the second composition (Claims 43 and 1-2), thus having the components separately stored. As noted above, Doxey et al. teach that the composition can be stored in a dual pump container or a dual dispensing container in a kit [0131, 0135]. As evidenced by Gonzalez et al., dual chamber dispensers include spray dispensers (Title; Abstract; Figures 1 and 3). Thus, in certain embodiments of Doxey et al. the composition of Doxey et al. is purposefully designed, hence configured to, for a dual dispensing pump device that can be sprayed.
Regarding claim 41, Doxey et al. teach methods of treating and/or preventing viral, bacterial, protozoan and/or fungal pathogen infection in and/or on a subject by administration of a nitric oxide releasing macromolecule (Claims 52 and 67; [00147, 0149, 0154]).
Regarding claim 1-6, Doxey2016 teach citric acid/citrate buffers in a concentration of about 100 mmol to about 750 mmol or about 200 mmol to about 500 mmol and present from about 0.1 to about 20% by weight [0057-0058] that achieves a pH range of about 4 to about 6 [0054]. Doxey2016 teach anhydrous citric acid at pH 5.5 and 6.5 (Page 19, Table 9).
Regarding claims 1, 3 and 24, Lulla et al. teach topical film forming compositions provided as a spray (Abstract) and “The compositions are preferably in a form suitable for application by spraying from an aerosol or pump spray container… The metered dose of the composition is preferably dispensed by spraying the composition from a pump or aerosol spray dispenser.” (Column 2, lines 23-25, 40-43).
Regarding claims 1, 3 and 24, Gonzalez et al. teach dual chamber dispensers include spray dispensers (Title; Abstract; Figures 1 and 3).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
1. The difference between the instant application and Doxey et al. is that Doxey et al. do not expressly teach wherein the composition is configured to be sprayed and/or is a sprayable composition, a buffer that comprises a citrate and/or citric acid or an anhydrous form thereof in an amount of at least 100 mM or at least about 100 mM to about 300 mM buffer or a buffer that consists of water and citric acid and wherein the buffer and/or composition is devoid of a diluent a preservative, an antioxidant, a suspending agent, a penetration enhancer, a surfactant, a viscosity-increasing agent, a humectant, a stabilizer, and/or a wetting agent. This deficiency in Doxey et al. is cured by the teachings of Doxey2016 and Gonzalez et al. and Lulla et al.
1. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the composition of Doxey et al. wherein the composition is configured to be sprayed and/or is a sprayable composition, as suggested by Lulla et al. and Gonzalez et al., and with a buffer that comprises a citrate and/or citric acid or an anhydrous form thereof in an amount of at least 100 mM or at least about 100 mM to about 300 mM buffer or a buffer that consists of water and citric acid, as suggested by Doxey2016, and wherein the buffer and/or composition is devoid of a diluent a preservative, an antioxidant, a suspending agent, a penetration enhancer, a surfactant, a viscosity-increasing agent, a humectant, a stabilizer, and/or a wetting agent and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because Doxey et al. expressly teach that the composition is “configured for application to the nail and/or skin of a subject” [0007, 0010-0011, 0037] and thus is a topically applied composition and Doxey et al. suggest a film forming composition and suggest a dual dispensing container such as dual pump container. The combined references of Lulla et al. and Gonzalez et al. provide such a dual dispensing container where it is known through Lulla et al. that topical film forming compositions are sprayed onto the skin. Thus, the ordinary artisan would have a reasonable expectation of success in configuring the topical composition and kit of Doxey et al. to be sprayed as a sprayable topical film forming composition in the absence of evidence to the contrary. Regarding the buffer limitations, a buffer that comprises a citrate and/or citric acid in an amount of at least 100 mM or at least about 100 mM to about 300 mM buffer is known by Doxey et al. in view of Doxey2016 as the concentration of a citrate and/or citric acid buffer to employ in these compositions. Furthermore, Doxey2016 teaches anhydrous citric acid. The ordinary artisan would employ a citrate and/or citric acid or anhydrous form thereof in an amount of at least 100 mM or at least about 100 mM to about 300 mM buffer in the composition of Doxey et al. with a reasonable expectation of success.
With regard to the limitations of wherein the buffer consists of water and citric acid the buffer and/or composition is devoid of a diluent a preservative, an antioxidant, a suspending agent, a penetration enhancer, a surfactant, a viscosity-increasing agent, a humectant, a stabilizer, and/or a wetting agent, the Examiner has this position. Doxey et al. teach: “This process yields 5 μmol NO/mg of Nitricil™ NVN1 drug substance as determined via assessment of NO content under acidic conditions (pH 3)” [0220]. Doxey et al. do not describe the acidic conditions. However, it would be obvious to make an acidic citric acid aqueous solution at pH 3 and add the NO-releasing compound for testing NO release of the NO-releasing compound for at least comparative purposes with the inventive compositions with a reasonable expectation of success. Especially when Doxey et al. suggest citric acid and a pH of about 3 [0064, 0066]. Such a buffer would consist of water and citric acid and be devoid of other components. The ordinary artisan would do so with a reasonable expectation of success.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Response to Arguments:
Applicants’ arguments filed on 7/16/26 have been carefully considered but are not persuasive.
Applicant asserts that: “Doxey and Doxey 2016 both fail to disclose or suggest a composition that includes a nitric oxide-releasing active pharmaceutical ingredient that comprises a diazeniumdiolate functionalized co-condensed silica network and that is configured to be sprayed and/or is a sprayable composition.” Respectfully, the Examiner has a different perspective. The composition of Doxey et al. is for topical application configured for application to the nail and/or skin of a subject and include film forming embodiments. Doxey et al. teach and suggest using a dual pump/dispensing container. In looking to the art, the artisan finds Lulla et al. teaching that topical film forming compositions are applied as sprays and Gonzalez et al. teach a dual chamber spray dispenser pump. It is then obvious to configure the composition of Doxey et al. for spraying from the dual chamber spray dispenser pump to form a topical film with a reasonable expectation of success. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). In the present case, the combined references render obvious a composition as claimed configured to be sprayed and/or is a sprayable composition. Respectfully, Applicant’s arguments are not persuasive.
Conclusion
No claims are allowed.
Applicants’ 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Y Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613
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