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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-23 and the species “(c): contacting a solid reducing agent with gaseous NO to form HNO in the gas phase”, in the reply filed on 12/09/25 is acknowledged. Note that claim 23 is directed to “F-PA and “NO2-PA” which are defined as N-hydroxy-4-nitrobenzenesulfonamide (NO2-PA) and N-hydroxy-4-fluorobenzenesulfonamide (F-PA) (USPGPUB [0010] and refer to non-elected base catalyzed HNO donor species.
Claims 2-12, 20, 21 and 23-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/9/25.
Claim Status
Claims 1-29 are pending.
Claims 2-12, 20, 21 and 23-29 are withdrawn.
Claims 1, 14-19 and 22 are presented for examination as they read upon the elected subject matter.
Priority
PNG
media_image1.png
96
1094
media_image1.png
Greyscale
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/16/25 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fine et al. (US20120285449).
Regarding claim 1, Fine et al. disclose methods of contacting a gas flow of nitric oxide gas with a reducing agent [0123] and a kit/system comprising a gas source of nitric oxide and a reducing agent (Claims 20-23; Figure 3) where the reducing agent includes a hydroquinone, glutathione, and/or one or more reduced metal salts such as Fe(II), Mo(VI), NaI, Ti(III) or Cr(III), a thiol, and an antioxidant such as ascorbic acid can be used dry or wet [0026] or in powder form ([0104]; Figure 4 [0097), hence a solid reducing agent. Fine et al. report an embodiment with moist silica gel coated with ascorbic acid [0100-0101]. The Examiner notes that Applicant also teaches a moist solid for the reaction between cysteine and gaseous NO (Example 4, [0254]. Figure 4 of Fine et al. also represents an embodiment with reducing agent ascorbic acid [0097]. Consequently, it is the Examiner’s position that the moist silica gel coated with ascorbic acid reads on the claimed solid reducing agent. The method and normal and usual operation of the delivery system of Fine et al. must result in formation of nitroxyl in the gas phase in the ordinary use of the method and system of Fine et al., which contacts gaseous nitric oxide with a solid reducing agent. "[A] prior art reference may anticipate when the claim limitation or limitations not expressly found in the reference are nonetheless inherent in it." MEHL/Biophile Int'l Corp. v. Milgraum, 192 F.3d 1362, 1364 (Fed.Cir.1999). "Under the principles of inherency, if the prior art necessarily functions in accordance with, or includes, the claims limitations, it anticipates." Id.; see also In re King, 801 F.2d 1324,1326-28 (Fed.Cir.1986). As noted above, "a prior art reference may anticipate when the claim limitation or limitations not expressly found in the reference are nonetheless inherent in it." Id. An inventor may not obtain a patent on a method of using that patented composition unless that method is "useful and nonobvious." Catalina Marketing Int'l, Inc. v. Coolsavings.com. Inc., 289 F.3d 801, 809 (Fed.Cir.2002). Said differently, "`if a previously patented [composition], in its normal and usual operation, will perform the function which an appellant claims in a subsequent application for process patent, then such application for process patent will be considered to have been anticipated by the former patented [composition].'" In re King, 801 F.2d at 1326 (quoting In re Ackenbach, 18 C.C.P.A. 769, 45 F.2d 437, 439 (Cust. & Pat.App.1930)). See also MPEP 2112.02(I).
Therefore, it is already known in the art to perform a method of contacting NO gas with a solid reducing agent and to have a delivery system comprising gaseous NO and a solid reducing agent that inherently produces nitroxyl in the gas phase even if Fine et al. did not recognize it. See MPEP 2112 II: “II. INHERENT FEATURE NEED NOT BE RECOGNIZED AT THE TIME OF THE INVENTION There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).”
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 and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Fine et al. (US20120285449) in view of Ellis et al. (British Journal of Pharmacology (2000) 129, 315 - 322) and Kumar et al. (Nitric Oxide 77 (2018) 96–105) and Saurez et al. (J. Am. Chem. Soc. 2015, 137, 4720−4727).
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:
PNG
media_image2.png
468
1096
media_image2.png
Greyscale
It is well settled that “a disclosure that anticipates under § 102 also renders the claim invalid under §103, for anticipation is the epitome of obviousness. See MPEP 1207.03(a)(II) states: “"lack of novelty is the epitome of obviousness." May, 574 F.2d at 1089, 197 USPQ at 607 (citing In re Pearson, 494 F.2d 1399, 1402, 181 USPQ 641, 644 (CCPA 1974))”. Accordingly, the claims rejected under §102 above are also invalid under §103.
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 research chemist focusing on synthesizing stable HNO-donating compounds with an interest in therapeutic applications of controlled HNO production. Such an artisan will have knowledge of inorganic chemistry to understand nitrogen oxides and their reactivity and analytical techniques to quantify HNO produced such as spectroscopic techniques including UV-vis, IR, chemiluminescence and Mass Spec to observe HNO formation and decay.
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, 14 and 16, Fine et al. teach methods of contacting a gas flow of nitric oxide with a reducing agent [0123] and a delivery system comprising a gas source of nitric oxide and a reducing agent (Claims 20-23; Figure 3) where the reducing agent includes a hydroquinone, a thiol, glutathione, and/or one or more reduced metal salts such as Fe(II), Mo(VI), NaI, Ti(III) or Cr(III), a thiol, and an antioxidant such as ascorbic acid can be used dry or wet [0026] in powder form ([0104]; Figure 4 [0097), hence a solid reducing agent. Fine et al. report an embodiment with moist silica gel coated with ascorbic acid [0100-0101]. It is the Examiner’s position that “moist” indicates the presence of H2O.
Regarding claims 1 and 14, Suarez et al. teach that “Azanone (HNO/NO−), also called nitroxyl, is the one electron reduction product of NO” (Page 4720, Introduction left column). Suarez et al. state: “The present work provides clear evidence of a possible biochemically relevant HNO source, resulting from the reaction of NO with aromatic or “pseudoaromatic” alcohols such as tyrosine, ascorbic acid, and hydroquinone.” (Page 4725, Conclusions, left column). Consequently, the ordinary artisan is aware that NO can be reduced by reducing agents such as ascorbic acid to HNO.
Regarding claims 14 and 15, Kumar et al. teach that the artisan in this art understands the equivalence of biological reductants such as ascorbic acid, glutathione and dithionite (Abstract).
Regarding claim 15, Ellis et al. teach that nitric oxide may be reduced to nitroxyl in a reaction coupled to L-cysteine (Page 319, left column 1st paragraph).
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)
The difference between the instant application and Fine et al. is that Fine et al. do not expressly teach an embodiment with naringenin, Ni2+-naringin, cysteine or dithionite as the reducing agent. This deficiency in Fine et al. is cured by the teachings of Suarez et al., Kumar et al. and Ellis et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ the reducing agents naringenin, Ni2+-naringin, cysteine or dithionite, as suggested by Fine et al., Suarez et al., Kumar et al. and Ellis et al., in the method/delivery system of Fine et al. and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because Fine et al. not only suggest thiols such as glutathione but that: “Any appropriate antioxidant can be used depending on the activities and properties as determined by a person of skill in the art.” [0094] It is known through Ellis et al. that cysteine is a thiol reductant that can reduce nitric oxide to nitroxyl through Kumar the equivalence of biological reductants such as ascorbic acid, glutathione and dithionite, thus rendering these reductants as functional equivalents for their intended purpose. Further, it is known through Suarez et al. that “a possible biochemically relevant HNO source, resulting from the reaction of NO with aromatic or “pseudoaromatic” alcohols such as tyrosine, ascorbic acid, and hydroquinone.” Taken together, the ordinary artisan understands that HNO is the reduction product from nitric oxide and the claimed reductants/antioxidants such as an alcohol, thiol such as cysteine or reducing inorganic solid dithionite would achieve that reduction in the method of Fine et al. with a reasonable expectation of success. Selection of known antioxidants such as naringenin and/or Ni2+-naringin for the reductant appears arbitrary and would fall into the category of “any appropriate antioxidant can be used” teaching of Fine et al.
Claims 1 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Fine et al. (US20120285449), as applied to claim 1 above, in further view of Heinecke et al. (J. Am. Chem. Soc. 2013, 135, 4007−4017) and Paolocci et al. (Pharmacol Ther. 2007 February ; 113(2): 442–458) and Moller et al. ( J. Biol. Chem. (2019) 294(40) 14776–14802) and Suarez et al. (J. Am. Chem. Soc. 2015, 137, 4720−4727).
Applicant claims:
PNG
media_image3.png
402
1090
media_image3.png
Greyscale
The reference of Fine et al. is discussed in detail above.
Regarding claims 1 and 17-19, Suarez et al. teach that “Azanone (HNO/NO−), also called nitroxyl, is the one electron reduction product of NO” (Page 4720, Introduction left column). Suarez et al. state: “The present work provides clear evidence of a possible biochemically relevant HNO source, resulting from the reaction of NO with aromatic or “pseudoaromatic” alcohols such as tyrosine, ascorbic acid, and hydroquinone.” (Page 4725, Conclusions, left column). Consequently, the ordinary artisan is aware that NO can be reduced by reducing agents such as ascorbic acid to HNO.
Regarding claims 17 and 19, Heinecke et al. teach using FTIR spectrophotometer to detect N2O (Page 4008, Instrumental Methods) in combination with GC analysis (Page 4009, Nitrous Oxide as a Product; Scheme 3) because “nitroxyl (HNO) as an intermediate product that undergoes dehydrative dimerization to give N2O” (Page 4015; Summary). Thus, infrared measurement of N2O is an indirect measurement of HNO. Heinecke et al. also teach using a mass spectrometer to analyze reaction products (Page 4008, Instrumental methods).
Regarding claim 17, Paolocci et al. provide a review of the biologically relevant chemistry of HNO (Abstract) and teach that detection of N2O has been used as an indication of the presence of HNO (Page 10, 4. HNO Detection) and is thus an indirect monitoring of HNO in the gas phase.
Regarding claim 18, Moller et al. teach detection methods for nitroxyl which include measurement of dimerization product N2O, mass spectrometry, electrochemical sensors (Page 14785, Detection of nitroxyl; Page 14786, Figure 5).
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)
The difference between the instant application and Fine et al. is that Fine et al. do not expressly teach monitoring HNO in the gas phase directly by mass spectrometry or an electrochemical sensor or indirectly by using infrared spectroscopy. This deficiency in Fine et al. is cured by the teachings of Moller et al., Suarez et al., Paolocci et al. and Heinecke et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform the method of Fine et al. by flowing nitric oxide gas over a solid reducing agent, as suggested by Fine et al., and monitor for HNO in the gas phase directly by mass spectrometry or an electrochemical sensor or indirectly by using infrared spectroscopy, as suggested by Moller et al., Suarez et al., Paolocci et al. and Heinecke et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because it is known through the teachings of Suarez et al. that HNO is the 1 electron reduction product of NO that can be achieved with reductants such as ascorbic acid. As discussed above, the method of Fine et al. contacts NO gas with the reductant ascorbic acid. Consequently, with the combined references in hand there is a reasonable expectation of producing HNO in the method of Fine et al. It is then obvious for the artisan to monitor for any HNO produced in the method of Fine et al. such as with indirect measurement of HNO through infrared spectroscopy of the dimerization product N2O as suggested by Heinecke et al., Moller et al., and Paolocci et al., as well as by direct measurement with mass spectrometry or electrochemical sensors as suggested by Moller et al. The ordinary artisan is motivated to do so because HNO is a biologically relevant molecule as taught by Paolocci et al. and it is important to characterize any biologically relevant molecules formed in the method of Fine et al. that are administered to a patient. 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.
Allowable Subject Matter
Claim 22 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The following is a statement of reasons for the indication of allowable subject matter: Fine et al. teach away from heating the delivery system and teach that the system is free of heating devices (Claim 26; [0030]). There is no guidance in Fine et al. to heat the system.
Conclusion
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERNST V ARNOLD/Primary Examiner, Art Unit 1613