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 (along with hypertensive disease as the elected species) in the reply filed on 06/25/2026 is acknowledged. Accordingly, claim 9 and 18-22 have been withdrawn further consideration pursuant to 37 CFR 1.142(b).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1–8 and 10–17 are rejected under 35 U.S.C. § 112(a), first paragraph, because the specification, while enabling for a method of improving or treating certain specific conditions benefited by increased nitric oxide levels, does not reasonably provide enablement for the full scope of the claimed improvement, treatment, or prevention of the recited conditions.
The specification does not enable any person skilled in the art, to which the invention pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with the claims. See In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
In determining whether a disclosure satisfies the enablement requirement, the following factors are relevant: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of ordinary skill in the art; (5) the level of predictability in the art; (6) the amount of direction or guidance provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation necessary to make or use the invention. Id.
1. Breadth of the claims
The claims are broad and encompass the prevention, improvement, or treatment of numerous disease states and conditions associated with increased nitric oxide signaling or activity. Under the broadest reasonable interpretation, the term “prevent” encompasses keeping a condition from occurring or existing. Accordingly, the claims are construed to cover the prevention or treatment of a wide range of disease states, including conditions known in the art and potentially future-discovered conditions, for which the specification does not provide sufficient enabling disclosure.
2. Nature of the invention
The invention is directed to the pharmaceutical arts. The claims encompass treatment or prevention of a large number of diverse conditions, including cardiovascular disease, pulmonary hypertension, pulmonary arterial hypertension, acute pulmonary hypertension-associated lung disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, lung infection, congestive heart failure, systemic hypertensive disease, erectile dysfunction, heart attack, stroke, and atherosclerotic disease, among others. The specification does not provide enabling disclosure commensurate with this breadth.
3. State of the prior art and 4. Level of predictability in the art
The pharmaceutical arts are highly unpredictable. In general, screening in vitro and in vivo is required to determine whether a compound exhibits a desired pharmacological activity and whether that activity will translate into treatment or prevention of a particular disease or condition. There is no certainty that a compound shown to affect nitric oxide signaling will predictably treat all conditions recited in the claims.
For example, conditions such as coronary artery disease, pulmonary hypertension, and congestive heart failure remain conditions for which no cure is known. See, e.g., Cleveland Clinic Health Condition (Apr. 13, 2022); Mayo Clinic, “Pulmonary Hypertension” (Apr. 11, 2025); Cleveland Clinic, “Congestive Heart Failure” (Mar. 10, 2023). The fact that nitric oxide signaling is involved in numerous physiological processes, including cardiovascular function, metabolism, neurotransmission, and immunity, does not establish that modulation of nitric oxide will yield predictable therapeutic results across the full scope of the claimed diseases and disorders. See Lundberg et al., “Nitric oxide signaling in health and disease,” Cell 185 (Aug. 4, 2022), pp. 2853–2872.
5. Level of ordinary skill in the art
The level of ordinary skill in the art is relatively high; however, even a skilled artisan would not be able to practice the full scope of the claimed invention without undue experimentation because of the unpredictability of pharmacological effects across the broad range of claimed conditions.
6. Amount of direction or guidance provided by the inventor and 7. Existence of working examples
The specification provides insufficient direction or guidance for preventing or treating each of the numerous disease conditions encompassed by the claims. The disclosure does not adequately explain how the in vitro data, if any, correlates to the claimed prevention or treatment of the assorted disorders recited in the claims. No reasonably specific guidance is provided for the full scope of prophylactic or therapeutic protocols, including heart attack, memory decline, decline in physical performance, coronary artery disease, and other claimed conditions, other than a general statement that the conditions are benefited by increased nitric oxide levels.
The specification also lacks working examples commensurate in scope with the full breadth of the claims. In cases involving physiological activity, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
8. Quantity of experimentation necessary
A person of ordinary skill in the art would be required to engage in undue experimentation to determine which diseases or conditions can be treated or prevented by the claimed compositions or methods and under what circumstances. The claims are therefore broader than the enabling disclosure of the specification.
A patent is not a hunting license. It is not a reward for search, but compensation for successful conclusion. Genentech, Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001. Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.
Accordingly, in view of the Wands factors and In re Fisher, the specification does not provide an enabling disclosure commensurate in scope with the full breadth of claims 1–8 and 10–17. To practice the claimed invention, one of ordinary skill in the art would be required to engage in undue experimentation to determine which diseases or conditions may be treated or prevented by the claimed compounds or combinations, without a reasonable assurance of success.
Further, there is no evidence of record enabling the skilled artisan to identify the individuals who would be susceptible to the numerous diseases, disorders, or conditions recited in the claims, nor is there competent evidence or sufficiently predictive testing disclosed to demonstrate that the claimed compound(s) or combinations are effective for preventing or treating all such recited conditions. Therefore, claims 1–8 and 10–17 fail to comply with the enablement requirement of 35 U.S.C. § 112(a), first paragraph.
Claim Rejections - 35 USC § 102
(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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1–4, 7-8, 10, 13, 14 and 15 are rejected under 35 U.S.C. § 102(a)(1) as anticipated by Joel Friedman (US 2023/0069711 A1), hereinafter “Friedman.”
Regarding claims 1 and 10, Friedman discloses a device (e.g., reservoir) or composition for generating nitric oxide comprising a nitrite source and a proton source or thiol source such as NAC (see, e.g., paras. [0008]–[0011], [0014], [0036], [0048]. [0074]-[0080]). Friedman further teaches that the disclosed device or composition where said composition is loaded into the reservoir is administered or applied to a subject’s body, including a human subject, for the treatment of disease conditions benefited by increased nitric oxide levels, including pulmonary hypertension, erectile dysfunction, peripheral vascular disease, and acute vascular inflammatory conditions (see paras. [0025], [0114]). Friedman also teaches that administration of nitrite and NAC results in formation of SNO-NAC, also identified as SNOAC, and release of nitric oxide (see Examples).
The use of the open-ended transitional term “comprising” does not avoid anticipation where the prior art discloses all of the claimed limitations. Accordingly, claims 1 and 10 are anticipated by Friedman.
Regarding claim 2, Friedman discloses that “NO plays a key role in various biological pathways. For instance, it can supplement the reduced endothelial NO production…and the decreased production of endogenous NO that contributes to the progressive damage from escalating inflammation. NO is also essential for maintaining/restoring crucial tissue perfusion and oxygenation caused by an uncontrolled cytokine storm…” (para. [0113]). This disclosure expressly teaches that reduced endogenous NO is involved in the pathophysiology of multiple disease conditions and that such conditions are benefited by increased levels of NO. Therefore, claim 2 is anticipated by Friedman.
Regarding claims 3, 4, 13 and 14, Friedman teaches a device or composition that permits water- or moisture-initiated production and release of nitric oxide (NO) from a variety of reservoir materials suitable for use as carriers in a body cavity, including the skin, buccal cavity, mucosal tissues, and gums (see paras. [0018], [0024]). Friedman further teaches administration of the composition to a body cavity and/or orally, such that the composition is brought into contact with bodily fluids. Although Friedman does not expressly state that nitrite and NAC, when so administered, react with saliva or gastric acid to generate SNOAC, such result is inherent in the disclosed use because the same composition is administered in a manner that necessarily causes dissolution over time and contact with bodily fluids, including saliva and gastric acid. In the absence of evidence to the contrary, a reference anticipates a claim if the missing descriptive matter is necessarily present in the prior art disclosure, even if not expressly recognized. Accordingly, claims 3, 4, and 13 are anticipated by Friedman.
Regarding claim 8, Friedman expressly discloses sodium nitrite as a nitrite source (see para. [0048]). Friedman identifies sodium nitrate as one member of a finite and clearly delineated group of nitrite species. In view of this explicit disclosure, one having ordinary skill in the art would have immediately “envisaged” sodium nitrate as being within the scope of Friedman’s teaching. Therefore, claim 8 is anticipated by Friedman.
Regarding claim 15, Friedman teaches that the disclosed method provides delivery of nitric oxide systemically and locally to the subject (see paras. [0012], [0014]). Friedman further teaches administering the same nitrite/NAC composition to a bodily cavity, where SNOAC is produced. Such administration necessarily permits dissolution, absorption, and diffusion into the subject’s circulation. Accordingly, the systemic delivery recited in claim 15 is inherently disclosed by Friedman, and claim 15 is anticipated.
Accordingly, claims 1–4, 8, 10, 13, 14 and 15 are rejected under 35 U.S.C. § 102(a)(1) as anticipated by Friedman.
Claim 7 is rejected under 35 U.S.C. § 102(a)(1) as anticipated by Joel Friedman (US 2023/0069711 A1), hereinafter “Friedman,” and, to the extent necessary, as further evidenced by Nagababu et al., “Effect of Nitrite and N-acetylcysteine treatment on Blood Pressure, Arterial Stiffness and Vascular Function in Spontaneously Hypertensive Rats,” Free Radical Biology and Medicine, Vol. 112, Suppl. 1, November 2017, pp. 118–119, hereinafter “Nagababu.”
Friedman expressly discloses a device and/or composition for generating nitric oxide comprising a nitrite source and a proton source or thiol source, such as N-acetylcysteine (NAC) (see, e.g., paras. [0008]–[0011], [0014], [0036], [0048]). Friedman further teaches administration or application of the disclosed composition to a subject’s body for treatment of disease conditions that are benefited by increased nitric oxide levels, including pulmonary hypertension, erectile dysfunction, peripheral vascular disease, and acute vascular inflammatory conditions (see paras. [0025], [0114]). Friedman also expressly teaches that administration of nitrite and NAC results in formation of SNO-NAC, also referred to as SNOAC, and release of nitric oxide.
Where a reference discloses a composition and method of use, anticipation is established if the claimed result is necessarily present, even if not expressly recognized. Here, the use of the same nitrite/NAC composition in Friedman necessarily yields SNOAC and nitric oxide release in the subject, and the prior art method therefore inherently results in the claimed therapeutic effect of lowering blood pressure when administered to the same patient population. Nagababu further confirms that nitrite and NAC treatment lowers blood pressure and protects against hypertension-induced endothelial dysfunction. Accordingly, claim 7 is anticipated by Friedman, and the claimed blood-pressure-lowering result is inherent in the prior art disclosure.
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.
Claims 5-6, 11-12, 16 and 17 are rejected under 35 U.S.C. § 103 as being unpatentable over Joel Friedman (US 2023/0069711 A1), hereinafter “Friedman,” as applied to claims 1–4, 7-8, 10, 13, 14 and 15 as previously discussed.
The teachings of Friedman have been set forth above and are incorporated herein by reference for purposes of this rejection.
Regarding claims 5-6,
Although Friedman does not expressly recite the exact claim language of “slow-dissolving tablet,” or “rapid-release tablet, the reference teaches that nitric oxide-generating composition can be formulated in multiple delivery forms including a solid dosage, such as tablet, a hard or soft capsule, a pouch, a cachet, a troche, an ampule or a lozenge (para. [0063]) and that the rate of NO release can be controlled by formulation variables, including nitrite/thiol ratio, water/proton source, gelling agents, viscosity modifiers, particle encapsulation and separation of immediate-release and extended-release portions. In particular: para. [0056] and [0060] teach that mole ratio of nitrite/thiol ratio controls the rate and phase of NO release; [0073] expressly teaches a combination of immediate release and extended-release portions, yielding dural release profiles with an initial burst and sustained release; and [0074] teaches devices in the form of sponges, inserts, capsules, and frangible containers, including forms that release upon moisture uptake or rupture. Given these teachings, it would have been an obvious design choice to implement the immediate-release portion as a rapid-release tablet and the sustained-release portion as a slow-dissolving tablet, because tablets are a conventional oral dosage from for achieving either immediate or modified release.
Regarding claim 11,
Friedman teaches that dosage amount and frequency may be adjusted individually based on the subject, weight, severity of disease, route of administration and physician judgment (para. [0103]). Friedman also teaches that the NO-generating composition may provide extended release over hours, days, or even longer, and may increase systemic or local NO levels over periods of 1 day, 3 days, 7 days, 30 days or more ([0086]). Given those teachings, it would have been obvious to administer the device/composition on a regular schedule for at least 30 days because: i) sustained or chronic dosing is a routine approach for therapies intended to maintain therapeutic NO levels, ii) the prior art expressly contemplates prolonged treatment periods “30 days or more”, and iii) selecting a repeated schedule over a month would have been a routine optimization in a clinical setting.
Regarding claim 12,
Friedman teaches nitrite amounts spanning a broad range, including values that encompass the claimed sodium nitrite range, and teach that the dosage can be adjusted based on the desired NO level (para. [0048] The art also teaches that the molar ratio of nitrite to proton or thiol source can be controlled to modulate NO release (para. [0052], [0056]).
[0048] The nitrite source can be synthetic, natural, or a combination of synthetic and natural sources. Nonlimiting examples of the nitrite source include alkali metal nitrite, an alkaline earth metal nitrite, a transition metal nitrite and an ammonium nitrite. In some embodiments, the nitrite source is potassium nitrite, sodium nitrite, rubidium nitrite, strontium nitrite, barium nitrite, calcium nitrite, copper nitrite, zinc nitrite, or mixtures thereof. Nitrite can also be obtained from a natural source such as extracts of lettuce and spinach. In some embodiments, the amount of the nitrite source (calculated by the weight of the nitrite (NCh-) group) in the device or a unit dosage ranges from about 0.0001 mg to about 5000 mg, from about 0.001 mg to about 5000 mg, from about 0.01 mg to about 5000 mg, from about 0.1 mg to about 5000 mg, from about 1 mg to about 1000 mg, from about 10 mg to about 500 mg, or from about 10 mg to about 100 mg. Nonlimiting examples of the amount of the nitrite group in a dosage unit or in a device include about 0.0001 mg, about 0.0002 mg, about 0.0004 mg, about 0.0006 mg, about 0.0008 mg, about 0.001 mg, about 0.002 mg, about 0.004 mg, about 0.006 mg, about 0.008 mg, about 0.01 mg, about 0.02 mg, about 0.04 mg, about 0.06 mg, about 0.08 mg, about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.06 mg, about 0.08 mg, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, about 1 g, about 2 g, about 5 g, and about 10 g.
[0052] The amount of water source or proton source can be controlled to adjust the rate of NO release. In some embodiments, the amount of water or proton source ranges from about 0.2 to about 10 equivalents of the nitrite source, from about 0.5 to about 10 equivalent of the nitrite source, from about 0.2 to about 5 equivalent of the nitrite source, from about 0.5 to about 10 equivalent of the nitrite source from about 1 to about 5 equivalent of the nitrite source, from about 0.5 to about 2 equivalent of the nitrite source, or from about 0.5 to about 1.5 equivalent of the nitrite source.
[0056]The mole ratio between the nitrite in the nitrite source and the thiol in the thiol source ranges for example from about 50:1 to about 1:10, from about 5:1 to about 1:5, from about 2: 1 to about 1:5, from about 1 : 1 to about 1:5, from about 1 : 1 to about 1 :2, or from about 1:1 to about 1:3. By controlling the mole ratio, the rate of NO release can be modified and a sustained release phase can be achieved with desirable rate of NO generation. In some embodiments, the thiol source is admixed with the nitrite source prior to the NO generation.
Accordingly, choosing a dosage of sodium nitrite in the claimed range and pairing it with NAC in the claimed range would have been obvious because: i) the claims recite amounts that fall within or near the broader ranges contemplated by the art, ii) the prior art teaches dose optimization to obtain a desired NO response, iii) and the art expressly recognizes that the nitrite/proton or the nitrite/thiol balance affects NO generation kinetics. In other words, the claimed dosage amounts represent a routine optimization of known variables rather than a nonobvious departure from the prior art.
Regarding claim 16, this limitation is likewise rendered obvious for substantially the same reasons above as applied to claim 12. The art teaches sodium nitrite as a nitrite source and teaches a broad dosage range that includes the claimed nitrite amount. It also teaches proton or thiol-containing agents as participants in NO generation and expressly discloses controlling the nitrite-to-proton ratio or nitrite-to-thiol ratio to affect release rate and sustained release behavior. Thus, selecting: sodium nitrite at about 1 to about 10 mg, and NAC at about 50 to about 100 mg would have been an obvious choice for a skilled artisan seeking to implement a therapeutically effective nitrite/proton and/or thiol system and adjust NO generation within the known range of workable formulations.
Regarding claim 17, Friedman discloses treatment of a “human” subject, but does not expressly recite an “adult human” subject. However, the selection of an adult human subject would have been an obvious matter of routine optimization and/or design choice to one of ordinary skill in the art at the time the invention was made.
Friedman further teaches that the appropriate mode of administration and in vivo dosage may be determined based on age, weight, and mammalian species treated using routine pharmacological methods (see para. [0127]). In view of this teaching, one of ordinary skill in the art would have been motivated to apply the disclosed method to an adult human subject, and would have had a reasonable expectation of success in doing so. Therefore, claim 17 would have been obvious over Friedman.
Claim 10 is rejected under 35 U.S.C. § 103 as being unpatentable over Joel Friedman (US 2023/0069711 A1), hereinafter “Friedman,” in view of claims 1–4, 7–8, 10, and 15 as previously discussed, and further in view of Nagababu et al., “Effect of Nitrite and N-acetylcysteine treatment on Blood Pressure, Arterial Stiffness and Vascular Function in Spontaneously Hypertensive Rats,” Free Radical Biology and Medicine, Vol. 112, Suppl. 1, November 2017, pp. 118–119, hereinafter “Nagababu.”
Friedman teaches the use of a nitrite source and NAC for administration to a subject, as discussed above. Although Friedman does not expressly teach treatment of systemic hypertensive disease, Nagababu teaches that nitrite and NAC treatment is effective against hypertension-induced endothelial dysfunction by lowering blood pressure. In view of Nagababu, one of ordinary skill in the art would have been motivated to modify the teachings of Friedman to treat patients having systemic hypertensive disease, such as hypertension, with a reasonable expectation of success. Accordingly, claim 10 would have been obvious over Friedman in view of Nagababu.
Conclusion
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/BRIAN-YONG S KWON/ Supervisory Patent Examiner, Art Unit 1613
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