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 .
Formal Matters
Applicant’s arguments in the reply filed on 28 July 2026 are acknowledged and have been fully considered. Claims 1-20 are pending. Claims 1-11 are under consideration in the instant office action. Claims 12-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claims. Applicant’s arguments did not overcome the rejections set forth in the previous office action under 35 USC 103 for reasons set forth in the previous office action and herein below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 27 January 2026 is noted and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the information disclosure statement. A signed copy is attached.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
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(a) 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.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), 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(a).
Note: The claims are examined with respect to the elected species potassium nitrate as source of nitrate; and citric acid as the type of acid.
Claims 1-4 and 7-11 remain rejected under 35 U.S.C. 103 as being unpatentable over Perrin et al. (2013/0011377, previously cited) in view of Kramer et al. (US Patent No. 8,466,187, IDS reference, 02/15/24, previously cited) and as evidenced by Cottrell et al. (J Physiol 595.15 (2017) pp 5095–5102, previously cited) and De Belder et al. (WO 96/17604, previously cited).
Note: Claims are examined with respect to the elected species of potassium nitrate as source of nitrate and citric acid as the type of acid.
Applicant Claims
Applicant claims a composition for human consumption comprising: elemental iron; and a source of nitrate anion (NOs) (potassium nitrate, elected species); wherein the composition is in a unit dosage form selected from one or more of the group consisting of: a capsule. a tablet. a pill, and a combination thereof.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Perrin et al. teach compositions, kits and methods for the administration of various vitamin, mineral and nutrient compositions, and in a specific embodiment, the compositions, kits and methods may utilize or include vitamin D, iodine, vitamin B1, vitamin B6, vitamin B12, vitamin B2, vitamin B9, vitamin B3, vitamin E, vitamin A, vitamin C, iron, zinc, copper, magnesium, omega 3 fatty acids and one or more pharmaceutically acceptable carriers (see abstract). A composition consisting of vitamin D, iodine, vitamin B1, vitamin B6, vitamin B12, vitamin B2, vitamin B9, vitamin B3, vitamin E, vitamin A, vitamin C, iron, zinc, copper, magnesium, omega-3 fatty acids and one or more pharmaceutically acceptable carriers (see claim 1). The composition of claim 1, wherein said iron is in the form selected from one or more of the group consisting of elemental iron, in the form of a salt, chelated form, non-chelated form, chelated to an amino acid, carbonyl iron, ferrous gluconate, ferrous fumarate, polysaccharide iron complex, elemental polysaccharide iron, polysaccharide iron, ferrous (II)-bis-glycinate chelate, ferrous asparto glycinate, ferrous bisglycinate, ferrous bisglycinate hydrochloride, ferrous bisglycinate, elemental ferrous bisglycinate, ferrous sulfate, ferronyl (micronized), as Iron Aid, iron protein succinylate, carbonyl iron, Sumalate iron, Heme iron complex, as Ferrochel amino acid chelate, Heme iron polypeptide as Proferrin-bovine source, as heme iron polypeptide (bovine source) as sodium iron EDTA (Ferrazone), ferric ammonium citrate, elemental iron, and ferric pyrophosphate; (see claim 2).
The compositions, kits and methods of the present invention may comprise or use iron. A primary function of iron is to carry oxygen to bodily tissues via the hemoglobin part of red blood cells. Supplemental intake of iron is critical to preventing anemia, a disorder associated with a variety of physiological states including, for example, pregnancy. Bothwell, 72(Supp.) AM. J. CLIN. NUTR. 257S-64S (2000). Severe anemia may have adverse effects upon a mother and a fetus. Specifically, significant depression of hemoglobin has been associated with poor pregnancy outcome. Black, supra; Sifakis & Pharmakides, 900 ANN. N.Y. ACAD. SCI. 125-36 (2000). The, compositions, kits and methods of the present invention may include iron in one or more of the forms of elemental iron, in the form of a salt, chelated form, non-chelated form, chelated to an amino acid, carbonyl iron, ferrous gluconate, ferrous fumarate, polysaccharide iron complex, elemental polysaccharide iron, polysaccharide iron, ferrous (II)-bis-glycinate chelate, ferrous asparto glycinate, ferrous bisglycinate, ferrous bisglycinate hydrochloride, ferrous bisglycinate, elemental ferrous bisglycinate, ferrous sulfate, ferronyl (micronized), as Iron Aid, iron protein succinylate, carbonyl iron, Sumalate iron, Heme iron complex, as Ferrochel amino acid chelate, heme iron polypeptide as Proferrin-bovine source, as heme iron polypeptide (bovine source) as sodium iron EDTA (Ferrazone), ferric ammonium citrate, elemental iron, and ferric pyrophosphate (paragraph 0094). The composition of claim 1, wherein said iron is present in an amount of about 29 mg (see claim 14). The composition of claim 1, wherein said vitamin D is present in an amount of about 500 I.U. to about 1500 I.U., said iodine is present in an amount of about 75 μg to about 225 μg, said vitamin B1 is present in an amount of about 0.8 mg to about 2.4 mg, said vitamin B6 is present in an amount of about 1.2 mg to about 3.8 mg, said vitamin B12 is present in an amount of about 6 μg to about 18 μg, said vitamin B2 is present in an amount of about 0.9 mg to about 2.7 mg, said vitamin B9 is present in an amount of about 0.5 mg to about 1.5 mg, said vitamin E is present in an amount of about 10 I.U. to about 30 I.U., said vitamin A is present in an amount of about 550 I.U. to about 1650 I.U., said vitamin C is present in an amount of about 15 mg to about 45 mg, said vitamin B3 is present in an amount of about 7.5 mg to about 22.5 mg, said iron is present in an amount of about 14.5 mg to about 43.5 mg, said zinc is present in an amount of about 12.5 mg to about 37.5 mg, said copper is present in an amount of about 1.0 mg to about 3.0 mg, said magnesium is present in an amount of about 10 mg to about 30 mg, and said omega 3 fatty acids is present in an amount of about 100 mg to about 300 mg (see claim 20). The term “dosage form,” as used herein, is the form in which the dose is to be administered to the subject or patient. The drug or supplement is generally administered as part of a formulation that includes nonmedical agents. The dosage form has unique physical and pharmaceutical characteristics. Dosage forms, for example, may be solid, liquid or gaseous. “Dosage forms,” may include for example, a capsule, tablet, caplet, gel caplet (gelcap), syrup, a liquid composition, a powder, a concentrated powder, a concentrated powder admixed with a liquid, a chewable form, a swallowable form, a dissolvable form, an effervescent, a granulated form, and an oral liquid solution. In a specific embodiment, the dosage form may be a gelcap (paragraph 0037). The ingredients of the present invention may thus be combined into a composition which may be in the form of capsule, tablet, caplet, gel caplet (gelcap), syrup, a liquid composition, a concentrated powder, and a concentrated powder admixed with a liquid, and which may be administered alone or in suitable combination with other components (paragraph 0140). In preparing the composition in oral dosage form, any of the usual media may be utilized. For liquid preparations (e.g., suspensions, elixirs, and solutions), media containing, for example water, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. Pharmaceutical acceptable carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used to prepare oral solids (e.g., powders, caplets, pills, tablets, capsules, and lozenges). Controlled release forms may also be used. Because of their ease in administration, caplets, tablets, pills, and capsules represent the most advantageous oral dosage unit form, in which case solid carriers are employed. If desired, tablets may be sugar coated or enteric coated by standard techniques (see paragraph 0142). The compositions, kits and methods of the present invention may be administered to or directed to a subject such as a human or any other organism (see paragraph 0044). Examples of rapidly water soluble fillers suitable for use with the present invention include, by way of example and without limitation, saccharides, amino acids and the like (paragraph 0152). Diluents also may be included in the compositions of the present invention in order to enhance the granulation of the compositions. Diluents can include, by way of example and without limitation, microcrystalline cellulose, sucrose, dicalcium phosphate, starches, lactose and polyols of less than 13 carbon atoms, such as mannitol, xylitol, sorbitol, maltitol and pharmaceutically acceptable amino acids, such as glycine, and their mixtures (paragraph 0155). The term “mouthfeel” refers to non-taste-related aspects of the pleasantness experienced by a person while chewing or swallowing a nutritional supplement. Aspects of mouthfeel include, for example and without limitation, the hardness and brittleness of a composition, whether the composition is chewy, gritty, oily, creamy, watery, sticky, easily dissolved, astringent, effervescent, and the like, and the size, shape, and form of the composition (tablet, powder, gel, etc.) (paragraph 0034).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Perrin et al. do not teach the inclusion of potassium nitrate and its amounts and the inclusion of citric acid. These deficiencies are cured by the teachings of Kramer et al.
Kramer et al. teach methods for increasing athletic performance, distribution of various Amino Acids to muscles, and solubility of various Amino Acids in a human or animal by administering an amino acid composition that includes: at least one constituent selected from the group consisting of a nitrate, a nitrite, and both; and at least one constituent amino acid selected from the group consisting of Arginine, Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine, Lysine, Methionine, Proline, Tyrosine, and Phenylalanine (see abstract). As used herein, “Nitrate” is a term used in its broadest sense and may refer to an Nitrate in its many different chemical forms including a salt of Nitric Acid, a single administration Nitrate, its physiologically active salts or esters, its combinations with its various salts, its tautomeric, polymeric and/or isomeric forms, its analog forms, and/or its derivative forms. Nitrate comprises, by way of non-limiting example, many different chemical forms including dinitrate and trinitrate. Nitrates may be salts, or mixed salts, of Nitric Acid (HNO3) and comprise one Nitrogen atom and three Oxygen atoms (NO3). For the exemplary purposes of this disclosure, Nitrate may comprise salts of Nitrate such as sodium nitrate, potassium nitrate, barium nitrate, calcium nitrate, and the like (column 7, lines 3-8). Composition 5 (Tablets Containing Arginine and Potassium Nitrate for Blood Pressure support). Per tablet: Arginine 250-700 mg. Potassium Nitrate 50-500 mg. Corn Starch till the desired volume for the tablet machine is obtained.
Empirical studies indicate that Nitrates are useful for their vasolidating effects. Nitrates exert their vasodilating effect through their reduction to Nitrites. In vivo, Nitrates are reduced to Nitrites and, in the blood vessels' epithelial cells, Nitrite reacts with a thiol donor (mainly glutathione) to yield Nitric Oxide (column 17, lines 29-32).
Implementations of an Amino Acid Compound or Composition may include diluents, or any inert substances added to increase the bulk of the Amino Acid Compound to make a tablet a practical size for compression. Diluents may include, for example, calcium phosphate, calcium sulfate, lactose, mannitol, magnesium stearate, potassium chloride, and citric acid, among other organic and inorganic materials (column 15, lines 63-67 and column 16, lines 1-2).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Perrin et al. by incorporating potassium nitrate and citric acid because Kramer et al. teach methods for increasing athletic performance, distribution of various Amino Acids to muscles, and solubility of various Amino Acids in a human or animal by administering an amino acid composition that includes: at least one constituent selected from the group consisting of a nitrate, a nitrite, and both; and at least one constituent amino acid selected from the group consisting of Arginine, Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine, Lysine, Methionine, Proline, Tyrosine, and Phenylalanine (see abstract). As used herein, “Nitrate” is a term used in its broadest sense and may refer to an Nitrate in its many different chemical forms including a salt of Nitric Acid, a single administration Nitrate, its physiologically active salts or esters, its combinations with its various salts, its tautomeric, polymeric and/or isomeric forms, its analog forms, and/or its derivative forms. Nitrate comprises, by way of non-limiting example, many different chemical forms including dinitrate and trinitrate. Nitrates may be salts, or mixed salts, of Nitric Acid (HNO3) and comprise one Nitrogen atom and three Oxygen atoms (NO3). For the exemplary purposes of this disclosure, Nitrate may comprise salts of Nitrate such as sodium nitrate, potassium nitrate, barium nitrate, calcium nitrate, and the like (column 7, lines 3-8). Composition 5 (Tablets Containing Arginine and Potassium Nitrate for Blood Pressure support). Per tablet: Arginine 250-700 mg. Potassium Nitrate 50-500 mg. Corn Starch till the desired volume for the tablet machine is obtained.
Empirical studies indicate that Nitrates are useful for their vasolidating effects. Nitrates exert their vasodilating effect through their reduction to Nitrites. In vivo, Nitrates are reduced to Nitrites and, in the blood vessels' epithelial cells, Nitrite reacts with a thiol donor (mainly glutathione) to yield Nitric Oxide (column 17, lines 29-32).
Implementations of an Amino Acid Compound or Composition may include diluents, or any inert substances added to increase the bulk of the Amino Acid Compound to make a tablet a practical size for compression. Diluents may include, for example, calcium phosphate, calcium sulfate, lactose, mannitol, magnesium stearate, potassium chloride, and citric acid, among other organic and inorganic materials (column 15, lines 63-67 and column 16, lines 1-2). One of ordinary skill in the art would have been motivated to do so because Kramer et al. teach that Empirical studies indicate that Nitrates are useful for their vasolidating effects. Nitrates exert their vasodilating effect through their reduction to Nitrites. In vivo, Nitrates are reduced to Nitrites and, in the blood vessels' epithelial cells, Nitrite reacts with a thiol donor (mainly glutathione) to yield Nitric Oxide (column 17, lines 29-32). One of ordinary skill in the art would have been motivated to include citric acid because implementations of an Amino Acid Compound or Composition may include diluents, or any inert substances added to increase the bulk of the Amino Acid Compound to make a tablet a practical size for compression. Diluents may include, for example, calcium phosphate, calcium sulfate, lactose, mannitol, magnesium stearate, potassium chloride, and citric acid, among other organic and inorganic materials (column 15, lines 63-67 and column 16, lines 1-2). It should be noticed that both Perrin et al. and Kramer et al. teach that in the preparation of their solid dosage forms the inclusion of diluents. Substituting one dilute with another is prima facie obvious as they all are functionally equivalent. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.) Furthermore, in the case where the claimed ranges for amounts of actives and ingredients “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. 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). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here 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). Thus, one of ordinary skill in the art would have had a reasonable expectation of success upon combination of the Perrin et al. and Kramer et al. because both references teach dietary supplement compositions in solid dosage forms containing various ingredients with different health benefits for humans. The examiner herein provides evidence or proof that supplementation or administration of nitrates during pregnancy is recommended and has been accomplished contrary to applicant’s assertions. Cottrell et al. with title “Dietary interventions for fetal growth restriction – therapeutic potential of dietary nitrate supplementation in pregnancy” recommending dietary nitrate supplementation during pregnancy. Cottrell et al. teach that given the beneficial effects of dietary nitrate supplementation in non-pregnant humans and animals, we hypothesised that this approach could be used to increase NO bioavailability and improve vascular function in complicated pregnancies. Moreover, it is likely that a dietary intervention, such as beetroot juice supplementation, may be more appealing to pregnant women and potentially have fewer off-target effects compared with pharmacological approaches, and therefore may encourage compliance. Our preclinical findings thus far have shown that maternal dietary nitrate supplementation (using beetroot juice) increases both maternal and fetal nitrate and nitrite concentrations and improves maternal uterine artery vascular function ex vivo in a mouse model of FGR associated with marked vascular dysfunction, the eNOS knockout mouse (Cottrell et al. 2015). Our ongoing studies using this approach aim to understand how the beneficial effects of nitrate supplementation are conferred in this model, and to establish the mechanisms involved in nitrate/nitrite bioactivation in uteroplacental tissues of pregnant animals (page 5098). Additionally, the examiner also provides De Belder et al. (WO 96/17604) who teach the use of a NO donor for the prophylaxis and/or treatment of hypertension and hypertensive disorders during pregnancy, in particular for the prophylaxis and/or treatment of pre-eclampsia, is disclosed. Preferably, the NO donor is an S-nitroso compound of the formula R-SNO wherein R is one or more amino acid derived fragments (see abstract and claim 1). The use according to any one of claims 1 to 4 wherein the NO donor is glyceryl trinitrate (see claim 1). Both references are clear evidence that nitrates can be administered during pregnancy.
In light of the forgoing discussion, one of ordinary skill in the art would have concluded that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 5-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Perrin et al. (2013/0011377, previously cited) in view of Kramer et al. (US Patent No. 8,466,187, IDS reference, 02/15/24, previously cited) and as evidenced by Cottrell et al. (J Physiol 595.15 (2017) pp 5095–5102, previously cited) and De Belder et al. (WO 96/17604, previously cited) as applied to claims 1-4 and 7-11 above, and further in view of Dennis et al. (EP 0454396) and Hughes et al. (WO2018071988).
Applicant Claims
Applicant claims a composition for human consumption. Dependent claims 5-6 recite the amount of citric acid in the composition.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
The teachings of Perrin et al. and Kramer et al. is described above in detail and are incorporated herein by reference.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Perrin et al. and Kramer et al. do not teach the amount of citric acid as recited. These deficiencies are cured by the teachings of Dennis et al. and Hughes et al.
Dennis et al. teach an improved tablet composition for drugs or active ingredients prone to poor tabletting properties is disclosed. The improved composition comprises a premixture, consisting essentially of between about 85 and 99.9 percent by weight of the active ingredient and between about 0.1 and 15 percent by weight of citric acid, and one or more other formulation ingredients added to the premixture. The present invention also involves the process for making such compositions and products therefrom (see abstract). It is known that certain pharmacologically active ingredients are extremely difficult to manufacture in tablet form due to the physical nature of the active compound itself. For example, many drugs which when utilized in free base form, i.e., not in salt form, e.g. atenolol, nadolol, salbutamol, chlordiazepoxide, temazepam, diazepam, sulpiride, d-sotalol, d-L-sotalol and the like, are prone to many undesirable tabletting problems including poor compression and dissolution properties, high lubricant requirement, formation of soft granules and "sticking" which refers to the film-forming adherence phenomenon wherein the compound adheres to tablet punches and other manufacturing apparatus. These problems can result in soft tablets of high friability and tablets of inelegant appearance due to loss of material to punch surfaces. Attempting to reduce the compression problems by increasing compression forces in the tablet press can result in high disintegration times and slow drug release which may compromise bioavailability. In all instances so far discussed high ejection forces are needed to remove tablets from dies which can result in inelegant product and machine wear (paragraph 0001). Increasing the level of certain excipient materials to compensate for these phenomena is not without difficulties. For example, increasing the level of hydrophobic tablet lubricants to reduce ejection forces and adhesion, e.g. magnesium stearate, decreases the attainable tablet hardness which in turn can result in poor handling properties and a decrease in the rate of drug release. Attempts to counter the decreased hardness with higher compression forces have given way to retardation of the tablet disintegration. Higher ratios of lubricant-to-drug can be provided without adversely affecting tablet hardness by proportionally increasing the levels of all of the other ingredients, except the drug itself. However, this results in a substantial increase in tablet size which is not at all desirable as this might compromise patient compliance (paragraph 0002). In accordance with the present invention, large improvements in the handling/manufacturing of drugs, prone to compression, lubrication, sticking and adherence problems, into tablet form is provided. Not only does the present composition and process substantially eliminate these problems, but a smaller, more elegant dosage form having significantly enhanced disintegration and dissolution times is also provided (paragraph 0011). In trying to overcome the undesirable tabletting problems, it was found that a 4:1 ratio of drug to citric acid provided some alleviation of the problems as compared to formulations with no citric acid. However, the present compositions unexpectedly provide less adherence, improved compression, reduced ejection forces and more rapid disintegration and dissolution with less citric acid resulting in smaller tablet size. Further, the present composition allows for tablet sizes much smaller than those practicable for non-citric acid compositions which must employ larger proportions of all excipients so as to "swamp" the adherence problem, and to reduce problems of flow, compression, wetting, disintegration and dissolution. This may be of particular benefit for high dose drugs or in case of long term medications or in elderly patients where larger tablets could produce problems of patient compliance (paragraph 0013).
Hughes et al. teach a preparation comprising an active ingredient, a suspension base and an effervescent agent wherein the active ingredient comprises one or more B vitamins (see claim 1). A preparation according to claim 2 wherein the thickening/viscosity component comprises one or more of: Xanthum gum, carboxymethyl cellulose, a hydratable methyl cellulose, sodium carboxyl methyl cellulose, sodium methyl cellulose, microcrystalline cellulose group, other gums such as guar gum, pectin, or other hydrocolloids, agar, carrageenan (see claim 5). A composition comprising: 0.1-100mg optionally 1 to 80mg, optionally 10 to 50mg, optionally 12 to 25mg, optionally 10 to 20mg L-methylfolate a physiologically acceptable salt, ester or derivative thereof; 10 to 1000 mg optionally 20 to 800mg optionally 40 to 400mg optionally 80 to 300mg, optionally 120 to 200mg flavour additive which is optionally a natural flavour additive and optionally pink grapefruit flavour or the like; 80 to 8000 mg optionally 200 to 4000 mg optionally 400 to 2000 mg, optionally 600 to 1000mg optionally 750 to 900mg inulin which is optionally instant inulin-fibriline; 3 to 300 mg optionally 10 to 200mg, optionally 15 to 100mg, optionally 25 to 50mg, optionally 25 to 35 mg sucralose; 80 to 8000 mg optionally 200 to 4000 mg optionally 400 to 2000 mg, optionally 600 to 1000mg optionally 750 to 900mg glucose syrup which is optionally glucose solids-rice; 40 to 5000 mg optionally 80 to 3000mg, optionally 100 to 1000mg, optionally 200 to 800 mg, optionally 400 to 600mg sodium carbonate; 150 to 15,000 mg optionally 300 to 10,000mg, optionally 500 to 5000mg, optionally 1000 to 2000 mg, optionally 1200 to 1700 mg citric acid anhydrous; 1 to 200 mg optionally 1 to 100 mg optionally 1 to 50 mg, optionally 1 to 30 mg, optionally 10 to 22 mg natural colour; 1 to 200 mg optionally 1 to 100 mg optionally 1 to 50 mg, optionally 1 to 30 mg, optionally 10 to 22 mg xanthan gum 200 mesh; 40 to 5000 mg optionally 80 to 3000mg, optionally 100 to 1000mg, optionally 200 to 800 mg, optionally 450 to 650mg sodium bicarbonate (see claims 10-12). A supplement as used herein may be a powder, tablet, capsule or take some other form. The skilled addressee will appreciate that a product according to the invention may contain other ingredients not listed herein (see page 8, lines 8-11).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the instant invention to modify the teachings of Perrin et al. and Kramer et al., by incorporating citric acid in the composition in amounts as recited because Dennis et al. teach an improved tablet composition for drugs or active ingredients prone to poor tabletting properties is disclosed. The improved composition comprises a premixture, consisting essentially of between about 85 and 99.9 percent by weight of the active ingredient and between about 0.1 and 15 percent by weight of citric acid, and one or more other formulation ingredients added to the premixture. The present invention also involves the process for making such compositions and products therefrom (see abstract). It is known that certain pharmacologically active ingredients are extremely difficult to manufacture in tablet form due to the physical nature of the active compound itself. For example, many drugs which when utilized in free base form, i.e., not in salt form, e.g. atenolol, nadolol, salbutamol, chlordiazepoxide, temazepam, diazepam, sulpiride, d-sotalol, d-L-sotalol and the like, are prone to many undesirable tabletting problems including poor compression and dissolution properties, high lubricant requirement, formation of soft granules and "sticking" which refers to the film-forming adherence phenomenon wherein the compound adheres to tablet punches and other manufacturing apparatus. These problems can result in soft tablets of high friability and tablets of inelegant appearance due to loss of material to punch surfaces. Attempting to reduce the compression problems by increasing compression forces in the tablet press can result in high disintegration times and slow drug release which may compromise bioavailability. In all instances so far discussed high ejection forces are needed to remove tablets from dies which can result in inelegant product and machine wear (paragraph 0001). Increasing the level of certain excipient materials to compensate for these phenomena is not without difficulties. For example, increasing the level of hydrophobic tablet lubricants to reduce ejection forces and adhesion, e.g. magnesium stearate, decreases the attainable tablet hardness which in turn can result in poor handling properties and a decrease in the rate of drug release. Attempts to counter the decreased hardness with higher compression forces have given way to retardation of the tablet disintegration. Higher ratios of lubricant-to-drug can be provided without adversely affecting tablet hardness by proportionally increasing the levels of all of the other ingredients, except the drug itself. However, this results in a substantial increase in tablet size which is not at all desirable as this might compromise patient compliance (paragraph 0002). One of ordinary skill in the art would have been motivated to include citric acid in the composition in amounts as recited during tablet preparation because Dennis et al. teach in accordance with the present invention, large improvements in the handling/manufacturing of drugs, prone to compression, lubrication, sticking and adherence problems, into tablet form is provided. Not only does the present composition and process substantially eliminate these problems, but a smaller, more elegant dosage form having significantly enhanced disintegration and dissolution times is also provided (paragraph 0011). In trying to overcome the undesirable tabletting problems, it was found that a 4:1 ratio of drug to citric acid provided some alleviation of the problems as compared to formulations with no citric acid. However, the present compositions unexpectedly provide less adherence, improved compression, reduced ejection forces and more rapid disintegration and dissolution with less citric acid resulting in smaller tablet size. Further, the present composition allows for tablet sizes much smaller than those practicable for non-citric acid compositions which must employ larger proportions of all excipients so as to "swamp" the adherence problem, and to reduce problems of flow, compression, wetting, disintegration and dissolution. This may be of particular benefit for high dose drugs or in case of long term medications or in elderly patients where larger tablets could produce problems of patient compliance (paragraph 0013). One of ordinary skill in the art would have been motivated to include citric acid in amounts as recited because Hughes et al. teach a preparation comprising an active ingredient, a suspension base and an effervescent agent wherein the active ingredient comprises one or more B vitamins (see claim 1). A preparation according to claim 2 wherein the thickening/viscosity component comprises one or more of: Xanthum gum, carboxymethyl cellulose, a hydratable methyl cellulose, sodium carboxyl methyl cellulose, sodium methyl cellulose, microcrystalline cellulose group, other gums such as guar gum, pectin, or other hydrocolloids, agar, carrageenan (see claim 5). A composition comprising: 0.1-100mg optionally 1 to 80mg, optionally 10 to 50mg, optionally 12 to 25mg, optionally 10 to 20mg L-methylfolate a physiologically acceptable salt, ester or derivative thereof; 10 to 1000 mg optionally 20 to 800mg optionally 40 to 400mg optionally 80 to 300mg, optionally 120 to 200mg flavour additive which is optionally a natural flavour additive and optionally pink grapefruit flavour or the like; 80 to 8000 mg optionally 200 to 4000 mg optionally 400 to 2000 mg, optionally 600 to 1000mg optionally 750 to 900mg inulin which is optionally instant inulin-fibriline; 3 to 300 mg optionally 10 to 200mg, optionally 15 to 100mg, optionally 25 to 50mg, optionally 25 to 35 mg sucralose; 80 to 8000 mg optionally 200 to 4000 mg optionally 400 to 2000 mg, optionally 600 to 1000mg optionally 750 to 900mg glucose syrup which is optionally glucose solids-rice; 40 to 5000 mg optionally 80 to 3000mg, optionally 100 to 1000mg, optionally 200 to 800 mg, optionally 400 to 600mg sodium carbonate; 150 to 15,000 mg optionally 300 to 10,000mg, optionally 500 to 5000mg, optionally 1000 to 2000 mg, optionally 1200 to 1700 mg citric acid anhydrous; 1 to 200 mg optionally 1 to 100 mg optionally 1 to 50 mg, optionally 1 to 30 mg, optionally 10 to 22 mg natural colour; 1 to 200 mg optionally 1 to 100 mg optionally 1 to 50 mg, optionally 1 to 30 mg, optionally 10 to 22 mg xanthan gum 200 mesh; 40 to 5000 mg optionally 80 to 3000mg, optionally 100 to 1000mg, optionally 200 to 800 mg, optionally 450 to 650mg sodium bicarbonate (see claims 10-12). A supplement as used herein may be a powder, tablet, capsule or take some other form. The skilled addressee will appreciate that a product according to the invention may contain other ingredients not listed herein (see page 8, lines 8-11). Furthermore, in the case where the claimed ranges for amounts of ingredients such as citric acid “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. 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). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here 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). Thus, an ordinary skilled artisan would have had a reasonable expectation of success upon combination of the Perrin et al., Kramer et al. Dennis et al., and Hughes et al. because all references teach compositions for health benefits in tablet forms. The examiner herein provides evidence or proof that supplementation or administration of nitrates during pregnancy is recommended and has been accomplished contrary to applicant’s assertions. Cottrell et al. with title “Dietary interventions for fetal growth restriction – therapeutic potential of dietary nitrate supplementation in pregnancy” recommending dietary nitrate supplementation during pregnancy. Cottrell et al. teach that given the beneficial effects of dietary nitrate supplementation in non-pregnant humans and animals, we hypothesised that this approach could be used to increase NO bioavailability and improve vascular function in complicated pregnancies. Moreover, it is likely that a dietary intervention, such as beetroot juice supplementation, may be more appealing to pregnant women and potentially have fewer off-target effects compared with pharmacological approaches, and therefore may encourage compliance. Our preclinical findings thus far have shown that maternal dietary nitrate supplementation (using beetroot juice) increases both maternal and fetal nitrate and nitrite concentrations and improves maternal uterine artery vascular function ex vivo in a mouse model of FGR associated with marked vascular dysfunction, the eNOS knockout mouse (Cottrell et al. 2015). Our ongoing studies using this approach aim to understand how the beneficial effects of nitrate supplementation are conferred in this model, and to establish the mechanisms involved in nitrate/nitrite bioactivation in uteroplacental tissues of pregnant animals (page 5098). Additionally, the examiner also provides De Belder et al. (WO 96/17604) who teach the use of a NO donor for the prophylaxis and/or treatment of hypertension and hypertensive disorders during pregnancy, in particular for the prophylaxis and/or treatment of pre-eclampsia, is disclosed. Preferably, the NO donor is an S-nitroso compound of the formula R-SNO wherein R is one or more amino acid derived fragments (see abstract and claim 1). The use according to any one of claims 1 to 4 wherein the NO donor is glyceryl trinitrate (see claim 1). Both references are clear evidence that nitrates can be administered during pregnancy.
In light of the forgoing discussion, one of ordinary skill in the art would have concluded that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 28 July 2026 have been fully considered but they are not persuasive.
Applicant argues the mention of thiamine mononitrate/“source of nitrate anion”.
The above assertions are not found persuasive because the rejection of claim 1 does not rest on inherency of nitrate from Perrin’s optional thiamine mononitrate. Kramer expressly teaches potassium nitrate as a nitrate source in a solid oral unit dose (Composition 5: 50–500 mg KNO₃ per tablet; col. 7, ll. 3–8; col. 17, ll. 29–32). That teaching supplies the claimed “source of nitrate anion (NO₃⁻).” The thiamine mononitrate passage was cited only to show that Perrin’s formulation space already includes nitrate-containing salts and is not chemically hostile to nitrate. Applicant’s construction that “source of nitrate anion” requires a particular intended use or a “pharmacologically meaningful” amount reads limitations from the specification into claim 1. Claim 1 recites no amount and no intended mechanism. In re Van Geuns, 988 F.2d 1181 (Fed. Cir. 1993). Claims 3–4 reciting 30–2000 mg and 50–600 mg NO₃⁻ are met by Kramer’s overlapping 50–500 mg KNO₃ range, not by 0.30 mg from 1.6 mg thiamine mononitrate. That Perrin also lists allithiamine as an equivalent B1 form does not negate Kramer’s independent teaching of inorganic nitrate salts.
Applicant argues the examiner has failed to articulate a sufficient record based motivation to combine Perrin and Kramer.
The above assertions are not found persuasive because the motivation is not mere co-membership in “dietary supplements.” Both references teach solid oral human nutritional compositions (capsules/tablets/pills) containing minerals and other actives. Kramer teaches that inorganic nitrates are useful for vasodilation via reduction to nitrite/NO and exemplifies KNO₃ in tablets. Perrin already administers iron in the same dosage forms to humans, including but not limited to subjects in physiologically stressful states (paragraphs 0002, 0004, 0010, 0044). Combining known ingredients each with known functions to yield a predictable composition is classic KSR obviousness. It is not required that Kramer address prenatal anemia or that Perrin address athletic performance. In re Kahn, 441 F.3d 977, 987; Cross Med. Prods., 424 F.3d at 1323. Applicant’s “design space” argument treats Perrin as pregnancy-only. It is not. Preferred embodiments are not a teaching away from the broader disclosure. In re Susi; In re Fulton.
Applicant also argues Cottrell and De Belder do Not supply an affirmative reason a person of ordinary skill in the art would have selected an inorganic nitrate salt for inclusion in a prenatal iron dietary supplement. Applicant continues to assert prior Exhibits A-C as well.
The above assertions are not found persuasive because Cottrell and De Belder were cited as evidence that nitrate/NO-donor administration in pregnancy is known and studied—not as the primary motivation to add KNO₃ to Perrin. Applicant now concedes Exhibits A–C do not forbid nitrate in pregnancy. A safety-monitoring literature on drinking-water nitrate does not criticize, discredit, or discourage adding a defined dose of an inorganic nitrate salt to a formulated supplement. Absence of a prenatal-guideline document “recommending” KNO₃ is not a requirement for obviousness. The combination is justified by Kramer’s known use of KNO₃ in human oral tablets plus Perrin’s iron oral supplements. Cottrell’s use of beetroot juice and De Belder’s use of GTN go to form of NO precursor, not to a prohibition on inorganic nitrate salts. The claims are composition claims, not method-of-treating-pregnancy claims.
Applicant further argues on the selection of elemental iron asserting that Neither Perrin nor Kramer teach specifically elemental iron and the examiner has not explained why a person of ordinary skill in the art would select elemental iron over the vastly more common salt forms.
The above assertions are not found persuasive because Perrin expressly lists elemental iron among usable iron forms (claim 2; paragraph 0094). A disclosed species is available for combination. Applicant’s preference for commercial salt forms does not remove elemental iron from the prior art. Selecting a known material for its known suitability is obvious. Claim 1 does not require that elemental iron be the only iron form, nor that it be selected “because of” a redox reaction with gastric HCl. That mechanistic theory is applicant’s own and is not a claim limitation. Even if Fe0 reacts with acid in the stomach, that is a property of a known material used in a known way.
Applicant further argues there was no reasonable expectation of success in co-formulating elemental iron, inorganic nitrate and an acid in a single solid unit dosage.
The above assertions are not found persuasive because both primary references already make compressed solid oral unit doses containing minerals, amino acids or vitamins, and optional acids/diluents (Perrin paragraphs 0140–0142, 0155; Kramer col. 15–16). Putting another known mineral form (elemental iron, taught by Perrin) in the same tablet with KNO₃ (taught by Kramer) and citric acid (taught as a diluent by Kramer) is ordinary formulation work. Applicant has not shown a known incompatibility that would have led the artisan to expect failure. Speculation that Fe0 + nitrate + acid “would be highly uncertain” is attorney argument, not evidence of record. Leo involved a recognized formulation problem in the cited art; that showing is absent here. Experiment 5 compares elemental magnesium vs magnesium salts. The claims require elemental iron. Results for a different metal do not establish unpredictability of the claimed iron composition.
Applicant further argues the claimed composition exhibit unexpected results that rebut any prima facie case of obviousness.
The above assertions are not found persuasive because the burden is on applicant to show results unexpected versus the closest prior art and commensurate in scope with the claims. In re Soni; In re Grasselli. The examiner indicates that the closest art is Perrin’s iron oral supplement plus Kramer’s KNO₃ tablets, not “magnesium alone” or literature nitrate-only averages. Additionally, experiments 1–12, as characterized, appear directed largely to magnesium + nitrate (and related metals), not to a side-by-side of claimed elemental iron + nitrate vs iron salt + nitrate vs nitrate alone in the claimed dosage forms and ranges. Even furthermore, claim 1 has no amount limits, no acid requirement, and is not limited to blood-pressure use. A few examples of large BP drops do not cover the full scope (1–800 mg iron; 30–2000 mg nitrate; any listed nitrate salt; capsule/tablet/pill; with or without acid). Furthermore, rapid onset and magnitude, even if accepted as fact, have not been shown to be unexpected to one combining Kramer’s known vasodilatory nitrate with an iron supplement. The evidence is therefore insufficient to rebut the prima facie case.
Applicant also argues Dennis and Hughes do not establish an overlapping range with the claimed composition, and any prima facie case based on range overlap is rebutted by criticality and unexpected results.
The above assertions are not found persuasive because the combination of Perrin and Kramer remains proper for claims 1–2, secondary references may supply the amount of citric acid. Kramer already lists citric acid as a tablet diluent. Dennis teaches citric acid in tablets to improve compression/sticking (0.1–15 wt% of active). Hughes teaches 150–15,000 mg citric acid (including 300–10,000 and 1,000–2,000 mg) in tablet/capsule/powder supplements. Those ranges overlap claims 5–6. Applicant’s argument that citric acid is an “active pH-management agent” rather than a diluent reads intended function into the claims. Claims 5–6 recite an amount of acid, not a pH result or a reaction mechanism. A compound known as a tablet excipient remains available even if applicant later ascribes a new purpose to it. Criticality of 50–20,000 mg or 300–1,000 mg has not been shown across the full claimed ranges or versus the closest prior-art acid-containing tablets. Secondary references need not themselves teach elemental iron plus nitrate; they are used only for the acid quantity once the base combination is made.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
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/TIGABU KASSA/
Primary Examiner, Art Unit 1619
