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 claim amendments and arguments in the reply filed on 11 February 2026 are acknowledged and have been fully considered. Claims 1 and 3-35 are pending. Claims 1, 3-5, and 8-13 are under consideration in the instant office action. Claims 6-7 and 14-35 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking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. Claim 2 is canceled. Applicant’s claim amendments and arguments did not overcome the rejections under 35 USC 103 set forth in the previous office action for reasons set forth in the previous office action and herein below.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 26 January 2026 and 26 November 2025 are noted and the submission are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the information disclosure statement. Signed copies are attached.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Note: Claims are examined with respect to the elected species of magnesium as type of metal; proline nitrate as the nitrate source; and citric acid as the type of acid.
Claims 1, 3-5 and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Perrin et al. (2013/0011377, newly cited) in view of Kramer et al. (US Patent No. 8,466,187, IDS reference, 06/13/22).
Applicant Claims
Applicant claims an oral composition for human consumption comprising: elemental metal selected from the group consisting of: elemental magnesium (elected species), elemental calcium, elemental zinc, and elemental iron; a source of nitrate anion (NO3-) (proline nitrate elected); and an acid (citric acid elected), wherein the composition produces an acidic pH when dissolved in an aqueous solution. Dependent claims thereof recite further limiting features.
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 magnesium is in the form selected from one or more of the group consisting of elemental magnesium, in the form of a salt, in a chelated form, in a non-chelated form, magnesium acetate, magnesium carbonate, magnesium gluconate, magnesium chloride, magnesium citrate, magnesium silicate, magnesium stearate, magnesium sulfate, magnesium oxide, and magnesium chelated to an amino acid (see claim 2).
The compositions, kits and methods of the present invention may comprise or use magnesium. Magnesium is found primarily in both bone and muscle and is important for over 300 different enzyme reactions. A primary function of magnesium is to bind to phosphate groups in adenosine triphosphate (ATP), thereby forming a complex that assists in the transfer of ATP phosphate. Magnesium also functions within cells as a membrane stabilizer. Magnesium plays roles in nucleic acid synthesis, glycolysis, transcription of DNA and RNA, amino acid activation, membrane transport, transketolase reactions, and protein synthesis. James L. L. Groff et al., ADVANCED NUTRITION AND HUMAN METABOLISM 341 (2d ed. 1996). It is also involved in the formation of cAMP, a cytosolic second messenger that plays a role in cell signaling mechanisms. Magnesium also functions both synergistically and antagonistically with calcium in neuromuscular transmission. RDA, supra at 188. Specifically, magnesium is critical for the maintenance of electrochemical potentials of nerve and muscle membranes and the neuromuscular junction transmissions, particularly important in the heart. Not surprisingly, magnesium deficiency is tied to cardiovascular disease and hypertension. Agus et al., 17 CRIT. CARE CLIN. 175-87 (2001). Indeed, oral magnesium therapy improves endothelial function in patients with coronary disease. Shechter et al., 102 CIRCULATION 2353-58 (2000) (paragraph 0100). Magnesium is available in a variety of salts and can be included in the compositions, kits and methods of the present invention in either chelated or nonchelated form. In one specific embodiment of the present invention, magnesium may be included in the forms of elemental magnesium, in the form of a salt, in a chelated form, in a non-chelated form, magnesium acetate, magnesium carbonate, magnesium gluconate, magnesium chloride, magnesium citrate, magnesium silicate, magnesium stearate, magnesium sulfate, magnesium oxide, and magnesium chelated to an amino acid (magnesium glycinate, magnesium aspartate) (paragraph 0101). In another specific embodiment, magnesium may be present in the amounts ranging from about 10 mg to about 30 mg. In another embodiment, magnesium may be present in the amounts ranging from about 16 mg to about 24 mg. In another embodiment, magnesium may be present in the amounts ranging from about 18 mg to about 22 mg. In another embodiment, magnesium may be present in the amount of about 20 mg (paragraph 0102).
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 proline 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 (the examiner notes that exemplary amount is applicable to proline nitrate). Corn Starch till the desired volume for the tablet machine is obtained. A method for increasing athletic performance in a human or animal, the method comprising administering to the human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a nitrite, and both, and Proline (see claim 20).
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 proline 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. A method for increasing athletic performance in a human or animal, the method comprising administering to the human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a nitrite, and both, and Proline (see claim 20). 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 diluent 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.
With regard to the limitation reciting “wherein the composition produces an acidic pH when dissolved in an aqueous solution.”, the combination teachings of Perrin et al. and Kramer clearly meet the claimed composition. Therefore, the oral composition taught by Perrin et al. and Kramer would necessarily produce an acidic pH absent evidence to the contrary. "[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195 ; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374 , 1381 , 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018) ("An inherent characteristic of a formulation can be part of the prior art in an obviousness analysis even if the inherent characteristic was unrecognized or unappreciated by a skilled artisan."). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578 , 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242 , 249 , 66 S. Ct. 81 , 90 L. Ed. 43 , 1946 Dec. Comm'r Pat. 611 (1945). We too have previously explained that "an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations," because "[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property." Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 , 1354 (Fed. Cir. 2012). In In re Kao, we found that the claimed controlled-release oxymorphone formulation was obvious because an inherent pharmacokinetic property of oxymorphone that was present in controlled-release oxymorphone "add[ed] nothing of patentable consequence." In re Huai-Hung Kao, 639 F.3d 1057 , 1070 , 98 U.S.P.Q.2D (BNA) 1799 (Fed. Cir. 2011). In In re Kubin, we found an inherent property obvious, explaining that "[e]ven if no prior art of record explicitly discusses the [limitation], the . . . application itself instructs that [the limitation] is not an additional requirement imposed by the claims on the [claimed protein], but rather a property necessarily present in [the claimed protein]." In re Kubin, 561 F.3d 1351 , 1357 , 90 U.S.P.Q.2D (BNA) 1417 (Fed. Cir. 2009). Our predecessor court similarly concluded that it "is not the law" that "a structure suggested by the prior art, and, hence, potentially in the possession of the public, is patentable . . . because it also possesses an [i]nherent, but hitherto unknown, function which [the patentees] claim to have discovered." In re [*1191] Wiseman, 596 F.2d 1019 , 1023 (C.C.P.A. 1979). Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195 . Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531 , 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511 -96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 , 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). On appeal, Persion contends that the district court erred in applying the inherency doctrine in its obviousness analysis because Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581 ); Reply Br. 19. To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to our prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607 , 610 . In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims.
With regard to unexpected or surprising results the examiner reminds Applicant that Applicant relying upon comparative showing to rebut prima facie case must compare his claimed invention with closest prior art In re Holladay, 584 F.2d 384, 199 USPQ 516 (CCPA 1978). The examiner reminds Applicant that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978). In the instant case, the examiner’s prima facie case outweighs applicant’s general allegations of unexpected results with no applicable comparison data. The examiner brings to Applicant’s attention that the data presented in the specification for instance examples 1-4, the composition contains two sources of magnesium which are elemental magnesium and magnesium nitrate. Both contain magnesium. If Applicant is alleging synergy "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.). Applicant must perform a controlled experiment reflecting data on the individual components as well as the composition demonstrating a greater than expected result. Furthermore, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). It must be known that Applicant’s claim 1 is drawn to any amounts to each of the recited components.
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) 8-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Perrin et al. (2013/0011377, newly cited) in view of Kramer et al. (US Patent No. 8,466,187, IDS reference, 06/13/22) as applied to claims 1, 3-5, and 10-13 above, and further in view of Dennis et al. (EP 0454396) and Hughes et al. (WO2018071988).
Applicant Claims
Applicant claims an oral composition for human consumption comprising: elemental metal selected from the group consisting of: elemental magnesium (elected species), elemental calcium, elemental zinc, and elemental iron; a source of nitrate anion (NO3-) (proline nitrate elected); and an acid (citric acid elected), wherein the composition produces an acidic pH when dissolved in an aqueous solution. Dependent claims 8-9 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 tableting 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 in claims 8-9 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 tablet based pharmaceutical compositions.
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 11 February 2026 have been fully considered but they are not persuasive.
Applicant argues no motivation, compatibility and expectation of success in the Perrin-Kramer combination. First, there is no art-based motivation to add nitrate salts to Perrin's prenatal micronutrient formulations. Perrin expressly characterizes its compositions as prenatal supplementation "optimizing specific nutrients before, during, and after the physiological processes of pregnancy and lactation (Perrin |[0044]). Perrin further identifies pregnancy anemia as the clinical context in which the magnesium supplementation is required (see Perrin [0094]). In that exact physiologic domain and from the knowledge generally available to one of ordinary skill in the art, there is no teaching and no suggestion whatsoever to add nitrate anion, much less an inorganic nitrate salt. Under In re Lee, 277 F.3d at 1344, the Examiner may not use "common sense" to supply a missing motivation where the art is silent. The pregnancy domain itself teaches a person having ordinary skill in the art to avoid introducing a source of nitrate into prenatal magnesium supplementation. Authoritative epidemiologic data demonstrates that pregnancy is not a domain in which nitrate salts are benign "nutrient add-ons," but rather a domain in which nitrate is treated as a risk-managed exposure. For example, a CDC/NIH-supported longitudinal cohort notes that: "Pregnant women are considered vulnerable to the effects of exposure to high levels of nitrates in drinking water due to their altered physiological states." Manassaram et al., Nitrates in Drinking Water and Methemoglobin Levels in Pregnancy: A Longitudinal Study, 9 Env't Health 60 (2010), Abstract, hereinafter Exhibit A. Moreover, a systematic review and meta-analysis (7.27 million participants) reported that "Increased nitrate in drinking water may be associated with an increased risk of preterm birth and some specific congenital anomalies." Li et al., Nitrate Contamination in Drinking Water and Adverse Reproductive and Birth Outcomes: A Systematic Review and Meta-Analysis, 13 Sci. Rep. 563 (2023), Abstract, hereinafter Exhibit B. Likewise, a 2023 narrative review concludes that prenatal nitrate exposure literature demonstrates "adverse health outcomes in the offspring." Clemmensen et al., Prenatal Exposure to Nitrate in Drinking Water and Adverse Health Outcomes in the Offspring: A Review of Current Epidemiological Research, 10 Current Envtl. Health Rep.250, 250-63 (2023), hereinafter Exhibit C. Applicant further argues the Perrin and Kramer references are directed to dissimilar formulation disciplines. Perrin is directed toward maternal-fetal nutrient sufficiency. Kramer does not discuss co-formulating nitrate with elemental magnesium. The nitrogen metabolism and performance-enhancement domain of Kramer is scientifically and clinically distant from prenatal supplementation. Nothing in Kramer suggests any motivation to introduce nitrate salts into prenatal magnesium tablets. Those are chemically and physiologically distinct design spaces and the law treats formulation incompatibility itself as a teaching away. Leo V. Rea held that ingredient incompatibility is a legally sufficient reason why a person having ordinary skill in the art would not make the combination. Leo Pharmaceutical Products, Ltd. v. Rea, 726 F.3d 1346 (Fed. Cir. 2013).
The above assertions are not found persuasive because the examiner contends that a proper motivation the references is indeed provided by the examiner. Kramer et al. teach compositions for human or animal consumption administered orally (capsules, tablets, powders, liquids, etc.) to enhance athletic performance, nutrient delivery to muscles, and solubility. Nitrates provide nitric oxide (NO) benefits (vasodilation, improved blood flow). This is not pregnancy specific contrary to Applicant’s assertions. The examiner maintains that one of ordinary skill in the art would have been motivated to combine Perrin et al. and Kramer et al. for several reasons for several reasons because first both references are in nutritional supplementation for humans. Perrin et al. supplies magnesium (and other minerals/vitamins) for general health/pregnancy needs; Kramer adds nitrate-enhanced amino acids (e.g. proline nitrate) for improved solubility, absorption, muscle support, and NO-mediated benefits (e.g., better circulation, which complements magnesium’s roles in muscle relaxation and cardiovascular health). The examiners notes that magnesium deficiency is common (including in pregnancy but not limited to it). Nitrates/NO precursors improve blood flow and nutrient delivery-combined with magnesium. Proline supports collagen/connective tissue, relevant broadly in pregnancy for tissue expansion. One of ordinary skill in the art would predictably combine them to create a more comprehensive oral supplement. Perrin et al. does not criticize or exclude nitrates, amino acids, or proline. It is silent on them leaving room for improvement. Kramer’s teachings apply broadly to human consumption, not excluding prenatal contexts. Pregnancy supplementation often builds on general nutritional knowledge; one of ordinary skill in the art would not view pregnancy as a special physiologic domain that forbids nitrate addition especially given known safe uses of nitrates in foods/diets and nitric oxide benefits in vascular benefits. Adding a known beneficial component such as proline nitrate to known base magnesium containing composition is predictable variation. Mere argument of no teaching/suggestion is unpersuasive as obviousness does not require the references to be identical purpose or explicitly suggest the exact combination. The examiner would like to bring to Applicant’s attention that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." Id. at 554, 31 USPQ2d at 1132.). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Perrin et al. is not limited to compositions for pregnant women. Perrin et al. teach compositions and methods of administering compositions for both prophylactic and therapeutic nutritional supplementation. Specifically, for example, the present invention relates to novel compositions of vitamins, minerals, and omega-3 fatty acids that can be used to supplement the nutritional deficiencies observed in patients throughout physiologically stressful states, which, in certain embodiments of the present invention, include prenatal, pregnant and breast-feeding women (see paragraph 0010). The present invention relates to various vitamin, nutrient and mineral compositions and kits for nutritional supplementation and methods of administration of compositions and kits for nutritional supplementation in, for example, subjects in physiologically stressful states, such as occur during pregnancy, lactation, or in need thereof (paragraph 0002). When increased nutrient needs occur during pregnancy, lactation, or any other physiologically stressful state, nutritional supplementation serves a vital role in maintaining good health. Nutritional supplementation is especially pertinent to women contemplating conceiving a child because optimizing specific nutrients before, during, and after the physiological processes of pregnancy or lactation can have profound, positive, and comprehensive impacts upon the overall wellness of the developing and newborn child as well as on the safety and health of the mother. The present invention provides compositions, kits and methods designed to supplement the nutritional needs of individuals in physiologically stressful states (see paragraph 0004). The examiner reminds Applicant that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed."). Additionally, the examiner notes that although Perrin et al. do not teach the inclusion of potassium nitrate (elected species), Perrin et al. do teach the inclusion of another compound that contains the nitrate anion. Perrin et al. teach in another specific embodiment, vitamin B1 may be included in specific ranges or amounts for each specific form. When provided in their specific forms, the provided numerical range or amount includes the amounts of the specific form and/or compounds that are equivalent to the specific form. For example, vitamin B1 may be in the form of thiamine mononitrate and may be included in the amount of about 1.6 mg. Accordingly, in this example, “thiamine mononitrate in the amount of about 1.6 mg” would include 1.6 mg of thiamine mononitrate and/or its equivalents and would, for example, include a product having 1.6 mg allithiamine instead of thiamine mononitrate (paragraph 0054). Furthermore, the examiner reviewed Exhibits A-C and would take the position that those studies are drawn to the correlation between exposure to nitrates in drinking waters and its effects on pregnancy. Exhibit A (Manassaram et al.) in its conclusion section teach that “Pregnant women potentially exposed to nitrate levels primarily below the MCL for drinking water were unlikely to show methemoglobin levels above the physiologic normal. Water use practices such as the use of treatment devices to remove nitrates varied according to water source and should be considered in the assessment of exposure to nitrates in future studies.” It is very clear from this conclusion the reference is not advising no nitrate should be included as Applicant suggests. It is actually about concentrations or amounts and perhaps also the type of nitrates present.
Exhibit B (Lin et al.) teach that under discussion section this review has some limitations. First, most of the studies were carried out in US and Europe. Given that nitrate levels in drinking water vary widely among different regions and countries, findings from these studies should be interpreted with caution when extrapolated to other regions. Second, the studies included in this systematic review do not consistently account for other potential confounding factors such as maternal diet, nitrosatable drug use, and antioxidant intake. Third, the concentration of nitrate in water often fluctuates with the season. Not all studies included in this review took seasonal variation of nitrate into account in the measurement of exposure or as a factor in the adjusted model. Nitrogen shows significant seasonal relationships with high-intensity agriculture, with the difference between summer and winter water quality increasing as the proportion of high intensity agriculture in a catchment increases. For example, spatial modelling in New Zealand showed that regions dominated by high-intensity agriculture typically have poorer clarity, turbidity and nutrient concentrations in winter than in summer. Fourth, in meta-analysis of observational studies, it is challenging or impossible to identify any unpublished studies, as pre-registration of a protocol is not mandatory⁷. Finally, of all the pre-specified outcomes, only a few outcomes could be incorporated into a meta-analysis to help determine the overall association. Sixteen studies have evaluated the nitrate in drinking water and adverse reproductive and birth outcomes, but the number of studies of any individual outcome was limited. Although some outcomes were reported by more than one study, studies using different designs cannot be combined. We conclude that currently there is sufficient evidence of a possible association between nitrate in drinking water and preterm birth and specific congenital anomalies, to warrant nitrate exposure monitoring and reporting, and regular review as new evidence becomes available. It is very clear the above conclusion cannot be equated to nitrates cannot be included in supplement compositions tailored to pregnant women.
Exhibit C (Clemmensen et al. ) teach in the summary section that the reviewed studies showed some indications of higher risk of preterm delivery, lower birth weight, birth defects, and childhood cancer related to prenatal exposure to nitrate. However, the numbers of studies for each outcome were sparse, and some of the results were conflicting. We suggest that there is a need for additional studies and particularly for studies that include information on water consumption patterns, intake of nitrate from diet, and intake of nitrosatable drugs. The examiner takes the position that the above teachings cannot be equated for avoiding or not including nitrates in supplement compositions tailored to pregnant women.
Thirdly, contrary to Applicant’s assertions, solely to rebut Applicant’s arguments the examiner as set forth below provides Cottrell et al. ( J Physiol 595.15 (2017) pp 5095–5102) as evidence 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. 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). It is a clear evidence that nitrates can be administered during pregnancy contrary to Applicant’s assertions.
Furthermore, in terms of the combinability of Perrin et al. and Kramer et al., the examiner reminds Applicant that the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below). The examiner indeed provided a proper motivation as described above which are incorporated herein by reference. Applicant failed to point in a substantive manner how, where, and why the examiner erred on the motivation. A prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983).
Applicant further argues Perrin only Teaches and Suggests a Supplement-Label Shorthand For Mg Content From Ionic Compounds, Not "Elemental Magnesium" as Disclosed and Claimed by Applicant. Applicant argues Elemental magnesium is not normally stable or used for oral administration in human supplement products. In regard to the previously submitted Declarations (hereinafter Exhibit-D_Cornett and Exhibit-E_Bannister), Dr. Cornett explains that "uncharged magnesium is not considered shelf-stable for such products" and that, because magnesium metal "is known tobe highly reactive in the presence of oxygen and water," "it would not be reasonable to contemplate the use of the elemental form of magnesium metal (in its unchanged state) in an ingestible formulation." Exhibit-D_Cornett, Paragraph 8. Dr. Bannister similarly confirms the commercial and technical baseline that daily mineral supplements "do not contain the elemental forms of metals (in their uncharged state)" but instead contain "ionic ('salt') forms of those metals," including oxides, because uncharged metals are "very poorly water soluble," whereas "charged state forms, such as salt forms or oxides, are used for providing metal supplementation in dietary supplement products." Exhibit-E_Bannister, Paragraph 7. Accordingly, when Perrin is read through the lens of ordinarysupplement practice (as confirmed by the Declarations), Perrin does not provide an explicit teaching that uncharged elemental magnesium is a suitable oral ingredient for human consumption. The presumption in this field is ionic magnesium compounds, not reactive Mg. Applicant further argues by contrast, for magnesium (and similarly zinc and calcium), Perrin does not say an example of "elemental magnesium" is "elemental magnesium". Instead, Perrin's elemental magnesium definition expressly sweeps in salts, chelates and other non-chelated inorganic compounds, including the formulations "elemental magnesium, in the form of a salt, in a chelated form, in a non-chelated form" followed by a list of such conventional magnesium forms. See Perrin [0018], which is reproduced below (emphasis added).
The above assertions are not found persuasive because a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed."). Perrin et al. indeed teach elemental magnesium contrary to Applicant’s assertions. 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 magnesium is in the form selected from one or more of the group consisting of elemental magnesium, in the form of a salt, in a chelated form, in a non-chelated form, magnesium acetate, magnesium carbonate, magnesium gluconate, magnesium chloride, magnesium citrate, magnesium silicate, magnesium stearate, magnesium sulfate, magnesium oxide, and magnesium chelated to an amino acid (see claim 2). The compositions, kits and methods of the present invention may comprise or use magnesium. Magnesium is found primarily in both bone and muscle and is important for over 300 different enzyme reactions. A primary function of magnesium is to bind to phosphate groups in adenosine triphosphate (ATP), thereby forming a complex that assists in the transfer of ATP phosphate. Magnesium also functions within cells as a membrane stabilizer. Magnesium plays roles in nucleic acid synthesis, glycolysis, transcription of DNA and RNA, amino acid activation, membrane transport, transketolase reactions, and protein synthesis. James L. L. Groff et al., ADVANCED NUTRITION AND HUMAN METABOLISM 341 (2d ed. 1996). It is also involved in the formation of cAMP, a cytosolic second messenger that plays a role in cell signaling mechanisms. Magnesium also functions both synergistically and antagonistically with calcium in neuromuscular transmission. RDA, supra at 188. Specifically, magnesium is critical for the maintenance of electrochemical potentials of nerve and muscle membranes and the neuromuscular junction transmissions, particularly important in the heart. Not surprisingly, magnesium deficiency is tied to cardiovascular disease and hypertension. Agus et al., 17 CRIT. CARE CLIN. 175-87 (2001). Indeed, oral magnesium therapy improves endothelial function in patients with coronary disease. Shechter et al., 102 CIRCULATION 2353-58 (2000) (paragraph 0100). Magnesium is available in a variety of salts and can be included in the compositions, kits and methods of the present invention in either chelated or nonchelated form. In one specific embodiment of the present invention, magnesium may be included in the forms of elemental magnesium, in the form of a salt, in a chelated form, in a non-chelated form, magnesium acetate, magnesium carbonate, magnesium gluconate, magnesium chloride, magnesium citrate, magnesium silicate, magnesium stearate, magnesium sulfate, magnesium oxide, and magnesium chelated to an amino acid (magnesium glycinate, magnesium aspartate) (paragraph 0101). In another specific embodiment, magnesium may be present in the amounts ranging from about 10 mg to about 30 mg. In another embodiment, magnesium may be present in the amounts ranging from about 16 mg to about 24 mg. In another embodiment, magnesium may be present in the amounts ranging from about 18 mg to about 22 mg. In another embodiment, magnesium may be present in the amount of about 20 mg (paragraph 0102).
Applicant further argues claim 1 does not recite "citric acid somewhere in the tablet." Claim 1 recites "an acid, wherein the composition produces an acidic pH when dissolved in an aqueous solution." A "diluent" selection rationale, especially one that is expressly framed as choosing "inert substances" for tablet size, does not teach or suggest selecting and dosing an "acid" to produce a particular aqueous pH outcome. The Office's statement that diluents are "functionally equivalent" and "substituting one diluent with another is prima facie obvious," does not reach the claim's functional requirement (acidic pH upon dissolution).
The above assertions are not found persuasive because first it should be noticed that Applicant elected citric acid as species for examination from the beginning of the history of prosecution of the instant Application. The examiner always indicated that the claims are examined with respect to the elected species throughout the record of prosecution. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, 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 diluent 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.). Additionally, the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below).
Applicant further argues with regard to the rejection over Dennis and Hughes, the rejection still fails as a matter of law because secondary references cannot cure a primary deficiency of motivation or expectation. See In re Ratti, 270 F.2d 810, 813 (C.C.P.A. 1959) ("a reference can be said to teach away when it discourages the route taken by the applicant"). Equally, Stratoflex holds that a defective prima facie case cannot be rehabilitated by merely appending more references after-the-fact. Stratoflex, 713 F.2d 1530, 1538 (Fed. Cir. 1983).
The above assertions are not found persuasive because as described above the rejection based on the combination teachings of Perrin et al. and Kramer et al. is maintained and addresses the claimed invention. Dennis et al. and Hughes et al. are merely added in the rejections to render obvious the amount of citric acid for reasons described above.
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
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