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 .
Priority
This application is a national stage entry of PCT/US2021/051104 filed on September 20, 2021, which claims priority to U.S. Provisional Application No. 63/081,205 filed on September 21, 2020.
Response to Amendment
Applicant’s amendment filed on August 5, 2026, amending claim 9 has been entered. Claims 1-7, 10-13, 26, 29-35, 39, 41-51 and 53-56 are cancelled. Claims 24, 25, 27-28, 36-38, 40 and 52 are withdrawn. Claims 8-9, 14-25, 27-28, 36-38, 40 and 52 are currently pending.
Response to Arguments
Due to Applicant’s amendment to claim 9, the previous rejection of claim 9 under 35 USC 112(b) is hereby withdrawn.
Applicant's arguments filed August 5, 2026 with respect to the rejection under 35 USC 103 have been fully considered but they are not persuasive.
Applicant argues that the claimed composition has been shown to achieve significantly improved efficacy, which is very much surprising and entirely unexpected even considering the teaching of the cited references. Applicant argues that the claimed composition comprises 4 compounds (spermidine, 1-MNA, PEA and OEA) or their precursors that were identified by the inventors to elicit beneficial functionalities of human plasma, mimicking the health effects observed after prolonged fasting, including cholesterol efflux capacity and altering the immunomodulatory capacity towards a more anti-inflammatory functional phenotype (see paragraph [0044] of the present application). Applicant argues that the claimed composition is capable of inducing anti-inflammatory, anti-oxidant, immune-modulatory effects and longevity enhancing effects. Applicant argues that the inventors identified four metabolites: spermidine, 1-MNA, PEA, and OEA, that were significantly upregulated in the plasma of humans who performed prolonged fasting in a clinical trial and these four metabolites were able to replicate the effects induced by plasma of prolonged fasting individuals in vitro and in vivo. Applicant argues that the four metabolites provided anti-inflammatory effects, anti-oxidant effects, immune-modulatory effects, reduced nitric oxide synthase (NOS) activity with a corresponding increase in arginase activity, longevity enhancement effects and maintenance in cholesterol efflux ability. Applicant argues that these therapeutic effects are significantly enhanced when the four metabolites were administered in combination. Applicant argues that these effects could not have been expected from the three cited references, either viewed separately or together and the cited references would not provide any hint that spermidine, 1-MNA, PEA and OEA would complement each other's activity in all the therapeutic effects tested in Figure 5 of the present application.
In response to applicant's argument that the cited references do not teach that the combination produces the same therapeutic effects as demonstrated in the instant specification, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the instant case, the prior art of record, renders obvious combining the same components as claimed for different reasons than Applicant.
Fu et al. teaches compositions comprising OEA and OEA-like compounds including PEA for use in reducing food intake and treating obesity. Fu et al. further teaches that these OEA-like compounds and OEA-like modulators of the invention may be used in combination with other compounds of the invention or with other drugs that may also be useful in dieting or the treatment, prevention, suppression or amelioration of body fat [0206]. Matsumoto et al. teaches that 1-methylnicotinamide, spermidine and their precursors nicotinic acid (niacin), arginine, ornithine and putrescine are useful as GLP-1 secretagogues for promoting insulin secretion, decreasing blood glucose level, preventing or treating diabetes, preventing or improving obesity, and suppressing appetite.
Accordingly, prior to the effective filing date of the claimed invention it would have been obvious to a person of ordinary skill in the art to combine the teachings of Fu et al. which teaches compositions comprising OEA and OEA-like compounds including PEA for use in reducing food intake and treating obesity and further teaches that these OEA-like compounds and OEA-like modulators of the invention may be used in combination with other compounds of the invention or with other drugs that may also be useful in dieting or the treatment, prevention, suppression or amelioration of body fat; with the teachings of Matsumoto et al. which teaches that 1-methylnicotinamide, spermidine and their precursors including nicotinic acid (niacin), arginine, ornithine and putrescine are useful as GLP-1 secretagogues for promoting insulin secretion, decreasing blood glucose level, preventing or treating diabetes, preventing or improving obesity, and suppressing appetite.
Thus, since the cited prior art teaches that each of the components as claimed in the instant composition are useful for treating obesity and suppressing appetite, a person of ordinary skill in the art would have been motivated to combine the components into one improved formulation for treating obesity and suppressing appetite. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980). Thus, based on the prior art cited, a person of ordinary skilled artisan would have been motivated to combine the claimed components with a reasonable expectation of providing an improved formulation as compared to each component individually.
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).
Thus Applicant’s arguments are found not persuasive.
In addition, with respect to Applicant’s allegations of unexpected results, 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) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
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In the instant case, Applicant’s claims are drawn to a composition comprising spermidine or a precursor thereof, 1-methylnicotinamide (1-MNA) or a precursor thereof, palmitoylethanolamide (PEA) or a precursor thereof, and oleoylethanolamide (OEA) or a precursor thereof in an amount sufficient to induce an anti-inflammatory, anti-oxidant, and/or anti-apoptotic effect in a subject. However, with the exception of nicotinamide, no data demonstrating improved effects comprising a combination comprising precursors of the claimed components has been shown. The data shown in the instant specification utilize a combination of spermidine, 1-methylnicotinamide (1-MNA) or nicotinamide, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA). Moreover, the data in the instant specification utilize specific amounts for each component and with the exception of claim 19, no specific amounts for each component are claimed. The doses utilized include 5mg of spermidine, 250mg of nicotinamide, 400mg of PEA, 200mg of OEA; 10mg of spermidine, 500mg of nicotinamide, 800mg of PEA, 400mg of OEA or 15mg of spermidine, 750mg of nicotinamide, 1200mg of PEA, 600mg of OEA (page 40 of specification). Thus, Applicant’s results are not commensurate in scope with the claimed invention.
In addition, Applicant’s findings are found not persuasive since as detailed in the rejection of record, the references cited teach dosages for each component that overlap with the dosages as claimed in claim 19, and therefore, in addition to treating obesity and inducing weight loss, the composition rendered obvious over the prior art teachings will also necessarily have the same properties as claimed and disclosed in the instant specification. In addition, Gut et al. also teaches that the nicotinamide riboside or NAD+ precursor can treat or prevent oxidative stress, a condition associated with oxidative stress, a reduced level of glutathione, or a condition associated with a reduced level of glutathione [0001]. Thus Gut et al. teaches the nicotinamide riboside and NAD+ precursors are antioxidants and anti-inflammatory. Furthermore, Fu et al. also teaches that the compositions comprising an OEA-like modulator of PPARa have anti-inflammatory properties as they can also treat inflammatory conditions ([0007], [0017]-[0019). Accordingly, prior to the effective filing date of the claimed invention, an ordinary skilled artisan would have been motivated to include effective amounts of each component to treat obesity and suppress appetite which will necessarily result in a composition having the additional properties of anti-inflammatory and antioxidant.
In addition, similar to the data in the instant specification, Fu et al. examined the effects of starvation on OEA and other FAE levels [0281]. Fu et al teaches in one embodiment, the invention provides methods of treatment wherein individuals needing to lose weight and/or body fat are tested for OEA levels before and/or during fasting, wherein individuals with low levels of OEA prior to or in response to fasting are particularly then targeted for OEA treatment [0282]. Fu et al. demonstrates results that indicate that circulating OEA levels increase transiently during starvation, which is selective for OEA and other FAEs, and coincides temporally with the rise in blood glycerol and b-hydroxybutyrate (Table 1), and signals the shift of energy metabolism from carbohydrates to fatty acids as primary fuel [0283]. Therefore, it would have been obvious to a person of ordinary skill in the art to administer OEA and other fatty acid components in amounts that correlate with the same level or higher than circulating levels of the components achieved through at least 20 hours of fasting, since said levels correlate with the shift of energy metabolism from carbohydrates to fatty acids as primary fuel and thus this shift in energy metabolism would have been expected to result in weight loss. Thus Fu et al. provides further motivation to administer the same amounts of OEA and PEA to arrive at the instant invention.
Thus, for these reasons and for reasons of record, the previous rejection under 35 USC 103 is hereby maintained and reproduced below. This action is FINAL.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 8, 9 and 14-23 are rejected under 35 U.S.C. 103 as being unpatentable over Fu et al. U.S. Publication No. 2005/0054730 A1 in view of Matsumoto et al. JP-2020097531 A (published on 06-25-2020) (Machine English translation provided) and Gut et al. WO 2020/064946 A2.
Claims 8, 9 and 14-23 are drawn to a composition comprising spermidine or a precursor thereof, 1-methylnicotinamide (1-MNA) or a precursor thereof, palmitoylethanolamide (PEA) or a precursor thereof, and oleoylethanolamide (OEA) or a precursor thereof in an amount sufficient to induce an anti-inflammatory, anti-oxidant, and/or anti-apoptotic effect in a subject.
Fu et al. teaches compounds, compositions, and methods for the treatment of disorders and conditions mediated by PPARa (abstract). Fu et al. teaches that the invention relates to the surprising discovery that oleoylethanolamide (OEA) is an endogenous high affinity and selective ligand of PPARa and the compounds of the invention include, but are not limited to, specific PPARa agonists sharing the receptor binding properties of OEA and fatty acid alkanolamides and their homologs which also are PPARa agonists (abstract).
Fu et al. teaches that the FAE (fatty acid ethanolamides) family is comprised for the most part of saturated and monounsaturated species, such as palmitoylethanolamide and oleoylethanolamide, which do not significantly interact with cannabinoid receptors [0014]. Fu et al. teaches that oleoylethanolamide (OEA) is a natural analogue of the endogenous cannabinoid anandamide, but unlike anandamide, OEA does not activate cannabinoid receptors [0015]. Fu et al. teaches that oleoylethanolamide is reported herein to be a potent and highly selective agonist of PPARa [0016].
Fu et al. teaches identifying other OEA-like compounds useful as PPARa agonists and for the treatment of diseases responsive to PPARa agonists such as obesity, an appetite disorder, overweight, a metabolic disorder, cellulite, Type II diabetes, insulin resistance, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, artherogenesis, an inflammatory disorder or condition, Alzheimer’s disease, Crohn's disease, vascular inflammation, an inflammatory bowel disorder, rheumatoid arthritis, thrombosis, asthma or cachexia [0017]-[0018].
Fu et al. further teaches pharmaceutical compositions comprising an OEA-like modulator of PPARa and methods of treating a disease or condition which is mediated by PPARa or therapeutically responsive to administration by a modulator of PPARa by administering an OEA-like modulator to a host or subject having the condition, wherein the disease or condition to be treated includes, but are not limited to, metabolic disorders, obesity, excess body fat, cellulite, Type II diabetes, insulin resistance, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, artherogenesis, an inflammatory disorder or condition, Alzheimer’s disease, Crohn's disease, a vascular inflammation, an inflammatory bowel disorder, rheumatoid arthritis, asthma, thrombosis or cachexia [0019].
Fu et al. teaches compounds, compositions, and methods for modulating appetite or treating an appetency disorder, reducing body fat and for treating or preventing obesity, and overweight in mammals and the diseases associated with these health conditions [0031]. Fu et al. teaches methods for reducing body fat or body weight and for treating or preventing obesity or overweight and for reducing food intake by administration of pharmaceutical compositions comprising an OEA-like compound in an amount sufficient to reduce body fat, body weight or prevent body fat or body weight gain [0031]. Fu et al. teaches in some embodiments, the fatty acid moiety of the fatty acid alkanolamide compound, homologue, or analog is a fatty acid selected from the group consisting of oleic acid, palmitic acid, elaidic acid, palmitoleic acid, linoleic acid, a-linolenic acid, and g-linolenic acid [0033]. Fu et al. further teaches in a further embodiment, the fatty acid alkanolamide is oleoylethanolamide [0034].
Fu et al. specifically teaches preferred compounds include those in which the fatty acid moiety comprises oleic acid, elaidic acid, or palmitic acid and such compounds include oleoylethanolamide, elaidylethanolamide and palmitoylethanolamide [0122]-[0127].
Fu et al. further teaches that generally, dosage forms are suitable for oral, nasal, pulmonary or transdermal administration and comprise from about 0.001 mg to about 1000 mg admixed with a pharmaceutically acceptable carrier or diluent [0199].
Fu et al. teaches that administration of an appropriate amount of the compounds may be by any means known in the art such as, for example, oral or rectal, parenteral, intraperitoneal, intravenous, subcutaneous, subdermal, intranasal, or intramuscular, and in some embodiments, administration is transdermal [0200].
Fu et al. teaches that formulations suitable for oral administration can consist of (a) liquid solutions, (b) capsules, sachets or tablets; (c) suspensions in an appropriate liquid; and (d) suitable emulsions [0201]. Fu et al. teaches injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described [0202]. With respect to transdermal routes of administration, dermal or skin patches are a preferred means for transdermal delivery of the compounds of the invention [0203].
Fu et al. further teaches that the OEA-like compounds and OEA-like modulators of the invention may be used in combination with other compounds of the invention or with other drugs that may also be useful in dieting or the treatment, prevention, suppression or amelioration of body fat [0206]. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention [0206].
Fu et al. specifically demonstrates suppression of Food Intake by OEA and Other FAEs, including Palmitoylethanolamide ([0287]-[0288], [0290],[0292]). Fu et al. further demonstrates that Oleoylethanolamide (OEA) decreases body weight not only by suppressing appetite, but also by possibly enhancing body fat catabolism and palmitoylethanolamide (PEA) also has a partial effect [0310].
Thus Fu et al. teaches compositions comprising OEA and OEA-like compounds including PEA for use in reducing food intake and treating obesity. Fu et al. further teaches that these OEA-like compounds and OEA-like modulators of the invention may be used in combination with other compounds of the invention or with other drugs that may also be useful in dieting or the treatment, prevention, suppression or amelioration of body fat [0206].
Fu et al. does not teach combining OEA and PEA with spermidine or a precursor thereof, and 1-methylnicotinamide (1-MNA) or a precursor thereof.
Matsumoto et al. teaches a GLP-1 secretagogue, a composition containing the GLP-1 secretagogue, and a food or drink containing the GLP-1 secretagogue (technical field). Matsumoto et al. teaches a GLP-1 secretion promoter containing one or more compounds selected from the group consisting of propionic acid, butyric acid, valeric acid, pantothenic acid, cholic acid, 3-amino isobutyric acid, γ-aminobutyric acid, 2-aminobutyric acid, pipecolic acid, ornithine, citrulline, tyrosine methyl ester, piperidine, taurine, pyridoxal, pyridoxamine, pyridoxine, sarcosine, N, N-dimethyl glycine, cytosine, 1,3-diamino propane, nicotinic acid, indole-3-acetamide, D-alanine, 5-hydroxy lysine, 1-methyl nicotinamide, thiamine, carnitine, gluconic acid, prostaglandin E2, methionine sulfoxide, spermidine and spermine (abstract).
Matsumoto et al. teaches that in the intestinal tract, there are endocrine cells that secrete gastrointestinal hormones and regulate the functions of other organs including incretins which are secreted into the blood with food intake, that act on pancreatic β cells and secrete insulin (background). This incretin not only promotes insulin secretion, but also promotes pancreatic β-cell regeneration and also acts on the central nervous system via the vagus nerve to suppress feeding behavior, and thus it is attracting attention as a target for therapeutic drug development for diabetes and obesity (background). There are two types of incretins, a glucose-dependent insulin secretion stimulating polypeptide (glucose-dependent insulinotropic peptide; GIP) and a glucagon-like peptide-1 (GLP-1) (background).
Matsumoto et al. teaches the use of natural substances useful as GLP-1 secretagogue agents (description page 3). The GLP-1 secretagogue agents include, ornithine, nicotinic acid, 1-methylnicotinamide, spermidine and spermine (page 3 and Table 1 page 10 of original patent). These substances are orally administered to a living body by inserting a carrier such as a capsule, or a mode in which a precursor of these substances is orally administered to a living body and enterobacteria produce these substances (page 3).
Matsumoto et al. teaches that the GLP-1 secretagogue may consist of one of the above compounds or a mixture of two or more, because each of the above compounds alone has the ability to promote GLP-1 secretion (page 3).
Matsumoto et al. teaches compositions containing GLP-1 Secretagogues for promoting insulin secretion, decreasing blood glucose level, preventing or treating diabetes, preventing or improving obesity, and suppressing appetite (pages 3-5). The composition of the present invention may be a pharmaceutical composition or a food composition, and in addition to ordinary foods and drinks, the food composition also includes modes such as seasonings and supplements (page 3-5).
Matsumoto et al. teaches that the administration method of the composition containing the GLP-1 secretagogue is not particularly limited and may be oral administration or parenteral administration (page 5). Matsumoto et al. teaches that the dose of the agent is generally in the amount of about 1 μg/kg to 1000 mg/kg per day for an adult and the range is preferably 10 μg/kg to 100 mg/kg, more preferably 100 μg/kg to 100 mg/kg (page 5).
Matsumoto et al. teaches in one aspect, this invention relates to food-drinks containing the GLP-1 secretion promoter of this invention, wherein the GLP-1 secretagogue can be added to any food or beverage, and the type of food or beverage is not particularly limited (page 5). The “food” can be used for all foods such as Japanese food, Western food, Chinese food, Asian food and the like, for example, it is seasoned, stir-fried, stewed, rice, soup, pasta sauce, pot, soup, stew and the like (page 5). "Beverages" include, for example, milk drinks, soups for drinks such as canned products, yogurt, soy milk, sports drinks, fruit juice drinks, alcoholic beverages, tea, coffee, green tea, cocoa and the like, and without limitation, the GLP-1 secretagogue may be included in seasonings such as soy sauce, sauce, soup, mirin, and cooking sake (page 5).
Thus Matsumoto et al. teaches that 1-methylnicotinamide, spermidine and their precursors nicotinic acid (niacin), arginine, ornithine and putrescine are useful as GLP-1 secretagogues for promoting insulin secretion, decreasing blood glucose level, preventing or treating diabetes, preventing or improving obesity, and suppressing appetite.
Accordingly, prior to the effective filing date of the claimed invention it would have been obvious to a person of ordinary skill in the art to combine the teachings of Fu et al. which teaches compositions comprising OEA and OEA-like compounds including PEA for use in reducing food intake and treating obesity and further teaches that these OEA-like compounds and OEA-like modulators of the invention may be used in combination with other compounds of the invention or with other drugs that may also be useful in dieting or the treatment, prevention, suppression or amelioration of body fat; with the teachings of Matsumoto et al. which teaches that 1-methylnicotinamide, spermidine and their precursors including nicotinic acid (niacin), arginine, ornithine and putrescine are useful as GLP-1 secretagogues for promoting insulin secretion, decreasing blood glucose level, preventing or treating diabetes, preventing or improving obesity, and suppressing appetite.
Thus, since the cited prior art teaches that each of the components as claimed in the instant composition are useful for treating obesity and suppressing appetite, a person of ordinary skill in the art would have been motivated to combine the components into one improved formulation for treating obesity and suppressing appetite. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Although Matsumoto et al. does not teach the 1-MNA precursors as claimed in claim 15 of the instant application, consisting of nicotinamide, niacinamide and nicotinamide riboside, prior to the effective filing date of the claimed invention the 1-MNA precursors as claimed in claim 15 were also known to be beneficial in treating obesity and suppressing appetite.
Gut et al. teaches the administration of at least one nicotinamide riboside or NAD+ precursor for the treatment of at least one physical state selected from the group consisting of pre-diabetes, gestational diabetes, type I diabetes, type II diabetes, complications from diabetes, insulin resistance, metabolic syndrome, dyslipidemia, overweight, obesity, etc. [0015]-[0017]. Gut et al. teaches the administration of nicotinamide riboside and NAD+ precursors including Tryptophan, Nicotinic Acid, Nicotinamide, reduced form of nicotinamide riboside (NRH), Nicotinamide Mononucleotide (NMN), Trigonelline, Nicotinic acid mononucleotide, Nicotinic acid riboside, and mixtures thereof [0078].
Gut et al. teaches that the daily doses for a 60 kg subject can be as follows Nicotinamide Riboside: 0.001 to 1,000 mg/day [00101]. Gut et al. also teaches that the nicotinamide riboside or NAD+ precursor can be administered in an amount of about 0.001 mg/day to about 2000 mg/day, preferably about 0.001 mg/day to about 1000 mg/day [00102].
Thus, Gut et al. teaches that 1-MNA precursors in addition to nicotinic acid (niacin), including Nicotinamide and nicotinamide riboside are useful in the treatment of obesity.
Accordingly, prior to the effective filing date of the claimed invention it would have been obvious to a person of ordinary skill in the art to combine the teachings of Fu et al. which teaches compositions comprising OEA and OEA-like compounds including PEA for use in reducing food intake and treating obesity and further teaches that these OEA-like compounds and OEA-like modulators of the invention may be used in combination with other compounds of the invention or with other drugs that may also be useful in dieting or the treatment, prevention, suppression or amelioration of body fat; with the teachings of Matsumoto et al. which teaches that 1-methylnicotinamide, spermidine and their precursors including nicotinic acid (niacin), arginine, ornithine and putrescine are useful as GLP-1 secretagogues for promoting insulin secretion, decreasing blood glucose level, preventing or treating diabetes, preventing or improving obesity, and suppressing appetite; and with the teachings of Gut et al. which teaches that 1-MNA precursors in addition to nicotinic acid (niacin), including Nicotinamide and nicotinamide riboside are useful in the treatment of obesity.
Thus, since the cited prior art teaches that each of the components as claimed in the instant composition, specifically spermidine and precursors thereof, 1-methylnicotinamide (1-MNA) and precursors thereof, palmitoylethanolamide (PEA) and precursors thereof, and oleoylethanolamide (OEA) and precursors thereof, are useful for treating obesity and suppressing appetite, a person of ordinary skill in the art would have been motivated to combine these components into one improved formulation for treating obesity and suppressing appetite. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
With respect to the amounts as claimed in instant claim 19, 5-15 mg spermidine, 400-1200 mg PEA, 300-600 mg OEA, and 250-1000 mg nicotinamide, and the ratio as claimed in instant claim 18, Fu et al. teaches dosages of OEA and PEA from about 0.001 mg to about 1000 mg [0199]; and Matsumoto et al. teaches dosages for the agents of about 1 μg/kg to 1000 mg/kg per day for an adult and the range is preferably 10 μg/kg to 100 mg/kg, more preferably 100 μg/kg to 100 mg/kg (page 5). Thus Matsumoto et al. teaches that for a 70 kg subject the range of dosages for 1-MNA or precursors thereof and spermidine or precursors thereof is preferably 7 mg to 7 g. In addition, Gut et al. teaches that the daily doses for a 60 kg for Nicotinamide Riboside is 0.001 to 1,000 mg/day and the nicotinamide riboside or NAD+ precursor can be administered in an amount of about 0.001 mg/day to about 2000 mg/day, preferably about 0.001 mg/day to about 1000 mg/day [00101]-[00102].
In the case where the claimed ranges "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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.").
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
Therefore, since the dosages as claimed for each component overlap with the dosages taught in the prior art, the composition rendered obvious over the prior art teachings is necessarily in an amount sufficient to induce an anti-inflammatory, antioxidant and/or anti-apoptotic effect in a subject as claimed. In addition, Gut et al. also teaches that the nicotinamide riboside or NAD+ precursor can treat or prevent oxidative stress, a condition associated with oxidative stress, a reduced level of glutathione, or a condition associated with a reduced level of glutathione [0001]. Thus Gut et al. teaches the nicotinamide riboside and NAD+ precursors are antioxidants and anti-inflammatory. Furthermore, Fu et al. also teaches that the compositions comprising and OEA-like modulator of PPARa have anti-inflammatory properties as they can also treat inflammatory conditions ([0007], [0017]-[0019). Accordingly, prior to the effective filing date of the claimed invention, an ordinary skilled artisan would have been motivated to include effective amounts of each component to treat obesity and suppress appetite which will necessarily result in a composition having the additional properties of anti-inflammatory and antioxidant.
Claim 9 is rendered obvious since the cited prior art references teach administration of overlapping amounts of each component and as such, said amounts taught in the prior art will necessarily result in the same effects as claimed which is amounts that are the same level or higher than circulating levels of the components achieved through at least 20 hours of fasting.
In addition, Fu et al. examined the effects of starvation on OEA and other FAE levels [0281]. Fu et al teaches in one embodiment, the invention provides methods of treatment wherein individuals needing to lose weight and/or body fat are tested for OEA levels before and/or during fasting, wherein individuals with low levels of OEA prior to or in response to fasting are particularly then targeted for OEA treatment [0282]. Fu et al. demonstrates results that indicate that circulating OEA levels increase transiently during starvation, which is selective for OEA and other FAEs, and coincides temporally with the rise in blood glycerol and b-hydroxybutyrate (Table 1), and signals the shift of energy metabolism from carbohydrates to fatty acids as primary fuel [0283]. Therefore, it would have been obvious to a person of ordinary skill in the art to administer OEA and other fatty acid components in amounts that correlate with the same level or higher than circulating levels of the components achieved through at least 20 hours of fasting, since said levels correlate with the shift of energy metabolism from carbohydrates to fatty acids as primary fuel and thus this shift in energy metabolism would have been expected to result in weight loss.
With respect to claim 20-23 of the instant application which claim the dosage forms of the composition, said claims are rendered obvious since as detailed above, each of the claimed dosages forms are taught in the prior art cited. Accordingly, it would have been within the skill of an ordinary skilled artisan to determine and prepare a suitable dosage form based on the teachings and suggestions of the prior art.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 8-9 and 14-23 are rejected. Claims 1-7, 10-13, 26, 29-35, 39, 41-51 and 53-56 are canceled. Claims 24, 25, 27-28, 36-38, 40 and 52 are withdrawn. 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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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM
