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
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of the Claims
This action is in response to papers filed 01/19/26 in which claims 13-15 and 22-26 were cancelled; claim 1 was amended; and claims 24-34 were newly added. All the amendments have been thoroughly reviewed and entered.
Claims 1-7, 16-21 and 27-34 are under examination.
Objection
Claims 32 and 34 are objected for “nicotinamideand/or”. Space is missing between “nicotinamide” and “and”. Application is suggested to amend the claim 34 to “nicotinamide and/or”.
Withdrawn Objections/Rejections
The Examiner has re-weighted all the evidence of record. Any rejection and/or objection not specifically addressed below is hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Maintained-Modified Rejections
Modification Necessitated by Applicant' s Claim Amendments
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 6-7 and 27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Frati et al. (EP 3636254 A1).
Frati discloses a pharmaceutical compositions and oral nutritional supplements comprising spermidine and nicotinamide in a weight ratio from 1:3-1:100 for the treatment of CVD, diabetes mellitus, hypertension or heart failure (entire, para. [0011], [0015], [0022], [0058]-[0059], [0060], claims 1, 5, 10, 12) wherein said composition/nutritional supplement is administered orally (para. [0064]-[0065]. Frati discloses that these compositions are "particularly suitable for contrasting inflammatory processes" by "counteracting the formation of free radicals through the synergistic effect exerted by the various components" (para. [0001], [0004]-[0006], [0008], claim 9). Thus, Frati implicitly discloses the utility of spermidine in the prevention and/or alleviation of side effects caused by nicotinamide.
With the respect to claims 1-3 and 27, it is interpreted that the prior art treatment of diabetes mellitus falls within the meaning of the side effects caused by nicotinamide such as “an increase in blood glucose level, type 2 diabetes and/or an increase in blood insulin level” and/or “a glucose intolerance and/or obesity”, Frati anticipates the claimed invention.
In addition, Merriam-Webster dictionary defines “prevent” as “to keep from happening or existing”. In other words, the term “prevent” which is consistent with the instant specification (see para. [0034]) implies taking advance measure against something possible or probable. Therefore, the prior art method directing the administration of spermidine (alone or in combination of nicotinamide) inherently possessing a preventive effect for the same ultimate purpose (e.g., treatment of diabetes which is associated with an increase in blood glucose level, an increase in blood insulin level, and/or a glucose intolerance or obesity) anticipates the instant claims. Applicant’s attention is directed to Ex parte Novitski 126 USPQ 1389 (BOPA 1993) illustrating anticipation resulting from inherent use, absent a haec verba recitation for such prophylactic utility. In the instant case, as in Ex parte Novitski, the claims are directed to preventing a malady or disease with old and well known compounds of compositions. The prior art administering compounds inherently possessing a protective utility anticipates claims directed to such protective use.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 4-5, 16-21 and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Frati et al. (EP 3636254 A1) as applied to claims 1-3, 6-7 and 27 above, and further in view of Yamada et al (US 20140378708).
The teaching of Frati has been discussed above 102 rejection.
Frati does not expressly teach i) the instantly claimed molar ratio of spermidine and nicotinamide in claims 4, 16-19 and 32, and ii) whether the spermidine is provided as a plant extract such as wheat germ extract or a soybean extract recited in claims 20-21.
With respect to the specific molar ratio recited in claims 4 and 16-19, Frati discloses the weight ratio range from 1:3 to 1:100 instead of the molar ratio. The molar ratio of spermidine to nicotinamide for 1:3 weight ratio is approximately 1:3.57 whereas 1:100 weight ratio is equivalent to approximately 1:159. For instance, 1:3 weight ratio can be converted to a molar ratio by using following calculation: based on spermidine (C₇H₁₉N₃): approximately 145.25 g/mol and nicotinamide (C₆H₆N₂O): approximately 122.12 g/mol; assume a starting mass 1gm of spermidine and 3 gm of nicotinamide; moles of spermidine: 1 g / 145.25 g/mol ≈ 0.006885 mol and moles of nicotinamide: 3 g / 122.12 g/mol ≈ 0.024566 mol; divide both mole values by the smallest one (0.006885 mol): spermidine: 0.006885 mol / 0.006885 mol = 1 and nicotinamide: 0.024566 mol / 0.006885 mol ≈ 3.57).
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists, thus addressing the specific ratio of spermidine and nicotinamide in a molar ratio ranging from 1:5 to 1:100, from 1:5 to 1:75, from 1:5 to 1:50, from 1:8 to 1:25, from 1:10 to 1:15 in claim(s) 4 and 16-19 respectively. See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”).
Alternatively, the selection of any particular ratio or quantity of active agent amounts to little more than optimization of a result-effective parameter via routine experimentation, and considered obvious thereby since both of the teaching of Frati and the instant invention are drawn to the same composition containing the spermidine and nicotinamide as the active ingredient and to be useful for the same purpose, particularly treatment of diabetes mellitus. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where 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.
With respect to the specific source of spermidine recited in claims 5, 20-21, Yamada teaches that the polyamine such as spermidine can be obtained from plant source such as what germ and soybean (para. [0021], [0044]-[0045], [0052] and claim 10). Yamada also disclose that the polyamine composition can be used by being added to cosmetics, foods, medical and pharmaceutical products, quasi drugs, etc…(para. [0002] and [0050]) and that they are having a low salt concentration while a high polyamine concentration, in particular spermidine, can be produced and increased in the production efficiency (para. [0022]). Therefore, one having ordinary skill in the art would have been motivated to use spermidine from natural origine such as plant extract (e.g., wheat germ extract or a soybean extract) with expectation that they provide advantages over the synthetic or other source that are known in the art.
Claims 28-31 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Frati et al. (EP 3636254 A1) as applied to claims 1-3, 6-7 and 27 above, and further in view of Eisenberg et al. (WO 2010081204 A2)
The teaching of Frati has been discussed above 102 rejection.
Frati is silent about whether the instantly claimed spermidine can be administered as i) “a pharmaceutical salt” (claim 28), namely “salt of an inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, and boric acid…” (claim 29), ii) “intravenously” (claim 30), and iii) “in an amount of 0.05 to 0.5 mg/kg weight per day” (claims 31 and 34).
Regarding the specific salt-form limitation recited in claims 28–29, the intravenous delivery recited in claim 30, and the claimed spermidine dosage of 0.05–0.5 mg/kg body weight per day, Eisenberg discloses the use of polyamine compounds such as spermidine to activate or restore a normal autophagic pathway (entire document; e.g., p. 1, first para.). Eisenberg teaches the use of spermidine for autophagy activation to “lower glucose and increase glucose intolerance and/or to lower insulin and improve insulin signaling and/or treat insulin resistance and diabetes” (pp. 5, third para.; 6, first para.; 7, first para.). The reference also describes spermidine as useful for treating metabolic defects including non–insulin-dependent Type 2 diabetes mellitus, low glucose tolerance, and insulin resistance (p. 8). Eisenberg discloses pharmaceutically acceptable salts, including salts of inorganic and organic acids such as sulfuric, citric, maleic, acetic, oxalic, hydrochloride, and hydrobromide (p. 33). The reference teaches dosage ranges of 100 μg (0.1 mg) to 50 mg/kg body weight, with preferred oral ranges of 250 μg (0.25 mg)/kg to 30 mg/kg, more preferred 500 μg (0.5 mg) to 25 mg/kg, and most preferred 1 to 15 mg/kg (pp. 35; 164). Comparable ranges are disclosed for parenteral dosage forms (p. 35). Eisenberg also states a typical effective human dose of about 10 μg (0.01mg)/kg/day to about 100 mg/kg/day, preferably about 50 μg (0.05mg)/kg/day to about 50 mg/kg/day, and most preferably about 100 μg (0.1mg)/kg/day to 20 mg/kg/day (p. 164). The reference teaches administration by various routes, including oral, intravenous, subcutaneous, intramuscular, and other parenteral routes (pp. 156; 163), and indicates that an effective dosage and treatment protocol can be determined by conventional means—starting at a low dose in laboratory animals, increasing the dose while monitoring effects (e.g., histology, disease activity scores), and systematically varying the regimen (p. 164).
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists, thus addressing the specific amount of spermidine in an amount of 0.05 to 0.5mg/kg body weight per day. See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”).
The cited references, in combination, teach that spermidine is useful for treating diabetes—by lowering glucose, improving glucose tolerance, lowering insulin, enhancing insulin signaling, and treating insulin resistance—an ultimate purpose that aligns with the instant claimed invention. Also, the prior art makes clear that the delivery of spermidine in oral and/or intravenous administration, with the claimed salt form, and/or in amount of 0.05 to 0.5 mg/kg body weight was well known at the time of the invention was made. The prior art in combination makes clear that the determination of effective dosage and treatment protocol is within the ordinary skill in the art and would have determined by conventional means including by a clinician when determining an optimal dosage for a given patients (pp. 164). Therefore, one having ordinary skill in the art would have motivated to arrive at the claimed invention with reasonable expectation of success.
Response to Arguments
Applicant's arguments filed 01/19/2026 have been fully considered but they are not persuasive.
In response to 102 rejection, applicant argues:
“Frati et al. does not anticipate the method of claim 1 because Frati does not disclose a method of treating a patient in need of prevention and/or alleviation of side effects caused by nicotinamide. Frati et al. discloses compositions comprising spermidine, nicotinamide, and trehalose/lentztrehalose (see claim 1 of Frati et al.). These compositions exhibit antioxidant properties and can be used for the treatment of diseases caused by oxidative stress (e.g. inflammation, arteriosclerosis, diabetes) (see claim 12 of Frati et al.)”.
“The present invention is based on the surprising and unexpected finding that spermidine and/or pharmaceutically acceptable salt thereof can be used to prevent and/or alleviate side effects caused by nicotinamide and/or pharmaceutically acceptable salt thereof”.
The Examiner disagrees with the applicant’s argument. Unlike the applicant’s characterization, dependent claims 2–3 expressly define “the side effects caused by nicotinamide” as conditions affecting glucose and/or insulin homeostasis, specifically an increase in blood glucose level, type 2 diabetes, and an increase in blood insulin level. The specification of the instant application also identifies beneficiaries of the claimed invention as individuals at high risk of cardiovascular complications who are elderly and/or obese and who suffer from hypertension and/or diabetes mellitus/metabolic syndrome (see para. [0001], [0005]). This treatment population corresponds to the population identified in Frati (“CVD, diabetes mellitus, hypertension, or heart failure”). It is well known in the art that diabetes mellitus, including type 2 diabetes, is associated with increased blood glucose, increased blood insulin, and/or glucose intolerance. Accordingly, the patient populations and the administration of spermidine (alone or in combination with nicotinamide) taught in Frati are identical to the populations and therapeutic context recited in the instant claims. For these reasons, Frati implicitly discloses utility of spermidine for preventing and/or alleviating the recited side effects associated with nicotinamide.
The Examiner acknowledges that Frati does not explicitly state that the claimed adverse effects result from nicotinamide. However, where the prior art discloses administration of nicotinamide together with spermidine to the same patient population (i.e., patients with diabetes), any prophylactic or protective effect attributable to that combination may be inherent in the prior art method. Claim 6 of the instant application expressly permits administration of the composition before, together, or after nicotinamide; therefore, the Examiner finds that the claimed method falls within the prior‑art teaching of administering spermidine and nicotinamide together.
The breadth of the instant claims includes prophylactic utility to prevent side effects caused by nicotinamide—namely conditions associated with increased blood glucose, increased blood insulin, and/or glucose intolerance. Merriam‑Webster defines “prevent” as “to keep from happening or existing,” which is consistent with the specification’s use of “prevent” to mean taking advance measures against a possible or probable event (see para. [0034]). Thus, a prior‑art method that administered spermidine (alone or with nicotinamide) for the same ultimate purpose (e.g., treatment or management of diabetes, which is associated with the recited metabolic effects-CVD, hypertension and heart failures) inherently anticipates claims directed to such a preventive use. See Ex parte Novitski (BPAI) for an illustration of anticipation arising from inherent properties of prior‑art compositions or methods directed to a protective utility.
With respect to the submitted data purporting to show surprising and unexpected results, that data cannot be relied upon to overcome the rejection under 35 U.S.C. § 102. A prima facie case of anticipation under § 102 is not overcome by a showing of unexpected results. See In re Malagari, 499 F.2d 1297, 1302 (CCPA 1974). Evidence of unexpected results may be relevant to a nonobviousness analysis under 35 U.S.C. § 103, but it does not negate a finding of anticipation under § 102.
Even assuming arguendo that the alleged unexpected result—namely, that co‑administration of spermidine eliminates the negative side effects of nicotinamide—is supported by the proffered data, the examiner determines that such a result is not unexpected. For example, Eisenberg et al. (WO 2010081204 A2) teaches the use of spermidine for lowering glucose, increasing glucose intolerance, lowering insulin, improving insulin signaling, and treating insulin resistance and diabetes. Although the prior art does not explicitly state that nicotinamide administration causes negative effects on glucose control or increases the incidence of new‑onset diabetes, these negative effects were already known at the time the invention was made (see Reith and Armitage, Atherosclerosis, 245 (2016): 161–170; see also instant specification, para. [0008]). In other words, those differences are insignificant or would have been obvious to a person having ordinary skill in the art under the meanings of 103.
In response to the rejection under 35 U.S.C. § 103, Applicant argues that “Yamada does not even describe nicotinamide. Yamada essentially discloses the isolation of polyamines from plants, nothing more…”. In addressing Applicant’s contention 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); KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). Yamada was cited as a supplemental reference to address the limitation recited in claims 5 and 20–21, namely the source of spermidine in “an extract,” “a plant extract,” and/or “a wheat germ extract or a soybean extract.” As discussed in the rejection under §103, at the time the invention was made it was well known that polyamines such as spermidine can be obtained from plant sources such as wheat germ and soybean (see paras. [0021], [0044]–[0045], [0052] and claim 10). Therefore, a person of ordinary skill in the art would have been motivated to use spermidine from natural sources, such as plant extracts (e.g., wheat germ or soybean extracts), with a reasonable expectation of success because such sources were known to provide advantages over synthetic or other sources known in the art.
In response to the applicant’s argument that “although spermidine might be used to treat obesity, it was entirely unexpected that spermidine can also be used in the prevention and alleviation of insulin resistance in non‑obese (i.e., normal‑weight) subjects…,” the Examiner notes that those limitations are not recited in the pending claims. Moreover, the claimed prophylactic utility of spermidine—specifically, preventing conditions associated with elevated blood glucose, elevated blood insulin, and/or glucose intolerance—is supported by, and necessarily flows from, the prior‑art disclosures discussed above in the 35 U.S.C. § 102 rejection over Frati. For the reasons set forth above and of record, the claims therefore remain rejected as obvious and unpatentable over the combined teachings of the cited references under 35 U.S.C. § 103.
Conclusion
No claim is 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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/BRIAN-YONG S KWON/ Supervisory Patent Examiner, Art Unit 1613