Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant elects, without traverse, Group I (claims 2 and 10-12).
Claims 3-9 and 13 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/23/2026
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.
Claim(s) 2 and 10-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hertin DE202017006840; Ma Sci Rep. 37486 (2016) (11 pages) and Zeana, "Magnesium orotate in myocardial and neuronal protection," Rom J Intern Med. 37(1):91-7 (1999). All references are Applicant provided references.
Hertin discloses food supplements containing 0.1 to 3 g zinc orotate dihydrate and 1 to 15 mg folic acid which can be in the form of an effervescent tablet, a beverage or a powder [ Hertin, claims 1-6]. Furthermore, Hertin discloses the use of such products for treating Alzheimer's disease, dementia [ Hertin, claim 9] or fatigue syndrome [ Hertin, paragraph 34]. The example in paragraph 37 of Hertin relates to the administration of 3 g-4 g of the product according to the invention three times per day over several weeks to patients with advanced Alzheimer's dementia.
Thus while the zinc salt rather than magnesium salt of orotic acid is taught by Hertin.
Ma teaches that folic acid increases cognitive function.
Zeana teaches that Magnesium orotate (MO) in myocardial and neuronal protection. The nervous tissue and the myocardium have in common many denominators, such as: the inability to renew to substitute the severely damaged or dead cells, the role of the membrane electric activity, the presence of similar systems for antioxidation protection
Magnesium orotate improves the survival of cells situated within the perinecrotic areas as well as of the cells secondarily damaged during the so-called "second wind". Zeana Table at page 96, inter alia, teaches higher ATP after treatment with orotic acid. that Zeana concludes that magnesium orotate has valuable myocardium and nervous
protecting valuable for the clinic and the adverse effects can be considered
negligible.
The combined teachings of Hertin, Ma and Zeana that a combination of folic acid and MO for the treatment of CNS diseases as per the instant claims.
Therefore, it would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the instant ingredients for their known benefit since each is well known for their use in treating CNS diseases. This rejection is based on the well-established proposition of patent law that no invention resides in combining old ingredients of known properties where the results obtained thereby are no more than the additive effect of the ingredients, In re Sussman, 136 F.2d 715, 718, 58 USPQ 262, 264 (CCPA 1943). Also "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) (citations omitted).
Again the recited MO and folic acid as well as orotic acid are known for the recited diseases. Thus, one of ordinary skill in the art would have had a reasonable expectation that the combination of these compounds would have synergistic or additive effect.
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Claim(s) 2 and 10-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hertin DE202017006840; Ma Sci Rep. 37486 (2016): Zeana, "Magnesium orotate in myocardial and neuronal protection," Rom J Intern Med. 37(1):91-7 (1999); Classen (2004). "Magnesium orotate--experimental and clinical evidence". Romanian Journal of Internal Medicine. 42 (3): 491–501; Coskuner , J Alzheimers Dis 2014;41(2):561-74. and Owen, Nutrients 2011, 3, 735-755.
Hertin discloses food supplements containing 0.1 to 3 g zinc orotate dihydrate and 1 to 15 mg folic acid which can be in the form of an effervescent tablet, a beverage or a powder [ Hertin, claims 1-6]. Furthermore, Hertin discloses the use of such products for treating Alzheimer's disease, dementia [ Hertin, claim 9] or fatigue syndrome [ Hertin, paragraph 34]. The example in paragraph 37 of Hertin relates to the administration of 3 g-4 g of the product according to the invention three times per day over several weeks to patients with advanced Alzheimer's dementia. Thus while the zinc salt rather than magnesium salt of orotic acid is taught by D1, the difference here is magnesium orotate.
Ma teaches that folic acid increases cognitive function.
Zeana teaches that Magnesium orotate (MO) in myocardial and neuronal protection. The nervous tissue and the myocardium have in common many denominators, such as: the inability to renew to substitute the severely damaged or dead cells, the role of the membrane electric activity, the presence of similar systems for antioxidation protection
Magnesium orotate improves the survival of cells situated within the perinecrotic areas as well as of the cells secondarily damaged during the so-called "second wind". Zeana Table at page 96, inter alia, teaches higher ATP after treatment with orotic acid. that Zeana concludes that magnesium orotate has valuable myocardium and nervous
protecting valuable for the clinic and the adverse effects can be considered
negligible.
The combined teachings of Hertin, Ma and Zeana that a combination of folic acid and MO for the treatment of CNS diseases as per the instant claims.
Therefore, it would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the instant ingredients for their known benefit since each is well known for their use in treating CNS diseases. This rejection is based on the well-established proposition of patent law that no invention resides in combining old ingredients of known properties where the results obtained thereby are no more than the additive effect of the ingredients, In re Sussman, 136 F.2d 715, 718, 58 USPQ 262, 264 (CCPA 1943). Also "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) (citations omitted).
Again the recited MO and folic acid as well as orotic acid are known for treatment of the recited CNS diseases. Thus, one of ordinary skill in the art would have a reasonable expectation that the combination of these compounds would have synergistic or additive effect.
Classen teaches that Magnesium orotate (MO) for the treatment of Mg depletion. Magnesium orotate, the magnesium salt of orotic acid, is a mineral supplement. It can be used in treating extracellular magnesium deficiency, as well as in mitigating magnesium depletion that inhibits the binding of adenosine triphosphate (ATP) via orotic acid, which provides binding sites.
Classen ABSTRACT: Magnesium orotate dihydrate (MO) has the sum formula C10H6MgN4O8 x 2H2O and a MG of 370.52. The salt is poorly soluble in water and hence does not bind gastric acid nor does it exhibit noteworthy laxative effects upon oral administration in contrast to easily dissociable Mg salts. As a source of magnesium (Mg), MO is indicated for the oral treatment of extracellular Mg deficiency. Orotic acid (OA), the second active ingredient of MO, is a key intermediate in the biosynthetic pathway of pyrimidines and is shown to improve the energy status of injured myocardium by stimulating, a.o., the synthesis of glycogen and ATP. Myocardial energy-rich phosphate levels are decreased during hypoxic conditions; subsequently, intracellular Mg is depleted and lost via the urine. Since binding sites for Mg (ATP) are provided by OA it can be classified as "Mg-fixing agent". Accordingly MO is also indicated for the treatment of Mg depletion as convincingly shown in animal experiments and also in coronary heart patients undergoing e.g. aortocoronary bypass surgery.
Coskuner, teaches that Adenosine Triphosphate (ATP) Reduces Amyloid-β Protein Misfolding in vitro
Coskuner Abstract: Alzheimer's disease (AD) is a devastating disease of aging that initiates decades prior to clinical manifestation and represents an impending epidemic. Two early features of AD are metabolic dysfunction and changes in amyloid-β protein (Aβ) levels. Since levels of ATP decrease over the course of the disease and Aβ is an early biomarker of AD, we sought to uncover novel linkages between the two. First and remarkably, a GxxxG motif is common between both Aβ (oligomerization motif) and nucleotide binding proteins (Rossmann fold). Second, ATP was demonstrated to protect against Aβ mediated cytotoxicity. Last, there is structural similarity between ATP and amyloid binding/inhibitory compounds such as ThioT, melatonin, and indoles. Thus, we investigated whether ATP alters misfolding of the pathologically relevant Aβ42. To test this hypothesis, we performed computational and biochemical studies. Our computational studies demonstrate that ATP interacts strongly with Tyr10 and Ser26 of Aβ fibrils in solution. Experimentally, both ATP and ADP reduced Aβ misfolding at physiological intracellular concentrations, with thresholds at ~500 μM and 1 mM respectively. This inhibition of Aβ misfolding is specific; requiring Tyr10 of Aβ and is enhanced by magnesium. Last, cerebrospinal fluid ATP levels are in the nanomolar range and decreased with AD pathology. This initial and novel finding regarding the ATP interaction with Aβ and reduction of Aβ misfolding has potential significance to the AD field. It provides an underlying mechanism for published links between metabolic dysfunction and AD. It also suggests a potential role of ATP in AD pathology, as the occurrence of misfolded extracellular Aβ mirrors lowered extracellular ATP levels. Last, the findings suggest that Aβ conformation change may be a sensor of metabolic dysfunction.
Owen teaches that Metabolic Agents that Enhance ATP can Improve Cognitive Functioning.
Even though Owen does not teach MO or folic acid or folate, Owen is invoked here for the knowledge that interventions that sustain adenosine triphosphate (ATP) levels may have importance for improving neuronal dysfunction and loss.
Owen Abstract: Over the past four or five decades, there has been increasing interest in the neurochemical regulation of cognition. This field received considerable attention in the 1980s, with the identification of possible cognition enhancing agents or “smart drugs”. Even though many of the optimistic claims for some agents have proven premature, evidence suggests that several metabolic agents may prove to be effective in improving and preserving cognitive performance and may lead to better cognitive aging through the lifespan. Aging is characterized by a progressive deterioration in physiological functions and metabolic processes. There are a number of agents with the potential to improve metabolic activity. Research is now beginning to identify these various agents and delineate their potential usefulness for improving cognition in health and disease. This review provides a brief overview of the metabolic agents glucose, oxygen, pyruvate, creatine, and L-carnitine and their beneficial effects on cognitive function. These agents are directly responsible for generating ATP (adenosine triphosphate) the main cellular currency of energy. The brain is the most metabolically active organ in the body and as such is particularly vulnerable to disruption of energy resources. Therefore interventions that sustain adenosine triphosphate (ATP) levels may have importance for improving neuronal dysfunction and loss. Moreover, recently, it has been observed that environmental conditions and diet can affect transgenerational gene expression via epigenetic mechanisms. Metabolic agents might play a role in regulation of nutritional epigenetic effects. In summary, the reviewed metabolic agents represent a promising strategy for improving cognitive function and possibly slowing or preventing cognitive decline.
MO and folic acid as well as orotic acid are known for the treatment of the recited CNS diseases (Hertin, Ma and Zeana) . The teachings of Classen, Coskuner and Owen
provide a biochemical rationale for using MO and folic acid, enhancing ATP which in turn is implicated in the treatment of CNS disorders such as Alzheimer's disease and dementia.
With the combined teachings in front, one of ordinary skill in the art would have a reasonable expectation that the combination of these compounds would have synergistic or additive effect.
Note that obviousness can 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. Further, a reference is relevant not only for what it expressly teaches, but also for what it would have conveyed to one of ordinary skill in the art. See In re Opprecht, 12 USPQ2d 1235, 1236 (Fed. Cir. 1989); In re Bode, 193 USPQ 12 (CCPA 1976). In light of the foregoing discussion, the Examiner finds that the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art at the time the invention was made, in view of the cited references and the knowledge generally available in the art. Accordingly, the claims are rejected under 35 U.S.C. § 103.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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