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 .
Election/Restrictions
Applicant’s response to the restriction/ election requirement is acknowledged. On further consideration of the art, the restriction/ election requirement is hereby withdrawn. Claims 1-20 are pending, and have been examined herewith across their breadth.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-20 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by US 20170296501 A1 to Lowery et al. (“Lowery”).
Regarding Claim 1, Lowery discloses:
-a method for raising blood ketone levels in a non-human mammal (compounds may be administered to an individual to elevate blood ketone levels (Abstract; the described systems and processes may be administered to other mammals, such as rats, dogs, Para. [0098])
-in order to therapeutically or prophylactically treat one or more conditions selected from obesity, muscle atrophy, body composition, gut health, disease, cancer, epilepsy, seizures, Alzheimer's, oxidative stress, vascular disease, disrupted mitochondria, metabolic decline, cognitive decline, brain function, brain metabolism, brain atrophy, mental acuity, neurological disorders, inflammation, joint health, motor control, memory, or mood (Administration of the pharmaceutically effective amount may induce and maintaining ketosis; maintaining and/or promoting weight loss; increase mental processes treat neurological disorders and combinations thereof, Para. [0004]): “For example, the pharmaceutically effective amount of the beta-hydroxybutyrate, related compounds, and/or one or more other compounds may be administered to cause weight loss, weight maintenance, elevate blood ketone levels, maintain blood ketone levels, reduce blood glucose levels, maintain blood glucose levels, improve focus, energy, cognitive function, traumatic brain injury, diabetes, neurological disorders, cancer, inflammatory conditions, suppressing appetite, anti-aging, anti-glycation, epilepsy, depression, performance, strength, muscle mass, fat loss, body composition, and/or use as a medicament etc.”; “and/or support barrier function(s) in the gut and/or reduce inflammation associated with ulcerative colitis” ([0046])
-the method comprising: orally administering an effective amount of a ketone body composition to a non human mammal in need thereof (a pharmaceutically effective amount of beta-hydroxybutyrate may be administered, Para. [0050]; the beta-hydroxybutyrate and/or one or more other compounds may be administered via pills, tablets, capsules, other oral administration forms, Para. [0099]) to raise blood ketone levels in the non-human animal and therapeutically or prophylactically treat the one or more conditions (The combination of beta-hydroxybutyrate salt and beta-hydroxybutyrate ester during administration may allow less salt to be utilized while producing elevated blood ketone levels elevated blood ketone levels may increase energy, mood, performance, and/or cognitive function in users, Para. [0043]),
-the ketone body composition comprising a ketone body component or precursor selected from the group consisting of beta-hydroxybutyrate salts, beta-hydroxybutyrate esters, beta-hydroxybutyrate acid, beta-hydroxybutyrate oligomers or polymers, acetoacetate salts, acetoacetate esters, acetoacetic acid, 1,3-butanediol, and combinations thereof (a pharmaceutically effective amount of beta-hydroxybutyrate may be administered, Para. [0050]; Beta-hydroxybutyrate may include beta-hydroxybutyrate salts and/or beta-hydroxybutyrate esters, Para. [0038]),
-wherein the ketone body composition is in a form conducive for oral intake by the non-human mammal through one or more of a flavored liquid carrier, a flavored gel, an electrolyte solution, a broth, or a coating material for animal food (The composition may include flavoring, Para. [0007]; the beta-hydroxybutyrate ester may be liquid and/or gel form, Para. [0043]; compositions may include flavorings electrolytes, Para. [0054]; composition may be provided in a powdered form that allows the described composition to be sprinkled on food, mixed with a liquid to provide a beverage, Para. [0093]). Regarding Claim 2, KPG discloses the method of claim 1, wherein the non-human animal is selected from a dog, cat, horse, cattle, sheep, or pig (the described systems and processes may be administered to dogs, Para. [0098]).
The Examples (e.g. 1-12) further recite Applicant’s claimed doses of BHB of claim 3. It is noted that the definition of “subject” in Lowery includes non-human animals, e.g. dogs. “[0098] Although a subject and/or an individual have been described as a human, a subject and/or individual may be a person or a group of people. Although various described systems and processes have been described as a being administered in humans, the described systems and processes may be administered to other mammals, such as rats, dogs, etc.”
Per Applicant’s claim 4, the composition may further include amino acids, e.g. leucine. ([0011]).
Per Applicant’s claim 5, additional compounds may include butyrate or tribytyrin. ([0009]).
Per Applicant’s claims 6 and 7: “For example, a pharmaceutically effective amount of one or more short chain fatty acids and/or one or more short chain triglycerides (e.g., butyric acid and/or butyrate) may be administered with a pharmaceutically effective amount of beta-hydroxybutyrate. In some implementations, approximately 1 g to approximately 10 g of beta-hydroxybutyrate and approximately 0.1 g to approximately 50 g of short chain fatty acid and/or triglyceride may be administered from once a day to approximately 5 times a day.” ([0046]).
Per Applicant’s claims 8 and 9, the ketone body component may be encapsulated or in a powder form. ([0005], [0043]).
Per Applicant’s claims 10-11, “Other compounds may include short chain fatty acids, short chain triglycerides, medium chain fatty acids, medium chain triglycerides, long chain fatty acids, long chain triglycerides, berberine, berberine metabolites, dihydroberberine, tetrahydroberberine and/or combinations thereof. One or more of the other compounds may be unencapsulated and/or encapsulated.”
Since the same composition is administered in a subject with the same disease or condition, it will achieve the same effect as in Applicant’s claims 12-16.
Applicant’s claims 17-19 are composition claims, the elements of which were discussed with the method claims above, except that claim 17 further discloses formulating as e.g. food. Lowery discloses formulating as food, beverage, etc.. ([0068], [0070]). Applicant’s claim 20 is directed to a method of administering the composition, and since it discloses the same compounds and their effective amounts for the same condition(s), they will also achieve the same effect of improving gut health in a non-human mammal.
The Examiner also notes the following prior art from various PCT search reports, which is cumulative, and over which no rejections were made solely in view of its cumulative nature.
Claims 1-13 and 15-20 lack novelty under PCT Article 33(2) as being anticipated by University of South Florida (hereinafter Florida).
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Regarding Claim 1. Florida discloses a method for maintaining ketosis in an individual (Florida Para. [0032] The invention exploits the metabolic and physiological advantages of sustained ketosis (e.g. keto-adaptation)), the method comprising: orally administering a composition comprising approximately 0.5 g to approximately 10 g of R-beta-hydroxybutyrate (Florida Para. [0033] a composition of ketone precursors is disclosed which comprises at least one medium chain fatty acid, or an ester thereof such as a medium chain triglyceride, and a beta-hydroxybutyrate ketone source or precursor. For example, the ketone compounds are optionally administered at 2 grams, 4 grams, 5 grams, 6 grams, 7 grams, 8 grams; Para. [0034] The compound is optionally a racemic D,L-beta-hydroxybutyrate or the single isomer R-beta hydroxy butyrate; Para. [0041] In an embodiment of the invention, the preferred route of administration of the mixture of BetaHB salts and MCT oil is oral); wherein administration induces or maintains ketosis in an individual (Florida Para. [0032] The present invention provides a strategy to elevate and sustain blood ketone body levels through the administration of novel combinations of ketogenic supplements and causes a rapid and sustained elevation of blood ketones with a single oral administration).
Regarding Claim 2. Florida discloses the method of claim 1 wherein the amount of the composition administered comprises 0.5 to 3 g of R-beta-hydroxybutyrate (Florida Para. [0033] a composition of ketone precursors is disclosed which comprises at least one medium chain fatty acid, or an ester thereof such as a medium chain triglyceride, and a beta-hydroxybutyrate ketone source or precursor For example, the ketone compounds are optionally administered at 2 grams, 4 grams, 5 grams, 6 grams, 7 grams, 8 grams; Para. [0034] The compound is optionally a racemic D,L-beta-hydroxybutyrate or the single isomer R-beta hydroxy butyrate).
Regarding Claim 3, Florida discloses the method of claim 1 wherein the composition further comprises at least one additional compound, and wherein at least one of the additional compounds comprises: a short chain fatty acid, an ester of short chain fatty acid; a medium chain fatty acid (Florida Para. [0033] a composition of ketone precursors is disclosed which comprises at least one medium chain fatty acid, or an ester thereof such as a medium chain triglyceride, and a beta-hydroxybutyrate ketone source or precursor), an ester of medium chain fatty acid; a long chain fatty acid, or an ester of long chain fatty acid.
Regarding Claim 4, Florida discloses the method of claim 1 wherein the composition is administered up to 5 times daily (Florida Para. [0040] As such, the composition is optionally administered once per day, twice per day, or three times per day to a subject desiring to promote and/or sustain a state of ketosis).
Regarding Claim 5, Florida discloses the method of claim 1 wherein the composition further comprises at least one of: a flavoring, a vitamin, a mineral, or a binder (Florida Para. [0039] The ketone precursors are preferably ingested along with nutritional substrates such as free amino acids, amino acid metabolites, vitamins, minerals).
Regarding Claim 6, Florida discloses the method of claim 1 wherein administration of the composition increases strength (Florida Para. [0032] The invention exploits the metabolic and physiological advantages of sustained ketosis (e.g. keto-adaptation) which utilizes ketones as an alternative fuel to improve metabolic health, physical performance and enhance disease prevention).
Regarding Claim 7, Florida discloses the method of claim 1 wherein administration of the composition increases mental acuity (Florida Para. [0011] Many people on a ketogenic diet report greater mental clarity, an enhanced ability to multi-task, and a more favorable and balanced mood).
Regarding Claim 8, Florida discloses the method of claim 1 wherein administration of the composition increases at least one of metabolism, fat loss, fat oxidation, motor function, or muscle mass (Florida Para. [0032] The invention exploits the metabolic and physiological advantages of sustained ketosis (e.g. keto-adaptation) which utilizes ketones as an alternative fuel to improve metabolic health, physical performance and enhance disease prevention).
Regarding Claim 9, Florida discloses the method of claim 1 wherein the 0.5 to 10 g of R-beta-hydroxybutyrate comprises R-beta-hydroxybutyrate and at least one of a polymer of R-betahydroxybutyrate or R-beta-hydroxybutyrate-complex (Florida Para. [0033] Nonlimiting examples of combinations of beta-hydroxybutyrate salts include sodium beta-hydroxybutyrate and arginine beta-hydroxybutyrate, or beta-hydroxy butyrate sodium salt and beta-hydroxy butyrate potassium salt).
Regarding Claim 10, Florida discloses a composition comprising: approximately 0.5 g to approximately 10 g of R-beta-hydroxybutyrate (Florida Para. [0033] a composition of ketone precursors is disclosed which comprises at least one medium chain fatty acid, or an ester thereof such as a medium chain triglyceride, and a beta-hydroxybutyrate ketone source or precursor. For example, the ketone compounds are optionally administered at 2 grams, 4 grams, 5 grams, 6 grams, 7 grams, 8 grams; Para. [0034] The compound is optionally a racemic D,L-beta-hydroxybutyrate or the single isomer R-beta hydroxy butyrate): and one or more additional compounds capable of increasing ketone levels independently (Florida Para. [0035] It is also contemplated that additional ketone precursors or supplements might be used in combination with beta hydroxy butyrate and medium chain triglycerides); wherein administration induces or maintains ketosis in an individual (Florida Para. [0032] The present invention provides a strategy to elevate and sustain blood ketone body levels through the administration of novel combinations of ketogenic supplements and causes a rapid and sustained elevation of blood ketones with a single oral administration).
Regarding Claim 11, Florida discloses the composition of claim 10, wherein the R-beta-hydroxybutyrate comprises at least one of R-beta-hydroxybutyrate salt (Florida Para. [0033] Nonlimiting examples of combinations of beta-hydroxybutyrate salts include sodium beta-hydroxybutyrate and arginine beta-hydroxybutyrate, or beta-hydroxy butyrate sodium salt and beta-hydroxy butyrate potassium salt), R-beta-hydroxybutyrate- amino acid complex, or R-beta-hydroxybutyrate polymer.
Regarding Claim 12, Florida discloses the composition of claim 10, wherein at least one of the additional compounds comprises: a short chain fatty acid, an ester of short chain fatty acid; a medium chain fatty acid (Florida Para. [0033] a composition of ketone precursors is disclosed which comprises at least one medium chain fatty acid, or an ester thereof such as a medium chain triglyceride, and a beta-hydroxybutyrate ketone source or precursor), an ester of medium chain fatty acid; a long chain fatty acid, or an ester of long chain fatty acid.
Regarding Claim 13, Florida discloses the composition of claim 10, wherein at least one of the additional compounds comprises at least one of a polymer of beta-hydroxybutyrate, D,L-beta-hydroxybutyrate (Florida Para. [0034] The compound is optionally a racemic DL-beta hydroxybutyrate), butyrate, butyric acid, or triglyceride tributyrin.
Regarding Claim 15, Florida discloses a composition for inducing or maintaining ketosis (Florida Para. [0032] The invention exploits the metabolic and physiological advantages of sustained ketosis (e.g. keto-adaptation)), the composition comprising: pharmaceutically effective amounts of R-beta-hydroxybutyrate and amino acid (Florida Para. [0033] a composition of ketone precursors is disclosed which comprises at least one medium chain fatty acid, or an ester thereof such as a medium chain triglyceride, and a beta-hydroxybutyrate ketone source or precursor; Para. [0039] The ketone precursors are preferably ingested along with nutritional substrates such as free amino acids, amino acid metabolites).
Regarding Claim 16, Florida discloses the composition of claim 15, wherein the composition is approximately 1 g to approximately 5 grams of R-beta-hydroxybutyrate (Florida Para. [0033] a composition of ketone precursors is disclosed which comprises at least one medium chain fatty acid, or an ester thereof such as a medium chain triglyceride, and a beta-hydroxybutyrate ketone source or precursor.. For example, the ketone compounds are optionally administered at 2 grams, 4 grams, 5 grams, 6 grams, 7 grams, 8 grams; Para. [0034] The compound is optionally a racemic D,L-beta-hydroxybutyrate or the single isomer R-beta hydroxy butyrate) and approximately 0.5 to 2 g of amino acid (Florida Para. [0039] Nonlimiting examples of nutritional cofactors include R-alpha lipoic acid, acetyl-1-carnitine, ketoisocaproate, alpha-ketoglutarate, alpha-hydroxyisocaproate, creatine, branched chain amino acids (leucine, isoleucine, valine); Para. [0101] Arginine alpha-ketoglutarate 1000 mg).
Regarding Claim 17, Florida discloses the composition of claim 15, wherein the amino acid comprises Leucine (Florida Para. [0039] Nonlimiting examples of nutritional cofactors include R-alpha lipoic acid, acetyl-1-carnitine, ketoisocaproate, alpha-ketoglutarate, alpha-hydroxyisocaproate, creatine, branched chain amino acids (leucine, isoleucine, valine)).
Regarding Claim 18, Florida discloses the composition of claim 15, wherein the composition comprises a mixture of the R-beta-hydroxybutyrate and amino acid (Florida Para. [0033] a composition of ketone precursors is disclosed which comprises at least one medium chain fatty acid, or an ester thereof such as a medium chain triglyceride, and a beta-hydroxybutyrate ketone source or precursor; Para. [0039] The ketone precursors are preferably ingested along with nutritional substrates such as free amino acids, amino acid metabolites).
Regarding Claim 19, Florida discloses the composition of claim 15, wherein at least a portion of the R-betahydroxybutyrate is complexed with the amino acid (Florida Para. [0033] Nonlimiting examples of combinations of beta-hydroxybutyrate salts include sodium beta hydroxybutyrate and arginine bela-hydroxybulyrate). Regarding Claim 20, Florida discloses the composition of claim 19, further comprising at least one R-betahydroxybutyrate salt (Florida beta-hydroxybutyrate). Para. [0033] Nonlimiting examples of combinations of beta-hydroxybutyrate salts include sodium beta-hydroxybutyrate and arginine
Claim 14 lacks an inventive step under PCT Article 33(3) as being obvious over University of South Florida (hereinafter Florida) in view of Sun Zhe (hereinafter Sun).
Regarding Claim 14, Florida discloses the composition of claim 10. Florida fails to explicitly disclose wherein at least one of the additional compounds comprises at least one of berberine, dihydroberberine, or tetrahydroberberine. Sun is in the field of treating keto imbalances (Sun Abstract, The present invention discloses a method for the treatment of diabetic ketoacidosis) and teaches wherein at least one of the additional compounds comprises at least one of berberine, dihydroberberine, or tetrahydroberberine (Sun Disclosure, Para. 3, Drug of the present invention to yam, astragalus, habitat, per reference (Scrophulariaceae), angelica, gardenia, herb, Scutellaria, goldenseal (berberine)). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the composition of Florida with the berberine teaching of Sun for the purpose of providing beneficial health effects on the body by means of natural agents that aid in sugar regulation (Sun Disclosure, Para. 1, The purpose of the present invention is to provide a method of treating diabetes mellitus handle acidosis syndrome Chinese medicine, which is: vital essence, cleaning and detoxifying, nourishing and blood, yin recovery, elimination of ketone bodies to achieve that is hypoglycemic and treatment of diabetes Concurrent effect ketosis poisoning).
Hu
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Regarding Claim 1, Hu discloses a method of managing glucose tolerance in an individual (Hu Abstract, an activity of promoting glucose absorption in muscle cells, and the whole animal tests show that the present compounds have effects on improving glucose-tolerance and insulin-resistance), the method comprising: administering, to an individual, a pharmaceutically effective amount of dihydroberberine (Hu Para. [0040] The present invention designs and synthesizes a series of 13,13a-dihydroberberine derivatives, which may promote glucose absorption in muscle cells. The animal tests showed that this series of compounds had effects on improving glucose tolerance and insulin resistance).
Regarding Claim 2, Hu discloses the method of claim 1 wherein the administration of dihydroberberine reduces fasting glucose levels (Hu Table I, 60 cases of type 2 diabetic patients were treated with berberine and the treatment was lasted for 1-3 months. The results showed that the fasting blood glucose decreased averagely by 5.1 mmol/L and the efficiency was 90%).
Regarding Claim 5, Hu discloses the method of claim 1 wherein the pharmaceutically effective amount of dihydroberberine comprises approximately 25 mg to approximately 800 mg of dihydroberberine (Hu Para. [0219] Dihydroberberine derivative 19 or its sulfate salt was mixed into the high-fat diet, and administered at a dose of 100 mg/kg/day for 2 weeks).
Regarding Claim 8, Hu discloses the method of claim 1 wherein the dihydroberberine is administered at least once daily (Hu Para. [0219] Dihydroberberine derivative 19 or its sulfate salt was mixed into the high-fat diet, and administered at a dose of 100 mg/kg/day for 2 weeks).
Regarding Claim 10, Hu discloses a method of increasing blood ketone levels in an individual (Hu Para. [0001] More particularly, the present invention relates to pharmaceutical compositions of 13,13a-dihydroberberine derivatives and the use thereof as an insulin sensitizer; Para. [0002] Clinically, diabetes mellitus is mainly characterized by hyperglycemia and may lead to damages to multiple organic systems as time goes on, and acute metabolic disorder such as ketoacidosis etc. may occur in serious conditions and stress), the method comprising: administering, to an individual, a pharmaceutically effective amount of dihydroberberine (Hu Para. [0040] The present invention designs and synthesizes a series of 13,13a-dihydroberberine derivatives, which may promote glucose absorption in muscle cells. The animal tests showed that this series of compounds had effects on improving glucose tolerance and insulin resistance).
Regarding Claim 11, Hu discloses the method of claim 10 wherein the dihydroberberine is administered approximately concurrently with meals (Hu Para. [0219] Dihydroberberine derivative 19 or its sulfate salt was mixed into the high-fat diet, and administered at a dose of 100 mg/kg/day for 2 weeks).
Claims 3 and 4 lack an inventive step under PCT Article 33(3) as being obvious over Hu in view of Pharnext.
Regarding Claim 3, Hu discloses the method of claim 1.
Hu fails to explicitly disclose wherein the dihydroberberine is administered as a complexed composition, and wherein the complexed composition further comprises at least one of complexed phytosomes or liposomes. Pharnext is in the field of treating blood glucose levels (Pharnext Abstract, More specifically, the present invention relates to novel therapies or combinatorial therapies of diabetes and related disorders, based on compositions controlling the blood glucose level) and teaches wherein the dihydroberberine is administered as a complexed composition, and wherein the complexed composition further comprises at least one of complexed phytosomes or liposomes (Pharnext Pg 6, Lns. 9-10, a compound selected from the group consisting of acarbose, acetohexamide, alogliptin, berberine; Pg. 32, Lns. 23-26, Thus, the drug is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner (single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes)). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method of Hu with the liposome teaching of Pharnext for the purpose of controlling the release of the active agent (Pharnext Pg. 32, Lns. 20-22, Controlled release may be obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings).
Claims 6, 7, and 12-20 lack an inventive step under PCT Article 33(3) as being obvious over Hu in view of University of South Florida (hereinafter Florida). Regarding Claim 6, Hu discloses the method of claim 1. Hu fails to explicitly disclose wherein the dihydroberberine is orally administered as a capsule or tablet. Florida is in the field of regulating glucose (Florida Abstract, Further, use of these supplements to achieve ketosis yields a significant elevation of blood ketones and reduction of blood glucose levels) and teaches wherein the drug is orally administered as a capsule or tablet (Florida Para. [0041] The product may be delivered as a powdered mixture, as a ready-to-drink liquid, in hard or soft gelatin caps, as hard-pressed tablets, concentrated gels, or any other dosage form known to those trained in the art). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the dihydroberberine of Hu with the tablet teaching of Florida for the purpose of maintaining an easy ketogenic state (Florida Para. [0042] Indeed, because the present invention facilitates the quick and easy transition into ketosis, should one need to depart from a strict ketogenic diet for a day or two, getting back into ketosis can be accomplished quickly and without the difficult symptoms which heretofore impeded the process). Regarding Claim 7, Hu discloses the method of claim 1. Hu fails to explicitly disclose wherein the dihydroberberine is orally administered as at least one of a food product or beverage product. Florida teaches wherein the drug is orally administered as at least one of a food product or beverage product (Florida Para. [0041] The product may be delivered as a powdered mixture, as a ready-to-drink liquid, in hard or soft gelatin caps, as hard-pressed tablets, concentrated gels, or any other dosage form known to those trained in the art). It would have been obvious to one of ordinary skill in the an at the time of the invention to modify the dihydroberberine of Hu with the food or beverage product teaching of Florida for the purpose of maintaining an easy ketogenic state (Florida Para. [0042] Indeed, because the present invention facilitates the quick and easy transition into ketosis, should one need to depart from a strict ketogenic diet for a day or two, getting back into ketosis can be accomplished quickly and without the difficult symptoms which heretofore impeded the process). Regarding Claim 12, Hu discloses the method of claim 10. Hu fails to explicitly disclose further comprising administrating, to the individual, a pharmaceutically effective amount of one or more additional compounds capable of independently increasing blood ketone levels. Florida teaches administrating, to the individual, a pharmaceutically effective amount of one or more additional compounds capable of independently increasing blood ketone levels (Florida Para. [0035] It is also contemplated that additional ketone precursors or supplements might be used in combination with beta hydroxy butyrate and medium chain triglycerides. These additional ketone precursors or supplements might include acetoacetate, ketone esters, and other compounds that cause a rise in blood ketone levels). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the method of Hu with the additional compound teaching of Florida for the purpose of allowing a more flexible diet, while maintaining a ketogenic state (Florida Para. [0040] A combination BetaHB/MCT composition is optionally administered in a range of 1:1 to 1:2 mixture to elevate blood ketones to a level that would be considered a state of nutritional ketosis; Para. [0042] Because the supplements and methods of the present invention will raise the level of blood ketones, the subject may enjoy greater flexibility in the diet that must be followed to maintain a state of ketosis). Regarding Claim 13, modified Hu discloses the method of claim 12 wherein the dihydroberberine and at least one of the additional compounds are administered approximately concurrently (Hu Table I, 57 cases of type 2 diabetic patients were treated with a second generation sulfonylureas drug alone or in combination with metformin. However, secondary failure occurred 3 years later. Thus, berberine was taken additionally). Regarding Claim 14, modified Hu discloses the method of claim 12 wherein the dihydroberberine and one or more of the additional compounds are administered at least one time daily (Hu Para. [0219] Dihydroberberine derivative 19 or its sulfate salt was mixed into the high-fat diet, and administered at a dose of 100 mg/kg/day for 2 weeks).
Regarding Claim 15, Hu discloses a composition to maintaining ketosis in an individual (Hu Para. [0001] More particularly, the present invention relates to pharmaceutical compositions of 3,13a-dihydroberberine derivatives and the use thereof as an insulin sensitizer; Para. [0002] Clinically, diabetes mellitus is mainly characterized by hyperglycemia and may lead to damages to multiple organic systems as time goes on, and acute metabolic disorder such as ketoacidosis etc. may occur in serious conditions and stress), the composition comprising: a pharmaceutically effective amount of dihydroberberine (Hu Para. [0040] The present invention designs and synthesizes a series of ,13a-dihydroberberine derivatives, which may promote glucose absorption in muscle cells. The animal tests showed that this series of compounds had effects on improving glucose tolerance and insulin resistance). Hu fails to explicitly disclose at least one additional compound capable of independently increasing blood ketone levels; wherein the amount of dihydroberberine administered to be pharmaceutically effective is less than the amount of dihydroberberine administered to be pharmaceutically effective when the dihydroberberine is administered without at least one of the additional compounds. Florida teaches at least one additional compound capable of independently increasing blood ketone levels (Florida Para. [0035] It is also contemplated that additional ketone precursors or supplements might be used in combination with beta hydroxy butyrate and medium chain triglycerides. These additional ketone precursors or supplements might include acetoacetate, ketone esters, and other compounds that cause a rise in blood ketone levels); wherein the amount of a compound administered to be pharmaceutically effective is less than the amount of compound administered to be pharmaceutically effective when the compound is administered without at least one of the additional compounds (Florida Para. [0070] The "therapeutically effective amount" for purposes herein is thus determined by such considerations as are known in the art. A therapeutically effective amount of individual beta-hydroxybutyrate salts in combination with medium chain triglycerides, derivatives, or any combination thereof is that amount necessary to provide a therapeutically effective result in vivo). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the composition of Hu with the second active agent teaching of Florida for the purpose of providing a novel combination that causes rapid and sustained elevation of blood ketones (Florida Para. [0032] The present invention provides a strategy to elevate and sustain blood ketone body levels through the administration of novel combinations of ketogenic supplements and causes a rapid and sustained elevation of blood ketones with a single oral administration). Regarding Claim 16, modified Hu discloses the composition of claim 15. Hu fails to explicitly disclose wherein one or more of the additional compounds comprises at least one of a beta-hydroxybutyrate, butyrate, a fatty acid, or ester of fatty acid. Florida teaches wherein one or more of the additional compounds comprises at least one of a beta-hydroxybutyrate, butyrate, a fatty acid, or ester of fatty acid (Florida Para. [0070] The "therapeutically effective amount" for purposes herein is thus determined by such considerations as are known in the art. A therapeutically effective amount of individual beta-hydroxybutyrate salts in combination with medium chain triglycerides, derivatives, or any combination thereof is that amount necessary to provide a therapeutically effective result in vivo). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the composition of Hu with the beta-hydroxybutyrate teaching of Florida for the purpose of providing a novel combination that causes rapid and sustained elevation of blood ketones (Florida Para. [0032] The present invention provides a strategy to elevate and sustain blood ketone body levels through the administration of novel combinations of ketogenic supplements and causes a rapid and sustained elevation of blood ketones with a single oral administration). Regarding Claim 17, modified Hu discloses the composition of claim 15. Hu fails to explicitly disclose wherein at least one of the additional compounds comprises a R-beta-hydroxybutyrate compound. Florida teaches wherein at least one of the additional compounds comprises a R-beta-hydroxybutyrate compound (Florida Para. [0034] The compound is optionally a racemic DL-beta hydroxybutyrate or the single isomer R-beta hydroxy butyrate). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the composition of Hu with the R-beta-hydroxybutyrate teaching of Florida for the purpose of providing a novel combination that causes rapid and sustained elevation of blood ketones (Florida Para. [0032] The present invention provides a strategy to elevate and sustain blood ketone body levels through the administration of novel combinations of ketogenic supplements and causes a rapid and sustained elevation of blood ketones with a single oral administration). Regarding Claim 18, modified Hu discloses the composition of claim 15. Hu fails to explicitly disclose wherein one or more of the additional compounds comprises at least one of a beta-hydroxybutyrate salt or beta-hydroxybutyrate polymer. Florida teaches wherein one or more of the additional compounds comprises at least one of a beta-hydroxybutyrate salt or beta-hydroxybutyrate polymer (Florida Para. [0070] The "therapeutically effective amount" for purposes herein is thus determined by such considerations as are known in the art. A therapeutically effective amount of individual beta-hydroxybutyrate salts in combination with medium chain triglycerides, derivatives. or any combination thereof is that amount necessary to provide a therapeutically effective result in vivo). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the composition of Hu with the beta-hydroxybutyrate teaching of Florida for the purpose of providing a novel combination that causes rapid and sustained elevation of blood ketones (Florida Para. [0032] The present invention provides a strategy to elevate and sustain blood ketone body levels through the administration of novel combinations of ketogenic supplements and causes a rapid and sustained elevation of blood ketones with a single oral administration). Regarding Claim 19, modified Hu discloses the composition of claim 15, wherein the dihydroberberine and at least one of the additional compounds are administered approximately concurrently (Hu Table I, 57 cases of type 2 diabetic patients were treated with a second generation sulfonylureas drug alone or in combination with metformin. However, secondary failure occurred 3 years later. Thus, berberine was taken additionally).
Regarding Claim 20, modified Hu discloses the composition of claim 15. Hu fails to explicitly disclose wherein the composition comprises at least two of the additional compounds, and wherein two or more of the additional compounds comprises a beta-hydroxybutyrate and at least one of a fatty acid or ester of a fatty acid. Florida teaches wherein the composition comprises at least two of the additional compounds, and wherein two or more of the additional compounds comprises a beta-hydroxybutyrate and at least one of a fatty acid or ester of a fatty acid (Florida Para. [0070] The "therapeutically effective amount" for purposes herein is thus determined by such considerations as are known in the art. A therapeutically effective amount of individual beta-hydroxybutyrate salts in combination with medium chain triglycerides, derivatives, or any combination thereof is that amount necessary to provide a therapeutically effective result in vivo). It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the composition of Hu with the two additional active agent teaching of Florida for the purpose of providing a novel combination that causes rapid and sustained elevation of blood ketones (Florida Para. [0032] The present invention provides a strategy to elevate and sustain blood ketone body levels through the administration of novel combinations of ketogenic supplements and causes a rapid and sustained elevation of blood ketones with a single oral administration). Claim 9 meets the criteria set out in PCT Article 33(2)-(3), because the prior art does not teach or fairly suggest: Regarding claim 9. the prior art of record, individually or in combination, does not teach or fairly suggest the method of claim 1, further comprising administrating a Cytochrome P450 inhibitor, wherein administration of the Cyctochrome P450 inhibitor allows decreasing of the amount of dihydroberberine administered to be sufficient to achieve the desired results.
Claims 11-17 lack an inventive step under PCT Article 33(3) as being obvious over KPG in view of US 8,071,641 B2 to Weiss et al. (hereinafter Weiss).
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Regarding claim 11, KPG teaches a composition for improving or maintaining glucose levels, the composition comprising: approximately 0.2 g to approximately 10 g of beta-hydroxybutyrate (para [0004], [0006], approximately 0.5g to approximately 10g), wherein the beta- hydroxybutyrate comprises a beta-hydroxybutyrate salt (para [0009]); and one or more other compounds that reduce glucose level (para [0052]). KPG does not teach said composition further comprising approximately 5 mg to approximately 300 mg of cannabidiol. However, Weiss teaches the use of an effective amount of cannabidiol, which is in the range of from approximately 5 mg to approximately 300 mg (col 10, In 11-13, 0.1 to 100 mg per day) for improving or maintaining glucose levels in a human subject (col 4, In 21-44, treatment and prevention includes. prevention or postponement of development of symptoms Such as, for example, hyperglycemia or glucosuria). It would have been obvious to one of ordinary skill in the art to combine the teachings of KPG and Weiss, as both are directed to methods for regulating glucose levels, and include approximately 5 mg to approximately 300 mg of cannabidiol as disclose din Weiss, in the composition of KPG, in order to enhance the efficacy of the resulting composition toward improving or maintaining glucose levels in the treated individual (Weiss, col 4, In 21-44).
Regarding claim 12, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches that the amount of beta- hydroxybutyrate comprises less than approximately 2g of beta-hydroxybutyrate (para [0011], approximately 1g to approximately 5 grams of R-beta-hydroxybutyrate).
Regarding claim 13, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches that the beta-hydroxybutyrate comprises approximately 95 weight percent to approximately 100 weight percent of R-betahydroxybutyrate and less than approximately 5 weight percent of L-betahydroxybutyrate (para [0039]).
Regarding claim 14, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches said composition further comprising a polymer of betahydroxybutyrate (para [0009], [0067]).
Regarding claim 15, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches said composition further comprising an ester of beta-hydroxybutyrate (para [0043]).
Regarding claim 16, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches said composition further comprising a fatty acid or ester thereof (para [0007]).
Regarding claim 17, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches said composition further comprising at least one of berberine or dihydroberberine (para [0069]).
Claims 18-20 lack an inventive step under PCT Article 33(3) as being obvious over KPG in view of WO 2012/024611 A1 to Natural Alternatives International, Inc. (hereinafter NAI).
Regarding claim 18, KPG teaches a composition for improving performance and strength, the composition comprising: approximately 0.2 g to approximately 10 g of beta-hydroxybutyrate (para [0004], [0006], approximately 0.5 g to approximately 10g; para [0080]), wherein the beta-hydroxybutyrate comprises a beta-hydroxybutyrale salt (para [0009]); and one or more other compounds that improve performance and strength (para [0037]). KPG does not teach said composition further comprising at least approximately 5 mg of cannabidiol. However, NAI teaches the use of cannabidiol (pg 39, In 27-33) in improving exercise tolerance in an individual (pg 39, In 14-18). While KPG or NAI does not specifically teach including at least approximately 5 mg of cannabidiol in the composition, it would have been obvious to one of ordinary skill in the art to combine the teachings of KPG and NAI, as both are directed to methods of improving exercise tolerance, and include cannabidiol as disclosed in NAI in the composition of KPG, and determine the effective amount of cannabidiol to be included, through routine experimentation, in order to enhance the efficacy of the resulting composition toward improving performance and strength in an individual (KPG, para [0080]).
Regarding claim 19, KPG and NAI teach the composition of claim 18, wherein KPG further teaches that the beta-hydroxybutyrate comprises approximately 95 weight percent to approximately 100 weight percent of R-betahydroxybutyrate and less than approximately 5 weight percent of L-betahydroxybutyrate (para [0039]).
Regarding claim 20, KPG and NAI teach the composition of claim 18, wherein KPG further teaches said composition further comprising a fatty acid or ester thereof (para [0007]).
Claims 1-10 lack an inventive step under PCT Article 33(3) as being obvious over US 2017/0296501 A1 to Keto Patent Group, Inc. (hereinafter KPG) in view of US 2009/0306221 A1 to Guy et al. (hereinafter Guy).
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Regarding claim 1, KPG teaches a composition for weight loss or weight management of an individual, the composition comprising: approximately 0.2 g to approximately 10 g of beta-hydroxybutyrate (para [0004], [0006], approximately 0.5 g to approximately 10g) and one or more other compounds that promote weight loss (para [0037]). KPG does not teach said composition further comprising at least approximately 5 mg of cannabidiol. However, Guy teaches a method of promoting weight loss by inducing suppression of appetite in a subject comprising administering an effective amount of cannabidiol (para [0050]-[0051], CBD; para [0092]-[0097], Table 3), wherein the effective amount is at least 5 mg (para [0047], 0.1 mg to 1000 mg). It would have been obvious to one of ordinary skill in the art to combine the teachings of KPG and Guy, as both are directed to methods for promoting weight loss, and include through routine experimentation, at least 5 mg of cannabidiol in the composition of KPG, in order to enhance the efficacy of the resulting composition toward promoting weight loss in an individual (Guy, para [0052]). Regarding claim 2. KPG and Guy teach the composition of claim 1, as above, but do not specifically teach wherein the amount of cannabidiol comprises less than approximately 300 mg of cannabidiol. However, Guy does teach that administration of 15 mg/kg of cannabidiol is effective in promoting weight loss in an animal model (para [0092]-[0097], Table 3). Based on such teachings in Guy, it would have been obvious to one of ordinary skill in the art to determine the amount of cannabidiol to be included in the composition of KPG, by taking into consideration, the age, weight and medical condition of the individual treated and the amount of beta-hydroxybutyrate present in said composition, through routine experimentation, in order to enhance the efficacy of the resulting composition toward promoting weight loss in said individual (Guy, para [0052]). Regarding claim 3, KPG and Guy teach the composition of claim 1, wherein KPG further teaches that the beta-hydroxybutyrate comprises approximately 95 weight percent to approximately 100 weight percent of R-betahydroxybutyrate and less than approximately 5 weight percent of L-betahydroxybutyrate (para [0039]). Regarding claim 4, KPG and Guy teach the composition of claim 1, wherein KPG further teaches that the beta-hydroxybutyrate comprises a betahydroxybutyrate salt (para [0009]). Regarding claim 5, KPG and Guy teach the composition of claim 1, wherein KPG further teaches that the beta-hydroxybutyrate comprises a betahydroxybutyrate salt and a polymer of beta-hydroxybutyrate (para [0009], [0067]). Regarding claim 6, KPG and Guy teach the composition of claim 1, wherein KPG further teaches that the beta-hydroxybutyrate comprises a belahydroxybutyrate salt and an ester of beta-hydroxybutyrate (para [0043]). Regarding claim 7, KPG and Guy teach the composition of claim 1, wherein KPG further teaches said composition further comprising a fatty acid or ester thereof (para [0007]). Regarding claim 8, KPG and Guy teach the composition of claim 1, wherein KPG further teaches said composition further comprising approximately 0.5 g to approximately 10 g of amino acid (para [0041]). Regarding claim 9, KPG and Guy teach the composition of claim 1, wherein KPG further teaches said composition further comprising at least one of berberine or dihydroberberine (para [0069]). Regarding claim 10, KPG and Guy teach the composition of claim 1, wherein KPG further teaches that the composition is at least one of encapsulated or in a powdered form (para [0070], capsule; powdered products).
Claims 11-17 lack an inventive step under PCT Article 33(3) as being obvious over KPG in view of US 8,071,641 B2 to Weiss et al. (hereinafter Weiss).
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Regarding claim 11, KPG teaches a composition for improving or maintaining glucose levels, the composition comprising: approximately 0.2 g to approximately 10 g of beta-hydroxybutyrate (para [0004], [0006], approximately 0.5g to approximately 10g), wherein the beta- hydroxybutyrate comprises a beta-hydroxybutyrate salt (para [0009]); and one or more other compounds that reduce glucose level (para [0052]). KPG does not teach said composition further comprising approximately 5 mg to approximately 300 mg of cannabidiol. However, Weiss teaches the use of an effective amount of cannabidiol, which is in the range of from approximately 5 mg to approximately 300 mg (col 10, In 11-13, 0.1 to 100 mg per day) for improving or maintaining glucose levels in a human subject (col 4, In 21-44, treatment and prevention includes. prevention or postponement of development of symptoms Such as, for example, hyperglycemia or glucosuria). It would have been obvious to one of ordinary skill in the art to combine the teachings of KPG and Weiss, as both are directed to methods for regulating glucose levels, and include approximately 5 mg to approximately 300 mg of cannabidiol as disclose din Weiss, in the composition of KPG, in order to enhance the efficacy of the resulting composition toward improving or maintaining glucose levels in the treated individual (Weiss, col 4, In 21-44). Regarding claim 12, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches that the amount of beta- hydroxybutyrate comprises less than approximately 2g of beta-hydroxybutyrate (para [0011], approximately 1g to approximately 5 grams of R-beta-hydroxybutyrate). Regarding claim 13, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches that the beta-hydroxybutyrate comprises approximately 95 weight percent to approximately 100 weight percent of R-betahydroxybutyrate and less than approximately 5 weight percent of L-betahydroxybutyrate (para [0039]). Regarding claim 14, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches said composition further comprising a polymer of betahydroxybutyrate (para [0009], [0067]). Regarding claim 15, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches said composition further comprising an ester of beta-hydroxybutyrate (para [0043]). Regarding claim 16, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches said composition further comprising a fatty acid or ester thereof (para [0007]). Regarding claim 17, KPG and Weiss teach the composition of claim 11, wherein KPG further teaches said composition further comprising at least one of berberine or dihydroberberine (para [0069]). Claims 18-20 lack an inventive step under PCT Article 33(3) as being obvious over KPG in view of WO 2012/024611 A1 to Natural Alternatives International, Inc. (hereinafter NAI). Regarding claim 18, KPG teaches a composition for improving performance and strength, the composition comprising: approximately 0.2 g to approximately 10 g of beta-hydroxybutyrate (para [0004], [0006], approximately 0.5 g to approximately 10g; para [0080]), wherein the beta-hydroxybutyrate comprises a beta-hydroxybutyrale salt (para [0009]); and one or more other compounds that improve performance and strength (para [0037]). KPG does not teach said composition further comprising at least approximately 5 mg of cannabidiol. However, NAI teaches the use of cannabidiol (pg 39, In 27-33) in improving exercise tolerance in an individual (pg 39, In 14-18). While KPG or NAI does not specifically teach including at least approximately 5 mg of cannabidiol in the composition, it would have been obvious to one of ordinary skill in the art to combine the teachings of KPG and NAI, as both are directed to methods of improving exercise tolerance, and include cannabidiol as disclosed in NAI in the composition of KPG, and determine the effective amount of cannabidiol to be included, through routine experimentation, in order to enhance the efficacy of the resulting composition toward improving performance and strength in an individual (KPG, para [0080]). Regarding claim 19, KPG and NAI teach the composition of claim 18, wherein KPG further teaches that the beta-hydroxybutyrate comprises approximately 95 weight percent to approximately 100 weight percent of R-betahydroxybutyrate and less than approximately 5 weight percent of L-betahydroxybutyrate (para [0039]). Regarding claim 20, KPG and NAI teach the composition of claim 18, wherein KPG further teaches said composition further comprising a fatty acid or ester thereof (para [0007]). Claims 1-20 have industrial applicability as defined by PCT Article 33(4), because the subject matter can be made or used in industry.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SVETLANA M IVANOVA whose telephone number is (571)270-3277. The examiner can normally be reached 8:30-5:00.
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/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627
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