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 .
DETAILED ACTION
Claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 are pending in the instant application.
Claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 are being examined on their merits herein.
In view of the Appeal conference of 8 April 2026 held on brief filed on 16 March 2026, PROSECUTION IS HEREBY REOPENED. New grounds of rejection are set forth below.
To avoid abandonment of the application, appellant must exercise one of the following two options:
(1) file a reply under 37 CFR 1.111 (if this Office action is non-final) or a reply under 37 CFR 1.113 (if this Office action is final); or,
(2) initiate a new appeal by filing a notice of appeal under 37 CFR 41.31 followed by an appeal brief under 37 CFR 41.37. The previously paid notice of appeal fee and appeal brief fee can be applied to the new appeal. If, however, the appeal fees set forth in 37 CFR 41.20 have been increased since they were previously paid, then appellant must pay the difference between the increased fees and the amount previously paid.
A Supervisory Patent Examiner (SPE) has approved of reopening prosecution by signing below:
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Response to arguments of 16 March 2026
New and modified rejections to claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 are made below.
Applicant argues (Appeal brief of 16 March 2026, pages 13-15) against the rejection of claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description/new matter. Applicant has argued that the text (Specification, [0015]) “the THC component of a ketannabis composition may reduce or eliminate symptoms of keto flu” provides support for the now claimed limitation “a method of administering ketone bodies and THC to a mammal […] wherein administration does not induce keto flu symptoms in the mammal.” This rejection is herein withdrawn.
A new rejection to claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 is made below.
Applicant argues (Appeal brief of 16 March 2026, pages 15-21) against the rejection of claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description/possession. The rejection focuses on the limitation
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which was added to the claims on 10 July 2025. This rejection is herein withdrawn.
A new rejection to claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 is made below.
Applicant argues (Appeal brief of 16 March 2026, page 22) against the rejection of claim 67 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Applicant argues that the Specification explains that the composition can be augmented with additional cannabinoid compounds. This is not persuasive, because claim 67 depends on claim 17, which does not recite administration of additional cannabinoids, and does not recite CBD. The rejection is herein maintained.
Applicant’s arguments (Appeal brief of 16 March 2026, pages 23-30) against the rejection of claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 under 35 U.S.C. 103 over D’Agostino and D’Souza have been considered.
Applicant argues that D’Agostino is not combinable with any of cited THC art.
Applicant argues (page 23, last paragraph) against a reference by Lile which is not part of the rejection. These arguments are not relevant to the rejection on record.
Applicant argues (page 24-page 27, first two paragraphs) that the Office has characterized D’Agostino’s purpose to reduce keto flu. This is incorrect. D’Agostino is used in the rejection for the teaching that ketone body supplementation results in greater mental clarity, more favorable and balanced mood (which can include anti-depressive treatment in subjects with depression, as in instant claims 24, 49), [0011], mood stabilizing effect [0012], and improvement in cognitive performance [0010], [0004].
Applicant argues (page 26, last paragraph, page 27, first two paragraphs) that there is no suggestion in the prior art to combine BHB and THC; that THC is known to increase appetite, which cross-purposes with achieving ketogenesis for the purpose of appetite reduction and weight loss. Applicant argues (page 27, second paragraph) that there must be a reason or a motivation to combine the references.
In response, the reason or motivation to combine the references by D/Souza and D’Agostino is as follows: D’Souza teaches that administration of D9 -THC, the main active psychoactive ingredient in cannabis, increases anxiety and produces cognitive deficits in healthy individuals who use THC for recreational purpose.
Although D’ Souza teaches that THC recreational use can cause cognitive side effects and increase in anxiety in the subject, he does not explicitly suggest a medical remedy. However, one of ordinary skill in the art would have a reasonable expectation of success in using BHB to remedy the side effects of THC, because BHB was known (D’Agostino) to help reduce anxiety, balance mood, and improve cognitive performance.
Applicant argues (pages 27, past paragraph- page 30) that D’Souza does not cure the deficiencies of D’Agostino.
Applicant argues (page 27, last paragraph) that D’Souza is non-analogous art. Applicant argues that THC “only agitates the CB-1 receptor”, D’Souza fails to teach administration of THC to provide a therapeutic benefit, and D’Souza “can be best understood as teaching against administering THC because it causes psychotic disorders”.
These arguments are a mis-interpretation of D’Souza. D’Souza is a scientific study that uses a well-defined protocol to measure anxiety and cognitive deficits in healthy individuals who are using THC recreationally, and who had been exposed to cannabis but had never been diagnosed with a cannabis disorder. Contrary to Applicant’s arguments, D’Souza does not teach against recreational use of THC or cannabis; rather, the purpose is to understand the effects of THC administration on anxiety and cognition performance in THC users.
Applicant argues (page 28, first two paragraphs) that D’Souza teaches that THC is harmful to mental health and THC administration may cause mental psychoses.
In response, D’Souza teaches that intravenous (parenteral) administration of D9 -THC 2.5 mg or 5 mg (page 1559, left column, third paragraph) to recreational cannabis users elicits an increase in anxiety (page 1562, left column, first paragraph) and impairs cognitive functioning.
Applicant argues (page 28, last paragraph, page 29, first paragraph) that there is no motivation to employ THC “for some unnamed reason that cannot be keto flu” in a composition (with BHB).
In response, contrary to Applicant’s arguments, the instant claims do not recite a composition comprising BHB and THC; rather they recite combined administration of a ketone body BHB and THC. The route of administration of the two components may not be the same.
Applicant argues (page 29, second paragraph) that it would not be obvious to combine the primary reference with the secondary reference to ameliorate the negative teachings of the secondary reference. Applicant argues (page 30, second and third paragraph) that “the Office has scoured D’Agostino for a completely random disclosure” and combined D’Agostino with a completely unrelated reference, and that the rejection “is like arguing that one should take an antiacid and drink sulfuric acid because the antiacid may diminish the negative effects of sulfuric acid.”
In response, as explained above, the motivation to use THC is not related to keto flu, as Applicant argues. Rather, because D’Souza teaches that THC recreational use can cause cognitive side effects and increase in anxiety in healthy subjects who consume THC/cannabis for recreational purpose, one of ordinary skill in the art would have a reasonable expectation of success in administering BHB to said subjects to remedy the side effects of THC, because BHB was known (D’Agostino) to help reduce anxiety, balance mood, and improve cognitive performance.
The rejection re-written below more clearly explains the reason and motivation to combine the two references.
Applicant argues (page 29, last paragraph) that “achieving mental clarity, more favorable and balanced mood, mood stabilizing effect and improvement in cognitive performance is not a problem that was facing D’Agostino”. Applicant argues (page 30, second and third paragraph) that “the Office has scoured D’Agostino for a completely random disclosure”.
This is not persuasive, D’Agostino clearly teaches that ketone body supplementation results in greater mental clarity, more favorable and balanced mood (which can include anti-depressive treatment in subjects with depression, as in instant claims 24, 49), [0011], mood stabilizing effect [0012], and improvement in cognitive performance [0010], [0004]. This teaching in D’Agostino cannot be contested.
For all the reasons above, the rejection of claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 under 35 U.S.C. 103 over D’Agostino and D’Souza is herein maintained and a modified rejection is made below.
Applicant’s arguments (Appeal brief of 16 March 2026, pages 30-35) against the rejection of claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-64, 66 under 35 U.S.C. 103 over Greenwood and Werner have been considered.
Applicant argues (page 31) no motivation to combine Greenwood and Werner.
Applicant argues (page 31, last paragraph) that Greenwood and Werner do not disclose compositions useful for the same purpose.
Applicant argues (page 32) that THC stimulates a subject’s appetite, which jeopardizes the state of ketosis in a subject. Applicant argues (page 32, second paragraph), based on a reference by Andries, that in patients with anorexia nervosa, dronabinol 2.5 mg twice daily predicted weight gain. This argument is not relevant to the rejection on record, because the patient population in the reference provided are subjects suffering from anorexia nervosa, and are not included in the patient population for which the rejection on record is written. Rather, the patient population in the rejection on record are patients suffering from pain, depression or anxiety.
Applicant argues (page 33, first paragraph) that in the instant Application, the ketone enhances the beneficial effects of the THC component and reduces its negative effects, as thus the two components are not used for the same purpose as each individually. Applicant argues (page 33, second paragraph) that In re Kerkhoven cannot apply to the instant claims because BHB and THC are not used for the same purpose, BHB is a source of caloric energy, THC provides no caloric energy, and that the Office “has found a tenuous, but illogical, link for combining them”.
This is not persuasive. Rationale different from Applicant’s is permissible. 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 MPEP 2144, IV. In this case, Greenwood teaches that the ketogenic material of the invention, sodium ( R)-3-hydroxybutyrate, administered in a pharmaceutical composition is useful to treat depression, anxiety, pain ([0013], [0015]). Werner teaches a pharmaceutical composition containing THC [0014] effective to treat pain [0021], depression, anxiety [0022]. It is maintained that the person of ordinary skill in the art would have co-administered sodium (R)-3-hydroxybutyrate with the THC to a subject suffering from depression, anxiety or pain, with the expectation that the combination is effective to treat depression, anxiety or pain. One of ordinary skill in the art would have reasonably expected that combining sodium (R)-3-hydroxybutyrate and THC, known to be useful for the same purpose, i.e. treating depression, anxiety or pain, would result in therapeutic effect. Since all compounds for co-administration herein are known to be useful to treat depression, anxiety or pain, it is considered prima facie obvious to co-administer them in a method used for the same purpose. At least additive therapeutic effects would have been reasonably expected. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
Applicant argues (page 33, third paragraph) that Greenwood is limited to the R-enantiomer forms of BHB and could not have guided the skilled person to the features of claims 65, 66. In response, claim 65 is not included in the rejection, a separate rejection is written for claim 65. Applicant’s argument regarding claim 66 is not persuasive, because an R-BHB form taught by Greenwood is actually a ketone body component enriched in R-BHB, as in instant claim 66.
Applicant argues (pages 34-35) that Greenwood and Werner do not teach the limitations
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In response, a new rejection to the claims under 35 U.S.C. 112(b) related to these limitations is made below.
Applicant argues (page 34, point (3), and page 35, first paragraph) a limitation in claim 67. In response, claim 67 is not included in the rejection over Greenwood and Werner.
For all the reasons above, the rejection of claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-64, 66 under 35 U.S.C. 103 over Greenwood and Werner is herein maintained and is reproduced below.
Applicant argues (page 35, third and fourth paragraphs) against the rejection of claims 17, 65 under 35 U.S.C. 103 over Greenwood and Werner, in view of D’Agostino. Applicant re-iterates the argument that In re Kerkhoven cannot apply to the instant claims because BHB and THC are not used for the same purpose. This argument has been addressed above.
The rejection of claims of claims 17, 65 under 35 U.S.C. 103 over Greenwood and Werner, in view of D’Agostino is herein maintained and is reproduced below.
The claims have been examined to the extent they read on the elected species, BHB salts (see election in the non-final office action mailed on 12 March 2021, page 3, last paragraph) as the specific ketone body component, and the following rejections are made below.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 are drawn to a method of administering ketone bodies and THC to a mammal […]
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Claim 17 is indefinite for reciting certain “wherein” clauses because one of ordinary skill in the art could not reasonably determine the metes and bound of the functional-descriptive limitations. Specifically, the second wherein clause states that there is a relationship between the amounts of the ketone body component and the THC component such that the method achieves “synergistic” action on various effects, such as neuroprotection, analgesic effects, and antitumorigenic effects. This synergy must be achieved in certain mass ratios between the ketone bodies and the THC, as established prior to this wherein clause. However, it would not be clear which mass combinations of the ketone bodies or THC component would achieve synergy, or, if there would be something else required to obtain the claimed result.
The specification provides little clarification other than speculation, as there are no working examples showing the claimed synergy or any effects, no specific teaching as to how synergy is achieved with either the mass amounts of ketone bodies and THC, or the addition of something else, for example, and absorption enhancer, that would initiate the synergistic effects. Mere statements such as those provided in the specification do not clarify how this wherein clause is further limiting to the other limitations of the claim:
“It is expected that the anti-inflammatory and analgesic effects of THC and ketone bodies are synergistically enhanced as a result of their combined administration. The ketone body component of the composition is expected to lead to reductions in inflammation by way of reduced reactive oxygen species and increased levels of adenosine, for example, and these effects may be further enhanced as a result of the ketone bodies inducing or sustain ketosis in the subject. The THC component is meanwhile expected to further reduce excessive inflammation and pain through its effects on endocannabinoid receptors. It is expected that the resulting anti-inflammatory and analgesic effects will be greater than that possible with either component alone and/or will be greater than the sum of the effects of each component when used independently. For example, a ketannabis composition with a given level of THC can provide more pain relief than the same amount of THC without a ketone body component. Likewise, a ketannabis composition may be able to provide the same amount of pain relief, with less THC, as a higher THC dose without a ketone body component. This allows for easier administration and dosing for pain management, since the user will be able to achieve greater analgesic effects for given THC levels.” Specification, paragraph [0128] (emphasis added).
The Specification provides no definition or description how one of ordinary skill in the art would understand how much of each compound is used, and whether there are further method steps or compositions required to obtain synergy for one of the listed conditions, just merely broad speculation at best.
Accordingly, the wherein clause referencing this synergy is indefinite. Applicant can overcome this rejection by amending the claim to recite specific mass amounts or ranges for the ketone bodies and THC. The analysis applied to claim 17 above is also applied to independent claims 49, 60.
Claim 17 is indefinite for reciting “wherein the administration does not induce keto flu symptoms” because one of ordinary skill in the art could not reasonably determine the metes and bound of the functional-descriptive limitations. Specifically, there is a relationship between the amounts of the ketone body component and the THC component administered such that the method achieves a certain effect, namely it does not induce keto flu symptoms. This effect must be achieved in certain mass ratios between the ketone bodies and the THC, as established prior to this wherein clause. However, it would not be clear which mass combinations of the ketone bodies or THC component would achieve this effect “it does not induce keto flu symptoms”, or, if there would be something else required to obtain the claimed result.
The specification provides little clarification other than speculation, as there are no working examples showing that the administration does not induce keto flu symptoms, no specific teaching as to how such elimination of keto flu symptoms is achieved with either the mass amounts of ketone bodies and THC, or the addition of something else, that would initiate the claimed effects. Mere statements such as those provided in the specification do not clarify how this wherein clause is further limiting to the other limitations of the claim.
The Specification teaches [0015] that a ketannabis composition lessens the negative side effects that can sometimes occur with ketone body supplementation. For example, the THC component of a ketannabis composition may reduce or eliminate symptoms of keto flu (which implies that keto flu symptoms are present in the mammal) associated with attempts to enter a metabolic state of ketosis.
The Specification teaches [0007] that the transition into ketosis is often accompanied by hypoglycemia which can cause lethargy and light-headedness, resulting in an uncomfortable physiological and mental state commonly referred to as the "low-carb flu" or "keto flu."
The Specification teaches that [0051]"Ketosis" refers to a subject having blood ketone levels within the range of about 0.5 mmol/L to about 16 mmol/L.
The Specification teaches [0052] that administering ketone bodies in doses disclosed herein can provide the same or similar benefits as being in a state of ketosis even if the subject has not achieved a sufficiently high blood ketone level to technically be in a state of ketosis.
The Specification teaches [0101] that supplementation with exogenous ketone bodies can be associated with one or more undesirable side effects. In particular, ketone body supplementation may be associated with keto flu symptoms when used to try to achieve a state of ketosis.
The Specification teaches [0103] that a ketannabis composition (of the invention) can beneficially reduce the duration and/or severity of the unpleasant keto flu symptoms and can therefore also promote greater user compliance to a ketogenic diet. The THC component can provide beneficial antiemetic (anti-nausea) activity, which is particularly beneficial during bouts of keto flu symptoms. The analgesic and the psychoactive, euphoric effects of THC also act to reduce the severity of keto flu symptoms and make the transition from a glycolytic state to a ketogenic state easier for the user.
However, it is unclear what is meant by “wherein administration does not induce keto flu symptoms in the mammal” because there is no clear teaching in the Specification on how such result is achieved, what amount of the ketone body component and of the THC component results in keto flu symptoms being eliminated, what route of administration is being used to achieve the claimed result, or what patient population is being targeted.
The Specification provides no definition or description how one of ordinary skill in the art would understand how much of each compound is used, and whether there are further method steps or compositions required to obtain the claimed result, namely that administration does not induce keto flu symptoms in the mammal, just merely broad speculation at best.
Accordingly, the wherein clause referencing that administration does not induce keto flu symptoms in the mammal is indefinite. The analysis applied to claim 17 above is also applied to independent claims 49, 60.
Claim 67 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 67 depends on claim 17 and recites the limitation "wherein the method omits administration of CBD”. When something is omitted, it means it has been left out or excluded, either intentionally or unintentionally. This act of omission naturally presumes or implies that the omitted item or action at least potentially existed or was relevant in the context from which it was excluded. In this case, claim 17 does not recite additional cannabinoids being administered. Administration of CBD is not listed in claim 17. As such, it is unclear how it can be omitted in dependent claim 67.
Appropriate clarification is required.
In the interest of compact prosecution, claim 67 is interpreted to be drawn to the method of claim 41, wherein the one or more additional cannabinoid compounds is not CBD.
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 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 are rejected under 35 U.S.C. 103 as being unpatentable over D’Souza et al. (Neuropsychopharmacology 2004, 29, 1558-1572, cited in PTO-892 of 03/13/2025) and D’Agostino et al. (US 2014/0350105, cited in PTO-892 of 12 April 2022).
D’Souza (Neuropsychopharmacology 2004, 29, 1558-1572) teaches THC recreational use (page 1568, right column, first paragraph) in healthy individuals who had been exposed to cannabis but have never been diagnosed with a cannabis abuse disorder (Abstract). D’Souza teaches (Abstract) that administration of D9 -THC, the main active psychoactive ingredient in cannabis, increases anxiety and produces cognitive deficits in healthy individuals. D’Souza teaches intravenous (parenteral) administration of D9 -THC 2.5 mg or 5 mg (page 1559, left column, third paragraph); the dosing paradigm was designed to achieve peak D9 -THC plasma levels compared to those achieved by smoking (administration by inhalation) standard cigarettes containing 1-3.5% D9 -THC (16-34 mg). Upon administration, D9 -THC elicits an increase in anxiety (page 1562, left column, first paragraph) and impairs cognitive functioning.
Although D’ Souza teaches that THC recreational use can cause cognitive side effects and increase in anxiety in the subject, he does not explicitly suggest a medical remedy. However, one of ordinary skill in the art would have a reasonable expectation of success in using BHB to remedy the side effects of THC, because BHB was known to help reduce anxiety, balance mood, and improve cognitive performance.
D’Agostino (US 2014/0350105) teaches BHB for mood stabilization, and improved cognition. D’Agostino teaches that ketone body supplementation results in greater mental clarity, more favorable and balanced mood (which can include anti-depressive treatment in subjects with depression, as in instant claims 24, 49), [0011], mood stabilizing effect [0012], and improvement in cognitive performance [0010], [0004].
D’Agostino teaches a method of administering ketone bodies to a mammal by administering a composition comprising (claim 1) at least one beta-hydroxybutyrate compound, wherein the beta- hydroxybutyrate compound is composed of a beta-hydroxybutyrate salt, beta- hydroxybutyrate precursor, or combination thereof.
The beta-hydroxybutyrate compound comprises one or more of: a beta-hydroxybutyrate salt comprising sodium beta-hydroxybutyrate, potassium beta- hydroxybutyrate, calcium beta- hydroxybutyrate, magnesium beta-hydroxybutyrate, arginine beta-hydroxybutyrate, lysine beta-hydroxybutyrate, histidine beta-hydroxybutyrate, ornithine beta- hydroxybutyrate (amino acid salt of BHB); a salt mixture further comprising beta-hydroxy butyrate sodium salt, beta- hydroxy butyrate potassium salt, beta-hydroxy butyrate calcium salt, beta- hydroxy butyrate magnesium salt or combination thereof; ethyl acetoacetate, or ethyl beta- hydroxybutyrate (which is a BHB ester); or a combination of a beta-hydroxybutyrate salt and ethyl acetoacetate, or ethyl beta-hydroxybutyrate, or a salt mixture and ethyl acetoacetate, or ethyl beta-hydroxybutyrate (claim 2), as in instant claims 17, 49, 60. The ketone precursor beta-hydroxybutyrate compounds are administered between 2 g and 50 g, or between 10 grams and 20 grams [0033].
By teaching [0033] a salt mixture comprising, for example, beta- hydroxy butyrate potassium salt, beta-hydroxy butyrate calcium salt, beta- hydroxy butyrate magnesium salt or combinations thereof, D’Agostino teaches one or more beta-hydroxybutyrate salts comprising at least one BHB salt which is not sodium BHB, as in instant claim 65.
D'Agostino specifically teaches [0045]-[0050] a method of administering 11 grams sodium beta-hydroxybutyrate and 7.1 grams of potassium hydroxybutyrate (Figures 1-3), which are BHB salts of instant claims 17, 49, 60, orally/by ingestion, as in the instant claims 17, 33, 49, 60, to a human subject, in an amount effective to raise blood ketone levels and provide caloric energy (of no more than 400 calories per day [0082]), as in the instant claims.
The human subject, at the time of administration, is not in a state of ketosis, as in the instant claims. D’Agostino teaches [0043] that a measurable increase in blood ketone levels is observed within hours of taking the supplements.
The dosage form is a solution, a liquid as in instant claim 39, but can be delivered as a powder [0041], as in instant claim 38.
The keto component administered by D’Agostino provides 11 + 7.1 g = 18.1 grams BHB salts, which is more than 2 grams of ketone bodies to the subject, as in instant claim 43.
The daily dose administered by D’Agostino 11 grams sodium beta-hydroxybutyrate and 7.1 grams of potassium hydroxybutyrate (Figures 2-3) on three consecutive days, is within the range in instant claims 18, 50, 60-64.
D’Agostino teaches (Figure 1, curve 4% BHB salt solution 450 ml)) administering of said BHB salts in the absence of a medium chain fatty acid having 6 or 12 carbons or a glyceride thereof, as in instant claims 35, 49, 50, 57-59.
D’Agostino teaches that the salt of BHB contains the racemic DL-beta hydroxybutyrate [0036], last three lines), or the single isomer R-beta hydroxybutyrate ([0034], last 3 lines), which satisfies the limitation of instant claim 66.
D’Agostino teaches that ketone body supplementation results in greater mental clarity, more favorable and balanced mood (which can include anti-depressive treatment in subjects with depression, as in instant claims 24, 49), [0011], mood stabilizing effect [0012], improvement in cognitive performance [0010], [0004].
Neither D’Souza, nor D-Agostino teach CBD being administered to the subjects, which satisfies the limitation of instant claim 67.
D’Agostino does not teach administering beta-hydroxybutyrate salts in combination with tetrahydrocannabinol (THC), as in the instant claims.
It would have been obvious to combine the teachings of D’Souza and D’Agostino to arrive at the instant invention. The person of ordinary skill in the art would have co-administered beta-hydroxybutyrate salts and THC to a subject, because
D’Souza teaches that parenterally (i.v.) administering 2.5 or 5 mg of THC (equivalent to smoking 16-34 mg THC) for recreational use increases anxiety and produces cognitive deficits in healthy individuals, and
D’Agostino teaches that ketone body supplementation by administering 11 grams sodium beta-hydroxybutyrate and 7.1 grams of potassium hydroxybutyrate/day by ingestion to a human subject who is not in a state of ketosis is effective to increase blood ketone levels within hours of taking the supplements, resulting in greater mental clarity, more favorable and balanced mood, mood stabilizing effect and improvement in cognitive performance.
Thus, the person of ordinary skill in the art would have co-administered the salts of beta-hydroxybutyrate taught by D’Agostino with the THC taught by D’Souza to a subject who is a recreational user of THC and is not in a state of ketosis, with the expectation that administration of salts of beta-hydroxybutyrate will reduce the negative effects, namely anxiety, impaired cognition, associated with administration of THC. The person of ordinary skill in the art would have reasonably expected that the addition of beta-hydroxybutyrate salts to THC will result, upon administration, in ketone body supplementation, which results in greater mental clarity, more favorable and balanced mood (including in patients with depression, as in instant claims 24, 49), mood stabilizing effect and improvement in cognitive performance.
Regarding claim 41, the person of ordinary skill in the art would be motivated to administer THC in the combination as a THC component which includes one or more additional compounds derived from the cannabis plant, because D’Souza teaches (page 1568, right column, first paragraph) cannabis joints or NIDA cigarettes used to deliver THC for recreational use.
Further, the person of ordinary skill in the art would be motivated to co-administer beta-hydroxybutyrate salts and THC in combination or simultaneously, as in instant claim 30, in the same dosage form, as in instant claim 37, or separately, as in instant claim 32, because such an optimization of frequency/time of administration in a method of treatment is routine, well within the skill of the artisan.
As such, claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 are rejected as prima facie obvious.
Claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-64, 66 are rejected under 35 U.S.C. 103 as being unpatentable over Greenwood et al. (US 2008/0058416, cited in PTO-892 of 20 February 2024) and Werner et al. (US 2004/0138293, cited in PTO-892 of 20 February 2024).
Greenwood (US 2008/0058416) teaches a method of administering a ketogenic material which is sodium (R)- 3-hydroxybutyrate (Table 1, [0014]), which is enriched in R-BHB, as in instant claim 66, and which is inherently present in sodium beta-hydroxybutyrate, which is a compound of instant claims 17, 49, 60, to a mammal to treat [0015] depression, anxiety, and/or pain.
Greenwood teaches [0002] that ketosis in mammals can be provided by administering of ketogenic materials such as acetoacetate, (R)-3-hydroxybutyrate or their conjugates with each others, or esters thereof; ketogenic materials produce a physiologically acceptable ketosis when administered to a patient.
Greenwood teaches [0009] that the ketosis produced is a state in which levels of one or both of acetoacetate and (R)-3-hydroxybutyrate concentrations in the blood of the subject are raised. Thus, Greenwood teaches administering a ketogenic material/ketone bodies to a mammal comprising administering beta-hydroxybutyrate salt, acetoacetate, or BHB ester of acetoacetate esters, as in instant claim 44, in an amount effective to raise blood ketone levels in the mammal, as in instant claims 17, 49, 60.
The mammal is not in a state of ketosis at the time of initial administration, as in the instant claims.
Greenwood teaches [0012] typical dose ranges 5 to 5000 mg/kg body weight for an ( R)-3-hydroxybutyrate material, most preferably 50-1000 mg/kg, which, for a subject weighing 50 or 60 kg, overlaps with the range in instant claims 18, 50, 60, and satisfies the limitation of instant claim 43.
Greenwood teaches [0012] that doses are conveniently given with meals when orally administered [0012]. Thus, Greenwood teaches that ketogenic materials such as ( R)-3-hydroxybutyrate are administered by ingestion, as in the instant claims, and as in instant claim 33.
Greenwood teaches that the ketogenic material of the invention, such as sodium ( R)-3-hydroxybutyrate, administered in a pharmaceutical composition which includes diluent, excipient and carrier materials [0015] is useful to treat depression, anxiety, pain ([0013], [0015]). Thus, Greenwood teaches administering sodium ( R)-3-hydroxybutyrate to a mammal suffering from depression, as in instant claims 24, 49, 50, 52, 57-59, to treat depression.
Greenwood teaches administering of sodium ( R)-3-hydroxybutyrate in the absence of a medium chain fatty acid having 6 or 12 carbons or a glyceride thereof, as in instant claims 35, 49, 50, 57-59.
Greenwood does not specifically teach that the dosage form is a solution, a liquid as in instant claim 39, or can be delivered as a powder, as in instant claim 38.
Greenwood does not teach administering sodium ( R)-3-hydroxybutyrate in combination with tetrahydrocannabinol (THC), as in the instant claims.
Werner et al. (US 2004/0138293) teaches a pharmaceutical composition containing THC : CBD 75:25 to 80:20, preferably 2:1 [0014] effective to treat pain, depression, anxiety. The THC composition includes one additional cannabinoid compound (CBD) derived from the cannabis plant, as in instant claim 41.
Werner teaches the therapeutic use of the composition of the invention on average 5 mg THC, in a dosage range 2.5 -20 mg THC administered daily as therapeutic dose [0016], which is within the range in instant claim 18, 50, 60, as tablets/coated tablets ([0015]), thus to be administered by ingestion, as in the instant claims.
Werner teaches the pharmacologic effects of the composition include analgesic/ pain-relieving effect [21], as well as anti-depressant and anxiolytic (anxiety-reducing) effect [0022].
Werner does not teach co-administration of THC and beta-hydroxybutyric acid or its salts, as in the instant claims.
It would have been obvious to combine the teachings of Greenwood and Werner to arrive at the instant invention. The person of ordinary skill in the art would have co-administered sodium (R)-3-hydroxybutyrate and THC to a subject having depression (as in instant claims 24, 49), anxiety or pain, because Greenwood teaches that administering sodium (R)-3-hydroxybutyrate by ingestion to a mammal is effective to treat depression, anxiety or pain, and Werner teaches that THC is effective to treat, for example, depression, anxiety, pain.
Thus, the person of ordinary skill in the art would have co-administered sodium (R)-3-hydroxybutyrate with the THC to a subject suffering from depression, anxiety or pain, with the expectation that the combination is effective to treat depression, anxiety or pain. One of ordinary skill in the art would have reasonably expected that combining sodium (R)-3-hydroxybutyrate and THC, known to be useful for the same purpose, i.e. treating depression, anxiety or pain, would result in therapeutic effect. Since all compounds for co-administration herein are known to be useful to treat depression, anxiety or pain, it is considered prima facie obvious to co-administer them in a method used for the same purpose. At least additive therapeutic effects would have been reasonably expected. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
The person of ordinary skill in the art would be motivated to determine the daily dose of sodium (R)-3-hydroxybutyrate and THC administered in the combination, because such optimization of daily dose of therapeutic agents in a method of treatment in order to achieve optimum therapeutic effect, is well within the skill of the artisan.
Further, the person of ordinary skill in the art would be motivated to co-administer sodium ( R)-3-hydroxybutyrate and THC in combination or simultaneously, as in instant claim 30, in the same dosage form, as in instant claim 37, or separately, as in instant claim 32, because such an optimization of frequency/time of administration in a method of treatment is routine, well within the skill of the artisan.
As such, claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-64, 66 are rejected as prima facie obvious.
Claims 17, 65 are rejected under 35 U.S.C. 103 as being unpatentable over Greenwood et al. (US 2008/0058416, cited in PTO-892 of 20 February 2024) and Werner et al. (US 2004/0138293, cited in PTO-892 of 20 February 2024) as applied to claim 17 above, in view of D’Agostino et al. (US 2014/0350105, cited in PTO-892 of 12 April 2022).
Greenwood and Werner are as above.
Greenwood (US 2008/0058416) teaches a method of administering a ketogenic material which is sodium ( R)- 3-hydroxybutyrate (Table 1, [0014]), which is inherently present in sodium beta-hydroxybutyrate, which is a compound of instant claims 17, to a mammal to treat [0015] depression, anxiety, and/or pain.
Greenwood teaches [0002] that ketosis in mammals can be provided by administering of ketogenic materials such as acetoacetate, (R)-3-hydroxybutyrate or salts thereof ([0010], line 7); ketogenic materials produce a physiologically acceptable ketosis when administered to a patient.
Greenwood teaches [0009] that the ketosis produced is a state in which levels of one or both of acetoacetate and (R)-3-hydroxybutyrate concentrations in the blood of the subject are raised. Thus, Greenwood teaches administering a ketogenic material/ketone bodies to a mammal comprising administering beta-hydroxybutyrate salt, in an amount effective to raise blood ketone levels in the mammal, as in instant claim 17.
The mammal is not in a state of ketosis at the time of initial administration, as in the instant claims.
Greenwood does not teach administering beta-hydroxybutyric acid salts comprising at least one BHB salt which is not sodium BHB, as in instant claim 65.
Greenwood does not teach tetrahydrocannabinol (THC) in combination with 3-hydroxybutyrate salts, as in the instant claims.
Werner et al. (US 2004/0138293) teaches a pharmaceutical composition containing THC : CBD 75:25 to 80:20, preferably 2:1 [0014] effective to treat pain, depression, anxiety.
Werner does not teach co-administration of THC and beta-hydroxybutyric acid or its salts, as in the instant claims.
D’Agostino teaches [0033] a method of administering ketone bodies to a mammal by orally administering (ingestion) a composition comprising at least one beta-hydroxybutyrate salt, comprising beta-hydroxy butyrate sodium salt, beta- hydroxy butyrate potassium salt, beta-hydroxy butyrate calcium salt, beta- hydroxy butyrate magnesium salt or a combination thereof in an amount effective to raise blood ketone levels. Thus, D’Agostino implicitly teaches that sodium salt of beta-hydroxybutyrate can be used interchangeably with for example, beta- hydroxy butyrate potassium salt, beta-hydroxy butyrate calcium salt, beta- hydroxy butyrate magnesium salt or in combinations thereof, which is consistent with one or more beta-hydroxybutyrate salts comprising at least one BHB salt which is not sodium BHB, as in instant claim 65.
D’Agostino teaches that the salt of BHB contains the racemic DL-beta hydroxybutyrate [0036], last three lines), or the single isomer R-beta hydroxybutyrate ([0034], last 3 lines).
It would have been obvious to combine the teachings of Greenwood and Werner to arrive at the instant invention. The person of ordinary skill in the art would have co-administered sodium ( R)-3-hydroxybutyrate and THC to a subject having depression, anxiety or pain, because Greenwood teaches that administering sodium ( R)-3-hydroxybutyrate by ingestion to a mammal is effective to treat depression, anxiety or pain, and Werner teaches that a composition comprising THC is effective to treat, for example, depression, anxiety, pain.
Thus, the person of ordinary skill in the art would have co-administered sodium ( R)-3-hydroxybutyrate with the THC composition taught by Werner, to a subject suffering from depression, anxiety or pain, with the expectation that the combination is effective to treat depression, anxiety or pain. One of ordinary skill in the art would have reasonably expected that combining sodium ( R)-3-hydroxybutyrate and THC, known to be useful for the same purpose, i.e. treating depression, anxiety or pain, would result in therapeutic effect. Since all compounds for co-administration herein are known to be useful to treat depression, anxiety or pain, it is considered prima facie obvious to co-administer them in a method used for the same purpose. At least additive therapeutic effects would have been reasonably expected. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
Regarding claim 65, the person of ordinary skill in the art would be motivated to replace sodium (R)-3-hydroxybutyrate with another BHB salt, or to add another BHB salt to sodium (R)-3-hydroxybutyrate, in a combination with THC, because Greenwood teaches broadly 3-hydroxybutyrate or salts thereof as ketogenic materials, and
D’Agostino teaches that sodium salt of beta-hydroxybutyrate can be used interchangeably with for example, beta- hydroxy butyrate potassium salt, beta-hydroxy butyrate calcium salt, or beta- hydroxy butyrate magnesium salt or in combinations thereof, in a composition orally administered to raise blood ketone levels. Thus, a person of ordinary skill in the art would have replaced sodium (R)-3-hydroxybutyrate with another BHB salt, or would have added an additional BHB salt to sodium (R)-3-hydroxybutyrate, such as beta- hydroxy butyrate potassium salt, beta-hydroxy butyrate calcium salt, or beta- hydroxy butyrate magnesium salt, in a combination with THC, with the expectation that said BHB potassium salt, calcium salt, or magnesium salt, will retain the therapeutic effect achieved with BHB sodium salt.
As such, claims 17, 65 are rejected as prima facie obvious.
Conclusion
Claims 17, 18, 24, 30-35, 37-39, 41, 43, 49, 50, 53-67 are rejected.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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