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 .
Status of the Claims
Per Applicant’s amendment to the claims, submitted on 10/25/2021, claim 14 is amended, claims 1-13 are canceled, and claims 15-25 are newly added. Currently, claims 14-25 are pending in the instant application.
Priority
The instant application is a 371 of PCT/GB2020/051080 filed on 05/01/2020, and claims foreign priority to GB1906261.1 filed on 05/03/2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/26/2023, 06/27/2023, and 10/02/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112 – Second Paragraph
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.
Claim 18 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 18 is indefinite for reciting “the CBD preparation”, because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. Parent claim 14 was amended such that it recites a CBD “drug substance” rather than a CBD “preparation”. Accordingly, the instant claim provides improper antecedence to claim 14. This rejection may be overcome by amending claim 18 to recite a “drug substance” rather than a preparation.
Claim 20 is indefinite for reciting “the CBD preparation”, because a person of ordinary skill in the art would not reasonably be able to understand the metes and bounds of the claim. Parent claim 14 was amended such that it recites a CBD “drug substance” rather than a CBD “preparation”. Accordingly, the instant claim provides improper antecedence to claim 14. This rejection may be overcome by amending claim 18 to recite a “drug substance” rather than a preparation.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
Claim(s) 14-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guy (US 20150359756 A1) in view of ElSohly (Life Sciences 78 (2005) 539–548) and Smith (Phytochemistry, 1977, Vol. 16, pp. 1088-1089).
Claim 14 recites a method of treating a patient suffering from seizures associated with tuberous sclerosis complex (TSC) comprising administering a cannabidiol (CBD) drug substance to the subject in need thereof, wherein the CBD drug substance comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) other cannabinoids, wherein the less than or equal to 2% (w/w) other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.
Guy teaches the treatment of absence seizures in patients suffering from TBS by administering CBD (specification [0001])1. In particular, Guy teaches the use of an exemplary CBD extract having the following constituency (specification [0074], Table 5):
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As can be seen from the above table, Guy makes use of a CBD substance comprising:
Greater than or equal to 98% w/w CBD
Less than or equal to 2% w/w other cannabinoids
Wherein the other cannabinoids comprise:
THC
CBDV
CBD-C4
Guy does not explicitly teach a CBD substance wherein the less than 2% w/w other cannabinoids comprise CBD-C1 and a mixture of cis and trans THC. However, the use of such a CBD substance comprising said cannabinoids would be obvious because:
ElSohly teaches that CBD-C1 is a well known cannabinoid in the art, being naturally occurring in cannabis sativa
Smith teaches that both trans and cis THC are well known cannabinoids in the art, being naturally occurring in cannabis sativa
Given the teachings of, Guy, ElSohly, and Smith, there would have been a reasonable expectation of success in both formulating a CBD substance of the instant claim, and utilizing it to treat seizures in TSC.
ElSohly provides an overview on the chemical constituency of cannabis sativa. Such constituency comprising the following CBD type cannabinoids (page 544, Table 4):
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As indicated in the table above, CBD-C1 is a naturally occurring cannabinoid in cannabis sativa. Given that Guy indicates the use of CBD extract of cannabis sativa (specification [0071])2, and ElSohly teaches that CBD-C1 is a readily available as a natural cannabinoid of cannabis sativa, there would be a reasonable expectation of success in formulating a CBD substance containing CBD-C1. Furthermore, in absence of evidence of the contrary, a person of ordinary skill would reasonably expect that such a CBD substance containing greater than or equal to 98% CBD and less than 2% (i.e., trace amounts) of CBD-C1 would still be effective to treat seizures in TSC; the reason being, that the teachings of Guy are directed to the use of CBD as a main active for treatment.
Smith provides an overview of the Δ1-3,4-THC (i.e., Δ9-THC or THC) content in cannabis sativa. Smith indicates that THC is present in cannabis sativa in both trans and cis configurations, wherein the trans configuration is the predominant isomer (page 1088)3, in plants having high ratios of CBD to THC. Smith further indicates that both cis and trans isomers of THC are able to be isolated from extract, and can be created synthetically. Given that Guy teaches the use of cannabis sativa to formulate CBD extract, and Smith teaches cannabis sativa having both cis and trans THC there would be a reasonable expectation of success in formulating a CBD substance containing both THC isomers. Furthermore, in absence of evidence of the contrary, a person of ordinary skill would reasonably expect that such a CBD substance containing greater than or equal to 98% CBD and less than 2% (i.e., trace amounts) of trans and cis THC would still be effective to treat seizures in TSC; the reason being, that the teachings of Guy are directed to the use of CBD as a main active for treatment.
In summary, Guy teaches treatment of seizures in TSC using a CBD substance comprising greater than or equal to 98% CBD, and less than or equal to 2% of other cannabinoids, wherein the other cannabinoids comprise THC, CBDV, and CBD-C4, but does not teach the inclusion of CBD-C1 or a mixture of cis and trans THC. ElSohly teaches that CBD-C1 is well known and readily available as a natural cannabinoid in cannabis sativa, while Smith teaches essentially the same but for both cis and trans THC. A person of ordinary skill in the art would have found it prima facie obvious to combine the teachings of each of the aforementioned to arrive at the method of the instant claim, and more specifically, the CBD substance being used, because each of the constituent cannabinoids are well known in the art and are readily available, and there would be a reasonable expectation that such a CBD substance would be successful in treating seizures of TSC.
Claim 15 further limits the method of claim 14 wherein the CBD drug substance is used in combination with one or more concomitant AED.
Guy indicates combination dosing with AEDs (specification [0040])4.
Claim 16 further limits the method of claim 15 wherein the one or more AED is selected from the group consisting of: valproic acid, vigabatrin, levetiracetam and clobazam.
Guy indicates valproic acid, vigabatrin, levetiracetam, and clobazam as acceptable AEDs for combination dosing (specification [0045])5.
Claim 17 further limits the method of claim 14 wherein the CBD is isolated from cannabis plant material.
Guy teaches the extraction and isolation of CBD from cannabis sativa plants.
Claim 18 further limits the method of claim 14 wherein at least a portion of at least one of the cannabinoids present in the CBD preparation is isolated from cannabis plant material.
Guy teaches that the CBD in composition may be CBD extracted from cannabis, or as a synthetic compound (specification [0043]-[0044])6.
Claim 19 further limits the method of claim 14 wherein the CBD is present as a synthetic preparation.
Guy teaches that the CBD in composition may be CBD extracted from cannabis, or as a synthetic compound (specification [0043]-[0044]).
Claim 20 further limits the method of claim 14 wherein at least a portion of at least one of the cannabinoids present in the CBD preparation is prepared synthetically.
Guy teaches that the CBD in composition may be CBD extracted from cannabis, or as a synthetic compound (specification [0043]-[0044]).
Claim 21 further limits the method of claim 14 wherein the dose of CBD is greater than 5 mg/kg/day.
Guy provides an exemplary dosing procedure wherein patients were initially administered 5 mg/kg/day, and further titrated up to a maximum dosing amount of 25 mg/kg/day (specification [0102]-[0103])7.
Claim(s) 22-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guy in view of ElSohly and Smith, and further in view of Devinsky (Lancet Neurol 2016; 15: 270–78).
Claim 22 further limits the method of claim 14 wherein the dose of CBD is 20 mg/kg/day.
As discussed above in the rejection of claim 14, the combined teachings of Guy, ElSohly, and Smith obviate the method of claim 14 wherein seizures of TSC are treated by administering a CBD drug substance. None of Guy, ElSohly, or Smith teach dosing of CBD at 20 mg/kg/day. However it would be obvious for a person of ordinary skill in the art to arrive at such a dosing regimen, because Devinsky teaches that CBD administration provides dose-dependent effect on seizure reduction, and there would be a reasonable expectation of success in treating seizure at the indicated dosing amount.
Devinsky conducts safety and efficacy testing for administration of cannabidiol in patients with treatment resistant epilepsy. Patients were dosed with cannabidiol at an initial baseline of 5 mg/kg/day, and titrated up to a maximum of either 25 mg/kg/day, or 50 mg/kg/day over 12 weeks (page 270)8. The following figure 2 depicts the monthly frequency of motor seizures over 12 weeks of dosing, while the following figure 3 depicts the percent change in monthly frequency of motor seizures over 12 weeks of dosing (page 275):
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As can be seen from Fig. 2, the dosing regimen of Devinsky provides a general reduction of median motor seizure frequency over the 12 weeks. In Fig. 3, Devinsky indicates a progressive decrease in the percentage of monthly motor seizures over the same 12 weeks. Such results indicate that the effects gained from administering CBD are dose-dependent, as the efficacy of the treatment appears to scale with the increasing dosing amounts of the titration.
Considering that the teachings of Devinsky indicate a dose-dependent relationship between CBD and anti-seizure effect, a person of ordinary skill in the art would have found it prima facie obvious to arrive at the recited 20 mg/kg/day dosing amount per the principle of routine optimization, as such a person would be motivated to find the optimal dosing amount for any given desired treatment or effect. The teachings of Devinsky provide a degree of predictability in the dosing of CBD for the treatment of seizure. See MPEP 2144.05(II):
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
Claim 23 further limits the method of claim 14 wherein the dose of CBD is 25 mg/kg/day.
The instant claim is rejected for the same obvious reasons as claim 22. Namely in that Devinsky teaches a dose-dependent relationship between CBD and anti-seizure effect. A person of ordinary skill in the art would have found an optimal dosing amount of 25 mg/kg/day per the principle of routine optimization.
Claim 24 further limits the method of claim 14 wherein the dose of CBD is 50 mg/kg/day.
The instant claim is rejected for the same obvious reasons as claim 22. Namely in that Devinsky teaches a dose-dependent relationship between CBD and anti-seizure effect. A person of ordinary skill in the art would have found an optimal dosing amount of 50 mg/kg/day per the principle of routine optimization.
Claim(s) 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guy in view of ElSohly and Smith.
Claim 25 further limits the method of claim 14 wherein the seizures that are associated with TSC comprise one or more of the following seizure types: focal motor seizures without impairment of consciousness or awareness; focal seizures with impairment of consciousness or awareness; or focal seizures evolving to bilateral generalized convulsive seizures and generalized seizures.
Guy indicates that, in an exemplary dosing procedure, patients having TSC and suffering from focal seizures without impairment were administered CBD (specification [0099]-[0100])9.
Conclusion
Claims 14-25 are rejected.
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/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “The present invention relates to the use of cannabidiol (CBD) in the treatment of absence seizures. In one embodiment the patients suffering from absence seizures are children and young adults. CBD appears particularly effective in reducing absence seizures in patients suffering with etiologies that include: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; CDKL5; Dup15q; Jeavons syndrome; Myoclonic Absence Epilepsy; Neuronal ceroid lipofuscinoses (NCL) and brain abnormalities in comparison to other seizure types.”
2 “In summary the drug substance used in the trials is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than 98% CBD.”
3 “Cannabinoid assay of numerous samples by extraction, preparative-TLC and GLC indicated that the only marijuana plants showing significant quantities of cis-THC were those which simultaneously exhibited high ratios of cannabidiol (CBD) to total THC [.] In typical cases, samples having CBD-THC ratios of about 16: 1 had trans-THC-cis-THC ratios of about 1 : 1 or 2: 1, whereas samples having phenotype ratios less than 1 had trans-THC-cis-THC > 10:1.”
4 “In a further embodiment the CBD is for use in combination with one or more concomitant anti-epileptic drugs (AED).”
5 “In a further embodiment of the invention the one or more AED is selected from the group consisting of: clobazam, clonazepam, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, gabapentin, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, nordiazepam, phenytoin, stiripentol, topiramate, trazodone, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.”
6 “In a further embodiment the CBD is present as a highly purified extract of cannabis… In an alternative embodiment the CBD is present as a synthetic compound.”
7 “The patients then received a highly purified CBD extract (greater than 98% CBD w/w) in sesame oil, of known and constant composition, at a dose of 5 mg/kg/day in addition to their baseline anti-epileptic drug (AED) regimen… The daily dose was gradually increased by 2 to 5 mg/kg increments until intolerance occurred or a maximum dose of 25 mg/kg/day was achieved.”
8 “Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks.”
9 “The epileptic syndromes that these patients suffered from were as follows: Lennox-Gastaut Syndrome; Myoclonic Absence Epilepsy; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Jeavons Syndrome; CDKL5; Dup15q; Neuronal ceroid lipofuscinoses (NCL) and brain abnormalities. Seizure types experienced by these patients included: tonic, clonic, tonic-clonic, myoclonic, atonic, absence, myoclonic-absence, focal seizures without impairment, focal seizures with impairment and focal seizures evolving to bilateral convulsive seizures.”
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