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 .1
Status of Claims, Response to Arguments and Cited References
Claims 36-38, 41-44 and 47-59 are pending. Applicant’s species election has been acknowledged.2 Applicant's arguments filed April 28, 2026 have been fully considered but they are not persuasive. See below Response to Attorney Arguments. Copy of Deiana et al., Psychopharmacology 219,3 (2012): 859-7, cited on the PTO-892 form.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 36-38, 41-44 and 47-59 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2011/063164 (WO 164), in view of Irving et al. Inflamm Bowel Dis Volume 24, Number 4, April 2018 and Borrelli et al., Biochem Pharmacol. 2013; 85 (9):1306-1316, as evidenced by US Pub 2005/0266108 (US Pub 108).
Claim 36 recites a method treating an inflammatory GI disorder (Irritable bowel disease) in a human subject comprising: oral administration of a therapeutically effective amount of oral pulse release dosage form, said form comprising: a first immediate release pulse-release component (C1)) formulation comprising cannabigerol (CBG); and a second delayed release pulse-release component (C2) formulation comprising CBG, wherein: total dose of the CBG is up to 150 mg; and at least 70% of the total dose of the CBG is comprised in one or more delayed-release formulations.
Regarding claim 36, WO 164 teaches a formulation comprising a cannabinoid formulation, partitioned immediate and delayed release compartments (claimed C1 and C2), i.e. composition with first/second pulsed components. See claim 36. WO 164 discloses tablet (oral) formulations comprising cannabinoid/dronabinol/other THC. See Table 7 (pellet in a capsule), see paragraph 248; and a bilayer/matrix tablet see Table 8, paragraph 255.
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See also Table 9 (paragraph 263) among other examples therein disclosing instant/delayed release formulations of WO 164.
WO 164 teaches its compositions comprise cannabinoids, i.e. any member of substances structurally related to THC, including a naturally occurring compound present in Cannabis plants; purified/synthesized cannabinoids per US Pub 2005/0266108, such as THC per se and the particular variant Delta 9 THC aka dronabinol. See paragraphs 49, 51 and 54. WO 164 teaches the present medicaments provide oral dosing of about 0.1 to about 75 mg of a cannabinoid, that overlaps the limitation of up to 150 mg claimed. See paragraph 18 and MPEP 2144.05(I).
WO 164 teaches ulcerative colitis and Crohn’s disease (i.e. claimed subject in need). See paragraph 17.
While WO 164 teaches an oral dosed pulsed formulation, comprising cannabinoid (THC/dronabinol) with a first immediate release pulse (C1) and a second pulse delayed release (C2) formulation in amounts that overlap those claimed, it does not recite the identity and amounts such as elected 150 mg of elected species: Cannabigerol (CBG), total dose up to 150 mg; Cannabidiol (CBD), total dose up to 40 mg; and THC, total dose up to 2mg; and at least 70% of the total dose of the CBG is comprised in one or more delayed-release formulations.
However, a person having ordinary skill in the art (PHOSITA) would look towards the use of CBG, CBD and THC for the treatment of an inflammatory GI disorder with a reasonable expectation of success as these are known in the art to treat inflammatory GI disorders; as well as at least 70% of the total CBG dose is comprised in one or more delayed-release formulations.
Initially, with regard to total CBG total dose of up to 150 mg, WO 164 teaches cannabinoid dosages of up 0.1 to 75 mg, which falls within the claimed range. MPEP 2144.05(I).
WO 164 provides a teaching, suggestion and motivation to look towards not only exemplified THC, but other cannabinoids such as CBG, and CBD where it explicitly teaches to a PHOSITA:
The compositions of the present invention provide one or more cannabinoids in a medicament that can deliver to a subject a desired target PK profile, where the PK profile achieves a therapeutic level of a cannabinoid during a therapeutic window. Cannabinoids of the present invention are any member of a group of substances that are structurally related to tetrahydrocannabinol and that bind to a cannabinoid receptor such as CB1 or CB2 or both (THC) . The cannabinoid can be a naturally occurring compound (e.g. present in Cannabis), a compound metabolized by a plant or animal, or a synthetic derivative. See paragraph 49.
The cannabinoids of the present invention are further meant to encompass natural cannabinoids, natural cannabinoids that have been purified or modified, and synthetically derived cannabinoids, for example, United States Patent Application Publication 2005/0266108, hereby incorporated by reference in its entirety, describes a method of purifying cannabinoids obtained from plant material. See paragraph 51.
WO 164 references and incorporates the teachings of US Pub 2005/0266108 (US Pub 108), where it is noted US Pub 108 teaches by definition, the class of cannabinoid compounds envisioned by WO 164 to be incorporated into its oral dosed pulsed formulation includes THC (delta 9 tetrahydro cannabinol), cannabidiol (CBD) and cannabigerol (CBG). See para. 4-5.
Further, WO 164 teaches the claimed immediate (C1) and delayed release (C2) compartments of the formulations with overlapping ranges, where it notes the portion of cannabinoid in the immediate release compartment can be any of the following percents (%): 10 - 75, 10 - 50, 20 - 50, 25 – 75. See paragraph 80. These taught ranges overlap those claims, i.e. where percentages of cannabinoid in the immediate release compartment/portion of up to 30 %, conversely indicate that at least 70 % of cannabinoid (i.e., CBG) is in the controlled/delayed release compartment. Note also claim 47’s limitation of at least 85% CBG and 15% in the immediate release compartment is also encompassed by these ranges.
WO ‘164 teaches an adjustment of percentages are routinely optimized by a PHOSITA, with the teachings provided herein, so that a PHOSITA can adjust the release properties of one or more release components (e.g. by varying the amount of drug therein or the relative amounts or types of release modifiers therein). See paragraph 82. Also note, that with the plurality of compartments designed to lease the claimed drugs, the medicament comprises an immediate release compartment and a plurality of delayed (e.g. timed) release compartments. See paragraph 94. “Optionally, a medicament comprises more than two or more compartments including a third compartment (C3) as per claim 47 (e.g. 3, 4, 5, or 6 compartments), , such as timed-release compartments having different times of cannabinoid release.” Id. at 94.
Therefore, WO 164 teaches the compatibility of its oral dosed pulsed formulation with the genus of cannabinoid compounds, including CBD and CBG (claimed), as well as THC, where the claimed cannabinoid occurs in the claimed percentages in the delayed release portion, as exemplified by WO 164 and claimed by Applicant.
With regard to choice of CBG, CBD and THC as cannabinoids Irving teaches a CBD (cannabidiol) rich extract contained not only CBD but also smaller amounts of other compounds such as cannabigerol (CBG) and THC. See page 715 column 1. Irving teaches that the CBD rich extract (comprising CBD, CBG and THC) when administered to inflammatory bowel disease patients, suggested its data that CBD rich botanical extract (comprising CBD, CBG and THC) may be beneficial for symptomatic treatment of ulcerative colitis (UC). See abstract. Irving teaches there is evidence that the combination of CBD and THC may offer additive effects in models of inflammatory bowel disease (IBD). See page 715, column 1. Irving teaches that a study by Jamontt 2010 that this combination not only reduced inflammation but also lowered the occurrence of functional disturbances, interpreted to be symptoms of IBD. Id.
Borrelli teaches the beneficial effect of the cannabinoid CBG in an experimental model of IBD, a murine model of colitis induced in mice models. See abstract. “CBG could be considered for clinical experimentation in IBD patients.” See abstract.
A PHOSITA following the teachings of WO 164 (as evidenced by US Pub 108) would have found it prima facie obvious to formulate the claimed pulse oral composition for use in treating IBS, Crohn’s disease or UC in view of Irving and Borelli, as these are taught by the combination of the cited prior art.
More specifically, the rationale to support a finding of obviousness includes the prior art elements of WO 164 noting oral pulsed dosage forms comprising a first immediate release formulation of a cannabinoid (dronabinol/THC), a second delayed release formulation of (dronabinol/THC) suggested for use in treating IBS, Crohn’s disease or UC, combined with known methods (CBD, CBG and/or THC treating inflammatory bowel diseases) to predictably arrive at the claimed invention.
Regarding claims 37, 41 and 44, official notice is given that UC, Crohn' s disease and IBS involve both upper and lower GI tract, as claimed. The GI tract consists only of an upper and lower tract and UC, Crohn' s Disease and IBS are known to affect the GI tract. As discussed above, the combination of WO 164, Irving and Borrelli teach IBS, Crohn's disease and UC, where the symptoms of claim 44 (pain, bloating, diarrhea) are noted to be associated with IBS, Crohn' s disease or UC. It would be routine for one of ordinary skill in the art to optimize the treatment of the upper and/or lower GI tract for the symptoms claimed.
Regarding claims 38, dosing the patient 1-4 times a day, and claims 42-43, where treatment disorder and/or symptoms occurs within 6, 12, 24 or greater than 24 hours post-dose, or 1-24 hours, or greater than 24 hours, WO 164 teaches its compositions are suitable for treating conditions by therapeutic levels for more than about 5 hours, i.e. about 6-8 hours or for as long as about 8 to about 12 hours. See paragraph 16. It would be routine to dose a patient 1-4 times a day based on the hours teachings of WO 164.
Also note, that with the plurality of compartments (third compartment) designed to release the claimed drugs, the medicament comprises an immediate release compartment and a plurality of delayed (e.g. timed) release compartments. See paragraph 94. “Optionally, a medicament comprises more than two or more compartments (e.g. 3, 4, 5, or 6 compartments), such as timed-release compartments having different times of cannabinoid release.” Id. at 94.
Regarding claim 48 and limitations of the first pulse component is 10-50% of total cannabinoid and cannabinoid of second pulse is 50-90% of total dose, WO 164 discloses various tablet formulations comprising cannabinoid pellets (dronabinol or other THC) see Table 7 (pellet in a capsule), see paragraph 248; and a bilayer/matrix tablet see Table 8, paragraph 255. See Tables 7 and 8 where 2.5 mg dronabinol is in first immediate release component (25% w/w of total 10 mg), 7.5 mg is in second delayed release (75% w/w of total 10 mg), thus teaching the limitations of claim 48.
Regarding claims 49 and 50, WO 164 discloses Tables 7 and 8 with the various claimed excipients including microcrystalline cellulose (Avicel PH 101).
Regarding claim 51, it is noted that WO 164 teaches that with Table 8, microcrystalline cellulose comprises 39.5 mg (out of 100 mg) of the immediate release component, for a percentage of 39.5% w/w, within the claimed range of 1-60% w/w.
Per claims 52-55, WO 164 discloses its formulations are selected from the various formulations with delayed release components (delayed cannabinoid API core claimed with polymers/methacrylic acid polymer Eudragit, layered or integrated, pH sensitive or not), such as bilayer/matrix type, monolithic/matrix-type, monolithic/coated -type, enteric coating-type, 2 pulse type, 3 pulse type, solid adsorbate type, pellet-type, and continuous release-type, see claim 26. These formulations are either coated or non-coated and either pH or non-pH sensitive. Further, with regard to polymer coated/integrated delayed release components, WO 164 discloses Table 9 paragraph 263, with both an instant release and delayed release component, where methacrylic acid co polymer type C (Eudragit) is used to coat the delayed release pellet component.
Regarding claim 56 (polymer being 4 to 25% weight of the delayed release portion), WO 164 discloses 13.2 mg of Eudragit out of the subtotal of 172.5 mg, which is 7.65%, see above Table 9.
As required by claims 57-59 (claimed pellets encapsulated) WO 164 Table 7 and Table 9 disclose pellets enclosed in a capsule, see above.
RESPONSE TO ATTORNEY ARGUMENTS:
Amended Claims and the Cited Prior Art
The Attorney response states that WO 164 does not teach that at least 70% of the cannabinoids be in delayed-release formulations (now amended claim 36, described to decrease systemic CBG absorption for GI tract enhanced delivery, Abstract), and US Pub 108 is silent regarding formulation or dose distribution in general. The Attorney response states Borrelli does not teach CBG pulse-release formulations, but only that CBG treats inflammatory bowel disease, Abstract.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as detailed above in the 103 obviousness rejection, the cited prior art teaches the newly amended claimed invention. In particular, WO 164 teaches the amended features of the claimed invention, i.e. the specific distribution of CBG in pulse-release formulations. See paragraphs 80 and 94 of WO 164.
B. Alleged Unexpected Results
The Attorney response states, Examples 66-67 of the instant application provide pulse release oral dosage form in which 100% of the CBG is comprised in a delayed-release formulation (pulse 3).3 The Attorney response states, First none of the cited art provides clinical/therapeutic data using CBG containing formulations to treat inflammatory GI disorders.4 As detailed in footnote 6 summarizing page 9 of the Attorney response, the Attorney response individually lists teachings of each cited art references.
In response to applicant's arguments (First) against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Second, the Attorney response contrasts the clinical efficacy of the oral formulations in the present application with the prior art's (Borelli, at page 1314 and reference 51, citing to Deiana et al., Psychopharmacology 219,3 (2012): 859-7) teaching lower bioavailability of orally administered CBG. The Attorney response states, Deiana teaches that oral administration of CBG has significantly lower bioavailability compared to i.p. (intraperitoneal) injection. See, e.g., Deiana at Table 4, showing oral administration of CBG having approximately 60 times lower maximum plasma concentration (Cmax) and 83 times lower Area Under the Curve (AUC) than i.p. injection in mice. In response (Second), while the Attorney arguments of unexpected results are not provided by a Rule 132 Declaration per MPEP 716, they are being treated with the evidentiary weight of such for purposes of rebuttal.
MPEP 716.02(b) III. requires unexpected results must be either direct or indirect comparative tests probative of nonobvious. Applicant’s statements regarding the teachings of Deiana and its orally dosed CBG is not comparable to those claimed.
Unlike the claimed controlled release formulations and rendered obvious as detailed above, the orally dosed CBG formulation from Deiana has the features of an in immediate release suspension comprising Cremophor EL/ethanol/saline 1:1:18 ratio. See page 863, column 2. Deiana’s oral dosed CBG formulation referenced to as unexpected results, is not a comparative test, or analysis. The formulation of Deiana has none of the delayed release aspects to overcome the obviousness rejection, but rather is a liquid suspension formulation, with features of an immediate release formulation as per its mostly saline/liquid carrier.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
RESPONSE TO ATTORNEY ARGUMENTS: Applicant traverses both rejections. Neither U.S. Patent 11,654,130 nor Application 18/455,378 discloses the feature of CBG dose distribution in the amended claims, where the claimed method of treating inflammatory GI disorder not obvious over the cited art as discussed above.
In response, as detailed below, the amended claims are rejected in modified rejections over the same cited prior art as detailed below.
Claims 36-38, 41-44 and 47-59 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 U.S. Patent No. 11654130 B2 (cited on PTO 892) in view of WO 2011/ 063164 (WO 164), Irving et al. Inflamm Bowel Dis Volume 24, Number 4, April 2018 and Borrelli et al. Biochem Pharmacol. 2013; 85 (9):1306-1316, as evidenced by US Pub 2005/0266108 (US Pub 108).
Regarding claim 36, reference patent claims 1 and 9 are directed to an oral pulse dosage form, comprising what is a near identical, if not identical, oral pulse dosage form comprising a first immediate pulse release dosage form (C1) of cannabinoid active pharmaceutical ingredient (API1) and second controlled/delayed release pulse dosage form (C2) of cannabinoid (API2) wherein the total dose is divided between API1 and API2.
While teaching the claimed oral dosage form as detailed above, the reference patent does not necessarily teach a total amount of CBG of up to 150 mg.
Also, while conflict reference patent, discloses the claimed composition as well as various cannabinoids including cannabigerol, it does not necessarily recite the treatment of GI disorders such as inflammatory bowel disease/disorder as claimed in claim 36.Nor does it specify the elected species of CBD, CBG and THC, or a total CBG dose of up 150 mg.
However, a PHOSITA would look towards the use of cannabinoids (elected species CBG, CBD and THC) for the treatment of an inflammatory GI disorder with a reasonable expectation of success as these are known in the art, as well as a total CBG total dosage of 150 mg.
Regarding claim 36 and limitation of total amount of cannabinoid of up to 150 mg CBG, WO 164 provides a teaching of a controlled release cannabinoid formulation, where the present medicaments provide oral dosing of about 0.1 to about 75 mg of a cannabinoid, that overlaps the limitation claimed. See paragraph 18.
While WO 164 teaches cannabinoid dosages of up 0.1 to 75 mg, which falls within the claimed range, it does not explicitly point to CBG or the other elected cannabinoids species, CBD and THC. With regard to choice of CBD, THC and CBG, the choice is taught as follows.
WO 164 provides a teaching, suggestion and motivation to look towards not only exemplified THC, but other cannabinoids such as CBG, and CBD where it explicitly teaches to a PHOSITA,
The compositions of the present invention provide one or more cannabinoids in a medicament. . . . Cannabinoids of the present invention are any member of a group of substances that are structurally related to tetrahydrocannabinol and that bind to a cannabinoid receptor such as CB1 or CB2 or both (THC) . The cannabinoid can be a naturally occurring compound (e.g. present in Cannabis), a compound metabolized by a plant or animal, or a synthetic derivative. See paragraph 49.
The cannabinoids of the present invention are further meant to encompass natural cannabinoids, natural cannabinoids that have been purified or modified, and synthetically derived cannabinoids, for example, United States Patent Application Publication 2005/0266108, hereby incorporated by reference in its entirety, describes a method of purifying cannabinoids obtained from plant material. See paragraph 51.
WO 164 incorporates the teachings of US Pub 2005/0266108 (US Pub 108), where US Pub 108 teaches by definition, the class of cannabinoid compounds envisioned by WO 164 to be incorporated into its oral dosed pulsed formulation includes THC (delta 9 tetrahydro cannabinol), cannabidiol (CBD) and cannabigerol (CBG). See paragraphs 4-5.
Further, WO 164 teaches the claimed immediate (C1) and delayed (C2) release compartments of the formulations with overlapping ranges, where it notes the portion of cannabinoid in the immediate release compartment can be any of the following percents (%): 10 - 75, 10 - 50, 20 - 50, 25 – 75. See paragraph 80. These taught ranges overlap those claims, i.e. where percentages of cannabinoid in the immediate release compartment/portion of up to 30 %, conversely indicate that at least 70 % of cannabinoid (i.e., CBG) is in the controlled/delayed release compartment. Note also claim 47’s limitation of at least 85% CBG and 15% in the immediate release compartment is also encompassed by these ranges.
WO ‘164 teaches an adjustment of percentages are routinely optimized by a PHOSITA, with the teachings provided herein, so that a PHOSITA can adjust the release properties of one or more release components (e.g. by varying the amount of drug therein or the relative amounts or types of release modifiers therein). See paragraph 82. Also note, that with the plurality of compartments designed to lease the claimed drugs, the medicament comprises an immediate release compartment and a plurality of delayed (e.g. timed) release compartments. See paragraph 94. “Optionally, a medicament comprises more than two or more compartments including a third compartment (C3) as per claim 47 (e.g. 3, 4, 5, or 6 compartments), , such as timed-release compartments having different times of cannabinoid release.” Id. at 94.
Therefore, WO 164 teaches the compatibility of its oral dosed pulsed formulation with the genus of cannabinoid compounds, including CBD and CBG (claimed), as well as THC, where the claimed cannabinoid occurs in the claimed percentages in the delayed release portion, as exemplified by WO 164 and claimed by Applicant.
Per Irving, a CBD (cannabidiol) rich extract contained not only CBD but also smaller amounts of other compounds such as cannabigerol (CBG) and THC. See page 715 column 1. Irving teaches the CBD rich extract when administered to patients, may be beneficial for symptomatic treatment of ulcerative colitis (UC). See abstract. Irving teaches there is evidence the combination of CBD and THC may offer additive effects in models of inflammatory bowel disease (IBD). See page 715, column 1. Irving teaches that a study by Jamontt 2010 discloses this combination not only reduced inflammation but also lowered the occurrence of functional disturbances, reasonably interpreted to be symptoms of IBD. Id.
Further, Borrelli teaches the beneficial effect of the cannabinoid CBG in an experimental model of IBD, a murine model of colitis induced in mice models. See abstract. “CBG could be considered for clinical experimentation in IBD patients.” See abstract.
A PHOSITA following the teachings of the reference patent would have found it prima facie obvious to formulate the claimed pulse oral composition for use in treating IBS, Crohn’s disease or UC in view of WO 164, Irving and Borelli, as these are taught by the combination of the cited prior art
The rationale to support a finding of obviousness are the prior art elements of the reference patent, noting oral pulsed dosage forms as claimed combined with the teachings of Irving and Borrelli (CBD, CBG and THC useful for treating IBS, UC and/or Crohn’s disease) to predictably arrive at the claimed invention.
Regarding claims 37, 41 and 44, official notice is given that UC, Crohn' s disease and IBS involve both upper and lower GI tract, as claimed. The GI tract consists only of an upper and lower tract and UC, Crohn' s Disease and IBS are known to affect the GI tract. As discussed above, the combination of WO 164, Irving and Borrelli teach IBS, Crohn's disease and UC, where the symptoms of claim 44 (pain, bloating, diarrhea) are noted to be associated with IBS, Crohn' s disease or UC. It would be routine for one of ordinary skill in the art to optimize the treatment of the upper and/or lower GI tract for the symptoms claimed.
Regarding claim 38 and dosing the patient 1-4 times a day, and claims 42-43, where treatment disorder and/or symptoms occurs within 6, 12, 24 or greater than 24 hours post-dose, or 1-24 hours, or greater than 24 hours, the reference patent discloses the pulse-release dosage form provides release of the API1P2 and the API2P2 beginning from 2 to 6 hours after release of the API1P1 and the API2P1 begins. See claim 1. It would be routine to dose a patient 1-4 times a day based on the hours teachings of WO 164.
Regarding claim 48 and the limitation of where the cannabinoid of the first pulse component is 10-50% of total and cannabinoid of second pulse is 50-90% of total dose, the reference patent teaches for each API, the first portion (P1) is independently selected from 25% to 75% of the total daily dose, and for each API the second portion (P2) is independently selected from 25% to 75% of the total daily dose. See claim 1.
Regarding claims 49 and 50, WO 164 discloses Tables 7 and 8 with the various claimed excipients including microcrystalline cellulose (Avicel PH 101).
Regarding claim 51, the reference patent teaches the binders comprise from 1 to 60% (w/w). See claim 7.
As required by claims 52-55, WO 164 discloses its formulations are selected from the various formulations with delayed release components (delayed cannabinoid API core claimed with polymers/methacrylic acid polymer Eudragit, layered or integrated, pH sensitive or not), such as bilayer/matrix type, monolithic/matrix-type, monolithic/coated -type, enteric coating-type, 2 pulse type, 3 pulse type, solid adsorbate type, pellet-type, and continuous release-type, see claim 26. These formulations are either coated or non-coated and either pH or non-pH sensitive. Further, with regard to polymer coated/integrated delayed release components, WO 164 discloses Table 9 paragraph 263, with both an instant release and delayed release component, where methacrylic acid co polymer type C (Eudragit) is used to coat the delayed release pellet component.
Regarding claim 56 (polymer being 4 to 25% weight of the delayed release portion), WO 164 discloses 13.2 mg of Eudragit out of the subtotal of 172.5 mg, which is 7.65%, see above Table 9.
As required by claims 57-59 (claimed pellets encapsulated) WO 164 Table 7 and Table 9 disclose pellets enclosed in a capsule, see above.
Claims 36-38, 41-44 and 47-59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-15, and 17-18 of copending Application No. 18455378 in view of WO 2011/ 063164, Irving et al., Inflamm Bowel Dis Volume 24, Number 4, April 2018 and Borrelli et al. Biochem Pharmacol. 2013; 85 (9):1306-1316, as evidenced by US Pub 2005/0266108 (US Pub 108). US 11654130, WO 164, Irving and Borrelli are cited on the IDS. US Pub 108 is cited on the PTO-892 form.
The subject matter of claim 36 has been discussed above and its contents are discussed below.
Regarding claim 36, reference application claim 1, among others discloses an oral pulse dosage form, comprising what is a near identical, if not identical, oral pulse dosage form comprising a first immediate pulse release dosage form (C1) of cannabinoid active pharmaceutical ingredient (API1) and second controlled/delayed release pulse dosage form (C2) of cannabinoid (API2) wherein the total dose is divided between API1 and API2
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While teaching the claimed oral dosage form as detailed above, the reference patent does not necessarily teach a total amount of CBG of up to 150 mg.
Further, although the reference application discloses the claimed composition as well as various cannabinoids including cannabigerol, it does not necessarily recite the treatment of GI disorders such as inflammatory bowel disease/disorder as claimed in claim 36.Nor does it specify the elected species of CBD, CBG and THC, or a total CBG dose of up 150 mg.
However, one of skill in the art would look towards the use of cannabinoids (elected species CBG, CBD and THC) for the treatment of an inflammatory GI disorder with a reasonable expectation of success as these are known in the art, as well as a total CBG total dosage of 150 mg.
While WO 164 teaches cannabinoid dosages of up 0.1 to 75 mg, which falls within the claimed range, it does not explicitly point to CBG or the other elected cannabinoids species, CBD and THC. With regard to choice of CBD, THC and CBG, the choice is taught as follows.
WO 164 provides a teaching, suggestion and motivation to look towards not only exemplified THC, but other cannabinoids such as CBG, and CBD where it explicitly teaches to a PHOSITA,
The compositions of the present invention provide one or more cannabinoids. . . . Cannabinoids of the present invention are any member of a group of substances that are structurally related to tetrahydrocannabinol and that bind to a cannabinoid receptor such as CB1 or CB2 or both (THC) . The cannabinoid can be a naturally occurring compound (e.g. present in Cannabis), a compound metabolized by a plant or animal, or a synthetic derivative. See paragraph 49.
The cannabinoids of the present invention are further meant to encompass natural cannabinoids, natural cannabinoids that have been purified or modified, and synthetically derived cannabinoids, for example, United States Patent Application Publication 2005/0266108, hereby incorporated by reference in its entirety, describes a method of purifying cannabinoids obtained from plant material. See paragraph 51.
WO 164 incorporates the teachings of US Pub 2005/0266108 (US Pub 108), where US Pub 108 teaches by definition, the class of cannabinoid compounds envisioned by WO 164 to be incorporated into its oral dosed pulsed formulation includes THC (delta 9 tetrahydro cannabinol), cannabidiol (CBD) and cannabigerol (CBG). See paragraphs 4-5.
Further, WO 164 teaches the claimed immediate and delayed release compartments of the formulations with overlapping ranges, where it notes the portion of cannabinoid in the immediate release compartment can be any of the following percents (%): 10 - 75, 10 - 50, 20 - 50, 25 – 75. See paragraph 80. These taught ranges overlap those claims, i.e. where percentages of cannabinoid in the immediate release compartment/portion of up to 30 %, conversely indicate that at least 70 % of cannabinoid (i.e., CBG) is in the controlled/delayed release compartment. Note also claim 47’s limitation of at least 85% CBG and 15% in the immediate release compartment is also encompassed by these ranges.
WO ‘164 teaches an adjustment of percentages are routinely optimized by a PHOSITA, with the teachings provided herein, so that a PHOSITA can adjust the release properties of one or more release components (e.g. by varying the amount of drug therein or the relative amounts or types of release modifiers therein). See paragraph 82.
Also note, that with the plurality of compartments designed to lease the claimed drugs, the medicament comprises an immediate release compartment and a plurality of delayed (e.g. timed) release compartments. See paragraph 94. “Optionally, a medicament comprises more than two or more compartments including a third compartment (C3) as per claim 47 (e.g. 3, 4, 5, or 6 compartments), , such as timed-release compartments having different times of cannabinoid release.” Id. at 94.
Therefore, WO 164 teaches the compatibility of its oral dosed pulsed formulation with the genus of cannabinoid compounds, including CBD and CBG (claimed), as well as THC, where the claimed cannabinoid occurs in the claimed percentages in the delayed release portion, as exemplified by WO 164 and claimed by Applicant.
Per Irving, a CBD (cannabidiol) rich extract contained not only CBD but also smaller amounts of other compounds such as cannabigerol (CBG) and THC. See page 715 column 1. Irving teaches the CBD rich extract when administered to patients, may be beneficial for symptomatic treatment of ulcerative colitis (UC). See abstract. Irving teaches there is evidence the combination of CBD and THC may offer additive effects in models of inflammatory bowel disease (IBD). See page 715, column 1. Irving teaches that a study by Jamontt 2010 discloses this combination not only reduced inflammation but also lowered the occurrence of functional disturbances, reasonably interpreted to be symptoms of IBD. Id.
Further, Borrelli teaches the beneficial effect of the cannabinoid CBG in an experimental model of IBD, a murine model of colitis induced in mice models. See abstract. “CBG could be considered for clinical experimentation in IBD patients.” See abstract.
A PHOSITA following the teachings of the reference application would have found it prima facie obvious to formulate the claimed pulse oral composition for use in treating IBS, Crohn’s disease or UC in view of WO 164, Irving and Borelli, as these are taught by the combination of the cited prior art
The rationale to support a finding of obviousness are the prior art elements of the reference application, noting oral pulsed dosage forms as claimed combined with the teachings of Irving and Borrelli (CBD, CBG and THC useful for treating IBS, UC and/or Crohn’s disease) to predictably arrive at the claimed invention.
Regarding claims 37, 41 and 44, official notice is given that UC, Crohn' s disease and IBS involve both upper and lower GI tract, as claimed. The GI tract consists only of an upper and lower tract and UC, Crohn' s Disease and IBS are known to affect the GI tract. As discussed above, the combination of WO 164, Irving and Borrelli teach IBS, Crohn's disease and UC, where the symptoms of claim 44 (pain, bloating, diarrhea) are noted to be associated with IBS, Crohn' s disease or UC. It would be routine for one of ordinary skill in the art to optimize the treatment of the upper and/or lower GI tract for the symptoms claimed.
Regarding claim 38 and dosing the patient 1-4 times a day, and claims 42-43, where treatment disorder and/or symptoms occurs within 6, 12, 24 or greater than 24 hours post-dose, or 1-24 hours, or greater than 24 hours, the reference application discloses the pulse-release dosage form provides release of the API1P2 and the API2P2 beginning from 2 to 6 hours after release of the API1P1 and the API2P1 begins. See claim 1. It would be routine to dose a patient 1-4 times a day based on the hours teachings of WO 164.
Regarding claim 48 and the limitation of where the cannabinoid of the first pulse component is 10-50% of total and cannabinoid of second pulse is 50-90% of total dose, the reference application teaches for each API, the first portion (P1) is independently selected from 25% to 75% of the total daily dose, and for each API the second portion (P2) is independently selected from 25% to 75% of the total daily dose. See claim 1.
Regarding claims 49 and 50, WO 164 discloses Tables 7 and 8 with the various claimed excipients including microcrystalline cellulose (Avicel PH 101).
Regarding claim 51, the reference application teaches the binders comprise from 1 to 60% (w/w). See claim 8.
As required by claims 52-55, WO 164 discloses its formulations are selected from the various formulations with delayed release components (delayed cannabinoid API core claimed with polymers/methacrylic acid polymer Eudragit, layered or integrated, pH sensitive or not), such as bilayer/matrix type, monolithic/matrix-type, monolithic/coated -type, enteric coating-type, 2 pulse type, 3 pulse type, solid adsorbate type, pellet-type, and continuous release-type, see claim 26. These formulations are either coated or non-coated and either pH or non-pH sensitive. Further, with regard to polymer coated/integrated delayed release components, WO 164 discloses Table 9 paragraph 263, with both an instant release and delayed release component, where methacrylic acid co polymer type C (Eudragit) is used to coat the delayed release pellet component.
Regarding claim 56 (polymer being 4 to 25% weight of the delayed release portion), WO 164 discloses 13.2 mg of Eudragit out of the subtotal of 172.5 mg, which is 7.65%, see above Table 9.
As required by claims 57-59 (claimed pellets encapsulated) WO 164 Table 7 and Table 9 disclose pellets enclosed in a capsule, see above. This is a provisional nonstatutory double patenting rejection.
Conclusion and Correspondence
No claims are allowed. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a CON of 18/304,808 04/21/2023 ABN
18/304,808 has PRO 63/333,982 04/22/2022
2 First species: CBG, total dose up to 150 mg; CBD, total dose up to 40 mg; and THC, total dose up to 2mg. Microcrystalline cellulose as the excipient, comprising from 1 % to 60% by weight of the immediate release (IR) formulation; and Methacrylic acid-ethyl acrylate copolymer as the polymer of the delayed release (DR) components of the pH sensitive delayed-release (DR)formulation, comprising from 4% to 25% by weight of the DR formulation.
Second species: Inflammatory Gastrointestinal (GI) Disease/disorder: Irritable Bowel Disease. Upon search and examination of the elected species, the inflammatory GI disorder encompasses species such as Crohn’s disease and ulcerative colitis (UC).
3 (i) 89.5% of patients (51 out of 57) reported that the oral pulse-release formulation had a
positive effect on their GI symptoms (FIG. 1); and (ii) 77.2% of patients indicated they would take the product again (FIG. 6-7).
4 In summary the Attorney states: WO 164 provides experimental data to treat sleep apnea (see WO 164 at Ex. 1-8). US Pub 108 relates to purification methods and does not provide any treatment data. Irving teaches treating ulcerative colitis using CBD-rich botanical extract with a small amount of CBG (see, e.g., Irving at page 715). Irving's study focuses on CBD and does not show data on effects of formulations with quantifiable CBG dosage. Borrelli describes CBG's effect on GI inflammation but uses a murine model via intraperitoneal (i.p., abdominal body cavity) injection, see, e.g., Borrelli at page 1310.
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