DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of Claims
Claims 49 and 51-66 are currently pending. Claims 1-48 and 50 are canceled.
The new rejections applied below are not necessitated by amendment and this action has been made Non-Final as a result.
Previous Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn. The following rejections and/or objections are either reiterated or newly
applied. They constitute the complete set presently being applied to the instant application.
Rejections Withdrawn
Claim Rejections - 35 USC § 103
Upon further consideration the rejection of claims 49, 51-63 and 65-66 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murty et al. US 2007/0104741 (5/10/2007) in view of Odidi et al. US 2009/0232887 (9/17/2009)(9/20/2019 IDS), Bromley et al. US 2010/0041622 (2/18/2010) )(9/20/2019 IDS), Devane et al. US 2007/0160675(7/12/2007) and Xi et al. Formulation Development and Bioavailability Evaluation of a Self-Nanoemulsified Drug Delivery System of Oleanolic Acid, AAPS PharmSciTech, 2009 Feb 18; 10(1):172-182 as evidenced by Hustvedt et al. US 2016/0206585 (7/21/2016) and the instant specification is withdrawn.
Upon further consideration the rejection of claim 64 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murty et al. US 2007/0104741 (5/10/2007) in view of Odidi et al. US 2009/0232887 (9/17/2009)(9/20/2019 IDS), Bromley et al. US 2010/0041622 (2/18/2010) )(9/20/2019 IDS), Devane et al. US 2007/0160675(7/12/2007) and Xi et al. Formulation Development and Bioavailability Evaluation of a Self-Nanoemulsified Drug Delivery System of Oleanolic Acid, AAPS PharmSciTech, 2009 Feb 18; 10(1):172-182 as evidenced by Hustvedt et al. US 2016/0206585 (7/21/2016) and the instant specification as applied to claims 49, 51-63 and 65-66 and further in view of Desai et al. US 4,816,247 (3/28/1989) is withdrawn.
New Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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(a) 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.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 49, 51-63 and 65-66 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murty et al. US 2007/0104741 (5/10/2007) in view of Odidi et al. US 2009/0232887 (9/17/2009)(9/20/2019 IDS), Bromley et al. US 2010/0041622 (2/18/2010) )(9/20/2019 IDS), Devane et al. US 2007/0160675(7/12/2007) and Faiyaz et al. Nanoemulsion as Vehicles for Transdermal Delivery of Aceclofenac, AAPS PharmSciTech, 2007; 8(4) Article 104 as evidenced by Hustvedt et al. US 2016/0206585 (7/21/2016) and the instant specification.
Murty et al. discloses a method of administering a cannabinoid such as cannabidiol so that the oral bioavailability is greatly enhanced when compared to known formulations. With enhanced absorption characteristics of oral delivery systems, Murty teaches that treatment could be useful for brain damage associated with stroke, head trauma, and cardiac arrest. This, however, requires sufficient bioavailability of the drug compound. (See Abstract, [0013] and claim 2). Treatment of brain damage from stroke is a disorder as called for in instant claim 52.
The composition is an oral dosage form of cannabinoids such as cannabidiol (CBD) in a self- emulsifying system comprising an oily medium of free fatty acids having from C6 to C32 carbon atoms and a surfactant which promotes self-emulsification. (See Murty claim 1). Cannabidiol (CBD) is called for in instant claim 54 and is a cannabinoid as called for in instant claim 53. The composition is a dispersible concentrate as called for in instant claim 32 and forms a dispersion upon contact with the GI tract fluids as called for in instant claim 49. (See [0029]).
Murty’s composition does not comprise curcumin as called for in instant claim 32. (See Murty throughout). Murty teaches a composition wherein the drug is formulated for administration in the same pharmaceutical formulation as called for in claim 57. (See [013] and claims 1 and 2).
Murty teaches that its composition may also comprise phospholipids as called for in instant claim 55. (See [0043]). Murty teaches that its method provides sufficient bioavailability for treatment with brain damage associated with stroke and head trauma and cardiac arrest. (See [0016]). This is a method for the treatment of at least one disease or disorder as called for in instant claim 52. This is also a teaching of increased bioavailability as called for in instant claim 49. Murty also teaches in Example 3 b) (0 active agent) in which a formulation is made that does not have a drug in it, thereby teaching a composition that is formulated for administration in separate formulations as called for in instant claim 58.
Fatty acids having from C6 to C32 carbon atoms are fatty acids that are solid components having a melting temperature about 25˚C as called for in instant claim 49. A surfactant which promotes self-emulsification is a surfactant as called for in instant claim 49. Sorbitan monolaurate is taught to be a suitable surfactant. (See [0042]). Sorbitan monolaurate is called for in instant claim 60. Sorbitan monooleate is also taught to be a suitable surfactant. (See [0042]). Sorbitan monooleate is called for in instant claim 61. Preferred co-solvents are taught to include ethanol, which is a hydrophilic organic solvent as called for in instant claim 66. (See [0074[). Murty also teaches that phospholipids are possible in its composition as called for in instant claim 55. (See [0043]).
Murty does not expressly teach nanoparticles or lower alkyl esters of lactic acid. Murty does not teach a combination of Span 80 and Tween 20 or the benefits of these surfactants. Murty does not teach a weight ratio of at least 2:1 of high HLB : low HLB surfactants. These deficiencies are made up for with the teachings of Odidi et al., Bromley et al., Devane and Faiyaz et al.
Odidi et al. (Odidi) teaches tetrahydrocannabinol in a formulation that is abuse resistant. (See Odidi [0058] and Abstract). Odidi also teaches ethyl lactate which is a lower alkyl ester of lactic acid as called for in instant claim 56. (See Odidi [0089]). Ethyl lactate is an amphiphilic solvent that is a hydrophilic oxygenated organic solvent as called for in instant claim 49, and ethyl lactate itself is called for in instant claim 65. (See Odidi [0083]). Odidi teaches that its compositions can contain other actives. (See Odidi [0060]). Additionally, Odidi teaches nanoparticles. (See [0331]).
Bromley et al. (Bromley) teaches a combination of Span 80 and Tween 20 as surfactants in an oral formulation that includes an emulsion. (See Bromley Abstract, [0026], [0270])). Bromley teaches that these surfactants increase the stability of the emulsion. (See Bromley [0026]).
As evidenced by Hustvedt et al., the HLB of Span 80 is 4.3, and the HLB of Tween 20 is 16. (See Hustvedt claim 149). 4.3 is less than about 5 and 16 is at least about 8 as called for in instant claim 49.
Devane et al. teaches a composition comprising cephalosporin and at least one surfactant. Devane teaches that surfactants can be enhancers of bioavailability of a pharmaceutical active by enhancing the net transport across the gastrointestinal tract.
Devane et al. teaches at [0131]:
[0131] As used herein, the term "enhancer" refers to a compound which is capable of enhancing the absorption and/or bioavailability of an active ingredient by promoting net transport across the GIT in an animal, such as a human. Enhancers include but are not limited to medium chain fatty acids; salts, esters, ethers and derivatives thereof, including glycerides and triglycerides; non-ionic surfactants such as those that can be prepared by reacting ethylene oxide with a fatty acid, a fatty alcohol, an alkylphenol or a sorbitan or glycerol fatty acid ester; cytochrome P450 inhibitors, P-glycoprotein inhibitors and the like; and mixtures of two or more of these agents.
Devane also teaches nanoparticles having a size of less than about 2000 nm. Less than about 2000 nm overlaps with the less than 50 nm called for in instant claim 49. Additionally, specific embodiments of less than 50 nm are also taught. (See [0046]). Less than 50 nm overlaps with the less than 50 nm called for in instant claim 49. Devane teaches that the nanoparticles are in a dispersion medium that can include ethanol. (See [0103]).
Faiyaz et al. (Faiyaz) teaches a study that formulates and evaluates bioavailability of a self-nanoemulsified drug delivery system of a poorly water soluble active component aceclofenac for transdermal delivery. (See Abstract). Faiyaz found that a 2:1 ratio of high-HLB Cremophor EL to low HLB Transcutol P optimizes a self-nanoemulsfiied drug delivery system for aceclofenac. (See Conclusion). The formulation with the 2:1 ratio achieved the highest drug permeation, lowest droplet size, lowest polydispersity, lowest viscosity and optimum surfactant and cosurfactant concentration. The in vivo studies revealed a significant increase in the anti-inflammatory effects as compared with aceclofenac gel and nanoemulsion gel.
A ratio of 2:1 high HLB surfactant: low HLB surfactant is called for in instant claims 49 and 51.
It would be obvious to one of ordinary skill in the art following the Murty method to add ethyl lactate as taught by Odidi in order to have an abuse resistant composition as taught by Odidi.
It would be obvious to one of ordinary skill in the art following the Murty method of administering an oral dosage dispersible concentrate of cannabidiol in a self- emulsifying system comprising an oily medium of C6 to C32 fatty acids and self emulsifying surfactants to use a combination of Span 80 and Tween 20 as surfactants in the composition as taught by Bromley in order to increase the stability of the emulsion as taught by Bromley and in order to increase the bioavailabilty of the cannabidiol active by increasing transport across the gastrointestinal tract as taught by Devane et al.
It would be obvious to one of ordinary skill in the art following the Murty method of administering an oral dosage dispersible concentrate of cannabidiol in a self- emulsifying system comprising an oily medium of C6 to C32 fatty acids and self emulsifying surfactants to use a combination of Span 80 and Tween 20 as surfactants in the composition as taught by Bromley in order to increase the stability of the emulsion as taught by Bromley and in order to increase the bioavailabilty of the cannabidiol active by increasing transport across the gastrointestinal tract as taught by Devane et al. It would be obvious to have the combination of Tween 20 and Span 80 be in a weight ratio of 2:1 or greater Tween 20: Span 80 in order to take advantage of the increases in bioavailability that a ratio of 2:1 high HLB surfactant to low HLB surfactant provides in a self-nanoemulsified composition as taught by Faiyaz.
With respect to the spontaneous formation of a homogenous and stable oil-in-water nanoemulsion of particles with a mean diameter of less than 50 nm and PDI of 0.2 or less and an increase in bioavailability for at least 10 minutes and stability maintained for at least two months in claims 49 and 51, the references are silent on the values of the homogenous and stable oil-in-water nanoemulsion that is spontaneously formed when contacted with an aqueous medium containing gastrointestinal fluids. However, Murty in view of Odidi, Bromley and Devane teach a method for increasing the bioavailability of an orally administered drug with the same components as those claimed in the same amounts (at the overlaps of the ranges) as those claimed and the method contain the same steps as those claimed.
Namely, the combined teachings of Murty in view of Odidi, Bromley, Devane and Faiyaz teach a method of orally administering an oral dosage dispersible concentrate of cannabidiol in a self- emulsifying system comprising an oily medium of C6 to C32 fatty acids and a combination of 2:1 Tween 20 : Span 80 surfactants in ethyl lactate. Orally administering a composition comprising these components would necessarily contact the composition with an aqueous medium containing GI tract fluids upon which the composition would spontaneously form a homogenous and stable oil-in-water nanoemulsion of particles with a mean diameter of less than 50 nm and PDI of 0.2 or less, bioavailability of 10 minutes and stability of at least two months as evidenced by Table 19, Table 17 and paragraphs [176], [0262] and [0271] of the instant specification. (CBD standing for cannabidiol)
The prior art composition with the same components as those claimed in the same amounts (at the overlaps of the ranges) that follows the same steps in the same method as that claimed would necessarily have the same properties as those of the claimed composition in the claimed method. See, Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements.”
Claim 64 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murty et al. US 2007/0104741 (5/10/2007) in view of Odidi et al. US 2009/0232887 (9/17/2009)(9/20/2019 IDS), Bromley et al. US 2010/0041622 (2/18/2010) )(9/20/2019 IDS), Devane et al. US 2007/0160675(7/12/2007) and Faiyaz et al. Nanoemulsion as Vehicles for Transdermal Delivery of Aceclofenac, AAPS PharmSciTech, 2007; 8(4) Article 104 as evidenced by Hustvedt et al. US 2016/0206585 (7/21/2016) and the instant specification as applied to claims 49, 51-63 and 65-66 and further in view of Desai et al. US 4,816,247 (3/28/1989).
Murty in view of Odidi, Bromley, Devane and Faiyaz et al. is described supra. Murty in view of Odidi, Bromley, Devane and Faiyaz et al. do not teach tripalmitin. This deficiency is made up for with the teachings of Desai.
Desai et al. (Desai) teaches a lipid emulsion form compositions that provide a solubilized drug form for oral and parenteral administration which enhances the drug absorption and the therapeutic efficacy of the drug. (See Desai Abstract, (0035)). Desai teaches that the oil phase may comprise semisynthetic mono, di or triglycerides such as tripalmitin or tristearin. (See (0035). Tripalmitin is called for in instant claim 64.
It would be obvious to one of ordinary skill in the art following the Murty in view of Odidi, Bromley, Devane and Faiyaz et al. method of administering an oral dosage dispersible concentrate of cannabidiol in a self- emulsifying system comprising an oily medium and a combination of Span 80 and Tween 20 as surfactants in the composition to use tripalmitin in the oily medium as taught by Desai in light of Desai’s teaching if its suitability in an emulsion for delivering a hydrophobic drug and enhancing the drug absorption and therapeutic efficacy of the drug as taught by Desai.
Response to Arguments
Applicants’ arguments of August 27, 2026 have been fully considered and are found to be mostly unpersuasive.
Applicants argue that Xi does not teach the claimed 2:1 high-HLB/low-HLB surfactant ratio. Applicants assert that Xi does not teach a 2:1 ratio of high-HLB Cremophor EL to low HLB Sefsol 218 which is relied upon as the basis for the Office’s assertion that it would have been obvious to use high-HLB surfactant to low-HLB surfactant (e.g. Tween 20 and Span 80) at a ratio of 2:1 or greater. Applicants assert that Xi teaches in Table 1 on page 176 that Sefsol 218 is not identified as a surfactant but as an oil. Therefore, Xi uses Sefsol 218 not as the second surfactant in this mixture but as an oil and evaluates the Cremophor EL/Labrosol mixtures for their ability to emulsify that oil. In short, the 2:1 ratio discussed on page 175 is a ratio between two high-HLB surfactants.
Applicants note that Transcutol P is not characterized by HLB value in Xi, but should it be characterized as a low HLB surfactant, the results in Xi show that increasing the amount of Transcutol P progressively increased the particle size and PDA and the reported particles sizes would not satisfy the claimed limitations.
Applicants’ arguments have been fully reviewed and are found to be sufficiently persuasive. The rejections have been withdrawn above. The remainder of Applicants arguments are moot in view of the new rejections applied above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH CHICKOS whose telephone number is (571)270-3884. The examiner can normally be reached on M-F 9-6.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on 571-272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAH CHICKOS/
Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
