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 .
Priority
This application is a 371 of PCT/US2021/057938, filed Nov. 3, 2021.
The Application claims domestic priority benefit of U.S. Patent Application No. 17/225,738 filed April 08, 2021, which claims priority to U.S. Provisional Application No. 63/114,194 filed November 16, 2020; U.S. Provisional Application No. 63/114,181 filed November 16, 2020; U.S. Provisional Application No. 63/147,453 filed February 09, 2021; U.S. Provisional Application No. 63/172,343 filed April 08, 2021; U.S. Provisional Application No. 63/172,362 filed April 08, 2021; U.S. Provisional Application No. 63/172,386 filed April 08, 2021; U.S. Provisional Application No. 63/172,368 filed April 08, 2021; and U.S. Provisional Application No. 63/180,193 filed April 27, 2021. None of these domestic applications, however, disclose the claimed method of treating an autoimmune disease.
The effective filing date of the claimed invention is Nov. 3, 2021.
Claim Status
Claims 1, 4-9, 12, and 15-35 are pending. Claims 1, 4-9, 12, 15 and 18-23 are currently active and subject to examination. Claims 12-14, 16-17 and 24-35 are withdrawn.
Claim Rejections – Withdrawn – Overcome by Amendment
The rejection of claim(s) 1-9, 15, and 18-19 under 35 U.S.C. 103 as being unpatentable over “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action) in view of Grother et al. (US 2023/0364013 A1; published Nov. 16, 2023; effectively filed Oct. 8, 2020), Monteith et al. (US20080152712A1; published June 26, 2008) and Amipara & Gupta (Journal of Drug Delivery & Therapeutics; 2013, 3(1), 85-92) is withdrawn.
The rejection of claim(s) 1-9, 15, and 18-21 under 35 U.S.C. 103 as being unpatentable over “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action) in view of Grother et al. (US 2023/0364013 A1; published Nov. 16, 2023; effectively filed Oct. 8, 2020), Monteith et al. (US20080152712A1; published June 26, 2008) and Amipara & Gupta (Journal of Drug Delivery & Therapeutics; 2013, 3(1), 85-92), as applied to claims 1-9, 15 and 18-19 above, and further in view of Elliot et al. (Front. Immunol., 02 August 2018, Sec. Multiple Sclerosis and Neuroimmunology, Volume 9 – 2018, p. 1-12).
The rejection of claim(s) 1-9, 15, and 18-23 under 35 U.S.C. 103 as being unpatentable over “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action) in view of Grother et al. (US 2023/0364013 A1; published Nov. 16, 2023; effectively filed Oct. 8, 2020), Monteith et al. (US20080152712A1; published June 26, 2008) and Amipara & Gupta (Journal of Drug Delivery & Therapeutics; 2013, 3(1), 85-92), as applied to claims 1-9, 15 and 18-19 above, and further in view of Booz (Free Radical Biology and Medicine, Volume 51, Issue 5, 1 September 2011, Pages 1054-1061) is withdrawn.
The above rejections were overcome by Applicant’s amendments to the claims.
Claim Rejections – Withdrawn – Overcome by Terminal Disclaimer
The provisional rejection of claim(s) 1-12, 15 and 18-23 on the ground of nonstatutory double patenting as being unpatentable over claims 21-24 and 31-32 of copending Application No. 18/307,228 in view of “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action), Elliot et al. (Front. Immunol., 02 August 2018, Sec. Multiple Sclerosis and Neuroimmunology, Volume 9 – 2018, p. 1-12), and Booz (Free Radical Biology and Medicine, Volume 51, Issue 5, 1 September 2011, Pages 1054-1061) is withdrawn.
The rejection of claim(s) 1-12, 15 and 18-23 on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 11,672,761 B2 (herein the ‘761 patent) in view of “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action), Elliot et al. (Front. Immunol., 02 August 2018, Sec. Multiple Sclerosis and Neuroimmunology, Volume 9 – 2018, p. 1-12), and Booz (Free Radical Biology and Medicine, Volume 51, Issue 5, 1 September 2011, Pages 1054-1061) is withdrawn.
The provisional rejection of claim(s) 1-12, 15 and 18-23 on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of copending Application No. 18/252,694 in view of “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action), Elliot et al. (Front. Immunol., 02 August 2018, Sec. Multiple Sclerosis and Neuroimmunology, Volume 9 – 2018, p. 1-12), and Booz (Free Radical Biology and Medicine, Volume 51, Issue 5, 1 September 2011, Pages 1054-1061) is withdrawn.
The provisional rejection of claim(s) 1-12, 15 and 18-23 on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 16-22 and 28-34 of copending Application No. 18/252,668 in view of “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action), Elliot et al. (Front. Immunol., 02 August 2018, Sec. Multiple Sclerosis and Neuroimmunology, Volume 9 – 2018, p. 1-12), and Booz (Free Radical Biology and Medicine, Volume 51, Issue 5, 1 September 2011, Pages 1054-1061) is withdrawn.
The provisional rejection of claim(s) 1-12, 15 and 18-23 on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of copending Application No. 18/252,741 in view of “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action), Elliot et al. (Front. Immunol., 02 August 2018, Sec. Multiple Sclerosis and Neuroimmunology, Volume 9 – 2018, p. 1-12), and Booz (Free Radical Biology and Medicine, Volume 51, Issue 5, 1 September 2011, Pages 1054-1061) is withdrawn.
The provisional rejection of claim(s) 1-12, 15 and 18-23 on the ground of nonstatutory double patenting as being unpatentable over claims 1-46 of copending Application No. 18/317,977 in view of “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action), Elliot et al. (Front. Immunol., 02 August 2018, Sec. Multiple Sclerosis and Neuroimmunology, Volume 9 – 2018, p. 1-12), and Booz (Free Radical Biology and Medicine, Volume 51, Issue 5, 1 September 2011, Pages 1054-1061) is withdrawn.
The provisional rejection of claim(s) 1-12, 15 and 18-23 is/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-44 of copending Application No. 18/317,964 in view of Fleury-Teixeira et al. (Front. Neurol., 30 October 2019, Sec. Neuropharmacology, Volume 10, No. 1145, p. 1-8) is withdrawn.
The above rejections were overcome by the terminal disclaimer filed Apr. 20, 2026.
Claim Rejections - 35 USC § 103 – Previously Presented
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.
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.
The rejection of claim(s) 1, 4-9, 12, 15, and 18-19 under 35 U.S.C. 103 as being unpatentable over “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action) in view of Grother et al. (US 2023/0364013 A1; published Nov. 16, 2023; effectively filed Oct. 8, 2020), Monteith et al. (US20080152712A1; published June 26, 2008), Amipara & Gupta (Journal of Drug Delivery & Therapeutics; 2013, 3(1), 85-92), and Marco (CBD Mania, Jan. 26, 2021, pp. 1-16) is maintained.
Response to Arguments
Applicant’s arguments filed April 29, 2026 regarding the rejection of claims 1-12, 15, and 18-19 under 35 U.S.C. 103 have been fully considered but are not persuasive. The rejections are maintained.
The “Solid Form” Amendment Does Not Patentably Distinguish the Claims
Applicant amended claim 1 to recite “solid form” CBD. This amendment is recite “solid form” CBD. This amendment is rendered obvious by the prior art of record. Grother specifically teaches the use of crystalline (i.e., solid form) epinephrine in Zydis ODTs because this makes the formulation stable (Grother, Specification, ¶ 0009). Amipara teaches that the “ideal candidate for Zydis technology should be chemically stable and water insoluble and particle size preferably less than 50 micron” (Amipara, p. 86-87), a description that requires a solid form of API. Marco teaches that CBD is commercially available in a solid crystalline form: “CBD crystals are a pure cannabidiol extract with a purity level of around 99% “(Marco, p. 3). The collective teachings of Grotehr, Amipara, and Marco establish that a person of ordinary skill in the art seeking to formulate a Zydis CBD ODT, as suggested by Catalent, would use a solid form of CBD with a reasonable expectation of success.
The “Purity Between 95 and 99.9 wt.%” Amendment is Rendered Obvious by Marco
Applicant amended claim 1 to recite CBD “having a purity between 95 and 99.9 wt.%.” This amendment is rendered obvious by Marco. As noted in the prior Office Action, Marco expressly teaches that “CBD crystals are a pure cannabidiol extract with a purity level of around 99% “(Marco, p. 3). A purity level of around 99% falls squarely within the claimed range. A person of ordinary skill in the art seeking a commercial source of solid CBD per Marco would obtain CBD at approximately 99% purity, thereby satisfying the claim limitation. See MPEP § 2144.05.
The Argument That a Person of Ordinary Skill Would Expect CBD Zydis to Be Swallowed and Not Absorbed by the Oral Mucosa is Contradicted by Catalent and Marco
Applicant argues, supported by Seager and the Mileto declaration under 37 C.F.R. § 1.132 that insoluble drugs in Zydis-type dosage forms disperse in the saliva, are swallowed, and are absorbed gastrointestinally rather than via the oral mucosa, such that a person of ordinary skill in the art would not have had a reasonable expectation of success in achieving oral mucosal administration of CBD. This argument is unpersuasive for the reasons set forth below.
First, Catalent expressly and unambiguously teaches the contrary with respect to CBD specifically. Catalent states that “CBDs and THCs are notoriously insoluble and poorly bioavailable so a Zydis sublingual dosage form provides a drug delivery solution by avoiding first pass metabolism.” (Catalent, p. 3). The express purpose of Catalent’s pharmaceutical develop program with Ethicann is to deliver CBD via a Zydis sublingual dosage form that avoids first pass metabolism. Avoidance of first pass metabolism necessarily requires absorption across the oral mucosa rather than absorption through the gastrointestinal tract, because gastrointestinally absorbed drugs are subjected to hepatic first pass metabolism. A person of ordinary skill in the art reading Catalent would therefore understand, despite CBD’s insolubility, that Zydis CBD ODTs are designed to and do achieve oral mucosal absorption. Catalent’s specific teaching regarding CBD controls over the general teachings of Seager and Mileto regarding insoluble drugs broadly.
Second, Marco specifically teaches sublingual administration of solid CBD crystals. Marco discloses that CBD crystals can be taken sublingually so that the active ingredient can quickly enter the circulatory system (Marco, p. 5). This confirms that a person of ordinary skill in the art, understood prior to the effective filing date, that solid CBD can be administered sublingually.
Third, Grother teaches that the Zydis dosage form is placed in the oral cavity, such as under the tongue or in the buccal region (¶ 0011) and rapidly dissolves to allow sublingual absorption (¶ 0100). Grother thus demonstrates that Zydis dosage forms containing solid forms APIs can be and are formulated for mucosal absorption.
Fourth, Amipara states that “[b]uccal, pharyngeal and gastric regions are all areas of absorption of the Zydis formulation” (Amipara, p. 89). Buccal absorption of Zydis formulations is therefore recognized by the prior art.
The combination of Catalent (sublingual Zydis CBD avoiding first pass metabolism), Marco (sublingual administration of CBD crystals to allow a fast onset), Grother (sublingual Zydis administration of crystalline API), and Amipara (buccal absorption of Zydis) provides a POSA with more than a reasonable expectation of success in achieving oral mucosal administration of solid CBD via a Zydis lyophilized rapidly infusing composition.
The Mileto Declaration Is Not Persuasive
The Declaration under 37 CFR 1.132 filed April 29, 2026 is insufficient to overcome the rejection of claims 1-12, 15, and 18-19 under 35 U.S.C. 103 as set forth in the last Office action because:
The declaration’s general theory is contradicted by the specific teaching of the closest prior art reference. The declaration asserts, citing Seagar (1998), that improved bioavailability in lyophilized dosage forms never occurred for insoluble drugs and that insoluble drugs would disperse in saliva and then absorbed through the gastrointestinal tract (Declaration, p. 2, point 5). However, Catalent – relied on as the lead prior art reference in this rejection – expressly teaches the contrary as applied to the specific drug at issue. Catalent states that “CBDs and THCs are notoriously insoluble and poorly bioavailable so a Zydis sublingual dosage form provides a drug delivery solution by avoiding first pass metabolism.” (Catalent, p. 3). Avoidance of first pass metabolism necessarily entails absorption across the oral mucosa rather than the gastrointestinal tract. Catalent’s specific teaching regarding Zydis CBD controls over Seager’s general statements regarding insoluble drugs in Zydis.
The declarant’s stated qualifications further illustrate that this contradiction is not minor. The declarant states in the declaration that he was previously employed as a contract manufacturer at Catalent – the developer and owner of Zydis technology and the entity that publicly announced the sublingual Zydis CBD development program with Ethicann – the declarant would be in a position to know that Catalent’s published understanding of Zydis CBD as of 2019 is that it achieves oral mucosal absorption sufficient to avoid first pass metabolism. The declaration, written in 2021, nevertheless asserts the general proposition that insoluble drugs in Zydis are swallowed without addressing Catalent’s contrary specific teachings as to CBD. The declaration’s failure to reconcile its general theory with Catalent’s specific contemporaneous teaching regarding Zydis CBD significantly diminishes the weight to be accorded to the declaration as evidence of what a person of ordinary skill in the art would have understood at the time of filing.
The declaration’s “unexpected results” assertions are not supported by factual evidence commensurate in scope with the claims. The declarantion further asserts that impure forms of oil-based CBD (i.e., less than 95% purity) in lyophilized ODTs produce an unstable, disordered matrix and that a person of ordinary skill in the art would not have expected to successfully manufacture an effective lyophilized ODT containing solid CBD which is pure (Declaration, p. 6). These assertions are not supported by comparative experimental data. To the contrary, the prior art directly suggests use of high-purity solid CBD: Marco teaches that commercially available CBD crystals have a purity level of around 99% (Marco, p. 3) and Grother teaches that crystalline (solid) APIs are stable in lyophilized matrices (Grother, Specification, ¶ 0009). The declaration provides no data demonstrating matrix collapse at any specific lower purity level, no data demonstrating the claimed improvement in bioavailability over the closest prior art formulations, and no data demonstrating superior efficacy at any point within the claimed range. The declaration does not meet the standard that unexpected results be compared with the closest prior art, but rather only addresses the prior art cited in rejections of a related application and not the closest prior art identified in the present rejection. See MPEP 716.02(e). Opinion testimony as to unexpected results must also be supported by factual evidence and must be commensurate in scope with the claims. MPEP § 716.01(c). Additionally, Mr. Mileto, the declarant, is the first named inventor of the present Application. While inventor declarations are entitled to considerations, statements regarding the state of the art and expectations of a person of ordinary skill in the art must be weighed against the contradictory written record based on the prior art. Id.
The asserted “unexpected” results are in fact what a person of ordinary skill in the art would have expected from the prior art. Marco expressly teaches that commercially available CBD have a purity of around 99% (Marco, p. 3) – falling with in the claimed range. Grother teaches that crystalline solid forms of APIs are preferred for stability in Zydis lyophilized matrices (Grother, Specification, ¶ 0009). Amipara teaches that the ideal API for Zydis technology is a chemically stable, water-insoluble solid with particle size preferably less than 50 microns (Amipara, p. 86-87). A person of ordinary skill in the art following these prior art teachings would have used solid, high-purity CBD crystals in a Zydis lyophilized matrix and would have expected matrix stability as a result. The declaration provides no factual bassi to conclude that the result obtained by following the prior art teachings is unexpected.
The Individual Reference Arguments Are Unpersuasive
Applicant separately argues that each of Grother, Monteith, Amipara, Marco, Elliot and Booze individually fails to disclose all of the elements of claim 1. These arguments are not persuasive because the rejections are based on the combined teachings of the references not on any single reference. One cannot show nonobviousness by attacking references individually when the rejections are based on a combination of references (MPEP § 2145.IV). Catalent provides the motivation to formulate a Zydis CBT ODT for the treatment of autoimmune disease (multiple sclerosis spasticity) administered via the oral mucosa to avoid first pass metabolism. Grother, Monteith and Amipara provide the conventional Zydis formulation parameters (gelatin matrix former, mannitol structure former, disintegration time, particle size, and solid/crystalline API preference). Marco supplies the solid form of CBD at the claimed purity range and confirms sublingual administration of solid CBD crystals. Elliot and Booze provide additional therapeutic indications (multiple sclerosis, rheumatoid arthritis) and dosing.
Conclusions as to 35 U.S.C. § 103
For the reasons set forth above, the cited references, in combination, render the claims as amended obvious to a person of ordinary skill in the art at the time of the effective filing date. The § 103 rejections are maintained.
Reiterated Rejection
Claim(s) 1, 4-9, 12, 15, and 18-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action) in view of Grother et al. (US 2023/0364013 A1; published Nov. 16, 2023; effectively filed Oct. 8, 2020), Monteith et al. (US20080152712A1; published June 26, 2008), Amipara & Gupta (Journal of Drug Delivery & Therapeutics; 2013, 3(1), 85-92) and Marco (CBD Mania, Jan. 26, 2021, pp. 1-16).
Claim 1 recites:
A method of treating an autoimmune disease and/or inflammatory condition in a subject, comprising: administering to the subject in need thereof, via the oral mucosa, a lyophilized rapidly infusing composition comprising (a) a pharmaceutically acceptable binder and/or excipient system comprising gelatin and a sugar alcohol, and (b) a therapeutically effective amount of solid form cannabidiol (CBD) having a purity between 95 and 99.9 wt.%, wherein the rapidly infusing composition has a disintegration time of approximately 1 to 30 seconds in deionized water maintained at 37° C.±2° C.
Catalent discloses an orally disintegrating tablet (ODT) comprising CBD using Zydis technology for the treatment of the autoimmune disease multiple sclerosis (Catalent, p. 1-2). Catalent teaches that “CBDs and THCs are notoriously insoluble and poorly bioavailable so a Zydis sublingual dosage form provides a drug delivery solution by avoiding first pass metabolism.” (Catalent, p. 3).
While Catalent does not teach that the ODT comprises mannitol and gelatin, one of ordinary skill in the art would have a reasonable expectation of success to formulate the ODT using gelatin and mannitol because Zydis technology is commonly known in the art to comprise gelatin and mannitol.
For example, Grother teaches Zydis Epinephrine, a freeze dried oral dispersible or disintegrating dosage form (Grother, Specification, ¶ 0096), comprising epinephrine, 10-40 wt.% of a matrix former and 10-40 wt.% of a structure former wherein the matrix former comprises gelatin and the structure former comprises mannitol (¶ 0010). Grother teaches that the dosage form is placed in the oral cavity, such as under the tongue or in the buccal region (¶ 0011) and rapidly dissolves to allow sublingual absorption (¶ 0100).
For example, Monteith teaches Zyprexa Zydis and Claritin RediTabs made with Zydis technology, both comprising gelatin and mannitol:
PNG
media_image1.png
281
307
media_image1.png
Greyscale
PNG
media_image2.png
125
305
media_image2.png
Greyscale
Monteith, Specification, p. 9, (¶ 0063).
In an interview with the Applicant for related Applications, (18/252,668 and 18/317,964) the Applicant asserted that an ordinary artisan would not know how to use Zydis technology with CBD because CBD is insoluble. These arguments were fully considered but are not persuasive. Insoluble solid forms are well known to be the preferred APIs for use with Zydis technology. For example, Amipara teaches that the ideal API is a water insoluble solid form:
The freeze-drying technique has demonstrated improved absorption and increase in bioavailability. The Zydis formulations consist of a drug physically trapped in a water-soluble matrix (saccharine mixture and polymer), which is freeze dried to produce a product that dissolves rapidly when placed in mouth. The ideal candidate for Zydis technology should be chemically stable and water insoluble and particle size preferably less than 50 micron. Water soluble drugs might form eutectic mixtures and not freeze adequately, so dose is limited to 60 mg and the maximum drug limit is 400 mg for water insoluble drug as large particle sizes might present sedimentation problems during manufacture.
Amipara, p. 86-87.
One of ordinary skill in the art would clearly have no difficulty in applying the teachings of Catalent to develop a CBD Zydis formulation. Zydis technology is well known and characterized in the art, particularly for solid water-insoluble substances, as demonstrated by Grother, Monteith and Amipara.
One of ordinary skill in the art would have a reasonable expectation that the CBD Zydis wafer would disintegrate in 1 to 30 seconds or 1 to 5 seconds in 37°C water because it is commonly known in the art that Zydis tablets can disperse in seconds. For example, Grother teaches that Epinephrine Zydis wafers can disperse in less than 7 seconds (fish gelatin) and less than 2 seconds (bovine gelatin) in 20°C water (Grother, Specification, ¶ 0164). For example, Amipara teaches that Zydis tablets are formulated to dissolve in 2-3 seconds when placed in the mouth:
Zydis, the best known of the fast-dissolving/disintegrating tablet preparations, was the first marketed new technology tablet. The tablet dissolves in the mouth within seconds after placement on the tongue. A Zydis tablet is produced by lyophilizing or freeze-drying the drug in a matrix usually consisting of gelatin. The product is very lightweight and fragile, and must be dispensed in a special blister pack. Patients should be advised not to push the tablets through the foil film, but instead peel the film back to release the tablet. The Zydis product is made to dissolve on the tongue in 2 to 3 seconds. The Zydis formulation is also self-preserving because the final water concentration in the freeze-dried product is too low to allow for microbial growth. The Zydis formulation utilizes flavors and sweeteners to optimize the taste of the dosage form. In addition, it utilizes microencapsulation with specialized polymers or complexation with ion exchange resins to mask the bitter tasting drug. The combination of lyophilization and taste masking creates a product that is both pleasing to the eye and also to the senses of taste and touch. A major claim of the Zydis product is increased bioavailability compared to traditional tablets. Because of its dispersion and dissolution in saliva while still in the oral cavity, there can be a substantial amount of pregastric absorption from this formulation. Buccal, pharyngeal and gastric regions are all areas of absorption of the Zydis formulation.
Amipara, p. 88-89 (emphasis added).
While Catalent does not teach that the Zydis CBD ODTs are formulated with a solid form of CBD, one of ordinary skill in the art would have a reasonable expectation of success to formulate the CBD ODTs with the solid form of CBD because it is commonly known in the art to formulate ODTs with solid/crystalline APIs and crystalline CBD is commonly known in the art.
For example, Grother teaches to use crystalline epinephrine in the ODTs because it is stable (Grother, Specification, ¶ 0009). For example, Amipara teaches that the ideal candidate for Zydis technology is a water insoluble compound with a particle size of less than 50 microns (e.g. it is a solid nanoparticle):
The freeze-drying technique has demonstrated improved absorption and increase in bioavailability. The Zydis formulations consist of a drug physically trapped in a water-soluble matrix (saccharine mixture and polymer), which is freeze dried to produce a product that dissolves rapidly when placed in mouth. The ideal candidate for Zydis technology should be chemically stable and water insoluble and particle size preferably less than 50 micron. Water soluble drugs might form eutectic mixtures and not freeze adequately, so dose is limited to 60 mg and the maximum drug limit is 400 mg for water insoluble drug as large particle sizes might present sedimentation problems during manufacture.
Amipara, p. 86-87.
CBD is an ideal candidate for Zydis technology because it is a water insoluble compound which can be readily extracted as a crystalline solid form which can be micronized for incorporation into the Zydis ODT. For example, Marco teaches crystalline CBD, a highly pure cannabidiol extract, which can be taken by a sublingual route (Marco, p. 3-5). Marco teaches that CBD crystals are very popular due to their versatility and ability to be incorporated into a variety of dosage forms:
CBD crystals are becoming increasingly popular due to their versatility, which leaves plenty of room for customisation when it comes to how they are taken. The main advantages of this type of cannabis derivative include the ability to easily mix the active ingredient into drinks or edible preparations, to apply it topically or to take it simply under the tongue, for example, just like CBD oil.
Marco, p. 4.
One of ordinary skill in the art would have a reasonable expectation of success to formulate the composition with CBD having a purity between 95 and 99.9 wt.% because Marco teaches that CBD crystals have a purity level of around 99%: “CBD crystals are a pure cannabidiol extract with a purity level of around 99% “(Marco, p. 3).
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 4 is directed towards the method of claim 1, wherein the rapidly infusing composition has a disintegration time of approximately 1 to 5 seconds in deionized water maintained at 37°C.
One of ordinary skill in the art would have a reasonable expectation that the CBD Zydis wafer would disintegrate in 1 to 30 seconds or 1 to 5 seconds in 37°C water because it is commonly known in the art that Zydis tablets can disperse in seconds. For example, Grother teaches that Epinephrine Zydis wafers can disperse in less than 7 seconds (fish gelatin) and less than 2 seconds (bovine gelatin) in 20°C water (Grother, Specification, ¶ 0164). For example, Amipara teaches that Zydis tablets are formulated to dissolve in 2-3 seconds when placed in the mouth:
Zydis, the best known of the fast-dissolving/disintegrating tablet preparations, was the first marketed new technology tablet. The tablet dissolves in the mouth within seconds after placement on the tongue. A Zydis tablet is produced by lyophilizing or freeze-drying the drug in a matrix usually consisting of gelatin. The product is very lightweight and fragile, and must be dispensed in a special blister pack. Patients should be advised not to push the tablets through the foil film, but instead peel the film back to release the tablet. The Zydis product is made to dissolve on the tongue in 2 to 3 seconds. The Zydis formulation is also self-preserving because the final water concentration in the freeze-dried product is too low to allow for microbial growth. The Zydis formulation utilizes flavors and sweeteners to optimize the taste of the dosage form. In addition, it utilizes microencapsulation with specialized polymers or complexation with ion exchange resins to mask the bitter tasting drug. The combination of lyophilization and taste masking creates a product that is both pleasing to the eye and also to the senses of taste and touch. A major claim of the Zydis product is increased bioavailability compared to traditional tablets. Because of its dispersion and dissolution in saliva while still in the oral cavity, there can be a substantial amount of pregastric absorption from this formulation. Buccal, pharyngeal and gastric regions are all areas of absorption of the Zydis formulation.
Amipara, p. 88-89 (emphasis added).
Therefore, claim 4 was prima facie obvious at the time of filing.
Claim 5 is directed towards the method of claim 1, wherein the gelatin is present in the rapidly infusing composition in an amount of 10 to 35 wt.%, based on a total weight of the rapidly infusing composition on a dry basis. Claim 7 is directed towards the method of claim 1, wherein the sugar alcohol is present in the rapidly infusing composition in an amount of 5 to 35 wt.%, based on a total weight of the rapidly infusing composition on a dry basis.
One of ordinary skill in the art would have a reasonable expectation of success to include the gelatin in an amount of 10 to 35 wt% and mannitol in an amount of 5 to 35 wt% because it is commonly known in the art to include gelatin in Zydis wafers in an amount of about 10 to 35 wt% and mannitol in an amount of 5 to 35 wt%.
For example, Grother teaches Zydis Epinephrine dosage form comprising epinephrine, 10-40 wt.% of a matrix former and 10-40 wt.% of a structure former wherein the matrix former comprises gelatin and the structure former comprises mannitol (Grother, Specification, ¶ 0010). In the specific examples, gelatin and mannitol are the only matrix formers and structure formers used (¶ 0147-0179). Grother teaches a specific example wherein the wafer consists of 4% w/w bovine gelatin, 3% w/w mannitol and 4% epinephrine prior to lyophilization (¶ 0160, Table 1), which would be about but less than 36% gelatin, about but less than less than 27% mannitol and about but less than less than 36% epinephrine after freeze drying to remove the water because there is also an undisclosed but small amount of citric acid which was used for pH adjustment (The pH modifier is present in an amount of 1-10 wt.% , about 1-5 wt.%, about 1-3 wt.%, about 2-3 wt.%, or about 2.51-2.57 wt.% (¶ 120)).
For example, Monteith teaches that a 10 mg Claritin RediTab comprises 33.8% Gelatin NF and 27.1 % Mannitol USP (Monteith, Specification, p. 9, (¶ 0063), Table 3, shown above in the rejection of claim 1).
Because the prior art ranges closely overlap the claimed ranges and the specific examples are so close to the claimed ranges, a prima facie case of obviousness exists (MPEP § 2144.05).
Therefore, claims 5 and 7 were prima facie obvious at the time of filing.
Claim 6 is directed towards the method of claim 1, wherein the gelatin is bovine gelatin. One of ordinary skill in the art would have a reasonable expectation of success to use bovine gelatin as the form of gelatin because Zydis tablets are commonly made with bovine gelatin. For example, Grother teaches a specific example wherein the wafer consists of 4% w/w bovine gelatin, 3% w/w mannitol and 4% epinephrine prior to lyophilization (Grother, Specification, ¶ 0160, Table 1).
Therefore, claim 6 was prima facie obvious at the time of filing.
Claim 8 is directed towards the method of claim 1, wherein the sugar alcohol comprises mannitol. As shown in the rejection of claims 1, 5 and 7 above, one of ordinary skill in the art would have a reasonable expectation of success to use mannitol in a CBD Zydis wafer because it is commonly known in the art to formulate Zydis wafers with mannitol. For example, see the teachings of Grother and Monteith above.
Therefore, claim 8 was prima facie obvious at the time of filing.
Claim 9 is directed towards the method of claim 1, wherein the CBD is present in the rapidly infusing composition in an amount of 20 to 70 wt.%, based on a total weight of the rapidly infusing composition on a dry basis.
One of ordinary skill in the art would have a reasonable expectation of success to include the CBD in an amount of 20 to 70 wt.% because it is commonly known in the art to formulate Zydis wafers with similar amounts of active ingredient.
For example, Grother teaches, “the dosage form (i.e., post lyophilization) can include about 10-75 wt.%, about 10-70 wt.%, about 15-70 wt.%, about 20-65 wt.%, about 25-65 wt.%, or about 26.03-60.86 wt.% API (e.g., epinephrine)” (Grother, Specification, ¶ 0145). For example, Monteith teaches that a 10 mg Claritin RediTab comprises 37.6% loratadine (API) (Monteith, Specification, p. 9, (¶ 0063), Table 3, shown above in the rejection of claim 1).
These ranges are overlap or lie within the claimed range of 20 to 70% so a prima facie case of obviousness exists (MPEP § 2144.05).
Therefore, claim 9 was prima facie obvious at the time of filing.
Claim 12 is directed towards The method of claim 1, wherein the rapidly infusing composition is formulated with a solid form of the CBD that has been micronized to have a D50 diameter between 1 and 50 µm.
One of ordinary skill in the art would have a reasonable expectation of success to formulate the composition with a solid form of the CBD that has been micronized to have a D50 diameter between 1 and 50 µm because it is commonly known in the art to formulate Zydis tablets with micronized APIs of this particle size. For example, Grother teaches to micronize the API to a diameter of about 10-40 microns (Grother, Specification, ¶ 0123), and teaches examples with a D50 of e.g. 38.024 microns and 21.495 microns (batch 3, Fig. 76). For example, Amipara teaches a particle size of less than 50 microns (Amipara, p. 86-87).
Therefore, claim 12 was prima facie obvious at the time of filing.
Claim 15 is directed towards the method of claim 1, wherein the rapidly infusing composition further comprises at least one selected from the group consisting of a sweetener, a flavorant, and a colorant. Claim 18 is directed towards the method of claim 15, wherein the rapidly infusing composition comprises the sweetener, and the sweetener comprises a mixture of sucralose and acesulfame-K.
One of ordinary skill in the art would have a reasonable expectation of success to further include a sweetener, for example sucralose and acesulfame K because it is commonly known in the art to include such sweeteners in Zydis ODTs.
For example, Grother teaches that the formulation can also include “coloring agents, flavoring agents, pH modifiers, sweeteners, taste-masking agents, and combinations thereof.” (Grother, Specification, ¶ 0102). Suitable sweeteners include sucralose and acesulfame K (Grother, Specification, ¶ 0103).
Therefore, claims 15 and 18 were prima facie obvious at the time of filing.
Claim 19 is directed towards the method of claim 1, wherein the rapidly infusing composition is administered to the subject via the buccal mucosa.
One of ordinary skill in the art would have a reasonable expectation of success to administer the composition to the subject via the buccal mucosa because it is commonly known in the art to administer ODTs via the buccal mucosa. For example, Grother teaches to administer the dosage form via the buccal region (Grother, Specification, ¶ 0011).
Therefore, claim 19 was prima facie obvious at the time of filing.
Claim Rejections - 35 USC § 103 – New Grounds of Rejection Necessitated by Amendment
Claim(s) 1, 4-12, 15, and 18-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action) in view of Grother et al. (US 2023/0364013 A1; published Nov. 16, 2023; effectively filed Oct. 8, 2020), Monteith et al. (US20080152712A1; published June 26, 2008), Amipara & Gupta (Journal of Drug Delivery & Therapeutics; 2013, 3(1), 85-92) and Marco (CBD Mania, Jan. 26, 2021, pp. 1-16), as applied to claims 1, 4-12, 15 and 18-19 above, and further in view of Booz (Free Radical Biology and Medicine, Volume 51, Issue 5, 1 September 2011, Pages 1054-1061).
The rejection of claims 1, 4-9, 12, 15 and 18-19 as being unpatentable over Catalent in view of Grother, Monteith, Amipara, and Marco is incorporated herein by reference.
Claim 20 is directed towards the method of claim 1, wherein the therapeutically effective amount of CBD is from 10 to 100 mg of CBD per dose.
While Catalent does not teach the therapeutically effective amount of CBD, one of ordinary skill in the art would have a reasonable expectation of success to include from 10 to 100 mg of CBD as the therapeutically effective dose because it is commonly known in the art that doses from 10 to 100 mg of CBD are therapeutically effective for autoimmune diseases.
For example, Elliot teaches that a therapeutically effective dose for multiple sclerosis is about 96 mg/day for a typical adult:
Multiple sclerosis (MS) is a chronic debilitating autoimmune disease without a cure. While the use of marijuana cannabinoids for MS has recently been approved in some countries, the precise mechanism of action leading to attenuate neuroinflammation is not clear. We used experimental autoimmune encephalomyelitis (EAE), a murine model of MS, to explore the anti-inflammatory properties of cannabidiol (CBD), a non-psychoactive cannabinoid. Treatment with CBD caused attenuation of EAE disease paradigms as indicated by a significant reduction in clinical scores of paralysis, decreased T cell infiltration in the central nervous system, and reduced levels of IL-17 and IFNγ.
Elliot, Abstract.
We chose to use a dose of 20 mg/kg body weight of CBD, which translates to 1.6 mg/kg when converted to human equivalent dose. This adds up to ~96 mg for an average human adult (60 kg).
Elliot, p. 8.
Therefore, claim 20 was prima facie obvious at the time of filing.
Claim 21 is directed towards the method of claim 1, wherein the rapidly infusing composition is administered to the subject 1 to 10 times per day.
While Catalent does not teach how many times per day to administer the rapidly infusing composition, one of ordinary skill in the art would have a reasonable expectation of success to administer the composition 1 to 10 times per day because these dosage regimens are commonly known in the art. For example, Elliot teaches that the CBD was administered daily in the mouse model (Elliot, col. 2, p. 3)
Therefore, claim 21 was prima facie obvious at the time of filing.
Claim(s) 1-9, 12, 15, and 18-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over “Catalent to Partner with Ethicann on New Fast-Dissolve Cannabinoid-Based Treatment for Multiple Sclerosis Spasticity” (Catalent, p. 1-3, Dec. 3, 2019) (herein “Catalent”) (of record, cited in prior office action) in view of Grother et al. (US 2023/0364013 A1; published Nov. 16, 2023; effectively filed Oct. 8, 2020), Monteith et al. (US20080152712A1; published June 26, 2008) a Amipara & Gupta (Journal of Drug Delivery & Therapeutics; 2013, 3(1), 85-92) and Marco (CBD Mania, Jan. 26, 2021, pp. 1-16), as applied to claims 1, 4-12, 15 and 18-19 above, as applied to claims 1-9, 12, 15 and 18-19 above, and further in view of Booz (Free Radical Biology and Medicine, Volume 51, Issue 5, 1 September 2011, Pages 1054-1061).
The rejection of claims 1, 4-9, 12, 15 and 18-19 as being unpatentable over Catalent in view of Grother, Monteith, Amipara, and Marco is incorporated herein by reference.
Claim 22 is directed towards the method of claim 1, wherein the autoimmune disease and/or inflammatory condition is a systemic autoimmune disease. Claim 23 is directed towards the method of claim 1, wherein the systemic autoimmune disease is rheumatoid arthritis.
Catalent teaches a CBD ODT for the treatment of the autoimmune disease multiple sclerosis. While Catalent does not teach that the autoimmune disease is a systemic autoimmune disease, or specifically rheumatoid arthritis, one of ordinary skill in the art would have a reasonable expectation of success to treat rheumatoid arthritis with the CBD composition because it is commonly known in the art to treat systemic autoimmune diseases such as arthritis with CBD. For example, Booz teaches that CBD may be an effective treatment for both multiple sclerosis and rheumatoid arthritis:
CBD may prove to have therapeutic utility in a number of conditions involving both inflammation and oxidative stress, including Parkinson disease, diabetes, rheumatoid arthritis, Alzheimer disease, and ischemia–reperfusion injury
Booz, col. 1, p. 1055;
As discussed by the authors [32], the lymphopenic effect of CBD was observed at a concentration shown to be efficacious in a number of animal models of neurodegenerative and inflammatory diseases, including blocking the progression of collagen-induced arthritis in a murine model of rheumatoid arthritis, decreasing damage to pancreatic islets in the nonobese diabetes-prone (NOD) mouse model of type 1 diabetes, lessening hyperalgesia in rat models of neuropathic and inflammatory pain, and preventing cerebral ischemia in gerbils.
Booz, col. 1, p. 1056;
Neuropathic pain is associated with microglia activation in the spinal cord and brain and their subsequent release of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-1β, and TNFα [33]. The etiology of neuropathic pain, which is common in cancer, diabetes, multiple sclerosis, and peripheral nerve injury, is poorly understood, but recent evidence indicates that increased ROS generation by microglial cells is the critical initiating factor [34]. The drug Sativex, which consists of Δ9 -THC and CBD, is approved in several countries for treatment of central and peripheral neuropathic pain and for spasticity associated with multiple sclerosis [35]… The antinociceptive effects of CBD were associated with less of an increase in microglial density and p38 MAPK activity in the dorsal spinal cord. Finally, the anti-inflammatory and immunosuppressive actions of CBD may be of use in treating rheumatoid arthritis and the associated pain [37,38].
Booz, col. 2, p. 1056.
Therefore, claims 22-23 were prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing. One of ordinary skill in the art would have no difficulty in obtaining a CBD Zydis ODT for the treatment of autoimmune conditions based on the teachings above.
Conclusion
No claim is found to be allowable.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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 86-217-9197 (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.
/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
Prosecution Insights