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 .
Status of Application
Receipt of the Applicant’s Remarks, and Amendments filed on 01/23/2026 is acknowledged.
Claims 29-44 are pending.
Claims 1-28, 37-39, and 42 are canceled.
Claim 29, is amended.
Claims 29-36, 40-41 and 43-50 are pending and are included in the prosecution.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
Claims 29-36, 40-41 and 43-50 are rejected under 35 U.S.C. 103 as being unpatentable over Bandi (Preparation of budesonide and indomethacin hydroxypropyl-β-cyclodextrin (HPBCD) complexes using a single-step, organic-solvent-free supercritical fluid process) in view of Lee (Controlled drug release applications of the inclusion complex of peracetylated-b-cyclodextrin and water-soluble drugs formed in supercritical carbon dioxide), Mishima (Microencapsulation of Proteins by Rapid Expansion of Supercritical Solution with a Nonsolvent), Misra (Supercritical fluid technology for solubilization of poorly water soluble drugs via micro- and nanosized particle generation), 임권택 (KR 101701203 B1) hereinafter the reference is referred as KR ‘203 in view of Jarho (US 2005/0153931 A1) hereinafter the reference is referred as Jarho, Cyclodextrins as Encapsulation Agents for Plant bioactive Compounds (hereinafter the reference is referred as Pinho) and further in view of Kucuksen et al. (WO 2018/135943 A1) hereinafter the reference is referred as Kucuksen.
Newly-presented independent claim 29 recites a pharmaceutical grade nanoparticle composition wherein a cannabinoid is encapsulated by a cyclodextrin, produced by a process comprising: (a) mixing the cannabinoid, a polymer, and a cyclodextrin in supercritical CO2 at 1,000–6,500 psi and 30–70°C; (b) depressurizing the mixture to obtain nanoparticles; (c) wherein 90% of the cannabinoid dissolves within 30 minutes; and (d) wherein the method does not include use of an organic solvent.(letter designations added for convenience).
Bandi teaches budesonide-HPBCD and indomethacin-HPBCD] complexes with enhanced dissolution rate can be formed using a single-step, organic solvent-free
scCO2 process (abstract), and The process places drug + HPBCD (a hydrophilic substituted beta-CD) in a high-pressure vessel, pressurizes with scCO2 at 211 bar / 40°C (= 3,061 psi / 40°C, within the claimed 1,000–6,500 psi / 30–70°C range), and depressurizes (page 161, left column 1st ¶; and Fig 2-Fig 6). Thus, No organic solvents are used at any step.
Lee teaches a simple and organic solvent-free method to molecularly encapsulate water-soluble drugs with a hydrophobic CD, peracetylated-beta-cyclodextrin (PAc-beta-CD) cavity to prepare pure inclusion complexes, by using supercritical carbon dioxide (scCO2) (¶ Introduction) and in conditions ~34.5 MPa (5,004 psi) / 45°C (page 631, left column) which is within the claimed range.
Regarding claim 1, component (A and B), previously rejected by KR ‘203 and secondary art, see below.
Regarding claim 1, component (C), Bandi discloses dissolution rates, suggesting the claimed 90 %-in-30-minutes limitation is taught. Bandi teaches scCO2-processed HPBCD complexes showed 2× (budesonide) and 3× (indomethacin) dissolution enhancement relative to unprocessed drug. The mechanism identified is loss of drug crystallinity (amorphization) caused by the scCO2 process (abstract). Moreover,
given that (1) scCO2 depressurization directly produces amorphous drug-CD nanoparticles with dramatically enhanced dissolution rates; (2) Bandi shows 2–3× enhancement; and (3) RESS processes yield >90% dissolution in minutes, a PHOSITA would have had a reasonable expectation that optimizing a scCO2-based cannabinoid/CD/polymer formulation would yield a product dissolving ≥90% within 30 minutes (¶ Discussion, pages 166-167). The claimed dissolution rate is therefore an expected, not unexpected, result of the claimed process.
Regarding claim 1, component (D), in view of Bandi and Lee, it would have been obvious to a PHOSITA to form cannabinoid-CD-polymer nanoparticles using scCO2 without any organic solvent because: (1) the entire field of scCO2 pharmaceutical processing was motivated by the known toxicity and regulatory concerns of organic solvent residues in pharmaceutical formulations; (2) both of the newly cited references explicitly teach that scCO2 is a viable and preferred solvent substitute; and (3) the same processing vessel / depressurization architecture used in the cited references is the architecture claimed in Claim 29.
Mishima teaches polymer in supercritical CO2 mixture (abstract).
Misra teaches the amorphous nanoparticles of cefuroxime axetil were produced directly by RESS technology, without any additive. The nanoparticles obtained were between 158 and 513 nm. More than 90 % of the nanoparticles dissolved in 3 min and
complete dissolution occurred within 20 min, while the commercial drug achieved only about 50 % dissolution in 60 min (page 357, ¶ 2).
Regarding claims 1 component (C), and 45-47, Mishima explicitly describes suspending or dissolving polymer in scCO2 together with the drug for co-precipitation upon depressurization. Polymers tested include PEG, PLA, and PMMA (¶ Materials, page 859; ¶ Results & Discussion, page 860), essentially the same class of polymers (PEG, PVP) and the drug and polymer are contacted simultaneously in the supercritical phase before rapid expansion, and Misra explicitly teaches Cefuroxime axetil nanoparticles prepared by RESS (pure scCO2, no organic solvent) achieved >90% dissolution in 3 minutes and complete dissolution within 20 minutes, compared to ~50% dissolution of commercial drug at 60 minutes (page 357, ¶ 2). This directly demonstrates that RESS/depressurization-based scCO2 nanoparticle formation inherently produces particles with dissolution rates exceeding the 90%-in-30-minutes threshold. Examiner notes that although Cefuroxime axetil is of a different drug class, the mechanism (scCO2-induced amorphization → rapid dissolution) is drug-independent, and this mechanism-based process is obvious to a PHOSITA.
KR ‘203 teaches peracetylated cyclodextrins (PAc-CD) using supercritical carbon dioxide, and superabsorbent microparticles of a drug and a method for producing, directed to an oral pharmaceutical composition comprising the superfine particle, wherein the superfine particle is produced by discharging a mixture of (PAc-CD) and drug in supercritical carbon dioxide through a capillary nozzle in a vapor phase or a solution phase, producing superfine particles that are excellent in porosity and dispersibility in an oral composition (abstract) and FIG. 2 is a view showing an apparatus for manufacturing a drug using supercritical carbon dioxide (1); wherein the apparatus comprises high pressure injection pump (2); check valve (3); storage cell (4); pressure gauge (5); reaction cell (6); stirrer (7) magnetic bar (8); on/off valve (9); valve (11); constant temperature system (12); flow meter (13); NOZZLE (14); collection container (15). Notably, KR ‘203 discloses conventional methods of making fine particles by rapidly expanding a substance dissolved in a supercritical fluid include a rapid expansion of solutions (RESS) and a rapid expansion of a supercritical solution into a liquid solvent (RESOLV), wherein the RESS method is based on the rapid expansion of the pressurized supercritical solution to the atmosphere, and the RESOLV method is based on the method of rapidly expanding the pressurized supercritical solution into an external solution containing a surfactant, mainly water, however, there has been no report on a method of atomizing a drug body using supercritical carbon dioxide (¶ 0010), and accordingly, there is a great demand for research on a method for producing ultrafine particulate drug cartilage using a non-toxic supercritical carbon dioxide medium (¶ 0011), and superfine particles can be produced, and the superfine particles are excellent in porosity and dispersibility and can be used as an oral composition (¶ 0046). Additionally, KR ‘203 disclose non-toxic supercritical carbon dioxide medium (¶ 0011).
Regarding claims 29 and 44, KR ‘203 teaches the size of the superfine particles was observed using an optical microscope and FESEM, and the result was measured to be about 100 nm (¶ 0052), about 90 nm (¶ 0055), and about 170 nm (¶ 0061). Moreover, KR ‘203 discloses the diameter of the superfine particle may be 10 to 1000 nm, 50 to 300 nm (¶ 0037). Furthermore, KR ‘203 discloses when the drug is mixed with PAc-CD in supercritical carbon dioxide, the ratio of PAc-CD to drug is 0.1 to 50, or 1:1, and although the drug does not dissolve in supercritical carbon dioxide, when the PAc-CD is dissolved, the inclusion body is formed and the supercritical carbon dioxide dissolves, wherein the reaction time is 1 minute to 36 hours, or in 20 hours (¶0027). Furthermore, KR ‘203 discloses in Fig. 6, the pure drug is released at 30% at the same time as the measurement, and is released 100% within 1 hour, and with the RESOLV method, 25-30% released after 1 hour, and greater than 95% released after hours, showing excellent discharge control ability of the superfine particles (¶ 0071). As noted above, KR ‘203 teaches the conventional method of producing superfine particles by a rapid expansion of a supercritical solution into a liquid solvent (RESOLV) and mixing peracetylated cyclodextrin (PAc-CD) and drug in supercritical non-toxic carbon dioxide and discharging the mixture through the capillary nozzle (¶ 0018). Therefore, the limitation of nanoparticle with average particle size between 100 nm and 40 µm is taught. It would have been obvious to a person having ordinary skill in the art (PHOSITA) to optimize the parameters of supercritical CO2 fluid, psi pressure and temperature, average particle size to achieve at least 90% of the nanoparticle composition dissolves within 5 minutes after being added to water. It is noted that the rapid expansion of a supercritical solution into a liquid solvent (RESOLV), mixing peracetylated cyclodextrin (PAc-CD) and drug is the same product-by-process method utilized to produce the superfine compound, and the same rapid expansion of a supercritical solution is disclosed in (Specification, ¶ 36) with solvent fluid CO2 (99.0%). Therefore, it would have been reasonable for a PHOSITA to expect the nanoparticle composition (superfine particles) to be stable at room temperature for at least 16 months because the same method of preparing was employed in the instant claims. As such, the limitations and structural features are taught. Additionally, KR ‘203 discloses (1) mixing peracetylated cyclodextrin (PAc-CD) and drug in supercritical carbon dioxide; and (2) discharging the mixture through the capillary nozzle to the outside (¶ 0022), and in the step (1), peracetylated cyclodextrin (PAc-CD) and the drug are mixed and stirred in supercritical carbon dioxide in the reactor (¶ 0023), and the supercritical carbon dioxide in the reactor is preferably at a pressure of 6 to 45 MPa and at a temperature of 30 to 60 ° C, more preferably at a pressure of 20.7 MPa and at a temperature of 45 ° C, but is not limited thereto, and if the temperature and pressure are below 20.7 MPa at 45 ° C (¶ 0024). The conversion of MPa to psi equates to 45 MPa = 6526.7 and 20.7 MPa = 3002.281 psi. Therefore the limitation of at least one cyclodextrin in supercritical CO2 fluid at a pressure between 1,000 psi to 6500 psi and at a temperature between 30 ° C to 70 ° C is met.
Regarding claims 31, 33, 34 and 49, KR ‘203 teaches the peracetylated cyclodextrin (PAc-CD) may be peracetylated alpha-cyclodextrin, peracetylated beta- cyclodextrin or peracetylated gamma-cyclodextrin, but is not limited to, for example 0.1 to 20 wt%, based on the critical carbon dioxide, and is well soluble in supercritical carbon dioxide (¶ 0025).
Regarding claim 32, KR ‘203 teaches Cyclodextrins are composed of a donut structure in the form of a ring, and have hydrophobic cavities inside and hydrophilic properties outside the molecule, and these characteristics enable various kinds of hydrophobic organic compounds to be recognized in the inner cavity to form inclusion
compounds of excellent physical properties, and studies have suggested the possibility of not only stabilizing unstable substances by using the potency of cyclodextrin or expanding the use by changing the solubility but also to recognize only specific substances and to easily isolate them (¶ 0008) and it is also known to manufacture
peracetylated cyclodextrins and suppositories of the hydrophilic drug morpholinium in supercritical carbon dioxide (¶ 0009). Therefore, it would have been obvious to a PHOSITA to select at least one hydrophilic cyclodextrin, either alpha, beta or gamma cyclodextrin to be utilized in the desired nanoparticle composition.
Regarding claim 40, KR ‘203 teaches when the drug is mixed with PAc-CD, the ratio of PAc-CD to drug is 0.1 to 50, and/or 1:1 (¶ 0027). Therefore, the limitation of API: acetylated cyclodextrin molar ratio is taught and overlaps with instant range 1:0.5, or 1:1. It would have been obvious to a PHOSITA to select a cannabinoid as the API in the composition to produce the PAc-CD and drug complex.
Regarding claim 41, KR ‘203 teaches use of an apparatus to form the nanoparticles in supercritical fluid and the step (2) is a step of discharging the mixture of PAc-CD and the drug in the supercritical carbon dioxide to the outside through the capillary nozzle (¶ 0028), and the mixture may be rapidly depressurized and released via a capillary nozzle in either a RESS mode or a RESOLV mode (¶ 0029), and the mixture of PAc-CD and drug in the supercritical carbon dioxide is injected through a capillary nozzle to form ultra-fine particles. Capillary phenomenon is caused by attraction between liquid molecules in a narrow tube and mutual attraction between the surface of the liquid and the surface of the tube and the capillary nozzle may have a narrow tube shape and may be formed of a material such as metal, glass, quartz, Teflon, and a polymer of a chemical resistant material (¶ 0034), wherein the capillary nozzle may be 25 to 1000 m (micron or µm), and the ratio of the capillary to the diameter may be 1 to 5000 (¶ 0035). Moreover, KR ‘203 teaches use of high pressure reactor cell 5 and the carbon dioxide from the carbon dioxide cylinder 1 was injected at a pressure of 20.7 MPa through the high pressure syringe pump 2 do (¶ 0051). Therefore, the limitation of high pressure nozzle is taught. It would have been obvious to a PHOSITA to use the conventional apparatus of a RESS (rapid expansion of supercritical solutions) system or RESOLV (rapid expansion of a supercritical solution into a liquid solvent) system to formulate the superfine nanoparticles with supercritical CO2, wherein the nozzle can be adjusted/optimize to the diameter of 1 µm to 10 µm to properly de-pressurized and release the API through a nozzle for short bursts to achieve supercritical, high-pressure gas or liquid status and recirculating carbon dioxide in the reaction chamber for the next batch processing as disclosed in specification page 15 (¶ 87). The recitation of using a high pressure nozzle with a nozzle diameter of 1 µm to 10 µm is describing a conventional apparatus used in a RESS/RESOLV system for formulate the composition and therefore it is obvious to use such a system for the desired superfine compound.
Regarding claim 43, KR ‘203 teaches in Fig. 6, the pure drug is released at 30% at the same time as the measurement, and is released 100% within 1 hour, and the results show excellent discharge control ability of the superfine particles (¶ 0071).
Regarding claims 45 - 47, KR ‘203 teaches poly (ethylene glycol) (PEG), Poly (N-vinyl-2-pyrrolidone, PVP), and poloxamer (¶ 0032).
KR ‘203 fails to specifically teach cannabinoid, cannabidiol (CBD), cannabigerolic acid (CBGA), cannabinol (CBN), tetrahydrocannabinol (THC), and tetrahydrocannabivarin (THCV).
Jarho teaches use of cyclodextrin (CD) complexes directed to a complex selected from the group consisting of α-CD, β-CD and γ-CD and a cannabinoid selected from the classical cannabinoid-group consisting of cannabinol, tetrahydrocannabinol and cannabidiol, the process comprising combining the selected cyclodextrin with the selected cannabinoid in solution, In a heterogenous state or in the solid state, including using methods of precipitation, freeze-drying, spray-drying, kneading, grinding, slurry-method, co-precipitation and neutralization (¶ 0011). Moreover, Jarho disclose that insoluble cannabinoid/natural cyclodextrin complexes can be used to significantly increase the dissolution rate of cannabinoids which can be used in sublingual cannabinoid formulation, and the increased dissolution rate of cannabinoids is due to the better solubility/dissolution properties of the solid cannabinoid/natural cyclodextrin inclusion complexes compared to pure cannabinoid, whereas the dissolution rate of pure cannabinoids is too slow for sublingual drug formulations (¶ 0013). Furthermore, Jarho discloses the solid cannabinoid/natural CD complexes can prepared by simply stirring (mixing) cannabinoids and natural CDs be in an aqueous solution which leads to the precipitation of solid complexes (i.e., the cannabinoid molecules are inside of the CD cavity and form inclusion complexes) (¶ 0014), leading to improve dissolution, solubility and bioavailability properties of cannabinoids, and thus improves the pharmaceutical usefulness of CDs in cannabinoid formulations (¶ 0015). Moreover, Jarho teaches the formation of inclusion complex can be facilitated by using organic solvents (methanol or ethanol) and the temperature can vary to some degree, but it is typically for convenience to ambient temperature (¶ 0019).
Regarding claim 29, as noted above, Jarho teaches cyclodextrins (CDs) complexes and a cannabinoid wherein the complex for the preparation of a pharmaceutical composition are intended for sublingual or buccal administration, in the form of a tablet, capsule, chewing gum, lozenge or pill (¶ 0009), and prepared by simply stirring (mixing) cannabinoids and natural CDs be in an aqueous solution (¶ 0014). Furthermore, Jarho disclose the CBD-CDs complexes is fully dissolved (> 90 % within 30 minutes (figures 2 & 3). Moreover, Jarho disclose hydroxypropyl- β-CD and methylated CDs have major differences over natural CDs and the CD derivatives above difference is that natural CDs have been shown to form low solubility complexes with various drugs, as opposed to water-soluble CDs derivatives, and water soluble CD derivatives form only water soluble complexes with lipophilic drugs (¶ 0005), and in drug formulations, the CDs have been used mainly to increase the aqueous solubility, stability and bioavailability of various drugs, food additives and cosmetic ingredients (¶ 0006). It is noted that cyclodextrins have an inner hydrophobic core and a hydrophilic exterior, and they form complexes with hydrophobic compounds (specification, page 8, ¶ 52). Therefore, cyclodextrin complexes reads on the limitation of cyclodextrin-encapsulated.
Regarding claims 30, 48, and 50, Jarho teaches a process for the preparation of a complex of a cyclodextrin selected from the group consisting of α-CD, β-CD and γ-CD and a cannabinoid selected from the classical cannabinoid-group consisting of cannabinol (CBN), tetrahydrocannabinol (THC) and cannabidiol (CBD), and the process of combining the selected cyclodextrin with the selected cannabinoid in solution, in a heterogenous state or in the solid state, using methods of precipitation, freeze-drying, spray-drying, kneading, grinding, slurry-method, co-precipitation, and neutralization, and optionally separating the complex (¶ 0011) and the cyclodextrin complexes can be administered orally in various forms, as noted above. Furthermore, Jarho disclose that use of CDs with cannabinoids (classical, non-classical and aminoalkylindol derivatives) have reported that the THC forms an inclusion complex with natural β-CD with increasing chemical stability of THC, and the THC/β-CD inclusion complex (in general) is used to improve the aqueous solubility, membrane permeability and bioavailability of THC, and that HP-β-CD complex increases the aqueous solubility of THC and co-administration of small amounts of water-soluble polymer (HPMC) enhances the complexation between HP-β-CD and THC. (¶ 0007).
Regarding claim 31, Jarho teaches the pharmaceutical composition comprising at least one sublingually or buccally acceptable carrier, adjuvant or additive and a therapeutically effective amount of a complex of a cyclodextrin selected from the group consisting of α-CD, β-CD and γ-CD and a cannabinoid selected from the classical cannabinoid-group consisting of cannabinol, tetrahydrocannabinol and cannabidiol is taught (claim 6). Therefore, the limitation of at least one cyclodextrin selected from the group consisting of α-CD, β-CD and γ-CD is taught.
Regarding claim 32, Jarho teaches CDs are cyclic oligosaccharides consisting of (α-1,4)-linked α-D-glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface, and CDs are able to form inclusion complexes with many drugs by taking up the whole drug, or more commonly, the lipophilic moiety of the molecule, into the cavity, and β-CD appears to be the most useful pharmaceutical complexing agent because of its cavity size, availability, low cost and other properties (¶ 0005). Furthermore, Jarho discloses, of these three CDs, β-CD appears to be the most useful pharmaceutical complexing agent because of its cavity size, availability, low cost and other properties, and there are also a number of CD derivatives available, for example hydroxypropyl-β-CD and methylated CDs. One of the major differences between natural CDs and the CD derivatives above is that natural CDs have been shown to form low Solubility complexes with various drugs, as opposed to water-soluble CDs derivatives, wherein water-soluble CD derivatives form only water-soluble complexes with lipophilic drugs (¶ 0005). Therefore, depending on the desired nanoparticle composition, it would have been obvious to a person having ordinary skill in art to select hydrophilic CDs to use in the composition.
Regarding claim 40, Jarho teaches typically cannabinoid and CD are used in a weight ratio (dry weight to dry weight) ranging between 1:3 and 1:1000 (¶ 0018, last 2 lines).
Regarding claim 43, as noted above, Jarho teaches cyclodextrin-complexes (encapsulated) with active pharmaceutical ingredients (cannabinoids) and in Fig. 1, exemplifies the dissolution profile (dissolved CBD as a function of time) of CBD from a gelatine capsule containing 1.0 mg of pure CBD, and Fig. 2 shows the same data with a capsule containing 9.1 mg of natural β-CD/CBD-complex (equivalent to 1 mg of THC) (¶ 0028), and Fig. 3 shows the same data with a capsule containing 7.7 mg of a natural y-CD/CED-complex (equivalent to 1 mg of THC) and 92.3 mg of lactose (Mean ±SD, n=4) (¶ 0032) and Figs. 1 and 3 show that the complexation of CBD with natural y-CD significantly increases the dissolution rate of CBD, and with a y-CD/CBD formulation, CBD is fully dissolved in 30 minutes, and without y-CD, the dissolution rate is much slower and CBD is not fully dissolved in 3 hours (¶ 0033). Therefore, the limitation of API have 99.9 % purity and 200 % increase bioavailability as compared to a non-cyclodextrin-encapsulated API formulation is taught.
Jarho fails to specifically teach ultrafine dry powder having average particle size between 100 nm and 5 µm, and acetylated CDs.
Pinho teaches use of cyclodextrins (CDs) as encapsulating agents for bioactive plant molecules in the pharmaceutical field (abstract) and CDs are used as drug carriers to enhance the solubility, stability and bioavailability of the bioactive molecules, and in nature, CDs appear as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, wherein the β-cyclodextrins (β-CD) are commonly employed for encapsulation purposes and they are able to form inclusion complexes (ICs) with poorly water-soluble molecules, to improve the molecule’s solubility, and in addition to the solubilization improvement, CDs protect bioactive molecules from side-effects from the environmental conditions (temperature, pH, and light) and therefore enhance their shelf-life and reduce the concentrations of the agent required to achieve a biological effect (page 122, ¶ 2 to page 123). Furthermore, Pinho discloses the CD-encapsulation of the bioactive molecule induces alterations on the physicochemical characteristics of both agents and thus it is possible to assess the stoichiometry of the complexes and their stability constant (K) by analyzing the modification the solubility, chemical reactivity and stability, UV-Vis absorbency, drug retention and permeability, and the stoichiometry of the IC represents the number of molecules that interact with the CD, wherein mostly 1:1 ratio IC is observed, however the same CD can interact with 2 or more molecules (1:2) or one guest can complex with more than one CD (2:1) (page 123, ¶ 2.1-IC formation process). Furthermore, Pinho discloses common β-CDs derivatives for encapsulating API (Table 1) are normally, distributed based in their interaction with the water molecules, i.e., hydrophilic, hydrophobic or ionizable derivatives (page 123, ¶ 2.2), wherein the first group (hydrophilic) has better solubility in water and are suitable for IC formation with poor water soluble “guest” molecules, and the 2,6-dimethyl- β-CD (DM- β-CD); acetylated cyclodextrins comprising acetylated-2,6-dimethyl-β-CD (DMA-β CD); 2,3,6,-trimethyl-β-CD (TM-β-CD); hydroxy alkylated CDs such as HP- β-CD and branched CDs like G-β-CD are some examples of hydrophilic CD derivatives (page 123, ¶ 2.2).
Regarding claims 31, 32, 33, 34, 35 and 36, as noted above, Pinho teaches at least one cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, and at least one selected from the group consisting of hydrophilic α-CD, hydrophilic β-CD, and hydrophilic γ-CD, and at least one selected from the group consisting of acetylated cyclodextrin and of at least one (acetylated α-CD, β-CD, γ-CD) and at least one hydrophilic α-CD, hydrophilic β-CD, and hydrophilic γ-CD and at least one selected from the group consisting of (acetylated α-CD, β-CD, γ-CD). Therefore, the combinations of cyclodextrins (α-CD, β-CD, γ-CD), acetylated CDs (acetylated α-CD, β-CD, γ-CD), and hydrophilic CDs (hydrophilic α-CD, β-CD, γ-CD) are taught.
Kucuksen teaches use of one or more cannabinoids and/or terpenes in combination with psilocybin and/or psilocin for use in the prevention or treatment of psychological or brain disorders, wherein the one or more cannabinoids are taken from the group cannabidiol (CBD), cannabigerolic acid (CBGA), cannabichromene acid (CBCA), cannabidiolic acid (CBDA), tetrahydrocannabivarinic acid (THCVA), cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD) (abstract). Moreover, Kucuksen discloses the cannabinoid extract from at least one cannabis plant is produced by extraction with supercritical or subcritical CO2 and alternatively the cannabinoid extract from at least one cannabis plant is produced by contacting plant material with a heated gas at a temperature which is greater than 100°C, sufficient to volatilise one or more of the cannabinoids in the plant material to form a vapor, and condensing the vapor to form an extract, and alternatively the one or more cannabinoids, including Phyto-cannabinoids, may be present in a substantially pure or isolated form (page, lines 1-9).
Regarding claim 43, Kucuksen teaches substantially pure preparation of cannabinoid greater than 99.5 % (page 11, lines 10-14).
Kucuksen fails to specifically teach acetylated cyclodextrins.
It would have been prima facie obvious to one having ordinary skill in the art as of the effective filing date of the claimed invention to prepare the cyclodextrin (CD) complexes selected from the group consisting of α-CD, β-CD and γ-CD and incorporate pure preparation of cannabinoid in the composition, wherein a cannabinoid selected from the classical cannabinoid-group consisting of cannabinol, tetrahydrocannabinol and cannabidiol as taught by KR ‘203 in view of Jarho, and further in view of Pinho and Kucuksen. One of ordinary skill in the art would have been motivated to improve the composition and formulate the cyclodextrin into peracetylated cyclodextrin (PAc-CD) and incorporate ultrafine particles of a drug (API) in order to overcome instability and solubility limitations of insoluble drugs as taught by KR ‘203. Moreover, peracetylated cyclodextrin (PAc-CD) mixed with an ultrafine nanoparticle drug not only stabilize unstable substances by using the potency of cyclodextrin or expanding the use by changing the solubility, but also to recognize only specific substances and to easily isolate them (KR ‘203, ¶ 0008). One of ordinary skill in the art would have been motivated to do this because all references are drawn to components of cyclodextrins used in encapsulation of cannabinoids in the composition for drug delivery. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to include these components and optimized the mixing ratios in methods to produce a cyclodextrin-encapsulated complex for drug carrier as taught by the references.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Response to Declaration
Examiner would like to note a critical contradiction in the Declaration data filed 08/07/2025. The declaration’s own date proves the scco₂ process is not the source of the improved dissolution. The Declaration presents four test compositions:
Composition
Process
Polymer?
30-Min Dissolution
Process Time
ESL-01
scCO₂ (claimed process)
None (no polymer)
5.7%
~1 hour
ESL-02
← Claimed Invention
scCO₂ (claimed process)
Poloxamer added
91.3%
~1 hour
JAR-03
Jarho/co-precipitation (ethanol)
None (no polymer)
6.8%
>18 hours
JAR-04
← Key Comparator — FAILED
Jarho/co-precipitation (ethanol)
Poloxamer added
N/A — emulsion failure
N/A
ESL-01 was produced by the same scCO₂ process as ESL-02, at the same pressure (3,500 psi) and temperature (40°C), but without poloxamer. ESL-01 achieved only 5.7% dissolution at 30 minutes — virtually identical to JAR-03 (Jarho method, no polymer) at 6.8%. The scCO₂ process alone produces the same poor dissolution as the prior art Jarho method. The 91.3% dissolution of ESL-02 is attributable to the addition of poloxamer, and a polymer that is expressly identified by name in KR '203 (¶0032) and that was known to PHOSITA.
The unexpected results must be attributable to the specific claimed feature that distinguishes the invention from the prior art — not to a feature already known in the art. The comparison in the Declaration actually establishes:
What Is Being Compared
Dissolution at 30 Min
Difference
ESL-01 (scCO₂, no poloxamer) vs. JAR-03 (Jarho, no poloxamer)
5.7% vs. 6.8%
−1.1% — NO meaningful difference
ESL-02 (scCO₂ + poloxamer) vs. JAR-03 (Jarho, no poloxamer)
91.3% vs. 6.8%
+84.5% — but see attribution below
ESL-02 (scCO₂ + poloxamer) vs. JAR-04 (Jarho + poloxamer)
91.3% vs. N/A
Comparator failed — cannot evaluate
A PHOSITA would reasonable conclude: the improvement in dissolution observed in ESL-02 is driven by the addition of poloxamer, not by the scCO₂ process. Poloxamer (Poloxamer 407 / Pluronic F127) is a well-known solubilizing and emulsifying agent — its ability to dramatically improve the dissolution and wettability of poorly water-soluble drugs such as CBD is thoroughly documented in the pharmaceutical literature and was known to PHOSITA at the time of the priority date.
Response to Arguments
In the previous action (filed 10/23/2025), Applicant argued that adding the polymer into the scCO2 phase (as opposed to the RESOLV external liquid) was not taught. This limitation is now directly addressed by Mishima in the rejection above.
Applicant's arguments and amendment filed 01/23/2026 have been fully considered but they are not persuasive.
A. Hindsight Reasoning (Argument I)
Applicant argues that the examiner improperly relied on hindsight in selecting and combining references. Examiner respectfully disagree. The motivation to add polymer to the scCO2 mixture (rather than external liquid) is explicitly stated in Mishima and co-dissolution in scCO2 produces uniform composite particles with better-controlled morphology. Thus, the rejection is supported by prior art rationale.
B. Unexpected Results / Oh Declaration (Argument II)
Applicant's Oh Declaration shows 91.3% dissolution of ESL-02 at 30 minutes versus 15–30% for KR '203 RESOLV compositions at 1 hour. The examiner acknowledges this comparison but notes the following regarding the new art of record:
The dissolution rate comparison must now be made against the newly cited references, not merely KR '203. Bandi demonstrates 2–3× dissolution enhancement from scCO2-processed CD complexes (no organic solvents), and the cefuroxime axetil example of Misra achieves >90% dissolution in 3 minutes. The relevant baseline is scCO2-processed, solvent-free CD-drug compositions and not KR '203 RESOLV (which uses organic solvent and targets controlled release).
The purported 3×–13.4× improvement over prior art comparators relied upon KR '203 RESOLV and Jarho as the closest prior art. With the new references, the improvement margin is substantially narrower, and dissolution rates of >90% at 30 minutes are reasonably expected from scCO2-processed amorphous CD complexes.
C. Applicant argues secondary considerations (Argument III)
Applicant's long-felt need and commercial success arguments are acknowledged. However:
Long-felt need: The existence of a long-felt need for water-soluble cannabinoid formulations is not disputed. However, Bandi demonstrates that the solution scCO2-based solvent-free CD complexation, was available and known to PHOSITA. Long-felt need cannot establish nonobviousness where the need was, in fact, met by the prior art.
Commercial success: The $95M co-development agreement and Avata Biosciences Phase 1 results are noted. However, Applicant has not established that commercial success is attributable to the specific claimed features (scCO2 processing without organic solvent) rather than to the cannabinoid-CD complexation concept generally, which was known in the art (Jarho). Nexus to the distinguishing claim limitations, specifically the organic-solvent-free scCO2 process must be demonstrated before commercial success can overcome the prima facie case of obviousness.
Therefore, it would have been obvious to a PHOSITA to reasonably achieve success in producing the product with the expectation of improved dissolvability and greater stability because the same components (acetylated-cyclodextrins, supercritical CO2, high pressure chamber, nozzle, cannabinoids and average particle size) and method of producing were similarly employed by the combined teachings of prior art.
Therefore, a prima facie case have been properly established and new grounds of rejections are necessitated by amendment.
Conclusion
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.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615