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 .
Response to Amendments
Applicant’s amendments to the claims of June 23, 2026, in response to the Office Action of December 23, 2025, are acknowledged.
Response to Arguments
The Double Patenting Rejection is withdrawn in view of the filing and approval of a Terminal Disclaimer on June 24, 2026.
The §112 rejection is withdrawn.
With respect to new claim 22, the examiner notes that Du teaches cannabidiol as the main chemical component in cannabis. Further, CBD is known to be isolated from cannabis. Even further, the teachings of Du focus on the presence of cannabidiol. As such, a POSA would understand that cannabidiol can be used as the predominant and sole cannabinoid in the compositions described.
Applicant argues that the references would not be combined.
The examiner notes that the cited references teach thermosensitive gels for administration of APIs to a subject wherein the components include a surfactant and a combination of poloxamers. There is a strong nexus linking the analogous prior art that is applied.
Du teaches glyceryl monooleate is used a non-ionic surfactant and includes other bioadhesive agents, including chitosan and carbomer. The aqueous solution taught by Du that includes poloxamers and a surfactant that forms a thermoreversible gel comprises micelles that form in solution.
Applicant argues that there is no reason to form the claimed composition in view of the prior art.
The examiner notes that micelles form with poloxamers in an aqueous environment. Moreover, the prior art teaches liquid micelle formulations that form the basis of a liquid that forms a gel when applied to a subject. A liquid to gel transition includes when the liquid is a micellar dispersion liquid as taught. Even further, the prior art teaches using non-ionic surfactants and teaches a synergy comprising the claimed combination of poloxamers. Moreover, Bodratti explains that poloxamers can form mixed micelles in the presence of added surfactants, wherein a non-ionic surfactant and claimed poloxamer are used in an example. See p5, 1st par. Modulating particle size and drug encapsulation efficiency can be achieved by adding other polymers and surfactants to a solution in different proportions. An example of this is Pluronic F127 and a non-ionic surfactant. See p13, 3rd full par. Additionally, Altuntas teaches developing a sol-gel mucoadhesive thermoreversible nasal gel that has claimed physical properties.
Du teaches a composition comprising a plurality of poloxamers, a surfactant, and cannabidiol in an aqueous solution that forms micelles and yields a thermoreversible sensitive nasal gel for administration of cannabidiol as active agent.
Ferrari teaches a micellar dispersion and this can be a water based solution. Polymeric micelles are contemplated. See par.’s 49, 53, 7,3, 109, and prior art claim 11. Administration can be through most routes of administration, including nasal and intranasal. See par. 10. Ferrari further teaches that the transition from a liquid to a gel enhance the bio-adhesiveness and enhancement to tissue adhesion of the mucosa or submucosa. See par. 76. The poloxamers used can be P188, P407 or a mixture, e.g. See par.’s 82-84. The polymer can be included in a concentration of 0.1 to 30%. See par. 86. Polysorbate 80 is a preferred non-ionic surfactant. See par. 92.
Bodratti explains that poloxamers can form mixed micelles in the presence of added surfactants. See p5, 1st par. Modulating particle size and drug encapsulation efficiency can be achieved by adding other polymers and surfactants to the solution in different proportions. An example of this is Pluronic F127 and the non-ionic surfactant. See p13, 3rd full par.
Thus, the use of micelles to encapsulate drugs and the use of additional surfactants including a non-ionic surfactant is recognized in the art. The specific poloxamers (P407 and P188) and non-ionic surfactant (polysorbate 80) are taught by the prior art as synergistic and preferred, respectively. Thus, the form and the components of the claimed composition are known in the art and the use of a thermos-sensitive gel comprising the same is contemplated and bestows advantages on drug delivery.
Ferrari also claims a drug delivery vehicle in a liquid formulation have multiple polymers, including poloxamers, and including a surfactant and/or co-surfactant. See prior art claims 1, 2, and 5. Further, the liquid composition can be a micellar dispersion. See prior art claim 11. Active substances can be formulated into the micellar dispersion. See par. 109. An appropriate liquid composition can include the non-ionic surfactant polysorbate 80. See par. 92.
The polymer combination forms a gel structure that can gel to enhance bioadhesiveness at the site of administration for a suitable period of time. It can bind to a mucosa or submucosa to allow bioadhesive targeting to control release of an active substance at a location and for a duration that is desirable. See par. 68. In one embodiment, the liquid becomes a gel at body temperature. See par. 71. A synergistic combination of poloxamers is taught to include, e.g., poloxamer 188 and poloxamer 407. See 84. Ferrari also explains that the dividing line between a microemulsion and a swollen micelle is not well defined. See par. 269.
The examiner notes that the prior art teaches compositions comprising the claimed components as well as the use of micelles and/or fine microemulsions. Even further, the ability to gel at an appropriate time to provide adherence to a mucoadhesive surface to release an active agent is also taught. Cannabidiol is taught for use and is taught as a most common medicinal chemical compound from cannabis.
Unexpected results are not alleged nor shown. As such, the examiner is determining if a prima facie showing is established in view of the cited prior art. In view of the teachings of compositions including compositions comprising micelles in liquid form that become a gel when contacting a desired location and wherein such compositions include an API, including cannabidiol, to remain in contact with a desired location to deliver an active agent to a subject, a prima facie showing is established.
Even further, the properties of the composition that are claimed are taught by the prior art and are taught to be modifiable by altering concentrations of the same. For example, Altuntas teaches developing a sol-gel mucoadhesive thermoreversible nasal gel that has a temperature tailored to prevent drainage of the formulation. Further, poloxamer 407 and a mucoadhesive polymer were used to gel below 34 degrees C in the nasal cavity. A favourable gelling temperature was approximately 30.1 degrees C and a mucoadhesion strength of about 2.9 was also developed. Concentration of P407 was optimizable as 18% PL407 was used and the gelation temperature correlation was determined. The amount used provided an optimum sol-gel temperature of 29.5 degrees C for nasal administration. See p2676. Gelation temperate and concentration of mucoadhesive polymer is shown in Figure 1. As concentration of mucoadhesive polymer increases, Tsol-gel decreased significantly from 50 degrees C to about 30 degrees C. Viscosity studies showed that the mucoadhesive polymer increased viscosity in a concentration-dependent manner. See p2677, 1st par. Mucoadhesive strength increased significantly as the mucoadhesive polymer increase from 0.15% to 0.35%. Formulations showed a mucoadhesive strength of 0.020 to 0.448 mJ. “Tsol-gel determination is a preliminary step in the formulation of thermoreversible gel (27). Zaki et al. (9) indicated the optimum Tsol-gel for nasal drug delivery as 25– 32°C.” See p2679, 4th full par. The hardness of the compositions ranged from about 4 to about 37 g; the adhesiveness ranged from approximately 0.09 to 1.6 mJ; and the cohesiveness ranged from approximately 0.2 to 1.2 mJ. Each of these parameters are optimizable through routine experimentation.
` Thus, the parameters appear to be achievable through routine optimization of known result-effective variables.
Applicant argues that the “deliberate” two-stage architecture claimed differs from that taught by the prior art.
The examiner notes that the prior art teaches liquid compositions comprising the claimed components and this includes those that are in micellar form, such as a micellular dispersion. The active agents can be formulated into the liquid composition in the form of a micellar dispersion. See par. 109. An increase in viscosity will slow down release and diffusion of the at least one active substance to prolong the therapeutic effect. See par. 115. The liquid composition can further comprise a surfactant, including a non-ionic surfactant. In view of the teachings of the prior art, when a liquid comprising the claimed components undergoes a phase transition, it would become a micellar dispersion, for example in the form of a gel because the liquid is taught to include a micellar dispersion.
Status of the Claims
Claims 1-11 and 13-22 are pending. Claims 17-21 are withdrawn. Claims 1-11, 13-16 and 22 are examined.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-11, 13-16, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Du et al., (CN110433133A) (cited in ISR), in view of Ferrari et al., (US20210154300) (filed December 12, 2021).
Du teaches a temperature sensitive gel for nasal administration of cannabidiol for targeting the brain to treat conditions such as PTSD and anxiety, among others. See Abstract. The temperature sensitive gel comprises poloxamer 407 and poloxamer 188. See Example 1. Further, glyceryl monooleate is used a non-ionic surfactant. The gel includes 15 to 35 parts water and 0.1 to 10 parts poloxamer 188 and 1 to 10 parts poloxamer 407. Cannabidiol can be present in an amount of 0.5 to 5 parts. A dosage can be 20 mg/ml (i.e., 2%) or 20 μl of unilateral nostril per day. A preparation includes a cannabidiol aqueous solution. Cannabinoids are known to have been isolated from plants and they include CBD, CBN, and CBG, among others.
Ferrari teaches a thermo-responsive gel in liquid formulation to deliver an active substance. See Abstract. The polymer can include those such as poloxamer 124, poloxamer, 188, poloxamer, 237, and poloxamer 338. See par. 10. The liquid composition can be suitable to be made to obtain a sol-gel transition composition. See par. 72. The transition can be at body temperature. See par. 74. The composition can comprise a non-ionic surfactant including: polyoxyethylene sorbitan fatty acid esters, such as polysorbate 20, polysorbate 60, polysorbate 80 and the like; polyoxyethylene alkyl ethers, such as PEG-20 cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1000 and the like; sorbitan fatty acid esters surfactants, such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate and the like. The composition can be a micellar dispersion and this can be a water based solution. Polymeric micelles are contemplated. See par.’s 49, 53, 7,3, 109, and prior art claim 11. Administration be through most routes of administration, including nasal and intranasal. See par. 10. Ferrari further teaches that the transition from a liquid to a gel enhance the bio-adhesiveness and enhancement to tissue adhesion of the mucosa or submucosa. See par. 76. The poloxamers used can be P188, P407 or a mixture, e.g. See par.’s 82-84. The polymer can be included in a concentration of 0.1 to 30%. See par. 86. Polysorbate 80 is a preferred non-ionic surfactant. See par. 92.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In this case, the claimed parameters are properties secondary to the components and percentages of those components used. Moreover, the claimed parameters are desired for administration of a sol-gel composition to gel and adhere to the nasal mucosa for a purpose of remaining at that location for a time to deliver an active agent. Not only is this taught, but the prior art provides a roadmap for the tunability and optimization of these parameters by modifying the concentrations of components- each of which are taught for use in a composition as described.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to combine the teachings of Du and Ferrari to arrive at the claimed methods. One would be motivated to do so because the prior art teaches a thermoreversible sol-gel comprising cannabidiol as an active agent delivered with a known thermoreversible poloxamer, including P407, P188, and each of those claimed. Moreover, the composition can include a plurality of micelles. Additionally, the claimed non-ionic surfactant is also taught for inclusion in the claimed composition. Not only are each of the claimed components taught, but a purpose for arriving at a claimed formulation is for the liquid to turn into a gel when administered to the nasal cavity to adhere to the nasal mucosa and remain there for a sufficient period of time to deliver an active agent. Thus, the claimed components are each known result effective variables that can be optimized through nothing more than routine experimentation to arrive at a composition with the claimed properties.
Claims 1-11, 13-16, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Du et al., (CN110433133A), in view of Ferrari et al., (US20210154300) (filed December 12, 2021), and in further view of Altuntas et al., “Formulation and Evaluation of Thermoreversible In Situ Nasal Gels Containing Mometasone Furoate for Allergic Rhinitis,” AAPS PharmSciTech, Vol. 18, No. 7, October 2017, and in view of Bodratti et al., “Formulation of Poloxamers for Drug Delivery,” J. Funct. Biomater. 2018, 9, 11.
Du teaches a temperature sensitive gel for nasal administration of cannabidiol for targeting the brain to treat conditions such as PTSD and anxiety, among others. See Abstract. The temperature sensitive gel comprises poloxamer 407 and poloxamer 188. See Example 1. Further, glyceryl monooleate is used a non-ionic surfactant. The gel includes 15 to 35 parts water and 0.1 to 10 parts poloxamer 188 and 1 to 10 parts poloxamer 407. Cannabidiol can be present in an amount of 0.5 to 5 parts. A dosage can be 20 mg/ml (i.e., 2%) or 20 μl of unilateral nostril per day. A preparation includes a cannabidiol aqueous solution. Cannabinoids are known to have been isolated from plants and they include CBD, CBN, and CBG, among others.
Ferrari teaches a thermo-responsive gel in liquid formulation to deliver an active substance. See Abstract. The polymer can include those such as poloxamer 124, poloxamer, 188, poloxamer, 237, and poloxamer 338. See par. 10. The liquid composition can be suitable to be made to obtain a sol-gel transition composition. See par. 72. The transition can be at body temperature. See par. 74. The composition can comprise a non-ionic surfactant including: polyoxyethylene sorbitan fatty acid esters, such as polysorbate 20, polysorbate 60, polysorbate 80 and the like; polyoxyethylene alkyl ethers, such as PEG-20 cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1000 and the like; sorbitan fatty acid esters surfactants, such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate and the like. The composition can be a micellar dispersion and this can be a water based solution. Polymeric micelles are contemplated. See par.’s 49, 53, 7,3, 109, and prior art claim 11. Administration be through most routes of administration, including nasal and intranasal. See par. 10. Ferrari further teaches that the transition from a liquid to a gel enhance the bio-adhesiveness and enhancement to tissue adhesion of the mucosa or submucosa. See par. 76. The poloxamers used can be P188, P407 or a mixture, e.g. See par.’s 82-84. The polymer can be included in a concentration of 0.1 to 30%. See par. 86. Polysorbate 80 is a preferred non-ionic surfactant. See par. 92.
Altuntas teaches developing a sol-gel mucoadhesive thermoreversible nasal gel that has a temperature tailored to prevent drainage of the formulation. Further, poloxamer 407 and a mucoadhesive polymer were used to gel below 34 degrees C in the nasal cavity. A favourable gelling temperature was approximately 30.1 degrees C and a mucoadhesion strength of about 2.9 was also developed. Concentration of P407 was optimizable as 18% PL407 was used and the gelation temperature correlation was determined. The amount used provided an optimum sol-gel temperature of 29.5 degrees C for nasal administration. See p2676. Gelation temperate and concentration of mucoadhesive polymer is shown in Figure 1. As concentration of mucoadhesive polymer increases, Tsol-gel decreased significantly from 50 degrees C to about 30 degrees C. Viscosity studies showed that the mucoadhesive polymer increased viscosity in a concentration-dependent manner. See p2677, 1st par. Mucoadhesive strength increased significantly as the mucoadhesive polymer increase from 0.15% to 0.35%. Formulations showed a mucoadhesive strength of 0.020 to 0.448 mJ. “Tsol-gel determination is a preliminary step in the formulation of thermoreversible gel (27). Zaki et al. (9) indicated the optimum Tsol-gel for nasal drug delivery as 25– 32°C.” See p2679, 4th full par. The hardness of the compositions ranged from about 4 to about 37 g; the adhesiveness ranged from approximately 0.09 to 1.6 mJ; and the cohesiveness ranged from approximately 0.2 to 1.2 mJ. Each of these parameters are optimizable through routine experimentation.
Even further, Bodratti teaches poloxamers exhibit an amphiphilic character in aqueous solution. “The association in aqueous solution of poloxamer unimers into micelles is well understood.” The micellization process commences when the PEO-PPO block copolymer concentration in solution reaches a certain critical micellization concentration (cmc) at a fixed temperature. Conversely, increasing the temperature to the critical micellization temperature (cmt) at a fixed block copolymer concentration also induces micellization. The temperature dependence of micellization can be interpreted and predicted by the use of a two-state model, which considers both polar and apolar interactions in the PEO and PPO segments [49]. The result of the reduced solubility is a microphase separation of the PPO blocks out of the aqueous environment and into the micelle core. Thus, the ability to form micelles as described by Ferrari is known and optimizable/achievable to a POSA.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In this case, the claimed parameters are properties secondary to the components and percentages of those components used. Moreover, the claimed parameters are desired for administration of a sol-gel composition to gel and adhere to the nasal mucosa for a purpose of remaining at that location for a time to deliver an active agent. Not only is this taught, but the prior art provides a roadmap for the tunability and optimization of these parameters by modifying the concentrations of components- each of which are taught for use in a composition as described.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to combine the teachings of Du, Ferrari, Altuntas and Bodratti to arrive at the claimed methods. One would be motivated to do so because the prior art teaches a thermoreversible sol-gel comprising cannabidiol as an active agent delivered with a known thermoreversible poloxamer, including P407, P188, and each of those claimed. Moreover, the composition can include a plurality of micelles. Additionally, the claimed non-ionic surfactant is also taught for inclusion in the claimed composition. Not only are each of the claimed components taught, but a purpose for arriving at a claimed formulation is for the liquid to turn into a gel when administered to the nasal cavity to adhere to the nasal mucosa and remain there for a sufficient period of time to deliver an active agent. Thus, the claimed components are each known result effective variables that can be optimized through nothing more than routine experimentation to arrive at a composition with the claimed properties. Even further, Altuntas teaches developing a sol-gel mucoadhesive thermoreversible nasal gel that has a temperature tailored to prevent drainage of the formulation. It uses P407 and describes advantages for arriving a compositions with the claimed properties. Altuntas also provides data indicating the hardness of the compositions range from about 4 to about 37 g; adhesiveness ranged from approximately 0.09 to 1.6 mJ; and cohesiveness ranged from approximately 0.2 to 1.2 mJ. Bodratti explains the ability and advantages of micelle formation with poloxamers through their self-assembly process in aqueous solution. Each of these processes/parameters are optimizable through routine experimentation with a reasonable and predictable expectation of success.
Conclusion
THIS ACTION IS MADE FINAL. 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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