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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/14/2025 has been entered.
Status of Claims
Amendments to filed on 11/14/2025 is acknowledged.
Claim 1 is amended. Claim 10 remains cancelled. Claim 8 is now cancelled. Claim 11-12 are new.
Claims 1-7, 9 and 11-12 are pending and being examined on the merits herein.
Priority
This instant application, filed 01/26/2023, claims domestic benefit to US provisional application 63/303250, filed 01/26/2022.
Information Disclosure Statement
The information disclosure statement (IDS), filed on 11/14/2025, is in compliance with the
provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the
Examiner.
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.
Claims 1-7, 9 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over to Allegrini et al. (WO2021089433, 05/14/2021, Record of 11/18/2024) in view of Williams et al. (WO2019051440, 03/14/2029, Record of 11/18/2024) and Baek at al. (WO2014073889, 05/15/2014, PTO-892).
Allegrini throughout the reference directs to a solid dispersion comprising a salt of ursolic acid (same as 3β-hydroxyurs-12-en-28-oic acid, Pg. 1, top paragraph), a phospholipid (a biological polymer), and one or more pharmaceutical or nutraceutical excipients (e.g., Abstract; Page 3, Lines 11-19).
Regarding instant claim 1, Allegrini points out that ursolic acid is classified as class IV molecule based on Biopharmaceutics Classification System (BCS) with poor water solubility and low membrane permeability, resulting in scarce bioavailability (Background, Page 1, Lines 11-14), although ursolic acid constitutes many bioactivities as a promising candidate for the nutraceutical market (Page 1, Lines 8-11) and pharmaceutical applications (Page 2, Lines 7-15). Allegrini indicates the solid dispersion process aims to improve ursolic acid solubility and bioavailability (Page 2, Lines 1-9). Thus, Allegrini teaches a process for preparing a solid dispersion of ursolic acid for improved therapeutic use.
Allegrini specifies that soluble and insoluble diluents, such as cellulose or cellulose ether polymers can be used as a type of excipients in the composition (Page 3, Lines 21-23) as shown in two exemplary embodiments containing a salt of ursolic acid, a phospholipid, cellulose or cellulose ether (Page 4, Line 4-Page 5, Line 4), while cellulose is a straight chain polymer, cellulose ether is known as a major class of water-soluble polymer. Therefore, Allegrini teaches instant claim 1 i) blending ursolic acid and a water-soluble polymer.
Allegrini describes the solid dispersion through a process comprises of: a-1) mixing the ursolic acid salt and a phospholipid in an alcohol to provide a suspension, b-1) heating the suspension obtained in previous step, c-1) removing the solvent (alcohol) to provide a solid dispersion SD. When the composition comprises adding one more excipient, the excipients can be added during step a-1) or optionally, at the end of step c-1) (Page 6, Lines 7-14; Page 8 Line 3-16).
Allegrini demonstrates the solubility of solid dispersion ursolic acid increases 2-13 folds in gastrointestinal fluids tested (Page 8 bottom-Page 9 top), thus the solid dispersion of ursolic acid has an increased bioavailability of at least two-folds over unprocessed material as instantly claimed.
Regarding instant claim 2, Allegrini discloses the exact same chemical structure of ursolic acid (Page 1, Lines 1-5) as recited.
Regarding instant claim 3, Allegrini states that salts of ursolic acid with alkali metals gain higher solubility than ursolic acid in solid dispersion (Page 3, Lines 3-10).
Regarding instant claim 6, Allegrini specifies the ursolic acid salt weight percentage as 16%-75% in the solid dispersion, preferably from 33% to 66%, or from 33-50%, or 50% (Page 6, Lines 3-6) (overlapping to ursolic acid amount about 5% to about 50% in instant claim 6).
Regarding instant claim 9, Allegrini demonstrates the solubility of solid dispersion ursolic acid increases 2-13 folds in gastrointestinal fluids tested (Page 8 bottom-Page 9 top), overlapping with bioavailability improved at least four folds over unprocessed material in instant claim 9.
Although Allegrini teaches solid dispersion of ursolid acid improves solubility, it does not teach the steps of ursolic acid solvent-free solid dispersion as recited in instant claim 1, and it does not expressly teach a water-soluble polymer with a glass transition temperature lower than 284 °C in the composition as recited in instant claim 1, or the species of water-soluble polymers as recited in instant claims 4-5 and its amount about 5% to about 50% as recited in instant claim 7. Allegrini does not teach the four heating zones as recited in instant claim 1, and does not specify the four heating zone overall temperature lower than 284 C as recited in instant claim 11 or each zone specific temperature range as recited in instant claim 12.
Williams throughout the reference teaches solid dispersion method through hot melt extrusion or fusion-based process free of solvent [0008, 0015] for improving compound solubility including BCS class IV molecules [0002-0003, 0009; Claims 15-16], such as poorly water-soluble lipophilic therapeutic agents [0065], while as evidenced by instant specification (Spec., Lines 9-10) ursolic acid is a naturally-derived lipophilic pentacyclic triterpene therapeutic agent.
Williams points out the increased risk of drug degradation when thermolabile drugs are processed above their melting point during the hot melt extrusion process (Page 2, Lines 24-26). It specifies that the thermal process is carried out at a temperature below the melting point of the therapeutic agent in some embodiments [0008, 0017]. Williams describes the hot melt extrusion (solid dispersion) method steps as following: the formulations were mixed until uniform using a mortar and pestle then heated at 150 °C for 10 minutes. The cooled sample was prepared by using a mortar and pestle to a uniform granule size. Then the formulation was processed utilizing the same conditions but then milled with a grinder to size the granulated/aggregated material obtained during the hot melt technique [0085]. These processes of solvent-free solid dispersion result in the four following steps: i) mixing the formulation (corresponding to instant claim 1 i), ii) melt extruding the mixture at 150 °C (corresponding to instant claim 1 ii), with overlapping with the melt extruding temperature about 50 °C to about 200 °C), iii) grinding the melt extrudate (corresponding to instant claim 1 iii), then iv) blending the milled extrudate (corresponding to blending the milled extrudate in instant claim 1 iv)).
Williams indicates that the extrudate comprising the therapeutic agent, mesoporous carrier, and polymer may be dried, formed, milled, sieved, or any combination of these processes to obtain a final composition, as routine and known processes in the art. Additionally, the extrudate may be milled and combined with one or more additional excipients to form the final composition [0081]. In other words, when there is additional excipient in the composition, step iv) above can be modified as following: iv) blending the milled extrudate with excipients to form a pharmaceutical composition (corresponding to blending the milled extrudate with excipients to form solid dispersion pharmaceutical composition in instant claim 1 iv)).
Williams specifies that heating and melting temperature of the composition can be 60-250 °C and many other temperatures can be used [0080], such as, 25-200 °C [0086], 50-180 °C [0097]. Williams describes the barrel configuration for processing the extrudates constituting four zones: a feed zone, closed barrel, closed venting zone, and a closed zone, mentioning the feeding zone is maintained at room temperature, while zones 1-3 for the barrel with temperatures at 160 °C before the extrudates are cooled to room temperature [0085, Table 2]. Since the highest melting temperature designated in solid dispersion taught by Williams is 250 °C as described above, the melting point of all the polymers mentioned in the list herein logically fall below 250 °C, lower than ursolic melting point 284 °C, corresponding to polymer glass transition temperature in instant claim 1 i).
Williams lists numerous proper cellulosic and non-cellulosic polymers for the composition including water-soluble polymers such as, polyvinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, hypromellose acetate succinate (same as hydroxypropyl methyl cellulose acetate succinate), and polymethacrylate or polyacrylate such as Eudragit® (e.g., [0072], [0073]), which read into instant claims 4 and 5.
Williams specifies the therapeutic agent amount is present in the composition at a level between about 50% to 98% w/w, between about 50% to 90% w/w, between about 50% to 80% w/w, between about 50% to 75% w/w, or between about 50% to 60% w/w of the total composition [0064], and Williams states about 1-49% polymer amount in the composition [0012, 0019] (overlapping to polymer amount about 5% to about 50% in instant claim 7).
Baek throughout the reference teaches solid dispersions of insoluble drug and preparation method comprising active drug, carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester, and a water-soluble polymer having a glass transition temperature lower than the melting point of the active ingredient as a carrier and it is prepared via melt extrusion. The solid dispersion remarkably increases the solubility and dissolution rate of the active ingredient which is an insoluble drug to efficiently improve the bioavailability (e.g. Abstract).
Baek teaches that the active ingredient is prepared in a solid dispersion with water soluble polymer having the glass transition temperature lower than the melting point of the active ingredient as a carrier (e.g., Claim 1; Claim 9), such as polyvinylpyrrolidone, hydromellose acetate succinate and their combination (Claim 3), wherein the water-soluble polymer is at 30 wt % or more (Claim 4) and the active ingredient is 10 to 50% of the total weight of the composition (Claim 7). Baek specifies that the step of melt-extruding the mixture at a temperature lower than the melting point of the active ingredient (Claim 13), and the melted mixture of the composition passes through four or more heating blocks whose temperature is sequentially lowered (Claim 15) (corresponding to the melted blend passes through at least four heating zones connected in series as recited in instant claim 1 ii)), wherein the heating blocks consist of the first to the fourth heating blocks wherein the melting temperature of the first heating block is controlled to 160 to 145°C, that of the second heating block to 144 to 120°C, that of the third heating block to 119 to 80°C, and that of the fourth heating block to 79 to 70°C (Claim 16), corresponding to a temperature of the heating zone is sequentially lowered while the blend passes sequentially through the at least four heating zones as recited in instant claim 1 ii), and evidently all four heating zones is controlled to a temperature lower than 284 C as recited in instant claim 11, while 284 C is the melting point of the active ingredient ursolic acid; and reading all temperature ranges exactly into the ranges in instant claim 12.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective
filing date to incorporate specific water-soluble polymers and steps taught in Williams and Baek into the ursolic acid solid dispersion composition from Allegrini to arrive at current invention. It would have been prima facie obvious for one of ordinary skill in the art to combine the prior art elements to modify the ursolic acid solid dispersion preparation with the known solvent-free solid dispersion method because ursolic acid belongs to lipophilic agents suitable for the method as taught by Williams and the solvent-free method taught by Williams and Baek do not require tedious solvent removal step in Allegrini method. One of ordinary skill in the art would have a reasonable expectation of success because all solid dispersion methods taught by prior art yield predictable results of increased solubility and bioavailability, while Williams and Baek provide step by step process with specific water-soluble polymers and temperature ranges in solvent-free solid dispersion process that would facilitate the process of solvent-free solid dispersion. This renders obviousness as “use of known technique to improve similar devices (methods, or products) in the same way” or as “applying a known technique to a known device (method, or product) ready for improvement to yield predictable results”. See MPEP §2143. (I)(C) and (I)(D). Moreover, It is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use (MPEP §2144.07). See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
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. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP §2144.05(I) states that “A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.” See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003), "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” Also see in re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). For this instance, melt extruding the mixture temperature, ursolic acid weight amount, polymer weight amount overlap with those taught in prior art. Furthermore, “[i]t would have been prima facie obvious for one of ordinary skill in the art to optimize additive amount through nothing more than “routine experimentation,” because of a reasonable expectation of success resulting from the optimization for desirable features of intended use of the composition (MPEP §2144.05 (II)). See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Response to Arguments
Applicant remarks filed on 11/14/2025 have been fully considered.
The argued subject matter regarding that Allegrini and Williams fail to teach sequentially lowering the temperature in heating zones connected in series, as indicated in amended claims filed on 11/14/2025, is addressed in this office action as presented above with additional prior art Baek.
Please take the entire office action above as a complete response to the remarks.
Conclusion
No claim is allowed.
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/DX.Z./Examiner, Art Unit 1616
/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616