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 .
Summary
Receipt of Applicant’s Preliminary/Remarks and Amendments filed on 10/29/2024 is acknowledged. Claims 1-3, 5, 7, 9, 11, 12, 14, 17, 19-20, 22-24, 26, and 28-31 are pending. Claims 4, 6, 8, 10, 13, 15-16, 18, 21, 25, 27, and 32-33 have been cancelled. Claims 1-3, 5, 7, 9, 11, 12, 14, 17, 19-20, 22-24, 26, and 28-31 are pending and under examination in this application.
Priority
This application is a continuation of prior Application No. 17/320,945, filed May 14, 2021, which was published as U.S. Patent Application Publication No. US 2022/0062223 on March 3, 2022, and which is a Section 371 U.S. National Stage of International Application No. PCT/IB2019/001381, filed November 8, 2019, which was published as International Publication No. WO/2020/099937 on May 22, 2020, and which claims the benefit of U.S. Provisional Application No. 62/767,197, filed November 14, 2018.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 5 and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites that “the matrix material comprises an amphiphilic block copolymer.” Claim 1, from which claim 5 depends, defines the matrix material by a closed Markush group (“selected from the group consisting of…”). The specification (p. 4, ll. 20–24) defines “amphiphilic block copolymer” by example as polystyrene-block-polyethylene glycol (PS-b-PEG), polylactic acid-block-polyethylene glycol (PLA-b-PEG), and poly(lactic-co-glycolic acid)-block-polyethylene glycol (PLGA-b-PEG) — none of which are recited, as such block copolymers, in claim 1’s Markush group. It is therefore unclear what species of matrix material claim 5 is intended to cover: if “amphiphilic block copolymer” is intended to be limited to a species already present in claim 1 (e.g., a poloxamer, which is a polyoxyethylene-polyoxypropylene block copolymer), the claim should be amended to clarify this; if it is intended to reach the PEG-block copolymers described in the specification, those species do not fall within claim 1’s closed group, rendering the metes and bounds of claim 5 unclear.
Claim 24 recites “the polymer matrix material,” but claim 1, from which claim 24 depends, establishes only “a matrix material” (not “a polymer matrix material”) and antecedent basis for “the polymer matrix material” does not otherwise appear in the claim. Moreover, claim 1’s Markush group encompasses non-polymeric species (e.g., N-methyl-2-pyrrolidone, polyoxyethylene sorbitan monooleate), so “the polymer matrix material” cannot be presumed to refer back to “the matrix material” of claim 1 without further clarification. It is unclear whether claim 24 is intended to (a) further limit the matrix material of claim 1 to a polymeric species, or (b) refer to a separate, unclaimed polymer matrix material. Clarification and correction of antecedent basis is required.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. As discussed above, claim 5’s recitation of “an amphiphilic block copolymer” is not clearly a species falling within claim 1’s closed Markush group for “matrix material,” and thus does not clearly further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. For example, Applicant may cancel this rejection by amending claim 5 to expressly tie the amphiphilic block copolymer limitation to a species already recited in claim 1 (e.g., the poloxamer), or by adding the relevant PEG-block copolymer species to claim 1’s Markush group.
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.
Claim(s) 1-3, 5, 7, 9, 11, 12, 14, 17, 19-20, 22-24, 26, and 28-31 are rejected under 35 U.S.C. 103 as being unpatentable over Babcock et al. (US 8,703,196 B2) hereinafter (“Babcock”) in view of Xu (CN 104666293 A), Hoerr et al. (US 2016/0235677 A1) hereinafter (“Hoerr”), Aungst (The AAPS Journal, Vol. 14, No. 1 (2012)), and further in view of Spray Drying in Pharmaceutical Industry: A Review, hereinafter (“Spray Drying”) and further in view of Powell (US 9,962,365 B2) and Brugel (US 9,492,550 B2).
Scope of prior art references:
Babcock teaches dispersions of the drug and matrix comprising mechanical, thermal, and solvent processes wherein mechanical processes include milling and extrusion; melt processes include high temperature fusion, solvent processes include non-solvent precipitation, spray coating and spray drying (col. 102, lines 7-15).
Xu teaches a preparation method directed to dihydromyricetin cyclodextrin inclusion compound wherein the method can be applied to food, medicine and health care products industries (p. 1, Technical field para.). Xu fails to teach HPMCAS as a matrix material, a permeabilizer, or supersaturation/solubility behavior in fed state simulated intestinal fluid (FeSSIF); these teachings are supplied by Babcock, Aungst, and Hoerr, respectively, as set forth below.
Hoerr teaches a method of making a poorly water soluble crystalline compound an amorphous compound, wherein the method comprises dissolving the crystalline compound and a polymer in a solvent to form a solution, electro-spraying the solution using an electrospray device, collecting the nanoparticles (0013).
Aungst teaches absorption enhancers are functional excipients included in formulations to improve the absorption of a pharmacologically active drug (abstract).
The article of interest, “Spray Drying” disclose manufacturing technique for the pharmaceutical industry since it uses a one-step process for formation and drying of powders, wherein the advantages are to transform the active pharmaceutical ingredients in a powder and to manufacture solid dosage forms containing peptides, proteins or poorly water soluble active pharmaceutical ingredients (introduction para.). Notably, Spray drying can be used to enhance the solubility and dissolution rate of poorly soluble drugs and this usually occurs via the formation of pharmaceutical complexes or via the development of solid dispersions (p. 78, Increased bioavailability para.).
Powell teaches a composition comprising dihydromyricetin (DHM) further comprising N-acetyl cysteine (NAC), and teaches that the composition can further include Prickly Pear Extract, Milk Thistle, Ginger Root, and Vitamins B, C, and E (Abstract; col. 1, lines 59 to col. 2, lines 54).
Brugel teaches that HPMC-AS (HPMCAS) is unique among matrix materials in its ability to inhibit the precipitation or crystallization of a broad range of sparingly soluble drugs from a supersaturated solution (col. 15, ll. 24–30).
Regarding claim 1, Babcock teaches the matrix material comprises a concentration-enhancing ionizable cellulosic polymer selected from a group including hydroxypropyl methyl cellulose acetate succinate (HPMCAS), cellulose acetate succinate, methyl cellulose acetate succinate, and numerous other cellulosic species substantially overlapping the instant Markush group (col. 4, l. 49 – col. 5, l. 14). Xu teaches dissolving dihydromyricetin (DHM) in a solvent (including acetone, ethanol, methanol, or water) to prepare a DHM solution and processing it via a spray drying process with a spray tower to form a solid powder (p. 2, Summary of the Invention; p. 5, Examples 6–7). Spray Drying teaches the general process of atomizing a liquid feed formulation into a hot drying medium, with droplets dried via solvent evaporation to form a collected dry powder (p. 74, Spray Drying Process para.).
It would have been prima facie obvious to one of ordinary skill in the art to prepare DHM in a pharmaceutically acceptable cellulosic matrix as taught by Babcock, using the spray drying process taught by Xu and Spray Drying, because all references are drawn to forming solid dispersions or powders of poorly water-soluble actives (here, DHM) via matrix materials and spray drying, with a reasonable expectation of success, and because combining known prior art elements according to known methods to yield predictable results is prima facie obvious. See MPEP § 2141(III)(A).
Regarding claims 2 and 3, Babcock explicitly teaches the cellulosic matrix material comprising HPMCAS (col. 4, l. 49 – col. 5, l. 14).
Regarding claim 5, Babcock teaches an amphiphilic block copolymer as a matrix material (col. 111, l. 65 – col. 112, l. 4; col. 112, l. 67 – col. 113, l. 2).
Regarding claim 7, Aungst teaches sodium caprate as a permeabilizer and absorption enhancer included in a solvent to improve absorption of a pharmacologically active drug (p. 14, left col., paras. 1–2). It would have been obvious to incorporate Aungst’s sodium caprate permeabilizer into the DHM/HPMCAS spray-dried composition of Babcock/Xu to improve the intestinal absorption of DHM, a compound already known in the art (per the instant specification and Xu, background section) to suffer from poor bioavailability.
Regarding claim 9, in addition to above, Powell further teaches that NAC may be replaced with a functional substitute such as L-Glutathione (col. 5, ll. 30–36: “the NAC (e.g., or any of its functional substitutes such as SAM-e or L-Glutathione, or other)”). Notably, the instant specification’s own background (Bibliography, ref. 1) cites the related U.S. Patent 9,603,830 B2, of the same assignee (Thrive+ Health, Inc., formerly ThrivePlus LLC), as disclosing a marketed DHM formulation (“Thrive+”), evidencing that this family of DHM/coactive compositions was already known to those in the art, including the applicant, prior to the effective filing date. It would have been prima facie obvious to one of ordinary skill in the art to incorporate the coactive combination of NAC (or its art-recognized functional equivalent, glutathione), Prickly Pear extract, Milk Thistle, Ginger Root, and Vitamins B, C, and E, as taught by Powell, into the DHM/HPMCAS spray-dried dispersion powder of Babcock, Xu, Hoerr, and Aungst, because Powell demonstrates that these specific coactives were already recognized in the art as beneficial companions to DHM for the identical purposes recited in the instant claims (antioxidant support, liver protection, and mitigation of oxidative stress associated with alcohol consumption), with a reasonable expectation of success in combining them with a spray-dried DHM/HPMCAS matrix.
Regarding claim 11, Babcock teaches a pH buffering agent — phosphate buffered saline (PBS) adjusted to pH 6.5 with NaOH (col. 120, l. 56 – col. 121, l. 5).
Regarding claim 12, Hoerr teaches amorphous nanoparticle dispersions preferably exhibiting supersaturation in a biorelevant fluid (e.g., FeSSIF) having a pH of at least 6.5 (¶0083), i.e., increased solubilization at higher (intestinal-range) pH. The complementary teaching that such enteric/ionizable cellulosic matrix materials (e.g., HPMCAS, as taught by Babcock) are, by their known chemical nature, insoluble at low (gastric) pH and soluble at neutral-to-alkaline pH is well understood in the art of enteric formulation and provides the motivation and reasonable expectation of success for a formulation not solubilized at pH ≤ 3.5 but solubilized at pH ≥ 5.5.
Regarding claim 14, Babcock teaches that the drug in the dispersion can be “almost completely amorphous,” meaning at least 90% of the drug is amorphous as measured by PXRD or DSC (col. 99, ll. 26–38), which reads on a crystallinity of at most 10%. The DHM loading of at least 40 wt% is a result-effective variable optimizable through routine experimentation to balance dose/bioavailability, particularly where Xu’s own examples already employ high proportional DHM loadings in a solvent-dissolved system.
Regarding claim 17, Babcock teaches the amorphous drug/matrix dispersion as a solid solution with drug homogeneously distributed throughout the dispersion (col. 99, ll. 26–38).
Regarding claim 19, “Spray Drying” teaches matrix microcapsules containing a drug substance and biodegradable/polymeric matrix prepared by spray drying to obtain controlled-release dosage forms, i.e., an encapsulated dosage form (p. 77, Encapsulation para.). Xu teaches DHM is developed into capsule and tablet dosage forms (p. 1, Background). Babcock’s HPMCAS and crystallinity teachings (as applied above) complete this combination.
Regarding claims 20, 22, and 23, Hoerr teaches amorphous nanoparticles preferably exhibiting supersaturation in a biorelevant fluid for a period of 60–300 minutes, at a pH of at least 6.5 (¶0083), and specifically in fed state simulated intestinal fluid (FeSSIF) (p. 5, ¶0083). This reads on a solvent-mixing result exceeding equilibrium crystalline solubility, in an aqueous solvent within the claimed pH range, using FeSSIF.
Regarding claim 24, as noted above, Brugel teaches that HPMC-AS (HPMCAS) is unique among matrix materials in its ability to inhibit the precipitation or crystallization of a broad range of sparingly soluble drugs from a supersaturated solution, and further teaches that spray drying effects rapid solvent removal such that “even phase separation of amorphous drug and the HPMC-AS polymer can largely be prevented or minimized” (col. 15, ll. 30–38). It would have been prima facie obvious to one of ordinary skill in the art to expect that the spray drying process applied to the DHM/HPMCAS composition of Babcock, Xu, Hoerr, and Aungst would exhibit the polymer-gelation-without-phase-separation behavior taught by Brugel as an inherent and well-understood property of HPMCAS-based spray-dried dispersions processed by rapid solvent evaporation, since Brugel’s teaching describes a fundamental physicochemical characteristic of the identical polymer (HPMCAS) under the identical process (spray drying) already relied upon in the base combination, with a reasonable expectation of success.
Regarding claim 26, Xu teaches DHM dissolved in a solvent selected from pure water, ethanol, methanol, and acetone or combinations thereof (p. 2, Summary of the Invention), and Babcock’s teaching of HPMCAS as the matrix material, combined with a motivation toward higher solids loadings for scalable, efficient production (an objective articulated generally in spray-drying process art), would have suggested optimizing total solids concentration and DHM:HPMCAS ratio through routine experimentation.
Regarding claims 28–31, Xu’s background section teaches that DHM has recognized effects including free radical scavenging, antioxidant activity, anti-tumor activity, anti-inflammatory activity, prevention of alcoholism/fatty liver, reduction of liver cancer incidence, liver protection, antibacterial activity, and regulation of blood sugar (p. 1, Background Technique). Powell similarly teaches DHM's use to combat oxidative stress and promote liver functionality in a composition addressing hangover and alcohol-related symptoms (Abstract; col. 5, ll. 10–36). These teachings directly correspond to the claimed therapeutic uses of claims 28–30 (reducing hangover symptoms, treating/preventing alcohol use disorder or overdose, and increasing antioxidant capacity) and, for claim 31, to the claimed anti-inflammatory effect, cancer, metabolic disorder/diabetes, bacterial infection, and liver protection limitations. Neither Xu nor Powell expressly teaches neuroprotection, Alzheimer's disease, or kidney protection. Nonetheless, it would have been prima facie obvious to one of ordinary skill in the art to expect DHM's art-recognized free-radical-scavenging and antioxidant activity (Xu, p. 1, Background Technique) to extend to neuroprotective and anti-Alzheimer's applications, since oxidative stress and free radical damage are well-understood mechanistic contributors to neurodegenerative disease, and antioxidant compounds are routinely evaluated for such applications as a predictable extension of their known activity, with a reasonable expectation of success. Similarly, it would have been obvious to expect DHM's demonstrated hepatoprotective activity (Xu; Powell) to extend to renal protection, as the liver and kidney share overlapping detoxification and antioxidant defense functions, such that an agent protecting one organ from oxidative or toxic insult would be expected to confer an analogous protective effect on the other.
One of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention from the combined teachings of these references, all of which are drawn to solid dispersions, spray drying processes, matrix materials, permeability enhancers, and/or DHM itself and its known therapeutic effects.
Conclusion
No claims are allowed.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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