031576DETAILED 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 .
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 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.
Priority
The instant application 18/031,576, filed 04/12/2023, is a 371 National Stage Entry of International Patent Application No. PCT/EP2021/078288, filed 10/13/2021, and claims foreign priority to BE 2020/5710, filed 10/13/2020.
Status of Application and Claims
The preliminary amendment filed 10/03/2023 is acknowledged. Claims 1-16 and 18-21 are currently amended. Claims 17 and 22-25 are canceled. Claims 1-16 and 18-21 are currently pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-16, in the reply filed on 08/15/2025 is acknowledged. The traversal is on the grounds that, as Applicant submits, patent statutes authorize, but do not require, restriction to a single disclosed species if two or more independent and distinct species are claimed in one application. Applicant states that, in view of the related technology of the groups and in view of the expense imposed upon the Applicant by multiple applications for patents, a withdrawal of the restriction requirement is requested (see Applicant’s Reply filed 08/15/2025, pages 1-2).
This is not found persuasive because, as reiterated from the office action dated 05/27/2025, the groups of inventions do not relate to single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical feature which makes a contribution over the prior art in view of Sermkaew. Accordingly, unity of invention is lacking (see office action dated 05/27/2025 pp. 3-4) and restriction is appropriate. Regarding the expense of filing multiple applications, Examiner wishes to reassure the Applicant that, where applicant elects claims directed to the product and all product claims are found allowable, withdrawn process claims that include all the limitations of the allowable product will be considered for rejoinder. See office action dated 05/27/2025 p. 6 for more information regarding the possibility of rejoinder.
Applicant’s election of single species of labdane diterpene (andrographolide), amino acid (glycine), peptides and polypeptides (aspartame), proteins (collagens and/or collagen hydrolysates), oligosaccharides (cyclodextrins), non-cellulose polysaccharides (starches), and plasticizing agent (glycerol) in the reply filed on 08/15/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement regarding the species election, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The restriction requirement is still deemed proper and is therefore made FINAL.
Claims 18-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 08/15/2025.
Claims 1-16 are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/12/2023 and 05/23/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Interpretation
Claim 1 is written towards a “composition in the form of a thermoformed extrudate comprising at least one labdane diterpene and at least one natural or synthetic polymer” (see at least instant claim 1 line 1). The instant specification defines the term “thermoformed extrudate” to mean “a material which exits from equipment, in particular which exits from an extruder, wherein it has undergone a transformation by the effect of heat” (see instant specification [0030]). Therefore, the recitation of the composition being “in the form of a thermoformed extrudate” is being interpreted as a recitation regarding the process from which the instantly claimed composition is made. Because the term “thermoformed extrudate” is defined by a process of forming the composition, claims 1-16 are being interpreted as product-by-process claims in relation to a composition (product) which comprises at least one labdane diterpene and at least one natural or synthetic polymer as defined by the claims. Per MPEP 2113 (I), product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). There does not appear in the instant disclosure to be any particular structure implied by the step of thermoform extrusion, and therefore, the recitation that the composition is in the form of a “thermoformed extrudate” does not impart further structural limitations to the claimed composition comprising at least one labdane diterpene and at least one natural or synthetic polymer.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 5-12 and 14-16 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 1 recites “at least one natural or synthetic polymer selected from the group consisting of amino acids…” etc, in lines 2-3. This recitation is unclear, because amino acids are small molecules, not natural or synthetic polymers; therefore, it is unclear if the amino acids in the composition are in polymeric form or present as small molecules in the composition.
Claims 1, 6-9, 11-12, and 14-16 all recite “derivatives thereof” in the final line of the claim after reciting a list of species within the Markush groups of each claim. It is unclear based on the claims and the instant disclosure as to what extent each recited species may be derivatized while still being encompassed by the claimed term of “derivatives thereof.” Therefore, the term “derivatives thereof” is considered indefinite.
Claim 5 recites that the labdane diterpene “comprises between 51% and 100% by mass of an amorphous phase” and “between 0 and 49% of a crystalline phase.” It is unclear what these percentages are based off of; i.e., is the “51% and 100% by mass of amorphous phase” by mass of the entire composition, or by the mass of the labdane diterpene; similarly, is the “0 and 49% of a crystalline phase” by mass of the entire composition, or by mass of the labdane diterpene? For the purposes of compact prosecution, these recitations of percentages will be interpreted as percentages in relation to the total mass of the labdane diterpene.
Claims 9-10 recite the term “collagens and/or collagen hydrolysates” in the second and third lines. The phrase “and/or” renders the claims indefinite because it is unclear if the limitations following the phrase should be considered as optional, or part of the claimed invention. Any claimed limitations following recitation of the phrase “and/or” will be interpreted as being optional limitations recited in the alternative, and not required for the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 6-12, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sermkaew, N. et al. (2013). “Liquid and solid self-microemulsifying drug delivery systems for improving the oral bioavailability of andrographolide from a crude extract Andrographis paniculata,” European Journal of Pharmaceutical Sciences, 50 (3), pp. 459-466 (cited in IDS 05/23/2023).
Sermkaew teaches a liquid self-microemulsifying drug delivery system (SMEDDS) composed of A. paniculata extract containing andrographolide (Abstract). Sermkaew teaches extrusion and spheronization of the SMEDDS mixed with excipients, including pregelatinized starch and microcrystalline cellulose, in order to form pellets (2.4.1. “Preparation of SMEDDS pellets of A. paniculata extract”). Andrographolide reads on the Applicant’s elected species of labdane diterpene recited in instant claims 1 and 6, and pregelatinized starch reads on the Applicant’s elected species of natural or synthetic non-cellulose polysaccharide recited in instant claims 1 and 12. Because claim 1 recites a Markush group which only requires the presence of at least one natural or synthetic polymer from the group including natural or synthetic non-cellulose polysaccharides, claims 7-11 are satisfied. As defined in the instant specification, microcrystalline cellulose is a lubricating agent (see instant specification [00122]) and reads on the additive of claim 15. The extrusion/spheronization technique produces a pellet product that reads on an extrudate, and, as reiterated in the Claim Interpretation section above, the instantly claimed composition being in the “form of a thermoformed extrudate” does not appear to impart any structural limitations to the claimed composition. The claimed product-by-process is therefore satisfied by the extrudate of Sermkaew.
Thus, Sermkaew anticipates instant claims 1, 6-12, and 15.
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.
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 1-12 are rejected under 35 U.S.C. 103 as being unpatentable over Song, B. (2019). “Andrographolide solid dispersions formulated by Soluplus to enhance interface wetting, dissolution, and absorption,” J. Appl. Polym. Sci. 48564 (cited in PTO-892) in view of CN 106727343 A (Yao, W. et al.) published 05/31/2017 (cited in PTO-892).
Song teaches preparation of an andrographolide (ADG) solid dispersion via hot-melt extrusion (p. 1 R. Col. 2nd para). Song teaches solid dispersion is designed as drug dispersion system wherein the drug is highly dispersed in a suitable solid carrier, which can effectively change drug physical state from crystalline to amorphous phase owing to the advantages of carriers in enlarging surface area and interacting with drug molecules (p. 1 L.-R. Col bridging para). Song teaches many polymers, including polyoxyethylene, pyrrolidone K30, polyethylene glycol, Eudragit, hydroxy propyl cellulose, poloxamer, and Soluplus have been considered as excipients for forming the dispersion (p. 1 R. Col. 1st para). Song teaches that solid dispersions formulated with the ADG exhibit XRD spectra which demonstrate that the carrier is efficient in transforming drug crystal state to amorphous phase by interacting with the ADG; amorphous ADG has stronger energy than crystal ADG, which means it can be better wetted and released from the solid dispersion carrier (p. 5 “X-Ray Diffraction”). Song’s hot-melt extrusion product being an andrographolide solid dispersion reads on the composition comprising at least the labdane diterpene of claims 1 and 6, and the characteristics of the extrudate in claim 2. Because the labdane diterpene is amorphous in Song’s solid dispersion, claims 4 and 5 are read upon (because an entirely amorphous ADG necessarily has 100% by mass of an amorphous phase). The instant specification defines a “glassy structure” as recited in claim 3 to mean a structure comprising/being formed by a molecular mixture of at least two
compounds/molecules, at least one of these two compounds/molecules being presented at least partially in a non-crystalline form, in particular being presented at least partially in
amorphous form (instant specification [0043]). Therefore, the glassy structure of claim 3 is read upon by Song because the ADG is present in the solid dispersion in an amorphous form.
Song differs from the instantly claimed invention in that it fails to teach that the at least one natural or synthetic polymer in the composition is from the group consisting of amino acids, natural or synthetic peptides and polypeptides, natural or synthetic proteins, natural or synthetic oligosaccharides, natural or synthetic non-cellulose polysaccharides, derivatives thereof and mixtures thereof, as recited in claim 1. Thus, Song fails to teach the polymer is the applicant’s elected species of natural or synthetic non-cellulose polysaccharide selected from the group including starches, as recited in claim 12. Song also fails to teach the limitations of claims 7-11.
Yao teaches a green and environmentally friendly solid dispersion with porous starch as carrier, which can improve the solubility of poorly soluble drugs ([0002]). Yao teaches the poorly soluble drug is andrographolide ([0038]). Yao teaches the solid dispersion having porous starch as carrier is green, environmentally friendly, easy to industrialize, eliminates the use of organic reagents, and provides a simple and safe method for achieving large-scale preparation ([0029]-[0031]). Yao teaches that preparation of the solid dispersion includes uniformly distributing the drug component on the surface and in the pores of the porous starch at least by physical mechanical force, but is not limited thereto ([0047]).
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to use porous starch as carrier in place of the Soluplus carrier of the solid dispersion of Song, and arrive at the instantly claimed invention. Per MPEP 2143 I(F), known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art. The ordinarily skilled artisan would have been motivated by the market forces and design incentives of using porous starch as carrier in Song’s solid dispersion, these incentives being greenness, environmental friendliness, ease of industrialization, elimination of the need for organic reagents, and provision of a simple and safe method for achieving large-scale preparation. Song establishes that many different polymers may be employed as carrier in its andrographolide-containing solid dispersion formed via hot-melt extrusion, and Yao establishes that porous starch is a carrier for andrographolide solid dispersions which can withstand physical mechanical forces during formation of solid dispersions with andrographolide. The ordinarily skilled artisan could have used these teachings, in view of the identified design incentives or other market forces, and could have implemented the claimed variation of the prior art (replacing the Soluplus carrier of Song with the porous starch carrier of Yao), and the claimed variation would have been predictable to one of ordinary skill in the art because there are no apparent deleterious effects of substituting the polymer carrier in the solid dispersion of Song. In performing this modification, the limitations surrounding the polymer within the composition of instant claims 1 and 12 are met, as well as the limitations of instant claims 7-11 (because the Markush group regarding the polymer of claim 1 is satisfied by the porous starch, and claims 7-11 only disclose further limitations of the Markush group of claim 1 which are not required to meet the claim limitations).
Claims 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Song, B. (2019). “Andrographolide solid dispersions formulated by Soluplus to enhance interface wetting, dissolution, and absorption,” J. Appl. Polym. Sci. 48564 (cited in PTO-892) in view of CN 106727343 A (Yao, W. et al.) published 05/31/2017 (cited in PTO-892), as applied to claims 1-12 above, and further in view of Li, Y. et al. (2013). “Interactions between drugs and polymers influencing hot melt extrusion.” Journal of Pharmacy and Pharmacology, 66, pp. 148-166 (cited in PTO-892), as evidenced by Eccles, R.; Mallefet, P. (2017) “Soothing Properties of Glycerol in Cough Syrups for Acute Cough Due to Common Cold” Pharmacy, 5(4) (cited in PTO-892).
The teachings of Song and Yao, as they pertain to instant claims 1-12, are addressed supra.
The collective references differ from the instantly claimed invention in that they fail to teach that the composition further comprises at least one plasticizing agent, particularly the Applicant’s elected species of plasticizing agent glycerol, as recited in instant claims 13 and 14. The collective references also fail to teach the composition further comprises at least one additive selected from a group which includes lubricating agents, as recited in instant claim 15.
Li teaches that, to obtain an amorphous solid dispersion product, hot-melt extrusion (HME) needs to be processed at enough high temperature for the purpose of softening the polymer or keeping it at a flowing state to facilitate the dispersion of drug molecules, however, high temperature increases the risk of thermal degradation of both drug and polymer; the intermolecular interactions between drug and polymer may lower the processing temperature through depressing the melting point of the drug or lowering the viscosity of the polymer (p. 149 R. Col. “Improving manufacturability through drug-polymer interactions”). Li teaches that plasticizer is always used to depress the processing temperature by reducing glass transition temperature and viscosity of polymer during pharmaceutical hot melt extrusion; conventional plasticizers used in pharmaceutical HME include glycerol (p. 150 R. Col. “Plasticizing effect of drug on polymer” 1st and 2nd paras). As evidenced by Eccles, glycerol is a lubricant as well as a plasticizer, as it decreases friction between moving surfaces (p. 2 2nd para).
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to incorporate a plasticizer such as glycerol into the mixture rendered obvious by the teachings of Song and Yao, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to do so because the composition taught by the combination of Song and Yao forms a solid dispersion product via hot melt extrusion, which, as taught by Li, has a risk of thermal degradation of both drug and polymer; therefore, the mixture being hot-melt extruded would benefit from the inclusion of a plasticizer, such as glycerol, in order to depress the processing temperature and therefore mitigate any issues surrounding drug or polymer degradation during the hot melt extrusion process. The ordinarily skilled artisan would have a reasonable expectation of success incorporating glycerol as plasticizer and lubricant into the mixture being hot melt extruded because glycerol is a plasticizer known in the art to be commonly employed during pharmaceutical hot melt extrusion.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Song, B. (2019). “Andrographolide solid dispersions formulated by Soluplus to enhance interface wetting, dissolution, and absorption,” J. Appl. Polym. Sci. 48564 (cited in PTO-892) in view of CN 106727343 A (Yao, W. et al.) published 05/31/2017 (cited in PTO-892), as applied to claims 1-12 above, and further in view of WO 2016/045902 A1 (Bansal, V. et al.) published 03/31/2016 (cited in PTO-892).
The teachings of Song and Yao, as they pertain to instant claims 1-12, are addressed supra. Song also teaches that andrographolide in solid dispersion form is orally bioavailable for many pharmacological actions (p. 1 L. Col. 1st para).
The collective references differ from the instantly claimed invention in that they fail to teach the composition further comprises at least one first additional compound of the polyphenol type selected from the group consisting of phenolic acids, stilbenes, phenolic alcohols, lignans, flavonoids, derivatives thereof, and mixtures thereof, as recited in claim 16.
Bansal teaches an oral anti-aging composition comprising resveratrol and an extract of Andrographis paniculata, wherein the composition comprises andrographolide and a daily dosage of resveratrol (p. 3 lines 6-11). Bansal teaches that the combination of resveratrol and aqueous extract of Andrographis paniculata synergistically up-regulates HO-1 protein levels in primary human dermal fibroblast cells (p. 7 lines 1-5). Bansal teaches that the composition is for use in evening skin tone, or treating or preventing hyperpigmentation (p. 3 lines 16-17). As evidenced by the instant specification, resveratrol is a stilbene (instant specification [00127]).
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to add an effective amount of resveratrol to the composition rendered obvious by Song and Yao, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to do so in order to harness the synergistic effects of andrographolide and resveratrol in the resulting oral composition, particularly their up-regulation of protein levels in primary human dermal fibroblast cells for evening skin tone, or treating or preventing hyperpigmentation. The ordinarily skilled artisan would have a reasonable expectation of success incorporating resveratrol into the composition rendered obvious by Song and Yao because the composition of Song and Yao is useful for oral bioavailability of andrographolide, and Bansal demonstrates the synergistic combination of resveratrol and andrographolide is effective when administered in oral form.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-11 of copending Application No. 17/918,866 in view of Song, B. (2019). “Andrographolide solid dispersions formulated by Soluplus to enhance interface wetting, dissolution, and absorption,” J. Appl. Polym. Sci. 48564 (cited in PTO-892), as evidenced by Battu, S. et al. (2010). “Physicochemical Characterization of Berberine Chloride: A Perspective in the Development of a Solution Dosage Form for Oral Delivery” AAPS PharmSciTech, 11(3), 1466 (cited in PTO-892).
App’866 claims a composition in the form of a thermoformed extrudate comprising at least one protoberberine alkaloid and at least one polymer of natural and/or synthetic origin selected from the group consisting of proteins of natural and/or synthetic origin, amino acids, peptides and polypeptides of natural and/or synthetic origin, lipids of natural and/or synthetic origin, dextrins of natural and/or synthetic origin, alginates of natural and/or synthetic origin, oligosaccharides of natural and/or synthetic origin, cyclodextrins of natural and/or synthetic origin, hyaluronates of natural and/or synthetic origin, carrageenans of natural and/or synthetic origin, derivatives thereof and mixtures thereof (claims 1 and 2). App’866 claims the protoberberine alkaloid comprises predominantly at least a first amorphous phase, or 51-100% by mass of an amorphous phase and 0 to 49% of a crystalline phase (claims 3 and 4). App’866 claims the proteins of natural and/or synthetic origin are selected from the group consisting: of glycoproteins, collagens, non-gelling collagen hydrolysates, non-gelling collagen peptides, non- gelling collagen polypeptides, vegetable proteins, animal proteins, derivatives thereof and mixtures thereof, wherein the non-gelling collagen hydrolysates and/or said non-gelling collagen peptides and/or said non-gelling collagen polypeptides have a molecular weight of between 50 and 300,000 Da (claims 6 and 7). The collective claims read on the thermoformed extrudate and polymer of instant claims 1, 4-5, and 9-10; therefore, the claims also read on claims 7-8 and 11-12, because the Markush group of the polymer of the composition of the extrudate is satisfied by the limitation of the collagen and/or hydrolysate. App’866 claims the composition comprises a plasticizer, selected from a group including glycerol (claims 8 and 9). This reads on the plasticizer of instant claims 13-14. App’866 claims the composition further comprises at least one additive selected from the group consisting: of lubricating agents, surfactants, antioxidants, chelating agents, derivatives thereof and mixtures thereof (claim 10), or it further comprising at least one polyphenolic first additional compound selected from the group consisting of: phenolic acids, stilbenes, phenolic alcohols, lignans, flavonoids, derivatives thereof and mixtures thereof (claim 11). These additives read on instant claims 15-16.
As evidenced by Battu, berberine, a quaternary protoberberine alkaloid, is a well-known naturally occurring medicine which is only very slightly soluble in water (Introduction).
App’866 differs from the instantly claimed invention in that it fails to teach the compound in the thermoformed extrudate is the labdane diterpene as recited in instant claims 1 and 6 (with the labdane diterpene having the amorphous phase as recited in claims 4-5), and therefore App’866 fails to teach the solid dispersion form and glassy structure recited in instant claims 2 and 3.
Song teaches preparation of an andrographolide (ADG) solid dispersion via hot-melt extrusion (p. 1 R. Col. 2nd para). Song teaches solid dispersion is designed as drug dispersion system wherein the drug is highly dispersed in a suitable solid carrier, which can effectively change drug physical state from crystalline to amorphous phase owing to the advantages of carriers in enlarging surface area and interacting with drug molecules (p. 1 L.-R. Col bridging para). Song teaches many polymers have been considered as excipients for forming the dispersion (p. 1 R. Col. 1st para). Song teaches that solid dispersions formulated with the ADG exhibit XRD spectra which demonstrate that the carrier is efficient in transforming drug crystal state to amorphous phase by interacting with the ADG; amorphous ADG has stronger energy than crystal ADG, which means it can be better wetted and released from the solid dispersion carrier (p. 5 “X-Ray Diffraction”). The instant specification defines a “glassy structure” as recited in claim 3 to mean a structure comprising/being formed by a molecular mixture of at least two
compounds/molecules, at least one of these two compounds/molecules being presented at least partially in a non-crystalline form, in particular being presented at least partially in
amorphous form (instant specification [0043]). Song also teaches that andrographolide in solid dispersion form is orally bioavailable for many pharmacological actions (p. 1 L. Col. 1st para).
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the protoberberine alkaloid in the thermoformed extrudate of App’866 with andrographolide in solid dispersion of the thermoformed extrudate, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have recognized the similarities between the medicinal active agents protoberberine alkaloid and andrographolide, particularly their low solubilities in water, and would have thus understood that the thermoformed extrudate of App’866 would impart improved solubility to andrographolide by imparting the same amorphous structure to the andrographolide that it does to protoberberine alkaloid (as claimed). Thus, the ordinarily skilled artisan would have substituted the active pharmaceuticals with predictable results due to the fact that andrographolide, when present in solid dispersion form in the thermoformed extrudate, would become amorphous and therefore be more soluble and more bioactive for oral delivery; this tendency is demonstrated by Song.
This is a provisional nonstatutory double patenting rejection.
Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 8, and 12-15 of copending Application No. 17/622,128 in view of Song, B. (2019). “Andrographolide solid dispersions formulated by Soluplus to enhance interface wetting, dissolution, and absorption,” J. Appl. Polym. Sci. 48564 (cited in PTO-892), as evidenced by US 5,314,877 (Suzuki, H. et al.) published 05/24/1994 (cited in PTO-892).
App’128 claims a composition in the form of a thermoformed extrudate comprising at least one triterpene and/or at least one triterpenoid and/or at least one of the glycosylated forms thereof and at least one polymer selected from the group consisting of: natural or synthetic proteins selected from the group consisting of collagens, hydrolysed collagens, collagen peptides, pea protein, rice protein, pumpkin protein, the derivatives thereof and the mixtures thereof, natural or synthetic oligosaccharides, natural or synthetic polysaccharides selected from the group consisting of corn starch, pregelatinized starch, p-glucan, inulin, dextrin, maltodextrin, hyaluronates, the derivatives thereof and the mixtures thereof, said at least one triterpene and/or said at least one triterpenoid and/or said at least one of the glycosylated forms thereof comprising at least one first amorphous phase (claim 1). App’128 claims the at least one triterpene and/or said at least one triterpenoid and/or said at least one of the glycosylated forms thereof predominantly comprises predominantly at least one first amorphous phase (claim 3), and the at least one triterpene and/or said at least one triterpenoid and/or said at least one of the glycosylated forms thereof comprises between 51 and 100% by mass of an amorphous phase and between 0 and 49% by mass of a crystalline phase (claim 4). App’128 claims the collagens have a molecular weight of between 50 and 300,000 Da (claim 8). The collective claims read on the thermoformed extrudate and polymer of instant claims 1, 4-5, and 9-10; therefore, the claims also read on claims 7-8 and 11-12, because the Markush group of the polymer of the composition of the extrudate is satisfied by the limitation of the collagen and/or hydrolysate. App’128 claims the composition comprises a plasticizer, selected from a group including glycerol (claims 12 and 13). This reads on the plasticizer of instant claims 13-14. App’128 claims the composition further comprises at least one additive selected from the group consisting: of lubricating agents, surfactants, antioxidants, chelating agents, derivatives thereof and mixtures thereof (claim 14), or it further comprising at least one polyphenolic first additional compound selected from the group consisting of: phenolic acids, stilbenes, phenolic alcohols, lignans, flavonoids, derivatives thereof and mixtures thereof (claim 15). These additives read on instant claims 15-16.
As evidenced by Suzuki, triterpenes classified in amyline, lupeol, nosterol, and squalene groups are compounds which have pharmacological functions but are insoluble in water (Col. 1 lines 14-17; lines 65-68).
App’128 differs from the instantly claimed invention in that it fails to teach the compound in the thermoformed extrudate is the labdane diterpene as recited in instant claims 1 and 6 (with the labdane diterpene having the amorphous phase as recited in claims 4-5), and therefore App’128 fails to teach the solid dispersion form and glassy structure recited in instant claims 2 and 3.
Song teaches preparation of an andrographolide (ADG) solid dispersion via hot-melt extrusion (p. 1 R. Col. 2nd para). Song teaches solid dispersion is designed as drug dispersion system wherein the drug is highly dispersed in a suitable solid carrier, which can effectively change drug physical state from crystalline to amorphous phase owing to the advantages of carriers in enlarging surface area and interacting with drug molecules (p. 1 L.-R. Col bridging para). Song teaches many polymers have been considered as excipients for forming the dispersion (p. 1 R. Col. 1st para). Song teaches that solid dispersions formulated with the ADG exhibit XRD spectra which demonstrate that the carrier is efficient in transforming drug crystal state to amorphous phase by interacting with the ADG; amorphous ADG has stronger energy than crystal ADG, which means it can be better wetted and released from the solid dispersion carrier (p. 5 “X-Ray Diffraction”). The instant specification defines a “glassy structure” as recited in claim 3 to mean a structure comprising/being formed by a molecular mixture of at least two
compounds/molecules, at least one of these two compounds/molecules being presented at least partially in a non-crystalline form, in particular being presented at least partially in
amorphous form (instant specification [0043]). Song also teaches that andrographolide in solid dispersion form is orally bioavailable for many pharmacological actions (p. 1 L. Col. 1st para).
It would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the triterpene in the thermoformed extrudate of App’128 with the labdane diterpene andrographolide in solid dispersion of the thermoformed extrudate, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have recognized the similarities between the medicinal active agents and structures of triterpenes and labdane diterpenes such as andrographolide, particularly their low solubilities in water, and would have thus understood that the thermoformed extrudate of App’128 would impart improved solubility to andrographolide by imparting the same amorphous structure to the andrographolide that it does to triterpene (as claimed). Thus, the ordinarily skilled artisan would have substituted the active pharmaceuticals with predictable results due to the fact that andrographolide, when present in solid dispersion form in the thermoformed extrudate, would become amorphous and therefore be more soluble and more bioactive for oral delivery; this tendency is demonstrated by Song.
This is a provisional nonstatutory double patenting rejection.
Claims 1-6 and 13-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of copending Application No. 18/541,626 in view of Song, B. (2019). “Andrographolide solid dispersions formulated by Soluplus to enhance interface wetting, dissolution, and absorption,” J. Appl. Polym. Sci. 48564 (cited in PTO-892) and Li, Y. et al. (2013). “Interactions between drugs and polymers influencing hot melt extrusion.” Journal of Pharmacy and Pharmacology, 66, pp. 148-166 (cited in PTO-892), as evidenced by Scala, C. et al. (2018). “Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter.” Biomolecules, 8(2), 31 (cited in PTO-892).
App’626 claims a composition in the form of a thermoformed extrudate in any suitable form allowing administration to an animal or a human being, comprising at least one natural or synthetic N-alkylamide as active substance and at least one support of natural origin chosen from the group consisting of amino acids, peptides, polypeptides, proteins, saccharides, lipids, their derivatives and their mixtures (claims 1 and 2). App’626 claims anandamide to be one of the N-alkylamides of the invention (claim 3). The thermoformed extrudate and polymer read on the extrudate and polymer of at least instant claim 1. App’626 claims the composition further comprises at least one plasticizing agent (claim 4). This reads on instant claim 13. App’626 claims the composition further comprises at least one additive chosen from the group consisting of lubricating agents, surfactant agents, antioxidant agents, chelating agents, their derivatives and their mixtures (claim 5). App’626 further comprises at least one first additional compound of polyphenol type chosen from the group consisting of phenolic acids, stilbenes, phenolic alcohols, lignans, flavonoids, their derivatives and their mixtures (claim 6). These additives read on instant claims 15-16.
As evidenced by Scala, anandamide (App’626’s claimed N-alkylamide) is a clinical agent with very low solubility in water (p. 4 1st para; p. 16 2nd para).
App’626 differs from the instantly claimed invention in that it fails to claim the compound in the thermoformed extrudate is the labdane diterpene and has the properties of the extrudate as recited in instant claims 1-6. App’626 also fails to claim the plasticizer is glycerol, as recited in instant claim 14.
Song teaches preparation of an andrographolide (ADG) solid dispersion via hot-melt extrusion (p. 1 R. Col. 2nd para). Song teaches solid dispersion is designed as drug dispersion system wherein the drug is highly dispersed in a suitable solid carrier, which can effectively change drug physical state from crystalline to amorphous phase owing to the advantages of carriers in enlarging surface area and interacting with drug molecules (p. 1 L.-R. Col bridging para). Song teaches many polymers have been considered as excipients for forming the dispersion (p. 1 R. Col. 1st para). Song teaches that solid dispersions formulated with the ADG exhibit XRD spectra which demonstrate that the carrier is efficient in transforming drug crystal state to amorphous phase by interacting with the ADG; amorphous ADG has stronger energy than crystal ADG, which means it can be better wetted and released from the solid dispersion carrier (p. 5 “X-Ray Diffraction”). The instant specification defines a “glassy structure” as recited in claim 3 to mean a structure comprising/being formed by a molecular mixture of at least two
compounds/molecules, at least one of these two compounds/molecules being presented at least partially in a non-crystalline form, in particular being presented at least partially in
amorphous form (instant specification [0043]). Song also teaches that andrographolide in solid dispersion form is orally bioavailable for many pharmacological actions (p. 1 L. Col. 1st para).
Li teaches that, to obtain an amorphous solid dispersion product, hot-melt extrusion (HME) needs to be processed at enough high temperature for the purpose of softening the polymer or keeping it at a flowing state to facilitate the dispersion of drug molecules, however, high temperature increases the risk of thermal degradation of both drug and polymer; the intermolecular interactions between drug and polymer may lower the processing temperature through depressing the melting point of the drug or lowering the viscosity of the polymer (p. 149 R. Col. “Improving manufacturability through drug-polymer interactions”). Li teaches that plasticizer is always used to depress the processing temperature by reducing glass transition temperature and viscosity of polymer during pharmaceutical hot melt extrusion; conventional plasticizers used in pharmaceutical HME include glycerol (p. 150 R. Col. “Plasticizing effect of drug on polymer” 1st and 2nd paras).
Regarding instant claims 1-6, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the N-alkylamide in the thermoformed extrudate of App’626 with the labdane diterpene andrographolide in solid dispersion as is demonstrated by Song, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have recognized the similarities between the medicinal active agents and structures of N-alkylamides and labdane diterpenes such as andrographolide, particularly their low solubilities in water, and would have thus reasonably inferred that the thermoformed extrudate of App’626 would impart improved solubility to andrographolide by imparting amorphous structure to andrographolide, akin to the extrudate of Song, due to the similar mechanism of formulation (thermoformed extrusion) and use of polymer carrier. Thus, the ordinarily skilled artisan would have substituted the active pharmaceuticals with predictable results due to the fact that andrographolide, when present in solid dispersion form in the thermoformed extrudate, would become amorphous and therefore be more soluble and more bioactive for oral delivery; this tendency is demonstrated in the comparable andrographolide/polymer extrusion product taught by Song.
Regarding instant claim 14, it would have been prima facie obvious for a person having ordinary skill in the art, before the effective filing date of the claimed invention, to incorporate a plasticizer such as glycerol into the mixture rendered obvious by the teachings of App’626 and Song, and arrive at the instantly claimed invention. The ordinarily skilled artisan would have been motivated to do so because the composition taught by the combination of App’626 and Song would form a solid dispersion product via hot melt extrusion, which, as taught by Li, has a risk of thermal degradation of both drug and polymer; therefore, the mixture being hot-melt extruded would benefit from the inclusion of a plasticizer, such as glycerol, in order to depress the processing temperature and therefore mitigate any issues surrounding drug or polymer degradation during the hot melt extrusion process. The ordinarily skilled artisan would have a reasonable expectation of success incorporating glycerol as plasticizer and lubricant into the mixture being hot melt extruded because glycerol is a plasticizer known in the art to be commonly employed during pharmaceutical hot melt extrusion.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sophia Marie Taylor whose telephone number is (571)272-5239. The examiner can normally be reached Monday-Friday 8 am - 4 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sue Liu can be reached at (571) 272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SOPHIA MARIE TAYLOR/Examiner, Art Unit 1616
/Mina Haghighatian/Primary Examiner, Art Unit 1616