DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12 November 2025, has been entered.
Status of Claims
The amendments, filed on 12 November 2025, are acknowledged.
Claims 11-12 and 14-19 are amended.
Claims 1-10, 13, and 20 are cancelled.
New claim 21 has been entered.
Claims 11-12, 14-19, and 21 are pending and under consideration in the instant Office Action.
Claim Objections
Claims 11 and 21 objected to because the recite “centrifugally spinning…at a strain rate between 2,000 and 20,000 rpm” in lines 13-14 of claim 11 and lines 18-19 of claim 21. Strain rate typically has a unit of inverse seconds (s-1) in the art and rpm is used as a unit of rotational speed. For the purpose of examination, 2,000-20,000 rpm is interpreted as limiting the rate of centrifugal spinning.
In response to this Office Action, Applicant is requested to confirm if this interpretation is correct and, if so, to appropriately correct claims 11 and 21.
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 16-18 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 16 recites the limitation "the surfactant polymer solution" in line 2. There is insufficient antecedent basis for this limitation in the claim because claim 11, upon which claim 16 depends, recites “a first surfactant polymer solution” (bold added for emphasis). Applicant may overcome this rejection by amending claim 16 to recite “the first surfactant polymer solution”.
Claim 17 recites the limitation "the non-water-soluble active therapeutic reagent" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim because claim 11, upon which claim 17 depends, recites “a first non-water-soluble active therapeutic reagent” (bold added for emphasis). Claim 18 depends from claim 17 and necessarily incorporates its limitations, does not resolve the issue detailed above, and is therefore also rejected as being indefinite. Applicant may overcome this rejection by amending claim 16 to recite “the first non-water-soluble active therapeutic reagent”.
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 11-12, 15-19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Nelson et al. (U.S. Patent Application No. US 2006/0193769 A1, published on 31 August 2006, hereafter referred to as Nelson) in view of Rampichová et al. (Cell Adhes. Migr. 2014, 8 (1), 36., hereafter referred to as Rampichová), Ajalloueian et al. (BioMed Res. International, 2014, 1, 1. provided by Applicant in IDS filed on 8 November 2023, hereafter referred to as Ajalloueian), and Zhang et al. (Drug Discov. Today 2017, 22 (9), 1351., hereafter referred to as Zhang).
Nelson teaches compositions capable of drug delivery and tissue engineering, methods of their preparation within three-dimensional matrices, and methods of “manipulating the rate of therapeutic agent release” (Abstract). The invention taught by Nelson comprises at least one fiber, each comprising two components - the “first component is a biodegradable polymer” and the “second component is selected from the group consisting of a gel and a hydrogel” (para. [0014] and claims 1, 21, and 35). The gel and hydrogel are defined by Nelson as being matrices formed from polymers, biopolymers, or polymer solutions, typically in an aqueous solution (para. [0061] and [0100]).
Nelson further teaches the use of “more than one kind of therapeutic agent within [the three-dimensional scaffold’s] one or more layers” (para. [0052]), including trehalose (para. [0107]), hydrophilic therapeutic agents (nicotinamide, insulin growth factor-1, tumor necrosis factor alpha, etc.; para. [0111]), and hydrophobic therapeutic agents (claims 13, 18, and 33) for anti-inflammatory and antioxidant effects (para. [0059]). Examples of tissues that Nelson teaches to be targeted include the pancreas, lymph nodes, and liver (para. [0124]). The three-dimensional polymer networks taught by Nelson consist of polysaccharides (chitosan and pullulan, para. [0105]), PDLLA (para. [0064]), PLGA (para. [0097] and [0139]), the poloxamer Pluronic (para. [0166]), and biodegradable polyesters (para. [0097], Table 1). In addition, polymers were disclosed by Nelson et al. as being useful for drug delivery and tissue therapy for possessing properties including thermal sensitivity (para. [0109] and [0130]), which is interpreted as being equivalent to the thermosensitive polymer recited in instant claim 18, and pH sensitivity (para. [0109]).
Nelson also teaches “methods of manipulating the rate of therapeutic agent release by changing both the biodegradable polymer properties as well as altering the properties of the incorporated gel or hydrogel” (para. [0013]). Drug release kinetics in a three-dimensional scaffold are modified in one embodiment by modifying “the size of the dispersed phase aqueous phase droplets”, which contain the drug or therapeutic agent(s) (para. [0090]), via changes in the identity of the surfactant(s) and/or polymer(s), mechanical energy imparted while forming a precursor emulsion, and concentrations of constituent parts (para. [0090] and [0167]). The order of solution creation and addition is taught to be important due to solubility and miscibility issues (para. [0139] and [0165]-[0167]).
In Example 16, Nelson teaches a solution comprising a surfactant, a solvent (A), which may be chloroform or dichloromethane (para. [0139]), a polymer, and one or more biomolecules of interest, which are considered equivalent to the active therapeutic reagent in instant claim 11 (para. [0166]). Separate aqueous and organic phases are taught to be emulsified using “some form of mechanical energy”, which in one embodiment is vortexing, a form of homogenizing solutions via spinning at a controlled speed and a predetermined time (para. [0167]). This emulsion is taught in one embodiment to be used as a precursor emulsion as part of a later emulsion to create a three-dimensional scaffold for drug release, as Nelson previously teaches in Example 1 (para. [0139-0141]). However, in this example, water may serve as a solvent in the aqueous solution or may not be a solvent and instead form dispersed droplets in which the active therapeutic reagent(s) are encapsulated.
The Supreme Court wrote on the determination of obviousness in the decision KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385 (2007). Quoting from Sakraida v. AG Pro Inc. (Id. at 417, 82 USPQ2d at 1395-96), the Court concluded that “when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” Further, the court stated that, when making a determination if a combination of known elements is obvious, the operative question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” See MPEP § 2141.I.
The therapeutic agents and polymers taught by Nelson (vide supra) were disclosed as parts of exemplary lists and their inclusion in the instant Office Action is a result of being deemed equivalent prior art elements. For example, trehalose was taught as a natural polymer (Nelson para. [0107]) and a therapeutic agent (instant claim 17), but a person of ordinary skill in the art would recognize trehalose as a disaccharide that can be metabolized by humans. When utilized for tissue engineering in humans, whether trehalose is intended as a polymer in a three-dimensional structure or a therapeutic agent, trehalose is functionally providing the same properties to the composition. MPEP § 2183 provides guidance on determining prima facie equivalence of prior art elements, including the following relevant sections:
The prior art element performs the identical function specified in the claim in substantially the same way, and produces substantially the same results as the corresponding element disclosed in the specification. Kemco Sales, Inc. v. Control Papers Co., 208 F.3d 1352, 1364, 54 USPQ2d 1308, 1315 (Fed. Cir. 2000)
A person of ordinary skill in the art would have recognized the interchangeability of the element shown in the prior art for the corresponding element disclosed in the specification. Caterpillar Inc. v. Deere & Co., 224 F.3d 1374, 56 USPQ2d 1305 (Fed. Cir. 2000)
There are insubstantial differences between the prior art element and the corresponding element disclosed in the specification. IMS Technology, Inc. v. Haas Automation, Inc., 206 F.3d 1422, 1436, 54 USPQ2d 1129, 1138 (Fed. Cir. 2000)
The Examiner acknowledges that elements from the instant claims have been selected from lists in the prior art, but following the guidance from the MPEP and Courts as discussed above, prima facie equivalence has been established.
Nelson does not teach centrifugal spinning (otherwise called Forcespinning® (see instant specification paragraph [0023]) to create a three-dimensional fiber structure, the rate at which the solution is spun, the sequential combination of solutions prior to centrifugation, nor the therapeutic reagents to be confined between fiber layers. These deficiencies are offset by the teachings of Rampichová, Ajalloueian, and Zhang.
Rampichová teaches the technique Forcespinning® as an alternative method to creating fibrous 3D scaffolds via electrospinning (Abstract). Electrospinning, a common method of producing fibrous 3D scaffolds, is taught to have numerous disadvantages including limited thickness, small pore sizes, and planar 2D structures following production (pg. 36, middle column, para. 1 – right column, para. 1). Forcespinning®, which uses centrifugal force to produce “ultra-thin fibers”, is taught to overcome the issues associated with electrospinning, particularly with respect to the thickness of fibers and the subsequent pore sizes when used to form 3D scaffolds (pg. 37, Forcespinning as an Alternative Method for Producing 3D Nanofibers). To demonstrate the efficacy of the technique, Rampichová teaches two experiments in which polycaprolactone (PCL) nanofibers are created and used to form a 3D scaffold on which mesenchymal stem cells (MSCs) were seeded and subsequently deeply penetrated the structure, indicating Forcespun structures have suitable pore sizes and fiber thickness for use in tissue engineering applications (pg. 38, left column, final para. – pg. 40, left column, para. 1). The rotational speed used during the Forcespinning® method was taught to be 10,000 rpm (pg. 38, middle column, para. 1).
Ajalloueian teaches the utility of creating precursor emulsions as a strategy to solve issues with water solubility and miscibility in the field of tissue engineering. Relevant to the instant application, Ajalloueian teaches that in a situation with “a water-soluble polymer (chitosan) and a water insoluble polymer (PLGA), an emulsion mixture could be the key to do successful electrospinning” (page 4, section 3.0, right column) of three-dimensional structures formed from biocompatible polymers. In addition, the creation of three separate solutions containing chitosan, the surfactant polyvinyl alcohol (PVA), and PLGA and combination to create a final precursor emulsion prior to electrospinning was taught (page 2, section 2.2, right column).
Zhang teaches the physicochemical and biological properties of polymeric fibrous scaffolds and their use in drug release (Abstract). Three-dimensional scaffolds are taught to be formed from polymers, including natural polymers such as chitosan, collagen, and hyaluronic acid which are biocompatible and possess “remarkable physicochemical properties (pg. 1352, right column, Natural polymers), synthetic polymers such as polylactic acid and polylactic-co--glycolic acid, which possess tunable properties and are easily manufactured at low cost (pg. 1353, left column, Synthetic polymers), and composite polymers which combine the advantages of natural and synthetic polymers (pg. 1353, right column, Composite polymers).
The type of drugs and method of drug-loading is taught to play a “vital part in fabrication of polymeric micro/nanofibrous scaffolds” (pg. 1353, right column, final para.). Zhang teaches that therapeutic agents may be immobilized on the surfaces of fibers, which is “a robust delivery platform as a result of an extremely high surface-area:volume ratio, leading to a very high drug-loading capacity” and allows for an “initial burst release” of drugs to the targeted area (pg. 1354, right column, para. 3). To achieve a sustained release over a longer time period, Zhang teaches that techniques such as blending the therapeutic agents with the polymer solution prior to forming the 3-D scaffold, loading the drugs into cores of hollow fibers, or dispersing drugs in droplets which are dispersed and then emulsified into polymer solutions are viable (pg. 1354, right column, Drug-loading techniques – pg. 1355, right column, para. 1 and Fig. 1).
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 Nelson, Rampichová, Ajalloueian, and Zheng to arrive at the claimed invention. One of ordinary skill would be motivated to combine the teachings of Nelson, Rampichová, and Ajalloueian due to the advantages provided by utilizing the centrifugal spinning manufacturing method (Forcespinning®) over traditional extrusion methods, including spinning methods that require coagulation baths or applied voltage, and the production of pore sizes and fiber thicknesses that are better suited to tissue engineering. Further, Nelson describes the importance of the order of solution creation and addition due to solubility and miscibility issues (para. [0139] and [0165]-[0167], Examples 1 and 16). Ajalloueian overcame similar issues with solubility and miscibility by creating several solutions, utilizing a surfactant, and preparing a final emulsion prior to spinning. Finally, the person of ordinary skill would be motivated to incorporate therapeutic agents both inside the polymeric fibers and between the polymeric fibers of the 3D scaffold in view of the teachings of Zheng because Zheng teaches such an orientation to enable a very high drug-loading capacity, which would be desirable to an artisan using the scaffold for drug delivery, and allows for modifiable drug release rates either through an “initial burst release” or sustained release over a longer time period via incorporation inside the polymeric fibers.
While the teachings of Nelson above include the two water-soluble active therapeutic reagents, non-water-soluble active therapeutic reagents, polymers, solvents, and surfactants in two solutions, rather than four distinct solutions that are subsequently mixed and Forcespun, rearranging the sequence of adding ingredients would have been prima facie obvious at the time of filing. This is supported by previous board and court decisions, including in Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959), where the Board of Appeals held that the “order of performing process steps is prima facie obvious in the absence of new or unexpected results” (see MPEP § 2144.04.IV.C.) In addition, the Court of Customs and Patent Appeals held that the selection of ay order of mixing ingredients is prima facie obvious in In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930), again in the absence of new or unexpected results. The teachings of Ajalloueian would motivate the ordinary artisan to create separate solutions based on solubility and stability, then sequentially mix the solutions to obtain stable precursor emulsions prior to spinning to obtain the desired 3D scaffolds. As a result, there is a reasonable expectation of success in arriving at the method of claims 11-12, 15-19, and 21 in view of the teachings of Nelson, Rampichová, Ajalloueian, and Zheng.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Nelson (U.S. Patent Application No. US 2006/0193769 A1, published on 31 August 2006) in view of Rampichová (Cell Adhes. Migr. 2014, 8 (1), 36.), Ajalloueian (BioMed Res. International, 2014, 1, 1. provided by Applicant in IDS filed on 8 November 2023), and Zhang (Drug Discov. Today 2017, 22 (9), 1351.) as applied to claims 11-12, 15-19, and 21 above, and further in view of Zabrecky (U.S. Patent Application No. 2010/0086627 A1, published on 8 April 2010).
Nelson, Rampichová, Ajalloueian, and Zhang teach the above.
Nelson, Rampichová, Ajalloueian, and Zhang do not teach the use of the following therapeutic agents: salvianolic acid, oleanolic acid, oxymatrine, or matrine. These deficiencies are offset by the teachings of Zabrecky.
Zabrecky teaches the administration of an anti-inflammatory and anti-fibrotic antioxidant formulation to treat diseases of the liver and chronic hepatitis (Abstract). Included in the antioxidants taught by Zabrecky are Salvia miltiorrhiza (as evidenced by the instant specification paragraph [0030], salvianolic acids are water soluble compounds extracted from this plant), oleanolic acid, and oxymatrine (para. [0074]). Oxymatrine is the oxide of matrine and is taught by Zabrecky to be “converted to matrine in the gastrointestinal tract” (para. [0147]). Zabrecky is analogous to the claimed invention because both utilize therapeutic agents for anti-inflammatory and anti-fibrotic effects (instant specification paragraphs [0035] and [0038]), in one embodiment specifically targeting the liver (instant spec. para. [0030]).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the filing of the instant application, to combine the teachings of Zabrecky with those of Nelson, Rampichová, Ajalloueian, and Zhang because combining prior art elements to impart a known benefit yields predictable results. Zabrecky teaches the delivery of therapeutic agents that achieve effects taught as desirable by Nelson. Nelson discloses examples of therapeutic agents that are anti-inflammatory and antioxidants (para. [0059]), but does not include all of the agents disclosed in instant claim 14. Zabrecky teaches these other agents as antioxidants (para [0030] and [0074]) and anti-inflammatory (para. [0146]) and it would have been obvious to the ordinary artisan to try using those agents in the invention rendered obvious above. As a result, there is a reasonable expectation of success in arriving at the method of claim 14 in view of the teachings of Nelson, Rampichová, Ajalloueian, and Zabrecky.
Response to Arguments
Applicant's arguments filed 12 November 2025, have been fully considered but they are not persuasive.
In the penultimate para. of pg. 7 of the remarks, Applicant argues that none of the cited references teach the preparation of, and subsequent homogenization of, solutions with a “water-soluble active therapeutic reagent” and a “non-water-soluble active therapeutic reagent” in the presence of a surfactant solution. The Examiner disagrees and points to the Nelson reference above, which teaches hydrophilic and hydrophobic active agents, preparation of solutions containing each in appropriate solvents, the addition of surfactants, and homogenization to create an emulsion that is then used to create a 3D scaffold. The Applicant further argues that the cited references also do not teach centrifugally spinning a precursor emulsion at a specified rate to form a 3D scaffold encapsulating the therapeutic reagents. The Examiner again disagrees and refers Applicant to the Zhang reference, which teaches the advantages of Forcespinning®, including the encapsulation of therapeutic agents both within and between polymeric fibers of a 3D scaffold.
In the final para. of pg. 7, Applicant argues that the instant invention has “distinct advantages not taught or suggested by” the references cited in the Office Action mailed on 12 June 2025. Among the advantages argued are improved physicochemical properties and more effective wound care. An argument against prima facie obviousness is not persuasive by merely recognizing additional advantages or latent properties present but not identified by the prior art. See MPEP § 2145.II. “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). Further, these advantages are recognized in the Zhang reference above, and the argument is unpersuasive.
In para. 1 of pg. 8, Applicant argues that “the claimed method provides an unexpected and nonobvious improvement over the teachings of the cited art”. To demonstrate that an invention provides unexpected results, the Applicant bears the burden to “establish results [that] are unexpected and significant”. See MPEP 716.02(a). Guidelines on determining whether results are expected or unexpected are provided throughout MPEP § 716.02. To demonstrate that results are unexpected and significant, the Applicant has the responsibility of presenting evidence that establishes “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims” (bold added for emphasis). See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). The Applicant has not demonstrated unexpected and nonobvious results nor have they compared their invention with the closest prior art. See MPEP § 716.02(e). Therefore, the argument that the instant invention provides unexpected and nonobvious results is not found persuasive.
Finally, in para. 3 of pg. 8, Applicant argues that claim 21 is patentable because the prior art does not teach fibrous 3D scaffolds that confine droplets which encapsulate one or more therapeutic agents and methods for forming said structures. This is not persuasive because, as stated above, the Nelson reference does teach fibrous 3D scaffolds which confine therapeutic agents in droplets and a method for forming the structure. The methods as recited in the instant application are prima facie obvious in view of the references cited above.
Conclusion
No claims are allowed.
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/S.J.S./
Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619