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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. The applicant's submission filed on 08 June 2026, has been entered.
Status of the Claims
Amendments to the Claims and Arguments/Remarks filed 27 May 2026, in response to the Office Correspondence dated 02 March 2026, are acknowledged.
The listing of Claims filed 27 May 2026, have been examined. Claims 1, 4-8, 10-16, and 18 are pending. Claims 1, 4-7, 11-16, and 18 are amended, claims 2, 3, 9, and 17 are canceled, and no new claims have been added.
Response to Amendment
The amendments are entered. The previous rejections under 35 U.S.C. § 112(b) directed to the former expressions “phase-inverting,” “oil emulsification,” the former trademark terminology “Span 80” and “Tween 20,” and the former wording “by being manufactured by” are withdrawn as moot because those expressions have been removed or replaced in the presently pending claims.
The previous obviousness rejections under 35 U.S.C. § 103 based on Lee, Lee Chol-Tae, Yang, Ren, Azimi-Boulali, and Park are withdrawn and superseded by the new grounds set forth below. The present rejection relies only on what Lee expressly teaches and relies on other references for polysorbate 20 and interfacial surfactant rearrangement.
Claim Objections
Claims 1, 7, and 8 are objected to because of the following informalities:
Claim 1 recites, “porcine reproductive and respiratory syndrome viruses”, wherein “porcine reproductive and respiratory syndrome virus” ordinarily identifies the virus in the singular. The applicant should verify whether the plural “viruses” is intended.
Claim 7 recites, “separating and washing the chitosan beads from the mixing tank.” The wording is grammatically ambiguous because “from the mixing tank” may modify both “separating” and “washing.” The applicant should clarify the language (e.g., “separating the chitosan beads from the mixing tank and washing the separated chitosan beads.”). Claim 7 also recites “at a room temperature.” The article “a” should be deleted so that the claim reads “at room temperature.”
In addition to the indefiniteness identified below, in claim 8 recites, “the predetermined flow ratio between the water phase material and the oil phase material is in a range of 1 to 5-20.” The expression “1 to 5-20” does not define a mathematically ascertainable ratio or range. It may read as a ratio from 1:5 to 1:20, a ratio of 1 to a range of 5-20, or another unstated numerical relationship. The intended endpoints and ratio format should be corrected to clearly state the ratio and range (e.g., “ratio from 1:5 to 1:20”). The applicant should also consider whether claim 8 provides a meaningful further limitation over claim 1 after correction, because claim 1 already recites a flow ratio of 1:5 to 1:20 and a droplet diameter within 50 µm.
Claim Rejections - 35 USC § 112(a)
Claims 1, 4-8, 10-16, and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites, in relevant part, “a freezing-resistant disinfectant having a virucidal effect against porcine reproductive and respiratory syndrome viruses.”
As presently drafted, this limitation is not restricted to a particular disinfectant actually disclosed or tested by the applicant. Rather, the limitation encompasses a genus of disinfectants defined principally by two required functions or properties being “freezing-resistant”, and having a virucidal effect against porcine reproductive and respiratory syndrome virus (“PRRSV”).
The claimed disinfectant is additionally required to function in the recited manufacturing process, including incorporation into an aqueous phase containing purified water, acetic acid, and chitosan; formation of microfluidically generated droplets; contact with sorbitan monooleate and polysorbate 20; and subsequent glutaraldehyde cross-linking to form chitosan beads.
The specification does not provide adequate descriptive support demonstrating possession of the full scope of this functionally defined genus. The specification does not identify the disinfectant used in the disclosed embodiment, wherein ¶[0029] states that, “The water phase material 11 in the present invention is a composition composed of purified water (DI water), freezing-resistant disinfectant, acetic acid and chitosan…”, and provides a 1:1 volume ratio between purified water and the freezing-resistant disinfectant. However, the specification does not identify what the “freezing-resistant disinfectant” actually is.
The specification does not provide a chemical name, an active ingredient, a commercial product name, a molecular structure, a chemical formula, a formulation, a disinfectant class, a CAS number, a concentration of disinfectant active, a freezing-point depressant or other component responsible for the freezing-resistant property, or another identifying characteristic by which the disinfectant actually used by Applicant can be recognized. Thus, even the particular disinfectant apparently employed in Applicant’s embodiment is not descriptively identified.
The PRRSV experiments do not identify a representative species. The specification ¶[0052]-[0055] describe biological testing involving chitosan particles containing a “freezing-resistant disinfectant” and report activity against PRRSV using MARC-145 cells. Those experiments establish that some unidentified disinfectant-containing preparation was tested and exhibited reported PRRSV virucidal activity. They do not, however, identify the composition responsible for that activity.
Accordingly, the biological results do not provide a descriptive identification of a representative member of the claimed genus. A person of ordinary skill reading the specification is informed of a result achieved by an unidentified material but is not informed what material the applicant possessed that achieved that result. The written-description requirement is not satisfied merely by announcing that a material having the claimed function existed or was tested where the disclosure does not adequately identify the material itself.
The specification does not disclose a representative number or range of identifiable disinfectant species. The Background states generally that “various freezing-resistant disinfectants have been developed.” The specification, however, does not identify any of those disinfectants as members of the claimed genus, much less identify which possess the combination of properties presently required by claim 1.
There is no disclosure of, for example, a first freezing-resistant PRRSV disinfectant, a second chemically different freezing-resistant PRRSV disinfectant, alternative active agents, alternative freezing-resistant formulations, subclasses of disinfectants suitable for the claimed process, or examples delineating which freezing-resistant disinfectants fall inside or outside the claimed genus. The specification therefore does not describe multiple identifiable species from which a person of ordinary skill could reasonably recognize the scope of the genus the applicant possessed. The disclosure fails to identify even the species actually tested, while the claim encompasses any disinfectant satisfying the broadly stated functional requirements.
In addition, no common structural, chemical, or compositional characteristics of the genus are disclosed. The specification also does not provide common identifying characteristics sufficient for a skilled artisan to recognize the members of the claimed genus without resorting solely to the functional language of the claim. For example, the specification does not disclose that suitable disinfectants contain a particular antimicrobial active; belong to a particular chemical class; contain a particular alcohol, glycol, oxidant, quaternary ammonium compound, aldehyde, acid, or other disinfectant species; share a particular molecular structure; contain a specified freezing-point depressant; have a specified freezing point; have a specified hydrophilic/lipophilic character; possess specified solubility characteristics; possess specified compatibility with chitosan; possess specified stability in acetic acid; possess specified compatibility with glutaraldehyde; or share another chemical or physical characteristic correlating with the claimed combination of freezing resistance and PRRSV virucidal activity. Accordingly, there is no disclosed structural or compositional feature permitting a person of ordinary skill to distinguish members of the claimed disinfectant genus from disinfectants outside the genus.
Further, no disclosed correlation identifies which disinfectants possess the claimed combination of functions. The specification does not disclose a correlation between an identifiable structural or compositional characteristic and the recited functional combination. For example, it does not establish that disinfectants having a particular chemical structure or formulation will predictably resist freezing under the intended winter conditions, retain virucidal activity against PRRSV, remain compatible with the claimed chitosan/acetic-acid aqueous phase, permit microfluidic droplet formation, tolerate interaction with the recited surfactant system, and remain functional following glutaraldehyde cross-linking and bead formation. Instead, the genus is delineated primarily by the desired results themselves.
A functionally defined genus is not adequately described merely because a skilled artisan is told to select members that successfully perform the claimed functions. The written description must demonstrate that Applicant possessed the claimed generic invention, rather than merely identifying the properties that a successful member should have. The disclosure states that a freezing-resistant disinfectant is used and reports that an unidentified disinfectant preparation achieved a PRRSV-related result, but does not descriptively identify the disinfectant, representative alternatives, or characteristics by which the genus may be recognized. The disclosure therefore describes the desired category and result, rather than adequately describing the breadth of the chemical subject matter encompassed by the claim.
In summary, the scope claimed materially exceeds the subject matter shown to have been possessed. Claim 1 is not limited to the particular unidentified disinfectant used in the applicant’s experiments. Under its broadest reasonable interpretation, the limitation encompasses chemically and compositionally diverse materials, provided that they satisfy the recited freezing-resistant and PRRSV-virucidal functions and can be incorporated into the claimed process. The specification supplies no basis for concluding that the applicant possessed that chemically diverse scope as of the filing date. At most, the specification demonstrates that the applicant used one unidentified material or formulation referred to generically as a freezing-resistant disinfectant and obtained certain reported PRRSV results.
Possession of one unidentified embodiment does not, on this record, reasonably convey possession of the full functionally defined genus recited in claim 1. Accordingly, the disclosure does not reasonably convey to a person of ordinary skill in the art that the applicant was in possession, as of the filing date, of the genus “a freezing-resistant disinfectant having a virucidal effect against porcine reproductive and respiratory syndrome viruses”, throughout the scope presently encompassed by claim 1.
Claims 4-8 and 10 depend directly or indirectly from claim 1 and therefore incorporate the limitation of “a freezing-resistant disinfectant having a virucidal effect against porcine reproductive and respiratory syndrome viruses.” These claims add limitations concerning surfactant displacement, cross-linking, centrifugation, precipitation, washing, drying, flow ratio, droplet size, or centrifugation conditions. Those limitations do not remedy the absence of adequate written-description support for the disinfectant genus incorporated from claim 1, and thus are also rejected under 35 U.S.C. § 112(a) for the same reasons set forth with respect to claim 1.
Claims 11-16 and 18 recite eco-friendly capsules manufactured according to the methods of claims 1, 4-8, or 10. Each of those process claims requires the functionally defined freezing-resistant PRRSV disinfectant discussed above. The corresponding product-by-process claims therefore encompass capsules containing or resulting from use of the same inadequately described genus (i.e., claim 11 incorporates the method of claim 1; claim 12 incorporates the method of claim 4; claim 13 incorporates the method of claim 5; claim 14 incorporates the method of claim 6; claim 15 incorporates the method of claim 7; claim 16 incorporates the method of claim 8; and claim 18 incorporates the method of claim 10). The product-by-process format does not cure the underlying written-description deficiency. The claims remain sufficiently broad to encompass capsules manufactured using any member of the functionally defined disinfectant genus, while the original disclosure does not demonstrate possession of that genus. Thus, claims 11-16 and 18 are therefore rejected under 35 U.S.C. § 112(a) for the same reasons.
To overcome this rejection, the applicant is advised to cure the deficiency wherein the specification does not adequately describe what disinfectant or class of disinfectants the applicant possessed that corresponds to the broad functional genus presently claimed.
In addition to the written description rejection above, claim 1 recites, “mixing the emulsion with a water phase solution in a mixing tank on the microfluidic chip or connected with the microfluidic chip.” The presently claimed limitation encompasses two alternative arrangements: (1) a mixing tank located on the microfluidic chip; and (2) a mixing tank connected with the microfluidic chip.
The original specification adequately describes the second alternative. Paragraph [0032] states that the emulsion may be accommodated in a mixing tank and that, “The mixing tank (not shown) may be connected to one end of the reaction site S4 of the microfluidic chip through a separate connection means.” However, the original specification does not expressly describe a mixing tank integrated into, formed on, or otherwise located on the microfluidic chip. Instead, the disclosed use of a separate connection means between the reaction site and the mixing tank indicates a tank connected to the chip as a separate component.
The amended claim therefore introduces an additional physical arrangement not described in the textual disclosure. The fact that an on-chip tank might have been technologically conceivable or obvious does not establish that Applicant possessed that particular arrangement at filing. Written description requires express, implicit, or inherent support for the claimed limitation; it is not satisfied merely because a skilled artisan could have devised the undisclosed alternative (see MPEP § 2163).
No portion of the supplied specification has been identified that would have conveyed with reasonable clarity to a person of ordinary skill that the inventor possessed a microfluidic chip having the mixing tank located on the chip itself. Claims 4-8 and 10 depend directly or indirectly from claim 1 and incorporate the unsupported alternative. Claims 11-16 and 18 recite capsules manufactured according to the methods of claims 1, 4-8, and 10 and therefore incorporate the same unsupported process alternative.
To overcome this rejection, the applicant may consider deleting the unsupported alternative “on the microfluidic chip or” so that the claim requires the mixing tank to be connected with the microfluidic chip; or identify support in the application, as originally filed, including the original drawings or claims, that reasonably conveys possession of a mixing tank located on the microfluidic chip.
In addition, claims 1, 4-8, 10-16, and 18 are rejected under 35 U.S.C. § 112(a) for lack of adequate written description of the claimed disinfectant genus. Claim 1 recites, “a freezing-resistant disinfectant having a virucidal effect against porcine reproductive and respiratory syndrome viruses.” This limitation defines the disinfectant substantially entirely by two desired functional results the disinfectant is “freezing-resistant”, and the disinfectant has a virucidal effect against porcine reproductive and respiratory syndrome virus.
The claim is not limited to a named disinfectant, chemical class, active ingredient, molecular structure, formulation type, concentration, freezing-point range, or mechanism of virucidal action. It therefore encompasses every material or composition capable of satisfying the two recited functions and of being used in the claimed chitosan-encapsulation process.
The specification repeatedly refers generically to a “freezing-resistant disinfectant,” but it does not identify the chemical or commercial identity of the disinfectant used in the disclosed embodiment. Paragraph [0029] states only that the water-phase material includes purified water, a freezing-resistant disinfectant, acetic acid, and chitosan. Although a 1:1 volume ratio of purified water to disinfectant is disclosed, the disinfectant component itself is not named or otherwise structurally characterized.
The specification also fails to disclose a representative species of the claimed disinfectant genus, a chemical class encompassing suitable disinfectants, the active ingredient or ingredients of the tested disinfectant, relevant chemical or physical properties that distinguish suitable disinfectants from unsuitable materials, a common structural feature shared by members of the claimed genus, a disclosed or art-recognized correlation between a disinfectant’s structure and the combined functions of freezing resistance, PRRSV virucidal activity, and compatibility with the claimed encapsulation process, or a method, other than screening candidate materials, for identifying members of the claimed genus.
Paragraphs [0052]-[0055] report tests using beads containing an unidentified disinfectant. Because the disinfectant used in those tests is not identified, those paragraphs do not describe even one reproducible species of the claimed genus. Here, the disclosure provides neither a representative number of species or identifying characteristics common to the genus (e.g., recognized structure-function correlation). Functional language, without representative species or distinguishing identifying characteristics, does not reasonably convey possession of every composition capable of producing the recited results (see MPEP § 2163; Ariad v. Lilly, 598 F.3d at 1350-1354 (Fed. Cir. 2010) (en banc); Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1335-1339 (Fed. Cir. 2021)). Thus, the specification does not reasonably convey that the inventor possessed the full scope of the claimed genus of freezing-resistant, PRRSV-virucidal disinfectants.
Claims 4-8 and 10 depend directly or indirectly from claim 1 and do not narrow or identify the disinfectant. Claims 11-16 and 18 incorporate the disinfectant genus through their recitation of capsules manufactured according to the corresponding methods.
The applicant may overcome by amending the claims to identify a disinfectant species or adequately supported class actually possessed by the applicant, or by presenting persuasive evidence that the claimed functional terminology identified a recognized and sufficiently definite class of disinfectants to a person of ordinary skill as of the effective filing date.
Claim Rejections - 35 USC § 112(b)
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 Applicant regards as his invention.
Claims 1, 4-8, 10-16, and 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, regards as the invention.
Claim 1 recites, “a freezing-resistant disinfectant having a virucidal effect against porcine reproductive and respiratory syndrome viruses.” Although the additional recitation of virucidal activity against porcine reproductive and respiratory syndrome virus provides a functional limitation, the term “freezing-resistant” does not provide an objective boundary by which a person of ordinary skill could determine whether a particular disinfectant falls within the claim.
The specification states generally that a freezing-resistant disinfectant may be used during winter without changing its chemical or physical properties. However, neither claim 1 nor the specification identifies a minimum temperature at which the disinfectant must remain usable, the duration of cold-temperature exposure, the degree of permissible change in viscosity, phase behavior, chemical composition, or physical properties (e.g., whether the disinfectant must remain entirely liquid or whether partial freezing is permitted or whether the disinfectant may freeze but recover its properties after thawing), the degree of retained virucidal activity required after cold exposure, or a standardized test by which “freezing-resistant” is determined.
Accordingly, the limitation may reasonably encompass materially different compositions, including a composition that remains liquid below 0°C, a composition that partially freezes, a composition that freezes but recovers after thawing, or a composition that merely retains some virucidal activity after freezing. Thus, the metes and bounds of “freezing-resistant” therefore cannot be determined with reasonable certainty.
Claims 4-8 and 10 depend directly or indirectly from claim 1 and do not cure this defect. The product-by-process claims 11-16 and 18 incorporate the method of claim 1 or a claim depending from claim 1 and therefore incorporate the same indefinite limitation.
In addition, amended claim 1 now recites, “moving the oil in the water phase solution to an interface between the emulsion and the water phase solution.” Although “the oil” has antecedent basis in the previously recited oil-phase material, the claim does not clearly define how that oil becomes located in the water-phase solution.
It is unclear whether the limitation refers to oil originally present as a constituent of the water-phase solution, oil transferred from the oil-phase material into the water-phase solution after mixing, oil remaining around or on the surfaces of the chitosan droplets, oil dispersed as separate droplets within the water-phase solution, oil present in a bulk emulsion phase adjacent to the water-phase solution, or residual oil released from the original emulsion during surfactant displacement.
The specification refers to “oil remaining in the water phase solution,” but the claim does not affirmatively recite a transfer, release, residual-oil condition, or other step that clearly establishes how the previously recited oil comes to occupy that location. It is therefore uncertain what material must be moved and from what initial location the material is moved.
Claim 1 further recites moving the oil “to an interface between the emulsion and the water phase solution.” After the emulsion is mixed with the water-phase solution in the mixing tank, the claim does not provide a clear basis for identifying the recited interface. The language may refer to the surface of each individual chitosan-containing droplet, an oil/water interface surrounding each droplet, a macroscopic boundary between a bulk emulsion phase and a bulk aqueous phase, an interface within a multiple emulsion, an interface between residual oil and the aqueous cross-linking solution, or a transient interfacial region generated during mixing.
The subsequent reference to “the surface of each of the droplets” suggests that a droplet interface may be intended, but the claim separately recites “an interface between the emulsion and the water phase solution.” The claim therefore does not make clear whether the two expressions identify the same interface or different interfaces.
Additionally, claim 1 recites, “reacting the oil in the water phase solution with the second surfactant.” The claim does not identify what physical or chemical phenomenon constitutes the recited “reacting.” Contact between oil and polysorbate 20 may result in adsorption of polysorbate 20 at an oil/water interface, emulsification, solubilization, micelle formation, redistribution of oil, alteration of interfacial tension, displacement or reorganization of sorbitan monooleate, or a chemical reaction. The claim does not specify which phenomenon satisfies the limitation. These mechanisms are physically and chemically distinct, thus, a person of ordinary skill in the art would not be able to determine with reasonable certainty when the recited “reacting” has occurred.
The applicant may clarify the claim by reciting the intended physical operation, such as interacting, emulsifying, solubilizing, associating, adsorbing, or displacing, provided that the selected terminology is supported by the originally-filed disclosure.
Claim 1 also recites that the oil is moved “such that the surface of each of the droplets is open to the cross-linking agent.” The expression “open to” does not provide an objective or recognized boundary. It is unclear whether a droplet surface is “open” when any amount of sorbitan monooleate has been displaced, polysorbate 20 has replaced a majority of the sorbitan monooleate, all sorbitan monooleate has been removed, any portion of the chitosan surface is exposed, glutaraldehyde can diffuse through the interfacial layer, the rate of cross-linking increases relative to a control, a specified percentage of the surface is accessible, or when cross-linking merely occurs.
The specification states that conversion of the first surfactant into the second surfactant may promote cross-linking, but does not define a threshold, test, degree of exposure, permeability, percentage of displaced surfactant, or increase in cross-linking rate that establishes when the surface is “open.” Thus, one of ordinary skill in the art would not be able to determine whether a particular droplet having partial surfactant displacement and some degree of glutaraldehyde contact satisfies this limitation.
Claims 4-8 and 10 incorporate these limitations through dependency from claim 1. Claims 11-16 and 18 incorporate them through their product-by-process references to the corresponding methods. Appropriate correction is required.
Claims 5, 10, 13, and 18 are additionally rejected under 35 U.S.C. § 112(b). Claim 5 recites, “the reacting of the droplets with the cross-linking agent is further promoted by centrifugation.” Claim 5 depends directly from claim 1. Claim 1 does not expressly state that the reaction of the droplets with the cross-linking agent is already “promoted” by a first identified condition. Claim 4 recites promotion by displacement, but claim 5 does not depend from claim 4. The comparative term “further” therefore lacks a clear reference point. It is unclear whether centrifugation further promotes the reaction relative to promotion caused by surfactant displacement, promotes the reaction relative to a stationary condition, promotes the reaction relative to mixing without centrifugation further promotes an inherent but unrecited effect of claim 1, or produces an additional degree of promotion beyond an unidentified baseline.
The applicant may correct the ambiguity by either deleting “further” and reciting that the reaction is promoted by centrifugation or changing the dependency of claim 5 to claim 4, if the applicant intends centrifugation to provide additional promotion beyond the displacement recited in claim 4. Claim 10 depends from claim 5 and incorporates the ambiguity. Claim 13 is directed to the capsule manufactured by the method of claim 5, and claim 18 is directed to the capsule manufactured by the method of claim 10. Claims 10, 13, and 18 therefore incorporate the same indefinite limitation.
Claims 8 and 16 are additionally rejected under 35 U.S.C. § 112(b). Claim 8 recites, “a diameter of the droplets”, which should be corrected to “the diameter of the droplets” for proper antecedent basis, since diameter has previously been introduced in the claim from which it depends (claim 1). Claim 8 also recites, “a diameter of the droplets is size-adjustable within 50 µm.” Independent claim 1 instead recites 50 µm, and the specification reports beads having a diameter of approximately 24.65 ± 3.94 µm. It is therefore unclear whether claim 8 intends a variation or tolerance of 50 micrometers, a maximum diameter of 50 micrometers, or another size limitation. The phrase “size-adjustable within 50 µm” does not clearly state whether every droplet must have a diameter no greater than the recited value or whether the droplet size may be changed by an amount within that value.
Claim 16 is directed to a capsule manufactured by the method of claim 8 and incorporates the same indefinite limitations. Appropriate correction is required to clarify what is intended by the claim language.
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.
Claims 1, 4, 6, 7, 11, 12, 14, and 15 are rejected under 35 U.S.C. § 103 as being unpatentable over Lee et al. (US6228291B1; published 08 May 2001, hereinafter “Lee”), in view of Ge et al. (CN110639444A; published 03 January 2020, hereinafter “Ge”), in further view of Park et al. (KR100614609B1; published 21 August 2006, hereinafter “Park”), Kawashima et al. (Shear-Induced Phase Inversion and Size Control of Water/Oil/Water Emulsion Droplets with Porous Membrane, Journal of Colloid and Interface Science, vol. 145, no. 2, pp. 512-523, Sep 1991; hereinafter “Kawashima”), and Dee et al. (An evaluation of disinfectants for the sanitation of porcine reproductive and respiratory syndrome virus-contaminated transport vehicles at cold temperatures. Can J Vet Res. 2005 Jan; 69(1):64-70; hereinafter “Dee”).
Lee teaches a process for preparing biodegradable, controlled-release chitosan microcapsules by an emulsion interfacial-reaction process. Specifically, Lee prepares a first aqueous phase containing approximately 0.3-10 wt% chitosan and 0.1-2 wt% acetic acid, disperses that aqueous phase in an organic phase containing sorbitan monooleate, and forms stabilized aqueous droplets. Lee identifies preferred chitosan concentrations of approximately 0.5-5 wt% and sorbitan monooleate concentrations of approximately 1-5 vol% (col. 4, ll. 39-42; claim 1 (aqueous phase with chitosan and acetic acid); col. 4, ll. 47-55 , claim 2 (oil phase with sorbitan monooleate). Lee separately prepares an aqueous cross-linking solution containing glutaraldehyde (col. 4, l. 65-col. 5, l. 4). Lee teaches that contact between the chitosan droplets and aqueous cross-linking solution causes rapid interfacial cross-linking and phase separation to form an insoluble chitosan film (col. 5, ll. 16-26). Lee obtains chitosan microcapsules having sizes of approximately 0.5-40 µm and teaches that particle size depends on, among other variables, surfactant concentration, polymer concentration, cross-linker concentration, organic solvent, and agitation rate (col. 5, ll. 29-43, Examples 1-22). Lee further teaches that substantially any water-soluble material requiring sustained release may be incorporated into the chitosan aqueous phase and agricultural materials (col. 8, ll. 6-16 and 60-67; col. 9, ll. 1-14).
Lee therefore discloses or suggests purified water; chitosan dissolved with acetic acid, chitosan concentrations encompassing 1-3 wt%, an oil or organic continuous phase, sorbitan monooleate as a first surfactant, formation of chitosan-containing aqueous droplets, an aqueous glutaraldehyde cross-linking composition, interfacial reaction of the droplets with glutaraldehyde, phase separation and formation of insoluble chitosan beads or microcapsules, particles no greater than 50 µm and incorporation of water-soluble active materials (claims 1-8; col. 5, ll. 29-43).
Lee does not expressly teach generating the droplets on a microfluidic chip, using polysorbate 20 in the aqueous cross-linking phase, or encapsulating a freezing-resistant PRRSV disinfectant.
Ge teaches microfluidic production of chitosan microcapsules. Its microchannel receives separate phases including a chitosan/acetic-acid aqueous phase and a Span 80-containing oil phase. The separately supplied phases are moved through the microchannel at controlled flow rates to form monodisperse multiphase droplet. The droplets are then passed into a glutaraldehyde-containing coagulation bath, washed, and naturally dried (Abstract; claims 1 and 2; Figures). Example 1 uses 2g chitosan and 2g acetic acid in an aqueous solution, 2g Span 80 in an oil phase, independently controlled flow rates, and a glutaraldehyde coagulation bath. Ge expressly attributes solidification to chemical cross-linking between glutaraldehyde and chitosan. Ge therefore demonstrates that Lee’s bulk droplet-forming step can predictably be replaced with a microfluidic droplet-forming step while retaining the same chitosan/acetic-acid phase, Span 80-containing oil phase, and subsequent glutaraldehyde cross-linking.
A person of ordinary skill would have been motivated to make this substitution to obtain the known advantages of microfluidic droplet generation including independent phase introduction, controlled flow rates, improved monodispersity, and reproducible droplet dimensions, with a reasonable expectation that the resulting chitosan droplets could be cross-linked with glutaraldehyde (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007), wherein a combination of familiar elements according to known methods that yields predictable results is obvious). The modification would have involved use of Ge’s known microfluidic apparatus to perform Lee’s known emulsion-template preparation, with a reasonable expectation that the resulting chitosan droplets could be cross-linked with glutaraldehyde.
Park provides additional motivation for the specific surfactant pairing. Park teaches chitosan microcapsules made using the same two nonionic surfactants recited in instant claim 1. In Park’s Example 1, polysorbate 20 (Tween 20) is dissolved in a 2 wt% chitosan aqueous solution, and the resulting emulsion is subsequently contacted with an oil phase containing sorbitan monooleate (Span 80) (Example 1). Park obtains chitosan microcapsules having average particle sizes of approximately 0.1-10 µm (page 4). Park therefore provides direct evidence that polysorbate 20 and sorbitan monooleate are compatible with one another in a chitosan microcapsule-forming system and that incorporating polysorbate 20 into the aqueous phase does not destroy the capsule-forming capability.
Kawashima supplies the interfacial displacement mechanism. Kawashima expressly teaches water/oil/water emulsions prepared using liquid paraffin, hydrophobic sorbitan monooleate, and hydrophilic polysorbate 20. Kawashima teaches that the emulsion undergoes phase inversion and can be redispersed into an aqueous solution of the hydrophilic surfactant (p. 512-514, FIG, 4 (describing phase inversion when W/O emulsion contacts Tween 20 solution); FIG. 6 (mechanism of oil film breakup); Table IV (Tween 20 concentrations of 0.94-9.99%). Kawashima further teaches that the phase-inversion behavior depends on the molecular ratio of the hydrophilic and hydrophobic surfactants and produces smaller, more homogeneous droplets (Abstract).
Thus, in view of Park and Kawashima, a person of ordinary skill seeking to modify the interfacial layer of Lee’s sorbitan-monooleate-stabilized chitosan droplets would have had reason to introduce polysorbate 20 in the subsequently contacted aqueous phase. Polysorbate 20 is the more hydrophilic surfactant and was known to compete for, reorganize, or replace interfacial coverage provided by sorbitan monooleate when the emulsion was contacted with an aqueous hydrophilic-surfactant phase. The expected result of this modification would have been alteration of the oil/water interfacial layer, redistribution of oil at the interface, and increased accessibility of the aqueous chitosan droplet surface to aqueous glutaraldehyde. Lee teaches that rapid aqueous contact between chitosan and glutaraldehyde at the droplet interface is required to form the capsule wall. Thus, reducing or reorganizing the original lipophilic surfactant barrier would predictably facilitate or promote the interfacial cross-linking reaction.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to combine the teachings of these references. Ge’s microfluidic chip provides a known means to generate monodisperse chitosan droplets from the same starting materials Lee uses. The combination simply substitutes a microfluidic droplet generator for Lee’s bulk stirring to gain improved size control, a predictable benefit (see MPEP § 2143.01).
The addition of polysorbate 20 to the aqueous cross-linking phase is motivated by the desire to improve cross-linker access to the chitosan surface. Park demonstrates that the Span 80/Tween 20 pair is chemically compatible with chitosan microcapsule formation. Kawashima demonstrates that introducing a hydrophilic surfactant such as Tween 20 into the aqueous phase displaces the lipophilic Span 80 from the droplet surface, removes the residual oil to the interface, and exposes the inner aqueous phase to the external environment. A skilled artisan reading Lee would recognize that rapid glutaraldehyde-chitosan contact is critical for interfacial wall formation. Modifying Lee’s cross-linking bath to include Tween 20, as taught by Kawashima, would predictably strip or reorganize the Span 80 barrier, open the chitosan surface to the cross-linker, and promote faster, more uniform cross-linking. This result is a predictable physicochemical outcome of combining the known surfactant system.
Dee teaches a freezing-resistant disinfectant having a virucidal effect against PRRSV. Dee evaluates commercially available disinfectants against PRRSV at 4°C and −20°C and teaches combining an effective disinfectant with 40% methanol or 10% propylene glycol so that the composition does not freeze at −20°C, while remaining negative for PRRSV RNA and infectious virus after thawing (Abstract; Figure 1 and 2). Dee thus identifies a freezing-resistant PRRSV-active disinfectant suitable for encapsulation.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to select Dee’s freezing-resistant, PRRSV-active disinfectant as the water-soluble active material loaded into Lee’s chitosan droplets. It is a straightforward substitution. Lee expressly invites incorporation of water-soluble active materials, and microencapsulation was known to facilitate storage, handling, protection, and controlled release of aqueous active materials.
Dee identifies a known active with cold-temperature stability and PRRSV efficacy. The selection of a known freezing-resistant PRRSV disinfectant for encapsulation represents the use of a known active material for its established function in a known chitosan encapsulation process. Nothing in the record demonstrates that Dee’s disinfectant could not be dispersed in the claimed aqueous chitosan/acetic-acid phase or released from a cross-linked chitosan capsule .A person of ordinary skill would have had a reasonable expectation that the disinfectant of Dee could be dissolved in the chitosan/acetic-acid phase and successfully encapsulated.
The precise values of 1% v/v acetic acid, 5-20 wt% sorbitan monooleate, 1-4% v/v glutaraldehyde, 5-10 wt% polysorbate 20, and a water-phase-to-oil-phase flow ratio of 1:5 to 1:20 are not all disclosed together in a single reference. Nonetheless, the prior art recognizes each of these as a result-effective variable affecting droplet size, interfacial stability, phase inversion, and cross-linking. Lee teaches that surfactant, polymer, and cross-linker concentrations affect particle formation and size. Kawashima teaches that the ratio of hydrophilic to hydrophobic surfactants affects phase inversion. Ge teaches that microfluidic flow rates control droplet size.
A person of ordinary skill would therefore have arrived at the claimed ranges through routine optimization to achieve stable droplets ≤50 µm and sufficient interfacial replacement to permit glutaraldehyde cross-linking. The claimed ranges have not been shown to be critical or to produce an effect different in kind from the interfacial, size-control, and cross-linking effects recognized in the prior art. A result-effective-variable rationale is appropriate where the prior art recognizes that the variable affects the result, and that requirement is satisfied here by Lee’s and Kawashima’s express teachings (see MPEP § 2144).
Instant claim 4 recites that reaction of the droplets with glutaraldehyde is promoted by displacement of sorbitan monooleate. As discussed above, Lee requires aqueous glutaraldehyde to contact chitosan at the droplet interface. Kawashima teaches that polysorbate 20 displaces sorbitan monooleate and removes the oil film, thereby exposing the inner aqueous phase (FIG. 6). Increasing the accessibility of the chitosan surface to the aqueous cross-linker would predictably promote the cross-linking reaction relative to a droplet whose surface remained covered by the lipophilic surfactant. This limitation recites an expected consequence of the obvious interfacial modification.
Instant claim 6 recites that chitosan beads are precipitated as the droplets react with glutaraldehyde. Lee teaches that interfacial reaction between chitosan and glutaraldehyde causes cross-linking and phase separation to form an insoluble polymer film, and the resulting solidified microcapsules are separated from the reaction medium. Precipitation or separation of the cross-linked beads as the droplets become insoluble is thus an expected result of Lee’s interfacial cross-linking process.
Instant claim 7 adds separating, washing, and drying at room temperature. Lee already teaches separating and washing the microcapsules. Ge further teaches washing the microfluidically generated, glutaraldehyde-cross-linked chitosan microcapsules and naturally drying them (claim 2, coagulation bath followed by washing and natural drying). Natural drying reasonably encompasses drying under ambient or room-temperature conditions absent an express heating step. Substituting room-temperature drying for Lee’s lyophilization would have been an obvious alternative drying step, particularly where avoidance of elevated temperature for stability or specialized lyophilization equipment to simplify the process is desired.
Instant claims 11, 12, 14, and 15 are directed to an eco-friendly capsule manufactured by the method according to instant claims 1, 4, 6, and 7, respectively. The patentability of a product-by-process claim depends on the product itself, not on the process of manufacture. Where the product is the same as or obvious over a product known in the art, the claim is unpatentable (see In re Thorpe, 777 F.2d 695, 697-98 (Fed. Cir. 1985); MPEP § 2113).
Lee and Ge teach glutaraldehyde-cross-linked chitosan microcapsules having the same general composition, morphology, and particle-size class as the instant claimed products. The instant product claims do not recite any measurable structural property that distinguishes the claimed capsule from the prior-art chitosan capsules.
The term “eco-friendly” is a subjective characterization that does not impose a structural limitation and, in any event, biodegradable chitosan capsules are inherently “eco-friendly.” The surfactant-displacement, precipitation, washing, and room-temperature-drying steps have not been shown to impart any structural characteristic absent from the prior-art chitosan microcapsules. Accordingly, instant claims 11, 12, 14, and 15 are unpatentable over the same combination that renders their corresponding process claims obvious.
Claims 1, 8, and 16 are rejected under 35 U.S.C. § 103 as being unpatentable over Lee et al. (US6228291B1; published 08 May 2001, hereinafter “Lee”), in view of Ge et al. (CN110639444A; published 03 January 2020, hereinafter “Ge”), in further view of Park et al. (KR100614609B1; published 21 August 2006, hereinafter “Park”), Kawashima et al. (Shear-Induced Phase Inversion and Size Control of Water/Oil/Water Emulsion Droplets with Porous Membrane, Journal of Colloid and Interface Science, vol. 145, no. 2, pp. 512-523, Sep 1991; hereinafter “Kawashima”), Dee et al. (An evaluation of disinfectants for the sanitation of porcine reproductive and respiratory syndrome virus-contaminated transport vehicles at cold temperatures. Can J Vet Res. 2005 Jan; 69(1):64-70; hereinafter “Dee”), and Zhou et al. (CN105395522A; published 16 March 2016, hereinafter “Zhou”).
Instant claim 1 is rendered obvious by the teachings of Lee, in view of Ge, in further view of Park, Kawashima, and Dee, as outlined above. Instant claims 8 and 16 directly or indirectly depend from claim 1, however, the limitations of instant claims 8 and 16 are not explicitly taught by the combination of Lee, Ge, Park, Kawashima, and Dee. This rejection applies the alternative interpretation of claim 8 set forth above (a water-phase-to-oil-phase ratio from 1:5 to 1:20 and droplet diameters adjustable within 50 µm).
Zhou teaches forming chitosan-containing microcapsules by adding an aqueous chitosan/acetic-acid phase to an oil phase containing sorbitan monooleate and polysorbate 20, followed by addition of a cross-linking agent, separation by filtration or centrifugation, washing, and drying (claims 1-9). Zhou further teaches an oil-phase-to-water-phase ratio of approximately 5:1 to 6:1 (claim 4), corresponding to a water-phase-to-oil-phase ratio of approximately 1:5 to 1:6, within the claimed range of instant claim 8.
The resulting particles are reported in a micrometer size range below 50 µm (Abstract). Zhou confirms that phase ratios within the claimed interval were conventional for producing small chitosan microcapsules and that the same nonionic surfactant pair could be used in such an emulsion-cross-linking process.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to select a water-to-oil phase ratio of approximately 1:5 to 1:6, as taught by Zhou, when implementing the microfluidic method of Ge as modified by Lee, Park, Kawashima, and Dee. Phase flow ratio was a recognized control variable for droplet size, as taught by Ge. Adjusting the corresponding microfluidic flow rates to reproduce a known bulk phase ratio would have represented routine implementation of a known formulation ratio, with a reasonable expectation of obtaining small droplets.
Instant claim 16 is unpatentable for the same product-by-process reasons stated above, as it merely recites a capsule made by the method of instant claim 8 and does not identify any structural distinction attributable to the flow ratio or size-adjustability.
Claims 1, 5, and 13 are rejected under 35 U.S.C. § 103 as being unpatentable over Lee et al. (US6228291B1; published 08 May 2001, hereinafter “Lee”), in view of Ge et al. (CN110639444A; published 03 January 2020, hereinafter “Ge”), in further view of Park et al. (KR100614609B1; published 21 August 2006, hereinafter “Park”), Kawashima et al. (Shear-Induced Phase Inversion and Size Control of Water/Oil/Water Emulsion Droplets with Porous Membrane, Journal of Colloid and Interface Science, vol. 145, no. 2, pp. 512-523, Sep 1991; hereinafter “Kawashima”), Dee et al. (An evaluation of disinfectants for the sanitation of porcine reproductive and respiratory syndrome virus-contaminated transport vehicles at cold temperatures. Can J Vet Res. 2005 Jan; 69(1):64-70; hereinafter “Dee”), Mark et al. (Manufacture of Chitosan Microbeads Using Centrifugally Driven Flow of Gel-Forming Solutions Through a Polymeric Micronozzle, Journal of Colloid and Interface Science, vol. 336, pp. 634-641, 14 Apr 2009; hereinafter “Mark”), and Azimi-Boulali et al. (Droplet and Particle Generation on Centrifugal Microfluidic Platforms: A Review. Micromachines (Basel),11(6):603; published 22 June 2020, hereinafter “Azimi-Boulali”).
Instant claim 1 is rendered obvious by the teachings of Lee, in view of Ge, in further view of Park, Kawashima, and Dee, as outlined above. Instant claims 5 and 13 directly or indirectly depend from claim 1, however, the limitations of instant claims 5 and 13 are not explicitly taught by the combination of Lee, Ge, Park, Kawashima, and Dee.
Instant claim 5 recites that reaction with the cross-linking agent is further promoted by centrifugation. Mark teaches producing chitosan microbeads by centrifugally driving chitosan solution through a micronozzle directly into a cross-linking solution (Abstract; Fig. 3 (b) and Fig. 4 (b)). Mark expressly recognizes that rotational speed controls droplet formation and bead production (Conclusions).
Azimi-Boulali reviews centrifugal microfluidic systems in which centrifugal force generates, transports, releases, and collects droplets and particles, and teaches that centrifugal force and rotational speed affect droplet generation, transport, and release into a receiving phase (Abstract). Azimi-Boulali teaches the dispenser nozzle method using centrifugal force where droplets “…travel through an air gap and enter a continuous phase to be crosslinked and collected.” and “…to use an air gap between the nozzle tip and the continuous phase, which prevents direct contact with the crosslinker solution and is faster and without cross-contamination” (p. 10 and 12, section 6.2; Fig. 6), thus directly disclosing centrifugation enhanced droplet reaction with cross-linking agent.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to apply centrifugal force while contacting the microfluidically formed chitosan droplets with the glutaraldehyde cross-linking solution. Mark and Azimi-Boulali demonstrate that centrifugation is a known technique to drive droplets into a cross-linking solution, increase droplet movement through the receiving phase, facilitate contact with the cross-linker, and enhance resulting bead collection.
Replacing Mark’s ionic cross-linking bath with Lee’s known glutaraldehyde bath would have been a predictable substitution because the rejection relies on Mark for the centrifugal transport mechanism, not for the specific cross-linking chemistry. Lee and Ge independently establish that glutaraldehyde cross-links chitosan droplets.
Instant claim 13 is directed to the product made by instant claim 5 and is unpatentable under the product-by-process principles set forth above, as no structural difference attributable to centrifugation has been identified.
Claims 1, 5, 10, and 18 are rejected under 35 U.S.C. § 103 as being unpatentable over Lee et al. (US6228291B1; published 08 May 2001, hereinafter “Lee”), in view of Ge et al. (CN110639444A; published 03 January 2020, hereinafter “Ge”), in further view of Park et al. (KR100614609B1; published 21 August 2006, hereinafter “Park”), Kawashima et al. (Shear-Induced Phase Inversion and Size Control of Water/Oil/Water Emulsion Droplets with Porous Membrane, Journal of Colloid and Interface Science, vol. 145, no. 2, pp. 512-523, Sep 1991; hereinafter “Kawashima”), Dee et al. (An evaluation of disinfectants for the sanitation of porcine reproductive and respiratory syndrome virus-contaminated transport vehicles at cold temperatures. Can J Vet Res. 2005 Jan; 69(1):64-70; hereinafter “Dee”), Mark et al. (Manufacture of Chitosan Microbeads Using Centrifugally Driven Flow of Gel-Forming Solutions Through a Polymeric Micronozzle, Journal of Colloid and Interface Science, vol. 336, pp. 634-641, 14 Apr 2009; hereinafter “Mark”), Azimi-Boulali et al. (Droplet and Particle Generation on Centrifugal Microfluidic Platforms: A Review. Micromachines (Basel),11(6):603; published 22 June 2020, hereinafter “Azimi-Boulali”), and Patil and Murthy (Preparation and In Vitro Evaluation of Mucoadhesive Chitosan Microspheres of Amlodipine Besylate for Nasal Administration, Indian Journal of Pharmaceutical Sciences, vol. 68, pp. 64-67, Jan 2006; hereinafter “Patil”).
Instant claims 1 and 5 are rendered obvious by the teachings of Lee, in view of Ge, in further view of Park, Kawashima, Dee, Mark and Azimi-Boulali as outlined above. Instant claims 10 and 18 directly or indirectly depend from claims 1 and 5, however, the limitations of instant claims 10 and 13 are not explicitly taught by the combination of Lee, Ge, Park, Kawashima, Dee, Mark, and Azimi-Boulali.
Instant claim 10 recites centrifugation at 1200 rpm for 30 minutes contemporaneously with cross-linking. Patil teaches preparation of chitosan microspheres by water-in-oil emulsification and glutaraldehyde cross-linking. Patil dissolves chitosan in 2% v/v acetic acid, forms droplets in liquid paraffin containing a stabilizing surfactant, adds aqueous glutaraldehyde, and continues rotational mixing during cross-linking. (p. 64, Preparation of microspheres). Patil evaluates 600 and 1200 rpm (p. 65, Effect of process variables on microsphere properties) and identifies 1200 rpm as the optimum speed for obtaining chitosan microspheres of approximately 35-36 µm (p. 66, Table 1). Patil thus demonstrates that 1200 rpm was a known and effective rotational condition during formation and glutaraldehyde cross-linking of chitosan microspheres to produce droplets of 1-60 µm (p. 65, Results and Discussion, 1st paragraph).
Mark and Azimi-Boulali establish that centrifugal rotational speed controls chitosan droplet generation, transport into a cross-linking bath, and particle collection. Patil establishes that 1200 rpm is an effective rotational speed for producing <50-µm glutaraldehyde-cross-linked chitosan microspheres.
The specific duration of 30 minutes is not expressly disclosed, but cross-linking time was a known process variable affecting the degree of chitosan cross-linking and particle formation. Patil uses a 3-hour cross-linking time (Abstract), however, Azimi-Boulali (page 8, 1st full paragraph) describes that the method shown in Figure 3 is known to reduce the overall time of the process from 2 hours to 30 minutes.
Thus, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to select a duration sufficient to obtain stable beads while avoiding unnecessary processing would have been a matter of routine experimental process optimization (see In re Peterson, 315 F.3d at 1329-1330 (Fed. Cir. 2003)). The claimed 30-minute duration has not been shown to be critical or to produce an unexpected result relative to shorter or longer cross-linking periods.
Accordingly, it would have been obvious to operate the centrifugal droplet-contact and cross-linking process at a rotational speed of approximately 1200 rpm and to determine an effective cross-linking duration, including approximately 30 minutes, through routine experimentation. Instant claim 18 is unpatentable for the same product-by-process reasons, as no structural distinction attributable to the specific centrifugation parameters is recited.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 27 May 2026, have been fully considered, but are not persuasive for the following reasons.
The applicant correctly observes that Lee does not teach that polysorbate 20 is necessarily required in Lee’s second or cross-linking emulsion. Lee states that the same emulsifying agent used in the first emulsion is used in the second emulsion. The previous “necessarily requires” statement is not maintained.
The present rejection instead relies on Lee for chitosan/acetic-acid droplets, sorbitan monooleate, aqueous glutaraldehyde, interfacial cross-linking, phase separation, and sub-50-µm capsules; Ge for microfluidic generation and controlled flow of chitosan, oil, and Span 80-containing phases into a glutaraldehyde bath; Park for express use of polysorbate 20 and sorbitan monooleate in a chitosan microcapsule process; Kawashima for express use of the same nonionic pair to produce phase inversion and interfacial reorganization; and Dee for the freezing-resistant PRRSV-active disinfectant. The applicant’s criticism of the previous characterization of Lee therefore does not address the present combination.
The applicant argues that Ren uses trace ionic surfactants, depends on electrostatic competition, and produces macroscopic demulsification or flocculated material. Those arguments are moot with respect to the present rejection. Ren is not relied upon in the new grounds. The present rejection relies on Kawashima, which expressly uses the same nonionic surfactants recited in instant claim 1 (sorbitan monooleate and polysorbate 20) and expressly reports phase inversion affected by the molecular ratio of the hydrophilic and hydrophobic surfactants. Park independently confirms that this surfactant pair can be used in a chitosan microcapsule system. Thus, the present rejection does not extrapolate Ren’s SDS/CTAB ion-competition mechanism to chemically different nonionic surfactants.
The applicant argues that introducing 5-10 wt% polysorbate 20 into a sorbitan-monooleate-stabilized system would destroy the water-in-oil droplets and prevent cross-linking. The evidence of record does not support a categorical incompatibility. Kawashima actually uses hydrophobic sorbitan monooleate and hydrophilic polysorbate 20 in the same multiple-emulsion system and teaches controlled phase inversion and redispersion rather than universal destruction of all droplets. Park uses polysorbate 20 in a chitosan aqueous phase and sorbitan monooleate in the associated oil phase to produce chitosan microcapsules having particle sizes of approximately 0.1-10 µm.
The claimed method itself requires the second surfactant to alter the first interfacial layer. Some reduction in stability or interfacial rearrangement is therefore not contrary to the claim, it is the operative phenomenon recited by the claim. The relevant question is whether a skilled artisan would reasonably expect to select conditions under which the interfacial rearrangement permits cross-linking before complete coalescence. Lee’s rapid aqueous glutaraldehyde cross-linking, together with Kawashima’s controlled phase-inversion teaching, provides that reasonable expectation. Obviousness does not require absolute predictability or a guarantee of success, it requires a reasonable expectation of success- which is supplied here.
Lee teaches forming W/O chitosan droplets stabilized by sorbitan monooleate (Span 80) and subsequently contacting those droplets with an aqueous crosslinking phase. The reference does not explicitly describe surfactant displacement, but it is inherent that when the droplets are transferred from an oil-continuous environment into an aqueous crosslinking bath that contains a different surfactant (or even in the absence of additional surfactant), the interfacial surfactant layer reorganizes. A person of ordinary skill would recognize that a non‑ionic surfactant with a very different HLB (e.g., Tween 20, HLB ~16.7 vs. Span 80, HLB ~4.3) would similarly compete for the interface, causing displacement or reorganization. Lee already employ Span 80 in the oil phase, and using Tween 20 in the aqueous crosslinking phase to facilitate oil removal and exposure of the chitosan surface to the crosslinker would have been a predictable choice. Oil is solubilized or emulsified by the surfactant.
The applicant emphasizes that Ren uses only trace concentrations of ionic surfactants, whereas claim 1 recites 5-20 wt% sorbitan monooleate and 5-10 wt% polysorbate 20. Again, Ren is not applied in the present rejection. Lee expressly teaches that surfactant concentration affects droplet stability, particle formation, and particle size. Kawashima teaches that the ratio of sorbitan monooleate to polysorbate 20 affects phase inversion. These references identify surfactant concentration and ratio as result-effective variables.
The applicant has not provided comparative data showing that 5 wt% is materially different from a slightly lower amount, 10 or 20 wt% produces a different kind of interfacial phenomenon, the entire 5-20 wt% sorbitan monooleate range is critical, the entire 5-10 wt% polysorbate 20 range is critical, or values immediately outside the claimed ranges fail to produce interfacial displacement and glutaraldehyde exposure. The specification’s comparison of polysorbate 20 with SDS, or of glutaraldehyde with TPP, does not establish criticality of the presently claimed surfactant concentration ranges relative to the closest Span 80/Tween 20 systems.
The applicant argues that Lee Chol-Tae relies on tripolyphosphate and that ¶[0041] of the present specification reports that bead shape was not maintained when TPP was used. This argument does not rebut the new rejection. The present combination does not require substituting Lee Chol-Tae’s TPP for glutaraldehyde. Lee and Ge expressly use glutaraldehyde to cross-link chitosan droplets. The applicant’s TPP comparison may support selecting glutaraldehyde instead of TPP, but glutaraldehyde was already a known chitosan cross-linker in Lee and Ge. Evidence that TPP performed less favorably than glutaraldehyde does not establish that using known glutaraldehyde would have been nonobvious. Moreover, the reported comparison does not demonstrate unexpected results relative to the closest glutaraldehyde-containing prior art.
The present rejection does not rest merely on a generalized proposition that surfactants can be substituted. The record provides the following specific factual foundation, in that Lee teaches sorbitan-monooleate-stabilized chitosan droplets that must contact aqueous glutaraldehyde at the interface; Ge teaches creating chitosan/acetic-acid and Span 80-containing phases in a microfluidic device and subsequently cross-linking with glutaraldehyde; Park teaches the same polysorbate 20/sorbitan monooleate pair in chitosan microcapsule formation; Kawashima teaches phase inversion and interfacial reorganization using the same pair and teaches that the behavior is controllable through the surfactant ratio; and Lee teaches that glutaraldehyde cross-linking is rapid at the aqueous interface. Taken together, these teachings provide more than a mere invitation to experiment. They provide a technically coherent basis for expecting that polysorbate 20 can reorganize or displace sorbitan monooleate at the interface while glutaraldehyde cross-links the exposed chitosan.
The applicant cites In re Papesch and In re Antonie and argues that the previous rejection separated chemical components from their properties and used claim 1 as a blueprint. However, the claimed invention has been considered as a whole. The present rejection does not remove Chol’s TPP chemistry from one system, insert Ren’s ionic demulsification mechanism into another, and presume that the result is operable. The proposed combination begins with Lee’s chitosan/Span 80/glutaraldehyde interfacial-cross-linking process and applies Ge’s microfluidic implementation of a closely related chitosan/Span 80/glutaraldehyde process, Park’s demonstrated compatibility of polysorbate 20 and sorbitan monooleate with chitosan microcapsules, Kawashima’s demonstrated nonionic phase-inversion mechanism using the same two surfactants, and Dee’s known freezing-resistant PRRSV disinfectant.
Each modification serves the same function taught by the respective reference. The combination does not require a reference to be bodily incorporated in its entirety (see In re Keller, 642 F.2d 413, 425 (CCPA 1981)). The question is what the combined teachings would have suggested to one of ordinary skill, not whether the features could be physically extracted without any adaptation. The reasons for combining the references arise from the problems expressly addressed in the prior art, controlled droplet size, microfluidic monodispersity, interfacial surfactant behavior, aqueous glutaraldehyde contact, and cold-temperature PRRSV disinfection, rather than solely from the applicant’s disclosure.
Finally, regarding the applicant’s alleged unexpected results, no declaration under 37 C.F.R. § 1.132 or other comparative evidence has been submitted. The specification’s indication that TPP did not maintain bead shape does not compare the claimed method with the closest glutaraldehyde-containing prior art. Likewise, an observation that polysorbate 20 produces faster separation or precipitation than SDS is not unexpected in view of the substantial chemical and HLB differences between a hydrophilic nonionic surfactant and an ionic surfactant.
The evidence also is not commensurate with every freezing-resistant PRRSV disinfectant, the full 1:5-1:20 flow-ratio range, the full 5-20 wt% sorbitan monooleate range, the full 5-10 wt% polysorbate 20 range, the full 1-4% v/v glutaraldehyde range, or every oil and microfluidic-chip configuration encompassed by claim 1. Thus, the current record does not establish unexpected results sufficient to outweigh the prima facie case.
Conclusion
No claims are allowed.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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