DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application is a continuation application of and claims foreign priority to PCT/CN2024/073964 filed 2024-01-25, which claims priority to CN 202310128830.1 filed 2023-02-17.
Status of the claims
The claims filed on 07/09/2026 accordingly with Applicant’s response to the non-final office action mailed on 05/19/2026 are entered onto the record. Claims 1-6, 8-21 are pending. Claim 7 was cancelled. Claims 1, 3-5, 9-13, and 15 have been amended. Claims 10-16 are withdrawn. Claims 17-21 are newly added. Claim 21 is withdrawn from further consideration pursuant to 37 CFR 1.42 (b) as being drawn to a nonelected group as it depends from previously withdrawn claim 12. Claims 1-6, 8-9, and 17-20 are currently examined.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/27/2025, 05/28/2025, 09/03/2025, 05/12/2026, and 05/13/2026 comply with the provisions of 37 CFR 1.97, 1.98, and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered on the merits.
Withdrawn Objections and Rejections
With respect to the objections and/or rejections mailed in the non-final office action mailed on 05/19/2026:
The rejection of Claims 3-5, 7, and 9 are rejected under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendments.
Response to Arguments
Applicant's arguments filed 2026-07-09 have been fully considered but they are not persuasive. The rejection of claims 1-9 under 35 U.S.C. 103 are all maintained.
Applicant Argues:
Rogers disclose “substituents R1 and R2 on the two nitrogen atoms of the imidazolium cation are defined as C1-C6 alkyl or C1-C6 alkoxyalkyl. Although the definition of R3-R5 mentions alkylamino, such alkylamino is attached to carbon atom rather than nitrogen atoms of the imidazole ring. By contrast, the substituent bonded to the nitrogen atom of the imidazole ring in the present application is aminoalkyl” and the “generic disclosure [of Col. 10, lines 53-56] covers an extremely large pool of potential compounds when taking both the broad scope of recited substituents and their variable attachment positions into account.” These arguments are not found persuasive because Roger’s teach imidazolium based ionic liquids, so even though the generic disclosure of Col. 10, lines 53-56 disclose alternative options, one of skill in the art producing imidazolium-based ionic liquids based on the teachings of Rogers would be motivated to modify the cation to include aminoalkyl substituents or substitute the cations with other similar chemical compounds with similar functional groups. Roger’s further teach “Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group, the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group.” (see id Col. 10, lines 57-63). Examiner further notes there is other supporting art in the field to motivate one of ordinary skill to modify cations of Rogers to reach the claimed invention. For example, a cation based on the teachings of Rogers include imidazolium where R1 and R2 on the nitrogen atoms of the imidazolium can be a C1-C6 alkyl. In this case, according to Barillari and Brown, the terminal CH3 is a known bioisotere for an NH2 amine group and can be substituted as such (see Table 2.2 of Barillari, C. and Brown, N. (2012). Classical Bioisosteres. In Bioisosteres in Medicinal Chemistry (eds R. Mannhold, H. Kubinyi, G. Folkers and N. Brown). https://doi.org/10.1002/9783527654307.ch2
Applicant argues “The ionic liquid compositions disclosed in Rogers are primarily intended for pharmaceutical applications… Such objectives are entirely distinct from the tissue treatment application of the present application.” However, claim 1 and dependent claims are drawn to a composition and the recitation of an intended use is not afforded any patentable weight when considering the structural limitations of the claimed formulation/composition. The recitation of an intended use of the claimed invention must result in a structural difference between the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the limit of the claim (see MPEP §2111.02 II).
Applicant argues that Wu “discloses the refractive index of ionic liquids, and the ionic liquids are applied to adjust the optical properties of photonic crystals (see, the first paragraph of the right column on page 9215). It can be seen that Wu's technical field and intended application are vastly different from those of the present application.” As discussed above, the claims are drawn to a composition and the recitation of an intended use is not afforded any patentable weight when considering the structural limitations of the claimed formulation/composition. In the instant case, Wu teaches the structural limitation (i.e., ranges of refractive index) that read on the instantly claimed invention.
Applicant further provides arguments regarding intended use of the claimed invention. However, in light of the above the prior art structure (I.e., the ionic liquids of Rogers and Wu) is capable of performing the intended use, then it meets the limit of the instant claims.
Thus, Applicant’s arguments have been fully considered but are not found to be persuasive.
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 1-5, 9, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rogers et al., (US 8,802,596 B2, published Aug. 12, 2014) (“Rogers”) and in view of Wu et al. “Determination of the refractive indices of ionic liquids by ellipsometry, and their application as immersion liquids” Applied Optics. 2018 Nov; 57, 9215-9222 (“Wu”).
Regarding claims 1 and 3, Rogers teach “ionic liquid compositions that can be used for or in biological, pharmaceutical, nutritional, cosmetic, industrial, and commercial compositions.” (see Rogers Col. 4, lines 19-21). Specifically, Rogers teach ionic compositions comprising a cation, an anion, and optionally can be combined with a pharmaceutical active compound (see id Col 14, lines 45-47).
The cation of the ionic compositions based on the teachings of Rogers may include a nitrogen-containing heterocyclic compounds (e.g., imidazolium), where “R1” may be an C1-6alkyl group (see id Col 19, lines 11- Col. 20, lines 1-22; and Col. 10, lines 53-56).
Therefore, a cation based on the teachings of Rogers encompasses an N-(aminoC1-6alkyl)-imidazole, such as 1-(3-aminopropyl)-imidazole, which reads on claim 1 and 3.
The anion of ionic compositions based on the teachings of Rogers may include may include salicylic acid (i.e., an aromatic monocarboxylic acid) (see id Col. 24, Lines 15-20), which reads on the required anion of claim 1.
Rogers additionally teach that water can be present in the ionic liquid formulations where “water is present at less than about 10,9,8,7,6, 5, 4, 3, 2, 1, 0.5, 0.25, or 0.1 wt.%, based on the total weight of the composition” (see Col 14, lines 54-56). The amount of water that Rogers teach overlap with the amount of water as instantly claimed. MPEP §2144.05(I) states “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists”, see also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941).
Regarding the amounts of the components of the composition required by instant claims 1 Rogers teach that compositions disclosed therein may contain “nonionic species... and the amount of such nonionic species is typically low (e.g., less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 wt % based on the total weight of the composition” (see Col. 13, lines 36-43). MPEP 2144.05 (II) states “differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” and, the instant application fails to provide evidence that the claimed amounts recited in instant claims 1 are critical.
See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382, “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) “It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”
Regarding instant claim 2, Rogers teach that “the particular ratio of ions will depend on the type of ion and their respective charges, the disclosed ionic liquids can have a cation to anion ratio of 1:1, 2:1, 3:1, 4:1, 1:3, …” (see id Col. 140, lines 43-53).
Regarding instant claim 4, Examiner also notes that Rogers teach the anion may also be benzoate (see id Col. 24, Lines 15-20). Examiner further points to Rogers Col. 14, line 57-Col. 15, line 2:
The disclosed ionic liquid compositions can be prepared by methods described herein. Generally, the particular cation(s) and anion(s) used to prepare the disclosed ionic liquids are selected as described herein. Then, with the particular cation(s) and anion(s) in hand, they can be combined, resulting in ionic liquid compositions as disclosed herein. Additionally, the method for the preparation of the disclosed ionic liquid compositions can include the reaction in which two neutral species: an anion precursor (e.g., in the form of an inorganic acid, carboxylic organic acid, non-carboxylic acid, or Zwitterion species) and a cation precursor (e.g., inorganic base, organic base, Zwitterion species) are combined resulting in ionic liquid compositions as disclosed herein.
Therefore, the anion as taught by Rogers encompasses the precursor of benzoate (i.e., benzoic acid), which is an aromatic monocarboxylic acid and reads on instant claims 1 and 4.
Regarding instant claims 5 and 18, which depend from claim 1, further limit the particular preparation of component C) (i.e., water) to be used in the composition of claim 1. Specifically, instant claims 5 and 18 further limit the degree to which the water has been purified. Examiner notes that the instant disclosure only discloses preferred embodiments “ultrapure water, preferably deoxygenated ultrapure water” (see specification. para. [0030]) but does not provide any specific rationale on the criticality of the purity of the water used in the compositions disclosed therein. Therefore, one of skill in the art at the time of filing of the instant application and based on the instant disclosure would be motivated through methods of routine optimization to test compositions that include water of various preparations (i.e., with different levels of purity) to limit impurities in the final products. MPEP §2144.05 (II)(A) states that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”).
In the instant case, where the prior art teaches compositions that read on instant claim 1 and the further limitations required by instant claims 5 and 18 only differ in the level of purity (or amounts of impurities) the use of ultrapure water and deoxygenated ultrapure water are obvious in view of Rogers.
Regarding claims 9, 19, and 20, Rogers is silent on the refractive index of the imidazolium-based ionic liquids disclosed therein. However, in the same field Wu teach that “In principle, ionic liquids (ILs) can serve as stable and less harmful high-refractive index liquids (n > 1.6)” (see Abstract). Wu further disclose that imidazolium-based ionic liquids are “high-index ionic liquids” with refractive indices greater than n = 1.7 (see Results and Discussion, para. B Figure 2; Table 3). Therefore, based on the teaching of Wu that imidazolium-based ionic liquids can have high refractive indices, one of skill in the art would be motivated to combine the teachings of Wu with the ionic liquid compositions of Rogers, or Davis, to make ionic liquid compositions that read on the instantly claimed invention with refractive indices greater than 1.5 with a reasonable expectation of success.
Thus, claims 1-5, 9, and 17-20 are obvious in view of Rogers and Wu.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Rogers et al., (US 8,802,596 B2, published Aug. 12, 2014) (“Rogers”), as applied to claims 1-5, 9, and 18-20 above, and in further view of Hettegger et al. “Fiber Spinning from Cellulose Solutions in Imidazolium Ionic Liquids: Effects of Natural Antioxidants on Molecular Weight, Dope Discoloration, and Yellowing Behavior” 2022 June, Fibers 2022, 10(6), 50; https://doi.org/10.3390/fib10060050 (“Hettegger”), and AlSwisi et al., ( US 9211336 B2, published Dec. 15, 2015) (“AlSwisi”).
Regarding claim 6, Rogers differs from the instantly claimed invention in that it does not explicitly teach that ionic liquids disclosed therein also include potassium pyrosulfite as an auxiliary agent. The instant disclosure includes pyrosulfite (i.e., metabisulfite) as a reducing agent (see para. [0024]).
AlSwisi teach stabilized pharmaceutical formulations comprising antioxidant stabilizers (i.e., an adjusting agent, and the reducing agent of the instantly claimed invention) including potassium metabisulfite (see Col. 2, lines 46-52). One of skill in the art of ionic liquids motivated to add adjusting and/or reducing agents to their formulations to prevent oxidation of other components in the mixture, would rely on the teachings of AlSwisi and be motivated to try various antioxidant compounds including potassium sulfite to achieve expected resultsSee MPEP §2143 (I)(C) and (E).
Thus, claim 6 is obvious in view of Rogers and in further view of AlSwisi.
Claims 8 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Rogers et al., (US 8,802,596 B2, published Aug. 12, 2014) (“Rogers”) as applied to claims 1-5, 9, and 18-20 above, and Hettegger et al. “Fiber Spinning from Cellulose Solutions in Imidazolium Ionic Liquids: Effects of Natural Antioxidants on Molecular Weight, Dope Discoloration, and Yellowing Behavior” 2022 June, Fibers 2022, 10(6), 50; https://doi.org/10.3390/fib10060050 (“Hettegger”), AlSwisi et al., ( US 9211336 B2, published Dec. 15, 2015) (“AlSwisi”), de Sousa Ramos et al., “Carboxyl-functionalized ionic liquids: synthesis, characterization and synergy with rare-earth ions”, May 2016, J Mater Chem C 2018 6, 6270-6279. https://doi.org/10.1039/c8tc00658j (“de Sousa Ramos”), Matsumoto et al., “Advanced CUBIC tissue clearing for whole-organ cell profiling”, Dec. 2019, Nat Protoc 14, 3506–3537 (2019). https://doi.org/10.1038/s41596-019-0240-9 (“Matsumoto”), Murakami et al., “A three-dimensional single-cell-resolution whole-brain atlas using CUBIC-X expansion microscopy and tissue clearing”, Mar. 2018, Nat Neurosci 21, 625–637 (2018). https://doi.org/10.1038/s41593-018-0109-1 (“Murakami”), and Zhu et al., “MACS: Rapid Aqueous Clearing System for 3D Mapping of Intact Organs”, Feb. 2020, Adv Sci (Weinh);7(8):1903185. doi: 10.1002/advs.201903185 (“Zhu”),
Regarding claim 8, which depends from claim 1, and recites a formulation of an ionic liquid:
Regarding the inclusion of 1-(3-aminopropyl)-imidazole, as discussed above, Rogers teach cations that read on this limitation.
Regarding the inclusion of phthalic acid, required in claims 8 and 17, Rogers teach the anion may also be saccharinate (see id Col. 4, Lines 15-20). As discussed above, Rogers teach that anions encompass the precursors of saccharinate (i.e., saccharic acid, which is a dicarboxylic acid. Although Rogers teach various aromatic monocarboxylic acids and dicarboxylic acids, Rogers does not disclose that the anion can be phthalate or its precursor phallic acid. However, de Souza Ramos teach synthetic methods of producing imidazolium-based ionic liquids and the use of phthalic anhydride to produce ((2-(3-methylimidazolyl-1-yl)-ethoxy) carboyl)-benzoic-phthalic acid bromide (see pg. 6271, para. 5). Examiner notes that the instant disclosure only discloses preferred embodiments “phthalic acid… or the like” (see specification. para. [0028]) but does not provide any specific rationale on the criticality of the particular use of phthalic acid in the compositions disclosed therein. One of skill in the art would be knowledgeable on various monocarboxylic acids and dicarboxylic acids and based on the teachings of de Souza Ramos in view of Rogers would be motivated to choose the particular species of phthalic acid as the dicarboxylic acid with a reasonable expectation of success as an anionic species to arrive at the instantly claimed invention. See MPEP§ 2143 (I) (B).
Thus, it would be obvious to one of skill in the art to substitute one dicarboxylic acid (e.g., phthalic acid) for another dicarboxylic acid as taught by Rogers (e.g., saccharic acid) to make compositions that read on the instantly claimed invention.
Regarding the inclusion of nicotinamide, Matsumoto disclose nicotinamide as a reagent used in the Tissue-clearing process (see pg. 3520), Tissue-clearing and nuclei-staining reagents; pg. 3523, CUBIC-R+(N)). One of skill in the art, would be motivated to include nicotinamide as an auxiliary agent for methods of tissue-clearing disclosed by the instant application based on its use in known methods of tissue clearing as taught my Matsumoto. See MPEP 2143(I)(A).
Regarding the inclusion of antipyrine, Murakami disclose antipyrine as a reagent used in the Tissue-clearing process (see pg. 626, para. 3) for its “remarkable water solubility and high molar refractivity (see pg. 6262, para. 5). Murakami demonstrated that methods that “achieve both tissue expansion and RI matching” the inclusion of antipyrine had “significant synergistic effect of imidazole and antipyrine” (see pg. 626, para. 4, Fig. 1F) One of skill in the art, would be motivated to include antipyrine as an auxiliary agent for methods of tissue-clearing disclosed by the instant application based on its use in known methods of tissue clearing as taught my Murakami. See MPEP 2143(I)(A).
Regarding the inclusion of m-xylylenediamine (i.e., MXDA), Zhu teach the use of m-xylylenediamine in tissue optical clearing techniques (see Abstract). Zhu disclose that “MXDA was found to have great potential in tissue clearing. MXDA is a colorless and water miscible liquid with good fluidity and has two NH 2 groups “and solutions including m-xylylenediamine “provided increased performance in both clearing effect and fluorescence preservation” (see pg. 2, para. 4; Fig. S1a, c-h). One of skill in the art, would be motivated to include m-xylylenediamine as an auxiliary agent for methods of tissue-clearing disclosed by the instant application based on its use in known methods of tissue clearing as taught my Zhu. See MPEP 2143(I)(A).
Regarding the inclusion of potassium pyrosulfite, as discussed above, one of skill in the art relying on the teachings based on Roger and in view of Hettegger would be motivated to include potassium pyrosulfite for its antioxidant and reducing properties.
Regarding the amounts of the components of the composition required by instant claim 8, Rogers teach that compositions disclosed therein may contain “nonionic species... and the amount of such nonionic species is typically low (e.g., less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 wt % based on the total weight of the composition” (see Col. 13, lines 36-43). MPEP 2144.05 (II) states “differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” and, the instant application fails to provide evidence that the claimed amounts recited in instant claims 1 are critical.
See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382, “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) “It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”
Thus claims 8 and 17 are obvious over the combined teachings of Rogers, Hettegger, AlSwisim, de Sousa Ramos, Matsumoto, Murakami, and Zhu.
Conclusion
No claims are allowed in this action.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALAN J FOWLER/ Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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