FINAL 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 .
Status of Claims
Claims 1-4, 6-15, 23-26, 28 and 30 are pending and presented for examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) filed 01/21/2026 has been considered by the Examiner. A signed and initialed copy of the IDS is included with the instant Office Action.
Rejections Maintained
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 6-11, 15, 23-26, 28 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over ZAKREWSKY (WO 2015/066647 A2) in view of DUFT (US 2010/0279921 A1, publication date of 04 November 2010) and KELLAR (US 2018/0093011 A1) as evidenced by CLEVELAND CLINIC (“Dermis”, electronic article, at URL: https://my.clevelandclinic.org/health/body/22357-dermis, Last reviewed 02/07/2022, obtained on 22 February 2025).
Zakrewsky is primarily directed towards compositions containing a complex that contains a cation with alkyl chains and a macromolecule anion, wherein the macromolecule anions include nucleic acids, and wherein the compositions have enhanced penetration across the skin barrier and into the skin cells (abstract).
Regarding claims 1-4, 6-8, 11 and 23, Zakrewsky discloses compositions topically applied to the skin (page 2, lines 23-24). Zakrewsky discloses that the compositions contain ILs (e.g., ionic liquids) that are able to direct delivery within the skin (paragraph bridging pages 2 and 3). Zakrewsky discloses that ionic liquids contain at least one cationic component and at least one anionic component (page 4, lines14-15). Zakrewsky discloses that the compositions preferably contain a drug to be delivered (page 4, lines 17-18). Zakrewsky discloses that the composition increases the transdermal drug delivery (page 4, lines 20-21). Zakrewsky discloses that in some embodiments, the IL (e.g., ionic liquid) is a deep eutectic solvent (DES) and exemplary DES include choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., choline cation and a fatty acid anion) (page 6, lines 20-24). Zakrewsky discloses that suitable drugs include siRNA (e.g., RNAi agent) (paragraph bridging pages 10 and 11; page 15, lines 3-4). Zakrewsky discloses use of the composition for including treating a wound (page 15, last paragraph).
Regarding claims 9 and 10, Zakrewsky discloses that exemplary molar ratios of cation:anion include 1:2 (page 5, lines 17-19). Zakrewsky discloses preparation of choline geranate by using 0.059 mol of geranic acid and 0.029 mol of choline bicarbonate (e.g., 2:1 molar ratio fatty anion to choline cation) (page 21, lines 8-11).
Regarding claims 1, 24-26, 28 and 30, Zakrewsky discloses that the composition may be selected to deliver a drug to a particular site, such as within the stratum corneum, epidermis and dermis, or through and beyond all of the layers of the skin (e.g., penetrate skin surface and reach a target depth within or beyond the skin) (page 10, lines3-5). As evidenced by Cleveland Clinic, the thickness of the dermis can be as thin as 0.6 mm and as thick as 4 mm (see the fifth page of the copy of the electronic literature).
Zakrewsky does not specifically teach from 1 µM to 500 µM of the siRNA as a drug. Zakrewsky does not specifically teach that the ionic liquid is present in the pharmaceutical composition at a concentration of from about 10% to about 90%. The deficiency is made up for by the teachings of Duft and Kellar.
Duft is primarily directed towards methods and composition comprising anti-connexin agent including anti-connexin polynucleotides for promotion and/or improvement of wounds and wound healing and/or tissue repair (abstract).
Regarding claim 1, Duft teaches use of including anti-connexin polynucleotides the treatment of wounds (paragraph [0009]). Duft teaches effective amounts of the anti-connexin polynucleotide to promote healing or tissue repair in a subject (paragraph [0011]). Duft teaches that anti-connexin polynucleotide includes siRNA (paragraph [0017]). Duft teaches that anti-connexin agent is applied at concentration of including about 10-200 µM, 200-300 µM, 300-400 µM and 400-500 µM (paragraph [0175]).
Kellar is primarily directed towards compositions for enhancing wound healing (abstract).
Regarding claims 1 and 15, Kellar teaches that the composition includes an ionic liquid. Kellar teaches that the ionic liquid is antimicrobial and that the ionic liquid includes choline geranate. Kellar teaches that the ionic liquid is present in an amount of about 0.1% w/w to about 99% w/w (paragraph [0012]). Kellar teaches an embodiment where the ionic liquid is present in an amount of about 40% w/v (paragraph [0012]). The amount of about 40% w/v lies inside the amount of “from about 10% to about 90%” and “from about 20% to about 80%”, recited in claims 1 and 15, respectively. Thus, the limitations in claims 1 and 15 are rendered prima facie obvious. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See also MPEP 2144.05.
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a topical composition comprising DES including choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., ionic liquid comprising a choline cation and a fatty acid anion) as an ionic liquid; and a drug including siRNA for promoting wound healing; wherein the concentration of the siRNA for promoting wound healing is 10-200 µM, 200-300 µM, 300-400 µM or 400-500 µM; and wherein the concentration of the DES including choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., ionic liquid comprising a choline cation and a fatty acid anion) is present in an amount of including about 40% w/v. The person of ordinary skill in the art would have been motivated to make those modifications to: 1) obtain a topical composition that provides wound healing by including siRNA promotes wound healing at a concentration of including 10-200 µM, 200-300 µM, 300-400 µM or 400-500 µM, which is taught by Duft; and 2) obtain a topical composition with optimal amount of ionic liquid to provide antimicrobial and increase in transdermal transport of the drug to be delivered (e.g., siRNA) by using the amount of ionic liquid that is taught by Kellar including of about 40% w/v. The person of ordinary skill in the art would have reasonably would have expected success because Zakrewsky discloses compositions topically applied to the skin (page 2, lines 23-24). Zakrewsky discloses that the compositions contain ILs (e.g., ionic liquids) that are able to direct delivery within the skin (paragraph bridging pages 2 and 3). Zakrewsky discloses that ionic liquids contain at least one cationic component and at least one anionic component (page 4, lines14-15). Zakrewsky discloses that the compositions preferably contain a drug to be delivered (page 4, lines 17-18). Zakrewsky discloses that the composition increases the transdermal drug delivery (page 4, lines 20-21). Zakrewsky discloses that in some embodiments, the IL (e.g., ionic liquid) is a deep eutectic solvent (DES) and exemplary DES include choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., choline cation and a fatty acid anion) (page 6, lines 20-24). Zakrewsky discloses that suitable drugs include siRNA (e.g., RNAi agent) (paragraph bridging pages 10 and 11; page 15, lines 3-4). Zakrewsky discloses use of the composition for including treating a wound (page 15, last paragraph). Duft teaches use of including anti-connexin polynucleotides the treatment of wounds (paragraph [0009]). Duft teaches effective amounts of the anti-connexin polynucleotide to promote healing or tissue repair in a subject (paragraph [0011]). Duft teaches that anti-connexin polynucleotide includes siRNA (paragraph [0017]). Duft teaches that anti-connexin agent is applied at concentration of including about 10-200 µM, 200-300 µM, 300-400 µM and 400-500 µM (paragraph [0175]). Kellar teaches that a composition includes an ionic liquid. Kellar teaches that the ionic liquid is antimicrobial and the that ionic liquid includes choline geranate. Kellar teaches that the ionic liquid is present in an amount of about 0.1% w/w to about 99% w/w (paragraph [0012]).
Regarding the recitation “to penetrate a healthy skin surface”, is directed towards the intended use of the claimed composition (e.g., used on healthy skin surface). Intended use of a claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02 [R-3]. In the instant case, Zakrewsky discloses that in some embodiments, the IL (e.g., ionic liquid) is a deep eutectic solvent (DES) and exemplary DES include choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., choline cation and a fatty acid anion) (page 6, lines 20-24). Zakrewsky discloses that the composition may be selected to deliver a drug to a particular site, such as within the stratum corneum, epidermis and dermis, or through and beyond all of the layers of the skin (page 10, lines 3-5). Zakrewsky discloses that the ionic liquid provides transdermal penetration through all layers of the skin (page 10, lines 5-9). Kellar teaches that the ionic liquid is antimicrobial and the that ionic liquid includes choline geranate. Kellar teaches that the ionic liquid is present in an amount of about 0.1% w/w to about 99% w/w (paragraph [0012]). Kellar teaches an embodiment where the ionic liquid is present in an amount of about 40% w/v (paragraph [0012]). It is obvious for one of ordinary skill in the art to determine the optimum amount of ionic liquid including an amount of about 40% w/v in order to provide a desired skin penetration and antimicrobial effect, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). In light of disclosure of Zakrewsky and the teachings of Duft and Kellar, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a topical composition comprising DES including choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., ionic liquid comprising a choline cation and a fatty acid anion) as an ionic liquid; and a drug including siRNA for promoting wound healing; wherein the concentration of the siRNA for promoting wound healing is 10-200 µM, 200-300 µM, 300-400 µM or 400-500 µM; and wherein the concentration of the DES including choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., ionic liquid comprising a choline cation and a fatty acid anion) is present in an amount of including about 40% w/v. The composition that is prima facie obvious is light of the disclosure of Zakrewsky and the teachings of Duft and Kellar contains the same ionic liquid (e.g., choline geranate) as the instantly claimed composition and in an amount that lies inside the instantly claimed amount (e.g., about 40% w/v). Thus, the composition that is prima facie obvious is light of the disclosure of Zakrewsky and the teachings of Duft and Kellar is capable of application to healthy skin surface and would penetrate the healthy skin surface.
Claims 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Zakrewsky in view of Duft and Kellar as evidenced by Cleveland Clinic as applied to claims 1-4, 6-11, 15, 23-26, 28 and 30 above, and further in view of AUNG-DIN (US 2018/0049994 A1).
Regarding claims 12-14, the composition of claim 1 is described above in section 7. Zakrewsky discloses that any dosage form suitable for delivery to the skin may be used and includes creams and lotions (page 15, lines 16-19).
Zakrewsky, Duft and Kellar do not specifically teach that the composition further comprises a pharmaceutically acceptable carrier (e.g., 12) and that the carrier is an aqueous carrier (e.g., claim 13) or comprises an ointment base (e.g., claim 14). The deficiencies are made up for by the teachings of Aung-Din.
Aung-Din is primarily directed towards a topical composition that contains a drug and a pharmaceutically acceptable topical carrier, such as including a cream and lotion (abstract).
Regarding claims 12-14, Aung-Din teaches a topical formulations comprising a drug in including an ointment and cream. Aung-Din teaches that the composition contains a carrier (paragraph [0168]). Aung-Din teaches that carrier materials suitable for the topical composition well-known for use in the cosmetic and medical arts as bases for including ointments. Aung-Din teaches that suitable carriers include water (paragraph [0188]).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a topical composition comprising DES including choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., ionic liquid comprising a choline cation and a fatty acid anion) as an ionic liquid; a drug including siRNA for promoting wound healing; and a carrier including bases for ointments or water; wherein the concentration of the siRNA for promoting wound healing is 10-200 µM, 200-300 µM, 300-400 µM or 400-500 µM; and wherein the concentration of the DES including choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., ionic liquid comprising a choline cation and a fatty acid anion) is present in an amount of including about 40% w/v. The person of ordinary skill in the art would have been motivated to make those modifications to obtain desired compositions for topical application by including carriers including bases for ointments or water. The person of ordinary skill in the art would have been motivated to make those modifications because Zakrewsky discloses that any dosage form suitable for delivery to the skin may be used and includes creams and lotions (page 15, lines 16-19). Aung-Din teaches a topical formulations comprising a drug in including an ointment and cream. Aung-Din teaches that the composition contains a carrier (paragraph [0168]). Aung-Din teaches that carrier materials suitable for the topical composition well-known for use in the cosmetic and medical arts as bases for including ointments. Aung-Din teaches that suitable carriers include water (paragraph [0188]).
Response to Arguments
Applicant argues, on pages 5 to 6, that Zakrewsky illustrates the high degree of unpredictability in the art with results that show that skin penetration differs greatly depending on the ionic liquid chosen and the compound being carried. Applicant points to figure 2A of Zakrewsky which shows that the transport and distribution of mannitol in skin layers differs depending on which ionic liquid is used as a carrier. Applicant points out that from the data of figure 2A of Zakrewsky only one out of five ionic liquids enhanced mannitol transport through the layers of skin and of the four ionic liquids that included choline as the cation, only LANL-21 enhanced mannitol transport. Applicant points out that Figure 2B of Zakrewsky shows that LANL-21 transport cefadroxil in different skin layers than mannitol. Applicant argues that in view of the difference in transport between a sugar alcohol and a cephalosporin antibiotic, a person having ordinary skill in the art would not be able to predict whether or to what degree any ionic liquid would transport any RNAi agent, which are known to pose formulation challenges due to their negative charge. Applicant cites https://www.creative- biolabs.com/gene-thierapy/sirma-in-dermatology-skinning-the-surface.htm on page 7 to show that it is known that the skin’s outermost layer called the stratum corneum has a physical and chemical barrier, and has a negative charge that prevents negatively charged molecules such as siRNA from penetrating. Applicant argues that although Zakrewsky lists “nucleic acids” amount a laundry list of drugs to be delivered, Zakrewsky fails to direct a person having ordinary skill in the art to any topical composition comprising “from 1 µM to 500 µM of each of one or more RNAi agents or pharmaceutically acceptable salts thereof, and an ionic liquid at a concentration of from about 10% to about 90% that is sufficient to allow the one or more RNAi agents or pharmaceutically acceptable salts thereof to penetrate a healthy skin surface and reach a target depth within or beyond the skin, wherein the ionic liquid comprises a choline cation and a fatty acid anion”. On page 7, applicant points to figure 1 of the instant application, and argues that it unexpectedly shows that siRNA in 50% CAGE enhances transport of siRNA through all layers of the skin, including the dermis, epidermis, and the receptor beyond. Applicant argues on page 8 that Duft recognizes the difficulty nucleotides have penetrating skin, and Duft proposes “a transdermal penetration agent such as urea”, however, Zakrewsky’s composition LANL-6 is composed of choline and urea and as show in figure 2A of Zakrewsky, fails to enhance penetration of mannitol through any layers of the skin. Applicant argues that it is unclear why a person having ordinary skill in the art would be motivated to combine Duft’s teachings concerning wound healing and/or tissue repair with Zakrewsky in a manner that would arrive at the claimed topical composition comprising an ionic liquid that allows one or more RNAi agents to penetrate a healthy skin surface and reach a target depth within or beyond the skin as claimed. Applicant argues that it is also unclear how a person having ordinary skill would reasonably expect that replacing Duft’s Pluronic gel with anionic liquid would allow an RNAi agent to penetrate a healthy skin surface. Applicant points out at the end of page 8 that Kellar is similarly directed to the field of wound healing and in particular, relates to composition for enhancing wound healing that include an ionic liquid and protein scaffold, which can be impregnated into a wound healing device such as a bandage or dressing. Applicant argues that there may have been a motivation to combine Duft and Kellar for wound healing applications or Zakrewsky and Kellar for antibiotic applications but there is not motivation to combine the cited references to arrive at the claimed topical composition that allows an RNAi agent to penetrate a healthy skin surface. Applicant argues that Kellar does not provide any reasonable expectation that any ionic liquid would successfully allow an RNAi agent to penetrate a healthy skin surface.
Applicant's arguments filed on 21 January 2026 have been fully considered but they are not persuasive. In response, In response, Zakrewsky discloses compositions topically applied to the skin (page 2, lines 23-24). Zakrewsky discloses that the compositions contain ILs (e.g., ionic liquids) that are able to direct delivery within the skin (paragraph bridging pages 2 and 3). Zakrewsky discloses that in some embodiments, the IL (e.g., ionic liquid) is a deep eutectic solvent (DES) and exemplary DES include choline oleate, choline hexanoate, choline geranate and choline malonate (e.g., choline cation and a fatty acid anion) (page 6, lines 20-24). Zakrewsky discloses that suitable drugs include siRNA (e.g., RNAi agent) (paragraph bridging pages 10 and 11; page 15, lines 3-4). Zakrewsky discloses that the composition may be selected to deliver a drug to a particular site, such as within the stratum corneum, epidermis and dermis, or through and beyond all of the layers of the skin (page 10, lines3-5). Zakrewsky discloses use of the composition for including treating a wound (page 15, last paragraph). Duft teaches effective amounts of the anti-connexin polynucleotide to promote healing or tissue repair in a subject (paragraph [0011]). Duft teaches that anti-connexin polynucleotide includes siRNA (paragraph [0017]). Duft teaches that anti-connexin agent is applied at concentration of including about 10-200 µM, 200-300 µM, 300-400 µM and 400-500 µM (paragraph [0175]). Kellar teaches that the composition includes an ionic liquid. Kellar teaches that the ionic liquid is antimicrobial and the that ionic liquid includes choline geranate. Kellar teaches that the ionic liquid is present in an amount of about 0.1% w/w to about 99% w/w, including 20% w/w (paragraph [0012]). Therefore, from the disclosure of Zakrewsky and the teachings of Duft and Kellar, one of ordinary skill in the art would have been motivated to substitute the siRNA for treatment of wound, taught by Duft, as the drug in the composition of Zakrewsky and optimized the amount of the DES including choline geranate, using the amount taught by Kellar of about 0.1% w/w to about 99% w/w, to obtain a composition with desired delivery of the drug to a desired site of the skin and, additionally, provide a desired antimicrobial effect. The composition that is prima facie obvious is light of the disclosure of Zakrewsky and the teachings of Duft and Kellar contains substantially the same ionic liquid (e.g., choline geranate) as the instantly claimed composition and in substantially the same amount (e.g., about 0.1% w/w to about 99% w/w). Thus, the composition that is prima facie obvious is light of the disclosure of Zakrewsky and the teachings of Duft and Kellar is capable of application to healthy skin surface and would penetrate the healthy skin surface.
Further, figure 2A and 2B of Zakrewsky shows that LANL-21 (e.g., cation is choline and anion is geranate) as an ionic liquid was able to provide penetration to the dermis and acceptor solution. Therefore, one of ordinary skill in the art would have been motivated to try at least the choline geranate as the ionic liquid to enhance the penetration of the siRNA of Duft as the active, and optimized the amount of the choline geranate using the amount of about 0.1% w/w to about 99% w/w, taught by Kellar, in order to obtain a composition with desired skin penetration and antimicrobial.
Thus, for the reasons of record and for the reasons presented above claims 1-4, 6-15, 23-26, 28 and 30 are rejected under 35 U.S.C. 103(a).
Conclusion and Correspondence
No claims are allowed.
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 extension fee 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 date of this final action.
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/JOHN P NGUYEN/
Examiner, Art Unit 1619
/BENNETT M CELSA/Primary Examiner, Art Unit 1600
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