DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/26/2025 has been entered.
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 08/26/2025, in which claims 1-14 are canceled and claims 15, 19, and 22 are amended.
Claims 15-25 are pending and examined on the merits herein.
Priority
The instant application claims foreign priority to KR 10-2021-0179982 filed on 12/15/2021.
Rejections Withdrawn
Applicant’s Amendment, filed 08/26/2025, with respect that claims 19-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gan has been fully considered and is persuasive, as claim 19 has been amended to limit a method of treating swelling. This rejection has been withdrawn.
Applicant’s Amendment, filed 08/26/2025, with respect that claims 15-25 are rejected under 35 U.S.C. 103 as being unpatentable over Tanizawa in view of Mehrara has been fully considered and is persuasive, as claims 15, 19, and 22 have been amended to limit a method of treating a subject who is not obese. This rejection has been withdrawn.
The following are new grounds of rejection.
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.
Claims 15-25 are rejected under 35 U.S.C. 103 as being unpatentable over Zampell et al. (Am J Physiol Cell Physiol., 2011; PTO-892) in view of Ekanayaka et al. (Journal of Ocular Pharmacology and Therapeutics, 2018; PTO-892) and Mollica et al. (Chemistry and Biology, 2007; PTO-892).
Zampell discloses a study of the spatial and temporal expression patterns of the endogenous danger signals high-mobility group box 1 (HMGB1) during wound healing and chronic lymphatic fluid stasis using a surgical mouse tail model of tissue injury and lymphedema. Zampell teaches that HMGB1 was highly expressed by lymphatic endothelial cells, and HMGB1 blockade significantly reduced inflammatory lymphangiogenesis within inflamed draining lymph nodes (abstract). Zampell teaches that sustained inflammatory responses are known to occur pathologically in lymphedema (paragraph bridging pages C1107-1108). The blockade of HMGB1 function attenuates inflammatory lymphangiogenesis (page C1108, paragraph 1). To inhibit HMGB1 function, animals in the experimental group received intraperitoneal injections of glycyrrhizin (GLZ), which is small molecule inhibitor previously described to directly bind and inhibit chemotactic and mitogenic activity of HMGB1 (page C1108, paragraph 6). Zampell concludes that blockade of HMGB1 with GLZ, a naturally occurring inhibitor of HMGB1, leads to significant reductions in inflammatory lymphangiogenesis within draining lymph nodes stimulated by CFA-OVA (page C1119, paragraph 4).
The teachings of Zampell differ from that of the instantly claimed invention in that Zampell does not teach topical administration of glycyrrhizin and thus also does not teach the claimed topical concentration range.
Ekanayaka discloses the treatment of Pseudomonas keratitis using topical glycyrrhizin (abstract). Ekanayaka states that the use of small molecule inhibitors such as glycyrrhizin or its derivatives attenuates HMGB1-mediated disease progression. The 18-β glycyrrhetinic acid moiety directly binds HMGB1, inhibiting extracellular secretion and proinflammatory effects (page 247, paragraph 2). Ekanayaka teaches that systemic administration of glycyrrhizin has side effects if used clinically, including anxiety, pain, and increased systemic drug toxicity and that the current study investigated the therapeutic efficacy of topical glycyrrhizin in order to overcome this limitation (page 239, paragraphs 2-3). Ekanayaka discloses the topical treatment of infected eyes of B6 mice with 20 mg/mL of glycyrrhizin or sterile phosphate-buffered saline as a control (page 240, paragraph 4). The topical administration of glycyrrhizin reduced HMGB1 expression in a manner consistent with other studies using glycyrrhizin administered by various routes (e.g., systemic) that also showed reduced expression of HMGB1. Ekanayaka concludes that glycyrrhizin has the ability to overcome drug delivery barriers to downregulate HMGB1 expression, regardless of the administration route (page 247, paragraph 3).
Mollica discloses a study in which glycyrrhizin, a natural anti-inflammatory and antiviral triterpene in clinical use, inhibits HMGB1 chemoattractant and mitogenic activities (abstract and paragraph bridging page 431-432). Mollica discloses the chemical structure of glycyrrhizin in Figure 1.A, which is reproduced below for convenience.
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Mollica teaches that HMGB1 has chemoattractant activity on endothelial, smooth muscle, and vessel-associated stem cells (page 432, paragraph 1), and that glycyrrhizin inhibits HMGB1-induced chemotaxis in endothelial cells (page 438, paragraph 2). Mollica discloses that glycyrrhizin inhibits the activity of HMGB1 in a dose-responsive manner (paragraph bridging paves 432-433 and figure 2).
One of ordinary skill in the art would have been motivated to modify the method of reducing reduced inflammatory lymphangiogenesis suggested Zampell by topically administering glycyrrhizin because Ekanayaka teaches that clinical systemic administration of glycyrrhizin has side effects, such as increasing systemic drug toxicity, that can be overcome by topical administration. One of ordinary skill in the art would have a reasonable expectation of success because Zampell teaches that HMGB1 blockade significantly reduced inflammatory lymphangiogenesis within inflamed draining lymph nodes and Ekanayaka teaches that glycyrrhizin has the ability to overcome drug delivery barriers to downregulate HMGB1 expression, regardless of the administration route.
Regarding the concentration range of glycyrrhizin administered in the topical composition, Mollica teaches that glycyrrhizin inhibits the activity of HMGB1 in a dose-responsive manner, and Zampell teaches that HMGB1 blockade by glycyrrhizin significantly reduced inflammatory lymphangiogenesis. It would have been prima facie obvious to optimize the dosage of glycyrrhizin in the topical compositions in the method of treating inflammatory lymphangiogenesis suggested by the combined teachings of Zampell and Ekanayaka, because Mollica teaches that the dosage of inhibits the activity of HMGB1 in a dose-responsive manner. Mollica thus teaches that dosage of glycyrrhizin is a result effective variable such that one of ordinary skill in the art would be motivated to optimize the dosage of glycyrrhizin in order to achieve an optimal effect on HMGB1 activity and thereby an optimal effect in the treatment of treating inflammatory lymphangiogenesis.
Regarding the limitation “wherein the subject is not obese”, one of ordinary skill in the art would recognize that the method of treating inflammatory lymphangiogenesis suggested by the combined teachings of Zampell, Ekanayaka, and Mollica depends on the modulation of HMGB1, which is a biochemical process that is present in the subject regardless of obesity. Therefore one of ordinary skill in the art would have a reasonable expectation of success in treating a subject who is not obese.
Regarding the limitation “wherein the application of the skin external composition to the skin increases a production and activity of reelin and/or VEGF-C, compared to control.” The instant specification indicates the effect on cells were treated with the compound represented by Chemical Formula E-1, which is glycyrrhizin. Experimental Example 2 (instant specification, beginning on page 20, line 15 and figure 2) indicates that the administration of Chemical Formula E-1 to dermal lymphatic endothelial cells further improved production and activity of reelin, compared with the control. Experimental Example 3 (instant specification, beginning on page 21, line 9 and figure 3) indicates that the administration of Chemical Formula E-1 to dermal lymphatic endothelial cells further improved production and activity of VEGF-C, compared with the control.
Although the combined teachings of Zampell, Ekanayaka, and Mollica do not teach that the application of the skin external composition to the skin increases a production and activity of reelin and/or VEGF-C compared to control, the combined teachings of the prior art teach and suggest the instantly claimed method steps, which would provide administration of a topical composition of the same chemical composition as that of the instantly claimed method, and thereby necessarily result in the same property of increasing a production and activity of reelin and/or VEGF-C. MPEP 2112.01(II) states that products of identical chemical composition cannot have mutually exclusive properties. Furthermore, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2112(I) states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer."
Response to Arguments
Applicant's arguments filed 08/26/2025 have been fully considered and are persuasive; the rejections of the Final Office Action dated 06/26/2025 have been withdrawn.
Insofar as the arguments are applicable to the instant rejections, Applicant argues that the prior art fails to teach or suggest treating a subject that is not obese and increasing a production and activity of reelin and/or VEGF-C and therefore fails to teach or suggest the limitations of amended claims 15-25. This is not persuasive.
The instant rejection renders obvious the limitation “wherein the subject is not obese”, because one of ordinary skill in the art would recognize that the method of treating inflammatory lymphangiogenesis suggested by the combined teachings of Zampell, Ekanayaka, and Mollica depends on the modulation of HMGB1, which is a biochemical process that is present in the subject regardless of obesity. Therefore one of ordinary skill in the art would have a reasonable expectation of success in treating a subject who is not obese.
Furthermore, the instant rejection renders obvious the limitation “wherein the application of the skin external composition to the skin increases a production and activity of reelin and/or VEGF-C, compared to control.” As discussed in the above grounds of rejection, the instant specification indicates that cells treated with glycyrrhizin experience improved production and activity of reelin and VEGF-C compared with the controls. Thus, although the combined teachings of Zampell, Ekanayaka, and Mollica do not teach that the application of the suggested skin external composition increases a production and activity of reelin and/or VEGF-C compared to control, the combined teachings of the prior art teach and suggest the instantly claimed method steps, which would provide administration of a topical composition of the same chemical composition as that of the instantly claimed method, and thereby necessarily result in the same property of increasing a production and activity of reelin and/or VEGF-C.
Conclusion
No claims are allowed.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693