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 .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 05/22/2026, in which claims 1-14 and 21 are canceled and claims 15, 19, and 22 are amended.
Claims 15-20 and 22-25 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.
Information Disclosure Statement
The information disclosure statement (IDS) dated 05/05/2026 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statement has been considered by the examiner.
Rejection Withdrawn
Applicant’s Amendment, filed 05/22/2026, with respect that claims 15-25 are rejected under 35 U.S.C. 103 as being unpatentable over in view of Ekanayaka and Mollica has been fully considered and is persuasive, as claims 15, 19, and 22 have been amended to limit a method of treating swelling caused by fatigue, lack of sleep, or excessive salt intake and claim 21 has been canceled. This rejection has been withdrawn.
The following are new grounds of rejection necessitated by Applicant’s amendment in which claims 15, 19, and 22 are amended to recite swelling caused by fatigue, lack of sleep, or excessive salt intake.
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 15-20 and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Cavezzi et al. (Veins and Lymphatics, 2019; PTO-892) in view of Zampell et al. (Am J Physiol Cell Physiol., 2011; PTO-892 02/25/2026), Ekanayaka et al. (Journal of Ocular Pharmacology and Therapeutics, 2018; PTO-892 02/25/2026), and Mollica et al. (Chemistry and Biology, 2007; PTO-892 02/25/2026).
Cavezzi reviews the state of the art in therapeutic management of lymphedema (abstract). Lymphedema is a chronic vascular disease resulting from an alteration of natural homeostasis with an accumulation of fluid in the interstitial matrix (page 24, paragraph 1). Among the foods which generate edema, salt, hydrogenated fats, omega 6 or 9, coffeine, theobromine, alcohol, dairies, cereals, sauces, processed meat, junk food, and sweets have been shown to increase inflammation and edema through different mechanisms (page 26, paragraph 7). In particular, excess sodium tends to retain water in the blood vessels, increases arterial pressure, and imbalances microcirculatory homeodynamics and lymphatic function, which subsequently worsens edema (page 26, paragraph 8).
The teachings of Cavezzi differ from that of the instantly claimed invention in that Cavezzi does not teach administration of a compound of formula 1.
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 (abstract). Zampell teaches that sustained inflammatory responses occur pathologically in lymphedema (paragraph bridging pages 1107-1108). The blockade of HMGB1 function attenuates inflammatory lymphangiogenesis in mouse models (page 1108, 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 1108, 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. HMGB1 thus plays a modulatory role in inflammatory lymphangiogenesis (page 1119, paragraph 4).
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.
PNG
media_image1.png
361
651
media_image1.png
Greyscale
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).
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Cavezzi, Zampell, Ekanayaka, and Mollica before the effective filing date to arrive at the instantly claimed invention. It would have been prima facie obvious to treat the lymphedema patients of Cavezzi who have worsened edema due to excess sodium by administering the glycyrrhizin of Zampell because it is prima facie obvious to apply the known technique of administering glycyrrhizin to lymphedema patients to arrive at the predictable result of attenuating inflammatory lymphangiogenesis in lymphedema patients who are experiencing worsened edema due to excess dietary sodium. One of ordinary skill in the art would have a reasonable expectation of success because Zampell teaches that glycyrrhizin is useful for the blockade of HMGB1 function, and demonstrates that the blockade of HMGB1 function attenuates inflammatory lymphangiogenesis and thereby provides treatment of the sustained inflammatory responses which occur pathologically in lymphedema.
One of ordinary skill in the art would have been motivated to topically administer the glycyrrhizin in the method of reducing reduced inflammatory lymphangiogenesis suggested by the teachings of Cavezzi and Zampell 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 discloses that glycyrrhizin inhibits the activity of HMGB1 in a dose-responsive manner, thus teaching that the 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 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 of treating cells with 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 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
Insofar as the arguments are applicable to the instant rejections, Applicant argues that because the prior art suggests administration of glycyrrhizin at a concentration of 20 mg/mL the instant disclosure obtaining an effect of increasing reelin/VEGF-C at a concentration range thousands of times lower than what is disclosed in the cited references represents an unpredictable and remarkable effect that transcends routine optimization of concentration (Remarks, page 9, paragraph 2). Similarly, Applicant argues that the prior art does not disclose activation of lymphatic function in non-inflammatory edema and that the instant claims recite substantially lower concentrations to achieve lymph activation via the promotion of reelin/VEGF-C such that one of ordinary skill in the art would not have arrived at the instant invention (Remarks, page 10, paragraphs 2-3). This is not persuasive.
The instant claims are not directed to a method of increasing the production and activity of reelin and/or VEGF-C in a subject. Rather, the instant claims are directed to a method of improving skin wrinkles or swelling caused by fatigue, lack of sleep, or excessive salt intake and further recite a property of the recited skin external composition. This property is that of increasing a production and activity of reelin and/or VEGF-C when applied according to the claimed method steps. As discussed in the above grounds of rejection, the instant specification indicates that the administration of glycyrrhizin to dermal lymphatic endothelial cells improved production and activity of reelin and VEGF-C compared to controls. The combined teachings of the prior art suggest administration of the same chemical composition through the same route 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. 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." Examiner further notes that the methods of the instant claims do not recite the treatment of non-inflammatory edema nor are they directed to methods of achieving lymph activation. Rather, the instant claims are directed to the treatment of skin wrinkles or swelling caused by fatigue, lack of sleep, or excessive salt intake.
Furthermore, Applicant does not demonstrate that unexpected results are achieved by the recited concentration, which would require showing a statistically significant comparison in a result achieved by administration of the claimed concentration as compared to the result achieved by the concentration in the closest prior art. MPEP 716.02(b) states that the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Thus the instantly claimed method is rendered obvious by the teachings of the prior art.
Applicant further argues that the prior art does not teach the wrinkle-improving effect achieved by enhancing lymphatic function in nonobese subjects (Remarks, page 9, paragraph 3). This is not persuasive.
Instant claims 15-18 and 22-25 recite a method of improving skin wrinkles or swelling. Instant claims 19-20 recite a method for improving swelling. The limitations of each of the instant claims are met by methods for improving swelling and do not require that the method be a method of treating skin wrinkles. Thus the combined teachings of the prior art suggesting treatment of swelling by topical administration of the claimed composition render obvious the limitations of the instant claims.
Applicant further argues that because the teachings of Ekanayaka are limited to administration of a higher concentration of glycyrrhizin to treat inflammation caused by Pseudomonas bacterial infection, one of ordinary skill in the art would not be motivated to modify the disclosure of Ekanayaka to arrive at a lower concentration composition for improving facial edema for cosmetic or maintenance purposes (Remarks, page 10, paragraph 1). This is not persuasive.
In the above grounds of rejection, Ekanayaka is relied upon to teach that one of ordinary skill in the art would have been motivated to administer glycyrrhizin topically in order to overcome the side effects of clinical systemic administration in the treatment of lymphedema suggested in the teachings of Zampbell, which is taught as proceeding through inhibition of HMGB1 function. Mollica discloses that glycyrrhizin inhibits the activity of HMGB1 in a dose-responsive manner, thereby teaching that the 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 the treatment suggested by the combined teachings of the prior art. Because Applicant does not demonstrate that the claimed range is critical the instantly claimed method is rendered obvious by the teachings of the prior art. Examiner further notes that the methods of the instant claims are not limited to improving facial edema nor are they limited to treatment for cosmetic or maintenance purposes.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah Grace Hibshman whose telephone number is (703) 756-5341. The examiner can normally be reached Monday-Thursday 7:30am-5:30pm (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached on (571) 270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
Prosecution Insights