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
This application is a national stage application of PCT/KR2022/006873 filed 13 May 2022, which claims priority to Korean Patent Application No. 10-2021-0082417 filed 24 June 2021, and Korean Patent Application No. 10-2021-0160931 filed 22 November 2021.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on December 05, 2025. Claims 1, 3-9 and 16 are pending and under examination. Claims 2, 10-15 are canceled.
Action Summary
Claims 3 and 16 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in light of the claim amendment.
Claims 1, 3-9 and 16 rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (Metabolism, Volume 103, February 2020, 154015) in view of Nair et al (Journal of Receptors and Signal Transduction, Volume 40, Issue 3, published online February 13, 2020) Kim et al (Cellular Physiology and Biochemistry (2016) 38 (2): 571–588). Kim is cited in the IDS filed on 03/10/2023, are maintained.
New Rejection necessitated by claim amendment
Claim Rejections - 35 USC § 112
(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 the applicant regards as his invention.
Claim 16 is 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 (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. It is not clear how claim 3 recites a composition whereas claim 1 recites a preparation. There is insufficient antecedent bases for composition in claim 3.
With respect to claim 16, the claim recites “…. administering a preparation containing a curcumin derivative or pharmaceutically acceptable salts thereof; and a TGF-β receptor inhibitor or pharmaceutically acceptable salts thereof, as active ingredients, in complex with a vehicle ….” It is not clear if it is the preparation (i.e. the combination of curcumin derivative and a TGF-β receptor inhibitor) that is in complex with a vehicle, or just the curcumin derivative that is in complex with a vehicle or just the TGF-β receptor inhibitor that is in complex with a vehicle. Additionally, the lack of specificity of a vehicle impacts the clarity of the claim. Without defining the vehicle, it is hard to pinpoint exactly what’s being protected. That means the claim is indefinite also because it recites in complex with a vehicle, because the specification fails to define or describe the vehicle. As a result, a person skilled in the art cannot determine the exact scope of the invention.
Maintained 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 1, 3-9 and 16 remain rejected under 35 U.S.C. 103 as being unpatentable over Lee et al (Metabolism, Volume 103, February 2020, 154015) in view of Nair et al (Journal of Receptors and Signal Transduction, Volume 40, Issue 3, published online February 13, 2020) Kim et al (Cellular Physiology and Biochemistry (2016) 38 (2): 571–588). Kim is cited in the IDS filed on 03/10/2023.
Lee teaches a method of treating non-alcoholic fatty liver disease (NAFLD) comprising administering an effective amount of 100 mg/kg Cur5-8 (a curcumin derivative and as an active ingredient)
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to a subject, where Cur5-8 CUR5–8, decreases the elevated liver triglyceride level induced by the high fat diet. (See Abstract) Moreover, Lee teaches the administration is oral as the rat fed the Cur5-8. (See Section 2.2.) Said feed encompasses a solution.
Lee does not teach a TGF-β receptor inhibitor.
Nair teaches during NAFLD, increased oxidative stress and production of enormous number of toxic free radicals activates a number of pro-inflammatory and inflammatory pathways. TGF-β signaling mechanisms play a central role in maintaining the normal homeostasis of liver. Transforming growth factor β (TGF-β) signaling mechanisms play a central role in maintaining the normal homeostasis of liver. TGF-β1, one of the three isoforms of TGF-β family has significant role in different stages of chronic liver conditions. TGF-β1 promotes hepatic stellate cells (HSC) activation and extracellular matrix production (ECM), which further contributes in the progression of NAFLD. In this review, we outline the role of TGF-β1 in different phases of progressive NAFLD along with the signaling mechanism. (See Abstract.)
Kim suggests the use of EW-7197 in the amount of 20 mg/kg and 40 mg/kg orally as an active ingredient and as potential treatment for liver fibrosis because inhibits TGF-β signaling. (See Abstract and Experimental design, and Discussion Section.) Nair further taches EW-7197 was dissolved in vehicle and administered orally. (See last paragraph of page 3.) The fact that EW-7197 was dissolved in a vehicle implies that mixture is a solution. While Kim does not expressly teach EW-7197 is a TGF-β receptor AKL4 (Activin receptor-like kinase 4) or AKL5 (Activin receptor-like kinase 5), the instant specification at the last paragraph of page 2 is taken as evidentiary that EW-7197 is a TGF-β receptor AKL4 (Activin receptor-like kinase 4) or AKL5 (Activin receptor-like kinase 5).
With respect to the molar ratio between Cur5-8 and EW-7197 is 1:15 to 15:1. The 100 mg/kg becomes 0.100 mg. The 40 mg becomes 0.040 mg. The formula weight for Cur5-8 is 339.39 g/mol and for EW-7197 is 399.42 g/mol>
To convert mg/kg to mol/g
Mol/g = (mg/kg) / (1000 g/kg * Fw g/mol).
Cur5-8; 100 mg/kg / 1000 g/kg * 339.39 g/mol = 2.946 mol/g
EW-7197; 100 mg/kg / 1000 g/kg * 399.42 g/mol = 2.504 mol/g, so
The molar ratio is 2.9: 2.5.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine the method taught by Lee with the method set forth in Kim in a ratio of 2.9: 2.5 because each is taught by the prior art to be useful for the same purpose (i.e., NAFLD). See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, a person of ordinary skill in the art would reasonably have expected to be successful because both compositions were shown to be useful separately for the exact same purpose and thus would be expected to be similarly useful when used together. EW-7197 is a TGF-β receptor can be reasonably be expected to treat NAFLD because Nair teaches Transforming growth factor β (TGF-β) signaling promotes hepatic stellate cells (HSC) activation and extracellular matrix production (ECM), which further contributes in the progression of NAFLD.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on December 05, 2025.
Applicant’s argument
Applicant argues none of the cited references suggest that EW-7197 could be administered together with CUR5-8 (or any other curcumin derivative) with any reasonable expectation of success in treating or ameliorating a metabolic liver disease. Nothing in the cited references suggests that the combination of CUR5-8 and EW-7197 could be used to successfully treat or ameliorate a metabolic liver disease, let alone with any degree of predictability.
Examiner’s response
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the present case, even though the references alone or in combination do not explicitly teach CuR5-8 and EW-7197 for treating NAFLD, the in re Kerkoven analysis drawn on their independent mechanism of action. The argument is that each compound has demonstrated efficacy in NAFLD, and their distinct pathways provide a plausible, even predictable, synergistic effect. A person of ordinary skill in the art would reasonably expect a combined effect for the treatment of NAFLD.
Applicant’s argument
Applicant argues surprising improvements are evidenced by the experimental data summarized in Applicant's specification. In Applicant's Example 1, treatment with EW-7197 alone exhibited antifibrotic effects in hepatocytes where fibrosis was induced (see Figures 2 and 3), but also showed increased lipid synthesis as a side effect (see Figures 8 and 9). However, co-treatment with [EW-7197 + CUR5-8] demonstrated both inhibition of epithelial- mesenchymal transition (EMT) and hepatic fibrosis, and a markedly improved inhibition of lipid synthesis. Notably, the lipid synthesis inhibition was superior even to the combination of [EW- 7197 + curcumin] (see in particular Figure 9, reproduced below).
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. Applicant’s Example studied the therapeutic effect of the preparation in an animal model of steatohepatitis. The CUR5-8 monotherapy group did not improve fibrosis, and the EW-7197 monotherapy group did not reduce lipid accumulation. However, the [EW-7197 + CUR5-8] combination group exhibited both antifibrotic and lipid accumulation-reducing effects, thereby demonstrating a synergistic therapeutic effect (see Figures 19-24). Furthermore, similar synergistic effects were observed in Examples 1-5 when EW-7197 was combined with other curcumin derivatives such as DHZ, DHZ103, or DHZ176. As shown in Figsures 16-18, co-treatment with [DHZ + EW-7197], [DHZ103 + EW-7197], or [DHZ176 + EW-7197] inhibited EMT and hepatic fibrosis, and reduced lipid accumulation to a degree comparable to [CUR5-8 + EW-7197]. In fact, the synergistic effects were superior to those of [curcumin + EW-7197] (see Figure 17, reproduced below).
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. In sum, the recited preparation overcomes the adverse effects of EW-7197 and produces a synergistic effect in the treatment and amelioration of metabolic liver diseases-an effect that is unexpected and could not have been predicted from the cited references.
Examiner’s response
In response, Applicant’s argument is not persuasive. While Applicant has provided in vitro data showing a synergistic effect of overcoming the adverse effect of EW-7197 and ameliorating liver function with a combination of 0.5 µM/10 µM EW-7197 and 0.1 µM/1µM Cur5-8, this data is limited to a controlled cellular environment and does not reflect the complexity of in vivo data pharmacokinetics, biodistribution, or actual administration to a subject that is defined to be an animal or a human and not a cell. Again, the cited references independently teach the use of CUR5-8 and EW-7197 alone for treating NAFLD, and there is no evidence that the observed synergy would be predictable or necessary to cover the full broad claimed scope. Thus, these in vitro findings do not constitute an unexpected result that would overcome the prior art teachings. Moreover, the experimental in vivo data, while unexpected using oral administration of 1g/kg (1000 mg/kg) CUR5-8 and 5 mg/kg/40 mg/kg EW-7197 in an animal subject for treating NAFLD/steatohepatitis, is not fully commensurate in scope with the claim. The claim broadly encompasses metabolic liver disease without specifying the type, administration route, or amount/doses. Thus, even though the animal model provides interesting and surprising synergistic results, it does not establish a direct correlation with the full scope of the claimed invention.
Conclusion
Claims 1, 3-9 and 16 are not 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 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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/JEAN P CORNET/Primary Examiner, Art Unit 1628