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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/14/2026 has been entered.
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
Claims 1, 3, 5, 7-9 and 16 are pending and under examination. Claims 2, 4, 6, 10-15, and 17-19 are canceled.
Action Summary
The rejection of claims 1, 3, 5, 7-9 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) is maintained.
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, 5, 7-9 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.
Applicant’s argument
Applicant’s arguments and evidence of unexpected results have been fully considered but are not persuasive.
Applicant argues that the combination of Cur5-8 and EW-7197 produces an unexpected synergistic effect, including suppression of lipid accumulation, while maintaining anti-fibrotic activity. Applicant relies, inter alia, on the in vivo results of Examples 2-1 and 2-2 obtained using an MCD diet-induced steatohepatitis mouse model.
The Examiner acknowledges that amended claims 1 and 16 are now limited to Cur5-8 in combination with EW-7197 and that Applicant’s in vivo experiments therefore concern the particular active agents presently claimed. The Examiner further acknowledges that the reported experiments provide evidence of advantageous effects for the tested combination under the particular experimental conditions employed. The evidence has accordingly been afforded appropriate probative weight.
Nevertheless, objective evidence of unexpected results must be reasonably commensurate in scope with the claims relied upon. MPEP §716.02(d); In re Clemens, 622 F2d 1029, 1036 (CCPA 1980); in re Peterson, 315 F.3d 1325, 1330-31 (Fed. Cir. 2003). Although evidence need not test every embodiment literally encompassed by the claim, a narrower experimental showing must provide an adequate basis for reasonably extending the demonstrated result to the broader claimed scope.
Here, Examples 2-1 and 2-2 employ particular experimental conditions. Cur5-8 was provided with the MCD diet at 1 g/kg diet, and EW-7197 was orally administered at particular tested doses, including 40 mg/kg in Example 2-1 and 5 mg/kg in Example 2-2. The amount of 1g Cur5-8/kg diet is a dietary concentration, not a Cur5-8 dose expressed as mg/kg body weight. Thus, the experiments provide evidence for particular orally administered Cur5-8/EW-7197 treatment regimens. Independent claims 1 and 16, however, are not limited to those doses, relative amounts, dosing frequencies, treatment durations, or routes of administration. Claim 5 additionally encompasses a broad Cur5-8/EW-7197 molar-ratio range of 1:15 to 15:1.
Applicant’s contention that the MCD model reproduces hepatic steatosis, liver fibrosis, and steatohepatitis has also been considered. Even accepting the MCD model as an appropriate model for studying the recited liver pathologies, this does not establish that the asserted synergistic effect demonstrated under the particular tested dosing and administration conditions reasonably extends throughout the broader treatment conditions encompassed by the claims. Moreover, the art (Li et al., Toxicology Sciences, 161(1), 2018, 23-33) cited solely to rebut Applicant’s argument, recognizes limitations associated with extrapolation from the MCD model. Li et al. explain that, due to recognized limitations of the model, use of the MCD model to examine metabolic parameters or study NASH pathogenesis should be discouraged. See p. 25, left col. paragraph immediately preceding the heading “MCD model reflecting ADME alterations in human NASH. Li et al. further identify that species-dependent differences in dru-metabolism enzymes and explain, in the context of CYP3A-associated drug metabolism, that the rodent MCD model may not accurately reflect human response. See p. 26, right col.
More importantly, Applicant has not identified experimental evidence or a demonstrated trend establishing that the asserted synergy persists across the substantially broader dosing, patient population, and administration conditions encompassed the claims. Claim 5 further encompasses a molar ratio of Cur5-8 to EW-7197 ranging from 1:15 to 15:1; whereas Applicant’s in vivo evidence is limited to the particular amounts and administration conditions, and patient population evaluated in Examples 2-1 and 2-2. Applicant has not established a trend from which one of ordinary skill in the art could reasonably extend the asserted synergistic effect throughout that claimed ratio range. See MPEP §716.02(d).
Accordingly, While Applicant’s evidence is probative of advantageous results for the particular Cur5-8/EW-7197 embodiments tested and has been afforded appropriate weight, the evidence is not reasonably commensurate in scope of the pending claims and is sufficient, when considered together with the evidence of record, to outweigh the prima facie case of obviousness. The rejection under 35 U.S.C. § 103 is therefore maintained.
Conclusion
Claims 1, 3, 5, 7-9 and 16 are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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