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 .
DETAILED ACTION
Status of claims
The amendment filed on October 21, 2025 is acknowledged. Claim 9 has been canceled and new claim 11 has been added. Claims 6-8 have been withdrawn. Claims 1-5 and 10-11 are under examination in the instant office action.
Applicants' arguments, filed on October 21, 2025, have been fully considered but they are moot in view of new grounds of rejections which are necessitated by the amendments (newly added limitation to claim 1 and new claim 11). Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Duplicate Claims, Warning
Applicant is advised that should claim 5 be found allowable, claim 10 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 706.03(k). By amending claim 10 to be dependent from claim 1, claim 10 as amended covers the same thing as claim 5.
Claim Rejections - 35 USC § 112 (a)
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention
New matter Rejection
Claims 1-5 and 10-11 are rejected 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 as amended recites “identifying the subject as having a metabolism-related fatty liver disease characterized by decreased hepatic LC3-II and increased hepatic mTOR expression relative to a reference range”. However, the original application provides no support for this newly added limitation. The specification only discloses the expression level of mTOR and LC3II protein in the control group (Con), high-fat group (HFD), and high-fat plus artemisinin group. However, this specific experimental example, which is limited to specific subject, i.e. mice fed with high-fat and high-sugar diet, does not provide a sufficient support for the claimed genus of patient population having any metabolism-related fatty liver disease characterized by decreased hepatic LC3-II and increased hepatic mTOR expression relative to a reference range. Also, the step of identifying the subject before administering step is not disclosed in the original disclosure. Therefore, it is considered as new matter.
It should be noted that a subgenus is not necessarily described by a genus encompassing it and a species upon which it reads. The written description requirement prevents an applicant from claiming subject matter that was not adequately described in the specification as filed. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (a subgenus is not necessarily described by a genus encompassing it and a species upon which it reads). Due to lack of sufficient disclosure as stated above, the specification does not allow persons of ordinary skill in the art to recognize that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the method recited in the amended claims.
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.
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.
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.
Claims 1-4, 9, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0133997 (hereafter, Tang) in view of Sun et al. (Am J Physiol Endocrinol Metab 309: E925–E935, 2015) and Shi et al. (Phytotherapy Research, 33:1413-1425, 2019).
Tang teaches a method for promoting lipolysis and/or preventing or treating a metabolism-related disease, said method comprises administering to a subject in need thereof a therapeutically effective amount of an artemisinin analogue represented by the following general formula A:
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and R is selected from hydroxyl, methoxy, ethoxy, butanedioic acid monoester group (succinate group), 2-aminoethoxy, 2R-3-tert-butylamino-2-hydroxypropoxy, thiomorpholinyl and 1,1-dioxidothiomorpholinyl, wherein the metabolism-related disease is hyperglycemia, insulin resistance, dyslipidemia, and/or fatty liver caused by obesity (metabolism-related fatty liver disease) (abstract, [0013], [0014], [0021], and claim 19).
Tang further teaches application of the artemisinin analogue in preparing a pharmaceutical product for promoting lipid catabolism and/or prevention or treatment of metabolism-related disease (abstract).
Tang specifically discloses the artemisinin analogue represented by the formula (A) is dihydroartemisinin, with R being hydroxyl; artemether, with R being ethoxy; artesunate, with R being butanedioic acid monoester group (-OC4H5O3) ([0027], [0028], and [0038]).
Tang specifically discloses that after eight weeks of high-fat diet feeding, obvious lipid accumulation was found in the liver of mice in control group, while only a small amount of lipid was found in the liver of mice injected subcutaneously with artemether (Example 8 and [0267]). Tang teaches that the condition of fatty liver was significantly improved than that of mice in control group and subcutaneous injection of artemether effectively inhibited fatty liver induced by high-fat diet (Example 8 and [0267]).
As to claims 3-4, the claims further recite the functional property of the claimed compound (enhancing a fatty acid beta-oxidation capacity fatty of the mitochondria). While the prior art is silent about such functional property, the prior art teaches application of the same compound for treating of the same disease as claimed. Thus, the artemisinin analogues of the prior art necessarily have claimed property because products of identical chemical composition cannot have mutually exclusive properties and a chemical composition and its properties are inseparable. Furthermore, it is generally well settled in the courts that a mechanistic property of a chemical compound, or combination of chemical compounds, when administered under identical conditions, is necessarily present, despite the fact that such a property may not have been readily apparent to, or recognized by, one of ordinary skill in the art. “[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.” See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Also see In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
As to new claim 11, Tang teaches a pharmaceutical composition for promoting lipolysis and/or preventing or treating a metabolism-related disease comprising the artemisinin analogue and a pharmaceutically acceptable carrier (claim 9).
Tang does not specifically disclose “identifying the subject as having a metabolism-related fatty liver disease characterized by decreased hepatic LC3-II and increased hepatic mTOR expression relative to a reference range” as amended.
Sun teaches that autophagy plays an important role in liver triglyceride (TG) metabolism and inhibition of autophagy could reduce the clearance of TG in the live (abstract). Sun further teaches that increased production and/or decreased clearance of triglyceride (TG) in the liver inevitably results in hypertriglyceridemia (HTG) and TG accumulation in the liver can lead to nonalcoholic fatty liver disease (NAFLD) (pE925, col 1, para 1). Also, Sun teaches that reduction of liver cell autophagic activity causes decreased lipolysis and provokes free fatty acid (FFA) β-oxidation, resulting in hepatic steatosis and often progresses to NAFLD and HTG (pE925, col 1, para 1). In addition, Sun specifically discloses that in the liver of HFD-fed mice, the level of LC3BII, a key protein required for autophagosome formation, is considerably decreased and the level of mTOR, which is a key negative regulator of autophagy, is increased (pE933, col 2, para 1, Fig. 7B, pE928, col 2, para 1, and Fig. 5D).
It was known in the art that dihydroartemisinin (DHA) is not only an autophagy promoter and a potent inhibitor of mTOR as evidenced by Shi (abstract). Shi discloses that the number of autophagosomes was significantly increased in the DHA groups compared with the NC control group (Figure 2c). Also, Shi determined the expression of several autophagy-related proteins such as LC3B, which is the widely accepted marker for autophagy activity assessment, and discloses that DHA promoted the conversion of LC3B-I to LC3B-II and the expression level of LC3B-II (Fig. 2 and p1418, col 1, para 1). The experimental evidence indicated that DHA inducted LC3B-II formation and showed that DHA promoted autophagy in liver cells (p1418, col 1, para 1). In addition, Shi discloses that DHA inhibited mTOR and promoted autophagy, that enhances caspase-1 activation in HepG2215 liver cells (p1428, col 2, para 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to identify the subject as having a metabolism-related fatty liver disease characterized by decreased hepatic LC3-II and increased hepatic mTOR expression relative to a reference range because of the following reasons. It was known in the art that reduction of liver cell autophagic activity causes decreased lipolysis and provokes free fatty acid (FFA) β-oxidation, resulting in hepatic steatosis and often progresses to NAFLD and HTG as evidenced by Sun. Also, Sun shows decreased hepatic LC3-II and increased hepatic mTOR expression in the liver of HFD-fed, indicating reduction of liver cell autophagic activity in such subjects. In addition, Shi teaches artemisinin analogue such as DHA promotes autophagy in liver cells by inducing hepatic LC3-II formation and inhibiting mTOR. Thus, the skilled artisan would have been motivated to identify whether the subject has metabolism-related fatty liver disease such as NAFLD associated with reduction of liver cell autophagic activity via determining the known makers such as LC3-II and mTOR. One of ordinary skill in the art would have reasonably expected that the artemisinin analogue would be effective for those subjects due to its effects on LC3-II and mTOR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 5 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0133997 (hereafter, Tang) in view of Sun et al. (Am J Physiol Endocrinol Metab 309: E925–E935, 2015) and Shi et al. (Phytotherapy Research. 2019;33:1413–1425) in further view of Wei et al. (World J Gastroenterol 2008 January 14; 14(2): 193-199) and Bai et al. (Int J Clin Exp Med;10 (12): 16064-16074, 2017).
Tang as applied supra is herein applied for the same teachings in their entirety.
Tang does not specifically disclose that the fatty liver disease caused by obesity has liver lesions caused by a mitochondrial dysfunction and a decreased fatty acid 3-oxidation capacity, including liver steatosis, inflammation, and fibrosis in claims 5 and 10.
However, it was known in the art that obesity, hyperglycemia, type 2 diabetes and hypertriglyceridemia are most important risk factors for non-alcoholic fatty liver disease (NAFLD) and NAFLD includes liver lesions such as steatosis, inflammation and fibrosis caused by mitochondrial dysfunction including impaired mitochondrial β-oxidation as evidenced by Wei et al. (abstract, Introduction, p195, col 2, and p197, conclusion).
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the artemisinin analogues of Tang for treating a fatty liver disease such as NAFLD because the artemisinin analogues are taught to be effective for promoting fatty acid catabolism and reducing lipid accumulation and useful for treating fatty liver caused by obesity. Also, Bai et al. disclose the application of artesunate for ameliorating non-alcoholic fatty liver disease (NAFLD) by regulating the inflammatory cytokines and oxidative stress in vitro (abstract). One of ordinary skill in the art would have been motivated to do so on the reasonable expectation that the artemisinin analogues of Tang would be similarly effective for NAFLD having steatosis, inflammation or fibrosis caused by mitochondrial dysfunction including impaired mitochondrial β-oxidation via promoting fatty acid catabolism and reducing lipid accumulation as taught by Tang and by regulating the inflammatory cytokines and oxidative stress as taught by Bai et al.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611