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 .
Response to Amendments
Applicant’s amendments to the claims of November 12, 2025, in response to the Office Action of August 21, 2025, are acknowledged.
Response to Arguments
Applicant argues that the structure of the compounds taught by Kwak are different from those claimed. Further, Applicant argues that Kwak only teaches combination therapy with a Bcl-2 inhibition and a Mcl-1 inhibitor. Further, Applicant argues that none of the examples disclose data on treating NASH. Applicant argues that Narain and Liu do not disclose the claimed compound. Further, Applicant argues that unexpected results are shown for treating NASH as compound 1 significantly reduced NAS score. This is argued to be unexpected.
The examiner has thoroughly considered Applicant’s arguments and allegations of unexpected results.
The examiner notes that the structure of a compound would not somehow make it unusable as a Bcl-2 inhibitor if it known as a Bcl-2 inhibitor. The claimed compound is known to inhibit Bcl-2 and compounds that inhibit Bcl-2 are taught to treat the claimed subject population. While combination therapy is taught by the prior art as advantageous, the purpose of using an Mcl-1 inhibitor is to “enhance” the activity of a Bcl inhibitor. Thus, some level of activity would be expected even without an Mcl-1 inhibitor. Moreover, the instant claims are open-ended using “comprising” as a transitional phrase and do not exclude additional agents such as a Mcl-1 inhibitor.
The examiner also notes that examples of treating NASH are not required to provide a teaching. The prior art describes that the treatment of NASH throughout the reference. The enablement of a teaching also does not require an example. The prior art teaches a POSA how to make and use the invention throughout nothing more than routine experimentation. In at least paragraphs 289-292, the administration of Bcl inhibitors can be used to treat NASH and a model of NASH, including the STAM™ model is described for use. Even further, NASH is claimed as one of only 3 conditions in prior art claim 22.
Overall, the claimed compound is taught as a Bcl-2 inhibitor and multiple references teach treating claimed subject populations, including those with NASH, by administering the same. Unexpected results have not been shown. Applicant’s allegation that compound 1 significantly reduces NAS score is not a comparison to the closest prior art or other Bcl inhibitors to show an unexpectedly advantageous ability to treat NASH. It is a showing of efficacy. However, the prior art as a whole provides a POSA a reasonable expectation that the claimed compound would work. Efficacy is not an unexpected result.
As such, the rejections of record are maintained.
Status of the Claims
Claims 1, 3-5, 7, and 14-24 are pending and examined.
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, 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.
Claims 1, 3-5, 7, and 14-24 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al., (US2018/0354950), in view of Kwak et al., (US2021/0379078), in view of Narain et al., (US2011/0020312), in view of Liu et al., (US20190083459).
Wang teaches the following claimed compound at page 11. See compounds 6 and 13, e.g.
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As such, the claimed compounds are known for treating diseases and disorders wherein Bcl-2 inhibition provides a benefit. See par. 2. They are Bcl-2 inhibitors. Cancers that can be treated include liver cancer and hepatocellular carcinoma, among others. See par.’s 156 and 160. The compounds can be administered once or more times daily in a dosage that ranges from 0.01mg to 10 mg, 100mg, or 500 mg, e.g. See par. 164. While the claimed isomers are taught in this case, “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.” In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious).
Wang does not teach using Bcl-2 inhibitors to treat other claimed liver conditions.
Kwak teaches treating senescence-associated diseases and disorders with a Bcl-2 inhibitor. See par.’s 17 and 22. The methods treat conditions including liver disease or disorders including NASH, primary biliary cholangitis (PBC), or primary sclerosing cholangitis (PSC). See par. 37. The treatment is to eliminate senescent cells that reside in and around the liver or site of disease. See par. 287. There is an increase in burden and distribution of senescent cells in mouse model of NASH that mirrors human patients. See par. 290. Further, the NASH model ablates pancreatic cells to induce metabolic diseases and insufficient insulin formation. See par. 289. There is an elevation of p16 cells though to progress disease into cirrhosis and HCC. The compounds of the invention can be used to treat or prevent liver disease at any stage including hepatitis, NAFLD, or NASH, e.g. See par. 292. Senolytic treatment will change AST and ALT scores, among others. See par. 293. Further, the disease or disorder to be treated can also be atherosclerosis. See prior art claim 18. Overall treatment can include atherosclerosis, liver disease, and kidney disease, as non-limiting examples. See par. 253. Chronic liver disease is a result of loss of hepatocytes, fibrosis, and ultimately an increased risk for liver cancer. Further, NASH and NAFLD and these can arise from a combination of metabolic disease, diet, and predisposition. See par. 286. See Hepatic Conditions discussion par.’s 285-293. Treatment can be shown by a reduction of fibrosis. See par. 291. With respect to atherosclerosis, claimed compounds can decrease lipid concentrations of atherosclerotic plaques. See par. 298.
Further, Narain teaches treating and preventing a metabolic disorder by administering an agent that inhibits Bcl-2. See prior art claims 1 and 10. The metabolic disorder includes insulin resistance, hyperglycemia, hypertension, hyperlipidemia, and hepatic steatosis, cardiovascular disease, and arteriosclerosis. See prior art claim 26.
Wang, Kwak, and Narain do not teach obeticholic acid.
Liu teaches treating and preventing NAFLD, diabetes, cardiovascular diseases, hepatitis, liver fibrosis, liver cirrhosis, NASH, and hyperlipidemia by administering a farnesoid receptor agonist, wherein said agonist compound is obeticholic acid. See prior art claims 2 and 15. In one example 5 mg/kg obeticholic acid was administered. See Example 5.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods in view of Wang, Kwak, Narain, and Liu. One would be motivated to do so because Zhang teaches the claimed compounds to be inhibitors of Bcl-2. Kwak teaches using inhibitors of Bcl-2 to treat and prevent NASH, NAFLD, hepatitis, atherosclerosis, and others. Similarly, Narain teaches using Bcl-2 inhibitors to treat and prevent metabolic disorder includes insulin resistance, hyperglycemia, hypertension, hyperlipidemia, and hepatic steatosis, cardiovascular disease, and arteriosclerosis. Even further, Liu teaches administering obeticholic acid to treat and prevent NAFLD, diabetes, cardiovascular diseases, hepatitis, liver fibrosis, liver cirrhosis, NASH, and hyperlipidemia. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, in view of the known mechanism of Bcl-2 inhibition as well as understand the claimed agents to be result effective variables in achieving the same, it would obvious to arrive at the claimed dosages that are effective for treating claimed conditions. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). This would include administering both medicines together, sequentially or otherwise, absent a known or expected drug-drug interaction (DDI). It would also yield an optimized dosage that would have an effect secondary to the administration of the same. This would include reducing fibrosis, ballooning, and inflammation, absent evidence to the contrary.
As such, no claim is allowed.
Conclusion
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 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628