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 .
Status of Claims
Claims 1, 3-5, 13, 17-18, 29-30, and 47-56 are pending.
Priority
Instant application 17/924,101, filed 11/08/2022 claims priority as follows:
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Information Disclosure Statement
All references from IDS(s) received 12/29/2025 and 01/15/2025 have been considered unless marked with a strikethrough.
Response to Amendment/Arguments
The amendment filed 12/23/2025 has been entered. Applicant has amended claims 1, 3, and 4. Claims 2, 6-12, 14-16, 19-28, and 31-46 are cancelled.
Claims 1, 3, and 4 were previously rejected under 35 U.S.C. 102(a)(1) as being anticipated by KEMP as evidenced by PUBCHEM. In view of the amendments to claims 1, 3, and 4, applicant has overcome the rejection under section 102 raised in the Non-Final action dated 6/25/2025. Therefore, the previous rejection under 35 U.S.C. 102(a)(1) is withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 13, 47-48, and 52-53 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 13 depends from a canceled claim; also claim 13 recites a frequency ranging from once weekly to three times a day but claim 1 already requires daily dosing (“1 mg/day to 100mg/day”). Claims 47-48 recite orally administering a plurality of doses and a frequency ranging from once weekly to three times a day but claim 3 already requires a plurality of doses and daily dosing. Claims 52-53 recite orally administering a plurality of doses and a frequency ranging from once weekly to three times a day but claim 4 already requires a plurality of doses and daily dosing.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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, 3-4, 12-13, 47-48, and 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over:
KIM (Emerging Trends Conference: Emerging Trends in Non-alcoholic Fatty Liver Disease. 2017; cited previously); as evidenced by
PUBCHEM (Larsucosterol. https://pubchem.ncbi.nlm.nih.gov/compound/11583880); and in view of
KEMP (EASL International Liver Congress. 2017; cited previously).
KIM teaches that DUR-928 (which is 25HC3S as evidenced by PUBCHEM) exhibits anti-inflammatory and anti-fibrotic activity in a mouse model of NASH. KIM teaches orally administering daily doses of 10 or 50 mg/kg DUR-928 for a period of four weeks (page 2, “Dosing regimen”). Additionally, KIM teaches the following conclusions of the study (page 6, “Summary and Conclusions”):
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The differences between KIM and the instant claims are that (i) KIM discloses administering DUR-928 to mice rather than human subjects; and (ii) KIM discloses doses in units of mg/kg rather than mg.
However, KEMP teaches that pre-clinical data have demonstrated that DUR-928 is well tolerated and can reverse certain histopathological changes associated with Non-alcoholic Steatohepatitis (NASH); and that previous studies in healthy subjects indicated that DUR-928 was well-tolerated with no significant drug-related adverse events (page 1, “Introduction”). Further, KEMP teaches orally administering DUR-928 to biopsy-confirmed human NASH patients in a dose of 50 mg or 200 mg (page 2, “Methods”), and teaches that such doses were well tolerated (page 3, “Results”).
Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (G), it would have been prima facie obvious to modify the method of KIM to treat human subjects having NASH using the doses taught by KEMP. A person having ordinary skill would have been motivated to modify KIM in view of KEMP’s teaching of doses that are safe and tolerable in human subjects, and in view of the improvement in biomarkers disclosed by KEMP. The modification would have resulted in a method comprising administering a plurality of doses at a dosing frequency of once per day, over a period of at least 28 days, in a dose of 50 mg or 200 mg to human subjects with NASH.
In addition to the individual teachings identified in the cited references, please also note that differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating the value of the result-effective variable is critical. See MPEP 2144.05. In the instant case, the dose of 25HC3S and the dosing period of 25HC3S are considered result-effective variables which, absent a showing of criticality, a person having ordinary skill could have optimized by routine experimentation.
Therefore, in view of the foregoing, claims 1, 3-4, 13, 47-48, and 52-53 are prima facie obvious.
Claims 5, 17-18, 49-50, and 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over:
KIM as evidenced by PUBCHEM, in view of KEMP applied to claims above, and further in view of
REN (US 20100273761 A1; cited in IDS).
The teachings of KIM in view of KEMP are disclosed above and at least those teachings are incorporated herein by reference.
With respect to claim 5, the difference is that KIM and KEMP are silent about the human subject having serum triglycerides greater than or equal to 200 mg/dL prior to treatment.
However, REN teaches 25HC3S to treat and prevent of conditions associated with high levels of serum lipids, wherein serum lipids include cholesterol and triglycerides (see e.g. claims 3-9 and para. [0010]). In particular, REN teaches treating the condition NASH (see e.g. claim 9), and teaches that the terms “high lipid level” and “high triglyceride level” generally related to cholesterol levels in the serum in the range of about 200 mg/dl or more, and triglyceride levels in the serum greater than 150 mg/dl or more (see e.g. [0055]).
Finding of prima facie obviousness
Applying KSR example rationale (G), it would have therefore been prima facie obvious to modify the method of KIM in view of KEMP to administer 25HC3S to human subjects having serum triglycerides greater than or equal to 200 mg/dL prior to treatment. A skilled artisan would have been motivated to modify the method of KIM in view of KEMP because REN teaches that 25HC3S is effective for lowering high triglyceride levels and for treating lipid-associated inflammation in a patient with NASH.
Therefore claim 5 is prima facie obvious.
With respect to claims 17-18, 49-50, and 54-55, the difference is that KIM and KEMP are silent about administering 25HC3S in a formulation comprising a pharmaceutically acceptable carrier, or administering 25HC3S as a salt.
However, it is routine in the pharmaceutical arts to administer compounds in formulations comprising a carrier, and to administer compounds as pharmaceutically acceptable salts. Moreover, REN teaches that 25HC3S may be administered in a pharmaceutically acceptable formulation including suitable carriers, or as pharmaceutically acceptable salts (see para. [0058]).
It would have therefore been prima facie obvious to formulate 25HC3S in the method taught by KIM in view of KEMP as a salt or with a carrier.
Therefore claims 17-18, 49-50, and 54-55 are prima facie obvious.
Claims 29-30, 51, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over:
KIM as evidenced by PUBCHEM, in view of KEMP applied to claims above, and further in view of
HARADA (US 20160030378 A1, cited in IDS).
The teachings of KIM in view of KEMP are disclosed above and at least those teachings are incorporated herein by reference.
With respect to claims 29-30, 51, and 56, the difference is that KIM and KEMP are silent about the human subject taking a lipid lowering drug or statin selected from those in the claims.
However, the lipid lowering drugs and statins recited in the claims were previously taught in the prior art for treating NASH. For example, HARADA teaches compositions and methods for treating NASH, and teaches those recited in the instant claims for treating NASH (see e.g. para. [0222], para. [0230], para. [0275], para. [0286]).
Finding of prima facie obviousness
As recognized in MPEP 2143, examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results.
Moreover, as recognized by MPEP § 2144.06(I):
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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Therefore, applying KSR example rationale (A), it would have been prima facie obvious to combine 25HC3S with the lipid lowering drugs and statins taught by HARADA to treat patients with NASH. As noted above, the motivation to combine flows logically from their having been individually taught in the prior art for treatment of the same disorder(s).
Accordingly, claims 29-30, 51, and 56 are prima facie obvious.
Response to Arguments
In the Remarks filed 12/23/2025 (“Remarks”) applicant appears to be arguing that the dose and dosing frequency of 25HC3S recited by the instant claims are critically relevant to achieve some unexpected result. See the Remarks at page 6:
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Applicant's arguments have been fully considered but they are not persuasive.
Please note that it is Applicant's burden to demonstrate unexpected results over the prior art. See MPEP 716.02, also 716.02 (a) - (f). Furthermore, the unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Moreover, evidence as to any unexpected benefits must be “clear and convincing” In re Lohr, 137 USPQ 548 (CCPA 1963), and be of a scope reasonably commensurate with the scope of the subject matter claimed, In re Linder, 173 USPQ 356 (CCPA 1972).
Applicant’s arguments that the claimed dosing range (1 to 100 mg/day) and claimed dosing period(s) (7, 14, 28 days; 3 months, 6 months; 1 year) are critically relevant to achieve the endpoints shown in the tables above are unpersuasive. The alleged unexpected result, which appears to be that the lowest tested dose (50 mg) produced superior reductions in serum triglycerides and liver stiffness compared to higher doses (150 mg or 300 mg BID), lacks both statistical rigor and practical clinical significance. The entire inverse-dose response argument for reduction in triglycerides relies on a single tested dose (50 mg), achieving a median reduction of 13%, compared to 3% and 2% for higher doses. However, the study was an open label Phase 1b trial with approximately 20 patients per dose group.
Moreover, applicant’s own data disclosed in the Specification contradicts the inverse dose-response argument. At page 34, the Specification states that patients with elevated baseline triglycerides (
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≥200 mg/dL; n=16) achieved a 24% reduction “across all dose groups at day 28 from baseline”, demonstrating that in the subpopulation targeted by claim 5, the triglyceride-lowering effect was dose-independent.
Similarly, the inverse dose-response for liver stiffness (Fibroscan) disappears entirely in the ≥10% MRI-PDFF responder subgroup, where the 150 mg dose (-9%) matched or exceeded the 50 mg dose (-7%), and the 300 mg BID dose (-9%) performed equally well (Specification, page 34):
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Even accepting the low-dose advantage argument at face value, a 13% median reduction in serum triglycerides is of marginal clinical significance. Note that REN cited above defines a “high triglyceride level” as ≥150 mg/dL (REN, [0055]). A 13% reduction in a patient with triglycerides of 200 mg/dL yields a post-treatment level of approximately 174 mg/dL, which is still above the 150 mg/dL threshold considered clinically normal.
Furthermore, because the higher doses demonstrated superior efficacy on other clinically important endpoints (e.g. APRI, -26% at 300 mg BID vs. 14% at 50 mg; CK-18 M65, -35% vs -18%; and AST, -18% vs -14%), a person of ordinary skill would have no reason to preferentially select 50 mg over higher doses on the basis of a modest triglyceride advantage that disappears in the high-triglyceride subpopulation.
Finally, the unexpected results are not commensurate in scope with the claims. The independent claims recite a dosage range of 1 mg/day to 100 mg/day, yet the purported inverse dose-response is supported by a single data point at 50 mg. There is no evidence that doses of 1 mg, 10 mg, 25 mg, 75 mg, or 100 mg would produce the same low-dose advantage. The next tested dose above 50 mg (150 mg) already showed the loss of the triglyceride effect in the overall population, and no doses below 50 mg were tested. A single data point cannot define, let alone support, a 100-fold dose range.
Accordingly, in view of the foregoing, the rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Copending Application No. 17/924,103
Claims 1, 3-5, 13, 17-18, 29-30, and 47-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 10, 15-16, 27-28, and 45-54 of copending Application No. 17/924,103 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application claims a method of treating NASH in a human subject comprising orally administering 25HC3S or salt thereof in an amount ranging from 100 mg/day to 300 mg/day. Dependent claims are directed to the same limitations recited in the instant claims (e.g. serum triglyceride levels, lipid lowering drugs, etc.). The claims therefore encompass subject matter overlapping with the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1, 3-5, 13, 17-18, 29-30, and 47-56 are rejected.
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 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 8:30 am - 5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621