Detailed Action
The present office action is in response to the application filed on amendments filed 24 Mar 2026.
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
Claims 6, 14-16, 20-23, and 26-27 of the pending application have been examined on the merits. Claims 9, 17-19, and 25 remain withdrawn. Acknowledgement is made of the amendments filed 24 Mar 2026. Acknowledgement is made of newly added claims 26-27. Acknowledgment is made of the cancellation of claims 1-5, 9, 14-23, and 25-27.
Priority
The instant application retains the priority date of 19 Feb 2020.
Response to Applicant Elections
In the amendment filed 24 Mar 2026, applicant amended the claims and limited the scope of species of chronic inflammatory autoimmune disease or disorder to species that did not include SLE. Because the instantly elected chronic inflammatory autoimmune disease or disorder is no longer within the scope of the instant claims, examiner extended the Markush search to lupus nephritis. This search returned prior art. Claims 26 and 27 are newly presented and have been examined on the merits.
Response to Applicant Arguments
Acknowledgement is made of the remarks filed 24 Mar 2026.
The rejections of and objections to claims 7-8, 10-13, and 24 are rendered moot following the cancellation of the claims.
The rejection of claims 6 and 20-23 under 35 U.S.C. § 112(a) is rendered moot following applicant amendments.
The rejection of claim 6 under 35 U.S.C. § 102(a)(1) over Jones Buie (MUSC Theses and Dissertations, 2015, 185; provided in the office action mailed 25 Nov 2025), hereinafter Jones Buie, is rendered moot following applicant amendments. However, a new rejection for claims 6, 14-16, 20-23, and 26-27 under 35 U.S.C. § 103 (see below) has been made. This rejection has been necessitated by applicant amendments. Applicant arguments against the 35 U.S.C. § 102(a)(1) over Jones Buie in the remarks filed 24 Mar 2026 have been fully considered but are not persuasive.
Applicant argues on pg. 5 of the remarks that Jones Buie does not teach treatment of SLE or any other autoimmune disease in a human subject, or any subject, because Jones Buie is wholly directed to in vitro techniques. Applicant argues that the pending claims recite, “treating lupus nephritis in a subject in need thereof, comprising administering to the subject…” and that the claims are therefore directed to in vivo treatment.
This is not persuasive. The specification defines the terms "patient," "subject," "individual," and the like as referring to "any animal, or cells thereof whether in vitro or in vivo, amendable to the methods described herein." (Specification, pg. 14, lines 22-24). Claim 6 is therefore not limited to human subjects or in vivo according to the claims. See MPEP 2145(VI). Therefore a new rejection under 35 U.S.C. § 103 over Jones Buie, Gilkeson et al. (PLoS One, 2013, 8:e64650; provided in IDS 05/22/23) hereinafter Gilkeson, Cheng et al. (Kidney Int, 2012, 82:1176-1183), hereinafter Cheng, hereinafter Boels, Smith et al. (Mol Genet Metab, 2019, 126, 406-412; available online 10 Feb 2019; provided in IDS 05/22/23), hereinafter Smith, and WO 2019/046849 (published 07 Mar 2019 and claims priority to Provisional Application #: 62/553,603, filed 01 Sep 2017), hereinafter ‘849, necessitated by applicant amendment, is made below.
The rejection of claims 6, 10, 14-16, and 20-23 under 35 U.S.C. § 103 over Jones Buie, Smith, and ‘849, has been rendered moot following applicant amendments.
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.
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.
Claim(s) Claims 6, 14-16, 20-23, and 26-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones Buie further in view of Gilkeson, Cheng, Smith, and ‘849.
The instant claims are directed to a method for treating lupus nephritis in a subject comprising administering a composition comprising L-sepiapterin (claim 1). The instant claims further limit the dosage of L-sepiapterin (claims 14-15, 21, and 26-27), the amount of stimulator of NO production in the composition (claim 20), and the formulation of the composition (claims 22-23).
Jones Buie teaches that enhanced NO production in response to L-sepiapterin may explain a role for endothelial nitric oxide synthase (eNOS) uncoupling and therapeutic possibilities for recoupling in SLE endothelial dysfunction (pg. iv). Jones Buie teaches that biopsies isolated from patients with severe lupus nephritis show diminished eNOS expression and in vitro serum studies show alterations in eNOS levels and diminished NO bioavailability from endothelial cells (pg. 87). Jones Buie further teaches that SLE serum suppresses NO production in HUVECs but L-sepiapterin restores NO production in lupus sera cultured endothelial cells and restoration of eNOS dimer/monomer ratios (pg. 88; and pg. 97). Jones Buie also that eNOS is protective against vascular disease manifestations in SLE and that lupus sera induced changes in NO production are reversed with the addition of L-sepiapterin (pg. 111; and pg. 112). Further, it was shown that biopsies isolated from patients with severe lupus nephritis have diminished eNOS expression (pg. 87). However, Jones Buie does not teach treatment of lupus nephritis in a human subject formulated as a solid composition or suspension at a dose of between 5 mg/kg/day and 50 mg/kg/day, between 10 mg/kg/day and 30 mg/kg/day, between 15 mg/kg/day and 25 mg/kg/day, or at 20 mg/kg/day.
Gilkeson teaches the impacts of eNOS on lupus prone MRL/lpr mice and that mice lacking eNOS developed more severe disease earlier (Abstract). The lack of eNOS modulated the formation of renal lesions which suggest that modulation of eNOS may be a novel therapeutic approach to treating lupus nephritis (Abstract).
Cheng teaches treating db/db mice with 10 mg/kg/day sepiapterin for 8 weeks (pg. 1181, column 1). It was found that sepiapterin treatment restored glomerular BH4 levels and that sepiapterin restored improved eNOS function in the mice indicated by restoration of eNOS dimerization (pg. 1178, column 1; Fig. 4).
Smith teaches a first-in-humans randomized, double-blind, placebo-controlled, dose-ranging, Phase 1 clinical trial testing a formulation of sepiapterin designated CNSA-001 (pg. 406, Abstract). Smith further teaches that CNSA-001 as a sepiapterin oral powder suspended in Medisca Oral Mix (pg. 407, column 2). Smith evaluated the safety, tolerability, and pharmacokinetics of CNSA-001 following single and multiple doses in fasted vs. fed subjects using doses of 2.5 mg/kg/day, 7.5 mg/kg/day, 20 mg/kg/day, 40 mg/kg/day, and 80 mg/kg/day (pg. 407, column 2; and Table 1). Smith concluded that oral administration of CNSA-001 was well tolerated, with no serious or dose-limiting toxicity, and no serious adverse events (pg. 406, Abstract; and pg. 412, column 1).
‘849 teaches pharmaceutical compositions comprising sepiapterin and methods of treatment of tetrahydrobioptein-related disorders with the pharmaceutical compositions (Abstract). '849 teaches the pharmaceutical composition will be about 20-95% sepiapterin by total weight (pg. 3, lines 37-42) and that in some embodiments the composition may be administered in a dosing vehicle including within MEDISCA oral mix with 2.5% glycerin and 27% sucrose in water (pg. 28, lines 25-31). '849 teaches that sepiapterin can be used in any suitable dose and that suitable doses and dosage regimens can be determined by conventional range finding techniques including initiating treatment with smaller dosages and increasing the dose by small increments to reach the optimum effect under the circumstances (pg. 30, lines 19-23). '849 further teaches that actual dosage amount of a composition of the reference can be determined by physical and physiological factors such as body weight, severity of condition, type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration and that the practitioner responsible for administration will determine the concentration of active ingredients in a composition and appropriate doses for the individual subject (pg. 34, lines 17-23). Finally, '849 teaches that in some embodiments, patients receive 2.5 mg/kg/day, 5 mg/kg/day 10 mg/kg/day, 20 mg/kg/day, 40 mg/kg/day, 60 mg/kg/day, or 80 mg/kg/day of sepiapterin (pg. 34, lines 24-25).
Based on the teachings of Jones Buie, Gilkeson, Cheng, Smith, and ‘849 a person of ordinary skill in the art would treat lupus nephritis murine models, taught in Gilkeson, with a compound such as L-sepiapterin, as taught by Jone Buie, to reverse eNOS uncoupling and treat the lupus nephritis. The artisan would have a reasonable expectation of success that sepiapterin would reverse the uncoupling of eNOS and increase NO production in vivo based on the teachings of Cheng. The artisan would further administer a composition of a solid sepiapterin oral powder prepared as a suspension in Medisca Oral Mix, as taught in ‘849 and Smith, to treat lupus nephritis in human patients, as taught by Jones Buie, Gilkeson, and Cheng. The artisan would be motivated to treat lupus nephritis with L-sepiapterin to decrease the formation of renal lesions, as taught by Gilkeson.
Further, based on the teachings of ‘849 and Smith, a person of ordinary skill in the art would have the skill to determine suitable doses and dosage regiments using conventional range finding techniques, including by administering to the human patient dosages of 2.5 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 40 mg/kg/day, 60 mg/kg/day, or 80 mg/kg/day as taught by ‘849. The artisan would be motivated to use conventional range finding techniques in order to find the optimum dosage in the circumstances presented to the artisan for the individual subject, as taught by ‘849. Based on the teaching of Smith, the artisan would have a reasonable expectation of success particularly in administering dosages to a human subject between 2.5 mg/kg/day and 80 mg/kg/day, as taught by Smith, where there is no expectation of adverse events or toxicity.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. 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 was 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 claim is 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 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan D. Mahlum whose telephone number is (703)756-4691. The examiner can normally be reached 8:30 AM - 5:00 PM ET, M-F.
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/J.D.M./Examiner, Art Unit 1625
/Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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