Detailed Action
The present office action is in response to the application filed on amendments filed 23 Jun 2025.
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 6-8, 10-16, and 20-24 of the pending application have been examined on the merits. Claims 9, 17-19, and 25 are withdrawn (see “Response to Applicant Elections” below). Acknowledgement is made of the amendments filed 23 Jun 2025. Acknowledgment is made of the cancellation of claims 1-5.
Priority
Applicants identify the instant application, Serial #: 17/800,207, filed 16 Aug 2022, as a National Stage Entry of International Patent Application #: PCT/US21/18723, filed 19 Feb 2021, which claims priority from Provisional Application #s: 62/994,386, filed 25 Mar 2020, and 62/978,468, filed 19 Feb 2020.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 22 May 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Response to Applicant Election
Applicant’s election without traverse of Group II, claims 6-25, in the reply filed on 23 Jun 2025 is acknowledged.
Applicant’s election without traverse of the following species in the reply filed on 23 Jun 2025 is acknowledged:
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Claims 9, 17-19, and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (requiring additional components to the elected formulation), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11 Jun 2025.
Prior art was found while searching for the elected species and so the restriction requirement stands.
Claim Objections
Claim 12 is objected to because of the following informalities: Claim 12 recites the limitation, “whereby the method prevents the method from becoming active” instead of “whereby the method prevents the disease from becoming active.” Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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.
Claims 6, 10-11, and 20-24 is rejected under 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Applicant lists in claim 6 a method of treating chronic inflammatory autoimmune disease by administering “a composition comprising a stimulator of nitric oxide (NO) production.” (claim 6, lines 3-4) The stimulator is limited by function and not structure, and a person of skill in the art would understand that this encompasses a broad range of stimulators not just limited to small molecules (as seen in claims 7-8 and 13-14). The artisan would then expect to see examples of these stimulators within the disclosure. As part of the specification, applicant further gives examples of what could be meant by a stimulator of nitric oxide production by stating, “In one embodiment, the stimulator of nitric oxide (NO) production is at least one of the group consisting of a chemical compound, a protein, a peptide, a peptidomimetic, and antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, [and] an antisense nucleic acid molecule.” (pg. 15, lines 28-31) There are, however, no amino acid sequences, nucleic acid sequences, or structures provided that would lead a person having skill in the art to the understanding that applicant had possession of the broad category of stimulators of NO production. The artisan would be left questioning how to treat inflammatory diseases with any and all stimulators of NO production. Claims 10-11 and 20-24 do not provide sufficient description to remedy the questions raised by claim 6 and so are also rejected.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 6-8, 10-12, 13, and 24 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jones Buie (MUSC Theses and Dissertations, 2015, 185), hereinafter Jones Buie.
The instant claims are directed to a method for treating or preventing a chronic inflammatory autoimmune disease or disorder in a subject comprising administering a composition comprising a stimulator of nitric oxide (NO) production (claim 1). Applicant elected systemic lupus erythematosus (SLE) as the chronic inflammatory autoimmune disease or disorder and L-sepiapterin as the stimulator of NO production in the remarks filed 23 Jun 2025.
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 SLE 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).
By teaching that eNOS is protective against vascular disease manifestations in SLE and that L-sepiapterin restores eNOS dimer/monomer ratios, Jones Buie inherently teaches that the administration of L-sepiapterin protects an inactive disease state from becoming an active disease state.
Therefore, Jones Buie teaches treating SLE endothelial dysfunction by administering a composition of L-sepiapterin in serum from subjects with SLE and anticipates the instant claims.
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 6-8, 10-16, and 20-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jones Buie, 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.
The instant claims are directed to a method for treating or preventing a chronic inflammatory autoimmune disease or disorder in a subject comprising administering a composition comprising a stimulator of nitric oxide (NO) production (claim 1). Applicant elected systemic lupus erythematosus (SLE) as the chronic inflammatory autoimmune disease or disorder and L-sepiapterin as the stimulator of NO production in the remarks filed 23 Jun 2025. The instant claims further limit the dosage of L-sepiapterin (claims 14-15 and 21), the type of subject that may receive the composition of the instant claims (claim 16), 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 SLE 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). However, Jones Buie does not teach treatment of SLE 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 or at 20 mg/kg/day.
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, Smith, and ‘849 a person of ordinary skill in the art would 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 uncoupled eNOS in SLE endothelial dysfunction in human SLE patients, as taught in Jones Buie. The artisan would be motivated to treat uncoupled eNOS in SLE endothelial dysfunction to protect against vascular disease manifestations in SLE.
Further, based on the teachings of Jones Buie, ‘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.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. WO 2019/232130 is considered pertinent for teaching that antioxidants minimize the oxidative degradation of sepiapterin. Kasper et al. (Harrison’s Principles of Internal Medicine (2005), 16th ed., Ch. 300, pgs. 1960-1967) is considered pertinent for teaching the common treatments of SLE including with immunosuppressive agents such as azathioprine.
Conclusion
No claim is allowed.
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