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
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 11/25//2025, wherein claim 1 is amended to recite effective amount of sepiapterin and claims 6, 12 and 33 are cancelled.
Election/Restriction
Applicant elected without traverse of composition containing no additional components , in the reply filed on 06/27/2025.
Status of Claims
Claims 1-5, 7-9, 20 and 22-29 are pending in the instant application.
Claims 7 and 24-26 remain withdrawn.
Claims 1-5, 8-9, 20, 22-23 and 27-29 are currently under examination in this office action.
Action Summary
Applicant’s Remarks filed on 11/25//2025 are fully considered. Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s remarks. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
As necessitated by amendment, claims 1, 4, and 20 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Curtius et al. ( US 4758571A) (newly reapplied as necessitated by amendment).
Applicant argument is fully considered, but NOT persuasive to overcome objection to specification and following rejections which are maintained/ reiterated as necessitated by amendment. Please see Response to Arguments following the objection or rejections.
Maintained/reiterated rejections necessitated by amendment:
Claims 1, 4-5, 20, 22-23 and 27 rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Levy (WO2019046849A1);
Claims 1-5, 8-9, 20 and 22 rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hasegawa et al. (US20180078557A1);
Claims 1-5, 20, 22-23 and 27 rejected under 35 U.S.C. 102(a)(2) as being anticipated by Smith et al. (WO2019232126A1, Smith’126);
Claims 1-5, 8-9, 20, 22-23 and 27-29 rejected under 35 U.S.C. 103 as being unpatentable over Levy (WO2019046849A1, Levy‘849), in view of Hasegawa et al. US20180078557A1,) and Oppenheimer et al.( US 7947681B2).
Rejections on the ground of nonstatutory double patenting over U.S. Patent Nos. 11617752, 12257252, 12329757 in view of Hasegawa et al. (US20180078557A1).
Priority
This application 17/794,357 filed on 07/21/2022 is 371 of PCT/US2021/014745 filed 01/22/2021, which claims benefit of US provisional application 62/965,442 filed 01/24/2020.
Claim Interpretation
Claim 1 is amended to recite “ method of reducing the total daily OFF time in a subject with Parkinson's disease...”. Independent claims 20 recite limitation “wherein the effective amount results in an increase in the level of serotonin and/or dopamine in the CSF of the subject ”. The limitation “reducing the total daily OFF time” and “increase in the level of serotonin and/or dopamine in the CSF of the subject“are construed as simply express intended function/result of a process step of administering sepiapterin or pharmaceutically acceptable salt thereof to a subject, which do not necessarily further limit instantly claimed method. As stated in MPEP 2111.04: “the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Please note biological/pharmaceutical activities are properties of sepiapterin or pharmaceutically acceptable salt thereof and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstance.
Specification
The specification is objected to as failing to provide proper support for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o)(maintained).
Instant claims are directed to a method of treating Parkinson’s disease in a subject in need thereof, comprising administering to the subject an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof. Claim 1 is amended to recite “ method of reducing the total daily OFF time in a subject with Parkinson's disease...”. Independent claims 20 recite limitation “wherein the effective amount results in an increase in the level of serotonin and/or dopamine in the CSF of the subject ”. However, instant specification did not provide working examples wherein subject diagnosed with Parkinson’s disease experiencing OFF time were actually administered with sepiapterin or salt thereof at instantly recited dosage regimen (e.g. with food or without food twice per day, etc.), and evaluated for instantly claimed result (e.g. decrease of OFF time, etc.). Since NO subject diagnosed with Parkinson’s disease experiencing OFF time was administered with sepiapterin or salt, instant specification failed to provide sufficient support for instantly claimed method of reducing the total daily OFF time in a subject with sepiapterin at instantly recited dosage regimen (e.g. with food or without food twice per day, etc.).
Response to Arguments
Applicant argues: “the specification describes measuring the OFF time used for evaluating the therapeutic treatment in Parkinson's disease and provide details as to the administration of sepiapterin for this indication. Thus, the person skilled in the art would understand that the Applicant was in possession of the claimed method of treating Parkinson's disease at the time of filing the application”.
RESPONSE: Applicant’s argument is NOT persuasive. When a claim is directed to a specific therapeutic/clinical result, the specification at the time of filing must reasonably convey that Applicant had actually achieved or possessed that result. Instant specification does not disclose working examples wherein sepiapterin is specifically administered to subject experiencing OFF time. There is no measurement of total daily OFF time is actually reduced in the subject. Prophetic examples do not necessarily establish instantly claimed method that actually achieves the claimed reduction in total daily OFF time. Please note written description is separate and different from enablement.
Claim Rejections - 35 USC § 102/103
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claims 1, 4, and 20 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Curtius et al. ( US 4758571A, Applicant’s IDS dated 11/21/2023)(newly reapplied as necessitated by amendment).
Curtius teaches method of treating Parkinson’s disease, comprising administering an effective amount of pterin derivatives (e.g. L-erythro-5,6,7,8-tetrahydrobiopterin BH4, sepiapterin) to a subject in need thereof (See abstract; Col.1, lines 18-22; claim 1).
Regarding limitation of dose regimen, Curtius teaches oral administering pterin derivatives to subject suffering idiopathic Parkinson’s (See Col. 2, line 66; Col. 3, line 2) and dosage regimen, e.g. 1 g/day (about 15 mg/kg of body weight), 500 mg (about 7.5 mg/kg) and 200 mg/day (about 3 mg/kg) (See Col.4, lines 3-8). Instant claims does not specifically define the subject is human or other mammal. According to FDA guidance for dose conversion, the dose amount for rat (multiple human dose by 6.2) would be 93mg (15 mg/kg *6.2)(which falls within instant amended dosage range).
Curtius teaches the dopamine/serotine concentration increased after administration of pterin derivatives ( See Table 1)(which reads on instant claim 20).
Curtius collectively teaches method of treating Parkinson's disease in a subject with sepiapterin/ pterin derivatives.
Curtius is silent about “reducing the total daily OFF time in a subject” in amended claim 1. However, biological/pharmaceutical activities are the properties of sepiapterin or pharmaceutically acceptable salt thereof and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstance. Curtius explicitly teaches treating Parkinson’s disease comprising administering an effective amount of sepiapterin or salt thereof to the subject suffering Parkinson’s disease. A skilled artisan would have known subjects having Parkinson’s disease might have OFF time. By practicing the method of treating Parkinson’s disease taught by Curtius, total daily off time in the subject would be reduced if instantly method functions as claimed.
In the alternative, even though the instantly claimed effect of reducing total daily OFF time with the amended dose amount is not expressly taught by prior art , the differences between what is disclosed in prior art and what is claimed are considered to be slight that the method taught by the cited reference is likely to possess the similar effects of instantly claimed method in view of the similar characteristics which they have been shown to share. Exploring different dose amount/dose adjustment for the desired treatment outcome is considered as routine optimization within the knowledge of skilled artisan Accordingly, the claimed invention as a whole was at least prima facie obvious, if not anticipated by the cited reference, especially in the absence of sufficient, clear, and convincing evidence to the contrary.
Response to Arguments
Applicant argues claim 1 is amended to incorporate the limitations of prior claims 6 and 33, which are free of rejection by Curtius. Thus, amended claim 1 and those dependent therefrom are novel over Curtius.
RESPONSE: Regarding the amended dose regimen in claim 1, Curtius teaches oral administering pterin derivatives to subject suffering Parkinson’s and dosage regimen, e.g. 1 g/day (about 15 mg/kg of body weight), 500 mg (about 7.5 mg/kg) and 200 mg/day (about 3 mg/kg) (See Col.4, lines 3-8). Instant claims does not specifically define the subject is human or other mammal. According to FDA guidance for dose conversion, the dose amount for rat (multiple human dose by 6.2) would be 93mg (15 mg/kg *6.2)(which falls within instant amended dosage range). In the alternative, exploring different dose amount/dose adjustment for the desired treatment outcome is considered as routine optimization within the knowledge of skilled artisan that’s prima facie obvious within the meaning of 35 USC § 103.
Maintained/reiterated Rejections Necessitated by Claim Amendment
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4-5, 20, 22-23 and 27 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Levy (WO2019046849A1, hereafter “Levy‘849”, published on March 07, 2019, Applicant’s IDS dated 11/21/2023) (maintained and reiterated as necessitated by amendment).
Levy‘849 teaches sepiapterin is precursor of tetrahydrobiopterin (BH4), an essential cofactor of critical intracellular enzymes, pharmaceutical composition comprising sepiapterin or a pharmaceutically acceptable salt, and a method of treating BH4 related disorder (e.g. Parkinson’s disease, phenylketonuria, depression, etc.) comprising administering an effective amount of aforementioned sepiapterin composition (See abstract; page 29, lines 20-26; claims 1-69).
Regarding dosage form of instant claim 22, Levy‘849 teaches sepiapterin or salt thereof in dosing vehicle are formulated into oral dosage form (e.g. powder, suspension, etc.) (See page 1, lines 40- 42; page 3, lines 5-6; page 31, lines 13- 28; page 33, lines 16-37).
Regarding the dosage regimen, Levy‘849 teaches sepiapterin or salt thereof can be formulated into unit solid oral dosage forms comprising suitable amount of sepiapterin or salt that could be administered at 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 once daily, twice daily or three times daily (See page 30, lines 23-31; page 34, line 24-27; Cohort 1 and Cohort 2 on page 38)(which reads on instant claim 27). Levy‘849 explicitly teaches sepiapterin administered at dose levels of 60 mg/kg (See Example 4, page 38)(which falls within the amended dose amount).
Regarding the limitation of instant claim 20, Levy‘849 teaches embodiments wherein effective dose of sepiapterin produce a therapeutic result, e.g., increased levels of serotonin or dopamine in the CNS, an increase in BH4 in the CNS (e.g., brain) measured in the CSF, etc. (See page 30, lines 32-37, claim 67).
Regarding the limitation of instant claim 23, Levy‘849 teaches variety of dosing vehicle (See page 28, lines 25- 35) and explicitly teaches suspending agent that can be used is a combination of glycerin and sucrose in water (e.g., MEDISCA® oral mix)(See page 28, line 29; page 36, line 4; Examples 2, 8, Table 21-24).
Levy‘849 is silent about “reducing the total daily OFF time in a subject” in amended claim 1. However, biological/pharmaceutical activities are the properties of sepiapterin or pharmaceutically acceptable salt thereof and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstance. Levy‘849 already teaches BH4, serotonin, and dopamine are increased by orally administering sepiapterin. As such, the functional effects of sepiapterin would be inherent based upon the fact that the formulation contains instantly claimed ingredients for oral administration as in instant application. By practicing the method of treating Parkinson’s disease ( BH4 related disorder) comprising administering an effective amount of sepiapterin or salt thereof taught by Levy‘849, total daily OFF in the subject would be decreased if instantly method functions as claimed.
Levy‘849 collectively teaches a method of treating Parkinson’s disease (BH4 related disorder), comprising administering an effective amount of sepiapterin crystalline or salt thereof. As such, Levy‘849 anticipates instant claimed invention.
Response to Arguments
Applicant argues: “subjects experience OFF time when Parkinson's disease symptoms are no longer mitigated - this experience by patients is not universal. Thus, the present claims are directed to reducing the total daily OFF time by administering sepiapterin only in the subset of subjects that are experiencing OFF time. Importantly, Levy does not disclose administering sepiapterin for reducing the total daily OFF time in subjects with Parkinson's disease that are experiencing OFF time, nor does Levy recognize this subset of Parkinson's disease patients”.
RESPONSE: Applicant’s argument is NOT persuasive. Instant specification does not disclose working examples wherein sepiapterin is specifically administered to subject experiencing OFF time and measurement of treatment outcome in that specific subset of Parkinson patient. As elaborated in Claim Interpretation, biological/pharmaceutical activities are the properties of sepiapterin or pharmaceutically acceptable salt thereof and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstance. A skilled artisan would have known subjects with Parkinson’s disease might have “OFF’ time. Levy‘849 already teaches BH4, serotonin, and dopamine are increased by orally administering sepiapterin. Increased dopamine is correlated with reduction in OFF time in Parkinson’s treatment. Thus, instantly claimed intended result of “reducing total daily OFF time” is anticipated because such effect naturally flows from the mechanism disclosed by Levy’ 849. By practicing the method of treating Parkinson’s disease ( BH4 related disorder) and increased level of dopamine taught by Levy, total daily OFF time in the subject would be reduced if instantly method functions as claimed.
Claims 1-5, 8-9, 20 and 22 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hasegawa et al. (US20180078557A1, Applicant’s IDS dated 11/21/2023) (maintained and reiterated as necessitated by amendment).
Hasegawa teaches a method of improving cerebral dysfunction/ facilitating biosynthesis of aromatic monoamine neurotransmitter (e.g. serotonin, dopamine, etc.)/ providing an elevated level of the aromatic monoamine in patient's brain by administering an effective dose of sepiapterin or a pharmaceutically acceptable salt thereof (See abstract, [0001], claims 1-15). Hasegawa teaches tetrahydrobiopterin (BH4) is an essential coenzyme associated with monoamine neurotransmitters (e.g. dopamine, serotonin) and pterin derivative(e.g. sepiapterin, tetrahydrobiopterin, etc.) might be used for treating BH4 associated disease/disorder including Parkinson's disease, depression, hyperphenylalaninemia, etc. (See [0012]-0014], [0020]- [0033], [0059], [0088]-[0089], Figure 1). Hasegawa teaches sepiapterin could pass through blood-brain barrier, the mechanism and benefit of sepiapterin for improving cerebral dysfunction, e.g. central motor disorder, etc. (See [0038]-[0041], [0060]-0063]). Hasegawa method of improving cerebral dysfunction/ facilitating biosynthesis of dopamine/ serotonin, etc. by administering sepiapterin or salt thereof is construed as encompassing a method of treating Parkinson’s disease.
Regarding the dosage form, Hasegawa teaches sepiapterin and salt thereof could be formulated into variety of dosage form (e.g. tablets, powder, suspensions, etc.) (See [0070],[0079]).
Regarding the dosage regimen and administration limitation, Hasegawa teaches sepiapterin and salt thereof could be administered through different route (e.g. orally, powders, parentally, etc. ) at various dose (e.g. from 0.1 to 100 mg/kg) once daily or in one to three divided doses ( See [0091]-[0092], Example 4-5; claims 2-3). Hasegawa teaches 20 mg/kg sepiapterin was orally administered twice to a subject fed ad libitum with a diet (See Example 5, [0155]), which is construed as sepiapterin being administered with or without food. Hasegawa also teaches sepiapterin and salt thereof in a form of food (See [0098], claim 9), which is construed as sepiapterin being administered with food.
Regarding instant claim 20, Hasegawa teaches administering sepiapterin increase serotonin level in the brain, as well as dopamine, noradrenaline and adrenaline (See Examples 4 and 5, Figure 6, [0156]-[0159],[0167]-[0168]).
Hasegawa is silent about “reducing the total daily OFF time in a subject” in amended claim 1. However, biological/pharmaceutical activities are the properties of sepiapterin or pharmaceutically acceptable salt thereof and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstance. Hasegawa already teaches serotonin in the brain was increased by orally administering sepiapterin. As such, the functional effects of sepiapterin would be inherent based upon the fact that the formulation contains instantly claimed ingredients for oral administration as in instant application. By practicing the method of treating BH4 related disorder comprising administering an effective amount of sepiapterin or salt thereof taught by Hasegawa, total daily OFF time in the subject would be decreased if instantly method functions as claimed.
Hasegawa teaches a method of improving cerebral dysfunction/ facilitating biosynthesis of dopamine/serotonin, etc., and treating BH4 related disorder (e.g. Parkinson’s disease) by administering sepiapterin or salt thereof . As such, Hasegawa anticipates instant invention.
Response to Arguments
Applicant argues “Hasegawa discloses a prophetic range of doses from 0.1 mg/kg to 100 mg/kg (paragraph [0091]-[0092]) when administered intravenously, or, in the Examples, describes the use of 20 mg/kg twice daily (Example 5, paragraph [0155]) or 10 mg/kg as a single dose (Example 6, paragraph [0164]). Hasegawa does not describe the specific method of reducing the OFF time in patients with Parkinson's disease by administering sepiapterin at between 50 mg/kg and 100 mg/kg per day, as in amended claim 1”.
Response: Applicant’s argument is NOT persuasive. Instant specification does not teach working examples wherein sepiapterin is specifically administered at recited dose to subject experiencing OFF time, thus, instant recited dose amount of sepiapterin is also considered as prophetic for the intended effect of reducing OFF time. Hasegawa teaches administering sepiapterin increase serotonin level as well as dopamine, noradrenaline and adrenaline in the brain. Increased dopamine is correlated with reduction in OFF time in Parkinson’s treatment. Thus, instantly claimed intended result of “reducing total daily OFF time” is anticipated because such effect naturally flows from the mechanism disclosed by prior art. By practicing the method of treating Parkinson’s disease ( BH4 related disorder) and increased levels of dopamine taught by Hasegawa, total daily OFF time in the subject would be reduced if instantly method functions as claimed.
Claims 1-5, 20, 22-23 and 27 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Smith et al. (WO2019232126A1, “Smith’126”, published on 12/05/2019, Applicant’s IDS dated 11/21/2023, patent family of US12257252 B2) (maintained and reiterated as necessitated by amendment).
The applied reference has a common inventor/applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Smith’126 teaches pharmaceutical composition comprising sepiapterin, or a pharmaceutically acceptable salt, and a method of treating BH4 related disorder (e.g. Parkinson’s disease, phenylketonuria, depression, etc.) comprising administering an effective amount of aforementioned sepiapterin composition (See abstract; page 4, lines 13-27; page 6, lines 6-22).
Regarding the food limitation, Smith’126 evaluates the food effect on the administration of sepiapterin and teaches administration of sepiapterin with food results in an increase in the maximum BH4 plasma concentration (Cmax) and cerebral spinal fluid (CSF) compared to administration without food (See page 7, lines 20-24; Example 1).
Regarding the dosage regimen, Smith’126 teaches sepiapterin or salt thereof can be formulated into unit solid oral dosage forms comprising suitable amount of sepiapterin or salt, e.g. about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 100 mg, etc. (see page 11, lines 27-35) that could be administered at 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 once daily, twice daily or three times daily (See page 15, lines 31-35; Examples 1-4 )(which reads on instant claims 12 and 27). It’s noted 60mg/kg per day could be administered twice 30mg each dose unit or 40mg/kg and 20mg/kg dose unit (which would read on instant claims 28 and 29).
Regarding the dosage form of instant claims 22 and 23, Smith’126 teaches sepiapterin or salt thereof are formulated into oral dosage form (e.g. powder, suspension, etc.) comprising variety of pharmaceutical expedients (See page 11, lines 35-41; page 14, lines 13-41). Smith’126 explicitly teaches MEDISCA® oral mix in dosing vehicle (See page 10, line 35).
Regarding the limitation of instant claim 20, Smith’126 teaches embodiments wherein effective dose of sepiapterin produce a therapeutic result/response, e.g., increased levels of serotonin or dopamine in the CNS, an increase in BH4 in the CNS (e.g., brain) measured in the CSF, etc. (See page 11, lines 17-26). Smith’126 evaluates CSF levels of neurotransmitters (e.g. sepiapterin, BH4, homovanillic acid HVA , and 5-hydroxyindoleacetic acid HIAA, etc.) after administrating sepiapterin 60mg/kg for seven days (See Example 3), and teaches neurotransmitter level in CSF at day 7 is increased/higher compared with placebo ( page 18, lines 24-28; Table 6).
Smith’126 is silent about “reducing the total daily OFF time in a subject” in amended claim 1. However, biological/pharmaceutical activities are the properties of sepiapterin or pharmaceutically acceptable salt thereof and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstance. Smith’126 already teaches BH4, serotonin, and/or dopamine are increased by orally administering sepiapterin. As such, the functional effects of sepiapterin would be inherent based upon the fact that the formulation contains instantly claimed ingredients for oral administration as in instant application. By practicing the method of treating Parkinson’s disease ( BH4 related disorder) comprising administering an effective amount of sepiapterin or salt thereof taught by Smith’126, total daily off time in the subject would be decreased if instantly method functions as claimed.
Smith’126 collectively teaches a method of treating Parkinson’s disease (BH4 related disorder), comprising administering an effective amount of sepiapterin or salt thereof. As such, Smith’126 anticipates instant claimed invention.
Response to Arguments
Applicant argues “Smith does not disclose administering between about 50 mg/kg and about 100 mg/kg per day for treating patients with Parkinson's disease experiencing OFF time”.
RESPONSE: Applicant’s argument is NOT persuasive. Smith’126 teaches sepiapterin or salt thereof can be formulated into unit solid oral dosage forms that could be administered at, 60 mg/kg/day, or 80 mg/kg/day once daily, twice daily or three times daily (See page 15, lines 32-34) which falls within the amended dose range. Regarding the “OFF time” limit, instant specification does not teach working examples wherein sepiapterin is specifically administered to subject experiencing OFF time. As elaborated in Claim Interpretation, biological/pharmaceutical activities are the properties of sepiapterin or pharmaceutically acceptable salt thereof and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstance. A skilled artisan would have known subjects with Parkinson’s disease might have “OFF’ time. Smith’126 teaches sepiapterin increased levels of serotonin or dopamine in the CNS . Increased dopamine is correlated with reduction in OFF time in Parkinson’s treatment. Thus, instantly claimed intended result of “reducing total daily OFF time” is anticipated because such effect naturally flows from the mechanism disclosed by prior art. By practicing the method of treating Parkinson’s disease ( BH4 related disorder) and increased levels of dopamine taught by Smith’126, total daily OFF time in the subject would be reduced if instantly method functions as claimed.
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 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 non-obviousness.
Claims 1-5, 8-9, 20, 22-23 and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Levy (WO2019046849A1, Levy‘849, published on March 07, 2019, Applicant’s IDS dated 11/21/2023), in view of Hasegawa et al. (US20180078557A1, Applicant’s IDS dated 11/21/2023) and Oppenheimer et al.( US 7947681B2, Applicant’s IDS dated 11/21/2023)(maintained and reiterated as necessitated by amendment).
The collective teachings of Levy‘849 are elaborated in preceding 102 rejection and applied as before. Levy‘849 collectively teaches a method of treating Parkinson’s disease (BH4 related disorder), comprising administering various amount of sepiapterin or salt thereof from about 0.001 to about 1000 mg/kg( e.g. 60mg/kg per day) one or more times a day in portions of unit dose.
Levy‘849 does not explicitly teach administering sepiapterin with or without food twice per day as recited in instant claims 2-3, 8-9 and 28-29. However, adjusting/ optimizing dosage regimen is within general knowledge of a skilled artisan for the treatment of BH4 related disorder (e.g. Parkinson’s disease). It’s noted 60mg/kg per day taught by Levy‘849 could be administered twice 30mg each dose unit or 40mg/kg and 20mg/kg dose unit (which would read on instant claims 28 and 29). Where 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. MPEP 2144.05.
The collective teachings of Hasegawa are elaborated in preceding 102/103 rejection and applied as before. Hasegawa teaches the mechanism and benefit of sepiapterin for improving cerebral dysfunction (e.g. Parkinson’s disease). Hasegawa teaches 20 mg/kg sepiapterin was orally administered twice to a subject fed ad libitum with a diet (See Example 5, [0155]), which is construed as sepiapterin being administered with or without food twice a day. Hasegawa explicitly teaches sepiapterin could pass through blood-brain barrier and administering sepiapterin increase serotonin level in the brain.
Oppenheimer teaches a method of treating BH4 related disease or conditions associated with decreased tyrosine or tryptophan levels ( e.g. Parkinson's disease, phenylketonuria, depression, etc.), comprising orally administering tetrahydrobiopterin BH4 at various dose (e.g. 20mg/kg daily) to a subject in need thereof, with or without food (See abstract, Col. 35, lines 48-66; Col. 36, line 3; claims 1, 8, 16). Oppenheimer teaches embodiments wherein tetrahydrobiopterin absorption (Cmax, AUC, etc.) was increased when it was administered with food compared to administered without food (in a fasting condition)(See Col. 2, lines 7-19; Col 9, lines 14-28; claims 2 and 7), indicating administering tetrahydrobiopterin/pterin derivatives with food might be beneficial for pharmacokinetics profile/bioavailability than without food (Col. 8, lines 38-43).
It’s common practice to explore different therapeutic effect for active compound/drug in pharmaceutical industry. It would have been obvious to one of the ordinary skilled in the art before the effective filing date of instant invention to further explore sepiapterin and salt thereof for treating Parkinson disease, a BH4-related disease, based on the beneficial teachings of prior art, together with experiment/ optimization(e.g. dosing regimen, patients populations, etc.) based on general knowledge of treating BH4-related disease (including Parkinson’s disease), and arrive at instantly claimed invention with reasonable expectation of success. Before the effective filing date of instant claimed invention, it was already known sepiapterin and salt thereof could be used for treating BH4-related disease (e.g. Parkinson disease) as taught by Levy‘849 and Hasegawa. It was also known administrating tetrahydrobiopterin B4 derivatives with food might be beneficial for PK profile and bioavailability as taught by Oppenheimer. A skilled artisan would also know to adjust/ optimize dosage regimen (with or without food) in the treatment of Parkinson disease.
A skilled artisan would be motivated to further explore therapeutic effect of sepiapterin and salt thereof for treating Parkinson disease because Hasegawa explicitly teaches sepiapterin could pass through blood-brain barrier and the mechanism/ benefit of sepiapterin for improving cerebral dysfunction, e.g. increasing dopamine and serotonin level in the brain. The further exploration of sepiapterin for treatment of Parkinson disease based on combined teachings of prior art , together with experiment/optimization(e.g. dosing regimen, patient populations, etc.) based on general knowledge of BH4-related disease(including Parkinson disease), would provide an alternative treatment comprising sepiapterin or salt thereof with potential beneficial pharmacokinetics /bioavailability profile for patients of Parkinson disease.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with experimentation /optimization based on the general knowledge of BH4-related disease including Parkinson disease. Therefore, the invention as a whole is 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.
Response to Arguments
Applicant argument is similar as in response to Levy’s: “not all patients with Parkinson's disease experience OFF time, and the claimed methods are consequently directed to treating a subset of Parkinson's disease patients that is not recognized in Levy, Hasegawa, or Oppenheimer... Oppenheimer is entirely directed to BH4 and does not even mention sepiapterin - Oppenheimer thus cannot remedy the deficiencies of Levy or Hasegawa”.
RESPONSE: Applicant’s argument is NOT persuasive. As elaborate above, biological
/pharmaceutical activities are the properties of sepiapterin or pharmaceutically acceptable salt thereof and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstance. A skilled artisan would have known subjects with Parkinson’s disease might have “OFF’ time. By practicing the method of treating Parkinson’s disease ( BH4 related disorder) taught by combined teachings of prior art, total daily OFF time in the subject would be reduced if instantly method functions as claimed.
Applicant’s argument about Oppenheimer is NOT persuasive. Please note Oppenheimer is teaching reference that tetrahydrobiopterin/pterin derivatives with food might be beneficial for pharmacokinetics profile/bioavailability than without food, which provides rationale for administering sepiapterin with food as recited in instant claim 2.
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.
Claims 1-5, 8-9, 20 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of US Patent No. 11617752 B2, in view of Hasegawa et al. (US20180078557A1, Applicant’s IDS dated 11/21/2023) (maintained and reiterated as necessitated by amendment).
Reference claims are directed to method of treating a BH4-related disorder in a subject in need thereof, comprising administering an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, with or without food.
Regarding the dose limitation of sepiapterin, reference claim 6 recites the effective amount is 2.5 mg/kg to 100 mg/kg per dose.
Regarding the food limitation, reference claims 5 and 7-8 recites administration of sepiapterin, or a pharmaceutically acceptable salt thereof, with food.
Regarding the limitation of instant claim 20, reference claim 2 recites increasing sepiapterin level in plasma, cerebrospinal fluid (CSF).
Reference claims are silent about Parkinson’s disease. However, a skilled artisan would have known Parkinson’s disease is a BH4-related disorder taught by Hasegawa as elaborated in preceding 102 and 103 rejections and applied as before. It’s common practice to explore different therapeutic effect of active compound in pharmaceutical industry. Hasegawa teaches the mechanism and benefit of sepiapterin for improving cerebral dysfunction (e.g. Parkinson’s disease) whereby sepiapterin could pass through blood-brain barrier and administering sepiapterin increase dopamine/serotonin level in the brain.
It would have been obvious to one of the ordinary skilled in the art to further explore sepiapterin or salt thereof for treating Parkinson’s disease based on the beneficial teachings of reference claims, Hasegawa and general knowledge of treating BH4-related disorder including Parkinson’s disease. A skilled artisan would be motivated to further explore therapeutic use of sepiapterin or salt thereof in other patients suffering BH4-related disorder (e.g. Parkinson’s disease) because reference claims and Hasegawa teach sepiapterin/ dopamine/serotonin level in plasma and cerebrospinal fluid (CSF) increased by administration of sepiapterin or salt thereof. Adjusting/ optimizing dosage regimen is within general knowledge of a skilled artisan for the treatment of BH4 related disorder (e.g. Parkinson’s disease). Where 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. MPEP 2144.05. Further exploration of sepiapterin or salt thereof in other patients suffering BH4-related disorder (e.g. Parkinson’s disease) would provide an alternative treatment for Parkinson’s disease.
The instant application shares at least one common inventor /applicant /assignee with the reference patent. Furthermore, the instant application is not related to the reference patent based on the record, thus no 35 USC 121 shield exists.
Claims 1-5, 8-9, 20 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US Patent No. 12257252B2, in view of Hasegawa et al. (US20180078557A1, Applicant’s IDS dated 11/21/2023)(maintained and reiterated as necessitated by amendment).
Reference claims are directed to method of treating a BH4-related disorder in a subject in need thereof, comprising administering an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, wherein the BH4-related disorder is BH4 deficiency, high plasma phenylalanine, or phenylketonuria.
Regarding the dose limitation of sepiapterin, reference claim 4 recites the effective amount is 2.5 mg/kg to 100 mg/kg per dose.
Regarding the food limitation, reference claims 5-9 recite administration of sepiapterin, or a pharmaceutically acceptable salt thereof, with or without food.
Reference claims are silent about Parkinson’s disease. However, a skilled artisan would have known Parkinson’s disease is a BH4-related disorder taught by Hasegawa as elaborated in preceding 102 and 103 rejections and applied as before. It’s common practice to explore different therapeutic effect of active compound in pharmaceutical industry. Hasegawa teaches the mechanism and benefit of sepiapterin for improving cerebral dysfunction (e.g. Parkinson’s disease) whereby sepiapterin could pass through blood-brain barrier and administering sepiapterin increase dopamine/serotonin level in the brain.
It would have been obvious to one of the ordinary skilled in the art to further explore sepiapterin or salt thereof for treating Parkinson’s disease based on the beneficial teachings of reference claims, Hasegawa and general knowledge of treating BH4-related disorder including Parkinson’s disease. A skilled artisan would be motivated to further explore therapeutic use of sepiapterin or salt thereof in other patients suffering BH4-related disorder (e.g. Parkinson’s disease) because reference claims and Hasegawa teach sepiapterin/ dopamine/serotonin level in plasma and cerebrospinal fluid (CSF) increased by administration of sepiapterin or salt thereof. Adjusting/ optimizing dosage regimen is within general knowledge of a skilled artisan for the treatment of BH4 related disorder (e.g. Parkinson’s disease). Where 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. MPEP 2144.05. Further exploration of sepiapterin or salt thereof in other patients suffering BH4-related disorder (e.g. Parkinson’s disease) would provide an alternative treatment for Parkinson’s disease.
The instant application shares at least one common inventor /applicant /assignee with the reference patent. Furthermore, the instant application is not related to the reference patent based on the record, thus no 35 USC 121 shield exists.
Claims 1-5, 8-9, 20 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- 6 of US Patent No. 12329757B2 in view of Hasegawa et al. (US20180078557A1, Applicant’s IDS dated 11/21/2023)( (maintained and reiterated as necessitated by amendment).
Reference claims are directed to method of treating a BH4-related disorder in a subject in need thereof, comprising administering an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, wherein the BH4-related disorder is phenylketonuria.
Regarding the dose limitation of sepiapterin, reference claim 4 recites the effective amount is 2.5 mg/kg to 100 mg/kg per dose.
Regarding the food limitation, reference claims 1 and 6 recite administration of sepiapterin, or a pharmaceutically acceptable salt thereof, with or without food.
Reference claims are silent about Parkinson’s disease. However, a skilled artisan would have known Parkinson’s disease is a BH4-related disorder taught by Hasegawa as elaborated in preceding 102 /103 rejections and applied as before. It’s common practice to explore different therapeutic effect of active compound in pharmaceutical industry. Hasegawa teaches the mechanism and benefit of sepiapterin for improving cerebral dysfunction (e.g. Parkinson’s disease) whereby sepiapterin could pass through blood-brain barrier and administering sepiapterin increase dopamine/serotonin level in the brain.
It would have been obvious to one of the ordinary skilled in the art to further explore sepiapterin or salt thereof for treating Parkinson’s disease based on the beneficial teachings of reference claims, Hasegawa and general knowledge of treating BH4-related disorder including Parkinson’s disease. A skilled artisan would be motivated to further explore therapeutic use of sepiapterin or salt thereof in other patients suffering BH4-related disorder (e.g. Parkinson’s disease) because reference claims and Hasegawa teach sepiapterin/ dopamine/serotonin level in plasma and cerebrospinal fluid (CSF) increased by administration of sepiapterin or salt thereof, and further exploration would provide an alternative treatment for Parkinson’s disease.
The instant application shares at least one common inventor /applicant /assignee with the reference patent. Furthermore, the instant application is not related to the reference patent based on the record, thus no 35 USC 121 shield exists.
Response to Arguments
Applicant argument is similar as in response to 35 USC§ 102 and 103 rejection: claim 1 is amended to specify that the sepiapterin is administered at an effective amount of between about 50 mg/kg and 100 mg/kg per day for reducing the total daily OFF time in subjects with Parkinson's disease. None of the claims of the reference patents explicitly describe the dose claimed by Applicant in connection with treatment of Parkinson's disease, nor do they describe that this effect results in a reduction in the total daily OFF time experienced by a subset of subjects with Parkinson's disease.
RESPONSE: Applicant’s argument is NOT persuasive. As elaborate above, biological
/pharmaceutical activities are the properties of sepiapterin or pharmaceutically acceptable salt thereof and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstance. A skilled artisan would have known subjects with Parkinson’s disease might have “OFF’ time. By practicing the method of treating Parkinson’s disease ( BH4 related disorder) by combined teachings of reference claims and Hasegawa , total daily OFF time in the subject would be reduced if instantly method functions as claimed.
Applicant also argues claims of the '252 patent specify treating specific disorders other than Parkinson's disease, i.e., a BH4 deficiency, high plasma phenylalanine, or phenylketonuria
RESPONSE: Applicant’s argument is NOT persuasive. A skilled artisan would have known Parkinson’s disease is a BH4-related disorder as taught by Hasegawa and it’s common practice to explore different therapeutic effect of active compound in pharmaceutical industry. A skilled artisan would have also known subjects with Parkinson’s disease might have “OFF’ time. Hasegawa teaches administering sepiapterin increase serotonin level as well as dopamine, noradrenaline and adrenaline in the brain. Increased dopamine is correlated with reduction in OFF time in Parkinson’s treatment. A POSA would be motivated to further explore treating Parkinson’s patient experiencing OFF time and reasonably expect sepiapterin would reduce OFF time that’s correlated with increase of dopamine.
Conclusion
No claims are allowed.
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 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 LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LIYUAN MOU/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628