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 .
Priority
This application is a 371 of PCT/US2020/052871 filed 09/25/2020 which claims benefit of U.S. Provisional Application No. 62/905,720 filed 09/25/2019.
Status of the Claims
Applicant’s response filed February 13, 2026 includes only arguments to the Office Action submitted October 23rd, 2025 and no additional amendments to the claims received August 26th, 2025 have been submitted.
Claims 1-3, 5, 7, 9, 11, 12, 16-19, 22, 24-26, 28, 29 and 33 are pending in the instant application and the subject of this Office Action below.
Response to Applicant’s Arguments (Telephonic Interview):
Applicant refers to a telephonic interview with the Examiner and the Supervisory Examiner held on January 20th, 2026 in which “the Office indicated that it viewed the cited references as teaching that treatment of PKU required establishing therapeutic ratios of BH4, BH2, and sepiapterin, based in part on Figure 1 of Curtius, and that the art therefore suggested the use of combination therapy of sepiapterin, BH2, and BH4 which would read on the instant claims.” For the record, the Examiner and Supervisory Examiner pointed to the complex pathway of BH4 and BH2 pathway as it pertains to PKU and requested the Applicant point to any new working examples to support the claims and to specifically detail the invention, as detailed in the interview summary. The Applicant has not provided any additional working examples.
35 U.S.C. § 103 Rejections Maintained
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.
Claims 1-3, 5, 7, 9, 11, 12, 16-19, 22, 24-26, 28, 29 and 33 are obvious over Curtius in view of Thomas, Harding, and Niederwieser:
Claims 1-3, 5, 7, 9, 11, 12, 16-19, 22, 24-26, 28, 29 and 33, are rejected under 35 U.S.C. 103 as being unpatentable over Curtius et. al., Clinica Chimica Acto, 1979, vol. 93, pages 251-262, in view of Thomas et al., Molecular Genetics and Metabolism, vol. 124 (2018) pp. 27-38, Harding et. al., Molecular Genetics and Metabolism, 2018, vol. 124, pages, 20–26, and Niederwieser et. al., Eur. J. Pediatr. 1982, vol. 138, pages 110-112, is maintained.
Response to Applicant’s Arguments:
Applicant argues the treatment of a specific group of patients with PKU with the drug sepiapterin; applied only to patients having a blood phenylalanine concentration greater than 120 micromole per liter and only to a subject wherein the subject failed to respond to treatment with sapropterin. Applicant specifically states in the remarks:
“Claim 1, the sole independent claim, is directed to the treatment of phenylketonuria in subjects that failed to respond to treatment with sapropterin by administering sepiapterin.
Claim 1 is reproduced below (emphasis added):
A method of treating phenylketonuria in a subject having a blood phenylalanine concentration greater than 120 micromole per liter, the method comprising administering to the subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof, wherein the subject failed to respond to treatment with sapropterin or a pharmaceutically acceptable salt thereof.”
The applicant goes into detail to describe the metabolic pathway of sepiapterin and tetrahydrobiopterin (BH4 or sapropterin) and suggests BH4 is the end product of the salvage pathway, and provision of any of BH4, BH2, or sepiapterin would be expected to result in an increase of BH4. As sepiapterin is converted into BH2, which is in turn converted into BH4, the enzyme cycle does not indicate that specific ratios of sepiapterin, BH2, and BH4 are required for treatment. Instead, the cycles show that administration of BH4, BH2, or sepiapterin is expected to have the same effect. The Examiner does not refute the metabolic pathway. The applicant shows a figure from Smith et al., Molecular Genetics and Metabolism, vol. 126 (4):406-412, 2019 (of record). Figure 1 of Smith is reproduced below (and acknowledged by the Applicant, that the figure is similar to the Figure 1 of Curtius):
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Smith et. al. Figure 1.
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Curtius et.al., Figure 1.
Applicant suggests, in the same line of argument, that Curtius, does not indicate that specific ratios of sepiapterin, BH2, and BH4 are required for treatment. Neither the Applicant’s claims or specification or the Office Action submitted October 23rd, 2025, mention the specific ratios of sepiapterin, BH2, and BH4 are required for treatment. This argument is considered moot.
Applicant further notes that sapropterin dihydrochloride (e.g., KUVAN®) and sepiapterin (SEPHIENCE™) are FDA approved monotherapy treatments for PKU, and nothing in the cited art or the medical field suggests that combinations of sepiapterin with either BH2 or BH4 are needed for treatment of PKU. Since sepiapterin is converted into BH4 in vivo, none of the cited references, whether considered singly or in combination, teach or suggest that sepiapterin could be effective where BH4 failed in treating PKU. Applicant emphasizes that the present invention is surprising because sepiapterin is converted to BH4 in vivo, and nothing in the art suggests that administering a metabolic precursor of BH4 would be effective where BH4 itself was ineffective.
For the record, KUVAN® was approved by the FDA in 2007, Pegvaliase approved in 2018 and SEPHIENCE™ in 2025 for the treatment of PKU as therapeutics. As stated above, the Examiner does not refute the metabolic pathway as outlined by the applicant. However, it does stand to reason that patients diagnosed with PKU would be administered FDA approved drugs (i.e. KUVAN® and Pegvaliase) before non-approved FDA drugs (i.e. SEPHIENCE™) for that particular condition. The applicant purports that the only patients with PKU that should be treated with the drug sepiapterin are only patients wherein the subject failed to respond to treatment with sapropterin.
Applicant points to the only evidence presented on page 52, lines 12-22 and Figure 8 of the specification of the application, as filed, that "[t]he mean change in blood Phe reduction was significantly larger for [sepiapterin] 60 mg/kg vs. sapropterin dihydrochloride (the LSM difference was -182.5 [SE 62.0] μmol/L, p=0.0158) (FIG. 8). The number of patients treated with [sepiapterin] showing blood Phe reduction of =:20% was 50% higher than the number of patients treated with sapropterin."
The results that the applicant points to as evidence of the effectiveness of sepiapterin versus sapropterin dihydrochloride (BH4) for the treatment of patients with PKU where sepiapterin reduces the Phe levels in the blood more than sapropterin dihydrochloride (BH4) is accurate. The results are based on a population of 24 individuals with varying degrees of PKU that were treated with both sepiapterin and sapropterin dihydrochloride (BH4). Although the applicant points to a greater reduction in Phe concentration, the study population is treated with both therapies. The Examiner finds figure 5 of the specification particularly noteworthy, where all 24 patients in the applicant’s example are responders to sapropterin dihydrochloride (BH4) and sepiapterin (as shown as PTC923 and CSNA-001; circled below) in reducing Phe. For example, Figure 5 (where the x-axis represents individual patients in the study and the y-axis represents the change in Phe levels):
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From the graph representing the 24 patients treated with both sapropterin dihydrochloride (BH4) and sepiapterin, it appears that all of the test subjects are all “responders” to sapropterin dihydrochloride (BH4) albeit not as responsive as to sepiapterin in reducing Phe levels in the same small sample group, but nonetheless responsive to sapropterin dihydrochloride (BH4). Applicant purports that nothing in the art suggests that administering a metabolic precursor of BH4 would be effective where BH4 itself was ineffective. The Applicant does not provide any further evidence that indicates that they have proven that the response to sepiapterin is only effective when treatment with sapropterin dihydrochloride (BH4) has failed in patients with PKU. This argument is not convincing.
Applicant refutes the teachings of Curtius and Niederwieser pointing to the notion that despite the use of sepiapterin at lowering blood level Phe in patients with PKU and the success of the treatment with sepiapterin; they do not acknowledge if the patients treated were BH4 responders. The applicant shows data of 24 patients with PKU that respond to both sepiapterin and sapropterin dihydrochloride (BH4), but do not clarify if the patients in the study were responsive to BH4 or not (as described above relating to Figure 5). This argument is not compelling.
Applicant refutes the teachings of Thomas and Harding because they treat patients that were non-responders to BH4 and were treated with pegvaliase, which includes a recombinant phenylalanine ammonia lyase enzyme. The mechanism of action of pegvaliase, an enzyme, is entirely different from that of BH4, which is an enzyme cofactor, and nothing about the need for alternatives to BH4 or the ability of pegvaliase to treat PKU would suggest that sepiapterin would be effective, where BH4 was not.
As stated above, KUVAN® was approved by the FDA in 2007, Pegvaliase approved in 2018 and SEPHIENCE™ (sepiapterin) in 2025 for the treatment of PKU as therapeutics. Each of the therapies listed above are used to treat PKU. At the time of the Applicant’s disclosure, there were only 2 therapies approved by the FDA for the treatment of PKU; KUVAN® (sapropterin dihydrochloride (BH4)) and Pegvaliase (a recombinant phenylalanine ammonia lyase enzyme). All of the references cited in the 103 rejection predate the approval of the therapies by the FDA. Nevertheless, the experimentation of Curtius and Niederwieser with sepiapterin show the effectiveness of the therapy to lower Phe in patients with PKU; regardless of the response to sapropterin dihydrochloride (BH4). The Applicant’s data show little more than 24 patients that respond to both sapropterin and sepiapterin in lowering Phe.
35 U.S.C. § 103—Reiterated Rejections:
Applicant’s invention is directed to a method of treating phenylketonuria (PKU) through the administration of a compound known as sepiapterin, a compound that the human body converts to the chemical BH4.
By way of background, phenylketonuria1 is a disease/disorder defined by high levels of phenylalanine in the blood, caused by the body's inability to process the amino acid phenylalanine. The condition is typically identified in newborns through blood tests performed shortly after birth. Without treatment, phenylalanine builds up in the blood and can cause irreversible brain damage, intellectual disability, and other neurological and developmental problems. Lifestyle modification involves a lifelong, low-phenylalanine diet to keep blood phenylalanine concentrations within a safe range.
Amended claim 1 is directed to the following:
A method of treating phenylketonuria in a subject having a blood phenylalanine concentration greater than 120 micromole per liter, the method comprising:
administering to the subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof,
wherein the subject failed to respond to treatment with sapropterin or a pharmaceutically acceptable salt thereof.
Curtius teaches methods for treating patients that suffer from PKU, and explains the metabolic pathway and deficiency that the human body relies upon in converting phenylalanine to tyrosine:
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Curtius, page 253, Fig. 1.
To further explain the hydroxylase system and the pathway of the biosynthesis of BH4 as presented in Fig. 1, above, Curtius details:
“Phenylketonuria (PKU) is caused by a genetic defect in the enzyme system that catalyses the conversion of phenylalanine to tyrosine. This hydroxylase system is composed of the two apoenzymes phenylalanine 4-hydroxylase, PH (EC 1.14.16.1) and dihydropteridine reductase, DHPR (EC 1.6.99.7) and the essential cofactor L-erythro-5,6,7,8 tetrahydrobiopterin, BH4 [l].”
Curtius, page 252, paragraph 4 (emphasis added).
Curtius teaches that sepiapterin is effective at reducing phenylamine concentration in blood serum of PKU patients:
“In the two patients Z.Y. and M.K. with BH2,-deficiency, trials with the precursors of BH2, L-sepiapterin and NeH4 were undertaken in order to localize the defect. It is worth noting that L-sepiapterin provoked a drastic decrease of serum phenylalanine in patients Z.Y. and M.K. with only 1.25 and 0.6 mg/kg body weight, respectively. The response to sepiapterin could be in favor of the hypothesis that L-sepiapterin is an intermediate stage in the biosynthesis of BH4.”
Curtius, page 260, paragraph 3 (emphasis added).
The concentration of blood phenylalanine is a critical measurement to evaluate the effectiveness or non-effectiveness of a treatment and is considered and further described by Curtius, et.al., to an evaluation of patients for treatment with PKU:
“Every case with a persistent positive Guthrie test (blood-phenylalanine > 4 mg/dl) should be loaded with a single oral dose of BH4, 2.5 mg/kg body weight, under a phenylalanine blood level of 10-20 mg/dl.
Curtius, page 261, paragraph 1 (emphasis added).
Curtius therefore teaches PKU patients with blood concentrations of phenylalanine greater than the claimed 120 micromoles/L (i.e., 4 mg/dl is equivalent to 171 micromoles per L of phenylalanine).
Curtius describes the condition of atypical PKU and prefers the term “BH4 deficiency” to describe the condition and administers:
“Since 1974 several patients with atypical PKU have been described [3-9] characterized clinically by progressive neurological illness unresponsive to phenylalanine restriction and even death mostly within the first years of life.
Biochemically they show normal liver PH activity but a low concentration of biopterin-like compounds in serum and liver [7,8,10]. Obviously, these patients suffer from BH, deficiency. Because of the clinical unresponsiveness to the classical dietary treatment of PKU it has been suggested to group these patients under the name of malignant hyperphenylalaninemia [9], but we prefer in the following the name “BH4 deficiency”.”
Curtius, page 252, paragraph 2 (emphasis added).
Although Curtius teaches treating patients suffering PKU with the compound sepiapterin, he does explicitly select the sub-populations of PKU patients that failed to previously respond to the therapeutic sapropterin. However, one of ordinary skill in the art would have had a reasonable expectation of success in treating this sub-population because it was known that a significant portion of the population suffering from PKU is not responsive to sapropterin treatment, and that alternative treatment methods for this group suffering PKU is still needed. Additionally, it is also known that sepiapterin is successful in lowering phenylalanine levels in other PKU disorder such as atypical PKU (hyperphenylalaninemia).
Thomas teaches that many PKU patients are placed on phenylalanine restricted diets as well as administered the drug sapropterin, however, not all PKU patients respond to sapropterin therapy and therefore need a different medical treatment:
“Treatment involves severe restriction of dietary Phe (found in natural protein foods), supplemented with Phe-free amino acid–modified medical foods and special low-protein foods, alone or with sapropterin dihydrochloride (sapropterin, KUVAN®, BioMarin Pharmaceutical Inc., Novato, CA).
Current treatments, however, are ineffective in many adults with PKU due to long-term adherence issues or inadequate Phe-lowering effects. Bik-Multanowski et al. found in a study of 53 adults with PKU, only 10 were able to adhere to Phe restriction for 9 months. The majority of adults with PKU become lost to follow-up for various reasons, and likely have suboptimal metabolic control due to poor adherence to treatment in the absence of support from a metabolic clinic. Yet even among patients who report dietary Phe restriction, many continue to experience blood Phe concentrations >1000 μmol/L. In PKU studies, only approximately 20% to 56% of patients in clinical trials of combination sapropterin with dietary Phe restriction responded to treatment, as sapropterin (a cofactor) is only effective in individuals who have residual PAH activity.
Recent publications further highlight the need for novel treatment approaches to help lower elevated blood Phe concentrations. A 2015 survey of US metabolic clinics with>1000 actively managed adults with PKU (ie, visited clinic within the last 3years) estimated that 67% of their patients had blood Phe>360μmol/L, 45% had blood Phe>600μmol/L, and 18% had blood Phe>1200μmol/L. Similar results were found in a patient self-reporting survey, with only 24% of adults with PKU reporting blood Phe ≤360μmol/L within the past year, even though approximately 40% were receiving sapropterin treatment”
Thomas, page 28, (emphasis added; citations removed).
The teaching in Harding are similar to Thomas, and support the finding that a significant population of the PKU patients do not respond to sapropterin and require a different therapeutic (see page 21, left column). Harding notes that patients that do not have only residual PAH activity still need therapies to lower phenylalanine levels.
Niederwieser teaches that sepiapterin can help lower phenylalanine levels in atypical PKU patients as a therapeutic mode. Niederwieser, et. al., describe the variety of enzymes related to the neurotransmitter pathway and the related deficit in biopterin metabolism. Each of these enzymes represent pathways that can be targeted to treat PKU by affecting the BH4 pathway.
“In phenylalanine-4-hydroxylase deficiency the neurotransmitter deficiency is caused by competitive inhibition of tyrosine-3-hydroxylase and tryptophan-5- hydroxylase by the elevated phenylalanine concentration in tissue [7]. Here, the neurotransmitter deficit can be corrected by normalization of the elevated phenylalanine concentration by dietary treatment. All these 3 enzymes need tetrahydro- biopterin (BH4) as a cofactor. In defects in biopterin metabolism, BH4 is lacking either because of defective dihydrobiopterin (BH2) biosynthesis [3, 5, 9,10] or insufficient regeneration of BH4 within the catalytic cycle (dihydropteridine reductase (DHPR) deficiency) [1, 2, 11].”
Niederwieser, page 110, paragraph 1 (emphasis added).
Niederwieser also describe a patient being treated for symptoms including ptosis, sleepiness, ataxia, muscular hypotonia and symptoms resembling severe drug intoxication, 36 hours after the neurotransmitter replacement therapy had been stopped. The treatment and the outcome are described below:
“Then, 400 mg of BH4-dihydrochloride (22 mg/kg) was administered orally. Within 3-4 h, all symptoms disappeared and the girl was running again and playing with other children. The effect of BH4 lasted for 4 days. The clinical symptoms re- appeared and were again removed by BH4. Serum phenyl- alanine concentration, dopamine and serotonin excretion in urine were normalized and the elevated neopterin excretion, which is characteristic for such patients, decreased (Fig. 1). The concentrations of these compounds became abnormal again after 2 days. A single dose of 200 mg BH • 2 HCl (11 mg/ kg) or even only 50 mg of L-sepiapterin (2.75 mg/kg) both had practically the same long-lasting effect. Unfortunately, L- sepiapterin, a precursor of BH2, is not yet available in greater amounts.”
Niederwieser, page 110, paragraph 3 (emphasis added).
Accordingly, the invention was prima facie obvious at the time it was filed.
Claim 2 further limits the subject to being treated is on a phenylalanine-restricted diet. As discussed above in the background of PKU, the condition can be managed by following a diet that is low in phenylalanine. To further illustrate:
“Under the guidance of metabolic specialists, individuals with PKU are counseled to severely restrict consumption of dietary Phe, an essential amino acid present in protein foods, and supplement their diets with low-Phe or Phe-free amino acid–fortified medical foods and special low-protein modified foods.”
Harding et. al., page 21, paragraph 2 (emphasis added). Note: Phe in the quotation refers to phenylalanine.
Therefore, Harding et. al teach a that individuals diagnosed with PKU are on a phenylalanine-restricted diet. Accordingly, the instant claim is rejected.
Claim 3 and claim 33 further limits claim 1 to treating a subject who has a blood phenylalanine concentration greater than 600 μmol/L (as in claim 3) and greater than 1200 μmol/L (as in claim 33).
As discussed in background to the rejection to claim 1, phenylketonuria is classified by the severity of hyperphenylalaninemia and the blood phenylalanine concentration of individuals affected with PKU are classified as having: classic PKU (blood Phe: >1200 μmol/l), mild PKU (blood Phe: 600–1200 μmol/l) or non-PKU hyperphenylalaninemia (blood Phe: 120–599 μmol/l). The Applicant’s range of greater than 600 μmol/L., corresponds to mild PKU and includes classic PKU. Curtius et.al. teach the use of sepiapterin to two patients described as having “classical PKU that did not respond to BH4.
“The patients with PH deficiency (“classical PKU”) did not respond to intravenous injections of BH4, 2.5 mg/kg body weight.”
Curtius, page 252, paragraph 2 (emphasis added).
Accordingly, Curtius et. al. teach the range of greater than 600 μmol/L., which corresponds to mild PKU Regarding the claimed, blood phenylalanine concentration MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
The instant claims are directed to the range of mild PKU (blood Phe: 600–1200 μmol/l) as in claim 3 and includes the and the range of classic PKU (blood Phe: >1200 μmol/l) as identified in claim 33. Curtius teach patients with classical PKU (blood Phe: >1200 μmol/l) treated with sepiapterin lower the blood phenylalanine concentration to Accordingly, the instant claims are rejected.
Claim 5 further limits claim 1 identifying a subject who has failed existing treatment for PKU with pegvaliase-pqpz (due to an adverse reaction and/or tolerability) respectively.
Harding et.al. teach that PKU treatment has utilized numerous therapies to treat PKU and that each of these have drawbacks as to the patient reactions and ability to tolerate each of the medications individually including pegvaliase as well as sapropterin.
“Sapropterin is currently the only pharmacologic agent approved to treat adults with PKU, though it is only effective in patients with residual PAH activity; in clinical trials, only 20%–56% of patients with PKU responded to sapropterin, as measured by a reduction in blood Phe concentration [2,6,14,15]. There remains a significant unmet need for new treatments to help patients achieve guideline-recommended Phe levels and to optimize long-term patient outcomes [2].”
Harding et. al., page 21, paragraph 3 (emphasis added).
Harding et.al. also teach adverse effects (AE) related to a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine
(Phe) and neuropsychiatric outcomes in adults with PKU in a clinical trial.
“A total of 83.3% and 93.1% of participants in the pooled pegvaliase and pooled placebo groups, respectively, reported AEs during the RDT. In the pooled pegvaliase and placebo groups, the most commonly reported AEs (by preferred term) were arthralgia, headache, anxiety, fatigue, and upper respiratory tract infection. AEs with a≥10% incidence
difference between the pooled pegvaliase and placebo groups
included headache and upper respiratory tract infection. (Table 2).”
Harding et. al., page 21, paragraph 3 (emphasis added).
The instant claim is directed to identifying candidates whose current prescribed treatment is not effective to lowering blood phenylalanine concentration to an acceptable level or because the adverse effects (AE) are not tolerated by the subject. Harding et. al. teach that both treatments including sapropterin and pegvaliase-pqpz have known AEs and discontinuation of the treatment with these therapies do occur.
Therefore, Harding et.al teach that patients being treated for PKU may be prescribed either sapropterin or pegvaliase-pqpz and that both treatments have tolerability issues for patients that can result in the discontinuation of the administration of the therapies. It would be obvious to one skilled in the art to use the teachings of Harding et.al to determine that the AEs observed in two previously prescribed drugs to have been recorded. Accordingly, the instant claim is rejected.
Claim 7 further limits claim 1 administering sepiapterin reduces the blood phenylalanine concentration of the subject to less than 360 micromole per liter.
The instant claim is taught by Curtius et.al who teach the drastic reduction in blood phenylalanine concentration by administering L-sepiapterin in concert with Harding et.al teach that the goal of PKU treatment is to reduce and maintain blood Phe concentration in the range of 120 μmol/L to 360 μmol/L, according to (ACMG) guidelines (page 21, paragraph 2.)
Therefore, the administration of the therapy to reduce a blood phenylalanine concentration of the subject to less than 360 micromole per liter is taught in the art and the applicant is simply identifying the expected end-point of the intended therapy. Accordingly, the claim is rejected.
Claim 9 further limits claim 1 wherein blood phenylalanine concentration of the subject is reduced by at least 35% compared to the blood phenylalanine concentration prior to administration of sepiapterin.
The instant claim purports to a reduction in blood phenylalanine concentration greater than or equal to 35% as compared to a patient with PKU prior to receiving sepiapterin and although the applicant fails to define the dosage or length of therapy to achieve these results; the result is taught by Curtius et.al. For example:
However, all children with hyperphenylalaninemia should be screened for BH4 deficiency by a BH4-administration test: in patients with BH4 deficiency the high serum phenylalanine concentration would decrease under this cofactor substitution [6,16]. Such a test was first proposed by Danks et al. [ 9]. In a 17 months old patient with atypical PKU serum phenylalanine decreased from 7.2 to 5.6 mg/dl two hours after administration of 10 mg BH4, and further to 1.5 mg/dl after administration of 50 and 100 mg of BH4 on the following two days [6].
Curtius et. al., page 253, paragraph 1 (emphasis added).
Here Curtius et.al. teach that administering BH4 to treat children with PKU. Sepiapterin is an oral synthetic form of a natural precursor of BH4, and can reduce HPA in some patients with PKU. Curtius et.al. provide an example from Danks et. al. that describes a decrease in serum phenylalanine of 22% in two hours after administration and down to 79% after increasing dosing; clearly establishing a dose-dependent response to reduction in PKU serum phenylalanine levels. Regarding the claimed, reduction blood phenylalanine concentration, MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
The instant claim is taught by Curtius et. al. Accordingly, the instant claim is rejected.
Claim 11 further limits claim 1 describing a BH4 concentration of at least 50 ng/ml in the plasma within 10 hours of administration of the therapy.
As described in the rejection to claim 9, Sepiapterin can be delivered ass an oral synthetic form of a natural precursor of BH4 and an increase in the levels of concentration would obviously coincide with the increase in the plasma after administration of the drug. Increasing or decreasing the dosage of the drug will have obvious physiological changes in the concentration of the BH4 blood plasma of an individual to change with the dose applied.
Accordingly, the claim is rejected for the same obviousness reasons as claim 9.
Claim 12 further limits claim 1 describing a dose of Sepiapterin is about 20 mg/kg to about 60 mg/kg per dose.
As described in the rejection to claim 1, Curtius et. al. teach the benefit of decreased PKU serum phenylalanine by utilizing administration of 50 and 100 mg of BH4. Although, the treatment is with BH4, sapropterin, the use of either of the two FDA-approved drugs would be obvious to try Accordingly, the instant claim is rejected for the same obviousness reason as claim 1.
Claims 16-23 further limit claim 1where the dose of the effective amount of Sepiapterin is administered once per day, twice per day, in two equal doses, and with food (either high fat or high protein).
As with all therapies, that treat diseases, risks and benefits of a treatment need to be considered by clinicians in determining the appropriate treatment approach for their patient. The instant claims provide no inventive step by simply stating the daily dose frequency and the subject’s dietary consumption before treatment.
Accordingly, the instant claims are rejected.
Claim 24 further limits claim 1 describes reduced risk of adverse events (AEs) compared to a subject administered at least 10 mg/kg sapropterin.
As described above in the rejection to claim 5, AEs are the result of treatments that are not tolerated by the subjects administered the drug therapy; an alternative therapy may improve AEs. Patients being treated with an FDA- approved drug for PKU can result for in AEs and may not be tolerated by the patient. The instant claim does not provide any technical feature other than reduced risk.
Accordingly, the instant claim is rejected for the same obviousness reasons as claim 5.
Claim 25 further limits claim 1 wherein the subject has an increase in neurocognitive function after administration of Sepiapterin.
Curtius et.al. teach:
“In “classical PKU” the defective PH apoenzyme leads to an accumulation of phenylalanine and its metabolites. The resulting brain damage can be prevented by correcting the serum phenylalanine concentration”
Curtius et. al., page 252, Introduction, paragraph 1 (emphasis added).
Curtius et.al. teach that brain damage can be prevented and, by obvious extension, cognitive ability improves with lowered serum phenylalanine concentration in patients with PKU. Accordingly, the instant claim is rejected.
Claim 26 and 28 further limit claim 1 identifying the subject to be treated is a child or subject more than 7 years old.
Curtius et.al. teach the treatment of a 17-month-old patient with atypical PKU that was treated and responded well to BH4 of which Sepiapterin, an oral synthetic form of a natural precursor of BH4. The condition of PKU in any of its severities is often identified at a very young age including infants. Harding et. al also teach the treatment of PKU is a life-long condition where the PKU goal of treatment is to reduce and maintain blood Phe concentration. Taken in concert, Curtius et.al. and Harding et. al teach that treatment of PKU can take place at any age.
Accordingly, the instant claims are rejected.
Claim 29 is amended and further limits claim 1 to a subject has been diagnosed with sepiapterin-responsive phenylketonuria.
Curtius et. al. teach that a “cofactor L-erythro-5,6,7,8 tetrahydrobiopterin, BH4” (pg. 251 paragraph 1), and further, that sepiapterin has provoked a drastic decrease of serum phenylalanine in patients with PKU.
Claim 31 is directed to a blood level greater than 1200 micromole per liter; this level addressed as needing treatment by Thomas.
Double Patenting Rejection Maintained
Claims 1-3, 5, 7, 9, 11, 12, 16-19, 22, 24-26, 28, 29 and 33 are rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-12 of US Patent No.11617752 B2; allowed April 4. 2023 (hereinafter ‘752), in view of Curtius, et.al., (Clinica
Chimica Acto, 1979, vol. 93, pages 251-262).
Response to Applicant’s Arguments:
Applicant argues that the '752 patent contains the "without food" limitation and relates to treating a BH4-related disorder, whereas the instant claims are directed to treating phenylketonuria in patients that failed to respond to treatment with sapropterin and make no mention of any food effect. The instant claims are directed to this entirely different discovery, and there is no mention of sapropterin resistance in the claims of the '752 patent at all.
Applicant purports that the treatment of a patient with a BH4 related disorder as described in ‘752, is somehow not related to phenylketonuria (PKU) unless the patient with PKU does not respond to sapropterin treatment. Although treating PKU is a complex process that includes dietary restrictions and early diagnosis. The effect of sepiapterin on patients with PKU with any degree of severity does not discriminate whether the patient has failed an initial treatment with sapropterin. See MPEP 2112.01:
"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty.").
Therefore, the applicant’s argument suggesting that the claims of ‘752 are distinctly different because the restriction of dietary intake before, or lack thereof, is a significantly different treatment with (sepiapterin) the same therapy as the instant claims is not convincing.
Double Patenting Reiterated Rejections:
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.
Claim 1 of the instant application is directed to treating phenylketonuria in a subject having a blood phenylalanine concentration greater than 120 micromole per liter, the method comprising administering to the subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof, wherein the subject failed to respond to treatment with sapropterin or a pharmaceutically acceptable salt thereof.
Curtius et.al. detail that phenylketonuria is a BH4-related disorder that can be treated with sepiapterin to reduce decrease of serum phenylalanine in patients with PKU as described to the rejection of claim 1 above.
Claim 1 of ‘752 identify a method of treating a BH4-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, without food.
The claim 1 of the instant application and the claim 1of ‘752 are nearly identical because they both use of the drug sepiapterin to treat a BH4-related disorder like phenylketonuria. The only difference is the “without food” requirement of ‘752. However, one of ordinary skill in the art would reasonably expect the use of the same drug to have the same results in treating a patient with a BH4-related disorder, like phenylketonuria to have the same effect on the patient.
Claim 12 of the instant application is directed to claim 1 wherein the effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, is about 20 mg/kg to about 60 mg/kg per dose.
Claim 6 of ‘752 describes the effective dose of sepiapterin wherein the effective amount is 2.5 mg/kg to 100 mg/kg per dose. The dosage range of ‘752 fully encompasses the range identified in the instant claim 12.
It would have been obvious to one of the ordinary skilled in the art to utilize the dosage range of sepiapterin identified in ‘752 that is broader than the dosage range of the instant application to treat phenylketonuria, a BH4-related disorder.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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.
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/P.R.G./ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
1 Blood phenylalanine concentrations greater than (120) µmol/L are considered a biochemical diagnosis of PKU. Classical PKU, and its less severe forms "mild PKU" and "mild hyperphenylalaninemia" are caused by a mutated gene for the enzyme phenylalanine hydroxylase (PAH), which converts phenylalanine to other essential compounds in the body, in particular tyrosine, which is a conditionally essential amino acid for PKU patients, because without PAH, it cannot be produced in the body through the breakdown of phenylalanine.
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