DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-8 and 14 are pending in this application. Claims 9-13 have been cancelled by applicant.
Claim Interpretation
Claims 3 and 14 refer to the method of treatment wherein the subject is an adult, child, or baby (infant and neonate). The specification does not define these terms. Elsevier discloses age groups, as defined in drug monographs, are as follows (Obtained from Elsevier.support [retrieved on 02/09/2026]<URL:https://www.elsevier.support/ckpharma/answer/how-are-age-groups-defined-in-drug-monographs> - previously cited):
Adults - 18 years and older.
Elderly - 65 years and older.
Adolescents - 13-18 years.
Children - 1-12 years.
Infants - 1 month - 1 year.
Neonates - Full-term newborn 0-4 weeks
Thus, for the purposes of applying art, an adult will be interpreted as a subject 18-65 years of age; a child will be a subject between 1-12 years of age; and a baby will be interpreted as encompassing neonates and infant (newborn-1 year of age). Groups between the ages of 13-18 and 65 and up are not being considered in the scope of this invention.
Claim Objections
Claims 1-2 are objected to because of the following informalities:
Claims 1-2 should read: “. . . related to MARS gene mutations, wherein the mutations comprise a double mutation . . .” or something to that effect.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-6, 8, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Lenz et al. (Pediatric Pulmonology. 2020; 55:3057–3066 – Cited in IDS – previously cited) (“Lenz”); in view of Comisso et al. (The FEBS Journal, 285, 2018, 2654–2661 – cited in IDS) (“Comisso”).
Regarding claim 1, Lenz discloses oral methionine supplementation led to apparent treatment benefit in pulmonary alveolar proteinosis (PAP) with MARS1 mutation (abstract). Lenz discloses biallelic variants of PAP exist, leading to an early onset PAP with rapid progression to pulmonary fibrosis and structural hepatopathy (page 3058, col. 1). Lenz specifically mentions “Controlled clinical trials are necessary to investigate the role of protein and methionine supplementation in individuals with biallelic pathogenic variants in MARS1” (page 3065, col. 2, para. 1). Regarding administration of the therapeutically effective amount of methionine every 6 hours; Lenz discloses close monitoring of methionine levels in the plasma of two subjects suffering from PAP related to MARS1 (see Section 3.2, page 3063). Lenz teaches blood sampling 4 hours postprandially, and in case of methionine supplementation, blood sampling was done prior to the intake of methionine. Lenz discloses a target range of blood methionine to be between 80-150 µM, and discloses increasing dosage when methionine levels in blood remained in the “normal range” (lower than predetermined value). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer methionine every six hours, or more or less frequently, in view of Lenz. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Lenz teaches close monitoring of plasma levels of methionine and administration of supplemental doses of methionine when levels were found to be under 80-150 µM. Applicant is advised that a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2143(E) KSR, 550 U.S. at 421, 82 USPQ2d at 1397. Applicant is also reminded that 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.
Regarding claim 2, Lenz discloses the treatment regimen of two children with PAP with MARS1 mutation (one < 3.5 and one <8.2 years old). Lenz discloses in cases of supplementation (administration of additional methionine), blood samples were taken before intake of methionine and found that methionine levels were in the normal range (“normal range” was disclosed to be 15‐45 µM (see Figure 5); while “target range”, or “predetermined reference value” in the instant claims, was 80 – 150 µM). Lenz discloses before supplementation (50 mg/kg/day), the methionine concentration was in the “normal range” (low – less than predetermined value). Following supplementation, Lenz discloses that plasma methionine rose to 177 µM for one of the subjects (see Section 3.2 and Figure 5) and discloses increasing dosage amount when methionine levels were below predetermined value. Thus, Lenz’s disclosure anticipates the instant method of: i) measuring level of methionemia from a biological sample; and ii) administering an increased supplementation dosage when the level of methioninemia (methionine) is less than the predetermined value.
While Lenz doesn’t specifically disclose patients with PAP related to biallelic mutation Ala393Thr/ Ser567Leu; the teachings of Comisso are relied upon for these disclosures.
Comisso teaches biallelic missense mutations in MARS are responsible for rare but severe cases of PAP (abstract). Comisso discloses A393T/S567L MARS mutants had the lowest activity, when compared to wild type, in terms of velocity of tRNAMet-aminoacylation reaction (page 2657, col. 1, para. 1; Figure 3B). Comisso specifically teaches that “MetRS mutants identified in patients with PAP are likely to be more sensitive to the availability of methionine, relative to WT, in agreement with previous studies showing that the growth retardation phenotype observed after introduction of these mutations in yeast MetRS can be rescued by methionine supplementation” (page 2659; col. 2).
Therefore, regarding claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to treat PAP related to MARS gene mutations, wherein the mutations comprise Ala393Thr/ Ser567Leu, by supplementing methionine, as taught by Lenz in view of Comisso. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Lenz teaches oral methionine supplementation led to treatment benefit in PAP with MARS1 mutation and suggests that controlled clinical trials be conducted to investigate the role of protein and methionine supplementation in individuals with biallelic pathogenic variants in MARS1; further because Comisso discloses biallelic missense mutations in MARS are responsible for rare but severe cases of PAP, that A393T/S567L MARS mutants had the lowest activity, when compared to wild type, in terms of velocity of tRNAMet-aminoacylation reaction, and that suggests that MetRS mutants identified in patients with PAP are likely to be more sensitive to the availability of methionine.
Similarly, for instant claim 2, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to treat PAP related to MARS gene mutations, wherein the mutations comprise Ala393Thr/ Ser567Leu, by: i) measuring level of methionemia from a biological sample; and ii) administering an increased supplementation dosage when the level of methioninemia (methionine) is less than the predetermined value, as taught by Lenz in view of Comisso. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Lenz discloses blood samples were taken before intake of methionine and found that methionine levels were in the normal range, while following supplementation the plasma methionine rose to 177 µM for one of the subjects (see Section 3.2 and Figure 5) and discloses increasing dosage amount when methionine levels were below predetermined value; further because Comisso discloses biallelic missense mutations in MARS are responsible for rare but severe cases of PAP, that A393T/S567L MARS mutants had the lowest activity, when compared to wild type, in terms of velocity of tRNAMet-aminoacylation reaction, and that suggests that MetRS mutants identified in patients with PAP are likely to be more sensitive to the availability of methionine.
Regarding claims 3 and 14, Lenz teaches methionine supplementation was started on a 2.5-year-old boy and another one under 8.2 years of age (reading on child – see claim interpretation) (Figure 2E; Figure 5; and abstract – results).
Regarding claim 4, Lenz discloses their target range for methionine in blood, or “predetermined reference value”, was 80 – 150 µM (see section 3.2) – thus anticipating the instant range of 45-500 µM.
Regarding claim 6, Lenz discloses oral administration of methionine (abstract – results).
Regarding claim 8, Lenz discloses administration of 50, 100, 150, and 125 mg/kg of methionine (Figure 2E, page 3061; and page 3063, col. 2, section 3.2) – thus anticipating the instantly claimed range.
Regarding claim 5, directed to a specific therapeutically effective amount of methionine, capable of resolving the issues mentioned in the claim; Applicant is advised that 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. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II. Applicant is further advised that 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.
Lenz teaches that PAP related to MARS1 not only provoke interstitial lung and cholestatic liver disease, but cause a multisystemic phenotype including growth retardation, neurodevelopmental delay, anemia, and muscular hypotonia (reading on rate of catch-up) (page 3065, col. 1, last para.). Lenz teaches methionine supplementation contributed to a significant improvement in growth (rate of catch-up growth), pulmonary (reading on respiratory symptoms), and neurodevelopmental state (page 3064, lines connecting col. 1-2; and page 3060, col. 2). Lenz teaches for immediate relief of respiratory compromise therapeutic whole lung lavage (WLL) were performed, followed by oral methionine administration (page 3060, col. 2) and that no more ventilation or supplemental oxygen was needed and chest imaging improved (reading on reduced inflammation and free bronchoalveolar lavage fluid).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claim invention to administer an effective amount of methionine that would result in control of respiratory symptoms, inflammation, cholestasis, increase rate of catch-up, and free bronchoalveolar lavage fluid. One of ordinary skill would have been motivated to do so in order to ameliorate these potentially life-threatening symptoms in the afflicted subject. One of ordinary skill would have had a reasonable expectation of success in view of the teachings of Lenz.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Lenz et al. (Pediatric Pulmonology. 2020; 55:3057–3066 – Cited in IDS – previously cited) (“Lenz”); in view of Comisso et al. (The FEBS Journal, 285, 2018, 2654–2661 – cited in IDS) (“Comisso”); as applied to claims 1-6, 8, and 14; in view of Douglas Laboratories (Obtained from Amazon.com [retrieved on 02/12/2026]<URL:https://www.amazon.com/Douglas-Laboratories-L-Methionine-Neurological-Antioxidant/dp/B0014WKE4U/ref=sr_1_1_sspa?dib=eyJ2IjoiMSJ9.3XGvymVcakpL3ycSPckUxt3EG42B8dAj9MKNsPDP1jN49aFpWXE8KO4KqKtmKH_Cyo219QH9gOZPlvau13YOn7_JcfRqSuowQVxdakLfesYk2hlAmxo7VwtnXkwTJxUB37_aad2DtQC9WQCYfFcK2z0nZ6inid3Avl_XkPOoM-NT3oTdyJxQzojpZbmUdheXiaKUI6uPdtqkOT2meRbDxfpQgfjYfpJlkEVtUCQ1z1lYp11gsPSm7TT0be4pDeeTumPa1cQHh0QNUWoFfRqurpAVa7rPm5zioQm5J7l1L88.-tdUFEZx78RBbTdJuhOGZJNH5xUTqOiFpi__c5DdqfA&dib_tag=se&keywords=dl+methionine&qid=1770937320&sr=8-1-spons&sp_csd=d2lkZ2V0TmFtZT1zcF9hdGY&psc=1> – Product First Available October 2nd, 2001 (see page 3, top) – previously cited) (“Douglas L”).
The teachings of Lenz and Comisso are disclosed above and incorporated herein.
While Lenz in view of Comisso does not teach a methionine formulation in the form of a gel capsule; the teachings of Douglas L are relied upon for these disclosures.
Douglas L teaches a gelatin capsule comprising L-methionine.
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Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to administer L-methionine in the form of a gel capsule for the treatment of PAP related to MARS1 with a Ala393Thr/ Ser567Leu mutation. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Lenz and Comisso teach oral administration of methionine for the treatment of PAP related to Ala393Thr/ Ser567Leu MARS double mutations; further because Douglas L discloses their capsule formulation of L-methionine, which is readily available for purchase to the public.
Response to Arguments
Specification/ Drawings
Amendments to the specification are acknowledged and have been entered. No new matter has been introduced. Objections to the specification and to the drawings have been withdrawn.
Claims/ Claim Objections
Claim amendments are acknowledged and have been entered. No new matter has been introduced. Objections to the claims have been withdrawn. However, in view of claim amendments, a new ground of objection has been raised herein.
Claim Rejections - 35 USC § 112(b)
In view of claim amendments, 35 USC § 112(b) rejections of record have been withdrawn.
Claim Rejections - 35 USC § 101
In view of claim amendments, 35 USC § 101 rejections of record have been withdrawn.
Claim Rejections - 35 USC § 102
In view of claim amendments, 35 USC § 102 rejections of record have been withdrawn.
Claim Rejections - 35 USC § 103
In view of claim amendments, 35 USC § 103 rejections of record over Lenz have been withdrawn. However, a new ground of rejections has been raised over Lenz in view of Comisso.
Applicant argues Lenz does not teach treatment of PAP related to MARS comprising Ala393Thr/ Ser567Leu MARS double mutations. Applicant argues Douglas is silent about methionine for use in the treatment of PAP. Applicant points to pages 2 and 11-18 of the instant application to say that claimed methionine allowed to free a patient from respiratory symptoms, inflammation, and cholestasis, as well as catchup in growth. Applicant cites pages 22-25 to say that methionine supplementation with a therapeutically effective amount, administered every 6 h, especially for patients with Ala393Thr/ Ser567Leu MARS double mutations, allowed for efficient and well tolerated treatment of PAP. Applicant references Hadchouel et al. (Eur. Respir. J. 2022, 59, 2101554 – cited in the IDS – hereafter Ref. 1) to allegedly confirm the success of the ‘every 6 h’ dosing regimen for patients with Ala393Thr/ Ser567Leu MARS double mutations, while Lenz teaches that it is difficult to maintain a stable level of methionine, and that the combination of the claimed features creates a synergy that is demonstrated herein. Applicant further argues that Lenz does not mention BALF or WLL, and relies on repetitive lavages to stabilize patient or that Lenz does not the instantly observed near- complete clinical remission.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). While Lenz or Douglass fail to specifically disclose PAP related to MARS comprising Ala393Thr/ Ser567Leu MARS double mutations, the teachings of Comisso have been relied upon for these disclosures. Therefore, one having ordinary skill in the art would have been able to arrive at the instant invention in view of Lenz and Comisso.
In response to Applicant’s arguments that the instant claimed method of administration of methionine every 6 h results in unexpected levels of methionine and creates synergy, citing the instant specification and Ref. 1 – as an initial matter, the instant specification shows no comparative studies wherein methionine was administered at different frequencies. Such a study is required to confirm that this frequency of administration is ‘special’ in achieving unexpected improvement of subjects’ condition. Furthermore, Ref. 1 also fails to show any study of dosing frequencies, and in fact, the Supplementary Materials of Ref. 1 - cited in the 892 Form provided along with this office action – admits that the “frequency of medication was based on the known half-life of the molecule and the peak was determined by performing kinetic measurements on the patients during the first day of supplementation” (see para. 1, page 1 of supplementary materials of Ref. 1). The instant specification states that “treatment every 6 h allowed getting reproducible residual and peak values during 24 h periods and also across days and months of treatment” (see page 13, lines 20-22). Again, in the instant spec., Applicant states administration every 6h – no other frequency of administration was attempted – see page 17, line 9 and page 20, line 22. Thus, nothing in Ref. 1 points to a special effect of dosing methionine every 6 h, as purported by Applicant.
In response to applicant's argument that Lenz does not show clinical remission, elimination of frequent lavages (BALF and WLL) in patients, free a patient from respiratory symptoms, inflammation, and cholestasis, as well as catchup in growth; the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
In response to Applicant’s arguments that Lenz does not provide motivation for dosing methionine every 6 h; Lenz discloses close monitoring of methionine levels in the plasma of two subjects suffering from PAP related to MARS1 (see Section 3.2, page 3063). Lenz teaches blood sampling 4 hours postprandially, and in case of methionine supplementation, blood sampling was done prior to the intake of methionine. Lenz discloses a target range of blood methionine to be between 80-150 µM, and discloses increasing dosage when methionine levels in blood remained in the “normal range” (lower than predetermined value). Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer methionine every six hours, or more or less frequently, in view of Lenz. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Lenz teaches close monitoring of plasma levels of methionine and administration of supplemental doses of methionine when levels were found to be under 80-150 µM. Applicant is reminded that a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Applicant is also reminded that 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.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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