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 .
Election/Restrictions
Applicant's election with traverse of subgroup 2 with the addition to the calcium salt of 5-methyl tetrahydro folate in the reply filed on 06/12/2025 is acknowledged.
Priority
This application is a U.S. national stage patent application under 35 U.S.C. § 371 of
International Application No. PCT/CN2020/113157, filed on September 3, 2020, which claims the benefit of, and priority to, Foreign Application No. CN201910828557.7, filed on September 3, 2019.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on January 02, 2026. Claims 1, 3-4, 6-11, 13-18, and 20 rare pending and under examination. Claims 2, 5, 12, and 19 are canceled.
Action Summary
Claims 1, 3-4, 6-11, 13-18, and 20 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bailey et al (US2014/0315853 A1), are maintained, but modified and revisited in light of the 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.
Claims 1, 3-4, 6-11, 13-18, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bailey et al (US2014/0315853 A1).
Claim interpretation: it is noted the specification does not define the term “preventing”. Preventing is taken by the Examiner to mean “not yet happen”. Therefore, the method of preventing claimed does not require to the patient to have the conditions/diseases.
Bailey teaches a method for rapidly repleting folate levels of a woman for whom there is reason to believe that she may be pregnant or of a woman who believes that she may soon become pregnant, said method comprising: administering to the woman two or more repletion doses of folate, wherein each of the repletion doses comprises no less than about 2.5 micromole of folate, wherein the repletion doses are administered no more than about one day apart, and wherein the total number of repletion doses administered to the woman is 72 or fewer. (See claim 1.) Tablet is an example of a suitable form of administration. (See paragraphs [0066] & [0064].) Moreover, Bailey teaches the folate administered to the woman is substantially chirally pure 5-methyl-(6S)-tetrahydrofolic acid or a polyglutamyl derivative thereof. (See claim 25.) The folate is administered as a food. (See paragraph [0074].) Furthermore, rapid elevation with the administration of 5-methyl-6S-tetrahydrofolate as trial B to pregnant women for preventing birth defects. (See paragraph [0153] & {00159].) Lastly, Bailey teaches and example of the salt form of folic acid of folate is calcium. (See paragraph [0062].)
With respect to “preventing neonatal congenial heart disease is selected from any one of the following subgroup diseases: 1. Congenial malfunction of great arteries, comprising any one of patent ductus arteriosus, aortic stenosis, pulmonary artery stenosis, pulmonary atresia or other congenital malformation of great arteries: 2. Congenital septal defects, comprising any one of atrioventricular septal defects (AVSDs), ventricular septal defects (VSDs), atrial septal defects (ASDs), tetralogy of Fallot, aortopulmonary septal defects or other congenital septal defects: and 3. Other congenital heart disease, comprising any one of congenital malformations of cardiac chambers and connections, congenital aortic or mitral valve malformation.” These limitations simply express the intended outcome of the method step positively recited and the patient population. The intended outcome would flow naturally form the fact that the prior art teaching the same method and the same patient population, i.e. a pregnant woman.
Moreover, with respect to the claimed limitation of the claimed peri-pregnant and/or pregnant woman is exposed to at least one environmental factor known to cause congenital heart disease of claim 1-further limited by heavy metal in claim 2-and by formaldehyde in claim 3-This limitation is considered inherent and ubiquitous in daily life. Formaldehyde and heavy metals (trace) are present in common household materials, air, and environments. Thus, this condition is met by the general population including the population of the prior art. Since the prior art already teaches administration step and the same patient population, this additional limitation does not confer novelty.
Lastly, as to the claimed method of making the salt of 5-methylhydrofolate, Applicant is reminded that product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps (MPEP 2113). As stated by the court in in re Thorpe (777 F.2d 695 (Fed. Cir. 1985), "even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a salt does not depend on its method of producing the salt. If the salt claimed in the product-by-process claims is the same from a product of the prior art, the claim is unpatentable even though the prior art product was made by a different process." As such, the claimed method by which the salt is produced does not carry patentable weight.
Acknowledgement is made of the receipt and entry of Applicant’s argument filed on January 02, 2026
Applicant’s argument
Applicant argues that Baily does not disclose explicit exposure to an environmental factor.
Examiner’ response
In response, Applicant’s argument is not persuasive. The Examiner maintains that such factors-like formaldehyde or heavy metals-are inherent everyday environments. Because the claim does not specify a threshold, ordinary exposure is reasonably contemplated. Thus, Baily’s teaching of administering the same compound to the same patient group anticipates the claim, as the prior art inherently includes such exposure.
Applicant’s argument
Applicant argues unexpected utility specifically for congenital heart disease.
Examiner’ response
In response, Applicant’s argument is not persuasive. Baily’s teaching of using the same compound for preventing birth defects broadly would reasonably include congenital heart defects as well. Further, the Applicant’s assertion of the environmental factor limitation, as previously stated, is inherent in everyday life. Thus, one of ordinary skill would see Baily’s teaching as including these circumstances, and the claim remains anticipated. In other words, the prior art’s broad teaching logically includes the claim’s scenario and no surprising gap exists.
Applicant’s argument
Applicant argues although insufficient maternal folic acid levels were known to be associated with increased risk of congenital heart disease, folic acid supplementation had not been conclusively demonstrated to be effective in preventing congenital heart disease. No statistically significant evidence had shown that folic acid has any effect on reducing rates of congenital heart disease or miscarriage. See Document 2, submitted herewith. In fact, although birth defects such as neural tube defects have been effectively controlled globally by folic acid supplementation, the incidence of congenital heart disease has shown an unexplained increase. See Document 1, submitted herewith.
Examiner’ response
In response, Applicant’s argument is not persuasive. Applicant’s evidence of efficacy is noted. However, patentability under 35 U.S.C. 102(a)(1) is not based on clinical proof of success. The prior art (Baily) teaches the same compound, administered to the same patient population, with the same goal of preventing birth defects, which would inherently include congenital heart disease. Therefore, the rejection stands, as the teaching is already present in the prior art, regardless of statistical outcomes.
Applicant’s argument
Applicant argues as reported in review articles published after the priority date of the subject application, high-dose folic acid supplementation may not reduce-and may even increase-the overall incidence of congenital heart disease. See Documents 3, 6, and 7, submitted herewith. Other folates, including dihydrofolate, tetrahydrofolate, and 5,10- methylenetetrahydrofolate, were further reported to cause malformations in zebrafish embryos and affect the development of SIZ blood vessels in zebrafish, suggesting that folic acid itself, and not just insufficient folic acid metabolism, are sufficient to increase the risk of congenital heart disease. See Document 4, submitted herewith. These findings directly challenge the traditional view that folic acid supplementation is generically beneficial for preventing birth defects.
Examiner’ response
In response, Applicant’s argument is not persuasive. Applicant’s submitted documents are noted. However, several of the documents appear to be post-priority studies that are not determined at the time of the claimed invention. Additionally, the submitted documents that are cited to support Applicant’s argument have not been submitted via an IDS and are not of record. The Examiner cannot formally consider these references in this response. The Applicant is advised to file and IDS if they wish these references to be entered into the record. In the present case, Baily teaches administration of 6S-5-methyltetrahydrofolate to pregnant women to prevent birth defects broadly, and the claim’s language aligns with that teaching. Later data or debates on outcomes do not change what the prior art disclosed.
Applicant’s argument
Applicant argues in the absence of effective drugs, the current approach for preventing congenital heart disease is limited to prenatal screening, with early termination of pregnancy recommended for cases involving abnormal and complex malformations with poor expected outcomes. Even with the promotion of prenatal screening, the incidence of congenital heart disease in Chinese newborns continues to rise. See Document 5, submitted herewith. High heterogeneity has been observed in the relationship between maternal folic acid supplementation and the risk of congenital heart disease across studies, and the risk of certain subtypes of congenital heart disease, such as atrioventricular septal defects, was shown to increase with folic acid supplementation. Id. Thus, the effective prevention of congenital heart disease, particularly in patients exposed to risk factors, is a long-felt but unmet need. Because a person of ordinary skill in the art would have expected folic acid and 6S-5 methyltetrahydrofolate to have the same technical effects, they would not been motivated to administer 6S-5-methyltetrahydrofolate to a peri-pregnant and/or pregnant woman in a method according to the claims with any reasonable expectation of success. However, unexpectedly, the subject application demonstrates that 6S-5-methyltetrahydrofolate has distinct effects from folic acid on embryonic heart development, making it potentially far superior to folic acid in preventing congenital heart disease. See Subject Application, Examples 1-11. Surprisingly, unmetabolized folic acid, which is present in the bloodstream of pregnant women following folic acid supplementation, was shown to be teratogenic in zebrafish and rats, leading to decreased survival rates and the development of heart defects. See Examples 3, 4, 8, and 9. These negative effects were not observed following administration of 6S-5-methyltetrahydrofolate. See Examples 1 and 10. The distinct effects of folic acid and 6S-5-methyltetrahydrofolate may be due to differential effects on transcription of genes associated with heart development (mef2c, bmp2b, vmhc, has2, and ephb4). See Example 4.
Examiner’ response
In response, Applicant’s argument is not persuasive. Specifically, MPEP 2131.04 states “Evidence of secondary considerations, such as unexpected results or commercial success, is irrelevant to 35 U.S.C. 102 rejections and thus cannot overcome a rejection so based. In re Wiggins, 488 F.2d 538, 543, 179 USPQ 421, 425 (CCPA 1973).” In the present case, Baily already teaches the use of 6S-5-methyltetrahhydrofolate-not folic acid-thus directly addressing the claimed compound. Since Baily anticipates the same compound and the same patient population, any potential unexpected result does not overcome the fact that the prior art already discloses administering the same compound and the same patient group.
Applicant’s argument
Applicant argues Examples 1-11. Surprisingly, unmetabolized folic acid, which is present in the bloodstream of pregnant women following folic acid supplementation, was shown to be teratogenic in zebrafish and rats, leading to decreased survival rates and the development of heart defects. See Examples 3, 4, 8, and 9. These negative effects were not observed following administration of 6S-5-methyltetrahydrofolate. See Examples 1 and 10. The distinct effects of folic acid and 6S-5-methyltetrahydrofolate may be due to differential effects on transcription of genes associated with heart development (mef2c, bmp2b, vmhc, has2, and ephb4). See Example 4. Moreover, 6S-5-methyltetrahydrofolate was shown to rescue survival and prevent heart defects in a zebrafish model of folic acid deficiency (see Example 2), and rescue heart defects and reduced survival rates caused by exposure to unmetabolized folic acid, formaldehyde, lead nitrate, ethanol, and aristolochic acid (see Examples 5, 6, and 11). These results would not have been expected by a person of ordinary skill in the art.
Examiner’ response
In response, Applicant’s argument is not persuasive. The Applicant presents potential difference in biological effects. However, Baily already teaches administration of 6S-5-methyltetrahydrofolate to prevent birth defects. Regardless of post-hoc mechanistic distinctions, the prior art disclosure of administering the same compound to the same patient group for the same purpose anticipates the claim. Thus, the rejection is maintained. In essence, the existence of the prior art’s teaching still stands.
Conclusion
Claims 1, 3-4, 6-11, 13-18, and 20 are not 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.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628