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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/05/2025 has been entered.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or
under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application receives foreign priority from EPO 18382898.7 filed 12/05/2018. Based on the filing receipt, the effective filing date of this application is December 5, 2018 which is the filing date of Application EPO 18382898.7 from which the benefit of priority is claimed.
Status of Claims
Claims 1, 3-5, 8, 11-17, 21-27, 29-30 and 32-33 are pending.
Claims 3-5, 8, 11-17 and 26-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/16/2020.
Claims 1, 21-25, 29-30, and 32-33 are under examination.
Withdrawn Rejections
The rejection of claims 1, 21-25, 29-30, and 32-33 on the grounds of 35 U.S.C. 112(b) has been withdrawn, necessitated by amendments filed 12/05/2025.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 21-25, 29-30, and 32-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and, (8) the breadth of the claims. In re Wands, 8 USPQ2d, 1400 (CAFC 1988).
The claims are directed to a method comprising: (a) obtaining a hair sample of a subject; (b) assaying said hair sample of said subject to determine a level of anti-mullerian hormone (AMH) in said hair sample; and (c) determining an assessment of antral follicle count (AFC) based on the determined level of AMH in said hair sample, wherein the subject is a human female.
Claim 1 does not establish the relationship between AFC and the determined level of AMH in said hair sample. The specification at FIG. 4 merely alleges a correlation of AMH levels in hair with AFC of the subject. The data has sample size N=8. With respect to FIG. 4, the correlation coefficient and linear regression equation are not disclosed in the specification. While the specification at Example 11 on p. 66 discloses the results are “strongly correlated”, an artisan would not be convinced of this by the data disclosed in FIG. 4 due to the low sample size. Prior art, such as the journal articles on fertility biomarkers of Horka et al. (“Matrix metalloproteinases in serum and the follicular fluid of women treated by in vitro fertilization”, published 2012-09-28, cited in PTO-892 dated 06/05/2025) and Gupta et al. (“Power of Proteomics in Linking Oxidative Stress and Female Infertility”, published 2014/05/12, cited in PTO-892 dated 06/05/2025), discloses biomarker measurements with N=58 and N=66, respectively (see, e.g., Horka, p. 1208, under “Subjects”, para. 2 and Gupta, p. 11, col. 2, para. 1). The biomarker measurements of Gupta and Horka have sample size multiples greater than the data disclosed in FIG. 4 of the instant application. An artisan would not be convinced of the relationship between AMH in hair and AFC partly due to the sample size, especially considering the sample size of other studies in the field. In addition, an artisan would not know the relationship between AMH and AFC because the correlation coefficient and linear regression equation was not disclosed. For context, in a journal article on biomarkers in reproductive medicine, Palmer, et al. (“Biomarkers in reproductive medicine: the promise, and can it be fulfilled?”, published 2013-03-15, cited in PTO-892 dated 06/05/2025) discussed the diagnostic power of biomarkers in the field of fertility. Even if the association between AMH and AFC was clearly presented, Palmer recites, “The difficulty is validating such an association and moving it into the clinical arena” (see, e.g., p. 956, col. 2, under “Biomarkers in Reproduction”). Palmer further recites, “Connecting the mechanistic dots of a marker to a condition will likely increase clinical uptake. […] it is possible that a woman can have “decreased ovarian reserve” and still have a normal antimullerian hormone” (see, e.g., p. 955, col. 2, under “UTILITY AND PITFALLS OF THE USE OF BIOMARKERS IN CLINICAL PRACTICE”). Palmer provides evidence that even if a clear association or correlation was presented, the invention would not be clearly enabled without validating the relationship between AMH in hair and AFC or presenting a mechanistic understanding of that relationship.
With respect to the quantity of experimentation necessary, claim 1 recites, “determining an assessment of antral follicle count (AFC) based on the determined level of AMH in said hair sample”. An artisan seeking to use the claimed invention would be required to execute undue experimentation because the Applicant has not clearly established the correlation between AMH in hair and AFC (as discussed above). Due to this lack of disclosure, the artisan would have to execute undue experimentation to establish the correlation.
With respect to determining an assessment of AFC, there is a lack of working examples. Example 11 on p. 66 of the specification does not explicitly estimate AFC based on the detection of AMH in the hair. Example 11 merely recites, “measuring AMH from hair samples may be an improved assay approach for measuring or estimating antral follicle count”. Without a working example disclosing the method for assessing AFC based on the level of AMH in hair, the Applicant has not enabled the use of their invention.
The instant invention is not considered to be enabled for a number of reasons. The claims are not enabled for assessment of AFC given that there is only a correlation of a biomarker as being decreased or increased in small sample sizes in subjects. The nexus between AFC and the claimed biomarker is extremely weak, given that the sample sizes are small due to the evidence provided by the prior art (see Horka and Gupta). The specification does not present the appropriate controls in the patient populations. The data provided in the specification does not enable assessment of AFC by determining AMH levels.
The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without such guidance, the changes which can be made and still maintain activity/utility is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Int. 1986).
Regarding the level of unpredictability in the art, prior art has established that hair analysis faces challenges that lead to a high level of unpredictability. In a journal article on methods of hair protein extraction, Wong et al. (“A High-Yield Two-Hour Protocol for Extraction of Human Hair Shaft Protein”, published 2016-10-14, cited in PTO-892 dated 06/05/2025) discloses, “Proteome analysis of the human hair remains challenging due to the poor solubility of hair proteins and the difficulty of their extraction” (see, e.g., p. 1, under “Abstract”). Adding further unpredictability is the fact that “[c]ollection procedures for hair analysis… have not been standardized” as evidenced by the third paragraph of the “Reminders” section of Villain et al. (“Hair analysis in toxicology”, published 2004, cited in PTO-892 dated 06/05/2025). Though the level of skill in the art is high, the level of disclosure needed to meet the enablement requirement is heightened due to the high level of unpredictability in the art of hair analysis.
With respect to the breadth of the claims, claim 1 recites, “assaying said hair sample of said subject to determine a level of anti-mullerian hormone”. The broadest reasonable interpretation of the claim includes any assay that could measure AMH in hair. However, the measurement of AMH in hair has only been disclosed by quantitative competitive enzyme immunoassay in Examples 1-4 of the specification. The disclosure of a single assay in the specification does not reasonably enable the measurement of AMH in hair by any other assay.
The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. Due to the large quantity of experimentation necessary to establish a true nexus between assessing AFC and AMH in hair recited by the claims, the breadth of the claims which encompasses assessing AFC with a paucity of true evidence supporting such assessment, the state of the prior art which establishes the unpredictability of such assessment, the lack of guidance or evidence in the specification supporting the assessing power of the claimed invention, and the complex nature of the invention, undue experimentation would be required of the skilled artisan to make and use the claimed invention.
Response to Arguments
The declaration under 37 CFR 1.132 filed 12/05/2025 is insufficient to overcome the rejection of claims 1, 21-25, 29-30, and 32-33 based upon 35 U.S.C. 112(a) as set forth in the last Office action because: the declaration does not provide sufficient evidence to remove the undue experimentation an artisan would have to execute to practice the invention of claims 1, 21-25, 29-30, and 32-33.
The declaration adds to the record that the Pearson correlation is 0.68 for AMH and AFC for the samples shown in Figure 4 of the applicant’s specification. While a Pearson correlation of 0.68 does indicate a positive correlation for AMH and AFC, the correlation is not strong, as evidenced by the NIH’s Learning Resources webpage on correlation (https://www.nlm.nih.gov/oet/ed/stats/02-300.html).
The declaration further points to the strong effect size and P value of the 8 measurements disclosed in Figure 4 of the applicant’s specification, shown in Table 10 of the applicant’s specification. The declaration states, “These results demonstrate that measuring AMH levels from hair samples may be an improved assay approach for measuring or estimating antral follicle count (AFC) as compared to methods of assaying AMH levels from plasma samples” (see p. 3, para. 1). While the results demonstrate that measuring AMH levels from hair samples may be an improved assay approach for measuring or estimating AFC, due to the small sample size of the results (N=8), an artisan would have undue experimentation to execute in order to establish the relationship between AMH levels in hair samples and AFC. The 35 U.S.C. 112(a) rejection above further discusses the lack of enablement, related to sample size of the disclosed results.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The NIH’s Learning Resources webpage on correlation (https://www.nlm.nih.gov/oet/ed/stats/02-300.html) provides evidence that a correlation coefficient of 0.68 is not strong.
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 MICHAEL C SVEIVEN whose telephone number is (703)756-4653. The examiner can normally be reached Monday to Friday - 8AM to 5PM PST.
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/MICHAEL CAMERON SVEIVEN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678