DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 26, 2025 has been entered.
2. Claims 46, 49 and 57-58 have been amended and new claims 59-61 have been added as requested in the amendment filed September 26, 2025. Following the amendment, claims 46, 49-50 and 57-61 are pending in the present application.
3. Claims 46, 49-50 and 57-61 are under examination in the current office action.
4. The objection to claim 58 for minor informalities is withdrawn in view of applicant’s amendment to the claim.
Maintained and New Claim Rejections
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.
5. Claims 46, 49-50 and 57-61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of detecting the amounts of Ab40 and Ab42 in a plasma sample of a subject, does not reasonably provide enablement for a method for identifying a subject likely to have Alzheimer’s disease (AD) or for a method of classifying subjects into a first group consisting of subjects who do not suffer from AD and a second group consisting of subjects who possibly suffer from AD before making decision on whether or not a subject suffers from AD as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. The rejection is maintained for reasons of record for claims 46, 49-50 and 57-58 and is further applied to new claims 59-61 as discussed below.
The basis of this rejection has been set forth previously (see section 7 of the 09/22/2023 Office action (OA), and section 5 of the 06/18/2025 OA), and therefore will not be fully reiterated here.
As amended, claim 46 is broadly drawn to a method for identifying a subject likely to have AD by determining an amount of Ab42 and Ab40, in a plasma sample from said subject, the method comprising determining the concentration of Ab42 and Ab40 in the sample, each by ELISA-based methodology, wherein if the concentration of Ab40 is equal to or less than a reference value, the concentration of Ab42 is equal to or less than a reference value, and the ratio of Ab40/Ab42 concentration is equal to or less than a reference value, the subject is likely to have AD. New claim 59 recites that the reference values for the concentration of Ab40, Ab42 and the ratio of Ab40/Ab42 are the maximum values for the plasma concentrations of Ab40, Ab42, and the ratio of Ab40/Ab42, respectively, in a reference population of patients know to suffer from AD. And new claim 60 further defines these reference value concentrations as 74.3 pg/ml for Ab40, 141.7 pg/ml for Ab42, and 1.90 for the ratio of Ab40/Ab42.
New claim 61 is directed to a method of classifying subjects into a first group consisting of subjects who do not suffer from AD and a second group consisting of subjects who possibly suffer from AD before making decision on whether or not a subject suffers from AD, comprising determining the concentrations of Ab42 and Ab40 in a subject sample by ELISA, wherein when the concentration of Ab40 is higher than 74.3 pg/ml, the concentration of Ab42 is higher than 141.7 pg/ml, and the ratio of Ab40/Ab42 concentration is higher than 1.90, the subject is classified into a first group; wherein when the concentration of Ab40 is 74.3 pg/ml or less, the concentration of Ab42 is 141.7 pg/ml or less, and the ratio of Ab40/Ab42 concentration is 1.90 or less, the subject is classified into the second group.
Accordingly, the claims broadly encompass the identification or classification of a subject as likely having AD based upon measured plasma concentrations of Ab peptides that meet three criteria: a concentration of Ab40 that 74.3 pg/ml or less, a concentration of Ab42 that is 141.7 pg/ml or less, and a ratio of Ab40/Ab42 that is 1.90 or less. However, the specification does not enable one of skill in the art to practice the full scope of the claimed methods without undue experimentation.
In particular, as stated previously, the prior art recognizes the unpredictability with respect to correlating plasma levels of Ab peptides to predicting the risk of AD in subject populations without also controlling for age, gender, education, ethnicity, and/or APOE genotype. Fukomoto et al. (2003; of record), for example, found that plasmas concentrations of Ab40 and Ab42 were not sensitive or specific for identifying mild cognitive impairment (MCI; which may be a precursor of AD) or AD, but instead Ab40 and Ab42 levels were positively correlated with age regardless of diagnostic category. And Kosaka et al. (1997; of record) noted that plasma levels and ratios of Ab40 and Ab42 in AD patients, regardless of disease stage, where indistinguishable from those non-AD neurologic disease patients and non-disease controls.
Along these lines, the instant specification demonstrates substantial overlap in the range of Ab40 and Ab42 concentrations and ratios in AD patients and healthy controls. As amended, the claims now recite that in order to identify a subject as likely to have AD, or to classify a subject as possibly suffering from AD, the plasma Ab40 concentration is 74.3 pg/ml or less, Ab42 is 141.7 pg/ml or less, and Ab40/Ab42 ratio is 1.90 or less. Conversely, the claims recite that a subject not suffering from AD has plasma Ab40 concentration higher than 74.3 pg/ml, Ab42 higher than 141.7 pg/ml, and Ab40/Ab42 ratio higher than 1.90. These reference values were obtained from Example 4 of the specification, which involved determining the Ab40 and Ab42 levels of 10 AD patients and 10 healthy control subjects. Importantly, the reference values that are recited in the claims are the highest individual plasma concentrations of Ab40 and Ab42 that were determined within an AD patient from the ten subjects that were tested (and not necessarily from the same subject); these are not average or mean values, they are absolute concentrations. Similarly, the Ab40/Ab42 ratio of 1.90 was the highest ratio found (range 0.17-1.90) in a single tested AD patient.
As stated previously, both the prior art and the instant specification recognize that there is significant variability in plasma Ab concentrations from person to person as well as great overlap in the Ab40 and Ab42 levels between healthy (non-AD) subjects and AD patients. Mehta et al. (Arch Neurol. 2000; 57:100-105; listed on 04/08/2019 IDS), for example, teaches that plasma concentrations of Ab40 in patients with sporadic AD have a median of 272 pg/ml (with a range of 100-770) and Ab42 median of 73 pg/ml (range 25-880), and in elderly nondemented control subjects the median plasma Ab40 is 219 pg/ml (range 35-490) and Ab42 is 81 pg/ml (range 25-905) (see Table 2 a p. 102). In contrast to the findings of the instant specification which report that both Ab40 and Ab42 plasma levels were higher in healthy controls than in AD subjects, Mehta found that plasma levels of Ab40 were higher in the AD group than in controls, and levels of Ab42 were similar in both groups. Calculating an Ab40/Ab42 ratio from these median values would give 2.70 for the control group and 3.73 for the AD group. Note that Mehta determined Ab plasma levels by ELISA using the same capture (6E10) and C-terminal Ab40- and Ab42-specific detection antibodies as presently claimed.
Mayeux et al. (Ann Neurol. 1999, 46:412-416; listed on 04/08/2019 IDS), using the same ELISA method as in Mehta (6E10 capture antibody; C-terminal specific detection antibodies), also found Ab40 plasma levels to be higher in AD patients (134.7 ± 5.8 pg/ml) compared to controls (111.8 ± 4.3 pg/ml). Unlike Mehta and the instant application, Mayeux found Ab42 plasma levels to be higher in AD patients (82.4 ± 8.6 pg/ml) than in control subjects (51.5 ± 4.1 pg/ml) (see Table 1 at p. 413). Thus, as can be seen by these prior art findings and as discussed previously, there is substantial unpredictability with respect to the measurement of Ab peptides in different laboratories even using highly similar techniques.
Furthermore, according to claimed identification/classification criteria, two of the healthy subjects tested by the instant specification would be identified as likely to have AD: MPG-8 and ARL-24. More problematic, however, is the fact that none of the healthy subjects meet all three of the recited criteria for a subject not suffering from AD. These subjects do not fall into either of the two groups recited in claim 61 (i.e., not AD or possible AD), and therefore the instant specification does not demonstrate that classification of a subject as being non-AD can be made by using the method as claimed. The instant specification does not provide sufficient guidance to aid in the classification of individuals that do not meet the criteria for either of the two groups, and there is insufficient guidance to successfully identify a subject as likely to have AD according to the claimed invention.
Accordingly, undue experimentation would be required of one of skill in the art to practice the full scope of the broadly claimed methods.
Response to Arguments
6. In the response filed 09/26/2025, applicant asserts that despite the two healthy subjects meeting the claimed criteria for possible AD, the claimed method is still clinically useful even if it is not 100% accurate, as it can be used as a screening procedure for further AD diagnosis using more expensive and/or invasive techniques.
Applicant’s argument has been considered but is not persuasive. The presently claimed method is rejected for a lack of enablement, not utility. The method may indeed have utility in a clinical sense, but it still lacks enablement because undue experimentation would be necessary to perform the pre-diagnostic assessment as claimed.
Applicant argues that the examiner did not take into account that the method requires all three markers to be jointly evaluated to determine the likelihood of suffering from AD. Applicant also argues that none of the cited prior art references suggest the combined use of the three markers in the context of the claimed methodology.
Applicant’s argument has been considered but is not persuasive. The above analysis has indeed taken into account the fact that all three reference values must be determined and compared in order to indicate likelihood of AD. The above cited art using methodology consistent with the instant invention demonstrates findings that are in opposition to the findings of the instant invention, even when all three markers are evaluated.
With respect to sample size and intra-assay reproducibility, applicant argues that the claimed method is clinically relevant in a “sufficiently high number of patients” and that that intra-assay reproducibility issues of are not of particular concern (according to Okereke et al.) and are routinely taken into consideration by those skilled in the art.
Applicant’s arguments have been considered but are not persuasive. As discussed above, the claimed reference values are the highest measured concentrations of Ab40 and Ab42 from individual subjects within the AD group, and the Ab40/Ab42 ratio is also the highest ratio from an individual subject within the group. Given the demonstrated variability in Ab peptide levels among individual subjects both within the healthy control group and the AD group, and the documented high variability in Ab plasma concentrations across multiple prior art studies (even those using highly similar methodology), the currently claimed reference values thus appear to be arbitrary and lack reproducibility. There is no evidence that the combination of the three selected values is predictive of identifying AD in a subject a reproducible manner, and indeed are not at all predictive of identifying a subject as “not suffering from AD”. And even when average or median values of Ab plasma levels are assessed using highly similar ELISA methodology, the prior art still evidences that great variability, as well as great overlap between different diagnostic groups, exists with respect to Ab concentrations and Ab40/Ab42 ratios. As such, performing the claimed method would likely lead to false positives, false negatives, and/or in the case when only one or two of the three diagnostic markers are met, subjects who remain unclassifiable. Further experimentation would therefore be required of the skilled artisan to obtain much larger sample sizes (AD and control) to account for such Ab level variability, and then to refine collected data to obtain more reliable reference criteria. Such additional necessary experimentation is considered undue.
Finally, applicant contends that the claimed method is not necessarily a diagnostic method per se, but it allows for the identification of patients who are likely to have AD by means of the combined equal evaluation of three markers, and therefore is clinically useful.
Again, applicant’s arguments have been considered but are not persuasive. While the instant application may support a specific and substantial utility for the claimed invention as well as a credible basis supporting that utility, this fact alone does not provide a basis for concluding that the claims comply with all requirements of 35 U.S.C. 112(a). As pointed out in Mowry v. Whitney, 81 U.S. (14 Wall.) 620 (1871), an invention may in fact have great utility, i.e., may be “a highly useful invention,” but the specification may still fail to “enable any person skilled in the art or science” to use the invention. 81 U.S. (14 Wall.) at 644. See also MPEP 2164.07.
The above rejection is therefore maintained.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
7. Claim 61 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 61 recites the limitation "the plasma sample" in line 6. There is insufficient antecedent basis for this limitation in the claim.
Conclusion
8. No claims are allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly A. Ballard whose telephone number is (571)272-2150. The examiner can normally be reached Mon-Fri 8AM - 5PM EST.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675