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 without traverse of Group I, species taupathy and treatment of NAP peptide in the reply filed on 7/23/25 is acknowledged.
Applicant states that the kit of claim 56 is entitled to rejoinder upon finding that the method claims are allowable. MPEP 821.04(b) pertains to rejoinder of process claims requiring an allowable product and not to rejoined of product claims related to a method, and does not set forth an entitlement that a kit claim will be rejoined if a method claim is found to be allowable. Rejoinder will be considered as appropriate.
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. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/902420, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The prior application does not describe a method for monitoring a response to a treatment of a disease or condition with the breadth of the instant claims, nor does it provide support for a method for detecting Adnp deficiency with the breadth of the instant claims. Therefore, the effective filing date of the instant claims is 9/16/2020.
Claim Objections
Claim 55 objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent must depend from prior claims in the alternative. See MPEP § 608.01(n).
Claim Rejections - 35 USC § 112
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.
Claims 54 and 55 are 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 54 is indefinite when it recites “the treatment” because claim 53 does not specifically recite a treatment.
Claim 55 recites “consulting monitoring a response” and it is not clear what this phrase means. It is possible that “consulting” is a typographical error for “comprising.” The claim has been interpreted as if “consulting” reads “comprising.” Furthermore, the claim recites “a response to the treatment” but no claim ever requires administering a treatment. Claim 53 recites providing “recommendations to treat” and but no claim actually requires administering a treatment, and so it is unclear what is being monitored.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 38-55 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature and an abstract idea without significantly more. The claim(s) recite(s) the naturally occurring relationship between changes in bacteria indicating normal levels of active ANDP and response to treatment which is a law of nature judicial exception. They also recite comparing the amount of bacteria in a first and later measurement which is a mental process judicial exception. This judicial exception is not integrated into a practical application because the claims do not apply or use the judicial exceptions in any way. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the element in addition to the judicial exception is “measuring the amount of at least one type of bacteria of a microbiome” which is a data gathering step that is presolution activity recited at an extremely high level of generality. Techniques to measure the amount of bacteria, for example comprising 16S RNA analysis of the microbiome were routinely practiced at the time of the invention. See specification ¶0045 and Pollack et al. (Appl Environ Microbiol 84:e02627-17. https://doi.org/10.1128/AEM.02627-17.).
Claims 38-55 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 monitoring response to treatment and detecting a response to treatment with NAP peptide in mice by assaying bacteria in fecal matter for the family Eubacteriaceae, Lactobacillus group, Bifidobacterium genus, and mouse intestinal Bacteroides in males does not reasonably provide enablement for claims with the breadth of the current claims with regard to bacteria that are indicative, sample, and species of animal. Further, the specification is additionally enabling for all of the bacterial groups in Figures 1 and Lactobacillus and Clostridium cluster in mice fecal samples as indicators of a mouse suffering from a ADNP deficiency in a sex specific way. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The claims are sufficiently broad so as to predict the presence of ADNP deficiency and also response to treatment in any species of animal, using any possible gut microbiota, for any possible ADNP disease, and for any possible treatment.
The specification teaches that an Adnp-mutated mouse model was produced (¶0103). These mice have developmental delays, impaired vocalizations, and motor dysfunction along with memory and social impairments, mimicking the ADNP syndrome in children (Hacohen-Kleinman J Clin Invest. 2018;128(11):4956–4969).
The specification teaches treating the mice with NAP peptide and conducting murine fecal microbiota analysis via 16S qRT-PCR. Figures 1 and 2 provide some results. Figure 1 illustrates in Figures 1A-C and 1E microbiota that were increased in Adnp+/- compared to Adnp+/+ mice, and which responded to NAP treatment by reduction in bacterial levels to normal in male mice. Figure 2A and 2C illustrate microbiota that were increased in Adnp+/- compared to Adnp+/+ mice, and which responded to NAP treatment by reduction in bacterial levels to normal in female mice. Figure 2B and 2D illustrates that Adnp+/- mice had lower levels of the tested bacteria than Adnp+/+ mice, but that NAP treatment did not return or restore the value to the same as Adnp+/+ mice.
The example demonstrates the unpredictability of the instant invention. The disclosure teaches that nine different “main bacterial groups” abundant in murine intestinal bacteira loads were determined (¶0110), and of these, the results were different for male and female animals, and there was no way to predict which bacterial group was associated with Adnp deficiency and of those, which responded to treatment. Lactobacillus group is shown in Figure 1B to be increased in the Adnp +/- model, and return to Adnp+/+ levels upon treatment with NAP in male mice. On the other hand, it was decreased in mutated female models and did not return to baseline upon treatment. There is no way to predict from these results which other bacterial groups would be predictive in males or females.
Furthermore, it is highly unpredictable if these results could be extrapolated to other sample types or to organisms other than mice or for the treatment of other conditions.
With regard to sample types, every surface and fluid of the body and fluid has a unique microbiome. The Human Microbiome Project teaches that clustering of principle coordinates among samples demonstrates that primary clustering is by body area. For example, the gastrointestinal microbiome clustered independently of the skin microbiome. See The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012). https://doi.org/10.1038/nature11234 , figure 1A and throughout. Following this, it is highly unpredictable whether the biomarkers biomarkers identified in stool of mice could be used as bacterial biomarkers of Adnp deficiency or response to treatment with NAP in any other sample type such as sweat or saliva since there is no way to predict that the same bacteria will be present in these samples, and if present that it will be indicative of the deficiency in the same way as it is in fecal samples.
Furthermore, it would have been highly unpredictable to extrapolate the findings in mice fecal samples to fecal samples in humans or other organisms. Overall, the gut microbiota of human and mice are dominated by two major phyla, Bacteroidetes and Firmicutes, but 85% of bacterial genera found in the mouse gut microbiota are not present in human (Nguyen et al. 2015, p. 3). Nguyen et al. found 79 genera occurring in both human and mouse gut microbiotas. The relative abundances of most of the dominant genera in mouse and human are quite different (Fig. 3A, p. 4). Hugenholt et al. teach the human and mouse intestinal microbiota show considerable similarity at the genus level but reveal large quantitative differences (Hugenholtz et al. Cell. Mol. Life Sci. (2018) 75:149–160; Fig. 3). Moreover, a total of 60 genera were detected in the mouse gut microbiome core, of which only 25 were shared with the core genera in the human gut microbiome, where the core was here defined as genera being present in all samples (p. 154, 2nd column). Given the differences between microbiomes between different animal species, it would have been highly unpredictable to extrapolate the biomarkers identified in mice to human patients, even in a sex specific manner.
Regarding the scope of the treatment and the disorder, the teachings of the specification are limited to demonstrating that only certain bacterial group abundances can be used as a biomarker for response to treatment, in mice models for ADNP deficiency, in a sex specific manner, and in response to administering NAP. It is highly unpredictable if other drugs will affect gut microbiota in the same way such that the limited results, which themselves were demonstrated to be unpredictable, could be extrapolated to predicting or identifying response to other drugs in Adnp deficient mouse models or in models for other disease.
Therefore, having carefully considered the breadth of the claims, the teachings in the specification and examples, and the high level of unpredictability in the prior art, it is concluded that it would require undue experimentation to practice the claimed invention commensurate in scope with the instant claims.
Claim Rejections - 35 USC § 102
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.
Claim(s) 38-55 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kapitansky et al. (Journal of Neural Transmission (2020) 127:251–263).
With regard to claim 38, the reference teaches a method that comprises measuring the amount of at least one type of bacteria of a microbiome in a biological (stool) sample from an ADNP deficient subject at two or more different time points. See methods and Figure 1. The preamble of the claim is a statement of intended use, and the “wherein” clause states an inherent property of the response. Neither require any further action than the measuring the amount of at least one type of bacteria of a microbiome.
With regard to claim 47, the reference teaches the measuring and comparing steps. See methods and Figure 1. The preamble of the claim is a statement of intended use, and the “wherein” clause states an inherent property of the response. Neither require any further action than the measuring the amount of at least one type of bacteria of a microbiome.
With regard to claim 39 and 48, the reference teaches a biological sample that is fecal.
With regard to claims 40, 41, 42, 49, and 50, the reference teaches male subjects and Eubacteria. See Figure 1. Claims 42 and 50 recite inherent properties of the method and do not require any further action. Nonetheless, the data presented in Figure 1 support these “wherein” clauses.
With regard to claims 43, 44, 51 and 52, the reference teaches female subjects and Lactobacillus. Claims 44 and 52 recite inherent properties of the method and do not require any further action. Nonetheless, the data presented in Figure 1 support these “wherein” clauses.
With regard to claim 53, the reference teaches treating the deficient mice with NAP, and thus the method inherently requires “recommending” the treatment as it is delivered to the subjects. The subjects have mild cognitive impairment associated with the deficiency, and with regard to claim 55, the response is montitored by the method of claim 38, as discussed.
With regard to claims and
Conclusion
The claims are free of the prior art. Hicks et al. (WO2018/175759) teaches a method for monitoring a response to a disease or condition comprising measuring bacteria of a microbiome in a biological sample from the subject at two or more different time points, wherein the patient response favorably to the treatment if the amount of said bacteria in the later measurement changes (Abstract and embodiments 2 and 27). Gozes (WO2017/130190) teaches the association between ADNPO and various neurological diseases (¶73) and further suggests an association with ASD (¶8). However, neither of these publications disclose monitoring a treatment in an ADNP-deficient subject, wherein the monitoring is based on differential amounts of said bacteria with respect to subjects having normal levels of active ADNP. In light of this, the claims herein would be free of the prior art if the claim to priority is established or if Kapitansky is otherwise removed as a reference.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682