DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. This action is in response to the papers filed April 27, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Claims 28, 30-31, 34, and 36-39 are currently pending and have been examined herein.
Claim Interpretation
3. Based on the arguments filed on 10/9/2024 page 6, the steps in claim 28 are mere data analysis steps, and the processing of the sample and running of the assay occurs before step "(a)". Thus the methods that are recited in claims 30-31 and 39 occur prior to step (a) of claim 28.
Claim Rejections - 35 USC § 112(b)
4. 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 28, 30-31, 34, 36-39 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 pre-AIA the applicant regards as the invention.
Claims 28, 30-31, 34, 36-37, and 39 are rejected over the recitation of the phrase “one or more surrogate variable”. This phrase in considered indefinite because it is not clearly defined in the claim or the specification and there is no art recognized definition for this phrase. As such the skilled artisan would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 28, 30-31, 34, and 36-39 are rejected over the phrase “the processed DNA methylation data” in claim 28 step b. There is insufficient antecedent basis for this limitation in the claim. Although the claim previously recites a step of “processing raw DNA methylation data”, it does not refer to “processed DNA methylation data”. Further it would be unclear at which point ((i), (ii), or (iii)) the raw DNA methylation data would be considered to be processed.
Response To Arguments
5. In the response the Applicants traversed the rejections under 35 USC 112(b). Regarding the recitation of the phrase “one or more surrogate variable” the Applicants argue that the specification clearly provides that the statistical model treated AOSI as the outcome of interest and adjusted for paternal age and ten surrogate variables as confounders (see specification at paragraph [0096]). Further, FIG. 7 (or Table 4) describes the discussed ten surrogate variables (SVs), which are race/ethnicity, study site, paternity status, education, income, hybridization date, shearing date, hydroshear machine, CHARM Gel ID, and Gel location. Applicant submits that measuring those SVs and applying them to the algorithms is part of the step of processing the raw DNA methylation. One of skill in the art would readily recognize and understand, notably based on the disclosure in the specification, that these steps are meant to ensure that the SVs, which should not infer with the results of the analysis, in fact have no impact (or that said impact is mitigated). The present claim language, in view of the detailed description provided, is clear and properly defined such that one of skill in the art is readily able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
This argument has been fully considered but is not persuasive. While the specification provides examples of “surrogate variables”, a complete definition for this phrase is not provided. It is unclear if the claims which recite “surrogate variables” are limited only to the variables that are recited in the specification and newly added claim 38 OR if other variables would also meet this limitation. Since the specification only provides examples of what could be included by this phrase, these teachings are not considered to be sufficient to provide a complete and fixed definition for the phrase “surrogate variables” and the rejection is maintained.
Claim Rejections - 35 USC § 112(a)-Enablement
6. 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 28, 30-31, 34, and 36-39 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 claim(s) contains 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.
Scope of the Claims/Nature of the Invention
The claims are drawn to a method for determining an offspring is high risk for autism spectrum disorder (ASD).
The claims recite identifying the offspring as having a high risk for developing ASD based on (i) the determined hypomethylation of one or more of the respective gene or regulatory regions (DMRs) and (ii) an AOSI score of 10 or more.
Claim 28 recites the DMRs reside in the following genes or regulatory regions of reference human genome assembly hg19:
Chr15:25,466,000-25,474,000 overlapping SNORD115-15 (8000 bp region);
Chr15:25,478,000-25,484,000 overlapping SNORD115-11 (6000 bp region); and
Chr15:25,446,000-25,452,000 overlapping SNORD115-17 (6000 bp region).
Claim 36 recites the DMRs reside in the following genes or regulatory regions of reference human genome assembly hg19:
Chr15:25,467,684-25,471,631 overlapping SNORD115-15 (3947 bp region);
Chr15:25,479,139-25,482,453 overlapping SNORD115-11 (3314 bp region); and
Chr15:25,448,132-25,450,278 overlapping SNORD115-17 (2146 bp region).
Claim 37 recites the DMRs reside at a locus of the human genome annotated as:
NR_003307 (81 bp region);
NR_003303 (82 bp region); and
NR_003309 (82 bp region).
The claims recite that the methylation status is determined by measuring an average methylation level across all CpG sites analyzed within the gene or regulatory region of b.
The claims further recite that a gene/regulatory region is hypomethylated when the average methylation level is less than 50% across all CpG sites analyzed within the respective gene or regulatory regions.
The number of CpG sites analyzed is totally dependent upon the type of assay that the user of the method performs. For example consider Chr15:25,466,000-25,474,000. While a sequencing assay might allow analysis of all CpG sites in this region, other types of assays would not. The Illumina 450k Methylation Array only has probes to 16 CpG sites in this region. A methylation specific PCR assay might only permit analysis of one or two CpG sites in this region. The claims require determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs.
The nature of the invention requires a reliable correlation between hypomethylation of any two or more CpG sites within the recited gene/regulatory regions and ASD. The nature of the invention further requires a reliable correlation between an AOSI score of 10 or more and ASD.
Teachings in the Specification and Examples
The specification (para 0076) teaches that genome wide DNA methylation was examined in paternal semen bio samples obtained from an ASD enriched-risk pregnancy cohort, the Early Autism Risk Longitudinal Investigation (EARLI) cohort, to estimate associations between sperm DNAm and prospective ASD development, using a 12-month ASD symptoms assessment, the Autism Observation Scale for Infants (AOSI). Methylation data from 44 sperm samples were analyzed on the CHARM 3.0 array, which contains over 4 million probes (over 7 million CpG sites), including 30 samples also run on the Illumina Infinium HumanMethylation450TM (450 k) BeadChipTM platform (~485,000 CpG sites).
The specification (para 0109) teaches that 2605 candidate DMRs were identified in paternal sperm associated with child AOSI score at 12 months, and after permutation analysis, the top 193 DMRs had genome-wide p<0.05. The top 10 ranked DMRs are shown in Table 2. The top four regions where DNAm associates linearly (genome-wide p=0.001) with AOSI score were highlighted in FIG. 1, with the average DNAm across the DMR shown in each inset. FIG. 1a shows hypomethylation with increased AOSI score on chromosome 15 overlapping SNORDI15-15 where the highest quartile of AOSI scores (>10) corresponded to 27.4% average sperm methylation compared with 46.9% average methylation for the lowest quartile (<3). Similarly, FIGS. 1b and 1c show hypomethylation with increased AOSI scores on chromosome 15 covering SNORD115-11 and SNORD 115-1 7, respectively, with differences in regional average methylation between the highest and lowest AOSI quartiles of 19.7% and 22.6%, respectively.
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The specification (para 0114) teaches that FIGS. 1A-1D are graphical representations of methylation plots for the top 4 statistical DMRs identified using CHARM and 12-month score in embodiments of the present invention. (A) SNORD115-15, (B) SNORD115-15, (C) SNORD115-17, (D) SMYD3. Top panels show individual methylation levels at each probe by genomic position. Dotted vertical lines represent the boundaries of the DMR, and colored lines represent the average methylation curve for samples grouped by quartiles of AOSI scores—the scores within each quartile are shown in the legend. Middle panel shows location of CpG dinucleotides (as black tick marks) and CpG density by genomic position (black curved line). Bottom panel shows location (boxes) and direction (+ or −) of refseq-annotated genes. Inset scatterplot reflects linear regression of average methylation across all probes within DMR per sample by AOSI 12-month score.
State of the Art and the Unpredictability of the Art
While methods of measuring the methylation status of CpG sites in a DMR are known in the art, correlating the methylation status of CpG sites with the presence of ASD is highly unpredictable. The unpredictability will be discussed below.
In the instant case the claims require identifying the offspring as having a high risk for developing ASD based in part on determined hypomethylation of one or more of the respective gene or regulatory regions. The claims state that a gene/regulatory region is hypomethylated when the average methylation level is less than 50% across all CpG sites analyzed within the region. In the instant case there is no disclosure of how many potential methylation sites (CpG positions) within any of the claimed genomic regions. For example the specification is silent with respect to how many potential methylation sites are found within Chr15:25,466,000-25,474,000. There is no data in the specification that compares how many potential methylation sites found within Chr15:25,466,000-25,474,000 are actually methylated in human subjects that produce offspring that develop ASD versus human subjects that do not product offspring that develop ASD. The teachings in the specification do not appear to be commensurate in scope with the claims. The data in the specification only shows how frequently particular CpG sites are methylated in groups of individuals having different AOSI scores. For example for the first CpG site, it is methylated in ~50% of the population with 0-2 AOSI scores and methylated in ~30% of the population with 10-12 AOSI scores.
Further it is relevant to note that even within a DMR, not all of the CpG sites will be useful for determining whether an offspring has ASD. For example, Widschwendter (US 2019/0323090 10/24/2019) discloses four DMRs (SEQ ID NOs: 1-4) that are hypermethylated in ovarian cancer. Notice that not all CpG sites are underlined, only the relevant CpGs are underlined.
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Consider SEQ ID NO: 4 which is 140 bp long and has 13 CpG sites. The CpG sites are located at positions 12, 28, 31, 34, 48, 54, 67, 70, 82, 88, 101, 104, and 123 of SEQ ID NO: 4. According to Table 1A only 11 of the 13 CpG sites in SEQ ID NO: 4 are disclosed as being relevant (28, 31, 34, 48, 54, 67, 70, 82, 88, 101, and 104) to ovarian cancer.
The specification (Table 2) also teaches the particular patterns of the epigenetic markers associated with the presence of ovarian cancer.
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It is noted that the underlined CpGs of SEQ ID NO: 66 correspond to the CpG sites located at positions 28, 31, 34, 48, 54, 67, 70, 82, 88, 101, and 104 of SEQ ID NO: 4. As shown in Fig 2B each one is methylated in ovarian cancer (1=methylated, X= methylated or unmethylated). This Table demonstrates that OC is present when the CpGs at positions 28, 31, 34, 48, 54, 67, 70, 82, 88, 101, and 104 sites are methylated in cell free DNA.
The instant specification is completely silent with respect to how many CpG sites are present in each of the following:
Chr15:25,466,000-25,474,000 overlapping SNORD115-15 (8000 bp region);
Chr15:25,478,000-25,484,000 overlapping SNORD115-11 (6000 bp region); and
Chr15:25,446,000-25,452,000 overlapping SNORD115-17 (6000 bp region).
Chr15:25,467,684-25,471,631 overlapping SNORD115-15 (3947 bp region);
Chr15:25,479,139-25,482,453 overlapping SNORD115-11 (3314 bp region); and
Chr15:25,448,132-25,450,278 overlapping SNORD115-17 (2146 bp region).
NR_003307 (81 bp region);
NR_003303 (82 bp region); and
NR_003309 (82 bp region).
The instant specification does not disclose any particular CpG sites within these regions that are relevant to ASD. Finally the specification does not disclose the methylation pattern of the CpG sites in these regions that are relevant to ASD. The claims broadly encompasses the analysis of ANY number of CpG sites in very large regions that are expected to have greater than a hundred CpG sites. As discussed above, the number of CpG sites analyzed is totally dependent upon the type of assay that the user of the method performs. There are 113 CpG sites in Chr15:25,466,000-25,474,000. It is highly unpredictable if one randomly selected 6 CpG sites within Chr15:25,466,000-25,474,000 overlapping SNORD115-15 (8000 bp region) and determined that only 2 of them were methylated then it would be indicative of the entire region being hypomethylated and the offspring being at risk for ASD.
Further it is highly unpredictable if hypomethylation of NR_003307 (81 bp region), NR_003303 (82 bp region); and NR_003309 (82 bp region) can be used to predict ASD. These regions have 1 CpG, 2 CpGs, and 2 CpG respectively. There is no data in the specification that shows that hypomethylation of these particular CpG sites is indicative of ASD. The specification does not provide enablement for this.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to identify an offspring as having a high risk for developing ASD based in part on determined hypomethylation of one or more of the respective gene or regulatory regions. Hypomethylation of the region occurs when average methylation level is less than 50% across all CpG sites analyzed within the respective gene or regulatory region.
In order to practice the claimed invention one of skill in the art would first have to determine how many potential methylation sites (CpG sites) are present in the recited genomic regions. This could be performed using online calculators. For example, for SNORD115-15, there are 113 CpG sites in Chr15:25,466,000-25,474,000, 60 CpG sites in chr15:25,467,684-25,471,631, and 2 CpG sites in NR_003307. Then one would have to perform methylation analysis of each of those sites in sperm samples from subjects that produced offspring with ASD and in sperm samples from subjects that did not produce offspring with ASD. Then extensive data analysis would need to be conducted to determine which CpG’s are relevant to ASD and which are not. Then the methylation pattern of the relevant CpG’s would have to be determined. Then additional analysis would be needed to determine which combinations of two or more particular CpGs are predictive. The specification has merely provided an invitation for further experimentation.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years’ work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a “predictable” factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the guidance presented in the specification and the working examples, the skill of those in the art and the unpredictability of the art, and the quantity of experimentation necessary, it is the conclusion that an undue amount of experimentation would be required to make and use the invention.
Response To Arguments
8. In the response the Applicants traversed the rejection under 35 USC 112(a). In the response (page 10), the Applicants argue that the claims as amended require analysis of all methylation sites (i.e., CpG sites) analyzed within the gene or regulatory region in which the DMRs reside to determine an average methylation level across all analyzed CpG sites, which does not encompass the analysis of any arbitrary and non-described subset of CpG sites.
This argument has been fully considered but is not persuasive. The claims recite that the methylation status is determined by measuring an average methylation level across all CpG sites analyzed within the gene or regulatory region of b. As discussed above, the number of CpG sites analyzed is totally dependent upon the type of assay that the user of the method performs. For example consider Chr15:25,466,000-25,474,000. While a sequencing assay might allow analysis of all CpG sites in this region, other types of assays would not. The Illumina 450k Methylation Array only has probes to 16 CpG sites in this region. A methylation specific PCR assay might only permit analysis of one or two CpG sites in this region. The claims still broadly encompass determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs.
In the response (page 10), the Applicants argue that the specification provides meaningful support that all CpG sites within the DMRs are analyzed and contribute to the average methylation level determination. The Applicants point to the specification (Figs 1A-1D and 2, paras 0117 and 0096) for support.
This argument has been fully considered but is not persuasive. The data in the specification is based on the results of CHARM analysis. It is unclear how many CpG sites within the claimed regions are detected using the CHARM array. Further it is noted that the claims do not require CHARM analysis. As discussed above, the breadth of the claims encompass determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs.
In the response (page 11) the Applicants argue that the instant methods are based on the determination of an overall/average regional methylation determination, that is measured by taking into account the methylation levels for all the CpG sites analyzed within a specified region. They argue that there is no need to determine how many CpG are methylated, nor whether some CpGs are relevant, instead it is the average methylation level across all analyzed CpGs sites of the claimed genomic location that is critical. Additionally, they argue that ASD and cancer are fundamentally different conditions, and that there is absolutely no indication whatsoever, in the Widschwendter, nor in the art in general, that one finding that was found relevant in a single study pertinent to ovarian cancer, holds any weight for a determination of ASD risk.
This argument has been fully considered but is not persuasive. The claims do not require analysis of all CpG sites in the recited regions, rather they require analysis of all CpG sites analyzed. One could look at the 8000 bp region and randomly select 2 CpG sites to analyze. In that situation it is entirely unpredictable if they would be able to determine the risk of ASD. While the examiner recognizes that cancer and ASD are different disorders, the teachings in Widschwendter are still relevant because they demonstrate that even within a DMR not all CpG sites will be hypermethylated/hypomethylated and that not all CpG sites are predictive. This is especially relevant since the claims encompass picking and choosing any two or more CpG sites for analysis.
In the response (page 11) the Applicants argue that there are fundamental differences in the methylation patterns, function and biology in general between a male sperm sample and a female somatic ovarian cancer sample. A person of ordinary skill in the art in sperm-based epigenetic diagnostics would not reasonably look to ovarian oncology for solutions or insight, and because the underlying methylation biology is so different, Applicant respectfully submits that Widschwendter 's teachings are not transferable.
This argument has been fully considered but is not persuasive. While the examiner recognizes that sperm and ovarian samples are different sample types, the teachings in Widschwendter are still relevant because they demonstrate that even within a DMR not all CpG sites will be hypermethylated/hypomethylated and that not all CpG sites are predictive. This is especially relevant since the claims encompass picking and choosing any two or more CpG sites for analysis and it is entirely unpredictable if it would be possible to determine the risk of ASD based on hypomethylation of just 2 CpG sites. Further there is no data in the specification showing that each of the CpG sites analyzed by the CHARM array where hypomethylated.
In the response (pages 11-12) the Applicants argue that the specification provides ample details related to multiple techniques for measuring methylation status at all CpG sites within a genomic region, as well as experimental evidence demonstrating that regional average methylation successfully correlates with ASD risk. They argue that the specification teaches regional analysis, not individual CpG analysis. They argue that the claim language indicates that all sites analyzed within the region are considered in making the hypomethylation determination. Absent any indication otherwise, one of skill in the art would not consider analyzing selected, identified CpGs within the claimed regions.
This argument has been fully considered but is not persuasive. The claims recite that the methylation status is determined by measuring an average methylation level across all CpG sites analyzed within the gene or regulatory region of b. As discussed above, the number of CpG sites analyzed is totally dependent upon the type of assay that the user of the method performs. For example consider Chr15:25,466,000-25,474,000. While a sequencing assay might allow analysis of all CpG sites in this region, other types of assays would not. The Illumina 450k Methylation Array only has probes to 16 CpG sites in this region. A methylation specific PCR assay might only permit analysis of one or two CpG sites in this region. The claims still broadly encompass determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs. If only 2 CpG sites were analyzed and the average amount of methylation was determined for those 2 CpG sites, it is highly unpredictable if it would be indicative of ASD.
Claim Rejections - 35 USC § 112(a)-Written Description
9. 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 28, 30-31, 34, and 36-39 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description rejection.
The claims are drawn to a method for determining an offspring is high risk for autism spectrum disorder (ASD).
The claims recite identifying the offspring as having a high risk for developing ASD based on (i) the determined hypomethylation of one or more of the respective gene or regulatory regions (DMRs) and (ii) an AOSI score of 10 or more.
Claim 28 recites the DMRs reside in the following genes or regulatory regions of reference human genome assembly hg19:
Chr15:25,466,000-25,474,000 overlapping SNORD115-15 (8000 bp region);
Chr15:25,478,000-25,484,000 overlapping SNORD115-11 (6000 bp region); and
Chr15:25,446,000-25,452,000 overlapping SNORD115-17 (6000 bp region).
Claim 36 recites the DMRs reside in the following genes or regulatory regions of reference human genome assembly hg19:
Chr15:25,467,684-25,471,631 overlapping SNORD115-15 (3947 bp region);
Chr15:25,479,139-25,482,453 overlapping SNORD115-11 (3314 bp region); and
Chr15:25,448,132-25,450,278 overlapping SNORD115-17 (2146 bp region).
Claim 37 recites the DMRs reside at a locus of the human genome annotated as:
NR_003307 (81 bp region);
NR_003303 (82 bp region); and
NR_003309 (82 bp region).
The claims recite that the methylation status is determined by measuring an average methylation level across all CpG sites analyzed within the gene or regulatory region of b.
The claims further recite that a gene/regulatory region is hypomethylated when the average methylation level is less than 50% across all CpG sites analyzed within the respective gene or regulatory regions.
The number of CpG sites analyzed is totally dependent upon the type of assay that the user of the method performs. For example consider Chr15:25,466,000-25,474,000. While a sequencing assay might allow analysis of all CpG sites in this region, other types of assays would not. The Illumina 450k Methylation Array only has probes to 16 CpG sites in this region. A methylation specific PCR assay might only permit analysis of one or two CpG sites in this region. The claims require determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs, wherein when the average methylation level is less than 50% across all CpG sites analyzed within the DMR, the DMR is considered to be hypomethylated and the offspring has a higher risk of developing ASD. The claims do not define the particular CpG sites in the DMRs that are associated with ASD in terms of sufficient relevant identifying characteristics.
As discussed above, for SNORD115-15, there are 113 CpG sites in Chr15:25,466,000-25,474,000, 60 CpG sites in chr15:25,467,684-25,471,631, and 2 CpG sites in NR_003307. Thus the claims potentially encompass a large number of CpG sites within the DMRs that are predictive of ASD. As demonstrated above, Widschwendter (US 2019/0323090 10/24/2019) provides evidence that not every CpG within a DMR will be relevant.
The teachings of the specification are discussed above (see enablement rejection). It is noted that the specification does not disclose how many CpG sites are in the claimed regions, how many particular CpG sites within these regions that are relevant to ASD, or the methylation pattern of the CpG sites in these regions that are relevant to ASD.
The specification does not provide an actual reduction to practice of particular CpG sites that are within the DMR that are associated with ASD. The specification does not disclose the structure of any CpG within the scope of the claimed genus of CpGs that are associated with ASD. The specification does not describe members of the genus by physical and/or chemical characteristics. All members of the genus have the same function, i.e., they are associated with ASD, but no correlation between their unknown structure and this common function is disclosed. The question is whether one of skill in the art would be able to distinguish CpGs in the DMRs that are associated with ASD from CpGs in the DMRs that are not associated with ASD.
The claims encompass the use of CpGs that are not disclosed in the specification but are associated with ASD. Discovering these CpGs using routine methods in the prior art is not a practical way to describe the full extent of the claimed genus because finding CpGs that are associated with ASD could be successful only empirically. There is no description of the CpGs that exist in nature, and there is no description of how the structure of one CpG would relate to the structure of any other CpG. The general knowledge in the art concerning CpG methylation does not provide any indication of how the structure of one CpG is representative of other mutations.
The existence of the CpG sites in the DMRs that are associated with ADS is unpredictable. The description given is not adequate to allow one of skill in the art to distinguish members of the claimed genus from non-members of the claimed genus. For these reasons, one of skill in the art would conclude that applicant was not in possession of the claimed genus.
Response To Arguments
10. In the response the Applicants traversed the rejection under 35 USC 112(a). In the response (page 14) the Applicants note that the claims have been amended to clarify that the method requires considering methylation level measured at all sites (i.e., CpG sites) analyzed within the gene or regulatory region in which the DMRs reside to determine an average methylation level across all CpG sites, which does not encompass the sole analysis of any arbitrary and no-described subset of CpG sites.
This argument has been fully considered but is not persuasive. The claims recite that the methylation status is determined by measuring an average methylation level across all CpG sites analyzed within the gene or regulatory region of b. As discussed above, the number of CpG sites analyzed is totally dependent upon the type of assay that the user of the method performs. For example consider Chr15:25,466,000-25,474,000. While a sequencing assay might allow analysis of all CpG sites in this region, other types of assays would not. The Illumina 450k Methylation Array only has probes to 16 CpG sites in this region. A methylation specific PCR assay might only permit analysis of one or two CpG sites in this region. The claims still broadly encompass determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs.
In the response (pages 14-15), the Applicants argue that the specification describes the use of regional average methylation analysis. The Applicants point to the specification (Figs 1A-1D and 2, paras 0117 and 0096) for support.
This argument has been fully considered but is not persuasive. The data in the specification is based on the results of CHARM analysis. It is unclear how many CpG sites within the claimed regions are detected using the CHARM array. Further it is noted that the claims do not require CHARM analysis. As discussed above, the breadth of the claims encompass determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs. If only 2 CpG sites were analyzed and the average amount of methylation was determined for those 2 CpG sites, it is highly unpredictable if it would be indicative of ASD.
In the response (page 15) the Applicants argue that the specification teaches that the CHARM 3.6 array "includes over 4 million probes and covers over 7 million CpGs arranged into probe groups (consecutive probes are within 300 bp of each other)." They argue that high-density probe coverage ensures that all CpG sites within the DMR boundaries are systematically analyzed.
This argument has been fully considered but is not persuasive. The data in the specification is based on the results of CHARM analysis. Table 2 says there are 51 probes in the region 25467684-25471631. Yet there are 60 CpG sites in this region so Applicants argument that all CpG sites were analyzed is incorrect. Further it is noted that the claims do not require CHARM analysis. As discussed above, the breadth of the claims encompass determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs.
In the response (pages 15-16) the Applicants argue that Widschwendter is fundamentally different from the present invention. Widschwendter analyzes individual CpG sites, selecting only specific "relevant" CpG positions within a DMR to create a methylation signature (see Widschwendter Table lA, which underlines only certain CpGs within each amplicon). In contrast, the present invention analyzes regional average methylation, wherein all CpG sites within the DMR contribute to a single regional average value. This regional approach is fundamentally different from selecting individual informative CpGs.
This argument has been fully considered but is not persuasive. The claims do not require analysis of ALL CpG sites in the claimed regions. The claims state “an average methylation level across all CpG sites analyzed”. The number of CpG sites analyzed is dependent on the methodology used for the analysis. As discussed above, the breadth of the claims encompass determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs. The written description rejection is maintained.
11. 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached on Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1634
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