DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 19, 2025 has been entered. 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 Any rejections or objections not reiterated herein have been withdrawn.
Claims 28, 30-31, 34, and 36-37 are currently pending and have been examined herein.
Claim Objections
3. Claim 30 is objected to because of the following informalities: it is suggested that the phrase “wherein the methylation status is further determined by measuring methylation levels in one or more of the respective gene or regulatory regions in corresponding reference samples not associated with ASD” be amended to recite “wherein the methylation status of the DMRs is further determined in corresponding reference samples not associated with ASD” for the sake of clarity.
Claim Interpretation
4. 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 and 31 occur prior to step (a) of claim 28.
Claim Rejections - 35 USC § 112(b)
5. 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, 37 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, and 37 are rejected over the recitation of the phrase “using a first algorithm that removes background signal and from data obtained with one or more control probes”. The claims are indefinite because it is unclear what “from data obtained with one or more control probes” means. While it is clear that the first algorithm removes background signal, it is unclear if it requires also removing signals from the control probes or some other type of data from the control probes. Clarification is required.
Claims 28, 30-31, 34, 36, and 37 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, 36, and 37 require a step of measuring a methylation status at differentially methylated regions (DMRs). In the instant case it is unclear if the methylation status is being measured in the sperm sample that was obtained from the parent (referred to in step (a) or some other sample. Clarification is required.
Claims 28, 30-31, 34, 36, and 37 recite “wherein the DMRs reside in a gene or regulatory region of reference human genome assembly hg19 as determined by Infinium HumanMethyaltion450 BeadChip array”. This recitation is confusing because it is unclear if the step of measuring the methylation status at the DMRs requires that this was performed using the Infinium BeadChip array or if other methods of measuring methylation (such as those recited in claim 30) could have been used to measure methylation. Clarification is required.
Claims 28, 30-31, 34, and 36-37 are rejected because claim 28 contains the trademark/trade name Infinium HumanMethylation450 BeadChip array. Infinium HumanMethylation450 BeadChip array is a registered trademark of Illumina, Inc. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a microarray and, accordingly, the identification/description is indefinite.
Claims 28, 30-31, 34, and 36-37 are drawn to a method for determining an offspring is high-risk for autism spectrum disorder (ASD). The claims recite steps of (a) processing raw DNA methylation data obtained from a human parental sperm sample covering one or more methylation sites and (b) measuring a methylation status at DMRs. The claims then recite step (c) of 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 in (b) and (ii) an AOSI score of 10 or more. The claims are confusing because it is unclear what the purpose of step (a) is and how it relates to the rest of the claim. Step (a) recites sub steps (i-iii) which use algorithms to manipulate data however, the manipulated data does not appear to be used in the determination step since the determination is based on hypomethylation of DMR and AOSI scores. Further it is unclear how steps (a)(ii) and (a)(iii) which recite surrogate variables and the age of the male parent relate to the rest of the method. Clarification is required.
Response To Arguments
6. In the response the Applicants traversed the rejection under 35 USC 112(b). Applicants note that they amended claim 28 to refer to the non-branded name "Infinium HumanMethylation450 BeadChip array" which is widely known to refer to a very well- known and widely used large sample-size genome wide DNA methylation array commercialized by the company Illumina, and covering over 450,000 methylation sites per sample, at a single nucleotide resolution.
This amendment has been fully considered and does not overcome the rejection. Infinium HumanMethylation450 BeadChip is a trademark of Illumina Inc., belonging to the Infinium product line for DNA methylation analysis, known for its extensive coverage of CpG sites across the genome for epigenome-wide studies. It is improper for claims to recite trademarks. This rejection can be overcome by amending the claims to delete reference to this microarray.
Claim Rejections - 35 USC § 112(a)-Enablement
7. 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 36-37 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 further recite that a gene/regulatory region is hypomethylated when methylation is in less than 50% of methylation sites analyzed across the respective gene or regulatory regions.
Each of the recited DMRs comprise a plurality of CpG sites. The claims require determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs, wherein when less than 50% of the CpG sites are methylated the DMR is considered to be hypomethylated and the offspring has a higher risk of developing ASD.
The nature of the invention requires a reliable correlation between hypomethylation of 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 methylation is in less than 50% of methylation sites analyzed across the respective gene or regulatory regions. 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 develop ASD versus human subjects that do not 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. 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 methylation is in less than 50% of methylation sites analyzed across the respective gene or regulatory regions.
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).
The Applicants argue that the specific nucleic acid sequences of the DMRs is not essential or necessary to practice the claimed invention. The claimed method relies on the identification of a methylation status (e.g., a percent of hypomethylation) at genomic locations that include several CpG regions and overlapping the claimed genes or regulatory regions. The Illumina Infinium Human Methylation450 assay used allows obtaining such methylation status without the need to know the sequence of said genomic regions. There is in fact no need for any determination of any CpG positions, as this has already been analyzed and is readily provided with the assay. When running an Illumina Infinium Human Methylation450 assay, one of skill in the art would undoubtedly be provided with all the analysis material from the manufacturer, including the manifest previously discussed, and would readily have access to every single CpG included in the claimed genomic regions.
This argument has been fully considered but is not persuasive. The claims do not recite an active process step of using the Infinium HumanMethyaltion450 BeadChip array to measure the methylation status of the CpG’s in the DMRs. The claims are not limited to the analysis of only the CpG sites on the Infinium HumanMethyaltion450 BeadChip array that fall within the recited DMRs. The claims broadly encompass using ANY method of measuring the methylation status of ANY CpG in the DMRs. 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. The Infinium HumanMethyaltion450 BeadChip array does not allow to analyze the methylation status of each of the CpG sites. The Infinium HumanMethyaltion450 BeadChip array only has probes for detecting 16 CpG sites in Chr15:25,466,000-25,474,000, 6 CpG sites in chr15:25,467,684-25,471,631, and 0 CpG sites in NR_003307. The assertion on the record that by using this array one has access to every single CpG included in the claimed genomic region is incorrect.
The Applicants argue that running an Illumina Infinium Human Methylation450 assay is routine, and it does not constitute undue experimentation. They further argue that the collection of samples at different time points, e.g., at or around time of conception of an offspring, at a time when a sibling has an ASD diagnostic or at least an AOSI score, does not account for years of work. Finally the Applicants sent forth the steps that one would need to do in order to practice the claimed invention.
This argument has been fully considered. It is noted that the rejection states that methods of measuring methylation at CpG sites within DMRs was known in the art. The rejection is based on the fact that correlations between the methylation status of CpG sites and risk of ASD is highly unpredictable. The instant specification is completely silent with respect to how many CpG sites are present in each of the DMRs. 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 specification is not enabling. It is maintained that in order to make and/or use the method one of skill in the art would have to perform additional undue experimentation. The additional experimentation is very complex and could require years of additional effort. The rejection is maintained.
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 36-37 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 further recite that a gene/regulatory region is hypomethylated when methylation is in less than 50% of methylation sites analyzed across the respective gene or regulatory regions.
Each of the recited DMRs comprise a plurality of CpG sites. The claims require determining the methylation status at ANY number (2, 20, 50, 100, etc.) of CpG sites within the DMRs, wherein when less than 50% of the CpG sites are methylated 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 assoicated 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 assoicated 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 assoicated 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 methyaltion 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.
10. 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