DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of Claims
Claims 1-8 are pending.
Claims 1-8 are rejected.
Claim 1 is objected to.
Priority
Applicant’s claim for the benefit of a prior-filed application, U.S. Nonprovisional App. Nos. 16/434,677 filed 07 July 2019 and 14/024,878 filed 12 Sept. 2023 and U.S. Provisional App. Nos. 61/821,563 filed 09 May 2013 and 61/701,009 filed 14 Sept. 2012 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Accordingly, the effective filing date of the claimed invention is 14 Sept. 2012.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 08 Dec. 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Drawings
The drawings filed 16 Aug. 2023 are accepted.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “individuals that are affected by a genetic disease or trait…” in lines 4-5. To increase clarity and use consistent language, the claim should be amended to recite “affected by the genetic disease or trait”, since the preamble already recites “a genetic disease or trait”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (Pre-AIA ), second paragraph
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 2 and 7 are rejected under 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 for pre-AIA the applicant regards as the invention.
Claim 2 is indefinite for recitation of “increased frequency mitochondrial variants”. The term “increased” is a relative term which renders the claim indefinite. The term “increased” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, it is not clear what frequency of mitochondrial variants in either the affected or unaffected individuals would be considered an ”increased frequency”. For purpose of examination, the limitation is interpreted to mean mitochondrial variants.
Claim 7 is indefinite for recitation of “annotating the variants…”. Claim 1, from which claim 7 depends, recites “comparing the presence or absence of genetic variants…” and “identify patterns of variants”. As a result, it is not clear if “the variants” in claim 7 is referring to the genetic variants present or absent in the subjects, the variants of the patterns, or both. Clarification is requested via claim amendment. For purpose of examination, the variants is interpreted to refer to variants of the identified patterns.
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 1-8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claim 1 being representative) is directed to a method of identifying variants. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 1 recites the following steps which fall under the mental processes groupings of abstract ideas:
mapping a plurality of sequencing reads from a plurality of subjects to a reference genome, the subjects including affected individuals that are affected by a genetic disease or trait and unaffected individuals that are not affected by the genetic disease or trait;
identifying differences between the plurality of sequencing reads from the subjects and the reference genome;
performing a quality check to validate a defined biological relationship between the subjects;
comparing the presence or absence of genetic variants in the subjects; and
….to identify patterns of variants found in the affected individuals and not in the unaffected individuals.
The identified claim limitations falls into one of the groups of abstract ideas of mental processes for the following reasons. In this case, mapping reads from subjects to a reference sequence and identifying differences between the sequence reads and reference genome broadly encompasses performing data comparisons between sequences to identify the existence of alterations, analogous to claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014). Performing a quality check to validate a defined biological relationship can be practically performed in the mind by, for example, determining one subject is a child of another subject based on verifying a percentage of matching alleles. Comparing the presence of absence of variants in the subjects can be practically performed in the mind by comparing the identified differences between the reads and reference genome in each subject to identify variants common and not in common between subjects. Identifying patterns of variants in affected individuals and not in unaffected individuals can be practically performed in the mind by comparing the variants in affected individuals versus unaffected individuals to identify a pattern, such as loss of heterozygosity. Other than reciting the step of identifying patterns is performed by a processor, nothing in the claims precludes the step from being practically performed in the mind. Therefore, the claims recite a mental process. See MPEP 2106.04(a)(2) III.
Dependent claims 2-8 further recite an abstract idea and/or are part of the abstract idea of claim 1. Dependent claim 2 further limits the mental process of identifying patterns of variants in claim 1 to identify loss of heterozygosity, trans-phased compound heterozygotes, increased frequency mitochondrial variants, or combinations thereof. Dependent claim 3 further limits the mental process of identifying patterns of variants in claim 2 to identify recessive, de novo, or sex-linked variants, or combinations thereof. Dependent claims 4-5 further limit the subjects for which the sequence reads are being analyzed in claim 1, and therefore are part of the abstract idea of claim 1 above. Dependent claim 6 further recites the mental process of identifying an allele inconsistency from the first to second biological relative. Dependent claim 7 further recites the mental process of annotating variants with functional annotations. Dependent claim 8 further recites the mental process of distinguishing between the first and second sets of polynucleotides based on sequence differences between the first and second barcode sequences, which encompasses analyzing sequence reads to identify reads with the first versus second barcode sequence.
The claims further recite the law of nature of a natural correlation between the presence of genetic variants and a disease or trait, analogous to the natural relationship between a patient’s CYP2D6 metabolizer genotype and the risk that the patient will suffer QTc prolongation after administration of a medication called iloperidone, Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals, 887 F.3d 1117, 1135-36, 126 USPQ2d 1266, 1281 (Fed. Cir. 2018) exemplified in MPEP 2106.04(b).
Therefore, claims 1-8 recite an abstract idea and law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Dependent claims 2-7 do not recite any elements in addition to the judicial exception.
The additional elements of claim 1 include:
using a processor; and
and outputting the identified patterns of variants.
The additional element of claim 8 include:
joining a first adapter having a first barcode sequence to a first set of polynucleotides from a first subject of the plurality of subjects;
joining a second adapter having a second barcode sequence to a second set of polynucleotides from a second subject of the plurality of subjects; and
sequencing the first and second sets of polynucleotides.
The additional elements of a processor and outputting data are a generic computer used to carry out the abstract idea and a generic computer function. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
Furthermore, the additional element of outputting the identified patterns of variants only serves to output data generated by the abstract idea, which amounts to insignificant post-solution activity that does not provide integration. See MPEP 2106.05(g).
The additional elements of claim 8 of joining first and second adapters with a first and second barcode sequence to a first and second set of polynucleotides, respectively, and then sequencing the first and second sets of polynucleotides only serve to collect the sequencing data necessary for the abstract idea, which amounts to insignificant pre-solution activity that does not provide integration. See MPEP 2106.05(g).
Therefore, the additionally recited elements amount to mere instructions to apply the exception and insignificant extra-solution activity and, as such, the claims as a whole do not integrate the abstract idea into practical application. Thus, claims 1-8 are directed to an abstract idea and law of nature. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
Dependent claims 2-7 do not recite any elements in addition to the judicial exception.
The additional elements of claim 1 include:
using a processor; and
and outputting the identified patterns of variants.
The additional element of claim 8 include:
joining a first adapter having a first barcode sequence to a first set of polynucleotides from a first subject of the plurality of subjects;
joining a second adapter having a second barcode sequence to a second set of polynucleotides from a second subject of the plurality of subjects; and
sequencing the first and second sets of polynucleotides;
The additional elements of a processor and outputting data are a generic computer used to carry out the abstract idea and a generic computer function. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
The additional elements of joining first and second adapters with a first and second barcode sequence to a first and second set of polynucleotides from a first and second subject, respectively, and then sequencing the first and second sets of polynucleotides are well-understood, routine, and conventional. This position is supported by Applicant’s own specification. Applicant’s specification at para. [0003[ discloses various methods such as sequencing by synthesis, sequencing hybridization, and sequencing by ligation are evolving to meat challenges with making sequencing high-throughput and less expensive, and at para. [0027] cites several publications describing next generation sequencing. Applicant’s specification at para. [0049]-[0051] and [0053] similarly disclose an adaptor may include bar code sequences, citing 7 different U.S. patent publications, and discloses when carrying out multiplex sequencing, it is generally desirable to identify the origin of each sample, and barcode adaptors may be used to identify a source sample. Applicant’s specification at para. [0023] further discloses the techniques and procedures described herein are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the instant specification. Accordingly, the additional elements relating to multiplexed sequencing are well-understood routine and conventional.
Even considering the additional elements in combination, Applicant’s specification at para. [0056] discloses various algorithms are known in the art for mapping reads to a reference genome, demonstrating the conventionality of computers and sequencing.
Therefore, taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea and natural correlation without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-8 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Need (2012) in view of Iossifov (2012).
Cited references:
Need et al., Clinical Application of Exome Sequencing in Undiagnosed Genetic Conditions, 11 May 2012, Journal of Medical Genetics, 49, pg. 354-361; and
Iossifov et al., De Novo Gene Disruptions in Children on the Autistic Spectrum, April 2012, Neuron, 74, pg. 285-299.
Regarding claim 1, Need discloses a method of applying exome sequencing in undiagnosed genetic conditions comprising the following steps:
Need discloses aligning (i.e. mapping) sequence reads from parents and probands of families (i.e. a plurality of subjects) to a reference genome (pg. 354, col. 1, para. 2-4; see Supplemental FIG after pg. 361 and Suppl. pg. 1, para. 2 for reference genome), wherein the probands are affected by a genetic trait of developmental delay and unaffected parents (Abstract, e.g. patients with genetic conditions with unaffected parents; pg. 353, col. 2, para. 3; Table 2).
Need discloses examining the aligned reads to identify variants based on a number of reads supporting a given single nucleotide variant (SNV) or insertion-deletion (INDEL) (pg. 354, col. 1, para. 1), wherein SNVs are differences between the reads and a reference.
Need discloses that in order for families to participate in the study, both biological parents were required to be available for biological testing (pg. 353, col. 2, para. 3), demonstrating a biological relationship is required.
Need discloses identifying candidate causal variants present in the parental and proband reads, including identifying variants present in the proband but not the parents (i.e. comparing the presence and absence of variants in the subjects) (pg. 354, col. 2, para. 1 and 3; pg. 354, col. 2, para. 3).
Need discloses screening the candidate causal variants to identify high-confidence causal variants including homozygous X-linked, compound heterozygous, and de novo variants (i.e. a pattern of variants) as a genetic diagnosis (pg. 354, col. 2, para. 3).
Need discloses outputting the identified patterns of variants (Table 2, e.g. variants of interest output, pg. 354, col. 2, para. 4 to pg. 356, col. 2, para. 4, e.g. identified variants in genes output).
Regarding claim 1, Need does not disclose the following limitations:
Regarding claim 1, while Need discloses a biological relationship between parents and offspring is required, as explained above, Need does not explicitly disclose performing a quality check to validate a defined biological relationship between the subjects.
However, Iossifov discloses a method of determining de novo mutations in children with a genetic condition (Abstract), which comprises analyzing sequencing data of family quads including parents, affected children, and a sibling control (Abstract) pg. 285, col. 2, para. 2). Iossifov further discloses checking that each family passed pedigree checks and that no families with a member of questionable pedigree were included (i.e. performing a quality check to validate a defined biological relationship) (pg. 286, col. 1, para. 2; pg. 296, col. 2, para. 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of Need to have further performed a quality check to validate family relationships as shown by Iossifov above. One of ordinary skill in the art would have been motivated to combine the methods of Need with Iossifov in order to exclude families with a questionable pedigree, as shown by Iossifov (pg. 286, col. 1, para. 2), , thus ensuring identified de novo mutations present in the proband but absent in the parents in Need were not actually inherited. This modification would have had a reasonable expectation of success given both Need and Iossifov analyze sequencing data of families to identify causal mutations.
Further regarding claim 1, Need does not explicitly disclose the step of identifying patterns of variants is performed using a processor. Instead, Need discloses using manual review (pg. 354, col. 2, para. 3). However, the court held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. See MPEP 2144.04 III. Therefore, simply automating the manual process of identifying patterns of variants is not sufficient to overcome the prior art.
Regarding the dependent claims:
Regarding claims 2-3, Need discloses the pattern of variants include homozygous X-linked, compound heterozygous, and de novo variants (i.e. a pattern of variants) as a genetic diagnosis (pg. 354, col. 2, para. 3).
Regarding claim 4, Need discloses the subjects include biological parents (i.e. a first and second biological relative) and a proband (pg. 353, col. 2, para. 3).
Regarding claim 5, Need discloses the subjects include other probands (i.e. offspring) not affected by developmental delay (i.e. unaffected by the genetic trait of developmental delay) (Table 2, e.g. see patient with speech delay). It is further noted Iossifov also discloses analyzing family quads including a control offspring in order to evaluate if new mutations have different incident rates in affected children versus their sibling controls (pg. 285, col. 2, para. 2).
Regarding claim 6, Need discloses identifying de novo putatively functional variants confirmed as de novo (i.e. inconsistent allele inheritance from the first biological relative and the second biological relative) within the identified high-confidence causal variants (i.e. based on the patterns of variants) (pg. 354, col. 2, para. 5).
Regarding claim 7, Need discloses all variants are annotated as functional or not (pg. 354, col.1 para. 1).
Regarding claim 8, while Need discloses performing exome sequencing samples of the subjects (Suppl. pg. 1, para. 2), Need does not disclose performing multiplex sequencing of the subjects, including joining a first adapter having a first barcode sequence to a first set of polynucleotides from a first subject of the plurality of subjects; joining a second adapter having a second barcode sequence to a second set of polynucleotides from a second subject of the plurality of subjects; sequencing the first and second sets of polynucleotides; and distinguishing between the first and second sets of polynucleotides based on the sequence differences between the first and second barcode sequences.
However, Iossifov discloses a method of determining de novo mutations in children with a genetic condition (Abstract) which comprises analyzing sequencing data of family quads including parents, affected children, and a sibling control (Abstract) pg. 285, col. 2, para. 2), as discussed above. Iossifov further discloses performing multiplex sequencing on DNA samples of the family, which includes ligating barcoding sequencing adapters prior to capture to allow multiplexing of samples (i.e. of a first and second individual), thus allowing for the sequencing DNA of two families per sequencing lane (i.e. multiplex sequencing where different barcodes are used to distinguish between DNA from different subjects) (pg. 296, col. 2, para. 2). Iossifov further discloses multiplex sequencing maximizes the efficiency and uniformity of sequencing (pg. 286, col. 1, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have further modified the method of Need to have performed multiplex sequencing on DNA samples of families to provide sequencing data of multiple families per a single sequencing lane, as disclosed by Iossifov above. One of ordinary skill in the art would have been motivated to combine the methods of Need and Iossifov in order to maximize the efficiency and uniformity of the sequencing of the subjects, as shown by Iossifov (pg. 286, col. 1, para. 2). This modification would have had a reasonable expectation of success given both Need and Iossifov analyze sequencing data of families, and thus the multiplex sequencing of Iossifov is applicable to the families of Need.
Therefore, the invention is prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 and 6-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. US 11,749,376 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claim 1¸ reference claims 1 and 13 anticipate claim 1. It is noted the reference claims are narrower in scope than the instant claims, and therefore the claims are not identical.
Regarding instant claims 2-3, reference claims 2-3 disclose the variants include a loss of heterozygosity and de novo variants.
Regarding instant claim 4, reference claim 1 discloses the subjects include an offspring, mother, and father.
Regarding instant claim 6¸ reference claim 3 discloses identifying de novo variants (i.e. an allele inconsistency with inconsistent allele inheritance.
Regarding instant claim 7, reference claim 5 discloses annotating the variants with functional annotations.
Regarding instant claim 8, reference claim 6 discloses the sequence reads are generated by sequencing polynucleotides of subjects wherein the polynucleotides are joined with different barcodes to distinguish the subjects.
Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable 1-13 of U.S. Patent No. US 11,749,376 B2, as applied to claim 4 above, further in view of Iossifov (2012).
Cited reference: Iossifov et al., De Novo Gene Disruptions in Children on the Autistic Spectrum, April 2012, Neuron, 74, pg. 285-299.
Regarding claim 5, the reference claims do not disclose the subjects further include an unaffected offspring.
However, Iossifov discloses a method of analyzing sequencing data of families to identify causal variants (Abstract), including analyzing family quads including a control offspring in order to evaluate if new mutations have different incident rates in affected children versus their sibling controls (pg. 285, col. 2, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of the reference claims to have further analyzed sequence reads of an unaffected offspring, as shown by Iossifov above. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims with Iossifov in order to evaluate if new mutations have different incident rates in affected children versus their sibling controls (pg. 285, col. 2, para. 2), as shown by Iossifov. This modification would have had a reasonable expectation of success given both the reference claims and Iossifov analyze sequencing data of families for variant identification, and thus the sibling analysis of Iossifov is applicable to the reference claims.
Conclusion
No claims are allowed.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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