DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 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.
Claim Status
Claims 1-20 are pending.
Claims 7, 13, 16-17, and 19 are objected to.
Claims 1-20 are rejected.
Priority
This application is a CON of 16/477,923, filed Jul 15 2019 (now USP 11,929,143), which claims priority to PCT/US2018/014714, filed Jan 22 2018, and PRO 62/448,594, filed Jan 20 2017.
Accordingly, each of claims 1-20 are afforded the effective filing date of Jan 20 2017.
Information Disclosure Statement
The information disclosure statement (IDS) filed on Aug 4 2025 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS document is included with this Office Action.
Drawings
The Drawings submitted Feb 1 2024 are accepted.
Claim Objections
The claims are objected to for the following informalities:
Claim 7, final limitation, recites “filtering out segments that has”, which should be amended to “have”. Claims 13 and 19 are similarly objected to.
Claims 16-17 recite “wherein the operations further comprising”, which should be amended to “wherein the operations further comprise” or similar.
Claim Rejections - 35 USC § 112
35 U.S.C. 112(a)
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.
Claims 9-20 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 9 recites “A system comprising: one or more processors; and memory coupled to the one or more processors, the memory encoded with a set of instructions configured to perform a process comprising: obtaining sequence constructs, wherein the sequence constructs are generated by ligating nucleic acid molecules with adapters, wherein the nucleic acid molecules are from a biological sample obtained from a subject and each sequence construct comprises an adapter ligated to an end of a nucleic acid molecule; sequencing the sequence constructs to obtain sequence reads”. Claim 15 recites “A non-transitory computer readable storage medium storing instructions that, when executed by one or more processors of a computing system, cause the computing system to perform operations comprising: obtaining sequence constructs, wherein the sequence constructs are generated by ligating nucleic acid molecules with adapters, wherein the nucleic acid molecules are from a biological sample obtained from a subject and each sequence construct comprises an adapter ligated to an end of a nucleic acid molecule; sequencing the sequence constructs to obtain sequence reads”. Claims 10 and 16, which depend from claim 9 and claim 15, respectively, further recite “obtaining library constructs for the sequence constructs, wherein the library constructs are generated using a first polymerase chain reaction (PCR); obtaining a subset of the library constructs, wherein the subset of the library constructs is captured using the probe oligonucleotides of the probe panel under hybridization conditions to enrich for one or more genomic regions of interest; and obtaining enriched library constructs for each library construct of the subset of the library constructs, wherein the enriched library constructs are generated using a second PCR, and wherein the sequencing sequences the enriched library constructs to obtain the sequence reads”. Claims 11 and 17, which depend from claim 10 and claim 16, respectively, recite “quantifying the enriched library constructs using capillary electrophoresis (CaliperGX) or a PCR-based method”. The specification as published provides support for a system comprising one or more machines, where each machine comprises one or more of memory, one or more microprocessors, and instructions [0328], or for a system which comprises a computing machine and a sequencing apparatus or machine, where the sequencing apparatus or machine is configured to receive physical nucleic acid and generate sequence reads [0329]. The specification as published provides support for preparing DNA for sequencing by ligating adapters to the DNA, performing PCR, and capturing a subset of the library constructs using a probe panel using a liquid handler for automated processing, followed by capillary electrophoresis or PCR-based methods for quantification [0382-0388; 0939-0395], and for performing sequencing on various sequencing instruments [0384; 0387; 0391; 0395]. However, the specification does not provide support for either a system comprising one or more processors and memory or a non-transitory computer readable storage medium capable of performing the recited limitations without the specialized liquid handling or sequencing instruments. It is noted that the specification does not provide support for automated performance of quantifying the enriched library as recited in claims 11 and 17. Therefore, the above indicated limitations lack sufficient written description. Claims 12-14 and 18-20 are rejected based on their dependence from claims 9 and 15.
35 U.S.C. 112(b)
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.
Claims 1, 3-9, 11-15, and 17-20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1, limitation 3, recites “generating an alignment computer file comprising on-target sequence reads and associated genomic positioning data, wherein generating the alignment computer file comprises aligning the sequence reads to a reference genome and matching the aligned sequence reads to genomic sequences corresponding to probe oligonucleotides of a probe panel to obtain the on-target sequence reads”. However, claim 9 does not previously recite probe oligonucleotides of a probe panel or their use to obtain the on-target reads. The claim only previously requires “obtaining sequence constructs, wherein the sequence constructs are generated by ligating nucleic acid molecules with adapters, wherein the nucleic acid molecules are from a biological sample obtained from a subject and each sequence construct comprises an adapter ligated to an end of a nucleic acid molecule; sequencing the sequence constructs to obtain sequence reads”. Therefore, the metes and bounds of the limitation are not clear. Claims 9 and 15 are similarly rejected. It is noted that claims 10 and 16 “obtaining a subset of the library constructs, wherein the subset of the library constructs is captured using the probe oligonucleotides of the probe panel under hybridization conditions to enrich for one or more genomic regions of interest”, which clarifies the issue present in claims2, 9, and 15 and are therefore not rejected. Claims 3, 5-8, 12-14, and 18-20 are rejected based on their dependence from claims 1, 9, and 15.
Claim 4 recites “capillary electrophoresis (CaliperGX)”. First, it is not clear if the parenthetical limitations are intended to be exemplary claim language or if they are intended to further limit the type of capillary electrophoresis required by the claims. As set forth in MPEP 2173.05(d), examples and preferences stated in the claims may lead to confusion over the intended scope of a claim. Second, claim 4 contains the trademark/trade name CaliperGX. 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 capillary electrophoresis and, accordingly, the identification/description is indefinite. Claims 11 and 17 are similarly rejected.
Claim 5 recites “wherein the probe panel is designed…”. It is unclear whether the wherein clause is intended to require designing the probe panel within the metes and bounds of the claimed invention, or if it is only further limiting the type of probe panel used in the invention such that designing the probe panel is not required within the metes and bounds of the invention. As set forth in MPEP 2111.04.I, “wherein” clauses raise the question as to the limiting effect of the language in a claim. As the claims do not recite an active performance of designing the probe panel, the metes and bounds of the claims are unclear. For compact examination, it is assumed that designing the probe panel is not required to be performed. The rejection may be overcome by clarifying what steps are required to be performed.
Claim 9 recites “obtaining sequence constructs, wherein the sequence constructs are generated by…”. It is unclear whether the wherein clause is intended to require generating the sequence constructs within the metes and bounds of the claimed invention, or if it is only further limiting the type of sequence constructs used in the invention such that generating the sequence constructs is not required within the metes and bounds of the invention. As set forth in MPEP 2111.04.I, “wherein” clauses raise the question as to the limiting effect of the language in a claim. As the claims do not recite an active performance of generating the sequence constructs, the metes and bounds of the claims are unclear. For compact examination, it is assumed that generating the sequence constructs is required to be performed. The rejection may be overcome by clarifying what steps are required to be performed. Claim 10 is similarly rejected and interpreted for the limitations “obtaining library constructs for the sequence constructs, wherein the library constructs are generated…”, “obtaining a subset of the library constructs, wherein the subset of the library constructs is captured…”, “obtaining enriched library constructs for each library construct of the subset of the library constructs, wherein the enriched library constructs are generated…”. Claims 15 and 16 are similarly rejected. Claims 11-14 and 17-20 are rejected based on their dependency from claims 9 and 15.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to a method, a system, and a non-transitory computer readable storage medium, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) as well as a law of nature or a natural phenomenon are as follows:
Independent claims 1, 9, and 15: generating an alignment computer file comprising on-target sequence reads and associated genomic positioning data, wherein generating the alignment computer file comprises aligning the sequence reads to a reference genome and matching the aligned sequence reads to genomic sequences corresponding to probe oligonucleotides of a probe panel to obtain the on- target sequence reads;
generating a probe coverage data file for the sample using the on-target sequence reads and the associated genomic positioning data, wherein generating the probe coverage data file comprises:
determining a position read coverage for each base in each probe oligonucleotide by quantifying the on-target sequence reads that map to each base in the genomic sequences corresponding to each probe oligonucleotide,
determining a probe coverage for each probe oligonucleotide based on the position read coverage for each base in the genomic sequences corresponding to the probe oligonucleotide, and
determining a normalized probe coverage quantification for each probe oligonucleotide based on the probe coverages, wherein the probe coverage data file comprises the normalized probe coverage quantifications;
generating segments and associated probe coverage quantification data for each segment using a segmentation model and the probe coverage data file;
identifying genes overlapping with the segments using a gene identifier model based on the segments and the associated probe coverage quantification data;
generating filtered segments using a segment filter model and based on the identified genes and the associated probe coverage quantification data for each segment; and
determining a presence or absence of a genetic variation in the sample based on the filtered segments.
Dependent claims 5-8, 12-14, and 18-19 recite further steps that limit the judicial exceptions in independent claims 1, 9, and 15 and, as such, also are directed to those abstract ideas. For example, claim 5 further limits the probe panel to being designed to cover the genetic variation; claims 6, 12, and 18 further limit generating the segments; and claims 7-8, 13-14, and 19-20 further limit generating the filtered segments.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually determine a presence or an absence of a genetic variation in a sample. Without further detail as to the methodology involved in “generating”, “determining”, “identifying”, and “normalizing”, under the BRI, one may simply, for example, use pen and paper to generate an alignment file by aligning sequence reads to a reference genome and matching aligned reads to sequences corresponding to probes; generate a probe coverage data file by determining a position read coverage for each base, determining a probe coverage for each probe oligonucleotide, and determining a normalized probe coverage quantification; generate segments and associated probe coverage quantification data using a model which could be a set of rules or a mathematical process; identify genes overlapping with the segments using a model which could be a set of rules or a mathematical process; generate filtered segments using a model which could be a set of rules or a mathematical process; and determine a presence or absence of a genetic variation based on the filtered segments. Such actions encompass observations, evaluations, judgments, which are concepts able to be performed in the human mind. Some of these steps, including determining a position read coverage for each base, determining a probe coverage for each probe, determining a normalized probe coverage quantification, and using a segmentation model (see the specification as published at [0082] which describes suitable segmentation models as including those that examine likelihood ratio statistics), require mathematical techniques as the only supported embodiments, as they express mathematical relationships in words.
Therefore, claims 1, 9, and 15 and those claims dependent therefrom recite an abstract idea [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, the claims recite the following additional elements:
Independent claim 1: ligating nucleic acid molecules with adapters to generate sequence constructs, wherein the nucleic acid molecules are from a biological sample obtained from a subject and each sequence construct comprises an adapter ligated to an end of a nucleic acid molecule; and
sequencing the sequence constructs to obtain sequence reads.
Independent claims 9 and 15: obtaining sequence constructs, wherein the sequence constructs are generated by ligating nucleic acid molecules with adapters, wherein the nucleic acid molecules are from a biological sample obtained from a subject and each sequence construct comprises an adapter ligated to an end of a nucleic acid molecule; and
sequencing the sequence constructs to obtain sequence reads.
Dependent claims 2, 10, and 16: generating, using a first polymerase chain reaction (PCR), library constructs for the sequence constructs;
capturing a subset of the library constructs using the probe oligonucleotides of the probe panel under hybridization conditions to enrich for one or more genomic regions of interest; and
generating, using a second PCR, enriched library constructs for each library construct of the subset of the library constructs, wherein the sequencing sequences the enriched library constructs to obtain the sequence reads.
Dependent claims 4, 11, and 17: quantifying the enriched library constructs using capillary electrophoresis (CaliperGX) or a PCR-based method; and
normalizing the enriched library constructs to a fixed concentration based on the quantification, wherein the sequencing sequences the normalized enriched library constructs to obtain the sequence reads.
Dependent claim 3: enriching nucleic acid molecules of a predetermined fragment length.
The claims also include non-abstract computing elements. For example, independent claim 1 includes a computer-implemented method; independent claim 9 includes a system comprising one or more processors and memory coupled to the one or more processors, the memory encoded with a set of instructions configured to perform a method; and independent claim 15 includes a non-transitory computer readable storage medium storing instructions that, when executed by one or more processors of a computing system, cause the computing system to perform a method.
Considerations under Step 2A, Prong Two
With respect to Step 2A, Prong Two, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to data gathering, such as “ligating”, “obtaining” sequence constructs”, “generating” library constructs, “capturing” a subset of library constructs using probe oligonucleotides, “enriching” nucleic acid molecules of a predetermined fragment length, “quantifying” constructs, “normalizing” constructs”, and “sequencing”, perform functions of collecting the data needed to carry out the judicial exceptions. Data gathering and outputting do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
Further steps/elements directed to additional non-abstract computer elements do not describe any specific computational steps by which the “computer parts” perform or carry out the judicial exceptions, nor do they provide any details of how specific structures of the computer, such as the computer-readable recording media, are used to implement these functions. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, and therefore the claim does not integrate that judicial exceptions into a practical application. The courts have weighed in and consistently maintained that when, for example, a memory, display, processor, machine, etc.… are recited so generically (i.e., no details are provided) that they represent no more than mere instructions to apply the judicial exception on a computer, and these limitations may be viewed as nothing more than generally linking the use of the judicial exception to the technological environment of a computer (MPEP 2106.05(f)).
Therefore, the additional elements do not clearly improve the functioning of a computer, or comprise an improvement to any other technical field. Further, the additional elements do not clearly affect a particular treatment; they do not clearly require or set forth a particular machine; they do not clearly effect a transformation of matter; nor do they clearly provide a nonconventional or unconventional step (MPEP2106.04(d)).
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the specification as published discloses that methods for enriching fragments from a select genomic region [0139-0140; 0172], using commercially manufactured enrichment probes and systems [0142; 0386], or size fractionation [0143], for preparing a nucleic acid/sequencing library [0155] (which encompasses ligation and PCR as instantly claimed), and for sequencing [0179], using commercially available sequencing kits and instruments [0191], can be done using methods known in the art. The specification as published also discloses that library quantification can be performed using commercially available equipment such as CALIPER LABCHIP GX or known PCR-based methods [0385]. Further, the prior art review to Ballester et al. (Expert Review of Molecular Diagnostics, 2016, 16(3):357-372; newly cited; Table 1 and Figure 1 in particular; entire document is relevant) and Kozarewa et al. (Current Protocols in Molecular Biology, 2015, 112(1):7-21; newly cited; p. 7, col. 1, par. 1; entire document is relevant) disclose that ligating nucleic acids, capturing nucleic acids with probes under hybridization conditions, performing PCR, size enrichment, and sequencing are well-understood, routine, conventional activities previously known to the industry. Additionally, the courts have found that receiving and outputting data are well-understood, routine, and conventional functions of a computer when claimed in a merely generic manner or as insignificant extra-solution activity (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, as discussed in MPEP 2106.05(d)(II)(i)). As such, the claims simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception (MPEP2106.05(d)). The data gathering steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
With respect to claims 1, 9, and 15 and those claims dependent therefrom, the computer-related elements or the general purpose computer do not rise to the level of significantly more than the judicial exception. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, which the courts have found to not provide significantly more when recited in a claim with a judicial exception (Alice Corp., 573 U.S. at 225-26, 110 USPQ2d at 1984; see MPEP 2106.05(A)). The specification as published also notes that computer processors and systems, as example, are commercially available or widely used at [0347]. The additional elements are set forth at such a high level of generality that they can be met by a general purpose computer. Therefore, the computer components constitute no more than a general link to a technological environment, which is insufficient to constitute an inventive concept that would render the claims significantly more than the judicial exceptions (see MPEP 2106.05(b)I-III).
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; See MPEP § 2106.05].
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
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 1-2, 5-10, 12-16, and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-9, 15, and 17 of U.S. Patent No. 11,929,143 in view of Boeva et al. (Bioinformatics, 2014, 30(24):3443-3450; cited on the Aug 4 2025 IDS).
Claims 3-4, 11, and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-9, 15, and 17 of U.S. Patent No. 11,929,143 in view of Boeva, as applied to claims 1-2, 9-10, and 15-16, and in view of Kozarewa et al. (Current Protocols in Molecular Biology, 2015, 112(1):7-21; newly cited).
Reference claims 1, 8-9, 15, and 17 disclose instant claims 1-2, 9-10, and 15-16, except for the limitations directed to “identifying genes overlapping with the segments using a gene identifier model based on the segments and the associated probe coverage quantification data” and “generating filtered segments using a segment filter model and based on the identified genes and the associated probe coverage quantification data for each segment”.
However, the prior art to Boeva discloses a method that includes a multifactor normalization and annotation technique enabling the detection of large copy number changes from amplicon sequencing data (abstract). Boeva teaches normalizing sample read counts and segmenting the resulting profiles (p. 3446, col. 1, par. 3). Boeva teaches a readjustment strategy (i.e., gene identifier model) of segmentation with a gene-aware model by identifying breakpoints that fall within a gene (i.e., genes overlapping with the segments) and examining the amplicons in the genes to determine whether they are correctly annotated (i.e., based on the segments and the associated coverage data) (p. 3446, col. 2, par. 6). Boeva teaches clustering segments based on the mean values of the normalized copy number changes expressed as integers in the segments to cluster segments with the same number of copies together (i.e., segment filter model) (p. 3446, col. 1, par. 4), where all segments with mean values clustered with zero are considered copy neutral (p. 3446, col. 1, par. 6). Boeva teaches filtering candidate copy number aberrations with a P--value above a threshold after performing a test to determine whether the target regions are copy-neutral (p. 3446, col. 2, par. 2-3).
Reference claims 1, 9, and 15 disclose instant claim 5.
Reference claims 1, 8-9, 15, and 17 disclose instant claims 6, 12, and 18.
The reference patent does not disclose instant claims 3-4, 7-8, 11, 13-14, 17, and 19-20.
However, the prior art to Kozarewa discloses an overview of target enrichment strategies for next generation sequencing (title; abstract).
Regarding instant claim 3, Kozarewa teaches PCR target enrichment strategies to produce amplicons with lengths compatible with existing sequencing platforms (i.e., enriching nucleic acid molecules of a predetermined fragment length) (p. 6, col. 2, par. 2).
Regarding instant claims 4, 11, and 17, Kozarewa teaches analyzing the concentrations of PCR products on a gel or with capillary electrophoresis for quantitative and qualitative DNA analysis, where Caliper GX may be used (p. 6, col. 2, par. 2). Kozarewa teaches equimolar pooling of PCR amplicons after quantification (p. 6, col. 2, par. 2).
Regarding instant claims 7-8, 13-14, and 19-20, Boeva teaches clustering segments based on the mean values of the normalized copy number changes expressed as integers in the segments to cluster segments with the same number of copies together (p. 3446, col. 1, par. 4), where all segments with mean values clustered with zero are considered copy neutral (i.e., segment filter model) (p. 3446, col. 1, par. 6). Boeva teaches that the targets are genes (p. 3444, col. 1, par. 3). Boeva teaches filtering candidate copy number aberrations with a P--value above a threshold after performing a test to determine whether the target regions are copy-neutral (p. 3446, col. 2, par. 2-3). As Boeva teaches that “zero” is considered copy neutral (p. 3446, col. 1, par. 6), and as the copy number changes are expressed in integers (p. 3446, col. 1, par. 4), it is considered that Boeva fairly teaches filtering out the copy neutral segments and keeping those that have an integer (i.e., less than 0.9 copy number loss or 1 copy number gain).
Regarding claims 1-2, 5-10, 12-16, and 18-20, 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 combine, in the course of routine experimentation and with a reasonable expectation of success, the reference patent and Boeva because each reference discloses methods for determining copy number variations in targeted sequencing data. The motivation would have been to use features of a method that would enable the detection of large copy number changes from targeted sequencing data, as taught by Boeva (abstract).
Regarding claims 3-4, 11, and 17, 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 combine, in the course of routine experimentation and with a reasonable expectation of success, the reference patent in view of Boeva and Kozarewa because each reference discloses methods for generating targeted sequencing data. The motivation would have been use methods known in the art for target enrichment for next-generation sequencing, thereby eliminating genomic regions that are not of interest for a particular experiment, obtain greater depth of DNA sequencing coverage for regions of interest, and increase the sampling numbers of individuals, thereby saving time and cost, as taught by Kozarewa (abstract).
Conclusion
No claims are allowed.
The claims appear to be free of the prior art. Neither the closest prior art to Paweletz et al. (Nature Medicine, 2016, 20, p. 1-9; cited on the Aug 8 2025 IDS), Benjamini et al. (Nucleic Acids Research, 2012, 40, p. 1-14; cited on the Aug 8 2025 IDS), any other cited art, or any art identified in the indicated searches fairly teaches, alone or in combination, the limitations “determining a position read coverage for each base in each probe oligonucleotide by quantifying the on-target sequence reads that map to each base in the genomic sequences corresponding to each probe oligonucleotide; determining a normalized probe coverage quantification for each probe oligonucleotide based on the probe coverages, wherein the probe coverage data file comprises the normalized probe coverage quantifications;” in independent claims 1, 9, and 15.
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/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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