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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/14/2025 has been entered.
Status of the Claims
Claims 1-4, 7–9, 11, 13–22, 24, 25, 27–37, and 40-44 are pending and examined on the merits.
Claims 5, 6, 10, 12, 23 and 26 were cancelled.
Claims 38 and 39 were withdrawn.
Withdrawn Rejections/Objections
Rejections and/or objections not reiterated from previous office actions are hereby
withdrawn in view of the amendments filed 08/14/2025.
The 35 U.S.C. 112(a) rejections to claim 37 in the office action filed 05/14/2025 has been withdrawn in view of amendments received 08/14/2025 specifically by amending claim 37 to recite “…steps a)-d) and f)-j)) of claim 1”.
The 35 U.S.C. 112(b) rejections to claim 37 in the office action filed 05/14/2025 has been withdrawn in view of amendments received 08/14/2025 specifically by amending claim 37 to recite “…steps a)-d) and f)-j)) of claim 1”.
The following rejections and/or objections are either maintained or newly applied. They constitute the complete set presently being applied to the instant application.
Priority
Applicant’s claim under 35 USC § 119(e) for the benefit of prior-filed Provisional Application No. 62/659495 is acknowledged.
In this action, all claims are examined as though they had an effective filing date of 18 Apr 2018. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further analysis of the disclosure(s) of the priority application(s).
Claim Rejections - 35 USC § 112
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.
Claim 37 is 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.
The claim recitation of “… wherein determining the diagnosis comprises step e) of claim 1 performed by a human” in claim 37 fails to enable one skilled in the art to make and use the claimed invention using the application as a guide.
The specification [0043] recites that “[0043] The method of the disclosure contemplates genetic sequencing. Sequencing may be by any method known in the art. Sequencing methods include, but are not limited to, Maxam- Gilbert sequencing-based techniques, chain-termination-based techniques, shotgun sequencing, bridge PCR sequencing, single-molecule real-time sequencing, ion semiconductor sequencing (Ion TorrentTMsequencing), nanopore sequencing, pyrosequencing (454), sequencing by synthesis, sequencing by ligation (SOLiDTM sequencing), sequencing by electron microscopy, dideoxy sequencing reactions (Sanger method), massively parallel sequencing, polony sequencing, and DNA nanoball sequencing …”. Instant specification further recites [0044] “sequencing of the nucleic acid from the sample is performed using whole genome sequencing (WGS) or rapid WGS (rWGS). In some embodiments, targeted sequencing is performed and may be either DNA or RNA sequencing. The targeted sequencing may be to a subset of the whole genome. In some embodiments the targeted sequencing is to introns, exons, non-coding sequences or a combination thereof. In other embodiments, targeted whole exome sequencing (WES) of the DNA from the sample is performed. The DNA is sequenced using a next generation sequencing platform (NGS), which is massively parallel sequencing. NGS technologies provide high throughput sequence information, and provide digital quantitative information, in that each sequence read that aligns to the sequence of interest is countable”.
Additionally, the state of prior art does not provide evidence that performing “genetic sequencing of a biological sample containing DNA… using… whole genome sequencing (WGS), rapid whole genome sequencing (rWGS), ultra-rapid whole genome sequencing, or whole exome sequencing (WES), or rapid whole exome sequencing (rWES)” can be done by human.
As such, based on the evidence regarding the state of the prior art, the specification, at the time the application was filed, does not teach one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation.
Claim 37 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.
The claim recitation of “… wherein a targeted treatment is administered to the subject by a human earlier than such treatment would be administered using a standard rapid testing result when the subject is diagnosed” in claim 37 is not supported in the Specification nor has Applicant pointed to support for such and thus the claim includes NEW MATTER.
The present specification [0016] recites “…by informing timely targeted treatments, rapid genetic or genomic sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric intensive care units (ICUs)', however, it does not describe administering a targeted treatment by a human. This is a new matter rejection.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “administering to the subject a targeted treatment earlier than such treatment would be administered using a standard rapid testing result, thereby providing an autonomous diagnosis”. However, it is unclear how a diagnosis is provided after administering a treatment.
Claim 37 recites “A system comprising: a controller including at least one processor and non-transitory memory, wherein the controller is configured to perform a)-d) and f)-j) of claim 1”. However, It is unclear if the system is performing steps e) and the controller is performing steps a)-d) and f)-j).
Additionally, claim 37 recites “wherein determining the diagnosis comprises step e) of claim 1 performed by a human”. However, it is unclear how performing “genetic sequencing of a biological sample containing DNA… using… whole genome sequencing (WGS), rapid whole genome sequencing (rWGS), ultra-rapid whole genome sequencing, or whole exome sequencing (WES), or rapid whole exome sequencing (rWES)” can be done by human, as oppose to for example, a sequencer (a specialized machine).
Moreover, claim 37 recites “wherein the report comprising results of the analysis is utilized by a human to determine a diagnosis for the subject earlier than such diagnosis would be determined using a standard rapid testing result, wherein determining the diagnosis comprises step e) of claim 1 performed by a human, and wherein a targeted treatment is administered to the subject by a human earlier than such treatment would be administered using a standard rapid testing result when the subject is diagnosed.”. However, it is unclear if there are any active steps of utilizing, determining, performing, and administering in said claim.
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.
Claim 37 is rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea 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 37 being representative) is directed a system. Therefore, the instantly claimed invention(s) fall into 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 37 recite the following steps which fall under the mathematical concepts, mental processes, and/or certain methods of organizing human activity groupings of abstract ideas:
Claim 37 recites determining a phenome of a subject from an electronic medical record; the limitation determining a phenome can be practically performed in human mind (mental process) because human mind is able to determine the phenome/ comprehensive expression of traits in a subject.
Claim 37 further recites translating the clinical phenotypes into standardized vocabulary using a hierarchical reference vocabulary for mapping terms associated with genetic diseases; the limitation translating can be practically performed in human mind (mental process), since human mind is able to translate phenotypes by mapping traits to standard terms.
Claim 37 further recites determining a phenotype matching score by quantifying the number of phenotype terms from the EMR that match phenotype terms of each genetic disease and weighting each genetic disease that has matched phenotypes according to the number of matched phenotypes and the information content of the matched phenotypes (mathematical calculation/mathematical concepts; see specification [0017] for calculating a mean).
Claim 37 further recites deriving a first list of weighted or scored differential diagnoses of the subject based on the translation step; the limitation deriving differential diagnosis list can be practically performed in human mind (mental process), since human mind is able to derive/generate a list based on the result of mapping.
Claim 37 further recites determining genetic variants of the DNA and a genotype of the subject based on the genomic sequencing step; the limitation determining genetic variants can be practically performed in human mind (mental process), since human mind is able to analyze obtained genetic sequences and determine/identify variations by, for example aligning to a reference genome.
Claim 37 further recites deriving a second list of differential diagnoses of the subject based on assessment of a pathogenicity of each of the genetic variants; the limitation deriving a second list can be practically performed in human mind (mental process), since human mind is able to derive/generate a list based on a comparison.
Claim 37 further recites integrating first and second differential diagnoses lists; the limitation integrating lists can be practically performed in human mind (mental process) since human mind is able to integrate/combine lists.
Claim 37 further recites ranking and ordering the differential diagnoses based on the results of the integrating step; the limitation ranking and ordering is considered a mathematical relationship in light of the present specification [0030], can be practically performed in human mind (mental process), since human mind is able to rank and order/classify data.
Claim 37 further recites generating a report comprising results of the analysis; the limitation generating a report can be practically performed in human mind (mental process, since human mind is able to generate/create a report based on the result of an analysis, by for example by utilizing pen and paper).
The identified claim limitations fall into one of the groups of abstract ideas of mental processes. Therefore, claim 37 recite an abstract idea. [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.
The additional elements of claim 37 include the following.
Claim 37 recites a controller including at least one processor and non-transitory memory.
The additional elements of at least one processor and non-transitory memory that ae included in a controller are generic computer components and/or processes. 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).
Therefore, the additionally recited elements amount to insignificant extra-solution activity and, as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claim 37 is directed to an abstract idea. [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. An inventive concept cannot be furnished by an abstract idea itself. 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.
The additional elements of claim 37 include the following.
Claim 37 recites a controller including at least one processor and non-transitory memory.
The additional elements of at least one processor and non-transitory memory that are included in a controller/computer system, are conventional computer components and/or processes. 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); TU Communications LLC v. AV Auto, LLC, 823 F.3d 607,613,118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Therefore, the additional element is not sufficient to amount to significantly more than the judicial exception.
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/or natural correlation) without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Response to Arguments
Applicant's arguments filed 08/14/2025 have been fully considered but they are not persuasive. Applicant states:
As an initial matter, claim 37 has been amended to include utilizing the report to determine a diagnosis for the subject and administering a targeted treatment to the subject earlier than such treatment would be administered using a standard rapid testing result.
Without agreeing with the Examiner's assertion that the claims recite mental processes, and therefore recite a judicial exception, Applicants submit that as currently amended, the claims require utilizing the results from the report of the analysis to determine a diagnosis and administering a targeted treatment. As outlined by Mayo Collaborative Services v. Prometheus Laboratories and Alice Corp. v. CLS Bank International integration of conventional steps such as utilizing the result for a clinical diagnosis and administering a treatment into the process that involves specific application is an inventive concept. Applicants submit that support for the amendments in claim 37 can be found throughout the specification, for example paragraphs [0021], [0026], [0028], [0128], and [0132].
It is respectfully submitted that this is not persuasive. The Applicant remarks are directed to Step 2B of 101 analyses, specifically evaluating additional elements to determine whether they amount to an inventive concept by considering them both individually and in combination to ensure that they amount to significantly more than the judicial exception itself.
As stated above in the 112(b) rejection above, there are no active steps of utilizing, determining, performing, and administering in claim 37. As such, the only recites additional elements to be evaluated in Step 2B are the additional elements of a system comprising a controller including at least one processor and non-transitory memory, which are conventional computer components and/or processes that does not provide significantly more (see above rejection).
With regards to Applicant stating that “as outlined by Mayo Collaborative Services v. Prometheus Laboratories and Alice Corp. v. CLS Bank International integration of conventional steps such as utilizing the result for a clinical diagnosis and administering a treatment into the process that involves specific application is an inventive concept”, Examiner submits that in Mayo Collaborative Services v. Prometheus Laboratories, the court explained that Mayo’s step of administering a drug to a patient was performed in order to gather data about the recited laws of nature, and this step was thus ancillary to the overall diagnostic focus of the claims. 887 F.3d at 1134-35, 126 USPQ2d at 1280, and it did not amount to significantly more/an inventive concept. Furthermore, in Alice Corp. v. CLS Bank, the patents at issue claimed a method of mitigating financial "settlement risk" using a third-party computer intermediary. The Court found this to be the abstract idea of intermediated settlement. The additional step of using a generic computer to perform conventional functions did not add an "inventive concept" and was therefore insufficient to make the claims patent-eligible.
As such, the rejection of claim 37 under U.S.C. 101 is maintained.
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1–4, 11, 13–22, 24, 25, 27–37, 40 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Reid et al. (US 2017/0286594 A1; on IDS of 11 Sep 2019), in view of Kingsmore et al. (US20170061070) "previously cited on the [11 Sep 2019] IDS form".
With respect to claim 1, Reid teaches a method comprising:
a) Determining a phenome of a subject from an electronic medical record (EMR), wherein the phenome comprises a plurality of clinical phenotypes extracted from the EMR (a phenotypic data component configured for determining one or more phenotypes for one or more patients (claim 1); algorithms can be utilized to analyze electronic medical record (EMR) and electronic health record (EHR) data" (0104)
b) Translating the clinical phenotypes into standardized vocabulary using a hierarchical reference vocabulary for mapping terms associated with genetic diseases (the Local Data/Processing Center can analyze the de-identified medical information to assign one or more phenotypes to each patient (for example, by assigning International Classification of Diseases 'ICD' and/or Current Procedural Terminology 'CPT' codes)" (0122); the one or more codes can be, for example, International Classification of Diseases codes (ICD-9, ICD-9-CM, ICD-10)" (0148)); Reid further discloses the binary phenotype component that can be configured for analyzing de-identified medical information to identify one or more codes assigned to a patient in the de-identified medical information. The one or more codes can be, for example, International Classification of Diseases codes (ICD-9, ICD-9-CM, ICD-10), Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) codes, Unified Medical Language System (UMLS) codes, RxNorm codes, Current Procedural Terminology (CPT) codes, Logical Observation Identifier Names and Codes (LOINC) codes, MedDRA codes, drug names, billing codes, and the like. The one or more codes are based on controlled terminology and assigned to specific diagnoses and medical procedures. The binary phenotype component 214 can identify the existence (or non-existence) of the one or more codes, determine a phenotype(s) associated with the one or more codes, and assign the phenotype(s) to the patient associated with the de-identified medical information via a unique identifier [0148]. See also, the quantitative, categorical, and clinical narrative phenotype components [0147-0152]).
c) determining a phenotype matching score by quantifying the number of phenotype terms from the EMR that match phenotype terms of each genetic disease and weighting each genetic disease that has matched phenotypes according to the number of matched phenotypes and the information content of the matched phenotypes (Reid discloses scoring and weighting EMR data: In an aspect, the clinical narrative phenotype component 220 can be a natural language processing (NLP) phenotype component configured for analyzing de-identified medical information to identify terms that can be used to assign a phenotype to a patient. The NLP phenotype component 220 can analyze, for example, narrative (unstructured) data contained in the de-identified medical information. The NLP phenotype component 220 can process text to extract information using linguistic rules. The NLP phenotype component 220 can break down sentences and phrases into words, and assign each word a part of speech—for example, a noun or adjective. The NLP phenotype component 220 can then apply linguistic rules to interpret the possible meaning of the sentence. In so doing, the NLP phenotype component 220 can identify concepts contained in the sentences. The NLP phenotype component 220 can link several terms to a concept by accessing one or more databases that standardize health terminologies, define the terms, and relate terms to each other and to a concept (e.g., an ontology). Such databases include the SNOMED CT, which organizes health terminologies into categories (such as body structure or clinical finding), RxNorm, which links drug names to other drug names in major pharmacy and drug interaction databases, and the Phenotype KnowledgeBase website (PheKB)[0151]; Reid further discloses factors involved in the number of genetic variant-phenotype association and/or gene-phenotype association results that can be generated include the number of genes and/or genetic variants, the number of phenotypes and the number of statistical tests or models that are performed. Thus, the genetic variant-phenotype association data component 206 is thus infinitely scalable. In one embodiment, a genetic variant-phenotype association result and/or gene-phenotype association result analysis for a desired number of genes and/or genetic variants, a desired number of phenotypes and the number of applied statistical tests or models [0163]). Additionally, Kingsmore discloses that upon entry of the clinical features of an individual patient, SSAGA or Phenomizer identified the corresponding superset of relevant diseases and genes, rank ordered by number of matching terms or probability [0071]. Kingsmore further discloses that Human Phenotype Ontology terms for the clinical features in each of the 51 affected children were mapped to ˜5,300 MIM diseases and ˜2,900 genes (ND Table s2). The Phenomizer rank of the correct diagnosis among the prioritized list of diseases matching the observed clinical features was a measure of the goodness of fit between the observed and expected presentations [0083];
d) Deriving a first list of weighted or scored differential diagnoses of the subject based on c) (Reid discloses that the method 500 can comprise determining one or more de-identified medical records (e.g., phenotype data, including medical information) associated with the one or more criteria at 504. The one or more de-identified medical records can be associated with the first cohort and that the method 500 can comprise grouping the one or more de-identified medical records into a first result [0176) Fig.5).
e) Performing genetic sequencing of a biological sample containing DNA from the subject using a method selected from whole genome sequencing (WGS), rapid whole genome sequencing (rWGS), ultra-rapid whole genome sequencing, or whole exome sequencing (WES), or rapid whole exome sequencing (rWES) (Reid discloses receiving a plurality of variants from exome sequencing data; assessing a functional impact of the plurality of variants; generating an effect prediction element for each of the plurality of variants; and assembling the effect prediction element into a searchable database comprising the plurality of variants [0021]. Reid further discloses that "the genetic variant data are obtained from genomic sequencing of the subjects for whom genetic variant and phenotype data are contained in the system. In another aspect, the genetic variant data are obtained from exome (for example, whole exome) sequencing of the subjects for whom genetic variant and phenotype data are contained in the system" (0103). “The NGS Sequencing Facility 106 can comprise one or more sequencers (e.g., Illumina HiSeq 2500, Pacific Biosciences PacBio RS II, and the like). The one or more sequencers can be configured for exome sequencing, whole exome sequencing, RNA-seq, whole-genome sequencing, targeted sequencing, and the like… resulting in annotated variant files for each sample” (0123-0124)).
f) Determining genetic variants of the DNA and a genotype of the subject based on d) ("variant identification component 210 can identify (e.g., call) one or more variants, including CNV identification" (0136); using the genetic information for diagnosis (0109), which can be done using variant pathogenicity information (0321–0324) and mode-of-inheritance information (0107; 0423–0424)).
g) Deriving a second list of differential diagnoses of the subject based on assessment of a pathogenicity of each of the genetic variants of e) ("the genetic variant-phenotype association data component 206 can be configured for determining, storing, analyzing, receiving, and the like, one or more associations between the one or more genetic variants in the genetic variant data and the one or more phenotypes in the phenotypic data" (0152); Reid further discloses variant restriction to those with a Pathogenic classification [0321-0322]. Reid further discloses that The variant annotation component 212 can be configured to determine and assign functional information to the identified variants. The variant annotation component 212 can be configured to categorize each variant based on the variant's relationship to coding sequences in the genome and how the variant may change the coding sequence and affect the gene product [0140]).
h) Integrating first and second differential diagnoses lists; (Reid discloses that "genetic variant-phenotype association data component can be configured to generate genetic variant-phenotype association results" (0163); this component combines the diagnoses from the genetic data component and the phenotypic data component (206; Fig. 2)).
i) Ranking and ordering the differential diagnoses based on the results of integrating in g) (determining the top 3 diagnoses based on the phenotype and genetic data (407 and 408; Fig. 4E))
j) Generating a report comprising results of the analysis of h), thereby providing an autonomous diagnosis; wherein at least one of the steps is performed using a computer. ("a data analysis component configured for generating, storing and indexing the one or more associations from the genetic variant-phenotype association data component" (0013); "a genetic variant-phenotype association data component to determine an association result between the variant and a phenotype of the cohort; passing the association result to a data analysis component to store and index the association result by at least one of the variant and the phenotype" (0022); the systems and methods disclosed herein can be implemented via a general-purpose computing device in the form of a computer (0237)).
k) administering to the subject a targeted treatment earlier than such treatment would be administered using a standard rapid testing result; (Reid discloses: The present methods and systems facilitate the nomination identification of biological drug targets [0011] and that the discloses method would improve diagnostic rates and eventually inform patient treatments [0409]; see also, present system and methods facilitate the study of the biological pathway(s) that are relevant to a phenotype identified as being associated with a genetic variant. The biological pathway can be studied in detail, for example, in support of drug development, to identify a putative biological target for pharmacologic intervention [0253]).
Further regarding claim 1, Reid discloses analyzing the de-identified medical information to assign one or more phenotypes to each patient (for example, by assigning International Classification of Diseases “ICD” and/or Current Procedural Terminology “CPT” codes) [0122] and the NLP phenotype component that can link terms to concepts by accessing one or more databases that standardize health terminologies, define the terms, and relate terms to each other and to a concept (e.g., an ontology) [0151], as well as identification of drugs [0011].
Reid does not expressly teach that the translating step uses Human Phenotype Ontology terms and administering to the subject a targeted treatment earlier than such treatment would be administered using a standard rapid testing result.
Kingsmore discloses a method of genetic disease diagnosis comprising genome sequencing, variant detection, comparing a database of genetic diseases with disease phenotype information to produce a prioritized list of probable genetic diseases, and integrating the superset of sensitive variant calls and the prioritized list of probable genetic diseases (claim 1).
Kingsmore further discloses examining electronic medical record for each affected individual and recording the clinical features of the patient's illness using Human Phenotype Ontology (HPO) terms [0056].
Kingsmore further discloses that earlier diagnosis of Mendelian diseases can enable earlier institution of specific treatments, which may engender improved patient outcomes [0001]. Kingsmore further discloses that saving costs of intensive care by earlier diagnosis, either through withdrawal of care where the prognosis rendered medical care futile, or as a result of institution of an effective treatment upon diagnosis was omitted [0088]. Kingsmore further discloses administering a treatment/ immunosuppressants [0051].
With respect to claim 2, Reid teaches a population of subjects who seek care at a medical system at which detailed longitudinal electronic health records are maintained on the subjects (0142).
With respect to claim 3, Reid teaches the clinical narrative phenotype component can be a natural language processing (NLP) phenotype component configured for analyzing de-identified medical information to identify terms that can be used to assign a phenotype to a patient. Reid further teaches, the NLP phenotype component can analyze, for example, narrative (unstructured) data contained in the de-identified medical information (0151).
With respect to claim 4, Reid teaches "a program can invoke parallel operations such as mapping, filtering, or reduction on [a resilient distributed data set] by passing a function to a scheduler, which then schedules the function's execution in parallel in the cluster" (0233).
With respect to claim 11, Reid teaches "the NLP phenotype component can link several terms to a concept by accessing one or more databases that standardize health terminologies, define the terms, and relate terms to each other and to a concept (e.g., an ontology)" (0151).
With respect to claim 13, Reid teaches one or more CNVs can be detected in all whole-exome sequencing samples using CLAMMS. Every CNV can be defined by start and end coordinates, expected copy number state, and/or confidence level. Reid further teaches Copy number state is the most likely state (# of copies) as predicted by the probabilistic CLAMMS (non-limiting example of a method for calling a copy number variant, [0135]) mixture models… [0137].
With respect to claim 14, Reid teaches within the pilot set, after bioinformatic filtration, 641 variants in the G76 were reviewed: 32 (5.0%) were considered "pathogenic", 23 (3.6%) were considered "likely pathogenic", and the remainder 586 (91.4%) were considered either variants of uncertain significance, likely benign, benign, or false positives [0324].
With respect to claim 15, Reid teaches sample size required for detecting a variant is influenced by both the frequency of the variant, for example the minor allele frequency (MAF), and the effect size of the variant [0112]. Reid further teaches within one embodiment the MAF of a genetic variant is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, while in another the MAF of a genetic variant is less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02% or 0.01% [0113].
With respect to claim 16, Reid teaches, after bioinformatic filtration, 641 variants in the G76 were reviewed: 32 (5.0%) were considered "pathogenic", 23 (3.6%) were considered "likely pathogenic", and the remainder 586 (91.4%) were considered either variants of uncertain significance, likely benign, benign, or false positives [0324].
With respect to claim 17, Reid teaches that of 641 variants in the G76 that were reviewed: 32 (5.0%) were considered "pathogenic", 23 (3.6%) were considered "likely pathogenic", and the remainder 586 (91.4%) were considered either variants of uncertain significance, likely benign, benign, or false positives. Furthering teaching, variants that are classified as "pathogenic" or "likely pathogenic" and confirmed in a CLIA-certified molecular diagnostic laboratory are considered as eligible for return to patients and providers [0324].
With respect to claim 18, Reid teaches the probability of observing at least one duplication or deletion in a gene relative to its rank by the pLI metric. Reid further teaches genes ranked by probability of SNV (genetic variant) loss-of-function intolerance (pLI; ExAC v0.3) correlate with the observed probability of observing CNVs (genetic variant) in the same gene [0381, see Fig. 37].
With respect to claim 19, Kingsmore teaches performing genetic sequencing of a DNA sample from a biological parent of the subject (STATseq was performed on both parents and affected infants simultaneously. Genomic DNA extraction from whole blood, library preparation, sequencing, and data analysis were performed using validated protocols (0140).)
With respect to claims 20 and 21, Kingsmore teaches the genetic sequencing is performed for both biological parents and only results in which trio diplotypes fit a known inheritance pattern of a specific genetic disease are obtained and that wherein parental health status is used to obtain only results in which parental diplotypes fit a known inheritance pattern of a specific genetic disease (all inheritance patterns were examined. Where a single likely causative variant for a recessive disorder was identified, the locus was manually inspected using the Integrated Genome Viewer in the trio for uncalled variants. Kingsmore further teaches familial relationships were confirmed by segregation analysis of private variants in STATseq diagnoses associated with de novo mutations. An infant was classified as having a definitive diagnosis if a pathogenic or likely pathogenic genotype in a disease gene that overlapped with a reported phenotype was reported in the medical record (0142)).
With respect to claim 22, Kingsmore teaches the genetic variants present in the subject's genome and not in the parental genome are utilized to determine a diagnosis for the subject (genome sequencing that refers to methods that decode the sequence of those regions of the genome that are relevant for disease diagnosis (0069)).
With respect to claims 24 and 25, Kingsmore teaches that the subject is less than 5 years old, an infant, fetus or neonate (Subjects are neonates and infants (0005) subject is a 5-month-old male (0174)).
With respect to claim 27, Reid teaches methods and systems disclosed support large-scale, automated statistical analysis of genetic variant-phenotype associations, on a rolling basis, as genetic variant and phenotype data for new subjects are added over time [0103].
With respect to claims 28 and 29, Reid teaches the present methods and systems also facilitate the identification of therapeutic methods for influencing the expression of a gene that contains the variant identified in the genetic variant-phenotype association. Non-limiting examples of suitable therapeutic methods include genome editing, gene therapy [0257].
With respect to claim 30, Reid teaches the phenotypic data component can be configured for determining, storing, analyzing, receiving, and the like, one or more phenotypes for a patient (subject) [0146]. Reid further teaches the binary phenotype component can be configured for analyzing de-identified medical information to identify one or more codes assigned to a patient in the de-identified medical information. Reid additionally discloses one or more codes can be, for example, International Classification of Diseases codes (ICD-9, ICD-9-CM, ICD-10), Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) codes, Unified Medical Language System (UMLS) codes…the one or more codes are based on controlled terminology and assigned to specific diagnoses and medical procedures. Further teaching the binary phenotype component can identify the existence (or non-existence) of the one or more codes, determine a phenotype(s) associated with the one or more codes, and assign the phenotype(s) to the patient associated with the de-identified medical information via a unique identifier [0148].
With respect to claims 31–34, Reid teaches, the genetic data component can comprise identification and functional annotation of variants derived from sequencing subjects in a general population, for example, a population of subjects who seek care at a medical system at which detailed longitudinal electronic health records are maintained on the subjects [0142]. Reid further teaches, the phenotypic data component can be configured for determining, storing, analyzing, receiving, and the like, one or more phenotypes for a patient (subject). The phenotypic data component can be configured to determine one or more phenotypes for each of at least 100,000 patients (subjects). The patients (subjects) can be patients for whom sequencing data has been obtained and analyzed by the genetic data component. A result of determining one or more phenotypes is generation of phenotypic data [0146].
With respect to claims 35 and 36, Reid teaches determining the frequency of a variant (in genetic data component or in another database to which data exchange interface is linked) [0189].
With respect to claim 37, Reid teaches the methods and systems may take the form of a computer program product on a computer-readable storage medium having computer-readable program instructions (e.g., computer software) embodied in the storage medium [0088-0090].
With respect to claim 40, Reid teaches that the phenotypes are derived from electronic medical record fields (0122).
With respect to claim 41, Reid teaches a plurality of subjects, each having their own electronic medical record (0176–0179).
With respect to claim 42, Reid discloses potential clinical actionability that includes opportunities for either preventive measures or early therapeutic interventions to ameliorate pathologic features of the condition [0322]. Additionally, Kingsmore discloses that earlier diagnosis of Mendelian diseases can enable earlier institution of specific treatments, which may engender improved patient outcomes. Kingsmore further discloses that it is possible to have molecular diagnosis in 50 hours by rapid whole genome sequencing (STATseq) [0001]. Kingsmore further discloses genome sequencing for diagnosis of genetic diseases with enhanced sensitivity in 24 hours [0005] [0013] [0046].
With respect to claim 43, Kingsmore discloses that the targeted treatment is immunoglobulin [0160].
With respect to claim 44, Reid discloses that the subject is pediatric [0421]. Further, Kingsmore discloses that the subject is a pediatric admitted to ICU [0160].
In KSR Int 'l v. Teleflex, the Supreme Court, in rejecting the rigid application of the teaching, suggestion, and motivation test by the Federal Circuit, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
Applying the KSR standard to Reid and Kingsmore, the examiner concludes that the combination of Reid and Kingsmore represents applying a known techniques to a known method. Both Reid and Kingsmore are directed to characterization of genetic diseases by genome sequencing. Reid disclosed determining a phenome from an electronic medical record, translating phenotypes by analyzing de-identified medical information to identify one or more codes assigned to a patient in the de-identified medical information, where, the one or more codes can be, for example, International Classification of Diseases codes (ICD-9, ICD-9-CM, ICD-10), Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) codes, Unified Medical Language System (UMLS) codes, RxNorm codes, Current Procedural Terminology (CPT) codes, Logical Observation Identifier Names and Codes (LOINC) codes, MedDRA codes, drug names, billing codes, and the like [0148]. In the same field of research, Kingsmore (previously cited on the (09/11/2019) IDS form) provided translating phenotypes using Human Phenotype Ontology (HPO) terms, for the purpose of describing phenotypic variations in humans, including those associated with diseases, as well as early drug administration. Combining the Phenotypic translation of Kingsmore using HPO terms with disease characterization of Reid would have allowed for assembling a more granular and phenotype-focused approach, particularly for rare diseases. One ordinary skilled in the art before the effective filing data of the claimed invention would have had a reasonable expectation of success at combining the method of Reid and Kingsmore. This combination would have been expected to have provided a more differential diagnosis. Therefore, the invention would have been prima facie obvious to one of skill in the art before the effective filing date of the claimed invention, absent evidence to the contrary.
Response to Applicant’s Argument
Applicant's arguments filed 08/14/2025 have been fully considered but they are not persuasive.
Applicants submit that Reid in view of Kingsmore fails to render the pending claims obvious. Neither Reid nor Kingsmore teach or suggest Applicants' innovative computational system and platform for genomic analysis.
Reid does not teach or suggest determining a phenotype matching score by quantifying the number of phenotype terms from the EMR that match phenotype terms of each genetic disease and weighting each genetic disease that has matched phenotypes according to the number of matched phenotypes and the information content of the matched phenotypes as required by the claims. In fact, Reid does not disclose phenotype term frequency at all. Reid also fails to disclose quantitative scoring based on the number of phenotype terms and information content as disclosed and claimed by Applicant, e.g., see Figure 3 of the specification as filed.
Kingsmore does not remedy the deficit of Reid. Even combining the disclosure of Reid and Kingsmore, one of skill in art would not arrive at the presently claimed invention. Combining the disclosure of Reid with Kingsmore does not teach or suggest an autonomous diagnostic method that includes the unique step of determining a phenotype matching score by quantifying the number of phenotype terms from the EMR that match phenotype terms of each genetic disease and weighting each genetic disease that has matched ph