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, 6-7, and 19-35 are pending.
Claims 2-5 and 8-18 are canceled.
Claim 26 is objected to.
Claims 1, 6-7, and 19-35 are rejected.
Priority
The instant Application claims domestic benefit to US provisional application 63/325,930, filed Mar 31 2022. Accordingly, each of claims 1, 6-7, and 19-35 are afforded the effective filing date of the Mar 31 2022.
Information Disclosure Statement
The information disclosure statement (IDS) filed on Sep 25 2023 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
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Nucleotide and/or Amino Acid Sequence Disclosures
The sequence listing submitted Mar 30 2023 has been accepted.
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
The size of the Sequence Listing file is presented in the specification [0001] in kilobytes. The size of the sequence listing text file is required to be described in bytes.
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to for the following informalities. It is noted that for purposes of the instant Office Action, any reference to the specification pertains to the specification as originally filed on Mar 30 2023.
Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it is less than 50 words, it uses implied phrasing (“Disclosed herein”), and contains grammatical issues at least in “Disclosed here include” and “a subject from sequence reads”, which appears to be disconnected from the first part of the sentence. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Disclosure
The disclosure is objected to because of the following informalities: The first two paragraphs starting on p. 1 are both numbered as [0001]. The paragraphs should be renumbered correctly.
Appropriate correction is required.
Claim Objections
The claims are objected to for the following informalities:
Claim 26, 5th line, recites “reference genome sequence from the the normalized number of the sequence reads aligned any”, which should be amended to recite “reference genome sequence from the to any”.
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.
Claim Interpretation: Claim 22 recites “wherein the one or more SNVs comprise T>G at position 296 and C>G at position 1264 of a copy of the KIV-2 domain of the LPA gene in the reference genome sequence, optionally wherein the copy of the KIV-2 domain comprises a sequence of SEQ ID NO: 1”. Claim 23 recites “wherein the one or more SNVs comprise G>T at chr6:160630428, 160635977, 160641520, 160624884, 160619338, and/or 160613786 of hg38 and/or G>C at chr6:160620306, 160625852, 160631396, 160636945, 160642488, and/or 160614754 of hg38 or at corresponding positions of another reference genome sequence”. The claims are therefore drawn to SNVs which are not specifically defined in terms of structure aside from reference to “the reference genome sequence” in claim 22 and “at corresponding positions of another reference genome sequence”. Therefore, the structures of the SNVs are structurally unlimited and are drawn to SNVs which are considered widely variable with respect to structure.
Claims 22-23 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.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
According to MPEP 2163.II.A.3.(a).ii), [s]atisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
Claim 22 recites “wherein the one or more SNVs comprise T>G at position 296 and C>G at position 1264 of a copy of the KIV-2 domain of the LPA gene in the reference genome sequence, optionally wherein the copy of the KIV-2 domain comprises a sequence of SEQ ID NO: 1”. Claim 23 recites “wherein the one or more SNVs comprise G>T at chr6:160630428, 160635977, 160641520, 160624884, 160619338, and/or 160613786 of hg38 and/or G>C at chr6:160620306, 160625852, 160631396, 160636945, 160642488, and/or 160614754… at corresponding positions of another reference genome sequence”. As stated above, the SNVs are unlimited. In this case, the genus of recited SNVs encompasses species that are considered to be widely variant with respect to both sequence.
The specification as published discloses the following representative species of the genus of recited variant sequences: “The one or more SNVs comprise T>G at position 296 and C>G at position 1264 of a copy of the KIV-2 domain of the LPA gene in the reference sequence. The copy of the KIV-2 domain can comprise a sequence of SEQ ID NO: 1 (chr6:160613491-160619042 of hg38). The one or more SNVs comprise T>G at chr6:160630428, 160635977, 160641520, 160624884, 160619338, and/or 160613786 of hg38 and/or C>G at chr6:160620306, 160625852, 160631396, 160636945, 160642488, and/or 160614754 of hg38 or at corresponding positions of another reference genome sequence (e.g., hg19)” [0006; 0014; 0059; 0082; 0102].
Regarding the level of skill and knowledge in the art of identifying KIV2 domain SNVs, the reference of Coassin et al. (Journal of Lipid Research, 2018, 60(1):186-199; newly cited) is relevant. Coassin makes apparent that KIV-2 variants identified from next-generation sequencing techniques must be described in relation to a specific sequence because the region is variant in terms of the number of repeats, and determining specific variants is based on sequencing data is therefore difficult (p. 187, col. 2, par. 4).
In view of the high level of unpredictability in the art of identifying KIV2 domain SNVs, because the genus of claimed KIV2 SNVs is widely variant with respect to structure, and the specification does not disclose the actual reduction to practice of the species among a widely variant genus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the recited genus of KIV2 domain SNVs. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
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 22-28 and 31-32 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.
Claims 22-23 recite “the one or more SNVs”. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of a one or more SNVs. It is noted that claim 21 recites “one or more single nucleotide variants (SNVs)”. It is therefore not clear whether claims 22-23 should depend from claim 21, which is assumed for compact examination. The rejection may be overcome by clarifying the antecedent basis of the limitations.
Claim 22 recites “wherein the one or more SNVs comprise T>G at position 296 and C>G at position 1264”. It is not clear whether the claim intends to require only one or more of the recited SNVs or both, because the claim recites “and” between the two SNVs. For compact examination, it is assumed that the only one of the SNVs is required and they should be separated by “and/or”.
Claim 22 recites “wherein the one or more SNVs comprise T>G at position 296 and C>G at position 1264 of a copy of the KIV-2 domain of the LPA gene in the reference genome sequence, optionally wherein the copy of the KIV-2 domain comprises a sequence of SEQ ID NO: 1”. The claim is indefinite for recitation of a substitution at positions 296 and 1264 of a gene without reciting a reference sequence for comparison, as one of skill in the art would be unable to determine the location of the required substitutions. The rejection may be overcome by clarifying the reference genome sequence.
Claims 22-28 recite “the reference genome sequence”. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of a reference genome sequence, as claim 19 recites only “a reference sequence”. It is noted that claim 20 recites “a reference genome sequence”. It is therefore not clear if claims 22-28 should depend from claim 20, or if they should recite “the reference sequence”. For compact examination, it is assumed that the claims should depend from claim 20. The rejection may be overcome by clarifying the antecedent basis of the limitations.
Claim 22 recites “a copy of the KIV-2 domain of the LPA gene in the reference genome sequence, optionally wherein the copy of the KIV-2 domain comprises a sequence of SEQ ID NO: 1”. However, claim 19 recites “one or more copies of the KIV-2 domain”. It is therefore not clear if claim 22 intends to limit only one copy of the KIV-2 domain, and if so, which one of the one or more copies. For compact examination, it is assumed that the claim should be amended to recite “a copy of the one or more copies of the KIV-2 domain of the LPA gene in the reference genome sequence, optionally wherein the copy of the one or more copies of the KIV-2 domain comprises a sequence of SEQ ID NO: 1”. However, Applicant is advised that such an amendment may not adequately define the reference genome sequence of the copy of the KIV-2 domain to identify the SNV, as discussed above.
Claim 23 recites “wherein the one or more SNVs comprise G>T at chr6:160630428, 160635977, 160641520, 160624884, 160619338, and/or 160613786 of hg38 and/or G>C at chr6:160620306, 160625852, 160631396, 160636945, 160642488, and/or 160614754 of hg38 or at corresponding positions of another reference genome sequence”. However, the specification as published discloses that “The copy of the KIV-2 domain can comprise a sequence of SEQ ID NO: 1 (chr6:160613491-160619042 of hg38). The one or more SNVs comprise T>G at chr6:160630428, 160635977, 160641520, 160624884, 160619338, and/or 160613786 of hg38 and/or C>G at chr6:160620306, 160625852, 160631396, 160636945, 160642488, and/or 160614754 of hg38 or at corresponding positions of another reference genome sequence (e.g., hg19)” [0006; 0014; 0059; 0082; 0102]. It is therefore not clear whether the claim intended to recite G>T and G>C SNVs as it currently does, or if it should recite T>G and C>G SNVs, as is disclosed in the specification. As set forth in MPEP 2173.03, correspondence between the specification and claims is required by 37 CFR 1.75(d)(1), which provides that claim terms must find clear support or antecedent basis in the specification so that the meaning of the terms may be ascertainable by reference to the specification, and that a claim, although clear on its face, may also be indefinite when a conflict or inconsistency between the claimed subject matter and the specification disclosure renders the scope of the claim uncertain as inconsistency with the specification disclosure or prior art teachings may make an otherwise definite claim take on an unreasonable degree of uncertainty. Therefore, the metes and bounds of claim 23 are not clear. The rejection may be overcome by stating, on the record, the correct language of the claim.
Claim 23 recites “wherein the one or more SNVs comprise G>T at chr6:160630428, 160635977, 160641520, 160624884, 160619338, and/or 160613786 of hg38 and/or G>C at chr6:160620306, 160625852, 160631396, 160636945, 160642488, and/or 160614754… or at corresponding positions of another reference genome sequence”. The claim is indefinite for recitation of a substitution at specific positions of a gene without reciting a reference sequence for comparison, as one of skill in the art would be unable to determine the location of the required substitutions. The rejection may be overcome by clarifying the sequence or the identity of the reference genome.
Claim 27 recites “wherein the correction factor is about 0.01 to about 0.1”. The term “about” in claim 27 is a relative term which renders the claim indefinite. The term “about” 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. Therefore, the correction factor is not clear.
Claim 31 recites “the likely concentration of Lipoprotein(a) in the subject”. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of a likely concentration of Lipoprotein(a) in the subject. It is noted that claim 30 recites “determining a likely concentration of Lipoprotein(a) in the subject”. It is therefore not clear if claim 31 should depend from claim 30, which is assumed for compact examination. The rejection may be overcome by clarifying the antecedent basis of the limitations.
Claim 32 recites “wherein the plurality of sequence reads comprises sequence reads that are about 100 base pairs to about 1000 base pairs in length each”. The term “about” in claim 32 is a relative term which renders the claim indefinite. The term “about” 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. Therefore, the length of the sequence reads is not clear.
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, 6-7, and 19-35 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 and a system, 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).
The claims also recite a law of nature or a natural phenomenon. The MPEP at 2106.04(b) further explains that laws of nature and natural phenomena include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature.
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 claim 1: aligning the plurality of sequence reads to a reference genome sequence, comprising one or more copies of the KIV-2 domain of the LPA gene, to obtain a plurality of aligned sequence reads comprising sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence;
determining a number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence;
determining a number of copies of a region of the LPA gene comprising the one or more copies of the KIV-2 domain based on the number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence; and
determining a total copy number of the KIV-2 domain of the LPA gene of the subject using (a) the number of copies of the region of the LPA gene comprising the one or more copies of the KIV-2 domain and (b) a number of copies of the KIV-2 domain of the LPA gene in the reference genome sequence.
Independent claim 19: aligning the plurality of sequence reads to a reference sequence, comprising one or more copies of the KIV-2 domain of the LPA gene, to obtain a plurality of aligned sequence reads comprising sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference sequence;
determining a number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference sequence;
determining a normalized, GC-corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference sequence;
determining a number of copies of a region of the LPA gene comprising the one or more copies of the KIV-2 domain using the normalized, GC-corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference sequence; and
determining a total copy number of the KIV-2 domain of the LPA gene of the subject using (a) the number of copies of the region of the LPA gene comprising the one or more copies of the KIV-2 domain and (b) a number of copies of the KIV-2 domain of the LPA gene in the reference sequence.
Dependent claim 21: determining (a) a number of copies of the KIV-2 domain of the LPA gene of a first allele of the subject and (b) a number of copies of the KIV-2 domain of the LPA gene of a second allele of the subject, based on one or more single nucleotide variants (SNVs) of the KIV-2 domain of the LPA gene.
Dependent claim 29: creating… a report… representing or comprising (i) the total copy number of the KIV-2 domain of the LPA gene of the subject and/or (iia) a number of copies of the KIV-2 domain of the LPA gene of a first allele of the subject and (iib) a number of copies of the KIV-2 domain of the LPA gene of a second allele of the subject.
Dependent claim 30: determining a likely concentration of Lipoprotein(a) in the subject using the total copy number of the KIV-2 domain of the LPA gene of the subject.
Dependent claim 31: determining a likelihood of myocardial infarction and/or coronary arterial disease in the subject using the total copy number of the KIV-2 domain of the LPA gene of the subject and/or the likely concentration of Lipoprotein(a) in the subject.
Dependent claims 6-7, 20, 22-28, and 32-35 recite further steps that limit the judicial exceptions in independent claims 1 and 19 and, as such, also are directed to those abstract ideas. For example, claim 6 further limits the number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene to being a normalized and/or GC-corrected number; claim 7 further limits determining the number of copies of the region of the LPA gene comprising the one or more copies of the KIV-2 domain to using a normalized and/or GC-corrected number of the sequencing reads; claim 20 further limits the reference sequences to comprising a genome; claims 22-23 further limit the one or more SNVs; claim 24 further limits the alignment of a sequence read to having a low alignment quality score; claim 25 further limits determining the normalized, GC-corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence to using certain metrics; claim 26 further limits determining the normalized, GC- corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence to using a GC content of the region of the LPA gene in the reference genome sequence; claim 27 further limits determining the total copy number of the KIV-2 domain of the LPA gene of the subject to scaling the number of copies of the region of the LPA gene; claim 28 further limits the number of copies of the KIV-2 domain in the reference genome sequence to 6; claim 32 further limits the plurality of sequence reads to being about 100-1000 base pairs in length; claim 33 further limits the plurality of sequence reads to being paired-end or single-end sequence reads; claim 34 further limits the plurality of sequence reads to being generated by whole genome sequencing; and claim 35 further limits the sample to comprising cells, cell-free DNA, cell-free fetal DNA, amniotic fluid, a blood sample, a biopsy sample, or a combination thereof.
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 total copy number of the KIV-2 domain of the LPA gene of a subject. Without further detail as to the methodology involved in “aligning”, “determining”, and “creating”, under the BRI, one may simply, for example, use pen and paper to align sequence reads to a reference genome sequence of the KIV-2 domain of the LPA gene, determine how many sequence reads aligned to the KIV-2 domain, determine a normalized, GC-corrected number of the aligned sequence reads, determine a number of copies of a region of the LPA gene comprising the KIV-2 domain, determine a number of copies of the KIV-2 domain of first and second alleles, determine a total copy number of the KIV-2 domain, create a report of results, determine a likelihood of Lipoprotein(a) in the subject using the total copy number of the KIV-2 domain, and determine a likelihood of myocardial infarction and/or coronary artery disease using the total copy number of the KIV-2 domain and/or the likely concentration of Lipoprotein(a).
Those steps directed to determining a number of reads, determining a normalized, GC-corrected number of reads, determining a number and a total number of copies, scaling the number of copies of the region, determining a likely concentration of Lipoprotein(a), and determining a likelihood of myocardial infarction and/or coronary arterial disease require mathematical techniques as the only supported embodiments, as they express mathematical relationships in words. These steps therefore recite mathematical techniques in addition to mental processes. The specification as published supports interpretation of the limitations as requiring mathematical techniques as the only supported embodiments at: normalizing by length and GC normalization using LOWESS regression [0081]; scaling copy number based on different numbers [0078]; and determining a likely concentration of Lipoprotein(a) in the subject using the total copy number of the KIV-2 domain of the LPA gene of the subject and a likelihood of myocardial infarction and/or coronary arterial disease in the subject using the total copy number of the KIV-2 domain of the LPA gene of the subject and/or the likely concentration of Lipoprotein(a) in the subject [0087; 0104].
The claims also recite the natural relationship between the amount of DNA and the number of copies of a domain of a gene, as well as the natural relationship between the number of copies of the KIV-2 domain of the LPA gene and the concentration of Lipoprotein(a) and a likelihood of myocardial infarction and/or coronary arterial disease in the subject. The specification as published discloses that plasma Lp(a) concentration is largely determined by LPA's kringle IV-2 (KIV-2) domain, where a decrease in KIV-2 repeat count correlates with an increase in plasma Lp(a) level, and risk of myocardial infarction increases with Lp(a) concentration (low KIV-2 copy number) [0087].
Therefore, claims 1 and 19 and those claims dependent therefrom recite an abstract idea and a law of nature/natural phenomenon [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: receiving a plurality of sequence reads generated from a sample obtained from a subject.
Dependent claim 29: creating a file… and/or generating a user interface (UI) comprising a UI element representing or comprising (i) the total copy number of the KIV-2 domain of the LPA gene of the subject and/or (iia) a number of copies of the KIV-2 domain of the LPA gene of a first allele of the subject and (iib) a number of copies of the KIV-2 domain of the LPA gene of a second allele of the subject.
The claims also include non-abstract computing elements. For example, independent claim 1 includes that the method steps are performed under control of a hardware processor; and claim 19 includes a system for determining a copy number of kringle IV type 2 (KIV-2) domain of LPA gene comprising: non-transitory memory configured to store executable instructions and a plurality of sequence reads generated from a sample obtained from a subject; and a hardware processor in communication with the non-transitory memory, the hardware processor programmed by the executable instructions.
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 “receiving” data, and to data outputting, such as “creating” a file or “generating” a user interface, 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 additional non-abstract computing elements of 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)).
The specification discloses that an allele-specific copy number (CN) estimation of KIV-2 is needed to improve the genetic diagnosis and understanding of the impact of KIV-2 on cardiovascular risk across ethnicities at [0053; 0055], but does not provide a clear explanation for how the additional elements provide these improvements. 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 prior art review to Yokoyama et al. (Journal of Human Genetics, 2020, 65(1):49-60.) discloses that creating files (p. 55, col. 2, par. 2; p. 57) and generating user interfaces (p. 58, col. 1, par. 2) for the display of copy number variation results (entire document is relevant) are data gathering elements that are routine, well-understood and conventional in the art. Further, the courts have found that receiving, storing (as in creating a file), and outputting data (as in generating a user interface) 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 and 19 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 [0106-0108]. 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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
A. Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zekavat et al. (Nature Communications, 2018, 9(1):2606, p. 1-11; cited on the Sep 25 2023 IDS).
Claim 1 discloses a method for determining a copy number of kringle TV type 2 (KIV-2) domain of LPA gene.
The prior art to Zekavat discloses the use of deep-coverage whole genome sequencing (WGS) to discover and interpret both single-nucleotide variants and copy number variation associated with Lipoprotein(a) (abstract). Zekavat teaches receiving computer files of sequencing outputs and processing them using computer algorithms (p. 9, col. 1, par. 6 through p. 11, col. 1, par. 5), which is considered to read on performing the steps under the control of a processor the following limitations.
The steps performed in the method of claim 1, under control of a hardware processor, comprise:
receiving a plurality of sequence reads generated from a sample obtained from a subject;
Zekavat teaches performing WGS sequencing on patients and receiving outputs from the sequencing for data processing (p. 2, col. 1, par. 5 through col. 1, par. 1; p. 9, col. 1, par. 5-7).
aligning the plurality of sequence reads to a reference genome sequence, comprising one or more copies of the KIV-2 domain of the LPA gene, to obtain a plurality of aligned sequence reads comprising sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence;
Zekavat teaches aligning the WGS output to the reference genome hg19 to generate aligned BAM files (p. 9, col. 1, par. 7). Zekavat teaches that there are 6.354 full copies of the repeating unit of the KIV2 protein domain of the LPA gene in the hg19 reference genome (p. 9, col. 2, par. 10). As Zekavat teaches aligning WGS reads to the hg19 reference genome, it is considered that Zekavat would have obtained sequence reads aligned to the copies of the KIV-2 domain of the LPA gene as instantly claimed.
determining a number of the sequence reads aligned to any copy of the KiIV-2 domain of the LPA gene in the reference genome sequence;
Zekavat teaches in order to estimate KIV-2 copy number, the algorithm Genome STRiP read-depth genotyping was run on an interval of the hg10 reference genome to capture an aggregate read-depth signal over every base position (i.e., number of sequence reads aligned to any copy) (p. 9, col. 2, par. 9).
determining a number of copies of a region of the LPA gene comprising the one or more copies of the KIV-2 domain based on the number of the sequence reads aligned to any copy of the KiIV-2 domain of the LPA gene in the reference genome sequence; and
Zekavat teaches obtaining a raw copy number estimate from Genome STRiP based on the read depth (p. 9, col. 2, par. 10), as described above.
determining a total copy number of the KIV-2 domain of the LPA gene of the subject using (a) the number of copies of the region of the LPA gene comprising the one or more copies of the KIV-2 domain and (b) a number of copies of the KIV-2 domain of the LPA gene in the reference genome sequence.
Zekavat teaches estimating the number of KIV2 protein domains from the raw copy number estimate (i.e., a) multiplied by the number of full copies of the repeating unit represented on the hg19 reference genome (i.e., b) (p. 9, col. 2, par. 10).
B. Claims 6-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zekavat, as applied to claim 1 above, and as evidenced by Handsaker et al. (Nature Genetics, 2011, 43(3):269-276; newly cited).
Regarding claims 6-7, Zekavat teaches claim 1 as described above. Claim 6 further adds that the number of the sequence reads aligned to any copy of the KiIV-2 domain of the LPA gene in the reference sequence comprises a raw number or a normalized and/or GC-corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference sequence. Claim 7 further adds that determining the number of copies of the region of the LPA gene comprising the one or more copies of the KiIV-2 domain comprises: determining the number of copies of the region of the LPA gene comprising the one or more copies of the KIV-2 domain using a normalized and/or GC-corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence.
Zekavat does not explicitly teach determining a raw, normalized, or GC-corrected number of the aligned sequence reads, but does teach using the algorithm Genome STRiP as described in Handsaker (p. 9, col. 2, par. 9). As evidenced by Handsaker, in Genome STRiP, sequence reads are aligned to a reference genome (p. 9, col. 1, par. 2) and locus-specific read depths are normalized in order to determine structural polymorphisms (p. 273, col., 2, par. 5; p. 9, col. 1, par. 3 through col. 2, par. 3). Therefore Zekavat, as evidenced by Handsaker, is considered to teach determining a normalized number of aligned sequence reads as instantly claimed.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
A. Claims 19-20 and 24-34 are rejected under 35 U.S.C. 103 as being unpatentable over Zekavat et al. (Nature Communications, 2018, 9(1):2606, p. 1-11; cited on the Sep 25 2023 IDS), as evidenced by Handsaker et al. (Nature Genetics, 2011, 43(3):269-276; newly cited), in view of Chudova et al. (US 2021/0371907; cited on the Sep 25 2023 IDS).
Claim 19 discloses a system for determining a copy number of kringle IV type 2 (KIV-2) domain of LPA gene comprising: non-transitory memory configured to store executable instructions and a plurality of sequence reads generated from a sample obtained from a subject; and a hardware processor in communication with the non-transitory memory, the hardware processor programmed by the executable instructions.
The prior art to Zekavat discloses the use of deep-coverage whole genome sequencing (WGS) to discover and interpret both single-nucleotide variants and copy number variation associated with Lipoprotein(a) (abstract). Zekavat teaches receiving computer files of sequencing outputs and processing them using computer algorithms (p. 9, col. 1, par. 6 through p. 11, col. 1, par. 5), which is considered to read on performing the steps under the control of a processor the following limitations. Zekavat teaches performing WGS sequencing on patients and receiving outputs from the sequencing for data processing (p. 2, col. 1, par. 5 through col. 1, par. 1; p. 9, col. 1, par. 5-7). Zekavat does not explicitly teach a system as claimed. See teachings by Chudova below regarding the system.
The steps performed by the system of claim 19 comprise:
aligning the plurality of sequence reads to a reference sequence, comprising one or more copies of the KIV-2 domain of the LPA gene, to obtain a plurality of aligned sequence reads comprising sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference sequence;
Zekavat teaches aligning the WGS output to the reference genome hg19 to generate aligned BAM files (p. 9, col. 1, par. 7). Zekavat teaches that there are 6.354 full copies of the repeating unit of the KIV2 protein domain of the LPA gene in the hg19 reference genome (p. 9, col. 2, par. 10). As Zekavat teaches aligning WGS reads to the hg19 reference genome, it is considered that Zekavat would have obtained sequence reads aligned to the copies of the KIV-2 domain of the LPA gene as instantly claimed.
determining a number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference sequence;
Zekavat teaches in order to estimate KIV-2 copy number, the algorithm Genome STRiP read-depth genotyping was run on an interval of the hg10 reference genome to capture an aggregate read-depth signal over every base position (i.e., number of sequence reads aligned to any copy) (p. 9, col. 2, par. 9).
determining a normalized, GC-corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference sequence;
Zekavat does not explicitly teach determining a normalized, GC-corrected number of the aligned sequence reads, but does teach using the algorithm Genome STRiP as described in Handsaker (p. 9, col. 2, par. 9). As evidenced by Handsaker, sequence reads are aligned to a reference genome (p. 9, col. 1, par. 2) and locus-specific read depths are normalized in order to determine structural polymorphisms (p. 273, col., 2, par. 5; p. 9, col. 1, par. 3 through col. 2, par. 3). Therefore Zekavat, as evidenced by Handsaker, is considered to teach determining a normalized number of aligned sequence reads as instantly claimed.
See below for teachings by Chudova regarding GC-correction.
determining a number of copies of a region of the LPA gene comprising the one or more copies of the KIV-2 domain using the normalized, GC-corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference sequence; and
Zekavat teaches obtaining a raw copy number estimate from Genome STRiP based on the read depth (p. 9, col. 2, par. 10), as described above.
determining a total copy number of the KIV-2 domain of the LPA gene of the subject using (a) the number of copies of the region of the LPA gene comprising the one or more copies of the KIV-2 domain and (b) a number of copies of the KIV-2 domain of the LPA gene in the reference sequence.
Zekavat teaches estimating the number of KIV2 protein domains from the raw copy number estimate (i.e., a) multiplied by the number of full copies of the repeating unit represented on the hg19 reference genome (i.e., b) (p. 9, col. 2, par. 10).
Zekavat does not teach a system or determining a GC-corrected number of the aligned sequence reads.
However, the prior art to Chudova discloses methods for determining copy number variation (CNV) associated with a variety of medical conditions (abstract). Chudova teaches that analysis of the sequencing data and the diagnosis derived therefrom are typically performed using various computer executed algorithms and programs, and embodiments also relate to apparatus for performing these operations, including a general use computer with processors selectively activated or reconfigured by a computer program and/or data structure stored in the computer on non-transitory computer readable media [0435-0436]. Chudova teaches deriving a fragment size parameter, such as a size-weighted coverage or a fraction of fragments in a size range, where the fragment size parameter is adjusted to remove within-sample GC-content bias (abstract). Chudova teaches that the sequence reads are first aligned to a reference genome which has been divided into bins and calculating coverages of the bins [0010]. Chudova teaches obtaining GC-corrected values of the coverages for the sequence of interest [0019-0021; 0139; 0148; 0227; 0269-0277]. Chudova also teaches normalizing the reads before GC correction [0269-0277].
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, Zekavat as evidenced by Handsaker with Chudova because Zekavat and Chudova each disclose methods for determining copy number variations. The motivation would have been to improve the sensitivity and/or specificity of sequence data analysis by removing within-sample GC-content bias, as taught by Chudova [0139]. Chudova further motivates examining the LPA gene and the number of kringle 4 repeat sequences [0434]. Therefore, it would have been obvious to one of ordinary skill in the art to use the method taught by Chudova to correct the GC bias in number of aligned reads to the KIV-2 domain, as taught by Zekavat. Further, it would have been obvious to include the system taught by Chudova to perform the method of Zekavat, as evidenced by Handsaker, in view of Chudova because such a modification represents the automating of a manual activity. The courts have 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 (In re Venner, 262 F.2d 91, 95, 120 USPQ 193, 194 (CCPA 1958); MPEP 2144.04(III)).
Regarding claim 20, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 20 further adds that the reference sequence comprises a reference genome sequence.
Zekavat teaches aligning the WGS output to the reference genome hg19 to generate aligned BAM files (p. 9, col. 1, par. 7).
Regarding claim 24, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 24 further adds that a sequence read of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence with a low alignment quality score.
Zekavat teaches using the custom setting of setting mapping quality to 0 when running Genome STRiP read-depth genotyping to determine as estimated copy number of KIV2 (p. 9, col. 2, par. 9), which reads on a sequence with a low alignment quality score as instantly claimed.
Regarding claim 25, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 25 further adds that determining the normalized, GC-corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence comprises: determining the normalized number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence using (1a) a depth of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence, (1b) a length of the region of the LPA gene in the reference genome sequence comprising the one or more copies of the KIV-2 domain, (2a) a depth of sequence reads of the plurality of sequence reads aligned to each of a plurality of regions of the reference genome sequence other than a genetic locus comprising LPA gene, and (2b) a length of each of the plurality of regions of the reference genome other than the genetic locus comprising LPA gene.
Zekavat does not explicitly teach using features 1a, 1b, 2a, and 2b as claimed, but does teach using the algorithm Genome STRiP as described in Handsaker (p. 9, col. 2, par. 9). Handsaker teaches that to utilize read depth in genotyping, for each deletion locus, the number of sequenced fragments falling within the deleted region was counted for each sample, and correcting for the ‘effective length’ of the deletion locus, and the expected number of fragments for each sample was estimated based on the genome-wide sequencing coverage and the effective length of the deleted region (p. 10, col. 1, par. 3). Therefore, it is considered that Zekavat using Genome STRiP to determine copy numbers and read depths of the KIV2 domain reads on using (1a) a depth of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence, (1b) a length of the region of the LPA gene in the reference genome sequence comprising the one or more copies of the KIV-2 domain, (2a) a depth of sequence reads of the plurality of sequence reads aligned to each of a plurality of regions of the reference genome sequence other than a genetic locus comprising LPA gene, and (2b) a length of each of the plurality of regions of the reference genome other than the genetic locus comprising LPA gene as instantly claimed.
Regarding claim 26, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claims 19 and 25. Claim 26 further adds that determining the normalized, GC- corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence comprises: determining the normalized, GC-corrected number of the sequence reads aligned to any copy of the KIV-2 domain of the LPA gene in the reference genome sequence from the the normalized number of the sequence reads aligned any copy of the KIV-2 domain of the LPA gene in the reference genome sequence using a GC content of the region of the LPA gene in the reference genome sequence comprising the one or more copies of the KIV-2 domain.
Zekavat teaches using the algorithm Genome STRiP as described in Handsaker to determine KIV2 copy number (p. 9, col. 2, par. 9). Handsaker teaches that Genome STRiP determines normalized reads per locus as described above (p. 10, col. 1, par. 3). Zekavat does not teach determining the GC-corrected number.
However, Chudova teaches adjusting coverages based on the GC content [0019], where every bin has its own fractional contribution from GC, where the per bin amount is determined and corrected on a per bin basis (i.e., GC content of the region of the LPA gene) [0269].
Regarding claim 27, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 27 further adds that determining the total copy number of the KIV-2 domain of the LPA gene of the subject comprises: scaling the number of copies of the region of the LPA gene comprising the one or more copies of the KIV-2 domain by a scaling factor to determine the total copy number of the KIV-2 domain of the LPA gene of the subject, wherein the scaling factor is based on the number of the copies of the KIV-2 domain of the LPA gene in the reference genome sequence, optionally wherein the scaling factor is the number of the copies of the KIV-2 domain of the LPA gene in the reference genome sequence adjusted by a correction factor, optionally wherein the correction factor is about 0.01 to about 0.1, and optionally wherein the scaling factor is the number of the copies of the KIV-2 domain of the LPA gene in the reference genome sequence.
Zekavat teaches multiplying (i.e., scaling) the raw copy number estimate determined by Genome STRiP by 6.354 (i.e., a scaling factor), which is derived from the number of full copies of the repeating unit of KIV2 in the hg19 reference genome, to determine the KIV2 copy number estimate (p. 9, col. 2, par. 10).
Regarding claim 28, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 28 further adds that the number of copies of the KIV-2 domain of the LPA gene in the reference genome sequence is six.
Zekavat teaches multiplying the raw copy number estimate determined by Genome STRiP by 6.354, which is derived from the number of full copies of the repeating unit of KIV2 in the hg19 reference genome, to determine the KIV2 copy number estimate (p. 9, col. 2, par. 10). Zekavat therefore teaches that the full number of copies of the repeating unit in the reference genome is 6.
Regarding claim 29, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 29 further adds that the hardware processor is further programmed by the executable instructions to perform: creating a file or a report and/or generating a user interface (UI) comprising a UI element representing or comprising (i) the total copy number of the KIV-2 domain of the LPA gene of the subject and/or (iia) a number of copies of the KIV-2 domain of the LPA gene of a first allele of the subject and (iib) a number of copies of the KIV-2 domain of the LPA gene of a second allele of the subject.
Zekavat teaches reporting the number of copies of the KIV2 repeats in the samples (p. 2, col. 2, par. 3).
Regarding claims 30-31, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 30 further adds that the hardware processor is further programmed by the executable instructions to perform: determining a likely concentration of Lipoprotein(a) in the subject using the total copy number of the KIV-2 domain of the LPA gene of the subject. Claim 31 further adds that the hardware processor is further programmed by the executable instructions to perform: determining a likelihood of myocardial infarction and/or coronary arterial disease in the subject using the total copy number of the KIV-2 domain of the LPA gene of the subject and/or the likely concentration of Lipoprotein(a) in the subject.
Zekavat teaches confirming that KIV2_CN is negatively associated with Lp(a) concentration and determining variants that influence the relationship between KIV2-CN (i.e., total copy number of the KIV-2 domain) and Lp(a) concentration and that knowledge of LPA genotypes can better inform incident cardiovascular disease risk prediction (p. 3, col. 1, par. 2 through col. 2, par. 1; p. 6, col. 1, par. 3; p. 8, col. 1, par. 2 through col. 2, par. 3; Fig. 3 and 5), which reads on determining a concentration of Lipoprotein(a) in claim 30 and a likelihood of coronary arterial disease in claim 31.
Regarding claims 32-34, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 32 further adds that the plurality of sequence reads comprises sequence reads that are about 100 base pairs to about 1000 base pairs in length each. Claim 33 further adds that the plurality of sequence reads comprises paired-end sequence reads and/or single-end sequence reads. Claim 34 further adds that the plurality of sequence reads is generated by whole genome sequencing (WGS), optionally wherein the WGS is clinical WGS (cWGS).
Zekavat teaches sequencing 151-bp paired-end reads for whole genome sequencing (p. 9, col. 1, par. 7).
B. Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Zekavat, as evidenced by Handsaker, in view of Chudova, as applied to claim 19 as above, and in further view of Coassin et al. (Journal of Lipid Research, 2019, 65(1):49-60; newly cited).
Regarding claim 21, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 21 further adds determining (a) a number of copies of the KIV-2 domain of the LPA gene of a first allele of the subject and (b) a number of copies of the KIV-2 domain of the LPA gene of a second allele of the subject, based on one or more single nucleotide variants (SNVs) of the KIV-2 domain of the LPA gene, which Zekavat does not teach.
However, the prior art to Coassin discloses a sequencing strategy for this region and report here the first map of genetic variation in the KIV-2 region, a comprehensively evaluated ultradeep sequencing protocol, and an easy-to-use variant analysis pipeline (abstract). Coassin teaches determining the level of multiple KIV-2B variants (p. 192, col. 1, par. 2 through col. 1, par. 1), as well as determining the number of repeats that variants were present in by multiplying the observed next generation sequencing level with the sum of genomic KIV-2 repeats that had been estimated by quantitative PCR (p. 191, col. 2, par. 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 combine, in the course of routine experimentation and with a reasonable expectation of success, Zekavat, as evidenced by Handsaker, in view of Chudova with Coassin because Zekavat and Coassin each disclose methods for examining the KIV2 domain of the lipoprotein(a) gene. The motivation would have been to analyze specific variants that could affect Lp(a) concentrations, as taught by Coassin (p. 187, col. 1, par. 2). Zekavat further motivates this modification by teaching that their work is limited because they only estimate total KIV2-CN, even though individuals may have different KIV2-CN alleles on each chromosome (p. 9, col. 1, par. 2). Therefore, it is considered that one of ordinary skill in the art would be motivated to extend the work of Zekavat to incorporate an estimation of the number of specific alleles in the KIV2 domain, and would expect the method taught by Coassin to provide such results, where the number of KIV2 repeats determined by the method of Zekavat could be substituted for the sum of genomic KIV-2 repeats that had been estimated by quantitative PCR in Coassin (p. 191, col. 2, par. 2).
C. Claims 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Zekavat, as evidenced by Handsaker, in view of Chudova, as applied to claim 19 as above, and in further view of Coassin et al. (Journal of Lipid Research, 2019, 65(1):49-60; newly cited) and Coassin et al. (Journal of Lipid Research, 2019, 65(1):49-60; newly cited), as evidenced by Coassin et al. (Journal of Lipid Research, 2019, Supplementary Material, p. 1-92; newly cited).
Regarding claims 22-23, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19 and, in view of Coassin, claim 21. Claim 22 further adds that the one or more SNVs comprise T>G at position 296 and C>G at position 1264 of a copy of the KIV-2 domain of the LPA gene in the reference genome sequence, optionally wherein the copy of the KIV-2 domain comprises a sequence of SEQ ID NO: 1. Claim 23 further adds that the one or more SNVs comprise G>T at chr6:160630428, 160635977, 160641520, 160624884, 160619338, and/or 160613786 of hg38 and/or G>C at chr6:160620306, 160625852, 160631396, 160636945, 160642488, and/or 160614754 of hg38 or at corresponding positions of another reference genome sequence. Neither Zekavat, Handsaker, or Chudova teach these variants.
However, the prior art to Coassin discloses a sequencing strategy for this region and report here the first map of genetic variation in the KIV-2 region, a comprehensively evaluated ultradeep sequencing protocol, and an easy-to-use variant analysis pipeline (abstract). Coassin teaches identifying exonic variants in the KIV2 domain (p. 193, col. 1, par. 2). As evidenced by Coassin Supplementary, Coassin Supplementary discloses T>G variants at least a positions 2688, 605, 624, 711, and 730 (Supplemental Tables S7-S8), C>G variants at least at positions 4576, 607, 645, and 734 (Supplemental Tables S7-S8), G>T variants at least at positions 585, 591, 597, 606, 623, 644, 708, and 717 (Supplementary Table S8), and G>C variants at least at positions 635, 641, 643, 661, 686, 687, and 741 (Supplementary Table S8). As the metes and bounds of the claims are unclear as to exactly what variants are required in reference to the exact reference genome sequences (see the above 35 USC 112(b) rejections), and because the claims are considered to encompass undefined variants (see the above 35 USC 112(a) rejections), it is considered that the variants described by Coassin and Coassin Supp read on the claimed SNVs.
Regarding claims 22-23, 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, Zekavat, as evidenced by Handsaker, in view of Chudova with Coassin and Coassin Supplementary because Zekavat and Coassin each disclose methods for examining the KIV2 domain of the lipoprotein(a) gene. The motivation would have been to analyze specific variants that could affect Lp(a) concentrations, as taught by Coassin (p. 187, col. 1, par. 2). Zekavat further motivates this modification by teaching that their work is limited because they only estimate total KIV2-CN, even though individuals may have different KIV2-CN alleles on each chromosome (p. 9, col. 1, par. 2). Therefore, it is considered that one of ordinary skill in the art would be motivated to extend the work of Zekavat to incorporate an estimation of the number of specific alleles in the KIV2 domain, and would expect the method taught by Coassin to provide such results, where the number of KIV2 repeats determined by the method of Zekavat could be substituted for the sum of genomic KIV-2 repeats that had been estimated by quantitative PCR in Coassin (p. 191, col. 2, par. 2).
D. Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Zekavat, as evidenced by Handsaker, in view of Chudova, as applied to claim 19 as above, and as evidenced by Zekavat et al. Supplementary Information (Nature Communications, 2018, 9(1):2606, p. 1-50; newly cited).
Regarding claim 34, Zekavat, as evidenced by Handsaker, in view of Chudova teaches claim 19. Claim 35 further adds that the sample comprises cells, cell-free DNA, cell-free fetal DNA, amniotic fluid, a blood sample, a biopsy sample, or a combination thereof.
Zekavat does not describe the samples. However, Zekavat Supplementary Information teaches that the samples examined in the study are based from blood samples (p. 2, par. 2-3). Therefore, Zekavat, as evidenced by Zekavat Supplementary Information, teaches analyzing blood samples.
Conclusion
No claims are allowed.
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/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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