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 .
Claim Status
Claim(s) 1-30 are currently pending and under examination herein.
Priority
This instant application claims the benefit of U.S. Provisional Applications: No. 63/253,122 filed October 6, 2021, U.S Provisional Application No. 63/281,579 filed on November 19, 2021, and U.S. Provisional Application No. 63/281,592 filed on November 19,2021. As such, the effective filling date of the claims is October 6, 2021.
The applicant is reminded that amendments to the claims and specification must comply with 35 U.S.C. § 120 and 37 C.F.R. § 1.121 to maintain priority to an earlier-filed application. Claim amendments may impact the effective filing date if new subject matter is introduced that lacks support in the originally filed disclosure. If an amendment adds limitations that were not adequately described in the parent application, the claim may no longer be entitled to the priority date of the earlier filing.
Specification
The disclosure is objected to because of the following informalities: line 0006 in the .
Appropriate correction is required.
Information Disclosure Statement
The Information Disclosure Statement(s) filed on 9 February 2023 and 3 August 2023 are in compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of the list of references cited from each IDS is included with this Office Action.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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.
Drawings
The drawings are objected to because Figures 38-41, 62, and 63 include enumerated amino acid
sequences without providing sequence identifiers (see above). Corrected drawing sheets in
compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid
abandonment of the application. Any amended replacement drawing sheet should include all of
the figures appearing on the immediate prior version of the sheet, even if only one figure is being
amended. The figure or figure number of an amended drawing should not be labeled as
"amended." If a drawing figure is to be canceled, the appropriate figure must be removed from
the replacement sheet, and where necessary, the remaining figures must be renumbered and
appropriate changes made to the brief description of the several views of the drawings for
consistency. Additional replacement sheets may be necessary to show the renumbering of the
remaining figures. Each drawing sheet submitted after the filing date of an application must be
labeled in the top margin as either "Replacement Sheet" or "New Sheet" pursuant to 37 CFR
1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and
informed of any required corrective action
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. A petition to accept color drawings filed September 26, 2022, was granted.
Claim Interpretation
The term gap amino acid as recited in the claims is interpreted as an amino acid that is removed or masked in structural analysis as stated in the specification at paragraph 267.
The term voxel as recited in the claims is interpreted as an element of a 3D object as discussed at paragraph 124, that can have any cubic dimensions---exemplifying a one angstrom cube.
The term Evolutionary conservation refers to the presence of similar genes, portions of genes, or chromosome segments in different species, reflecting both the common origin of species and an important functional property of the conserved element as stated in the specification paragraph 315.
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 1-30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 2A, Prong 1
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step
1: YES) are then analyzed to determine if the claims recite any concepts that equate to an
abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant
application, the claims recite the following limitations that equate to an abstract idea:
Claim 1,29, and 30 recite:
specifying a particular amino acid at a particular position in a protein as a gap amino acid, and specifying remaining amino acids at remaining positions in the protein as non-gap amino acids;
generating a gapped spatial representation of the protein that includes spatial configurations of the non-gap amino acids, and excludes a spatial configuration of the gap amino acid;
determining an evolutionary conservation at the particular position of respective amino acids of respective amino acid classes based at least in part on the gapped spatial representation;
based at least in part on the evolutionary conservation of the respective amino acids, determining a pathogenicity of respective nucleotide variants that respectively substitute the particular amino acid with the respective amino acids in alternate representations of the protein.
Claim 2 recite:
the spatial configurations of the non-gap amino acids are encoded as amino acid class-wise distance channels,
each of the amino acid class-wise distance channels has voxel-wise distance values for voxels in a plurality of voxels,
the voxel-wise distance values specify distances from corresponding voxels in the plurality of voxels to atoms of the non-gap amino acids.
Claim 3 recites wherein the spatial configurations of the non-gap amino acids are determined based on spatial proximity between the corresponding voxels and the atoms of the non-gap amino acids (mental process).
Claim 4 recites wherein the spatial configuration of the gap amino acid is excluded from the gapped spatial representation by disregarding distances from the corresponding voxels to atoms of the gap amino acid
Claim 5 recites method of claim 4, wherein the spatial configuration of the gap amino acid is excluded from the gapped spatial representation by disregarding spatial proximity between the corresponding voxels and the atoms of the gap amino acid.
Claim 6 further describes the data of claim 1, wherein the particular amino acid is a reference amino acid that is a major allele of the protein.
Claim 7 recites wherein an evolutionary conservation predictor determines the evolutionary conservation by processing, as input, the gapped spatial representation; and generating, as output, respective evolutionary conservation scores for the respective amino acids.
Claim 8, the respective evolutionary conservation scores are rankable by magnitude.
Claim 9 recites classifying a nucleotide variant as pathogenic when an evolutionary conservation score generated by the evolutionary conservation predictor for a corresponding amino acid substitution is below a threshold (mental process).
Claim 10 recites classifying a nucleotide variant as pathogenic when an evolutionary conservation score generated by the evolutionary conservation predictor for a corresponding amino acid substitution is zero (mental process).
Claim 11 recites classifying a nucleotide variant as benign when an evolutionary conservation score generated by the evolutionary conservation predictor for a corresponding amino acid substitution is above a threshold (mental process).
Claim 12 recites classifying a nucleotide variant as benign when an evolutionary conservation score generated by the evolutionary conservation predictor for a corresponding amino acid substitution is above a threshold (mental process).
Claim 13 recites wherein the evolutionary conservation predictor is trained on a conserved training set and a non-conserved training set.
Claim 14 recites wherein the conserved training set has respective conserved protein samples for respective conserved amino acids at respective positions in a proteome, wherein the non-conserved training set has respective non-conserved protein samples for respective non-conserved amino acids at the respective positions
Claim 15 recites wherein each of the respective positions has a set of conserved amino acids and a set of non-conserved amino acids
Claim 16 recites wherein a particular set of conserved amino acids for a particular position in a particular protein in the proteome includes at least one major allele amino acid observed at the particular position across a plurality of species.
Claim 17 recites wherein the particular set of conserved amino acids includes one or more minor allele amino acids observed at the particular position across the plurality of species.
Claim 18 recites wherein a particular set of non-conserved amino acids for the particular position includes amino acids not in the particular set of conserved amino acids.
Claim 19 recites wherein the particular set of conserved amino acids and the particular set of non-conserved amino acids are identified based on evolutionary conservation profiles of homologous proteins of the plurality of species. Claim 20 recites wherein the evolutionary conservation profiles of the homologous proteins are determined using a position-specific frequency matrix (PSFM) (mathematical concept).
Claim 21 recites the computer-implemented method of claim 19, wherein the evolutionary conservation profiles of the homologous proteins are determined using a position-specific scoring matrix (PSSM).
Claim 22 recites wherein the major allele amino acid is a reference amino acid.
Claim 23 recites where NC= 20-C -Ce CP = a number of the respective positions * C, and wherein the non-conserved training set has NCP non-conserved protein samples, where NCP = the number of the respective positions * (20-C)
Claim 23 recites wherein each of the respective positions has C conserved amino acids in the set of conserved amino acids, wherein each of the respective positions has NC non-conserved amino acids in the set of non-conserved amino acids,
Claim 24 recites wherein the C ranges from one to ten.
Claim 25 recites wherein the C varies across the respective positions.
Claim 26 recites wherein the C is same for some of the respective positions
Claim 27 recites wherein the respective conserved and non-conserved protein samples have respective gapped spatial representations generated by using respective reference amino acids at the respective positions as respective gap amino acids.
Claim 28 recites wherein the evolutionary conservation predictor trains on a particular conserved protein sample and estimates an evolutionary conservation of a particular conserved amino acid at a particular position in the particular conserved protein sample by processing, as input, a particular gapped spatial representation of the particular conserved protein sample, wherein the particular gapped spatial representation is generated by using a particular reference amino acid at the particular position as a gap amino acid, and by using remaining amino acids at remaining positions in the particular conserved protein sample as non-gap amino acids; and generating, as output, an evolutionary conservation score for the particular conserved amino acid. (mental)
The limitations regarding specifying a particular amino acid as gap or non-gap, determining evolutionary conservation (predictor), and determining pathogenicity are generally recited and describe a mental process, a step that can easily be done in the human mind. Claims 7 and 28, provide further detail on how the abstract step of evolutionary conservation prediction occurs. Likewise, the limitations on classifying nucleotide variants as pathogenic or benign in claims 9-12 and estimating an evolutionary conservation in claim 28 also fall under the “Mental processes” groupings of abstract ideas. Dependent claim 6, further describes the data used in the abstract steps of claim 1.
The limitations on spatial configuration of non-gap amino acids, encoding spatial configurations, and excluding spatial of gap amino acid represent geometric and spatial mathematical operations for modeling molecular structures. Claim 8, describes a mental technique of ranking a score by magnitude. Claims 13 and 28 discuss the evolutionary conservation rained on a conserved and non-conserved training set which constitutes a mathematical calculation that can be performed mentally with pen and paper (e.g., linear regression, logistic regression, decision trees, k-means clustering), the subsequent dependent claims 14-19, 22, and 27 are claim elements that further limit the mathematical concept. Claims 20 and 21 describe determining the evolution conservation profiles using position-specific frequency matrix and position-specific scoring matrix that also involve math. The remaining limitations explicitly recite numerical formulas, values, and relationship that and all fall under the “Mathematical concepts” and “Mental processes” groupings of abstract ideas.
While claims 1, 29, and 30 recite performing some elements on a computer, computer memory, and computer readable media, there is there are no additional limitations that indicate improvement in the functioning of a generic computer nor requires anything other than carrying out the recited mental process or mathematical concept in a generic computer environment. Merely reciting that a mental process is being performed in a generic computer environment does not preclude the steps from being performed practically in the human mind or with pen and paper as claimed. If a claim limitation, under its broadest reasonable interpretation covers performance of the limitation in the mind but for recitation of generic computer components, then it falls within the “Mental processes” grouping of abstract ideas. As such claims 1-30 recite an abstract idea (STEP 2A, Prong 1: YES).
Step 2A, Prong 2
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further
analyzed to determine if the claims as a whole integrate the recited judicial exception into a
practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a
practical application because the claims do not recite an additional element that reflects an
improvement to technology or applies or uses the recited judicial exception in some other
meaningful way. Rather, the instant claims recite additional elements that amount to mere
instructions to implement the abstract idea in a generic computing environment or insignificant
extra-solution activity. Specifically, the claims recite the following additional elements:
Claims 1,29, and 30 use a computer-implemented method, a non-transitory computer readable storage medium and the computer.
There are no limitations that indicate that the processor, the storage, nor computer require anything other than a generic computing system. As such, these limitations equate to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984.
The above recited additional elements do not provide a practical application of the recited judicial exception. As such, claims 1-30 are directed to an abstract idea (Step 2A, Prong 2: NO).
Step 2B
Claims found to be directed to a judicial exception are then further evaluated to
determine if the claims recite an inventive concept that provides significantly more than the
judicial exception itself (Step 2B). The claims do not include additional elements that are
sufficient to amount to significantly more than the judicial exception because the claims recite
additional elements that equate to mere instructions to apply the recited exception in a generic
computing environment or well-understood, routine and conventional activity.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional element of a computer, computer memory, and computer readable media of claims 1, 29, and 30 are conventional computer components as recognized by the courts in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. MPEP 2106.05(d): “If, however, the additional element (or combination of elements) is no more than well-understood, routine, conventional activities previously known to the industry, which is recited at a high level of generality, then this consideration does not favor eligibility.” (STEP 2B: No). As such, claims 1-30 are not patent eligible.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 9-22, and 27-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11538555B1. in view of Sundaram et al. (Nature genetics, Vol. 50, pg. 1161-1175 (2018); IDS dated 2/09/2023). Although the claims at issue are not identical, they are not patentably distinct from one another for the following reasons:
With respect to independent claims 1,29, and 30 of the instant application, claims 1, 29, and 30 of U.S. Patent No. 11,538,555 B1 (the 'reference patent’ hereinafter) are substantially identical in scope regarding:
accessing a protein with amino acids at positions;
specifying a particular amino acid as a gap amino acid and others as non-gap amino acids;
generating a gapped spatial representation that:
includes non-gap amino acids, and
excludes the gap amino acid; and
using that representation to determine pathogenicity of nucleotide variants.
a non-transitory computer readable storage medium with instruction to determine pathogenicity
a system including one or more process, coupled to memory, the memory loaded with computer instructions to determine pathogenicity
The primary difference is that the reference patent explicitly recites a neural network pathogenicity predictor, whereas the instant application recites determining evolutionary conservation and using it to determine pathogenicity. However, this distinction does not render the claims patentably distinct. The difference between a neural network–based pathogenicity predictor ( reference patent), and an evolutionary conservation–based predictor (instant application), represents an obvious variation in predictive methodology as evidenced by Sundaram et al.
Sundaram teaches “For each variant, the pathogenicity prediction network takes as input the 51-length amino acid sequence centered at the variant of interest….outputs secondary structure (Fig. 3a and Supplementary Fig. 4) with the missense variant substituted in at the central position….. generated from multiple sequence alignments of 99 vertebrates, including 11 primates...50 mammals…and 38 vertebrates.” The neural network utilizes the evolutionary history of a protein to determine whether a missense variant is likely to be pathogenic or benign. A person of ordinary skill in the art would have understood that evolutionary conservation metrics are a well-known feature used in pathogenicity prediction, and such metrics can be implemented via statistical models, machine learning models, or neural networks (as described in specification). The motivation is found in Sundaram “Using hundreds of thousands of common variants from population sequencing of six non-human primate species, we train a deep neural network that identifies pathogenic mutations in rare disease patients with 88% accuracy”. Sundaram demonstrates here that an artisan in the field would have found success. Therefore, it is prima facie obvious.
Accordingly, substituting an explicit neural network model (as in the reference patent), with a conservation-based predictive framework (as in the instant application), constitutes a predictable variation and an obvious design choice, amounting to different computational pathways to achieve the same predictive result.
The limitations of claim 2 in the instant application and claim 2 in the reference patent are identical: “wherein the spatial configurations of the non-gap amino acids are encoded as amino acid class-wise distance channels, wherein each of the amino acid class-wise distance channels has voxel-wise distance values for voxels in a plurality of voxels, and wherein the voxel-wise distance values specify distances from corresponding voxels in the plurality of voxels to atoms of the non-gap amino acids.”
The limitations of claim 3 in the instant application and claim 3 in the reference patent are identical: “wherein the spatial configurations of the non-gap amino acids are determined based on spatial proximity between the corresponding voxels and the atoms of the non-gap amino acids.”
The limitations of claim 4 in the instant application and claim 4 in the reference patent are identical: “wherein the spatial configuration of the gap amino acid is excluded from the gapped spatial representation by disregarding distances from the corresponding voxels to atoms of the gap amino acid when determining the voxel-wise distance values.”
The limitation of claim 5 in the instant application and claim 5 in the reference patent are identical: “wherein the spatial configuration of the gap amino acid is excluded from the gapped spatial representation by disregarding spatial proximity between the corresponding voxels and the atoms of the gap amino acid.”
The limitation of claim 6 in the instant application and claim 6 in the reference patent are identical: “wherein the particular amino acid is a reference amino acid that is a major allele of the protein.”
Instant claim 7 and reference claim 7 are both similar in scope regarding a predictor that processes the gapped spatial representation and generates a score related to amino acid substitution. The primary distinction lies in the instant application being directed to an evolutionary conservation predictor while the reference patent is directed to a pathogenicity predictor. This limitation was known in the art, as shown by Sundaram et al. As disclosed above in instant claim 1, Sundaram teaches that evolutionary conservation is accounted for in pathogenicity prediction (Fig. 3a and Supplementary Fig. 4). Therefore, reference claim 7 anticipates instant claim 7.
Regarding instant claims 9-12, the claims contain contingent limitations that are not required to be met if the conditions precedent are not met (see MPEP 211.04); therefore, these claims are rejected for the same reasons as discussed above regarding instant claims 1 and 7.
Regarding instant claim 13, reference claim 8 and 18 teach a pathogenicity predictor trained on a benign and pathogenic training set. As discussed in instant claim 1, pathogenicity encompasses evolutionary conservation, therefore the reference claim 8 ‘benign’ training set reads on ‘conserved’ training set and reference claim 18 ‘pathogenic’ training set reads on ‘non-conserved training set’. This is demonstrated by Sundaram et al. “common missense variants in other primate species are largely clinically benign in human, enabling pathogenic mutations to be systematically identified by the process of elimination”.
Regarding instant claim 14, reference claims 9 and 19 teach a respective protein sample for the benign and pathogenic training set. For the same reasons discussed in instant claim 13, pathogenicity encompasses evolutionary conservation, therefore the reference claims 9 and 19 that teach a benign and pathogenic training set anticipates a ‘conserved protein sample’ and ‘non-conserved protein sample’.
Regarding instant claim 15, reference claims 9 and 19 teach that at each of the respective positions there are sets of benign and pathogenic samples for respective reference amino acids. For the same reasons discussed in instant claim 13, pathogenicity encompasses evolutionary conservation, therefore the reference claims 9 and 19 discussing benign and pathogenic sample reads on a “set of conserved and non-conserved amino acids”. In Sundaram the model demonstrates that amino acid substitutions occurring at highly conserved positions across primate species are much more likely to be clinically damaging (pathogenic) in humans. Conversely, variants that are common in primates are generally well-tolerated and clinically benign (pg. 1169 col. 1 para 3).
Regarding instant claim 16, reference claim 10 discloses respective reference amino acids are major allele amino acids of the proteome. However, the reference claims do not speak to wherein the set of conserved amino acid and least one major allele amino acid observed at the particular position across a plurality of species. This limitation was known in the art, as shown by Sundaram et al. Sundaram teaches observing common variants (major alleles) at particular variant position amongst different species, the variants must be conserved in order to compare them across a plurality of species(pg. 1167, col. 1, para 3; Fig 5d)
Regarding instant claim 17, the reference claims are silent to “wherein a particular set of conserved amino acids includes one or more minor allele amino acids observed at the particular position across the plurality of species. However, this was known in the art, before the effective filing date of the claimed invention, as shown by Sundaram. Sundaram discloses that rare singleton variants (minor alleles) that are observed only once in the cohort (plurality of species) closely match the expected 2.2:1 1 missense: synonymous ratio predicted by de novo mutation. They have to be conserved in order to observe in the cohort(pg. 1161, col. 2, para 2).
Regarding instant claim 18, reference claim 19 teaches pathogenic protein samples, which encompasses non-conserved amino acids. The reference claims are silent to “the particular position includes amino acids not in the particular set of conserved amino acids.” However, this was known in the art before the effective filing date of the claimed invention as shown by Sundaram. Sundaram teaches training the deep learning network to discriminate between a set of labeled benign variants and an unlabeled set of variants (pg. 1171, col.2, para 3).
Regarding instant claim 19, the reference claims are silent to “wherein the particular set of conserved amino acids and the particular set of non-conserved amino acids are identified based on evolutionary conservation profiles of homologous proteins of the plurality of species.” However, this was known in the art before the effective filing date of the claimed invention as shown by Sundaram. Sundaram teaches position weight matrix conservation profiles calculated from 99 vertebrate species with homologous sequences (depicted in Fig 3a), this is used as an input for the variant pathogenicity prediction model to identify whether the score produced is pathogenic or benign. The conserved regions will be identified by the benign scores, while non-conserved pathogenic scores (pg. 1164, Fig 3a).
Regarding instant claim 20, the reference claims are silent to “wherein the evolutionary conservation profiles of the homologous proteins are determined using a position-specific frequency matrix (PSFM).” However, this was known in the art before the effective filing date of the claimed invention as shown by Sundaram. Sundaram teaches position frequency matrices (PFMs) are generated from multiple sequence alignments of 99 vertebrates (pg. 1171, col. 2 para. 4).
Regarding instant claim 21, the reference claims are silent to “wherein the evolutionary conservation profiles of the homologous proteins are determined using a position-specific scoring matrix (PSSM).” However, this was known in the art before the effective filing date of the claimed invention as shown by Sundaram. Sundaram teaches “the network takes as input the human amino acid (AA) reference and alternate sequence (51 AAs) centered at the variant, the position weight matrix (PWM) conservation profiles calculated from 99 vertebrate species,” (Fig. 3).
Regarding instant claim 22, the reference claims are silent to “wherein the major allele amino acid is a reference amino acid.” However, this was known in the art before the effective filing date of the claimed invention as shown by Sundaram. Sundaram teaches the accepted variants as identical-by-state if they occurred in either reference/alternative orientation (pg. 1171 col.1 para 3).
Regarding instant claim 27, reference claims 12 and 22 are similar in scope to instant claim 27, the difference is that the instant application is directed to ‘conserved’ and ‘non-conserved’ protein samples whereas the reference is directed to ‘benign’ and ‘pathogenic’ protein samples. For the same reasons discussed above in claim 13, pathogenicity encompasses evolutionary conservation. Therefore, reference claims 12 and 22 anticipates instant claim 27.
Regarding instant claim 28, reference claim 14 and 24 are similar in scope to instant claim 28, the difference lies in that the instant application is directed to an evolutionary conservation predictor whereas the reference claim is directed to a pathogenicity predictor. As disclosed above in instant claim 1, Sundaram teaches that evolutionary conservation falls under pathogenicity prediction (Fig. 3a and Supplementary Fig. 4). Therefore, reference claims 14 and 24 anticipates instant claim 28.
It would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art with the reference claims to arrive at the claimed invention. Sundaram teaches “using hundreds of thousands of common variants from population sequencing of six non-human primate species, we train a deep neural network that identifies pathogenic mutations in rare disease patients with 88% accuracy”(Abstract). One of ordinary skill in the art would have understood that evolutionary conservation metrics are a well-known feature used in pathogenicity prediction, and such metrics can be implemented via statistical models, machine learning models, or neural networks (as described in specification). The motivation found in Sundaram demonstrates here that an artisan in the field would have found success. Therefore, it is prima facie obvious.
Claim 8 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11538555 B1 in view of Sundaram et al. (Nature genetics, Vol. SO, Z. 1161-1175 (2018); IDS dated 2/09/2023) as applied to instant claims 1-7, 9-22, and 27-30 above in further view of Zhang et al. (Amino Acids 35, 495—501 (2008)).
The reference patent claims and Sundaram et al. are silent to wherein the respective evolutionary conservation scores are rankable by magnitude. However, this was known in the art, before the effective filing date of the claimed invention, as shown by Zhang et al.
Zhang discloses a calculation for the residue evolutionary conservation, then further discloses ranking function that assigns a score to each of the residues concerned, and according to the scores they
can be sorted in the order of the presumably decreasing evolutionary pressure they experience (pg. 496-
497).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective
filling date of the claimed invention if some motivation in the prior art would have led that person to
combine the prior art teachings, to arrive at the claimed invention. Zhang discloses "the importance of a residue is reflected by its evolutionary conservation," (Zhang et al. pg. 495 col. 1 Para. 2). One skilled in the art would have had a reasonable expectation of success because Zhang and Sundaram both discuss conservation scores.
Claims 23-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11538555 B1 in view of Sundaram et al. (Nature genetics, Vol. SO, Z. 1161-1175 (2018); IDS dated 2/09/2023) as applied to instant claims 1-7, 9-22, and 27-30 above in further view of Ng et al. (Genome Research May 2001;11(5): pg. 863-74).
The reference claims 11 and 21 discuss the benign and pathogenic and Sundaram et al. do not teach:
wherein each of the respective positions has C conserved amino acids in the set of conserved amino acids, wherein each of the respective positions has NC non-conserved amino acids in the set of non-conserved amino acids, wherein the conserved training set has CP conserved protein samples, where CP = a number of the respective positions * C, and wherein the non-conserved training set has NCP non-conserved protein samples, where NCP = the number of the respective positions * (20-C) of instant claim 23.
The computer-implemented method of claim 23, wherein the C ranges from one to ten of instant claim 24.
The computer-implemented method of claim 24, wherein the C varies across the respective positions of instant claim 25.
wherein the C is same for some of the respective positions of instant claim 26.
However, this was known in the art, before the effective filing date of the claimed invention, as shown by Ng et al.
Regarding instant claim 23, Ng teaches evaluating each position in a multiple sequence alignment to determine which of the twenty standard amino acids are evolutionarily tolerated and which are not tolerated at that position. Ng recognizes that only a subset of amino acids is conserved at a given position, while the remaining amino acids are non-conserved substitutions. Thus, if a position contains C conserved amino acids, the remaining 20 − C amino acids represent non-conserved amino acids. (pg. 873 col. 1 para. 5; col. 2 para. 1, 2)
Regarding instant claim 24, Ng teaches “where c ranges from 1 to l and a is any one of the 20 amino acids” (pg. 873 col. 1 para. 2).
Regarding instant claim 25, Ng teaches that sequence conservation can differ from one alignment position to another (pg. 865 col. 1 para. 1; Figure 1)
Regarding instant claim 26, Ng teaches “At each position, the stack of letters indicates which amino acids appear in the alignment, and the total height of the stack is a measure of conservation”, this is illustrating the same conserved amino acid at respective positions (Figure 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective
filling date of the claimed invention if some motivation in the prior art would have led that person to
combine the prior art teachings, to arrive at the claimed invention. Ng teaches “Because SIFT uses sequence-specific information, it can distinguish between the conserved and variable positions to get better prediction performance”. One skilled in the art would have expectation of success because they are both analogous art pertaining to missense variants and conservation.
Therefore, the claims of the instant application are not patentably distinct from the claims of the reference patent because they constitute obvious variations of the same invention.
Conclusion
No claims are allowed.
The closest prior art of record, Sundaram et al (IDS document) discloses using hundreds of thousands of common variants from six primate species, to train a deep neural network to identify pathogenic mutations in humans by process of elimination. Sundaram further teaches a predicted pathogenicity score calculated at each amino acid position in the SCN2A gene, annotated for key functional domains. Plotted along the gene is the average PrimateAI score for missense substitutions at each amino acid position.
However, Sundaram does not disclose or make obvious generating a gapped spatial representation of the protein that includes spatial configurations of the non-gap amino acids, and excludes a spatial configuration of the gap amino acid nor determining an evolutionary conservation at the particular position of respective amino acids of respective amino acid classes based at least in part on the gapped spatial representation;
Additional prior art made of record and not relied upon is considered pertinent to applicant’s disclosure:
WON 2021 “3Cnet: pathogenicity prediction of human variants using multitask learning with evolutionary constraints” teaches a pathogenicity predictor, 3Cnet, that uses recurrent neural networks to analyze the amino acid context of human variants; trained on simulated variants reflecting evolutionary conservation and clinical data, it can find disease-causing variants in patient genomes with 2.2 times greater sensitivity than currently available tools (IDS document)
APRINO 2014 “Random Single Amino Acid Deletion Sampling Unveils Structural Tolerance and the Benefits of Helical Registry Shift on GFP Folding and Structure” teaches deletion mutations and registry shifts enhance proteins through structural rearrangements--not possible by substitution mutations alone.
CHOI 2012 “Predicting the Functional Effect of Amino Acid Substitutions and Indels” teaches alignment-based score measures the change in sequence similarity of a query sequence to a protein sequence homolog before and after the introduction of an amino acid variation to the query sequence; showing that the scoring scheme performs well in separating disease-associated variants (n = 21,662) from common polymorphisms.
HEIFETS 2019 (US 20190164021 A1) teaches protein classification and function
prediction using voxel maps of 3D structure, and a convolutional neural network
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/ABENA A ASIAMAH/Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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