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 .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 7-13, in the reply filed on 14 May 2026 is acknowledged.
Claims 1-6 and 14-22 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 14 May 2026.
Status of Claims
Claims 1-22 are pending.
Claims 1-6 and 14-22 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 7-13 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application, PCT/US2021/047025 filed 20 Aug. 2021 and U.S. Provisional App. No. 63/166,803 filed 26 March 2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Accordingly, the effective filing date for the instant application is 26 March 2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 17 June 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The application is in compliance with the requirements of 37 CFR 1.821 - 1.825.
Drawings
The drawings filed 13 May 2022 and 18 March 2022 are objected to for the following reasons:
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description: #800B, 800C, 801B, and 801C at para. [0213].
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. 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 in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 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 7-13 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, or for pre-AIA the applicant regards as the invention.
Claim 7, and claims dependent therefrom, are indefinite for recitation of “a non-coding gene such as a miRNA, tRNA, rRNA, or snoRNA”. In lines 2-3. Regarding claim 7, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For purpose of examination, the limitations following “such as” are not considered part of the invention, and the claim only requires identifying “a non-coding RNA gene”.
Claim 7, and claims dependent therefrom, are indefinite for recitation of “determining, based on a similarity score using a prediction algorithm, a genetic element…”. Due to a grammatical error in the phrase, it is not clear if the “using a prediction algorithm” is intended define how the similarity score was determined (i.e. based on a similarity score generated using a prediction algorithm), or if “using a prediction algorithm” is intended to modify how the determining a generic element is performed (i.e. determining, based on a similarity score and using a prediction algorithm..). Clarification is requested. For purpose of examination, the claim is interpreted to mean the similarity score was generated using a prediction algorithm.
Claim 7, and claims dependent therefrom, are indefinite for recitation of “the first similarity score of a normal genetic element and the second similarity score of a mutated genetic element of the non-coding RNA gene” in lines 7-9. There is insufficient antecedent basis for “the first similarity score of a normal genetic element” and “the second similarity score of a mutated genetic element of the non-coding RNA gene”, because claim 7 only previously recites “determining, based on a similarity score using a prediction algorithm, a genetic element…of the non-coding RNA gene”, but does not recite a first and second similarity score. It is not clear if claim 7 intends to require 3 different similarity scores, or if one of the first or second similarity score is intended to be the same as the “similarity score” recited in the second limitation.
Claim 8 is indefinite for recitation of “an allowable mono, di, tri or longer oligo-nucleotide and a disallowed mono, di, tri or longer oligo-nucleotide”. The term “allowable” and “disallowed” in claim 8 is a relative term which renders the claim indefinite. The terms are 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. In other words, the terms “allowable” and “disallowed” oligonucleotides are subjective terms, that depend on the purpose or goals of a user carrying out the invention. See MPEP 2173.05(b) IV. For purpose of examination, the claim is interpreted to mean the signatures are determined from a mono, di, tri, or longer oligo-nucleotide. Clarification is requested.
Claim 8 is indefinite for recitation of “graphically marking a mutation of the nucleotide string on the positive signature and the negative signature; and determining a deleterious effect of the mutation based on whether the mutation occurs within the positive signature or the negative signature”. If the determination of a deleteriousness effect is based on whether the mutation is in the positive signature or the negative signature (i.e. one or the other), it is unclear in what way a mutation is marked on both the positive signature and the negative signature. In other words, it is not clear if the mutation is intended to be on one of the negative or positive signature, or both the negative or positive signature (as suggested by the graphically marking limitation). Clarification is requested. For purpose of examination, the limitation is interpreted to mean graphically marking a mutation on the positive signature of the negative signature.
Claim 9 is indefinite for recitation of “the processing steps of the non-coding RNA gene”. There is insufficient antecedent basis for this limitation in the claim because claim 7, from which claim 9 depends, does not recite any processing steps of the non-coding RNA gene. As a result it is not clear what processing steps are being referenced.
Claim 9 recites “processing steps of the non-coding RNA gene into an active element”. The metes and bounds of an “active element” are not cleared. A review of the specification merely repeats the term, but does not serve to clarify the metes and bounds of the term. As a result it is not clear what is meant by an “active element”. Clarification is requested.
Claim 10 is indefinite for recitation of “the processing of the non-coding RNA gene” in line 3. There is insufficient antecedent basis for this limitation in the claim because claim 7, from which claim 10 depends, does not recite any processing of the non-coding RNA gene. As a result it is not clear what processing is being referenced.
Claim 10 is indefinite for recitation of “the non-coding RNA gene such as the miRNA, tRNA or rRNA”. Regarding claim 10, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For purpose of examination, the limitations following “such as” are not considered part of the invention, and the claim.
Claim 10 is indefinite for recitation of “constructing a position weight matrix (PWM) for regulatory…sequences…; and constructing the PWM for a processed functional non-cording RNA gene…; and constructing the PWM for the non-coding RNA gene…”. It is unclear if claim 10 intends to require constructing a single PWM, as suggested by reciting “the PWM” in the second and third limitations of the claim, or if the claim intends to require constructing a separate PWM for each of the “regulatory…sequences”, “processed functional non-coding RNA gene product”, and “the non-coding RNA gene”, as suggested by language specifying a PWM is “for” different elements in each of the three limitations. In light of Applicant’s specification at para. [0074], the claims are interpreted to mean a PWM is constructed for each of the different elements (i.e. the sequences, the processed functional non-coding RNA gene, and the non-coding RNA gene). Clarification is requested via claim amendment.
Claim 11 is indefinite for recitation of “the position weight matrix (PWM)”. There is insufficient antecedent basis for this limitation in the claim because claim 7, from which claim 11 depends, does not recite a position weight matrix.
Claim 11 is indefinite for recitation of “…, calculated from the position weight matrix (PWM)”. It is not clear what is intended to be calculated from the position weight matrix. For example, it is not clear if (1) Applicant intends for the difference between the first similarity score and the second similarity score to be calculated from the position weight matrix, (2) if Applicant intends for the deleteriousness score to be calculated from a position weight matrix, or (3) if Applicant intends for the non-coding RNA gene, regulatory, splicing recognition sequence elements, or a processed functional non-coding RNA product to be calculated from a position weight matrix. Applicant’s specification at para. [0125] discusses that motifs and elements that are targets of sequence specific promoter binding proteins and genes can be identified using PWM methods, and at para. [0137] and [0139] that enhancer and silencer motifs are determined based on PWM methods. Clarification is requested via claim amendment. For purpose of examination, the limitation is interpreted to mean that sequence elements were calculated from a position weight matrix, which is a product by process limitation. Clarification is requested via claim amendment.
Claim 12 is indefinite for recitation of “determining the similarity score” in lines 2 and 5. Claim 7, from which claim 12 depends, recites “a similarity score” in line 4, “the first similarity score” in line 7, and “the second similarity score” in line 8. As a result, it is not clear which similarity score, “the similarity score in claim 12 is referring to. Furthermore, it is not clear if claim 12 intends for “the similarity score” to be determined from an algorithm (as recited in lines 2-4) or to be determined from a modified algorithm (as recited in lines 5-7), or if these are intended to be different similarity scores. Clarification is requested.
Claim 12 is indefinite for recitation of “an algorithm selected from a group consisting of algorithms such as Shapiro-Senapathy algorithm…” in lines 2-4 and “a modified algorithm selected from a group consisting of algorithms such as Shapiro-Senapathy algorithm…” in lines 5-7. The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Furthermore, given claim 12 requires selecting an algorithm from a closes set of algorithms, if the limitations following “such as” are not part of the invention, it is further unclear what group of algorithms each algorithm is required to be selected from. Clarification is requested via claim amendment. For purpose of examination, the similarity score is determined using any algorithm or modified algorithm.
Claim 12 is indefinite for recitation of “characteristics of splicing element sequence signals such as length or variability” in lines 8-9. The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For purpose of examination, the limitations following the phrase are not interpreted to be part of the claimed invention.
Claim 12 is indefinite for recitation of “determining a combined score of the group of algorithms”. It is unclear if “the group of algorithms” is referring to the group of algorithms in line 3 or the group of algorithms in line 6 of claim 12. Furthermore, Given claim 12 previously recited determining the similarity score from an [modified] algorithm selected from a group consisting of algorithms…” in each of lines 2-3 and 5-6, it is further unclear if Applicant intends to require a score to be generated from each algorithm in the group of algorithms, as suggested by the “combined score of the group of algorithms” or if a score is generated from an algorithm selected from the group. Clarification is requested regarding what scores from what algorithms are being combined.
Claim 13 is indefinite for recitation of “multiple non-coding RNA genes of the same type”. The metes and bounds of non-coding RNA genes of the same type are not clear because it is unclear what the non-coding RNA genes are intended to be the same type as, and furthermore, claim 7 does not previously recite “a same type”. Clarification is requested.
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 7-13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claim 7 being representative) is directed to a method. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 7 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
identifying, in a nucleotide string, based on a chromosomal position, a non- coding RNA gene such as a miRNA, tRNA, rRNA, or snoRNA (mental process);
determining, based on a similarity score using a prediction algorithm, a genetic element comprising a regulatory, splicing, or a functional RNA element of the non-coding RNA gene (mental process and mathematical concept);
identifying, a difference between the first similarity score of a normal genetic element and the second similarity score of a mutated genetic element of the non- coding RNA gene (mental process and mathematical concept);
determining the causality of a phenotype by a sequence variant based on the difference between the first similarity score and the second similarity score (mental process); and,
graphically marking…the nucleotide string at a location indicative of an exon, an intron, regulatory, splicing or functional RNA element when the first similarity score or the second similarity score is higher or lower than, or equal to, a pre-selected threshold on a gene structure or sequence view (mental process).
The identified claim limitations falls into one of the groups of abstract ideas of mathematical concepts and/or mental processes for the following reasons. First, identifying a non-coding RNA gene in a nucleotide string based on chromosomal positions encompasses mentally evaluating a portion of a sequence (i.e. a nucleotide string) and determining a non-coding RNA gene in the sequence based on chromosomal positions of each nucleotide. Determining a genetic element based on a similarity score determined using a prediction algorithm, amounts to a mere analysis of information involving identifying a regulatory element that has a similarity score above some threshold. Identifying a difference between a first and second similarity score can be practically performed in the mind by performing subtraction; this limitation further recites the mathematical concept of a mathematical calculation (i.e. subtraction). Determining a causality of a phenotype by a sequence variant can be practically performed in the mind by analyzing known associations of variants and various phenotypes to determine that a sequence variant causes a phenotype. Last, graphically marking the nucleotide string at a specific location when the first or second similarity score is higher than, lower than, or equal to a threshold encompasses comparing a number to a threshold and then marking a sequence at a location of an exon via pen and paper. Overall, the above limitations are similar to a claim "collecting information, analyzing it, and displaying certain results of the collection and analysis," where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016). Other than reciting the steps are “computer-implemented”, nothing in the claims precludes the steps from being practically performed in the mind.
Dependent claims 8-13 further recite an abstract idea and/or further limit the abstract idea identified above. Dependent claim 8 further recites the mental process of identifying a positive and negative signature from various oligonucleotides, graphically marking a mutation of the nucleotide string on the negative and positive signature, and determining a deleterious effect based on analyzing whether the mutation occurs within the positive or negative signature. Dependent claim 9 further recites the mental process of depicting processing steps of the non-coding RNA gene into an active element, elaborating the processing steps in the gene structure or sequence view, indicating mutations and the processing steps at which a processing error occurs, and elaborating on a mechanism of aberrations causing a biological or clinical phenotype. Dependent claim 10 further recites the mental process and mathematical concept of construction a position weight matrix for regulatory elements, for a processing functional non-coding RNA gene product, and by aligning nucleotide sequences. Dependent claim 11 further recites the mental process of constructing a variable sequence signature based on a number or frequency of oligonucleotides at each position, the mental process and mathematical concept of determining a deleteriousness score based on the difference between the first similarity score and the second similarity score. Dependent claim 12 further recites the mental process and mathematical concept of determining the similarity score using two algorithms, and then determining a combined score based on an average or differentially weighted scores. Dependent claim 13 further recites the mental process of determining and graphically marking variable nucleotides by stacking a non-redundant oligonucleotide at each position of an additional nucleotide string, and the mental process and mathematical concept of applying a position weight matrix methodology for detecting multiple-non coding RNA genes. Therefore, claims 7-13 recite an abstract idea. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Dependent claims 8 and 10-13 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
The additional elements of claim 7 include:
a computer;
a display for a user;
The additional element of claim 9 includes:
displaying a recognition sequence, regulatory, splicing, or processed functional element on the gene structure.
The above additional elements only invoke the user of a computer and display to carry out the abstract idea identified above, and/or invoke a computer in its ordinary capacity to display information. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
Furthermore, the use of a display for a user only serves to generally link the abstract idea of marking a nucleotide string to the technological environment of computers. Limitations that amount to merely indicating a field of use or technological environment in which to apply a judicial exception cannot integrate a judicial exception into a practical application. See MPEP 2106.05(h).
Last, the step of displaying a recognition sequence, regulatory, splicing, or processed functional element on the gene structure only serves to output data generated by the abstract idea, which amounts to insignificant extra-solution activity and does not integrate the recited judicial exception into a practical application. See MPEP 2106.05(h).
Therefore, the additionally recited elements amount to insignificant extra-solution activity, amount to mere instructions to apply the exception, and/or generally link the abstract idea to a technological environment, and, as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 7-13 are directed to an abstract idea. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception.
The additional elements of claim 7 include:
a computer;
a display for a user;
The additional element of claim 9 includes:
displaying a recognition sequence, regulatory, splicing, or processed functional element on the gene structure.
The above additional elements only invoke the user of a computer and display to carry out the abstract idea identified above, and/or invoke a computer in its ordinary capacity to display information. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Therefore, taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 7-9 and 11-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jaganathan (2020).
Cited reference: Jaganathan et al. EP3622519 B1; Pub. Date: 18 March 2020.
Regarding claim 7, Jaganathan discloses a method for detecting splice sets, comprising the following steps:
Jaganathan discloses identifying long noncoding RNAs (i.e. a non-coding RNA gene) based on chromosomal position in a genome (i.e. in a nucleotide string) ([0100]; [0123], e.g. identify genetic locus; [0178], e.g. locus is long ncRNA; FIG. 42A-B, e.g. chr1…145-211…).
Jaganathan discloses determining a splicing RNA element of the non-coding RNA gene ([0178], e.g. splice junction predicted in lc ncRNA; FIG. 42A-B), based on a splice site score measuring similarity to known training donor/accepted splice sites, output using a trained neural network (i.e. a prediction algorithm) (claim 1; [0177]-[0178]; [0214], e.g. NN produces a score for a likelihood that a nucleotide in target is a donor splice site or acceptor splice site; FIG. 34).
Jaganathan discloses determining a difference between a splice site score for a reference sequence (i.e. a first similarity score of a normal genetic element) and a splice site score for an alternate sequence containing a variant for a given target locus (i.e. a second similarity score of a mutated genetic element of the ncRNA gene) ([0184]; FIG. 34; FIG. 38A).
Jaganathan discloses determining if the variant causes aberrant splicing, and therefore is pathogenic (i.e. the causality of a phenotype by a sequence variant), based on whether the difference in the splice site scores (i.e. the first similarity score and the second similarity score) is above a predetermined threshold (FIG. 34; [0262][0263]).
Jaganathan discloses marking the reference nucleotide string at a location indicative of a splicing RNA element where a splice-site predicted (FIG. 38; FIG. 41; FIG. 42, e.g. see “splice acceptor” and “splice donor” markings based on classifications), wherein the splicing RNA element is determined if its corresponding score is grater than a threshold (i.e. the marking occurs when a similarity score is higher than a threshold) ([0421]).
Regarding claim 8, Jaganathan discloses detecting a first differential splicing pattern in a reference target sub-sequence by classifying each nucleotide in the reference target sub-sequence as a donor splice site, an acceptor splice site, or a non-splicing site (i.e. a positive splicing signature) [0278]
Jaganathan discloses detecting a second differential splicing pattern in the variant target sub-sequence by classifying each nucleotide in the variant target sub-sequence as a donor splice site, an acceptor splice site, or a non-splicing site (i.e. a negative splicing signature) ([0279]).
Jaganathan discloses marking a splicing mutation in the nucleotide string on the second differential splicing pattern (i.e. the negative signature (FIG. 38A, e.g. see gray bar highlighting splicing mutation between mutant and wild type).
Jaganathan discloses determining a difference between the first differential splicing pattern (i.e. the positive signature) and the second differential splicing pattern (i.e. the negative signature) by comparing splice site classifications on a nucleotide-by-nucleotide basis to determine a delta score ([0280]; FIG. 38A, e.g. Δ). Jaganathan discloses if the difference is above a threshold (i.e. the mutation is in the negative signature and not the positive signature), the mutation is classified as causing aberrant splicing (i.e. a deleterious effect) and therefore pathogenic ([0280]).
Regarding claim 9, Jaganathan discloses displaying a splicing functional element on the gene structure (FIG. 38 and FIG. 42).
Jaganathan discloses depicting a visual representation of the non-coding RNA gene undergoing splicing (i.e. processing into an active element) (FIG. 41, e.g. “intron retention”, “exon skipping”, etc.; FIG. 39; [0387]).
Jaganathan discloses depicting the splicing (i.e. processing steps) in the gene structure or sequence view, including marking mutations in the sequence relative to the control and which introns were retained, which exons were skipped, and/or which exons were extended (FIG. 41, e.g. .see mutated vs control sequence with triangles indicating mutations, in addition to plots of coverage depicting splicing processing).
Jaganathan discloses elaborating on a variant causing a cryptic splice mutation and causing particular phenotypes such as delayed speech, autism, etc. (FIG. 41, see Table; [0202]).
Regarding claim 11¸Jaganathan discloses detecting a differential splicing pattern (i.e. interpreted to be a variable sequence signature, given splicing results in variable sequences) in a variant target sequence by classifying each nucleotide in the target sequence as a donor splice site, an acceptor splice site, or a non-splicing site ([0279]). Jaganathan discloses the splicing pattern is determined based on a number of mono-oligonucleotides at each position of the target from aligned sequences ([0233]; FIG. 29, e.g. input to model for detecting pattern is values representing each nucleotide of the target sequence; [0147], e.g. target sequence being encoded is determined from aligned reads)
Jaganathan discloses determining a delta score, wherein a delta score > 0.5 indicates a pathogenic variant (i.e. a deleteriousness score) (FIG. 34; [0262];[0263]) , using a difference between a splice site score for a reference sequence (i.e. a first similarity score of a normal genetic element) and a splice site score for an alternate sequence containing a variant for a given target locus (i.e. a second similarity score of a mutated genetic element of the ncRNA gene) ([0184]; FIG. 34; FIG. 38A). Regarding the limitation “calculated from the position weight matrix (PWM)”, as discussed above under 35 U.S.C. 112(b) this limitation is interpreted to be a product by process limitation, but there is not requirement that the claim calculates something (e.g. a genetic element) from a position weight matrix. Given the products are the same (e.g. the deleteriousness score, splicing element, and difference), Jaganathan discloses the limitation. See MPEP 2113 I.
Regarding claim 12, Jaganathan discloses determining a splice site score measuring similarity to training donor/accepted splice site, output using a trained neural network (i.e. a prediction algorithm) (claim 1; [0177]-[0178]; [0214], e.g. NN produces a score for a likelihood that a nucleotide in target is a donor splice site or acceptor splice site; FIG. 34; [0178], e.g. splice junction predicted in lc ncRNA; FIG. 42A-B).
Jaganathan discloses determining a splice site score measuring similarity to training donor/accepted splice site, output using a trained neural network (i.e. a prediction algorithm) (claim 1; [0177]-[0178]; [0214], e.g. NN produces a score for a likelihood that a nucleotide in target is a donor splice site or acceptor splice site; FIG. 30; FIG. 34; [0178], e.g. splice junction predicted in lc ncRNA; FIG. 42A-B).
Jaganathan discloses determining a combined score of the neural network based on differentially weighted scores (FIG. 1; FIG. 4, e.g. neural networks outputs combined scoring using weighted values from nodes in a previous layer; FIG. 30).
Therefore, Jaganathan anticipates the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 13 are rejected under 35 U.S.C. 103 as being unpatentable over Jaganathan (2020) in view of Mohanan.
Cited reference:
Jaganathan et al. EP3622519 B1; Pub. Date: 18 March 2020; and
Mohanan, Computational Analysis of Cryptic Splice Sites, 2017, SjSU ScholarWorks, pg. 1-53.
Regarding claim 13, Jaganathan discloses a method for detecting splice sets, comprising the following steps:
Jaganathan discloses identifying long noncoding RNAs (i.e. a non-coding RNA gene) based on chromosomal position in a genome (i.e. in a nucleotide string) ([0100]; [0123], e.g. identify genetic locus; [0178], e.g. locus is long ncRNA; FIG. 42A-B, e.g. chr1…145-211…).
Jaganathan discloses determining a splicing RNA element of the non-coding RNA gene ([0178], e.g. splice junction predicted in lc ncRNA; FIG. 42A-B), based on a splice site score measuring similarity to known training donor/accepted splice sites, output using a trained neural network (i.e. a prediction algorithm) (claim 1; [0177]-[0178]; [0214], e.g. NN produces a score for a likelihood that a nucleotide in target is a donor splice site or acceptor splice site; FIG. 34).
Jaganathan discloses determining a difference between a splice site score for a reference sequence (i.e. a first similarity score of a normal genetic element) and a splice site score for an alternate sequence containing a variant for a given target locus (i.e. a second similarity score of a mutated genetic element of the ncRNA gene) ([0184]; FIG. 34; FIG. 38A).
Jaganathan discloses determining if the variant causes aberrant splicing, and therefore is pathogenic (i.e. the causality of a phenotype by a sequence variant), based on whether the difference in the splice site scores (i.e. the first similarity score and the second similarity score) is above a predetermined threshold (FIG. 34; [0262][0263]).
Jaganathan discloses marking the reference nucleotide string at a location indicative of a splicing RNA element where a splice-site predicted (FIG. 38; FIG. 41; FIG. 42, e.g. see “splice acceptor” and “splice donor” markings based on classifications), wherein the splicing RNA element is determined if its corresponding score is greater than a threshold (i.e. the marking occurs when a similarity score is higher than a threshold) ([0421]).
Further regarding claim 13, Jaganathan does not disclose determining and graphically marking variable nucleotides by stacking a non- redundant mono, di, tri or longer oligo-nucleotides at each position of an additional nucleotide string from a multiple sequence alignment of multiple non-coding RNA genes of the same type; and, applying a position weight matrix (PWM) methodology using these oligo- nucleotides for detecting the multiple non-coding RNA genes and corresponding genetic elements.
However, Mohanan discloses a method of analyzing cryptic splice sites, which comprises determining and graphically marking variable nucleotides by stacking a nucleotide (i.e. a mono-nucleotide) at each position of additional nucleotide strings (pg. 6, para. 1-2; Figure 2, e.g. graphical marking of variable nucleotides; Figure 6). Mohanan further discloses determining a position weight matrix from the stacked oligonucleotides (pg. 7, para. 1-3; Figure 4, e.g. the PWM). Mohanan further discloses the PWMs may be used to identify authentic and cryptic splice sites, which can be utilized for further research to prevent the harmful effect of genetic diseases caused by mutations (pg. 49, para. 3-4).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Jaganathan to have determined and graphically marked variable nucleotides by stacking mono oligo-nucleotides and apply a position weight matrix to the oligonucleotides as claimed, as shown by Mohanan. One of ordinary skill in the art would have been motivated to combine the methods of Jaganathan and Mohanan in order to identify authentic and cryptic splice sites and aid in further research to prevent the harmful effect of genetic diseases caused by mutations, as shown by Mohanan (pg. 49, para. 3-4), given Jaganathan similarly analyzes splice sites in non-coding genes. This modification would have had a reasonable expectation of success because both Jaganathan and Mohanan analyze sequencing data to determine splice sites, and thus the methods of Mohanan complement those of Jaganathan.
Therefore, the invention is prima facie obvious.
Conclusion
No claims are allowed.
Claim 10 is free of the prior art. Claim 10 requires constructing a position weight matrix (PWM) for regulatory or splicing elements and recognition sequences, a PWM for a processed functional non-coding RNA gene for a type of the non-coding RNA gene, and a PWM for the non-coding RNA gene, thus requiring three separate position weight matrices corresponding to different genetic components.
Mohanan, cited in the 35 U.S.C. 103 rejection above, discloses a method of analyzing cryptic splice sites, which comprises determining a position weight matrix from the stacked oligonucleotides (pg. 7, para. 1-3; Figure 4, e.g. the PWM). Mohanan further discloses the PWMs may be used to identify authentic and cryptic splice sites, which can be utilized for further research to prevent the harmful effect of genetic diseases caused by mutations (pg. 49, para. 3-4). Mohanan discloses determining a PWM for random splice sites that are neither authentic or cryptic sites) (figure 9; pg. 17, para. 1), a PWM for neighboring splice cites (i.e. for splicing elements and recognition sequences for processing a non-coding gene), as well as a PWM for each of authentic and cryptic splice sites (Figure 6-8; pg. 15, para. 1 to pg. 16, para. 1). However, each of these various PWMs is determined for splice sites in pre-processed nucleic acid, and not for a processed functional non-coding RNA gene product for the non-coding RNA gene in addition to the for the non-coding RNA gene, in combination with the PWM for splicing elements and the limitations of claim 7.
It is noted the above statement is made with respect to the claim interpretation of claim 10 set forth under 35 U.S.C. 112(b) above.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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