DETAILED ACTION
Claim Status
Claims 1-11, 13-21 are rejected.
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 .
Priority
This application is a 371 of application #PCT/CN2022/083275, filed 03/28/2022. Domestic Benefit is acknowledged. Therefore, the effective filing date of claims 1-11 and 13-21 is 03/28/2022.
Information Disclosure Statement
The Information Disclosure Statement filed on 09/18/2023 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of list of references cited from each IDS is included with this Office Action. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings submitted on 03/21/2023 are accepted.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9, 17-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites the limitation "the targeted sequencing result" in paragraph 3, line 4. There is insufficient antecedent basis for this limitation in the claim. Claims 7 and 8 are dependent on claim 6, and repeat this limitation without resolving the issue. For these reasons claims 7 and 8 are thus additionally rejected.
The term “strongly supported split reads” in claims 2, 16, 18, and 20 is a relative term which renders the claim indefinite. The term “strongly supported split reads” 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. There is no standard for how the split reads are determined to be strongly supported.
The term “low quality” in claims 3, 17, 19, 21 is a relative term which renders the claim indefinite. The term “low quality” 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. There is no standard for what level of quality is considered low.
The term “proper aligner characteristic value” in claim 7 is a relative term which renders the claim indefinite. The term “proper aligner characteristic value” 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. There is no standard for what a proper value is and how it is distinguished from other values.
The term “similar” in claim 7 is a relative term which renders the claim indefinite. The term “similar” 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. There is no standard for what level of closeness is considered similar.
Claims 4-5 and 9 depend from rejected claims without resolving them, and are thus additionally rejected.
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 1-11, and 13-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
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:
1, 13, 14 15. (Currently Amended) A method for identifying a fusion gene, comprising: aligning the target gene sequencing sequence to the reference gene sequence, and acquiring distribution and targeted capturing results of spanning reads and split reads of the target gene sequencing sequence located in a target area; screening a target fusion gene pair from the reads based on the distribution and the targeted capture results;
2. (Original) The method according to claim 1, wherein the step of screening the target fusion gene pair from the reads based on the distribution and the targeted capture results comprises: calculating a breakpoint position of the read according to the number of the split reads and the number of strongly supported split reads; and screening the target fusion gene pair from the reads according to the breakpoint position and positions of the spanning reads.
3. (Original) The method according to claim 2, wherein the step of screening the target fusion gene pair from the read according to the breakpoint position and the positions of the spanning reads comprises: filtering a read that does not have the supported spanning read, at the upstream and downstream of the breakpoint position included in the read; regarding the reads reserved after filtration as candidate fusion gene pairs in the case that the first end and the second end of the read reserved after filtration are located in different genes; and filtering a low-quality fusion gene pair in the candidate fusion gene pairs to obtain the target fusion gene pair.
4. (Original) The method according to claim 3, wherein the step of filtering the low-quality fusion gene pair in the candidate fusion gene pairs to obtain the target fusion gene pair comprises: filtering paralogous genes in the candidate fusion gene pairs to obtain first candidate fusion gene pairs; calculating a number of gene mappings contained in the first candidate fusion genes; filtering the first candidate fusion gene pairs in which the number of the gene mappings is greater than or equal to a number threshold of gene mappings to obtain a second candidate fusion gene pair; calculating a fusion gene score of the second candidate fusion gene pair according to a distance between the breakpoint positions of the second candidate fusion gene pair, and an average sequencing depth in the target area; and filtering the second candidate fusion gene pair whose fusion gene score is less than a fusion gene score threshold to obtain the target candidate fusion gene pair.
5. (Original) The method according to claim 4, wherein the step of calculating the fusion gene score of the second candidate fusion gene pair according to the distance between the breakpoint positions of the second candidate fusion gene pair, and the average sequencing depth in the target area, comprises: solving a difference between a sum of the distances between the spanning read in the second fusion gene pair and two breakpoints, and a peak value of an insert length of a genome methylated sequencing sequence, as a first factor score; regarding a ratio of distances between two ends of the spanning read in the second fusion gene pair and the breakpoint position to a length of the read as a second factor score; regarding a ratio of distances between two ends of the split read in the second fusion gene pair and the breakpoint position to a multiplication length of the read as a third factor score, wherein the multiplication length is a product of the length of the read and a multiplication parameter; and regarding a ratio of a sum of the first factor score, the second factor score and the third factor score to the average sequencing depth in the target area as the fusion gene score of the second candidate fusion gene pair.
6. (Original) The method according to claim 2, wherein the step of aligning the target gene sequencing sequence to the reference gene sequence, and acquiring the distribution and targeted capturing results of the spanning reads and split reads of the target sequencing sequence located in the target area comprises: aligning the target gene sequencing sequence to the reference gene sequence to obtain an alignment result; and screening the spanning reads from the targeted sequencing result based on the alignment result in spanning read screening conditions, and screening the split reads and the strongly supported split reads from the targeted sequencing result based on the alignment result in split read screening conditions.
7. (Original) The method according to claim 6, wherein the step of screening the spanning reads from the targeted sequencing result based on the alignment result in the spanning read screening conditions comprises: screening a spanning read that meets the following spanning read screening conditions at the same time from the reads: a sum value obtained by summing a length of a left-end read, a length of a right-end read and a distance between the left-end read and the right-end read of the read is greater than a product of the lower quartile of a length of the read and a target parameter, wherein the target parameter is a parameter that controls a number of outputted mappings and degree of stringency; neither the left-end read nor the right-end read in the reads has a similar sequence; and multiple alignment values of the left-end read and the right-end read in the reads comprise a proper aligner characteristic value and a secondary alignment characteristic value, and does not include a segment unmapped characteristic value and a next segment unmapped characteristic value.
8. (Original) The method according to claim 6, wherein the step of screening the split reads and the strongly supported split reads in the targeted sequencing result based on the alignment result in the split read screening conditions, comprises: screening a split read that meets the following split read screening conditions at the same time from the reads: an alignment length of each position in the read is greater than a length threshold, and the alignment length is greater than one-third of a total length of the read; a sequence whose length of the read is the alignment length has no similar sequence in the alignment result; and a quality value of a number of alignment times of the read is greater than or equal to a number of alignment times; and determining the split read that meets the above split read conditions, in the case that alignment positions of the left-end read and the right-end read overlap, to be a strongly supported split read.
9. (Original) The method according to claim 2, wherein the step of calculating the breakpoint position of the read according to the number of the split reads and the number of the strongly supported split reads comprises: regarding a maximum value of a weighted sum of the number of the split reads and the number of the strongly supported split reads in the reads as the breakpoint position.
10. (Original) The method according to claim 1, wherein, before acquiring the target gene sequencing sequence to be identified and the reference gene sequence, the method further comprises: counting a base number, base quality and base lengths in the obtained target gene sequencing sequence; and identifying sequences to be filtered in the targeted gene sequencing sequence according to the base number, the base quality and the base lengths, and filtering the sequences to be filtered.
11. (Currently Amended) The method according to claim 10, wherein the step of identifying the sequences to be filteredlinker sequences in the target gene sequencing sequence according to the number of the bases, the quality of the bases and the lengths of the bases comprises: regarding sequencing sequences whose base quality is a quality threshold, minimum base length is a base length threshold, and average quality value of the sequencing sequence is lower than the quality threshold, as the sequences to be filtered; and supplementing a sequencing sequence containing a left-end sequencing sequence or a right- end sequencing sequence whose overlap degree with the sequences to be filtered linker sequence reaching a preset degree, to the sequences to be filtered.
16. (New) The computing processing device according to claim 13, wherein the operation of screening the target fusion gene pair from the reads based on the distribution and the targeted capture results comprises: calculating a breakpoint position of the read according to the number of the split reads and the number of strongly supported split reads; and screening the target fusion gene pair from the reads according to the breakpoint position and positions of the spanning reads.
17. (New) The computing processing device according to claim 16, wherein the operation of screening the target fusion gene pair from the read according to the breakpoint position and the positions of the spanning reads comprises: filtering a read that does not have the supported spanning read, at the upstream and downstream of the breakpoint position included in the read; regarding the reads reserved after filtration as candidate fusion gene pairs in the case that the first end and the second end of the read reserved after filtration are located in different genes; and filtering a low-quality fusion gene pair in the candidate fusion gene pairs to obtain the target fusion gene pair.
18. (New) The computer program product according to claim 14, wherein the operation of screening the target fusion gene pair from the reads based on the distribution and the targeted capture results comprises: calculating a breakpoint position of the read according to the number of the split reads and the number of strongly supported split reads; and screening the target fusion gene pair from the reads according to the breakpoint position and positions of the spanning reads.
19. (New) The computer program product according to claim 18, wherein the operation of screening the target fusion gene pair from the read according to the breakpoint position and the positions of the spanning reads comprises: filtering a read that does not have the supported spanning read, at the upstream and downstream of the breakpoint position included in the read; regarding the reads reserved after filtration as candidate fusion gene pairs in the case that the first end and the second end of the read reserved after filtration are located in different genes; and filtering a low-quality fusion gene pair in the candidate fusion gene pairs to obtain the target fusion gene pair.
20. (New) The non-transitory computer-readable medium according to claim 15, wherein the operation of screening the target fusion gene pair from the reads based on the distribution and the targeted capture results comprises: calculating a breakpoint position of the read according to the number of the split reads and the number of strongly supported split reads; and screening the target fusion gene pair from the reads according to the breakpoint position and positions of the spanning reads.
21. (New) The non-transitory computer-readable medium according to claim 20, wherein the operation of screening the target fusion gene pair from the read according to the breakpoint position and the positions of the spanning reads comprises: filtering a read that does not have the supported spanning read, at the upstream and downstream of the breakpoint position included in the read; regarding the reads reserved after filtration as candidate fusion gene pairs in the case that the first end and the second end of the read reserved after filtration are located in different genes; and filtering a low-quality fusion gene pair in the candidate fusion gene pairs to obtain the target fusion gene pair.
The limitations for “calculating,” “filtering,” “regarding,” “determining,” and “counting” all refer to a series of mathematical transformations and algorithmic steps made to a set of sequencing data. The limitations are recited so broadly that in some embodiments a human being with a pen and paper could make these data transformations and arrive at the results. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. The limitations for “aligning” and “screening” are so broadly recited that in some embodiments a human being could take these steps in their mind with the aid of a pen and paper. Therefore, these limitations fall only under the “mental process” grouping of abstract ideas. While claims 1-4, 6-15, 17-18 and 20 recite performing some aspects of the analysis with a “computing processing device,” “computer program product”, or “non-transitory computer-readable medium”, there are no additional limitations that indicate that this “computing processing device,” “computer program product”, or “non-transitory computer-readable medium” 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 the recitation of generic computer components, then if falls within the “Mental processes” grouping of abstract ideas. As such, claims 1-11, 13-21 recite an abstract idea ( Step 2A, Prong 1 : YES).
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 to effect a particular treatment for a condition. Rather, the instant claims recite additional elements that amount to mere instructions to implement the abstract idea in a generic computing environment or mere instructions to apply the recited judicial exception via a generic treatment. Specifically, the claims recite the following additional elements:
13. (Currently Amended) A computing processing device, comprising: a memory, configured to store a computer-readable code therein; and one or more processors, when the computer-readable code is executed by the one or more processors, causes the computing processing device to execute the method for identifying the fusion gene operations according to claim 1.
14. (Currently Amended) A computer program product, comprising a computer-readable code, which when being operated on the computing processing device, causes the computing processing device to execute the method for identifying the fusion gene according to claim 1
15. (Currently Amended) A non-transitory computer-readable medium, storing a computer program therein for performing the method for identifying the fusion gene according to claim 1.
1. acquiring a target gene sequencing sequence to be identified and a reference gene sequence;
1. and outputting an identification result regarding the target fusion gene pair.
There are no limitations that indicate that the claimed “computing processing device,” “computer program product”, or “non-transitory computer-readable medium” or the formats of the provided data require anything other than generic computing systems. 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 steps for acquiring the sequence and outputting the result are “mere data gathering” and “mere data output” steps, similar to Storing and retrieving information in memory, Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93. As such, claims 1-11, 13-21 are directed to an abstract idea ( Step 2A, Prong 2 : NO).
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 way or in a generic computing environment. The instant claims recite additional elements enumerated above, in the section on step 2A.
The steps for acquiring the sequence data and outputting the result are well-understood, routine, and conventional activity, similar to storing and retrieving information in memory, Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93. As discussed above, there are no additional limitations to indicate that the claimed “computing processing device,” “computer program product”, or “non-transitory computer-readable medium” requires anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself ( Step 2B : No). As such, claims 1-11, 13-21 are not patent eligible.
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.
Claim(s) 1-3 and 13-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by McPherson et al. (PLoS Computational Biology May 2011 | Volume 7 | Issue 5, henceforth “McPherson”).
Regarding claim 1, McPherson teaches acquiring a target and reference gene sequences (pg 2 right col ¶ 4). Sequence alignment is performed (abstract).
An “inferred fragment length distribution”, equivalent to the “distribution” of the instant application, is derived from the alignment in a target area in Mcpherson (pg 5 left col ¶ 1).
McPherson compares the targeted, captured results of spanning reads and split reads in a certain area to screen a gene fusion pair (pg 4 right col ¶ 1). An identification is produced as output (abstract).
Regarding claim 2, a breakpoint position is calculated based on the positions and number of spanning reads as well as the number of split reads (pg 4 left col ¶ 1-2, fig. 1).
Regarding claim 3, McPherson filtered reads without supporting spanning reads at the upstream and downstream of the breakpoint position (pg 8 left col ¶ 4). McPherson used location of read ends in different genes as candidate fusion gene pairs (pg 7 left col ¶ 3). Low-quality gene fusions were filtered out (pg 8 left col ¶ 5).
Claims 13 and 16-17, claims 14 and 18-19, and claims 15 and 20-21 are each restatements of claims 1-3, recited as occurring on a “computing processing device,” a “computer program product,” and a “non-transitory computer-readable medium,” respectively. McPherson teaches computer implementations of the method (pg 8 left col ¶ 3). The arguments against claims 1-3 apply, mutatis mutandis.
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.
Claims 6-11are rejected under 35 U.S.C. 103 as being unpatentable over McPherson as applied to claims 1-3 and 13-21 above, and in further view of Kumar et al. (Wiley Interdiscip Rev RNA. 2016 November ; 7(6): 811–823, henceforth “Kumar”).
McPherson teaches the limitations these claims are dependent upon. Regarding claim 6, aligning a target sequence to a reference is taught by Kumar, and split reads and spanning reads are screened from the result (pg 3 ¶ 3) (fig. 2).
Regarding claim 9, Kumar describes a workflow where a weighted sum of split reads and supported split reads are used to calculate a breakpoint position (page 6 ¶ 2).
Regarding claim 10, Kumar suggests using base number, quality and length for filtering out sequences (pg 6 ¶ 2) (pg 4 ¶ 4).
Regarding claim 11, Filtering based on a threshold of base number, quality and length is suggested by Kumar (pg 6 ¶ 2) (pg 4 ¶ 4). A sequence to be filtered will always overlap with itself.
Regarding claims 1-3, 6, 9-11, 13-21, an invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching, suggestion, or motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a suggestion to use multiple filters for spanning and split reads in the text of Kumar (pg 5 ¶ 3). There would be a reasonable expectation of success in making this combination to a person of ordinary skill in the art, as the filters and the different fusion gene identification algorithms are explained and cited in Kumar, and McPherson is directed to fusion gene identification as well. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of McPherson by adding new filters, in order to find breakpoints more accurately (abstract).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over McPherson and Kumar as applied to claims 1-4, 6, 9-11, 13-21 above, and further in view of Heydt et al. (BMC Med Genomics (2021) 14:62, henceforth “Heydt”).
Regarding claim 4, filtering paralogous genes is taught by Kumar (pg 8 ¶ 3). Filtering based on distance between candidate pairs using a threshold is taught by Kumar (pg 5 ¶ 3). Kumar is silent as to a numerical threshold of gene mappings. A numerical threshold of gene mappings is taught by Heydt (pg 7 left col ¶ 1).
Regarding claim 4, An invention would have been prima facie obvious to one of ordinary
skill in the art at the time of the effective filing date of the invention if some teaching, suggestion, or motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a teaching to use a numerical threshold of gene mappings in the text of Heydt, in order to find gene fusions more accurately (pg 7 left col ¶ 1). There would be a
reasonable expectation of success in making this combination to a person of ordinary skill in the art, as all are gene fusion identification algorithms. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of McPherson and Kumar by employing the numerical threshold of gene mappings from Heydt, in order to in order to arrive at more accurate gene mappings (pg 7 left col ¶ 1).
Conclusion
The limitations for “solving,” “screening,” and “determining” in claims 5, 7 and 8, respectively, were found to be free from the prior art under 35 U.S.C. § 103, but the applicant is reminded that the rejections under 35 U.S.C. § 101 still apply.
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/G.M.H./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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