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 .
Applicant Response
Applicant's response, filed 09/18/2025, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claim 1-26 are pending and under examination herein.
Claims 1-26 are rejected.
Priority
The instant application is the National Stage entry of PCT/EP2018/068523, International Filing Date: 07/09/2018, which claims the benefit of foreign priority to 17182324.8, filed 07/20/2017. As such, the effective filing date assigned to each of claims 1-26 is 07/20/2017. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings were accepted by the examiner in the office action mailed 01/16/2020.
Claim Rejections - 35 USC § 101
MAINTAINED REJECTIONS:
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 1-26 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea/law of nature/natural phenomenon without significantly more. Newly recited portions are necessitated by claim amendments.
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 and a law of nature or natural phenomenon:
Claim 1 recites (a) aligning nucleic acid sequencing reads obtained from massively parallel sequencing of one or more genomic regions of the sample to the reference sequence; (b) selecting nucleic acid sequencing reads which only partially map to the reference sequence, wherein each of the selected nucleic acid sequencing reads comprises a portion at the start or at the end of the nucleic acid sequencing read that remains unmapped and that comprises a soft-clipped region of at least 8 nucleotides, wherein one or more of the at least 8 nucleotides of the soft-clipped region do not correspond with respective nucleotides of the reference sequence; (c) creating groups of the nucleic acid sequencing reads with the soft-clipped regions wherein each group is defined by an identical start position of the soft-clipped region at the end of the nucleic acid sequencing reads in the group or an identical end position of the soft-clipped region at the start of the nucleic acid sequencing reads in the group; (d) generating a synthetic consensus sequence for each group as obtained in step (c) by selecting the most abundant nucleotide at each position of the soft-clipped regions within each group and obtaining synthetic consensus sequences for all the groups created in step (c); (e) generating combinations of positions between the groups of the nucleic acid sequencing reads comprising the soft-clipped region at the start of the nucleic acid sequence and the groups of nucleic acid sequencing reads comprising the soft- clipped region at the end of the nucleic acid sequence reads by repeatedly comparing the synthetic consensus sequences of step (d) with the reference sequence; (f) detecting the structural genomic rearrangement by detecting that both synthetic consensus sequences of the pair obtained in step (e) match at the respective positions in the reference sequence and comprise a distance between the soft-clipped region at the start of the synthetic consensus sequence and the soft-clipped region at the end of the synthetic consensus sequence relative to the reference sequence of less than 100 kilobases (kb).
Claim 2 recites wherein the structural genomic rearrangement is a deletion, a duplication or an inversion of a length between 10 basepairs and 100,000 basepairs.
Claim 3 recites wherein each of the soft-clipped regions is at least 8 to 15 nucleotides long.
Claim 4 recites wherein the aligning and the comparing are performed with a string matching algorithm.
Claim 5 recites wherein the nucleic acid sequencing reads obtained from massively parallel sequencing is provided in a format providing information on alignment and the soft-clipped regions.
Claim 6 recites where the nucleic acid sequencing reads have a length of about 50 nucleotides to 50 kb.
Claim 8 recites wherein, in step (c), the groups which comprise less than a predefined number of members are discarded.
Claim 9 recites wherein said predefined number of members is 1, 2, 3, 4, 5, 6, 7 or 8.
Claim 10 recites wherein each of the synthetic consensus sequence is identical to a predefined number of sequencing reads in the group of nucleic acid sequencing reads as defined in step (c).
Claim 11 recites wherein said predefined number of sequencing reads is 1, 2, 3, 4 or more.
Claim 12 recites wherein, in step (e), combinations of positions between groups of nucleic acid sequencing reads comprising repetitive consensus sequences and/or a distance between the soft-clipped positions of the nucleic acid sequencing reads with respect to the reference sequence of more than 35 kb are discarded from further analysis.
Claim 13 recites further comprising determining sequencing depth at a position of the detected structural genomic rearrangement in the nucleic acid molecule and/or determining a position of the detected structural genomic rearrangement with respect to an annotated functional information.
Claim 14 recites wherein the structural genomic rearrangement detected in step (f) represent: (i) a duplication, when the nucleotide number in the reference sequence of the end position of the soft-clipped regions of at the start of the matched synthetic consensus sequences is smaller than the nucleotide number in the reference sequence of the start position of the soft-clipped regions at the end of the matched synthetic consensus sequences; (ii) a deletion, when the nucleotide number in the reference sequence of the end position of the soft-clipped regions at the start of the matched synthetic consensus sequences is larger than the start position of the soft-clipped regions at the end of the matched synthetic consensus sequences; or (iii) an inversion, when both members of the pair of said synthetic consensus sequences have the soft-clipped region at the start of the matched synthetic consensus sequences, or when both members of the pair have the soft- clipped region at the end of the matched synthetic consensus sequences.
Claim 15 further recites wherein the sample is from a patient with cancer.
Claim 19 recites wherein said cancer is breast cancer, prostate cancer, ovarian cancer, renal cancer, lung cancer, pancreas cancer, urinary bladder cancer, uterus cancer, kidney cancer, brain cancer, stomach cancer, colon cancer, melanoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), glioblastoma or hematological leukemia and lymphomas, both from the myeloid and lymphatic lineage.
Claim 20 recites providing the report to a patient or to another person or entity, a caregiver, a physician, an oncologist, a hospital, clinic, third party payor, insurance company or government office.
Claim 21 recites wherein the report comprises one or more of (i) output from the method, comprising the identification of the structural genomic rearrangement or wild-type sequence associated with a tumor of the type of the sample; (ii) information on the role of a genomic alteration, or corresponding wild-type sequence, in a disease, wherein said information comprises information on prognosis, resistance, or potential or suggested therapeutic options; (iii) information on the likely effectiveness of a therapeutic option, the acceptability of the therapeutic option, or the advisability of applying the therapeutic option to a patient having a structural genomic rearrangement identified in the report; or (iv) information, or a recommendation on the administration of a drug, the administration at a preselected dosage, or in a preselected treatment regimen, in combination with other drugs, to the patient; (v) wherein not all structural genomic rearrangements identified in the method are specified in the report, and the report can be limited to alterations in genes of clinical relevance.
Claim 23 recites wherein the annotated functional information comprises a gene name or a location in an intron, exon, promoter, enhancer, telomere, pseudogene, or in a repetitive region.
Claim 24 recites wherein detecting the structural genomic rearrangement comprises detecting a breakpoint in the nucleic acid molecule relative to the reference sequence.
These recitations equate to steps of collecting information, analyzing data and making observations, evaluations and judgements that can be carried out in the human mind. Specifically, aligning reads obtained from massively parallel sequencing of genomic regions to reference sequences, selecting reads that only partially map to the reference sequence and comprises a soft-clipped region of at least 8 nucleotides long, creating groups of reads with the soft-clipped regions defined by the position of the soft-slipped read at the end of the nuclei acid sequencing or identical end positions of the soft-clipped regions at the start of the read, generating a synthetic consensus sequence for each group by selecting the most abundant nucleotide at each position of the soft-clipped regions within each group, obtaining synthetic consensus sequences for all groups, repeatedly comparing the synthetic consensus sequence to the reference sequence until a pair of the synthetic consensus sequences with soft-clipped regions which match at respective positions in the reference sequence is detected and generating combinations of positions between groups, detecting the structural genomic rearrangement when both synthetic consensus sequences of the pair match at respective positions in the reference sequence and comprise a distance between the soft-clipped region at the start of the synthetic consensus sequence and the soft-clipped region at the end of the synthetic consensus sequence relative to the reference sequence of less than 100 kilobases (kb), discarding groups with less than a predefined number of members discarding combinations of positions between groups with distance greater than 35kb to the reference sequence, and determining sequencing depth at the position of the detected structural genomic rearrangement or determining a position of the detected structural genomic rearrangement with respect to an annotated functional information can be practically performing the human mind as claimed and are similar to the concepts of collecting and comparing known information in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011) and collecting information, analyzing it, and reporting certain results of the collection and analysis in Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016) that the courts have identified as concepts that can be practically performed in the human mind. Therefore, each of the above recited limitations fall under the “Mental Processes” grouping of abstract ideas. Furthermore, the steps as claimed of providing a report to a patient or to another person or entity, a caregiver, a physician, an oncologist, a hospital, clinic, third party payor, insurance company or government office equate to the social activity of providing information to a person without interfering with the person’s primary activity as found in Interval Licensing LLC, v. AOL, Inc., 896 F.3d 1335, 127 USPQ2d 1553 (Fed. Cir. 2018), and therefore these limitations fall under the “Certain Methods Of Organizing Human Activity” grouping of abstract ideas. Claims 15-21 also recite a natural correlation between the presence of structural variants and response to a cancer therapy, and therefore fall under the “Laws of Nature or Natural Phenomena”. Claims 2-6, 9-11, 14, 19, 21 and 23-24 further qualify the judicial exceptions. As such, claims 1-26 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 affect a particular treatment for a condition. Rather, the instant claims recite additional elements that amount to mere data gathering and outputting, and mere instructions to implement the abstract idea in a generic computing environment:
Claim 1 recites (h) reporting the structural genomic rearrangement of greater than 5 nucleotides, with exact location of breakpoint in the nucleic acid molecule, and comprising a deletion, a duplication, or an inversion in an electronic, web-based, or paper form.
Claim 7 recites wherein, in the nucleic acid sequencing reads comprising the soft- clipped sequencing reads obtained in step (b), information on the position of mapped portion of said reads is stored electronically.
Claim 16 recites comprising a preparation step for the nucleic acid molecule, which precedes step (a), comprising a hybrid-capture based nucleic acid enrichment for a genomic region of interest.
Claim 17 recites wherein said genomic region of interest is a gene or region known to be relevant in cancer.
Claim 18 recites wherein said sample comprises one or more premalignant or malignant cells; cells from a solid tumor, soft-tissue tumor or a metastatic lesion; tissue or cells from a surgical margin; a histologically normal tissue obtained in a biopsy; one or more circulating tumor cells (CTC); a normal, adjacent tissue (NAT) from a subject having a tumor or being at risk of having a tumor; or a blood, plasma or serum sample from a subject having a tumor or being at risk of having a tumor; or an paraffin or formalin-fixed paraffin-embedded (FFPE) tumor sample.
Claim 22 recites wherein the format comprises Binary Alignment Map (BAM) or Compressed Columnar File Format (CRAM).
Claim 25 recites wherein the format comprises Sequence Alignment Map (SAM).
Claim 26 recites wherein the string matching algorithm is Burrows-Wheeler Aligner (BWA).
Claims 2-6, 8-15, 19-21, and 23-24 do not recite any elements in addition to the recited judicial exception. Claim 16 recites limitations of how data is gathered and claims 17-18, 22 and 25-26 further recite limitations on the type of data gathered. These limitations equate to selecting a particular data source or type of data to be manipulated to perform the mental evaluations and judgements (see MPEP 2106.05(g)). Claim 1 recites limitations on data outputting. There is no indication that any of these additional elements provide a practical application of the recited judicial exception outside of the judicial exception itself. Claims 7, 22 and 25 also merely recite storing data electronically and using digital data formats and claim 26 recites using a computer program to perform abstract ideas, which equate to using a generic computing systems and computer program products to carry out instructions to implement an abstract idea on a computer. The computer program product as claimed fails to recite details of how a solution to a problem is accomplished and only recites the idea of a solution or outcome. There are no limitations that indicate that the claimed steps 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. Furthermore, 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 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).As such, claims 1-26 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). Further analyzing the additional elements under step 2B, the additional elements as described above do not rise to the level of significantly more than the judicial exception. As directed in the Berkheimer memorandum of 19 April 2018 and set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims under the 2B analysis, the instant specification discloses that a hybrid-capture based nucleic acid enrichment for a genomic region of interest as a preparation step for nucleic acid molecules for sequencing is well-known and conventional in the art (p 32, line 4-28). Furthermore, the prior art to Zhongwu Lai et al. (01/17/202 IDS, NPL ref #11; previously cited; hereafter referred to as Zhongwu) and Holland et al. (Forensic Science International: Genetics 2017, 28, 90-98; previously cited; hereafter referred to as Holland) disclose obtaining massively parallel sequencing information is a data gathering element that is routine, well-understood and conventional in the art (Zhongwu, abstract and p 2, col 1, para 1-2; Holland, abstract). Holland further discloses performing massively parallel nucleic acid sequencing and saving the output electronically (p 91, col 1, para 2-col 2, para 4). Guan and Sung (Methods 2016, 102, pp.36-49; previously cited) reviews structural variation detection using next-generation sequencing data and discloses that storing sequencing reads in SAM/BAM format and aligning reads with generic read mappers such as BWA is conventional in the art (title; p 40, col 1, para 4-5; p 40, col 2, para 5). The instant specification discloses BWA is well-understood, routine and conventional in the art (p 17, lines 26-28). Zhongwu further discloses receiving the data as a BAM file and using their program to detect tumor DNA for PCR-based targeted sequencing in diagnostic settings (abstract; p 2, col 1, para 1-2). Furthermore, Zhongwu and Holland both disclose outputting data on the structural genomic rearrangement (Zhongwu, fig 4 and table 2; Holland fig 5). As such, activities such as data gathering and outputting do not provide a non-conventional or unconventional step. Rather, the data gathering and outputting steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
Furthermore, the computer system limitations of claims 7 and 22 are generically recited and are well-understood, routine, conventional activities, as evidenced by Zhongwu and Holland. Zhongwu’s and Holland’s methods are inherently computer implemented as they utilize computer software and computer file formats (Zhongwu, abstract and p 2, col 1, para 2; Holland, abstract). Furthermore, 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, 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, and the claims do not amount to significantly more than the judicial exception itself (Step 2B: NO). As such, claims 1-26 are not patent eligible.
Response to applicant’s arguments
Applicant states the claims do not recite a mental process because none of the steps requiring the soft-clipped regions as claimed recited in the instant claims can practically performed in the human mind, as the claims recite two separate alignment and comparison steps using soft-clipped regions which are achieved through the transformation of the nucleic acid sequencing reads with the soft-clipped regions into the synthetic consensus sequences with the soft-clipped regions and the human mind, even with the aid of tools, is unequipped to perform an alignment and comparisons of numerous nucleic acid sequencing reads from MPS of one or more genomic regions of a sample (Applicant’s Arguments, p 8, para 2-p 11, para 2).
It is respectfully submitted that this is not persuasive. The analysis steps for performing two separate alignment and comparison steps using soft-clipped regions to create consensus reads can be practically performed in the mind, because under the broadest reasonable interpretation of the recited claim limitations, the data set size is not inherently large. Even if the data consisted of millions of data points, it is noted that such computations performed mentally, or with paper and pencil, may take considerable time and effort, but that is, of course, the singular purpose of computers and computer networks, to perform large numbers of calculations, via algorithms, rapidly, and without error (assuming no error in user input). Although a general-purpose computer can perform calculations at a rate and accuracy that can far outstrip the mental performance of a skilled artisan, the nature of the activity is essentially the same, and constitutes an abstract idea. See Bancorp Serves., L.L. C. v. Sun Life Assur. Co. of Canada (U.S.), 687 F.3d 1266,1278 (Fed. Cir. 2012) (holding that “the fact that the required calculations could be performed more efficiently via a computer does not materially alter the patent eligibility of the claimed subject matter”); see also See SiRF Tech., Inc. v. Int’l Trade Comm ’n, 601 F.3d 1319,1333 (Fed. Cir. 2010) (holding that: In order for the addition of a machine to impose a meaningful limit on the scope of a claim, it must play a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, i.e., through the utilization of a computer for performing calculations). Therefore, the recited limitations fall under the “Mental Processes” grouping of abstract ideas, as discussed above.
Applicant further states the amended claims do not recite concepts that can be practically performed in the human mind, as the reads are provided in specialized electronic file formats, such as BAM or CRAM, which are compressed binary data for computer-to-computer communication and the use of a sting matching algorithm in claims 4 and 26, and as the method steps are performed using specialized computer programs for multi-step manipulation of data and are inherently computer implemented, and that recognition of Zhongwu’s and Holland’s methods as inherently computer implemented that utilize computer software and computer file formats is an acknowledgement that the method steps recited by the instant claims could not be performed in the human mind as they are computer implemented (Applicant’s Arguments, p 11, para 2 – p 12, para 2). Applicant further asserts the method steps performed using specialized computer programs for multi-step manipulation of data and are inherently computer implemented, and thus cannot be practically performed in the mind, and that recognition of Zhongwu’s and Holland’s methods as inherently computer implemented that utilize computer software and computer file formats is an acknowledgement that the method steps recited by the instant claims could not be performed in the human mind as they are computer implemented (p 12, para 1-2).
It is respectfully submitted that this is not persuasive. There is nothing in the instant claims to suggest the use of specialized bioinformatics instruments versus software that can be implemented on a generic computer. As discussed in MPEP 2106(I), the programmed computer or "special purpose computer" test of In re Alappat, 33 F.3d 1526, 31 USPQ2d 1545 (Fed. Cir. 1994) (i.e., the rationale that an otherwise ineligible algorithm or software could be made patent-eligible by merely adding a generic computer to the claim for the "special purpose" of executing the algorithm or software) was also superseded by the Supreme Court’s Bilski and Alice Corp. decisions. Eon Corp. IP Holdings LLC v. AT&T Mobility LLC, 785 F.3d 616, 623, 114 USPQ2d 1711, 1715 (Fed. Cir. 2015) ("[W]e note that Alappat has been superseded by Bilski, 561 U.S. at 605–06, and Alice Corp. v. CLS Bank Int’l, 573 U.S. 208, 110 USPQ2d 1976 (2014)"). And as discussed in the MPEP 2406.04(a)(2)(III), the courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer, and therefore, the argument that the steps are inherently computer implemented similar to Zhongwu’s and Holland’s method and is not a mental process is not persuasive.
The argument that claims 1 and 22 are not mental processes because the method steps (a)-(f) require the use of the BAM or CRAM formats is not commensurate with the claim as claims 5, 22 and 26 only require the nucleic acid sequencing reads are provided in a file format, but there is no requirement that steps (b)-(g) use the file. However, the examiner agrees that the limitations of using of specific file formats as recited in claims 22 and 26 are not mental processes, and therefore these limitations was analyzed as an additional element. The use of string matching algorithm in claim 4 was considered an abstract idea, as discussed above. The examiner also agrees that the use of BWA cited in claim 26 are not mental processes, and therefore it was also analyzed above as an additional element.
Applicant maintains that the soft-clipped regions are not insignificant and their use in not an insignificant extra-solution activity, because it imposes meaningful limits on the claims because ethe claimed improvement in variant calling through an improved reporting of the structural genomic rearrangement of greater than 5 nucleotides at the exact breakpoint, is only achieved when the soft-clipped regions with the characteristics as claimed are positioned at the start or end of the reads and does not all uses of the alleged judicial exception require such data gathering or data output, since the judicial exceptions can be used reads of less than 8 nucleotides long, reads with unmapped regions at the center of the reads or reads without soft-clipped regions as claimed, and similarity not all uses of the all uses of the alleged judicial exceptions would provide the improved recited in step(g), as it is the combination of additional elements and judicial exceptions that provide the improvement, and that prior to the earliest filing date of the application, the art was unable to accurately detect and report structural genomic rearrangements as claimed (Applicant’s Arguments, p 12, para 3-p 19, para 2).
It is respectfully submitted that this is not persuasive. The soft-clipped regions of 8 nucleotides were a part of the nucleic acid sequence reads, and are simply the region of the sequence that remains unmapped after aligning the nucleic acid sequence read to a reference read, and performing steps such as creating groups with identical positions for these soft-clipped regions at the start or end of the sequence read, and subsequent steps of comparison based on these regions can be performed mentally. Therefore, the use of the soft-clipped regions are part of the abstract idea itself. The improvements to variant calling appear to be to the judicial exceptions themselves (i.e. the steps of identifying and determining on of the structural genomic rearrangements, in which the soft-clipped regions were part of the data used in the identification and determination. There is nothing in this specific region of data that precludes it from being analyzed mentally. As discussed in MPEP 2106.05(a), the improvement cannot be to or provided solely by the judicial exception itself. And as discussed above, the additional elements of the claim amount to mere data gathering and outputting, and mere instructions to implement the abstract idea in a generic computing environment. Therefore, there is no indication that any of these additional elements provide a practical application of the recited judicial exception outside of the judicial exception itself.
Applicant further states the additional elements of the use of the soft-clipped region amounts to significantly more than the recited judicial exception and the additional elements in combination with the judicial exception provide an improvement in sequencing technology under Step 2B, and the additional element of the soft-clipped regions cannot be considered insignificant extra-solution activity because its omission or modification robs the claim of its stated improvement (Applicant’s Arguments, p 19, para 3 – p 20 para 2). Applicant further states that the prior art to Zhongwu and Holland do not disclose detecting complex structural variants and genomic rearrangements as disclosed by the instant invention, and therefore the applicant’s claimed method improves the fired of detecting structural genomic rearrangements the soft-clipped regions are significant features that impose meaningful limits on the claims and do not provide amount to mere data gathering and outputting, and therefore the rejection should be withdrawn (Applicant’s Arguments, p 23, para 3 - p 21, para 3).
It is respectfully submitted that this is not persuasive. As discussed above, the use of the soft-clipped regions is a judicial exception and is not considered an additional element, and as discussed in MPEP 2106.05(a), the judicial exception alone cannot provide the improvement in Step 2A, Prong 2.
With respect to Step 2B, as discussed in MPEP 2106.05, an "inventive concept" is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and an inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself. As discussed above, the limitations using soft-clipped regions, which are abstract ideas, appears to provide the improvement, and therefore these limitations cannot provide the inventive concept. Furthermore, as discussed above, the steps for detecting genomic structural rearrangements using the soft-clipped regions of the reads are also judicial exceptions, and therefore these limitations are not analyzed under Step 2B, and therefore cannot provide the inventive concept.
Furthermore, it is additional elements of data gathering (such as hybrid-capture based nucleic acid enrichment and obtaining nucleic acid sequencing reads from massively parallel sequencing) and outputting, and use of a generic computer or computer systems which is analyzed under Step 2B, and these elements are disclosed by the prior art to Zhongwu et al. and Holland et al. as being well-understood, routine and conventional in the art. Therefore 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, and the claims do not amount to significantly more than the judicial exception itself. Therefore the rejection is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-15, 18-24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Zhongwu Lai et al. (01/17/202 IDS, NPL ref #11; previously cited; hereafter referred to as Lai) as evidenced by Eberle et al. (Genome research 2016, 27(1), pp. 1-9; previously; hereafter referred to as Eberle) , and further in view of Jung et al. (US20150142328A1; previously cited; hereafter referred to as Jung) and Bartenhagen et al. (Briefings in Bioinformatics 2016, Volume 17, Issue 1, pp. 51–62; previously cited; hereafter referred to as Bartenhagen). Newly recited portions are necessitated by claim amendments and after further consideration.
With respect to claim 1, 2, and 12, Lai et al. discloses VarDict, a variant caller that simultaneously calls SNV, MNV, InDels, complex and structural variants (title; abstract).
Lai discloses NA12878 WGS data was downloaded from Platinum genome project (p 3, col 2, para 2). Eberle discloses NA12878 WGS data was generated using the HiSeq 2000 (p 2, col 1, para 2-3; p 7, col 1, para 3).
Lai discloses VarDict works on Binary Alignment/Map (BAM) files that contain aligned sequence reads against a reference genome (p 2, col 1, para 1-2).
Lai discloses selecting reads which only partially map to the reference sequence and contain soft-clipped regions, including soft-clipped regions of at least 8 nucleotides in which one or more of the nucleotides do not correspond with the respective nucleotides of the reference sequence (p 2, col 1, para 3; fig 1).
Lai discloses VarDict first derives the consensus sequences from soft-clipped reads clipped at the same genomic location (i.e. creating groups of soft-clipped regions defined by their genomic location and generating a consensus sequence ( p 2, para 2).
Lai also discloses VarDict takes a two-step approach to call SVs, in which it will first use soft-clipped reads to build a consensus sequence from clipped sequences, and then search whether this consensus can be uniquely aligned within 5 kb of the given region (p 2, col 2, para 3).
Lai discloses VarDict is a publicly available software that can detect and report deletions, duplication and inversions, with no size limits (p 4, col 2, para 3-4; p 10, col 1, para 4-5).
However, Lai does not appear to discloses that the consensus sequence was created using the most abundant nucleotide at each position of the soft-clipped region.
Lai also does not appear to disclose generating combinations of positions between the groups of the nucleic acid sequencing reads comprising the soft-clipped regions at the start of the nucleic acid sequence reads and the groups of nucleic acid sequencing reads comprising the soft- clipped regions at the end of the nucleic acid sequence reads by repeatedly comparing the synthetic consensus sequences with the reference sequence until a pair of the synthetic consensus sequences with soft-clipped regions which match at respective positions in the reference sequence is detected.
However, the prior art to Jung discloses creating a soft-clipped read overlap read list (SCRORL), which includes soft-clipped regions at the start and end of the reads, and then generating a consensus sequence using the SCROR, so that a fair number of soft clipped reads generated by sequencing errors during the process of generating the soft clipped read overlap consensus read may be eliminated (para 0013; para 0045-0048; fig 3). For further clarification, Jung discloses using a de Brujin graph assembly algorithm to create the consensus read (the SCROR), which uses abundance (para 0013).
The prior at to Bartenhagen, in the same field of endeavor, also discloses robust and exact structural variation (SV) detection, such as deletions as small as 10-20 bp, with paired-end and soft-clipped alignments of data from datasets, including those sequenced by NGS sequencing platforms, like HiSeq2000, by detecting and categorizing SVs, performing paired-end alignment to a reference genome, computing approximate breakpoint regions, adding and extracting soft-clipped reads (SC)within breakpoint regions, and aligning soft-clipped reads to each other (i.e. obtained from massively parallel sequencing) (title; abstract; fig 1-2; p 55, col 1, para 4; p 56, col 1, para 3-6). Bartenhagen further discloses SCs can be interconnected in a graph structure by sequence homology and form a maximal clique, which spans both breakpoints (BP1 and BP2) and two reads from different BPs of the same SV are connected if the SC of one matches the sequence of the other read, and further that for reads at the same BP, the soft-clips of both reads are compared (fig 1-2). Bartenhagen elaborates, SCs at the same breakpoint have to share a common soft-clipped sequence, and taken together, all SCs, which belong to a true SV, can be interconnected by aligning soft-clipped and non-soft-clipped sequences among all SC (p 55, col 1, para 7-col2, para 3). Bartenhagen also discloses computing consensus breakpoints from these SC coordinates (fig 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention modify the method for detecting structural variants as disclosed by Lai with creating a SCRORL and creating a consensus sequence from the SCRORL as disclosed by Jung or by comparing SCs that are interconnected and form a maximal clique and computing consensus breakpoints from these SC coordinates, as disclosed by Bartenhagen, because a fair number of soft clipped reads generated by sequencing errors during the process of generating the soft clipped read overlap consensus read may be eliminated, as disclosed by Jung, and further because SCs at the same breakpoint have to share a common soft-clipped sequence, and taken together, all SCs, which belong to a true SV, can be interconnected by aligning soft-clipped and non-soft-clipped sequences among all SC, as disclosed by Bartenhagen. There would be a reasonable expectation of success, because further creating consensus reads that reduce the impact of sequencing error would not impede the analysis steps of Lai.
With respect to claim 3, Lai discloses soft-clipped regions of about 15bps (fig 1).
With respect to claims 4-5, 7, 22, and 26 , Lai discloses VarDict works on Binary Alignment/Map (BAM) files that contain aligned sequence reads against a reference genome. VarDict is compatible with BAM files generated from common DNA-Seq aligners, such as BWA, Novoalign, Bowtie, and Bowtie2, as well as RNA-Seq aligners, such as Tophat and STAR (p 2, col 1, para 2; p 3, col 2, para 2). The instant specification discloses BWA uses string matching algorithm (p 17, lines 24-28).
With respect to claim 6, Lai discloses NA12878 WGS data was downloaded from Platinum genome project (p 3, col 2, para 2). Eberle discloses NA12878 WGS data was generated using an Illumina HiSeq2000 to an average depth of 50× using 2 × 100 bp reads (p 2, col 1, para 2-3; p 7, col 1, para 3).
With respect to claims 8-9, while Lai does not appear to explicitly disclose the groups which comprise less than a predefined number of members are discarded, where in the predefined number is any of 1-8 member, Lai does disclose that creating consensus sequences from the soft-clipped reads and searching using the consensus read, which would not exist if there were no members in the group to create a consensus read (p 2, col 1, para 3-p 3, col 1, para 1). Therefore, this indicates that only groups with 1 or more members are used.
With respect to claims 10-11, Lai does not appear to explicitly disclose each of the synthetic consensus sequences is identical to a predefined number of sequencing reads in the respective group of nucleic acid sequencing reads defined in step (c) (although a consensus sequence of a group with one member would match the sequence of its one member).
However, the prior art to Bartenhagen, discloses the soft-clipped sequence (SC) at BP1 matches the non-soft-clipped sequence at BP2 and vice versa, and further, SCs at the same breakpoint have to share a common soft-clipped sequence, so that all SCs which belong to a true SV, can be interconnected by aligning soft-clipped and non-soft-clipped sequences among all SCs (fig 1-2; p 55, col 1, para 7-col 2, para 5).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention modify the method for detecting structural variants as disclosed by Lai with synthetic consensus sequence comprising soft-clipped sequences (SCs) that are identical to others as disclosed by Bartenhagen, because so that all SCs which belong to a true SV, can be interconnected by aligning soft-clipped and non-soft-clipped sequences among all SCs, as disclosed by Bartenhagen. There would be a reasonable expectation of success, because including sequences in the consensus sequence that match to others would not impede the analysis steps of Lai.
With respective to claim 12, Lai discloses using soft-clipped reads consensus sequence from clipped sequences, and then searching whether this consensus can be uniquely aligned within 5 kb of the given region, and when no soft-clipped reads are found, VarDict will then uses only clustered discordant mates to call SVs based on both distance and orientation, and estimate the breakpoints as well as AF based on number of discordant mates (p 2, col 2, para 2-p 3, col 1, para 1).
With respect to claims 13 and 23, Lai discloses VarDict uses soft-clipped reads for detecting SVs, such as deletions, using annotated functional information (such as location of exons) for regions of interest (fig 1; p 3, col 2, para 1).
With respect to claim 14, Lai should a deletion, when the nucleotide number in the reference sequence of the end position of the soft-clipped regions at the start of the matched nucleic acid sequencing reads is larger than the start position of the soft-clipped regions at the end of the matched nucleic acid sequencing reads (fig 1-3). Lai further discloses using consensus sequences from soft-clipped reads clipped at the same genomic location to perform InDel calling and detect structural variants (p 2, col 1, para 3-p 3, col 1, para 1)
With respect to claim 15, Lai discloses that VarDict reprocessing of The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma dataset called known driver mutations in KRAS, EGFR, BRAF, PIK3CA and MET in 16% more patients than previously published variant calls (abstract).
With respect to claims 18-19, Lai discloses VarDict has been successfully applied to longitudinally monitor tumor variants in cfDNA in a recent non-small-cell lung cancer clinical study of treatment with the EGFR inhibitor Tagrisso AZD9291 (p 8, col 1, para 3-col 2, para 1).
With respect to claim 20, Lai discloses VarDict is a publicly available software that could be useful and have a big impact in cancer research and clinics, suggesting the reports can be provided to another person, entity, office or company (p 4, col 2, para 3-4; p 8, col 2, para 3-p 10, para 5).
With respect to claim 21, Lai discloses VarDict simultaneously calls SNV, MNV, InDels, complex and structural variants, expanding the detected genetic driver landscape of tumor (abstract).
With respect to claim 24, Lai discloses detecting breakpoints and that all structural variants reported by VarDict have precise breakpoints (p 4, col 2, para 3; fig 1-3; p 6, footnote).
Therefore, the invention is prima facie obvious.
Claims 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhongwu Lai et al. (01/17/202 IDS, NPL ref #11; previously cited; hereafter referred to as Lai) as evidenced by Eberle et al. (Genome research 2016, 27(1), pp. 1-9; previously cited; hereafter referred to as Eberle), in view of Jung et al. (US20150142328A1; previously cited; hereafter referred to as Jung) and Bartenhagen et al. (Briefings in Bioinformatics 2016, Volume 17, Issue 1, pp. 51–62; previously cited; hereafter referred to as Bartenhagen) as applied to claims 1 and 15 above, and further in view of Erwin L. van Dijk et al. (01/17/202 IDS, NPL ref #12; previously cited; hereafter referred to as Erwin L. van Dijk). This rejection is newly recited after further search and consideration.
With respect to claims 16 and 17, Lai, as evidenced by Eberle, in view of Jung and Bartenhagen, discloses the method of claims 1 and 15 as discussed above.
However, with respect to claim 16, Lai does not appear to disclose a preparation step for the nucleic acid molecule, which precedes step (a), comprising a hybrid-capture based nucleic acid enrichment for a genomic region of interest.
However, the prior art to Erwin L. van Dijk, in the same field of endeavor discloses common sample preparation for NGS technology included steps for hybrid-capture based nucleic acid enrichment for a genomic region of interest (box 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention modify the method for detecting structural variants as disclosed by Lai with a preparation step for the nucleic acid molecule comprising a hybrid-capture based nucleic acid enrichment for a genomic region of interest as disclosed by Erwin L. van Dijk, because it was a commonly performed technique in NGS, as disclosed by Erwin L. van Dijk.
With respect to claim 17, Lai discloses that VarDict reprocessing of The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma dataset called known driver mutations in KRAS, EGFR, BRAF, PIK3CA and MET in 16% more patients than previously published variant calls (abstract).
Therefore, the invention is prima facie obvious.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Zhongwu Lai et al. (01/17/202 IDS, NPL ref #11; previously cited; hereafter referred to as Lai) as evidenced by Eberle et al. (Genome research 2016, 27(1), pp. 1-9; previously cited; hereafter referred to as Eberle), in view of Jung et al. (US20150142328A1; previously cited; hereafter referred to as Jung) and Bartenhagen et al. (Briefings in Bioinformatics 2016, Volume 17, Issue 1, pp. 51–62; previously cited; hereafter referred to as Bartenhagen) as applied to claims 1 and 5 above, and further in view of Li et al. (01/17/202 IDS, NPL ref #19; previously cited; hereafter referred to as Li). This rejection is newly recited after further search and consideration.
With respect to claim 25, Lai, as evidenced by Eberle, in view of Jung and Bartenhagen, discloses the method of claims 1 and 5 as discussed above.
With respect to claim 25, Lai discloses VarDict works on Binary Alignment/Map (BAM) files that contain aligned sequence reads against a reference genome and that VarDict is compatible with BAM files generated from common DNA-Seq aligners, such as BWA, Novoalign, Bowtie, and Bowtie2, as well as RNA-Seq aligners, such as Tophat and STAR (p 2, col 1, para 2; p 3, col 2, para 2).
However, Lai does not appear to using SAM.
However, the prior art to Li, in the same field of endeavor, discloses BWA outputs alignment is the new standard SAM format (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention modify the method for detecting structural variants as disclosed by Lai with the use of SAM, as BWA outputs alignment is the new standard SAM format, as disclosed by LI. There would be a reasonable expectation of success since VarDict is compatible with files generated from common DNA-Seq aligners, such as BWA, as disclosed by Lai. Therefore, the invention is prima facie obvious.
Response to applicant’s arguments
Applicant states the cited art to Lai does not discloses the most abundant nucleotides within the sequences of the soft-clipped regions in each group are used to generate the synthetic consensus sequences, and Jung only generates a consensus sequence when they overlap vs. as defined by an identical start or end position, and the other cited art do not remedy this, and that the methods of the instant claims are an improvement from other methods at the time of filing and therefore requests withdrawal of the rejection (Applicant’s Arguments, p 21, para 7-p 27, para 6).
It is respectfully submitted that this is not persuasive. As discussed above, Lai discloses creating consensus sequences based on positions (p 2, col 1, para 3), and for further clarification, Jung discloses using a de Brujin graph assembly algorithm to create the consensus read (the SCROR), which uses abundance (para 0013). Bartenhagen discloses the steps for repeated comparison (title; abstract; fig 1-2; p 55, col 1, para 4-col 2, para 3; p 56, col 1, para 3-6). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention modify the method for detecting structural variants as disclosed by Lai with creating a SCRORL and creating a consensus sequence from the SCRORL as disclosed by Jung or by comparing SCs that are interconnected and form a maximal clique and computing consensus breakpoints from these SC coordinates, as disclosed by Bartenhagen, because a fair number of soft clipped reads generated by sequencing errors during the process of generating the soft clipped read overlap consensus read may be eliminated, as disclosed by Jung, and further because SCs at the same breakpoint have to share a common soft-clipped sequence, and taken together, all SCs, which belong to a true SV, can be interconnected by aligning soft-clipped and non-soft-clipped sequences among all SC, as disclosed by Bartenhagen. There would be a reasonable expectation of success, because further creating consensus reads that reduce the impact of sequencing error would not impede the analysis steps of Lai. Therefore, the invention is prima facie obvious and the rejections are maintained.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.D./ Examiner, Art Unit 1686
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
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