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 .
Claims 1-13 are pending and under examination.
This application is a CON of US 15/977,659, which claims priority to a US provisional application, filed 5/12/2017. The effective filing date for the pending claims is that of the provisional, 5/12/2017. The examiner has reviewed the prosecution history.
This application has published as US PG-Pub 2022/0336050 A1.
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The claims are not directed to the design of discriminatory primers, but to data analysis of genomic sequence data.
Applicant is requested to amend the specification to update any US Application Serial numbers in the specification with the related US PG-Pub, or US Patent number, if available.
The preliminary amendment filed 6/15/2022 has been entered.
The amendment to the specification related to the Sequence Listing, and all associated papers have been entered.
Five IDS statements have been entered and considered.
The Drawings, as filed 1/10/2022, are suitable for examination.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation (BRI) using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
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 1-13 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental steps, mathematic concepts, organizing human activity, or a natural law without significantly more.
Applicant is directed to MPEP 2106 and the Federal Register notice (FR89, no 137 (7/17/2024) p 58128-58138) for the most current and complete guidelines in the analysis of patent- eligible subject matter. The current MPEP is the primary source for the USPTO’s patent eligibility guidance.
With respect to step (1): YES, the claims are drawn to statutory categories: a process, a computer system to carry out the process, and a nontransitory computer-readable storage medium storing instructions to carry out the process.
With respect to step (2A) (1): YES, the claims explicitly recite elements that, individually and in combination, constitute one or more judicial exceptions (JE).
Mathematic concepts, Mental Processes or Elements in Addition (EIA) in the claim(s) include:
1. (Currently Amended) A method for identifying nucleic acid sequence regions comprising:
(Preamble setting forth a method, and the goal of the method.)
at a system comprising one or more processors and memory storing instructions executable by the processor:
(EIA: recitation of a general-purpose computer system MPEP 2106.05(c))
receiving genomic data representing a plurality of nucleic acid sequences;
(EIA- data gathering step of receipt of nucleic acid sequence data. MPEP 2106.05(d, g))
creating and storing data in a first index representing a first set of the plurality of nucleic acid sequences, wherein the first index comprises at least 412 elements representing respective permutations of nucleic acid sequences, and wherein the data created and stored in the first index comprises a first plurality of data structures each associated with a respective nucleic acid sequence of the first set;
creating and storing data in a second index representing a second set of the plurality of nucleic acid sequences, wherein the second index comprises at least 412 elements representing respective permutations of nucleic acid sequences, and wherein the data created and stored in the second index comprises a second plurality of data structures each associated with a respective nucleic acid sequence of the second set;
(Mental Process and Mathematic Concept: The creation of the index requires “dividing the nucleic acid sequence into substrings” which is a step of observing nucleic acid sequence data, and separating each nucleic acid sequence string into smaller strings with a given length, which requires the mathematic concept of counting bases, and the mental steps of data annotation/ modification of separating each substring from the initial string, and modifying that substring with “respective permutations”. Determining the index has 412 entries/ elements requires the mathematic concept of counting. Associating a data structure with a sequence is a mental step of observing the sequence, determining the data structure should be associated, and annotating the index with the data structure. The “associated data structures” have no particular aspects. MPEP 2106.05(a)(2) Section I and III)
identifying, by the first index, a region appearing in every nucleic acid sequence in the first set;
(Mental step of observation of a region present in one sequence, and determining whether it appears in all sequences of the first subset of nucleic acid sequences. The determining requires comparison or matching of nucleic acid region data, one at a time, for the nucleic acid sequences of the first subset, and making a judgement as to whether or not the region is present. MPEP 2106.05(a)(2) Section III. “by the first index” does not clearly indicate how the index is used to carry out this step.)
confirming, by the second index, that the region appears in none of the nucleic acid sequences in the second set; and
(Mental step of observing the region from the previous step, and comparing it to the second set of nucleic acid sequences, to make a judgement as to whether or not the region is present. MPEP 2106.05(a)(2) Section III. “by the second index” does not clearly indicate how the index is used in this step.)
generating and outputting data representing the identified region.
(EIA- routine output step. No data is specifically generated in this step, the identified region from the previous step is output. MPEP 2106.05(g).)
2. (New) The method of claim 1, wherein creating and storing data in the first index comprises: for each of the nucleic acid sequences in the first set, dividing the nucleic acid sequence into a plurality of sub-strings; for each of the plurality of sub-strings, storing a respective one of the first plurality of data structures in the first index, wherein the respective one of the first plurality of data structures indicates an identity of the nucleic acid sequence, a permutation of bases forming the sub-string, and a position of the sub-string in the nucleic acid sequence.
(EIA and Mental Process and Mathematic Concept: The creation of the index requires “dividing the nucleic acid sequence into substrings” which is a step of observing nucleic acid sequence data, and separating each nucleic acid sequence string into smaller strings with a given length, which requires the mathematic concept of counting bases. Storing data is a routine step carried out by general-purpose computer systems. Associating a data structure with a sequence is a mental step of observing the sequence, determining the data structure should be associated, and annotating the index with the data structure and associated data. The “associated data structures” have no particular structural or functional aspects. MPEP 2106.05(a)(2) Section I and III)
3. (New) The method of claim 2, wherein identifying the region appearing in every nucleic acid sequence in the first set comprises determining, for a given sub-string of a first nucleic acid sequence of the first set, that a corresponding first data structure stored in the first index indicates a common permutation of bases as a second data structure stored in the first index for a second nucleic acid sequence in the first set.
(Mental process of observing information about “a given sub-string”)
4. (New) The method of claim 3, wherein identifying the region appearing in every nucleic acid sequence in the first set comprises determining that the second data structure indicates: an identity for the second nucleic acid sequence that matches an identity of a nucleic acid sequence that has been determined to include a previously-matched sub-string, wherein the previously-matched sub-string matches the first nucleic acid sequence at a span occurring immediately before the given sub-string in the first nucleic acid sequence; and a position in the second nucleic acid sequence corresponding to a span occurring immediately after the previously-matched sub-string.
(Mental processes of observation of a match, the location of the match, and the position of the match.)
5. (New) The method of claim 3, wherein the determination is performed iteratively with respect to different sub-strings of the first nucleic acid sequence and different data structures in the first index, until a plurality of adjacent sub-strings of the first nucleic acid sequence are determined to occur in a same order in each of the other nucleic acid sequences in the first set, wherein the plurality of adjacent sub-strings of the first nucleic acid sequence together are at least a predefined minimum number of bases in length.
(Mental process of repeating the determination of the previous step, for different substrings, and mathematic concept of counting the adjacent substring nucleic acids to meet a minimum length requirement.)
6. (New) The method of claim 2, wherein confirming that the region appears in none of the nucleic acid sequences in the second set comprises: determining, for at least one given sub-string of a nucleic acid sequence of the first set, whether a data structure stored in the second index for a nucleic acid sequence in the second set indicates all three of: a common permutation of bases as indicated by a data structure stored in the first index for the nucleic acid sequence of the first set; an identity for the nucleic acid sequence of the second set that matches an identity of a nucleic acid sequence that has been determined to include a previously-matched sub-string, wherein the previously-matched sub-string matches the nucleic acid sequence of the first set at a span occurring immediately before the given sub-string in the nucleic acid sequence of the first set; and a position in the nucleic acid sequence of the second set corresponding to a span occurring immediately after the previously-matched sub-string.
(Mental processes of comparing one substring of the first set, to data present in the second index, observing the results, and making a judgement as to whether the three conditions are met.)
7. (New) The method of claim 6, wherein the determination is performed iteratively with respect to different sub-strings of the nucleic acid sequence of the first set in order to determine that, for every nucleic acid sequence in the second index, at least one data structure fails at least one of the three conditions for at least one sub-string in the region of the first nucleic acid sequence.
(Mental process of performing the steps of claim 6 iteratively, with different substrings, comparing one substring of the first set, to data present in the second index, observing the results, and making a judgement as to whether one of the three conditions are met.)
8. (New) The method of claim 1, wherein the plurality of nucleic acid sequences comprises one of DNA, cDNA, RNA, mRNA, PNA.
(EIA- data gathering limitation, describing an aspect of the data gathered.)
9. (New) The method of claim 1, wherein creating and storing data in the second index comprises: for each of the nucleic acid sequences in the second set, dividing the nucleic acid sequence into a plurality of sub-strings; for each of the plurality of sub-strings, storing a respective one of the second plurality of data structures in the second index, wherein the respective one of the second plurality of data structures indicates an identity of the nucleic acid sequence, a permutation of bases forming the sub-string, and a position of the sub-string in the nucleic acid sequence.
(EIA and Mental Process and Mathematic Concept: The creation of the index requires “dividing the nucleic acid sequence into substrings” which is a step of observing nucleic acid sequence data, and separating each nucleic acid sequence string into smaller strings with a given length, which requires the mathematic concept of counting bases. Storing data is a routine step carried out by general-purpose computer systems. Associating a data structure with a sequence is a mental step of observing the sequence, determining the data structure should be associated, and annotating the index with the data structure and associated data. The “associated data structures” have no particular structural or functional aspects. MPEP 2106.05(a)(2) Section I and III)
10. (New) The method of claim 1, wherein the first set of the plurality of nucleic acid sequences comprises one or more complete genomic sequences.
(EIA- data gathering limitation, describing an aspect of the data gathered.)
11. (New) The method of claim 1, wherein the second set of the plurality of nucleic acid sequences comprises one or more complete genomic sequences.
(EIA- data gathering limitation, describing an aspect of the data gathered.)
12. (New) A system for identifying nucleic acid sequence regions, the system comprising:
one or more processors;
memory storing one or more programs, the one or more programs configured to be executed by the one or more processors and including instructions to: [snip]
(EIA- routine general-purpose computer system)
The remainder of the analysis is the same as claim 1.
13. (New) A non-transitory computer-readable storage medium storing one or more programs for identifying nucleic acid sequence regions, the one or more programs configured to be executed by one or more processors and including instructions to: [snip]
(EIA- routine general-purpose computer readable media)
The remainder of the analysis is the same as claim 1.
With respect to step 2A (2): NO, the claims do not integrate any JE into a practical application (MPEP 2106.04(d)). The claimed additional elements are analyzed alone, or in combination to determine if the JE is integrated into a practical application (MPEP 2106.05(a-c, e, f and h)).
Claim(s) 1, 8 and 10-13 recite the additional non-abstract element(s) of data gathering, or a description of the data gathered.
Data gathering steps are not an abstract idea, they are extra-solution activity, as they collect the data needed to carry out the JE. The data gathering does not impose any meaningful limitation on the JE, or how the JE is performed. The additional limitation (data gathering) must have more than a nominal or insignificant relationship to the identified judicial exception. (MPEP 2106.04/.05, citing Intellectual Ventures LLC v. Symantec Corp, McRO, TLI communications, OIP Techs. Inc. v. Amason.com Inc., Electric Power Group LLC v. Alstrom S.A.).
Claim(s) 1, 2, 9, 12-13 recite the additional non-abstract element (EIA) of a general-purpose computer system or parts thereof.
The EIA do not provide any details of how specific structures of the computer elements are used to implement the JE. The claims require nothing more than a general-purpose computer to perform the functions that constitute the judicial exceptions. The computer elements of the claims do not provide improvements to the functioning of the computer itself (as in DDR Holdings, LLC v. Hotels.com LP); they do not provide improvements to any other technology or technical field (as in Diamond v. Diehr); nor do they utilize a particular machine (as in Eibel Process Co. v. Minn. & Ont. Paper Co.). Hence, these are mere instructions to apply the JE using a computer, and therefore the claim does not recite integrate that JE into a practical application.
Dependent claim(s) 2-7, 9 recite(s) an abstract limitation to the JE reciting additional mathematic concepts, or mental processes. Additional abstract limitations cannot provide a practical application of the JE as they are a part of that JE.
In combination, the limitations of data gathering, for the purpose of carrying out the JE, using a general-purpose computer merely provide extra-solution activity, and fail to integrate the JE into a practical application.
With respect to step 2B: NO, the claims do not provide a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). The additional elements were considered individually and in combination to determine if they provide significantly more than the judicial exception. (MPEP 2106.05.A i-vi).
With respect to claim(s) 1, 8, 10-13: The limitation(s) identified above as non-abstract elements (EIA) related to data gathering do not rise to the level of significantly more than the judicial exception.
Glick (2009; PTO-1449) receives genomic sequence data comprising a plurality of nucleic acid sequences, including DNA.
Cardonha (2014; PTO-1449) receives genomic sequence data comprising a plurality of nucleic acid sequences, including DNA.
Ning (2001; PTO-1449) receives genomic sequence data comprising a plurality of nucleic acid sequences, including DNA.
Tsaltaris (2007; PTO-1449) receives genomic sequence data comprising a plurality of nucleic acid sequences, including DNA.
These elements meet the BRI of the identified data gathering limitations. As such, the prior art recognizes that this data gathering element is routine, well understood and conventional in the art (as in Alice Corp., CyberSource v. Retail Decisions, Parker v. Flook).
In the specification at [0061] it is disclosed that the steps identified as data gathering can be met by downloading or obtaining genomic sequence data from publicly available databases, such as those available at NCBI.
Activities such as data gathering do not improve the functioning of a computer, or comprise an improvement to any other technical field. The limitations do not require or set forth a particular machine, they do not effect a transformation of matter, nor do they provide an unconventional step (citing McRO and Trading Technologies Int’l v. IBG). Data gathering steps constitute a general link to a technological environment. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception are insufficient to provide significantly more (as discussed in Alice Corp.,).
With respect to claim(s) 1, 2, 9, 12-13: the limitations identified above as non-abstract elements (EIA) related to general-purpose computer systems do not rise to the level of significantly more than the judicial exception.
Each of Glick, Cardonha, Ning and Tsaltaris disclose computer systems or computing elements which meet the BRI of the claimed computer system or computer system elements, comprising input, output/ display, a processor, and memory. These include computer system elements capable of storing 4 ^ k elements.
As such, the prior art recognizes that these computing elements are routine, well understood and conventional in the art.
The specification, at [0026-0036] discloses the use of routine general-purpose computers for carrying out the invention, and/or the use of commercially available computer system elements.
These elements do not improve the functioning of the computer itself, or comprise an improvement to any other technical field (Trading Technologies Int’l v IBG, TLI Communications). They do not require or set forth a particular machine (Ultramercial v. Hulu, LLC., Alice Corp. Pty. Ltd v. CLS Bank Int’l), they do not effect a transformation of matter, nor do they provide an unconventional step. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception are insufficient to provide significantly more (as discussed in Alice Corp., CyberSource v. Retail Decisions, Parker v. Flook, Versata Development Group v. SAP America).
Dependent claim(s) 2-7, 9 each recite a limitation requiring additional mathematic concepts or mental processes. Additional abstract limitations cannot provide significantly more than the JE as they are a part of that JE (MPEP 2106.05).
In combination, the data gathering steps providing the information required to be acted upon by the JE, performed in a generic computer or generic computing environment fail to rise to the level of significantly more than that JE. The data gathering steps provide the data for the JE, which is carried out by the general-purpose computers. No non-routine step or element has clearly been identified.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether the additional limitations integrate the judicial exception into a practical application. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether those additional limitations provide an inventive concept which provides significantly more than those exceptions. For these reasons, the claims, when the limitations are considered individually and as a whole, are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
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 1-13 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.
The metes and bounds of claim 1, 12 and 13 are unclear with respect to the data elements stored in each index. The indices are formed, as simply a first subset of a plurality of nucleic acid sequences, and “respective” permutations, and a second subset of a plurality of nucleic acid sequences, and “respective” permutations. The subsets have no further description, nor are they foreclosed from containing some of the same sequences. The subsets are not chosen on any particular basis. The two indices have no intended commonality or differences, beyond the “first” and “second” subsets. It is entirely unclear how each subset is intended to be selected from the initial plurality, and how these subsets are related to the identification of a “region”. The nature and use of these indices is further unclear because the method “confirms by the second index that the (identified) region appears in none of the sequences in the second set” which appears to imply that the two indices are intended to be created from mutually exclusive sets (or at least different sets) of nucleic acids, or that the point of the method is to identify discriminatory regions; however, neither the preamble nor the steps of creating the indices indicate that the point of the method is to identify a discriminating region between two indices, nor is there any expectation that these indices or sets of nucleic acid sequences are intended to be mutually exclusive by the creation steps. Each is created from the same “genomic data representing a plurality of nucleic acid sequences” which have no further description. The plain meaning of the word “confirming” is to establish the truth or correctness of something believed, suspected or thought to be true. Use of the word “confirming” implies one already knew the indices or subsets of sequences were mutually exclusive, as opposed to using a word such as “determining” which could imply investigation to see if the sets of nucleic acid sequences were mutually exclusive with respect to the identified region. While claims are read in light of the specification, limitations from the specification cannot be read into the claims.
The metes and bounds of claims 1, 12 and 13 are unclear with respect to the term “respective permutations” of each nucleotide sequence in the set of nucleotide sequences used for each index. This does not clearly point out and distinctly claim what particular permutations are to be generated for each received sequence from each subset of the “plurality of nucleic acid sequences” received in the first step. Using “respective” fails to provide a type or description of the permutations. It is unclear if this is intended to represent known SNP or SNV data, or other known variant information, or whether this step generates every possible permutation of a nucleic acid sequence where each nucleotide, in turn, is changed to another, across the entire set of sub-strings. This second interpretation appears to be the case, as each created index must comprise at least 412 elements/ permutations related to the initial set of sequences, but the claim does not clearly reflect that interpretation. The sequences used to create the first index are not all clearly from the same region of a genome, the same chromosome, or even the same genome. The sequences used to create the second index are not all clearly from the same region of a genome, the same chromosome, or even the same genome. If the identified region is intended to be compared back to the initial “first set” of nucleotide sequences, it is unclear how this is to be determined, as it is unclear there is a way to search/ compare a region to that initial first set of sequences using the created index, or how any relevant region is to be identified by that comparison.
The metes and bounds of the identification step of claims 1, 12 and 13 are unclear, with respect to what region is identified, and how, with respect to the first index and first set of nucleic acid sequences. One interpretation of this limitation is that the initial first set, a subset of the plurality of nucleic acid sequences, is aligned or mapped within itself, to identify the presence of some common sequence or region. If this is the proper interpretation, the two indices with all the permutations and the “data structures” do not appear to be required to carry out the identification of a common region within the first set of nucleic acid sequences. Merely performing alignments within the first subset of nucleic acid sequence data could identify the presence of a common region, without the need for all the permutation data, or associated data structures. Then the identified common sequence could be aligned against/ compared to the second subset of nucleic acid sequence data, without the need for the permutation data of the second index, or the first index. The “identifying” does not clearly require any permutation data, associated data structures, nor does it set forth and distinctly claim any particular type or way to make the identification.
The metes and bounds of claims 1, 12 and 13 are unclear with respect to the “data structures each associated with a respective nucleic acid sequence of the first/second set.” The claim fails to set forth what these structures are, what they store, and how they interact with the permutation data and the initial sequence data. It is entirely unclear what these associated data structures are intended to carry out within the method, or how they are related to identifying a region present in one subset of sequence data, and not in another set.
The metes and bounds of claims 1- 13, overall are unclear, with respect to how the created indices affect the remainder of the steps of the claims. The purpose of creating the two indices with all the permutations is entirely unclear with respect to the other steps performed by the independent claims. The 412 elements and associated data structures created for each index are not clearly used in any subsequent step of the independent claims, nor does their presence provide any particular information, data, or data structure necessary to carry out any subsequent step. The “identifying by the first index” does not clearly require any permutation data, associated data structures, nor does it set forth and distinctly claim any particular type or way to make the identification. The “confirming” step allegedly uses “by the second index” however it is entirely unclear how this is to be performed, and it is further unclear how this would provide any relevant information, as the point of the method appears to be to identify a common region in one subset of nucleic acid sequences, that is not present in another subset of nucleic acid sequences: this is not the comparison of the identified common region with the permutations in the second index, as the method is not attempting to identify or confirm the presence or absence of the permutated sequences, but the presence or absence of the common region with the second set of nucleic acid sequences from the initial plurality. The point of creating these indices is entirely unclear.
The metes and bounds of claims 2 and 9 are unclear with respect to how the sequences are divided and permutated. Claim 2 sets forth that the creation of the first index comprises “dividing the (each) nucleic acid sequence into a plurality of sub-strings” without any further description as to how or why any sequence would be subdivided into sub-strings. Claim 9 sets forth that the creation of the second index comprises “dividing the (each) nucleic acid sequence into a plurality of sub-strings” without any further description as to how or why any sequence would be subdivided into sub-strings. The partitioning of each nucleic acid sequence appears to be random, and can encompass from substrings of a single nucleotide, up to the full length of the genome. The specification suggests this is the generation of k-mers of a given length, however this is not clearly recited. Further, in claims 2/9, each substring “stores” data structures which comprise information not clearly provided by claim 1, from which claims 2/9 depend. The data stored in the data structure is intended to be a) an identity of the original nucleic acid from which each substring was created, b) “a permutation of bases forming the substring” and c) a position of the substring in the original nucleic acid sequence. It is entirely unclear how these elements are determined or generated with the data at hand. The data at hand is merely “genomic data” which comprised “a plurality of nucleic acid sequences.” No additional information was clearly provided. Claims 2 and 9 do not set forth how any of the information, such as the identity of the nucleic acid sequence, is obtained or determined. Further, the metes and bounds of “a permutation of bases forming the substring” are unclear. It is unclear if this is intended to be the identification of known variant data (i.e. SNP, SNV), from some unknown, outside source, or whether this is intended to record a change made in the creation of the 412 members of the index. This step fails to set forth how the permutations were made, or what the permutations are intended to be. It is further unclear how any of these limitations further affect any step of claim 1, as the claims fail to set forth and particularly claim how the permutations, the data structures, or any other information are used to carry out the “identifying, by the first index” “confirming by the second index” and “generating and outputting” steps of claim 1.
The metes and bounds of claim 3 are unclear, with respect to how identifying a common (unspecified) permutation between two sub-strings of a first nucleic acid from the first set leads to “identifying the region appearing in every nucleic acid in the first set” as required. Only two sub-strings are analyzed from the first subset of sequences, not all sub-strings. It is entirely unclear how, if these two sequences have a difference (permutation) from the “genomic data comprising a plurality of nucleic acid sequences” then they are not clearly present in that set at all. The claim does not set forth what the permutation is, or how it is identified, or how that identification leads to the identification of a common region in the first subset. It is unclear if this is a matching of the “associated data structure” information and data values, or whether this is intended to be a matching operation on the sequence string data of the sub-strings, or some other procedure. It is unclear if just identifying two sub-strings (of any sequence, not necessarily of the same nucleic acid sequence) which have a mutation at position 2, provides the information required to determine a common region. It is not clearly a mapping process where a genomic location is identified for the sub-string, where the presence of a mutation in that sub-string might be compared to known SNV data for that genomic location. There is no expectation that any two nucleic acid sequences from that first subset of nucleic acid sequences would be from the same genomic region, or that they would overlap, or have a common permutation in either permutation index.
The metes and bounds of claims 4-5 are unclear with respect to how the second data structure from claim 3, which was associated with the second nucleic acid sequence from the first subset of nucleic acid sequences, could have “previously” been matched to a sub-string. No data representing prior matching operations is clearly provided by any other claim. How any time-dependent parameter is to be determined is completely unclear. The limitations to “at a span occurring immediately before the given sub-string” are completely unclear, as there was no expectation that the second nucleic acid sequence from that first subset of nucleic acid sequences would be from the same genomic region, or that they would overlap, or have some positional relationship with the first nucleic acid sequence, or have a common permutation in the permutation index. What the sub-strings are intended to “span” is unclear. The sub-strings are not made in any particular way, nor in any particular order. Claim 5 allegedly sets forth that they are adjacent to one another within the first nucleic acid sequence, without providing how this is determined with the data at hand. Claim 5 appears to compare elements of the first index with a different set of substrings of the first nucleic acid sequence. How this occurs is unclear. It is further unclear how the second data structure comprises any of the required information related to the previously-matched strings, and any positional information, as these “associated data structures” are generated in claim 1 without any of that knowledge.
The metes and bounds of claim 6 are unclear with respect to how the confirmation of a discriminatory region is actually carried out, when the steps only compare data within the first set (a common permutation in the first set, an identity in the first set with positional information, and a position from the second set that locates the substring “immediately after” the previously matched substring of the first set). If the determination finds that substring A meets these conditions, it is entirely unclear how it is determined not to be within the second subset of nucleic acid sequences.
The metes and bounds of claim 7 are unclear with respect to the iteration, the arrangement of the (random) sub-strings, and “failing” one of the “three conditions” from claim 6. It is entirely unclear how the elements of the claim “determine that, for every nucleic acid sequence in the second index, at least one data structure fails at least one of the three conditions…” Claim 6 does not clearly set forth a process capable of being iterated to achieve this goal. Claim 6 sets forth conditions, but not how they are to be compared, or used to analyze the 412 substrings and 412 associated data structures of the indexes in any iterative manner.
The metes and bounds of claims 10-11 are unclear with respect to how the description of the first or second set of nucleic acid sequences as “comprises one or more complete genomic sequences.” The metes and bounds of the term “complete” are unclear with respect to how it differs from the genomic sequence information already obtained. It is unclear if these are multiple copies of the same complete genomic sequence (repeated copies of HG26), different genomes of the same species (individual complete genomic sequences from more than one human), or whether this is intended to encompass different genomes of different species/ organisms (mouse and man). It is further unclear how the presence of a full genome affects the generation of the indexes of claim 1, or the identification of a “region” present in one index.
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.
Claim(s) 1-13 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Glick (2009).
Glick et al. Method for indexing nucleic acid sequence for computer-based searching. US 2009/0270277 A1, published 10/29/2009. (PTO-1449)
The independent claims are drawn to methods, systems, and computer program products for carrying out the identification of a nucleic acid sequence region. Two indices are created from initial genomic nucleic acid sequence data, that contain “respective permutations” of nucleic acid sequences, and additional data structures associated with the nucleic acid sequence data. One region appearing in every nucleic acid sequence in the first set is identified, and determined not to be present in the second set.
Glick is directed to computer-implemented methods of indexing nucleic acid sequence data, by breaking up the nucleic acid sequences into kmers, and creating an index comprising the substrings of kmers, with associated data- named MICA (Fig 1). Systems and computer program products are disclosed.
With respect to claims 1, 12 and 13 and
“A method for identifying a nucleic acid sequence region, comprising: at a system comprising one or more processors and memory storing instructions executable by the processor: receiving genomic data representing a plurality of nucleic acid sequences;
Glick receives the genomic nucleic acid sequence data, such as the complete human genome, as set forth in Fig 2 and [0006]. This also meets dependent claims 10-11. The methods of Glick use computer systems and instructions, as set forth throughout and in [0019-0023, 0048, etc].
With respect to claims 1, 12 and 13 and
“creating and storing data in a first/second index representing a first set of the plurality of nucleic acid sequences, wherein the first/second index comprises at least 412 elements, wherein each of the 412 elements representing respective permutations of nucleic acid sequences, and wherein the data created and stored in the first/second index comprises a first plurality of data structures each associated with a respective nucleic acid sequence of the first/second set;”
Glick discloses selecting a subset of polynucleotide sequences from the genomic sequence data at [0007], and creating indexes from that subset. The genome can be broken into subsets or chunks, representing separate subsets of the genomic nucleic acid sequences [0008]. For each chunk or subset, Glick generates all substrings of the sequence of a particular length K (K-mer, or Kmer) which meets the BRI of a “substring” or “sub-string”. The method then determines all of the unique base sequences of length K. The Kmers may have degenerate or permutated bases [0007]. The computer stores each Kmer, and in an associated data structure, the position of each Kmer in the overall nucleotide sequence of the genome [0009].
[0009] “The position of each non-degenerate K-mer is recorded in a non-degenerate data array in the file. In one embodiment, the non-degenerate data array is divided into 4K partitions corresponding to all of the possible 4K non-degenerate K-mers. Each partition contains a list of integers representing the number of times a particular non-degenerate K-mer is present in each of the chunk sections, followed by a list of integers representing intra-chunk section positions of the particular K-mer in each of the chunk sections. The position of each partially degenerate K-mer is recorded in a degenerate data array in the file. Each particular partially degenerate K-mer is represented as an integer that marks the absolute position of the particular K-mer, followed by a string that encodes the sequence of the particular K-mer.”
Each index for each chunk of the genomic sequence data received by Glick meets the BRI of the two created indexes of claims 1, 12 and 13. The indexes of Glick can comprise 4k elements. The indexes of Glick can comprise entire genomic sequences, as shown in Fig 2, and [0006]. The kmers of Glick can comprise permutations (degenerate bases) [0005]. The indexes can comprise additional data structures with information linked to the sequence.
“[0011] In another embodiment, the invention provides a data structure for recording information regarding a nucleic acid, the information being stored in a computer file. The data structure contains information on the K-mer's of the nucleotide sequence. The data structure comprises a non-degenerate data array containing the position of each particular non-degenerate K-mer of a nucleotide sequence; a degenerate data array containing the position of each particular partially degenerate K-mer and a string encoding the sequence of each particular partially degenerate K-mer; a sequence segment format field that contains an integer identifying this segment as the sequence segment; a sequence segment size field containing an integer representing the total number of bytes occupied by the sequence segment; a sequence properties field containing an integer representing the topology and the strandedness of the nucleotide sequence; a DNA sequence field containing the base sequence of the nucleotide sequence; an index segment format field that contains an integer identifying this segment as the index segment; an index segment size field containing an integer representing the total number of bytes occupied by the index segment; an index properties field containing an integer representing the byte order of the index; a chunk counts summary field containing a list of integers representing the total number of times a particular non-degenerate K-mer appears in the nucleotide sequence; a degenerate K-mer count field containing an integer representing the total number of partially degenerate K-mers in the nucleotide sequence; an N-stretch count field containing an integer S representing the number of separate stretches of K or more consecutive N's in the nucleotide sequence; and an N-stretch data array containing S pairs of integers that represent the starting positions and lengths of the separate stretches of consecutive N's in the nucleotide sequence.”
“[0029] The main body of a MICA index is the Chunk Data Array, which stores the positions of the nondegenerate K-mers (FIG. 1). The total number of position values is largely independent of K. However, there are 4.sup.K different nondegenerate K-mers, so the Chunk Data Array is divided into 4.sup.K partitions. Each partition is divided into C sub-partitions that contain the intra-chunk position values. The sizes of these sub-partitions are recorded in a list at the beginning of the partition.”
With respect to claims 1, 12 and 13 and:
“identifying, by the first index, a region appearing in every nucleic acid sequence in the first set;”
Glick provides identifying a Kmer of a given length, that appears in a chunk of the genomic nucleic acid sequence data, and how many times it appears [0012].
“[0012] In another embodiment of the invention, the invention provides a method of searching for a specific base sequence in a nucleotide sequence using a computer. In one embodiment, the invention comprises using a computer to access the data structure of the invention containing information on a nucleotide sequence and having the computer search the information in the data structure for the presence and location of the specific base sequence. The computer accesses a data structure file of the present invention containing information on the nucleotide sequence desired. The computer then loads the data from the index segment format field, the index segment size field, the index properties field, the chunk counts summary field, the degenerate K-mer count field and the N-stretch Count field into main memory. The computer then divides the specific base sequence that is being searched for into specific K-mers. The computer accesses the data loaded into the main memory and the information in the degenerate data array, the non-degenerate data array, and the N-stretch data array and uses this information to generate the position of the unique K-mers in the nucleotide sequence. The computer then uses this K-mer position data to determine the location of the specific base sequence in the nucleotide sequence if present.”
“[0025] … The absolute positions of a K-mer within a full DNA sequence can then be calculated with the aid of a list specifying the number of instances of the K-mer within each chunk.”
“[0037] The query length Q can range from one base to the length of the subject DNA sequence. Both strands of the DNA molecule are searched. For a query that is palindromic--i.e., identical to its reverse complement--a single search is performed. For a query that is nonpalindromic, two successive searches are performed, one with the query and another with the reverse complement of the query. If the DNA molecule is circular, the initial search is followed by a secondary search for matches that span the origin. One step in this secondary search involves dividing the query in half and then checking for one of two possibilities: either the first half-query matches within the last Q-1 bases of the DNA sequence, or the second half-query matches within the first Q-1 bases of the DNA sequence.”
“[0039] … This strategy of starting with the rarest K-mer can significantly accelerate searches because some K-mers are found less frequently than others and therefore result in fewer comparisons…”
With respect to claims 1, 12 and 13 and:
“confirming, by the second index, that the
generating and outputting data representing the identified region.”
The methods of Glick can search the identified Kmer in a second chunk of the initial genomic sequence data, to determine whether or not it is present in that chunk. The identified Kmer is stored, and output as required.
“[0040] Each successive K-mer search is limited to the range of chunks that generated hits for the current working list... If a working list contains no hits, the search is terminated. This range limitation method can accelerate searches when a query has a small number of matches to the subject sequence.”
“[0043] … MICA therefore uses an alternative intersection algorithm for partially degenerate K-mers. A boolean array of 65,535 elements is used to represent the positions in a chunk. For a given chunk, all of the individual K-mer lists are scanned, and the 2-byte position values are recorded by setting the corresponding boolean elements to true, yielding a boolean array that indicates which positions in the chunk match one of the K-mers. Then the intersection is obtained by checking whether each working list element corresponds to a value of true in the boolean array. This method is efficient due to the relatively small number of operations and the sequential nature of the memory accesses.”
With respect to claims 2 and 9, and the creation of the indexes, Glick teaches that for each nucleic acid sequence in the chunk, Kmers are generated which meet the BRI of sub-strings, as set forth above. For each sub-string, Glick stores information regarding the identity of the sequence [0071], a permutation as set forth above, and a position, as set forth above.
With respect to claim 3, Glick teaches that common permutations can be identified within substrings.
With respect to claim 4, Glick teaches that identities can be determined by comparison or previous matching operations at [0071]. Location of the substring in the overall sequence can be determined as set forth above.
With respect to claims 5-7, Glick iterates their method with different lengths of Kmers, which are different substrings, to identify sequences containing a certain number of Kmers in a certain order.
With respect to claim 8, Glick indexes any kind of genetic sequence information, including at least DNA.
Claims 10-11 are met by the indexing of the complete human genome as set forth above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,222,712 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are broader in scope than the patent, but contain all the same steps, and indices. The difference is that the claims of the patent are used to design and output primers that are not in a given set of sequences in the second index, while the claims of the instant application merely identify a region of a sequence.
Claims 1-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 10,560,552 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because while the patent is directed, overall, to compression and decompression of a genomic sequence, the same indices are created, using the same steps to identify discriminative sequences in one genome that are not present in another.
Claim 1-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 16-41 of copending Application No. 17/937,866 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘866 application is drawn to systems for carrying out the same method, creating indexes representing nucleic acid sequences, permutations, and associated data, to identify a target region present in one index and not another, and outputting the sequence of the region.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Figueroa et al. (2009) speeding up permutation-based indexing with indexing. 2009 Second International Workshop on Similarity Search and Applications. P107-114.
Hunt et al. (2002) Database Indexing for large DNA and protein sequence collections. The VLDB Journal, vol 11: 256-271.
Huang et al. (2010) Indexing similar DNA structures. AAIM 2010; LCNS 6124, p180-190.
Lederman (2013) A random-permutations-based approach to fast read alignment. BMC Bioinformatics, vol 14: suppl 5, e58, 10 pages.
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/MARY K ZEMAN/ Primary Examiner, Art Unit 1686
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