Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 1-20 are pending and under examination.
Claims 1, 4-10, and 13-18 are amended.
Claims 1-20 are rejected.
Claims 1, 10 and 19 are independent.
Claims 19-20 are new.
No claims are allowed, canceled, or withdrawn.
Office Action Outline
Rejections applied
Abbreviations
x
112/b Indefiniteness
PHOSITA
"a Person Having Ordinary Skill In The Art before the effective filing date of the claimed invention"
112/b "Means for"
BRI
Broadest Reasonable Interpretation
112/a Enablement,
Written description
CRM
"Computer-Readable Media" and equivalent language
112 Other
IDS
Information Disclosure Statement
x
102, 103
JE
Judicial Exception
x
101 JE(s)
112/a
35 USC 112(a) and similarly for 112/b, etc.
101 Other
N:N
page:line
Double Patenting
MM/DD/YYYY
date format
Priority
As detailed in the 10/12/2023 filing receipt, this application is a CON of 16/530,015 filed 08/02/2019, now abandoned; which is a CON of 13/623,709, filed 09/20/2012, now abandoned; which claims priority to U.S. Provisional Application Nos. 61/644,771, filed 05/09/2012; 61/584,391, filed 01/09/2012; 61/545,450, filed 10/10/2011; and 61/536,967, filed 09/20/2011.
Claims 1-20 are not given the benefit for the claim for priority to Provisional Application
No. 61/536,967 because the provisional application does not provide support for "flow space information," and "flow space representation of at least a portion of the reference genome sequence" as required in independent claims 1, 10, and 19.
Claims 1-20 are given the benefit for the claim for priority to Provisional Application No. 61/545450, filed 10 October 2011.
Nucleotide and/or Amino Acid Sequence Disclosures
The sequence listing received 10/10/2023 has been entered into the application file,
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 1-20 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. Claims depending from rejected claims are rejected similarly, unless otherwise noted, and any amendments in response to the following rejections should be applied throughout the claims, as appropriate.
Claims 1, 10, and 19 recite "the sequence deviation within the read" in which both "the sequence deviation" and "the read" require but lack clear antecedent. If this recitation refer to previously instantiated instances, then it is not clear which instances those are. If this recitation instantiates these claim elements, this is not clear. This rejection might be overcome by for example amending to recite "[[the]]a sequence deviation within [[the]]a read."
Claims 4 and 13 recite "the mapped read" in which requires but lacks clear antecedent. If this recitation refers to a previously instantiated instance, then it is not clear which instance that is. If this recitation instantiates this claim element, this is not clear. This rejection might be overcome by for example amending to recite "[[the]]a mapped read."
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 details the following framework to analyze Subject Matter Eligibility:
• Step 1: Are the claims directed to a category of statutory subject matter (a process, machine, manufacture, or composition of matter)? (see MPEP § 2106.03)
• Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. an abstract idea, a law of nature, or a natural phenomenon? (see MPEP § 2106.04(a); 2106.04(a)(2); & 2106.04(b))
• Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application? (see MPEP § 2106.04(d))
• Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept? (see MPEP § 2106.05)
Step 1:
Claims 1-9 are directed to a 101 machine or manufacture, here a system. Claims 10-18 are directed to a 101 process, here a method. Claims 19-20 are directed to a 101 machine or manufacture, here a non-transitory computer-readable medium (CRM). As such, claims 1-20 are directed to a related system, method, and CRM, which fall under categories of statutory subject matter. (See MPEP § 2106.03). (Step 1: Yes.)
Step 2A, Prong One:
The claims are found to recite abstract ideas in the form of mental processes (and mathematical concepts, where indicated), as follows:
• map sequence reads to a reference genome sequence (claims 1, 10, 19)
• align flow space information for the mapped reads to a flow space representation of part of a reference genome to form aligned flow space information (claims 1, 10, 19)
• identify sequence deviations between the aligned flow space information and the flow
space representation of the reference genome sequence (claims 1, 10, 19)
• group sequence deviations identified for multiple reads by position (claims 1, 10, 19)
• calculate a read score for each sequence deviation for a position on a per-read and
per-variant basis (claims 1, 10, 19; also considered a mathematical concept)
• calculate a variant score for the sequence deviations at the position on a per-variant basis (claims 1, 10, 19; also considered a mathematical concept)
• identify a variant at the position if there is sufficient evidence of the variant at the
position (claims 1, 10, 19)
• calculating an average of the read scores (claims 2 and 12; also considered a mathematical concept)
• calculating a Bayesian posterior probability (claims 3, 11, and 20; also considered a mathematical concept)
• indicate whether the mapped read matches (claims 4 and 13)
• identifying a no-variant status (claims 5 and 14)
• identifying a no-call status (claims 6 and 15)
• mapping uses base space representations of the plurality of nucleic acid sequence reads and a base space representation of the reference genome sequence to form the mapped reads (claims 7 and 16)
• converting a portion of the base space representation of the reference genome
sequence corresponding to the mapped reads to the flow space representation of the reference genome (claims 8 and 17)
• converting uses a flow order and an order of bases to determine the flow space representation of the reference genome (claims 9 and 18)
Step 2A Prong One Summary: The claims recite mental processes and mathematical concepts. When considering the broadest reasonable interpretation (BRI) of the claims, the mental processes recited in independent claim 1, 10, or 19 (e.g., "map reads to a reference," "align flow space information," "identify sequence deviations," etc.) are directed to processes that may be performed in the human mind, or with pen and paper, as there are no particular limitations recited in claim 1, 10, or 19 which would prevent the mental processes from being performed in the human mind or with pen and paper. The claims recite mathematical processes in performing calculations of read scores, variant scores, averages, and Bayesian posterior probabilities; these calculations are discussed at Specification paragraphs [0077-0078]. Such analysis performed mentally, or with paper and pencil, may take considerable time and effort, and although a general-purpose computer can perform these calculations at a rate and accuracy that can far exceed the mental performance of a skilled artisan, the nature of the activity is essentially the same, and therefore constitutes an abstract idea. Therefore, the claims recite elements that constitute a judicial exception in the form of an abstract idea(s). (Step 2A, Prong One: Yes.)
Step 2A, Prong Two:
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs). Here at Step 2A, Prong Two, any remaining steps and/or elements not identified as JEs are therefore in addition to the identified JE(s), and are considered additional elements. Because the claims have been interpreted as being directed to judicial exceptions (abstract ideas in this instance) then Step 2A, Prong Two provides that the claims be examined further to determine whether the judicial exception is integrated into a practical application [see MPEP § 2106.04(d)]. A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
MPEP § 2106.04(d)(I) lists the following five example considerations for evaluating whether a judicial exception is integrated into a practical application:
(1) An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a).
(2) Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2).
(3) Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b).
(4) Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c).
(5) Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
The claims recite additional elements as follows:
Additional elements of data gathering: Claims 10 and 19 recite receiving data. Data gathering steps are additional elements which perform functions of inputting, collecting, and outputting the data needed to carry out the abstract idea. These steps are considered insignificant extra-solution activity, and are not sufficient to integrate an abstract idea into a practical application as they do not impose any meaningful limitation on the abstract idea or how it is performed, nor do they provide an improvement to technology (see MPEP § 2106.04(d)(I)).
Additional elements of computer components and sequencers: Claim 1 recites a system, a nucleic acid sequence analysis device, and a processor. Claim 10 recites a computer, a nucleic acid sequence analysis device, and a processor; claim 19 recites a non-transitory machine-readable storage medium, a nucleic acid sequence analysis device, and a processor. The claims require only generic computer components and sequencers, which do not improve computer technology, and do not integrate the recited judicial exception into a practical application (see MPEP § 2106.04(d)(1) and MPEP § 2106.05(f)).
Step 2A Prong Two summary: The claims have been further analyzed with respect to Step 2A, Prong Two, and no additional elements have been found, alone or in combination, that would integrate the judicial exception into a practical application. At this point in examination, it is not yet the case that any of the Step 2A Prong Two considerations enumerated above clearly demonstrates integration of the identified JE(s) into a practical application. Referring to the considerations above, none of: (1) an improvement, (2) a treatment, (3) a particular machine, or (4) a transformation is clear in the record. For example, regarding the first consideration for improvement at MPEP 2106.04(d)(1), the record, including the Specification, does not yet clearly disclose an explanation of improvement over the previous state of the technology field, and the claims do not yet clearly result in such an improvement. (Step 2A, Prong Two: No).
Step 2B analysis:
Because the additional claim elements do not integrate the abstract idea into a practical application, the claims are further examined under Step 2B, which evaluates whether the additional elements, individually and in combination, amount to significantly more than the judicial exception itself by providing an inventive concept. An inventive concept is furnished by an element or combination of elements that is recited in the claim in addition to the judicial exception, and is sufficient to ensure that the claim, as a whole, amounts to significantly more than the judicial exception itself (see MPEP § 2106.05).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are well-understood, routine, and conventional. Those additional elements are as follows:
Additional elements of data gathering: The receiving of data (claims 10 and 19) does not cause the claims to rise to the level of significantly more than the judicial exception. The courts have recognized receiving or transmitting data over a network; storing and retrieving information in memory; and analyzing DNA to provide sequence information or detect allelic variants, [see MPEP§2106.05(d)(II)], as well-understood, routine, conventional activity when they are claimed in a merely generic manner (e.g., at a high level of generality) or as extra-solution activity.
Additional elements of computer components and sequencers: The additional elements of a system, a nucleic acid sequence analysis device, a processor, a computer, and a non-transitory machine-readable storage medium of claims 1, 10, and 19 do not cause the claims to rise to the level of significantly more than the judicial exception, and as such do not provide an inventive concept; these are conventional computer components and sequencers. Additionally, Specification paragraphs [0080] and [0082] details generic embodiments of the computer components and sequencers.
Further regarding the conventionality of additional elements, the MPEP at 2106.05(b) and 2106.05(d) presents several points relevant to conventional computers and data gathering steps in regard to Step 2A Prong 2 and Step 2B, including:
• A general purpose computer that applies a judicial exception, such as an abstract idea, by use of conventional computer functions, does not qualify as a particular machine (see 2106.05(b)(I)), as in the case of claims 1, 10, and 19, which are interpreted to recite conventional computer components.
• Integral use of a machine to achieve performance of a method may integrate the recited judicial exception into a practical application or provide significantly more, in contrast to where the machine is merely an object on which the method operates, which does not integrate the exception into a practical application or provide significantly more (see 2106.05(b)(II). In the instant claims, the recited processor, computer, and non-transitory machine-readable storage medium are used in mapping, aligning, calculating, etc., as such, the processor, computer, and non-transitory machine-readable storage medium act only as a tool to perform the steps of sequence data analysis, and do not integrate the exception into a practical application or provide significantly more.
• Use of a machine that contributes only nominally or insignificantly to the execution of the claimed method (e.g., in a data gathering step or in a field-of-use limitation) would not integrate a judicial exception or provide significantly more (see 2106.05(b)(III). The sequence analysis device, processor, computer, and non-transitory machine-readable storage medium of the claim used in performing data analysis does not impose meaningful limitations on the claims.
• The courts have recognized “receiving or transmitting data over a network”, “performing repetitive calculations”, and “storing and retrieving information in memory”, as well-understood, routine, and conventional functions when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)(II)). The storing of data in claims 10 and 19 is recited in a generic manner.
All limitations of claims 1-20 have been analyzed with respect to Step 2B, and none provides a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception, and thus do not transform the judicial exception into a patent eligible application of the exceptions. Step2B: NO.
Therefore, the claims, when the limitations are considered individually and as a whole, are rejected under 35 U.S.C. § 101 as being directed to non patent-eligible subject matter.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Leamon (U.S. 2006/0040297 A1, published 02/23/2006; cited on the attached form PTO-892) in view of DePristo (Nature genetics, vol. 43(5), pp.491-498 plus 18 pages supplementary material, document 26 pages total (10 April 2011); cited on the attached form PTO-892)
Regarding claim 1, 10, and 19, the recited processor, sequence analysis device, storage medium, and processor read on "an apparatus for sequencing nucleic acids...connected to at least one computer for controlling the individual components of the apparatus and for storing and/or analyzing the information obtained from detection of the sequence reaction event." (Leamon, [0215])
Regarding claims 10 and 19, the recited receiving nucleic acid sequence reads is shown by "a total of 31,785 reads were obtained..." (Leamon, [0693].)
Regarding claims 1, 10, and 19, the recited mapping a plurality of nucleic acid sequence reads to a reference genome reads on ..."aligned each High Quality Read to the reference genome at 70% stringency, using flow-space mapping..." (Leamon, [0804].)
Regarding claims 1, 10, and 19, the recited aligning flow space information for the mapped reads to a flow space representation of part of the reference genome reads on "To map the query flowgram to the target, we divide the query flowgram into sliding sub-flowgrams having the length that was used in the indexing step and search the space of indexed ideal sub-flowgrams. A perfect match anchors the query flowgram against the reference genome." (Leamon, [0922].)
Regarding claims 1, 10, and 19, the recited identifying sequence deviations between the aligned flow space information and the flow space representation of the reference genome sequence reads on "A perfect match anchors the query flowgram against the reference genome....The reads are aligned to the reference at a very low level of stringency in order to detect mutations or other genomic variations." (Leamon, [0922].)
Regarding claims 1, 10, and 19, the recited the recited grouping the sequence deviations by position reads on "To map the query flowgram to the target, we divide the query flowgram into sliding sub-flowgrams having the length that was used in the indexing step and search the space of indexed ideal sub-flowgrams." (Leamon, [0922].)
Regarding claims 7 and 16, the recited using base space representations of the plurality of nucleic acid sequence reads and a base space representation of the reference genome to form mapped reads on "To map the query flowgram to the target, we divide the query flowgram into sliding sub-flowgrams having the length that was used in the indexing step and search the space of indexed ideal sub-flowgrams. A perfect match anchors the query flowgram against the reference genome" (Leamon, [0922]).
Regarding claims 8 and 17, the recited converting a portion of the base space representation of the reference genome corresponding to the mapped reads to the flow space representation of the reference genome reads on "To map the query flowgram to the target, we divide the query flowgram into sliding sub-flowgrams having the length that was used in the indexing step and search the space of indexed ideal sub-flowgrams. A perfect match anchors the query flowgram against the reference genome" (Leamon, [0922]).
Regarding claims 9 and 18, the recited a flow order and an order of bases in the base space representation of the reference genome reads on "Given the order in which nucleotides are flowed, a given reference genome implies a known succession of ideal signal values. This ideal flowgram is divided into contiguous, overlapping, sub-flowgrams of a particular length..." (Leamon, [0922]).
Leamon does not show calculating a read score of claims 1, 10, and 19 (shown by DePristo).
Leamon does not show calculating a variant score of claims 1, 10, and 19 (shown by DePristo).
Leamon does not show calculating an average of the read scores of claims 2 and 12 (shown by DePristo).
Leamon does not show calculating a Bayesian posterior probability of claims 3, 11, and 20 (shown by DePristo).
Leamon does not show indicating whether the mapped read matches the reference genome reads of claims 4 and 13 (shown by DePristo).
Leamon does not show identifying a no-variant status at the position reads of claims 5 and 14 (shown by DePristo).
Leamon does not show identifying a no-call status at the position of claims 6 and 15 (shown by DePristo).
Regarding claims 1, 10, and 19, the recited calculating a read score reads on " developed a base quality recalibration algorithm that provides empirically accurate base quality scores for each base in every read." (DePristo, p.9, col.2, paragraph 6.)
Regarding claims 1, 10, and 19, the recited calculating a variant score reads on "Given a set of putative variants along with SNP error covariate annotations, variant quality score recalibration employs a variational Bayes Gaussian mixture model (GMM) to estimate the probability that each variant is a true polymorphism in the samples rather than a sequencer, alignment or data processing artifact." (DePristo, p.10 of 29, col.2, paragraph 3.)
Regarding claims 1, 10, and 19, the recited identifying a variant at the position if there is sufficient evidence reads on "Multi-sample SNP calling: We apply a Bayesian algorithm for variant discovery and genotyping...Given Di aligned bases at a specific genomic position for individual i, we estimate the genotype likelihoods" (DePristo, p.10 of 29, col.1, paragraph 3); and reads on "(a) mixture model is used to estimate the probability of each variant call being true" (DePristo, p.10 of 29, col.2, paragraph 3).
Regarding claims 2 and 12, the recited calculating an average of the read scores reads on "Figure 3 Raw (pink) and recalibrated (blue) base quality scores for NGS paired-end read sets...(T)he middle panel shows the difference between the average reported and empirical quality score for each machine cycle..." (DePristo, p.495 (p.5 of 29), Figure 3).
Regarding claims 3, 11, and 20, the recited calculating a Bayesian posterior probability reads on "...apply a Bayesian algorithm for variant discovery and genotyping..." (DePristo, p.10 of 29, col.1, paragraph 3).
Regarding claims 4 and 13, the recited indicating whether the mapped read matches the reference genome reads on "Mapping algorithms placed reads with an initial alignment on the reference genome" (DePristo, p.492 (p.2 of 29), paragraph 3).
Regarding claims 5 and 14, the recited identifying a no-variant status at the position reads on "The read with the greatest sum of quality scores is taken from the queue. If it matches exactly any of the putative haplotypes, it is added to that haplotype’s read set" (DePristo, p.26 of 29, col.1, under paragraph 2, point #2).
Regarding claims 6 and 15, the recited identifying a no-call status at the position reads on "The ~20% of the missed variant sites from these three datasets had little to no coverage in the NA12878 sample in the low-pass data and, therefore, could not be assigned a genotype using only the NGS data" (DePristo, p.49 (p.4 of 29), col. 2, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the flow-space mapping method of Leamon and the variant calling method of DePristo, to come to a method for variant calling using flow-space mapping, because DePristo provides motivation to combine in showing their method to assess the likelihood that an identified variable site is a true biological DNA variant greatly improves the sensitivity and specificity of variant discovery from NGS data. Additionally, one would have had a reasonable expectation of success in combining Leamon with DePristo, because the references are generally drawn to related teaching regarding sequencing technology and data analysis, and as such, the combination would have been obvious.
Conclusion
No claims are allowed.
This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
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/M.A.V./Examiner, Art Unit 1687
/G. STEVEN VANNI/Primary patents examiner, Art Unit 1686
Prosecution Insights