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 .
Status of the Claims
Claims 1-25 are pending and examined herein.
No claims are canceled.
Priority
As detailed on the 13 September 2023 filing receipt, the application claims priority as early as 31 August 2022 to provisional application 63/402,507. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
Information Disclosure Statement
Information disclosure statements (IDS) were filed on 22 February 2024 and 11 April 2024. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the references are being considered by the examiner except for Zhou (reference 24) in the 22 February 2024 IDS form because the attached document appears to only be an abstract and references and not the article itself.
Specification
The disclosure is objected to because of the following informality: it is disclosed that p.D538G, p.Y537S, p.E380Q, and p.Y537N are the most common mutations and are labeled using FAM for p.D538G and CY5 for p.Y537S, p.E380Q, and p.Y537N (pg. 29, lines 15-19). Then, less frequent mutations p.Y537N, p.Y537H, and p.Y537D are disclosed as labeled using ROX (pg. 29, lines 21-22). Therefore, the instance of p.Y537N in line 17 should likely read Y537C, which is consistent with Fig. 1 where it is disclosed as labeled with a combination of CY5 and FAM.
Similarly, it is disclosed that Fig. 4 shows p.Y537N (pg. 11, last paragraph) but Y537C is shown in Fig. 4.
Appropriate correction is required.
Claim Objection
Claim 5 is objected to because of the following informality: the phrase “amplified by one primer pair the amplifying step” should read “amplified by one primer pair during the amplifying step” similar to claim 22.
Claim 16 is objected to because of the following informality: the list elements are not joined by the conjunction “and” or “or”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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.
Claim 12 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 is dependent on claim 6 and recites further limitation on the step of performing digital PCR. However, performing digital PCR is introduced in neither parents claim 1 or 6, and thus the step has unclear antecedence.
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 1-3 and 5-17 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of detecting nucleic acid variants.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of
nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The claims are directed to a method (claims 1-25), which falls within one of the categories of statutory subject matter. [Step 1: Yes]
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Claim 1 recites a mathematical concept in the form of generating a plot of points representing the signals, where a plot is a representation of a mathematical relationship among the variables.
Claim 1 recites a mental process in the form of identifying the presence of each variant in the plot based on clustering, where the human mind is practically equipped to identify clusters.
Claim 2 recites mapping signals, where mapping is interpreted as a mental step of evaluating and organizing the data.
Claim 3 recites assigning a vector to each cluster, where making an assignment of a descriptor for the data is a step of data evaluation and organization practically performed by the human mind.
Claims 7-8 and 10 recite what the variants indicate, where indication of disease is interpreted as data evaluation and thus a mental process.
Claim 9 recites obtaining an estimate of abundance, interpreted as counting variants and thus a mathematical process, and designing probes, where probe design is, under a broadest reasonable interpretation, a mental process of selecting the probe composition.
Claims 13-15 recite determining tranche composition, where tranches are variants analyzed at the same time, where such a selection is a mental process.
Claim 18 recites performing an identification based on clusters and designing probes, where identifying and designing are steps practically performed in the human mind.
Thus, the claims recite abstract ideas and thus must be examined further to determine whether elements in addition to the abstract ideas integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). [Step 2A Prong One: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Because the claims recite judicial exceptions, direction under Step 2A Prong Two provides that the claims must be examined further to determine whether they recite elements in addition to the abstract ideas which integrate the judicial exceptions into a practical application (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. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d)(III)).
The claims recite the following additional elements that are not abstract ideas: partitioning a sample (claim 1), amplifying using probes with detectable labels (claim 1), detecting signals (claim 1), amplification using the same primer pair (claim 5), optical labels (claim 6), sequencing tumors (claim 11), digital PCR (claim 12), the labels themselves (claim 16), and sequencing cfDNA (claim 17). These steps are all directed to data collection to perform the identification of clusters, and thus are interpreted as insignificant extra-solution activity (MPEP 2106.05(g)), which do not integrate the abstract ideas into a practical application. Furthermore, generating a plot based on the output may be interpreted as an additional element in the form of a display, but is also directed to data collection in the form of generating the clusters from which the identification is performed.
Thus, the claims recite elements in addition to the abstract ideas which do not integrate the abstract ideas into a practical application, and must be examined further to determine whether elements in addition to the abstract ideas provide significantly more (MPEP 2106.05). [Step 2A Prong Two: Yes]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
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 of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
The claims recite the following additional elements that are not abstract ideas: partitioning a sample (claim 1), amplifying using probes with detectable labels (claim 1), detecting signals (claim 1), amplification using the same primer pair (claim 5), optical labels (claim 6), sequencing tumors (claim 11), digital PCR (claim 12), the labels themselves (claim 16), and sequencing cfDNA (claim 17).
In a review, Rodda (ACS Sensors 3: 540-560, 2018; newly cited) teaches applying digital PCR (Fig. 6) to cfDNA (abstract). Rodda teaches the use of droplets (pg. 548, col. 2, last paragraph), where droplets are partitions, and amplification where multiple mutations can be examined concurrently in a single region of color space (pg. 548, col. 2, last paragraph), meaning multiple mutations are summarized by fewer colors. The results are representing in a plot where the axes are channels labeled with the optical labels FAM and HEX (Fig. 7D). Cancer-related SNVs in tumors have been analyzed with this method (pg. 552, col. 1,second paragraph). A review by Whale (Biomolecular Detection and Quantification 10: 15-23, 2016; newly cited) also teaches partitioned fluidics for dPCR to determine cluster data based on optical channels, where multiple probes for different variants may have the same label (Fig. 2 caption). Whale teaches application to cancer (pg. 16, col. 1, second paragraph),
Therefore, the recited additional elements, alone or in combination, do not appear to provide an inventive concept. [Step 2B: No]
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole,
are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not
constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as
being directed to non-statutory subject matter.
Claims 4, 19, and 20-25 are not rejected under 35 USC 101 because they recite, in addition to the above treated elements in addition to the abstract ideas, additional elements which are unconventional in combination the above treated additional elements, including concentration differences of probes for discrimination (claims 4 and 19) and specific combinations of probes and which labels they share (claim 20 and its dependent claims).
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 1-2, 4-8, 10-12, and 16-17
Claims 1-2, 4-8, 10-12, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Rodda (ACS Sensors 3: 540-560, 2018; newly cited) in view of Whale (Biomolecular Detection and Quantification 10: 15-23, 2016; newly cited).
Claim 1 recites partitioning a sample comprising target nucleic acids into a plurality of partitions.
Claim 1 recites amplifying the nucleic acids in the partitions in the presence of a set of variant-specific probes each of which anneal to a respective variant, wherein each variant-specific probe includes
a detectable label and wherein the set of probes has a number of distinct detectable labels that is lower than a number of the respective variants.
Claim 1 recites detecting signals from the partitions.
Rodda teaches digital PCR (Fig. 6) and use of droplets (pg. 548, col. 2, last paragraph), where droplets are partitions, and amplification where multiple mutations can be examined concurrently in a single region of color space and thus is non-discriminative (pg. 548, col. 2, last paragraph), meaning multiple mutations are summarized by fewer colors.
Rodda points to Whale, where it is evidenced that the process reviewed by Rodda involves a tranche of 7 probes have the same channel label (Fig. 2D caption).
Claim 1 recites generating a plot of points representing the signals and identifying the presence of each variant in the sample from the presence of a corresponding cluster of points in the plot.
Rodda teaches generating a plot representing the signals where ethe plot indicates clusters based on the fluorescence that suggest different mutations (Fig. 7D).
Claim 2 recites the generating step comprises mapping the detected signals onto a space defined by the number of distinct detectable labels.
Rodda teaches plotting on axes corresponding to the fluorescence channels (Fig. 7 caption).
Claim 4 recites at least one of the probes detects a number of the variants in the sample, and at least a second of the probes is specific to fewer than the number of the variants, is present at a different concentration than the one probe, and is used to discriminate among the variants by causing the points in the plot to form distinct clusters.
Whale teaches probes multiple channels and multiple concentrations, with different concentrations for at least targets C and D for distinguishing them (Fig 2A caption).
Claim 5 recites two or more of the different variant sequences occur at positions on the target nucleic acid that will be amplified by one primer pair the amplifying step.
Whale teaches a single primer pair for determining rare mutant detection with clusters based on the presence of a single SNP (Fig. 1B).
Claim 6 recites the detectable label is an optical label.
Rodda teaches at least FAM and HEX (Fig. 7), which are optical labels.
Claim 7 recites the presence of one or more variant sequences indicates a diseased state, optionally wherein the diseased state is cancer.
Rodda teaches mutated and non-mutated alleles with respect to cancer or non-cancer conditions (pg. 541, col. 1, second paragraph).
Claim 8 recites the presence of one or more variant sequences indicates a minimal residual disease in the subject.
Rodda teaches tracking minimal residual disease based on a single mutation (Fig. 10 caption).
Claim 10 recites identifying the presence or absence of one or more of the variant sequences indicates a progression or regression of the diseased state.
Rodda teaches regular, repeating sampling of ctDNA over time for monitoring an individual (Table 1), interpreted as identifying variant sequences for progress (good response to therapy) or not (minimal residual disease).
Claim 11 recites the variants include tumor mutations determined by sequencing tumor nucleic acid from a tumor sample.
Rodda teaches liquid biopsy as well as biopsy localized to a solid tumor (pg. 540, col. 2, first paragraph).
Claim 12 recites the step of performing digital PCR further comprises using probes specific for a wild-type sequence.
Rodda teaches a probe for the wildtype as WT (Fig. 7D).
Claim 16 recites the optical labels are selected from FAM, HEX, SUN, VIC, TAMRA, ATTO550, Cy5, ROX, ATTO700, Cy5.5, Yakima Yellow, ABY, and JUN.
Rodda teaches at least FAM and HEX (Fig. 7), which are optical labels.
Claim 17 recites the sample comprises cell-free DNA (ctDNA). Rodda teaches cell-free DNA (pg. 540, col. 1, first paragraph).
Combining Rodda and Whale
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Whale with that of Rodda because Whale teaches multiple probes for mutant SNVs with the same probe color (Fig. 2D caption), thus further explaining Rodda’s non-discriminative multiplexing (Fig. 7 caption). Both Rodda and Whale are directed to the shared field of endeavor of analysis of low abundance mutations and their combination is prima facie obvious.
Claim 3
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Rodda in view of Whale as applied to claims 1-2, 4-8, 10-12, and 16-17 above and further in view of Quinn (Experimental Design and Data Analysis for Biologists, Cambridge University Press: New York, 552 pgs., 2002; newly cited).
Claim 3 recites assigning a vector to each cluster of points, wherein each vector uniquely and specifically identifies one of the variants in the sample.
Rodda and Whale teach clustering to identify variants but do not teach vectors for the clusters.
Quinn teaches discrimination between clusters based on differences in group centroids (pg. 437, col. 2, first paragraph), where a group centroid is a vector in multivariate feature space.
Combining Rodda, Whale, and Quinn
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Quinn with the previously combined works because Rodda and Whale teach clustering of biological data, in this case fluorescence based on SNP presence, in a multivariate plot. Quinn discriminant functions to distinguish between groups, where each group has a group centroid (pg. 437, col. 2, first paragraph). The coordinates of the points for the groups are vectors and thus their group centroid would also be considered a vector, which can be used to distinguish the groups. The previously combined works and Quinn are directed to analysis of biological data and thus their combination is prima facie obvious.
Claim 9
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Rodda in view of Whale as applied to claims 1-2, 4-8, 10-12, and 16-17 above and further in view of Collins (US 20190284552 A1; newly cited).
Claim 9 recites obtaining an estimate of relative abundances of the variants prior to the partitioning step and designing the variant-specific probes based on the estimate.
Collins teaches designing probes to control for biases related to relative abundance of target molecules (paragraph [163]).
Combining Rodda, Whale, and Collins
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Collins with the previously combined works because Collins teaches having similar relative abundances can be used to normalize the data and avoid false negative results (paragraph [163]). The previously combined works and Collins are directed to detecting genetic variation and thus their combination is prima facie obvious.
Claims 13 and 15
Claims 13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Rodda in view of Whale as applied to claims 1-2, 4-8, 10-12, and 16-17 above and further in view of Xie (Journal of Molecular Diagnostics 24(8): 878-892; previously cited on the 11 April 2024 IDS form).
Claim 13 recites assigning the variants to tranches and, for at least one tranche, providing at least one probe that detects multiple variants in the tranche and at least one probe that discriminates between the multiple variants in the tranche.
Xie teaches FAM for variants 3 and 12 and CY5 added for variant 12 for discriminating between variants 3 and 12 (Figure 4A).
Claim 15 recites each tranche is defined as a set of variants that can be amplified by one primer pair.
Rodda teaches multiple detections in a shared color space (pg. 548, col. 2, last paragraph), which is interpreted as multiple mutations with the same fluorescence. Rodda does not teach number of primers specifically, but Whale teaches single primer pairs for rare mutant detection Table 1) and different primer pairs for amplicons of the same binding site (pg. 16, col. 2, Section 2).
Combing Rodda, Whale, and Xie
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Xie with the previously combined works because Xie teaches a detection channel, here FAM, and a discrimination channel to distinguish among the detected variants, here using CY5. Xie teaches such a step of color-mixing can be used for detecting a polymorphism in a consistent way (pg. 885, col. 2, third paragraph). Xie and the previously combined art are directed to the shared field of endeavor of detecting multiple genetic alterations using fluorescence combinations and their combination is prima facie obvious.
Claims 14
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Rodda in view of Whale and Xie as applied to claims 1-2, 4-8, 10-13, and 15-17 above and further in view of Collins.
Claim 14 recites the tranches are determined based on genomic position or information about probable relative frequency of the variants in the sample.
Collins teaches to design sets of probes for different targets that have, on average, the same abundance in cfDNA samples (paragraph [163]).
Combining Rodda, Whale, Xie, and Collins
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Collins with the previously combined works of Rodda, Whale, and Xie because Collins teaches “to design sets of probes for different targets that have, on average, the same abundance in cfDNA samples” (paragraph [163]), interpreted as similar variant frequency, as having the advantage of being able to provide more consistent densities of labeled molecules on single molecule arrays, which in turn can reduce biases caused by the accuracy of counting molecules at different densities (paragraph [163]), where avoiding such biases would be advantages in quantifying low abundance variants. The previously combined works and Collins are directed to detecting genetic variation and thus their combination is prima facie obvious.
Subject Matter Free of the Prior Art
Claim 18 recites prior to the partitioning step, identifying a first pair of first and second variants among the variants that form overlapping clusters on a 2D dPCR plot and designing a probe set that includes: detection probes for both variants of the pair, wherein the detection probes both have a
detection optical label of a first color and at least one discrimination probe having a discrimination optical label of a second colors. The prior art does not teach or fairly suggest performing a step before the wet labe steps of identifying variants with overlapping clusters and designing probes to specifically discriminate between them using a detection probe and a discrimination probe. While Xie teaches multi-color detection and discrimination (Fig. 4) and Whale teaches distinguishing mutant types from wild type using different colors (Fig. 2D), a step of designing probes based on previously determined overlap to disentangle and discriminate between the overlapping probes is not considered to be taught and so claim 18 and its dependent claims are free of the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert J Kallal whose telephone number is (571)272-6252. The examiner can normally be reached Monday through Friday 8 AM - 4 PM EST.
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/R.J.K./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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