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 .
Please note: The examiner handling this application has changed. The new examiner on this case is Kailey Cash (kailey.cash@uspto.gov) in AU1683. Any correspondence relating to the instant application should be directed to this examiner.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-11 and 15) in the reply filed on 9/17/2025 is acknowledged. Given Applicant’s cancellation of the claims of Group II (12-14) in the amendment to the claims filed on 9/17/2025, the requirement for Election/Restriction has been withdrawn.
Claims 1-11 and 15 are pending and being examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (for example, see paragraph [003] Turner et al., 2008). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of the terms “KAPA” and “AMPure” (paragraph [0040]), which are trade names or marks used in commerce, have been noted in this application. These terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The examples above are not an exhaustive list of unmarked trade names or marks used in commerce throughout the specification. Please carefully read through and properly notate each instance.
Claim Objections
Claims 1, 9, and 11 are objected to because of the following informalities:
Claims 1 and 9 read “with one or more pairs of a forward and a reverse oligonucleotide primers” and should read “with one or more pairs of a forward and a reverse oligonucleotide primer[[s]]”. Claims 1 and 9 also read “wherein the position of the binding sites for the primers in a genome comprising a genomic rearrangement is adjacent” should read “wherein the position of the binding sites for the primers in a genome comprising a genomic rearrangement [[is]]are adjacent”.
Claim 11 reads “wherein one or more pairs of a forward and a reverse oligonucleotide primers comprise” and should read “wherein one or more pairs of a forward and a reverse oligonucleotide primer[[s]] comprise”. Claim 11 also reads, in (c), “the genome comprising gene amplification” and should read “the genome comprising a gene amplification” to remain consistent with the rest of the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112b - Indefiniteness
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 6 and 7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 is indefinite for failing to define the variable “x” in the claim or in the specification. “x” base pairs apart does not provide any meaningful limitation to the claim. Furthermore, the variable “x” could be different depending on the nucleic acid being analyzed (such as genomic DNA vs. cell-free DNA as in claims 3 and 4 in regards to the varying definitions of “adjacent”). For purposes of examination, the variable of x can be any amount, as long as the distance in the genome comprising the deletion is less than x in the reference genome. However, clarification is required.
Claim 7 is directed to the method of claim one “wherein the genomic rearrangement creates a breakpoint sequence and one of the binding sites for the forward and reverse primers spans the breakpoint sequence”. The phrase “one of the binding sites for the forward and reverse primers” makes it unclear whether the forward or reverse primer are binding the breakpoint itself, or if it’s one of the binding sites for a pair of forward and reverse primers that spans the breakpoint and thus would provide an amplification product of the breakpoint sequence. If it’s the latter, the claim could be amended to read “wherein the genomic rearrangement creates a breakpoint sequence and one of the pairs of forward and reverse primers produces an amplification product spanning the breakpoint sequence”.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 5-7, and 9 are rejected under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by Woodhouse (Woodhouse et al., US 2019/0241974 A1).
Claim 1: Woodhouse teaches a method of detecting genomic rearrangements through targeting of genomic regions of interest with pools of primers that are no close enough to produce an amplification product in a reference genome, but in genomes with the genomic rearrangement present, can produce an amplification product (Abstract). Woodhouse teaches contacting a sample with one or more pairs of forward primers and reverse primers that are not adjacent (not “in sufficient proximity”) in a reference genome, but in the presence of a genomic rearrangement are in sufficient proximity (reads on adjacent) to produce an amplification product (paragraph [0012]). Woodhouse teaches a method in which the primers are not adjacent in a reference genome and then are adjacent in a genome containing a rearrangement (paragraph [0012]). Woodhouse teaches performing amplification to detect the genomic rearrangement (paragraph [0012]).
Claim 2: Woodhouse teaches sequencing the amplified nucleic acids thereby detecting the genomic rearrangement (paragraph [0012]).
Claim 5: Woodhouse teaches detecting a gene fusion and that in designing the primer set one primer is on a different chromosome than the other primer and only a gene fusion that puts the primers on the same chromosome will produce an amplification product (paragraph [0012 and 0081]).
Claim 6: Woodhouse teaches detecting a genomic rearrangement that is a deletion in which the primer binding sites are located a sufficient distance apart to prevent amplification in a reference genome and then are close enough upon genomic rearrangement to produce an amplification product (paragraph [0077], Figure 7 and Figure 8).
Claim 7: Woodhouse teaches detecting the sequence of a breakpoint (“junction of the genomic rearrangement”) by designing primer sets that span the breakpoint and thus create an amplicon containing this sequence when the genomic rearrangement is present (paragraph [0049, 0091-0098 and 0206]).
Claim 9: Woodhouse teaches a method of detecting genomic rearrangements through targeting of genomic regions of interest with pools of primers that are no close enough to produce an amplification product in a reference genome, but in genomes with the genomic rearrangement present, can produce an amplification product (Abstract). Woodhouse teaches contacting a sample with one or more pairs of forward primers and reverse primers that are not adjacent (not “in sufficient proximity”) in a reference genome, but in the presence of a genomic rearrangement are in sufficient proximity (reads on adjacent) to produce an amplification product (paragraph [0012]). Woodhouse teaches a method in which the primers are not adjacent in a reference genome and then are adjacent in a genome containing a rearrangement (paragraph [0012]). Woodhouse teaches a method in which multiple types of genomic rearrangements can be detected in one reaction by multiple sets or pools of primers (paragraph [0012]). Woodhouse teaches performing amplification to detect the genomic rearrangement(s) (paragraph [0012]), followed by library formation, and sequencing (paragraphs [0022-0023]).
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.
Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Woodhouse (Woodhouse et al., US 2019/0241974 A1) in view of Liu (Liu et al., PLOS One 2007; cited on IDS of 10/3/2022 NPL #6).
The teachings of Woodhouse as they apply to claim 1, from which claims 3 and 4 depend, are detailed in the 102 rejection above. Briefly, and relevant to the instantly rejected claims, Woodhouse teaches a method of detecting genomic rearrangements in which primer pairs are designed to be distant (not adjacent) in reference genomes, but upon genomic rearrangement are brought into close enough proximity to produce a PCR amplicon (paragraph [0012]).
Woodhouse teaches that non-adjacent in genomic DNA is much farther than in cell free DNA (at least 10kb for genomic DNA versus at least 1kb for cell-free DNA; paragraph [0081]). Woodhouse also teaches an example in which “close proximity” is about 150bp (paragraph [0067]), but does not explicitly say whether this is genomic or cell-free DNA.
However, proximal PCRs in which “proximity” is in the range of less than 2000 base pairs in cellular genomic DNA is demonstrated in the art, as taught by Liu.
Liu teaches a method of primer approximation multiplex PCR (PAMP) in which breakpoint sequences are enriched by designing primers “approximated” flanking primers preferentially produce shorter PCR fragments in genomes in which a genomic rearrangement has occurred (pg 2, col 1 and Figure 2). Figure 2 of Liu demonstrates that efficient PCR product is generated in the presence of a deletion that brings primer pairs flanking the deletion region into close enough proximity to generate a product. In this example, the primers are spaced on average about 1kb apart meaning that the highlighted squares in Figure 2B would correspond to products around 2kb (or 2000 base pairs; relevant to claim 3). In the working example of Figure 6B, Liu demonstrates the creation of an about 2kb product that was produced by primer pairs proximal to the breakpoint created by a genomic deletion (pg 4, col 1-2 and Figure 6).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Woodhouse with the teachings of Liu. One would be motivated to consider “adjacent” or “proximal” as less than 2000 base pairs given the teaching by Liu that products less than 2000 base pairs are preferentially amplified compared to larger PCR products (Figure 2). One would have a reasonable expectation of success given that Liu successfully utilizes this principle to detect genomic fusion breakpoints in cellular genomic DNA.
Woodhouse in view of Liu do not explicitly teach that “adjacent” for cell-free DNA is less than 175 base pairs. However, Woodhouse teaches that “adjacent” for cell-free DNA would be a smaller distance than for cellular genomic DNA given that cell-free DNA is generally fragmented into smaller pieces than cellular genomic DNA (paragraph [0081]). Woodhouse teaches performing selective PCR in which adjacent is considered about 150 bp (relevant to claims 3 and 4; paragraph [0067]). While Woodhouse does not specify whether this is genomic or cell-free DNA, 150 bps is less than 2000 bp and less than 175 bp. The exact definition of “adjacent” as provided in claims 3-4 could be achieved through “routine optimization” through experimentation commonly employed when optimizing PCR conditions and thus are not patentably distinct from the prior art (see MPEP 2144.05 II.A. Routine Optimization). Additionally, where Liu teaches different amounts of amplification of different amplicon lengths, the prior art recognizes primer distance as a results effective variable (Figure 2 in Liu).
Claims 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Woodhouse (Woodhouse et al., US 2019/0241974 A1) in view of Arlt (Arlt et al., AJHG 2009).
The teachings of Woodhouse as they apply to claim 1, from which claim 8 depends, and claim 9, from which claim 11 depends, are detailed in the 102 rejection above. Briefly, and relevant to the instantly rejected claims, Woodhouse teaches a method of detecting genomic rearrangements in which primer pairs are designed to be distant (not adjacent) in reference genomes, but upon genomic rearrangement are brought into close enough proximity to produce a PCR amplicon (relevant to claim 11a; e.g., a gene fusion; paragraph [0012]). Woodhouse teaches that multiple types of genomic rearrangements can be detected in one reaction by multiple sets or pools of primers (paragraph [0012]). Woodhouse teaches performing amplification to detect the genomic rearrangement(s) (paragraph [0012]), followed by library formation, and sequencing (paragraphs [0022-0023]). Woodhouse also teaches detecting the sequence of a breakpoint (“junction of the genomic rearrangement”) by designing primer sets that span the breakpoint and thus create an amplicon containing this sequence when the genomic rearrangement is present (relevant to claim 11b; paragraph [0049, 0091-0098 and 0206]).
Woodhouse does not teach detecting a genomic rearrangement that is an amplification through the use of primers that are inward-facing in the genome comprising the amplification (claims 8 and 11c). However, detection of genomic amplifications through the use of primers that are outward-facing in a reference genome but inward-facing in a genome containing the amplification is known in the art, as taught by Arlt.
Alrt teaches a method of detecting aphidicolin induced duplication events in which PCR primers are designed pointing outward within the reference genome, and only upon genomic rearrangement are they placed in the correct orientation to amplify and sequence the breakpoint of the amplification event (pg 342, col 2 and Figure 5B).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Woodhouse with the teachings of Arlt. One would be motivated to examine amplifications given the assertion by Arlt that copy number variants (CNVs, e.g., amplifications/duplications) are “known to be a major cause of genetic and developmental disorders” (Abstract). One would be motivated use the outward vs inward facing primer design given the assertion by Arlt that this allows for selective amplification of chromosomes in which the genomic rearrangement had occurred, and that the primer design allows for determination of the amplification breakpoint no matter the orientation of the amplification (pg 342, col 2 and Figure 5B legend). One would have a reasonable expectation of success given that Arlt successfully sequences and determines the duplication breakpoints in several different APH-treated clones.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Woodhouse (Woodhouse et al., US 2019/0241974 A1) in view of Xie (Xie et al., Oncotarget 2016).
The teachings of Woodhouse as they apply to claim 9, from which claim 10 depends, are detailed in the 102 rejection above. Briefly, and relevant to the instantly rejected claims, Woodhouse teaches a method of detecting genomic rearrangements in which primer pairs are designed to be distant (not adjacent) in reference genomes, but upon genomic rearrangement are brought into close enough proximity to produce a PCR amplicon (paragraph [0012]).
Woodhouse does not teach aligning the sequencing reads toa reference genome to determine the genomic source of the genomic rearrangement. However, mapping breakpoints by aligning reads to a reference genome is known in the art, as taught by Xie.
Xie teaches a method of mapping deletion breakpoints at the CDKN2A locus through the use of primer approximation multiplex PCR and inverse PCR techniques (Abstract). Xie teaches determining the source of the genomic rearrangements by mapping (aligning) the genomic sequences with known data of a reference genome hg19 (Results - Breakpoint cloning with PAMP and inverse PCR, Figure 1 and 2).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Woodhouse with the teachings of Xie. One would be motivated to map to known reference genome datasets given the teaching by Xie that this enables one to determine the precise genomic breakpoints of complex deletions (Introduction). Xie also teaches that this enables one to determine exonic sources of transcript fusions (Results - Screening for fusion transcripts in additional melanoma cell lines and primary melanoma tumors). One would have a reasonable expectation of success given that Xie is using a similar method of PAMP, or selective PCR of smaller transcripts, to selectively amplify genomic rearrangements followed by sequencing, as in Woodhouse.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Woodhouse (Woodhouse et al., US 2019/0241974 A1) in view of Bieche (Bieche et al., International Journal of Cancer, 1998).
Woodhouse teaches a method of detecting genomic rearrangements through targeting of genomic regions of interest with pools of primers that are no close enough to produce an amplification product in a reference genome, but in genomes with the genomic rearrangement present, can produce an amplification product (Abstract). Woodhouse teaches contacting a sample with one or more pairs of forward primers and reverse primers that are not adjacent (not “in sufficient proximity”) in a reference genome, but in the presence of a genomic rearrangement are in sufficient proximity (reads on adjacent) to produce an amplification product (paragraph [0012]). Woodhouse teaches a method in which the primers are not adjacent in a reference genome and then are adjacent in a genome containing a rearrangement (paragraph [0012]). Woodhouse teaches performing amplification to detect the genomic rearrangement (paragraph [0012]). Woodhouse teaches separating the sample into a plurality of reaction volumes and performing the method on each reaction volume and detecting the presence or absence of the genomic rearrangement in each volume (paragraph [0412]). Woodhouse teaches determining the number of volumes in which the genomic rearrangement is detected in order to eliminate false positives (paragraph [0412]).
Woodhouse does not teach adding a detectably-labeled first probe capable of hybridizing to an amplicon of the first and second primers and performing a step of detection with the probe during the amplification reaction. However, use of detectably labeled probes to detect the presence of an amplicon during amplification is known in the art, as taught by Bieche.
Bieche teaches a method of detecting gene amplification in samples through the use of fluorescently labeled probes that specifically hybridize to the amplicons of interest to allow for real time detection of amplification products (pg 661, col 2, paragraph 4 to pg 662, col 1, paragraphs 1-3).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Woodhouse with the teachings of Bieche. One would be motivated to do so given the numerous assertions of the advantages of this system by Bieche including “(i) the probe-based homogeneous assay provides a real-time method for detecting only specific amplification products, since specific hybridation of both the primers and the probe is necessary to generate a signal…(iv) The real-time PCR method is run in a closed-tube system and requires no post-PCR sample handling, thus avoiding potential contamination; (v) the system is highly automated, since the instrument continuously measures fluorescence in all 96 wells of the thermal cycler during PCR amplification and the corresponding software processes, and analyzes the fluorescence data; (vi) the assay is rapid, as results are available just one minute after thermal cycling is complete; (vii) the sample throughput of the method is high, since 96 reactions can be analyzed in 2 hr” (pg 662, col 1, paragraph 2). One would have a reasonable expectation of success given that the method of Woodhouse produces specific amplicons and the method of Bieche would allow specific detection of those amplicons.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683