DETAILED ACTION
Status of the Application
Claims 1-28 are pending.
Claims 1-28 are under examination.
The following Office Action is in response to Applicant's communication dated 01/11/2024.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112 (a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 28 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 28 recites a method for treating the particular type of cancer in the subject. However, the specification fails to reasonably convey to a person of ordinary skill in the art that the inventors were in possession of the claimed method. Specifical, the specification does not describe how the detection of a gene alteration using the claimed method determine a specific regiment, dosage, timing, or therapeutic selection. While the specification lists categories of therapeutic agents (e.g. siRNA, inhibitor, anticancer agents, genome editing) it does not provide sufficient guidance enabling a skill artisan to perform the claimed treatment step without undue experimentation. The disclosure lacks any working examples, treatment protocols, or demonstrated a linkage between a detected gene alteration and administration of a particular therapy. Therefore, the specification does not demonstrate possession of the full scope of the claimed method of treatment as of the effective filing date.
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.
Claim(s) 23 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Liu et al. (US20210180051A1, Filed Dec 31st, 2018)
Regarding claim 23, Liu discloses a kit for detecting a gene alteration in a biological sample, comprising:(a) a template switch oligo comprising a first universal primer;[paragraph 0069]
(b) the RT primer comprises a linear structure having at least 5 random nucleotides. (e.g. Molecular barcodes are random nucleotides and can be as long as 3 to 50 nucleotides, or even longer. They are usually synthesized as a part of the primer or adapter” [paragraph 0034]).
(c) one or more gene specific primers each comprising a first or second adapter sequence and universal primers each comprising a first or second adapter sequence, respectively, wherein the first adapter sequence of the gene specific primer is different from the second adapter sequence of the universal primer or the second adapter sequence of the gene specific primer is different from the first adapter sequence of the universal primer; (d) a primer pair complementing the first and second adapters, respectively, wherein each primer of the primer pair comprises a third or fourth adapter sequence, respectively, and wherein the third and fourth adapter sequences are different from each other; [paragraph 0072, table 1]
(e) a reverse transcriptase;(e.g. SMARTScribe™ Reverse Transcriptase [paragraph 0069]) (f) a DNA polymerase (e.g. Multiplex PCR Master Mix [paragraph 0071]); and (g) deoxy-ribonucleoside triphosphate (dNTP). [paragraph 0069]
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.
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.
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.
Liu et. al. and Picelli et al.
Claim(s) 1, 2, 7, 9-12, 13, 14, and 18-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20210180051A1, Filed Dec 31st, 2018) in view of Picelli et al. (Nat Protoc 9, 171–181 (2014))
Regarding claim 1, Liu discloses a method for detecting a gene alteration in a biological sample, comprising steps of: (a) mixing a target RNA obtained from the biological sample, a template-switching oligo, a reverse transcriptase, and a reverse transcription (RT) primer in a mixture, wherein the template switch oligo comprises a first universal primer sequence; (b) subjecting the mixture to a condition under which reverse transcription occurs to provide a target DNA complementary to the target RNA, (c) amplifying the target DNA with a first pair of primers to obtain a first PCR product, wherein the first set of primers comprise a gene specific primer and a universal primer, the gene specific primer comprises a 5'-end first or second adapter sequence and a 3'-end sequence that hybridizes to a target gene under stringent conditions, the universal primer comprises a 5'-end first or second adapter sequence and a 3'-end sequence comprising the first or second universal primer sequence, and the first and second adapter sequences are different from each other; (e.g. method generates cDNA from RNA using one universal primer at 5′ end and one target specific primer at 3′ end. A universal adapter is added on the 3′ end of the newly synthesized cDNA by template switching while the RNA is converted into cDNA from random hexamers in reverse transcription. The resulting cDNA serves as template for target amplification in multiplex PCR with a universal primer and a panel of target specific primers. The resulting cDNA serves as template for target amplification in multiplex PCR with a universal primer and a panel of target specific primers. [paragraph 0026])
(d) amplifying the first PCR product with a second pair of primers to obtain a second PCR product, wherein each of the second pair of primers comprises a 5'-end third or fourth adapter sequence and a 3'-end sequence that hybridizes to the first or second adaptor sequence, respectively, and the third and fourth adapter sequences are different from each other; and (e) analyzing the second PCR product to detect the presence of the gene alteration (e.g. The amplification products can be further amplified while sample barcodes and sequencing adapters are added. The final library can then be used in downstream analysis, such as NGS sequencing.[paragraph 0014]. Further, fig. 3 shows cDNA in a multiplex PCR reactions.)
However, Liu does not disclose the RT primer comprises a second universal primer sequence;
Picelli discloses initiating reverse transcription using oligo(T) primer that includes a 5’ universal adapter sequence, thereby incorporating adapter into cDNA during first-strand synthesis. The incorporated adapter sequence subsequently serves as universal priming site for PCR amplification of cDNA [Fig 1].
As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to combine these teachings to incorporate the RT primer design of Picelli into Liu’s method in order to introduce reverse transcription , thereby simplifying downstream amplification and enabling efficient PCR amplification and sequencing of the resulting cDNA products. Additionally, a one of ordinary skill in the art would have recognize that the oligo(T) portion of the RT primer in Picelli’s protocol could be replaced with target specific sequence taught by Liu, depending on the desired transcript capture strategy. Substitution of primer binding regions to achieve desirable cDNA sequence was well known in the art of reverse transcription and represent routine design choice. Accordingly, a POSITA would have reasonably expected success in modifying Picelli’s primer to use in Liu’s method and simplifying downstream cDNA amplification. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, A and B)
Regarding claim 2, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu further discloses the RT primer comprises a linear structure having at least 5 random nucleotides. (e.g. Molecular barcodes are random nucleotides and can be as long as 3 to 50 nucleotides, or even longer. They are usually synthesized as a part of the primer or adapter” [paragraph 0026]).
Regarding claim 7, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Picelli further discloses second universal primer is less than 30 bp in length. (e.g. T7 primer as shown in Fig 1 is 25 nucleotides long)
Regarding claim 9, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu further discloses at least one of the first adapter sequence or the second adapter sequence comprises a barcode sequence.[paragraph 0023]
Regarding claim 10-12, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu further discloses target DNA is at least 100 bp/ 100 bp to 4000 bp/ 100 bp to 500 bp in length. (e.g. target on DNA fragments of 160 bp in length [paragraph 0015])
Regarding claim 13, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu further discloses the target DNA is amplified by multiplex PCR with at least two gene specific primers (e.g. “A plurality of target-specific primers (e.g., >6, >10, >100, >1000, >10,000, etc.) can be used.”[paragraph 0014]).
Regarding claim 14, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu further discloses amplification of short RNA derived DNA using single-gene-specific primer in combination with universal primer added by template switching, where in amplification products are generated depending on which side of the target sequence the gene-specific primer binds, thereby producing direction-dependent PCR products corresponding to 5’ or 3’ target regions as recited in claim 14 [paragraph 0015].
Regarding claim 18, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu further discloses a gene fusion comprising a sequence of a known gene selected from the group consisting of ABL1, AKT3, ALK, ARV7, BCR, BRAF, CD74, EGFR, ERBB2, ERBB4, ERG, ESR1, ETV1, ETV4, ETV5, ETV6, EZR, FGFR1, FGFR2, FGFR3, KIT, KMT2A, MET, NRG1, NRG2, NTRK1, NTRK2, NTRK3, NUTM1, PDGFRA, PDGFRB, PIK3CA,RAF1, RARA, RET, ROS1, RSPO2, SDC4, SLC34A2 and TMPRSS2. [table 2]
Regarding claim 19, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu further discloses the biological sample is from a solid tumor. [paragraph 0005]
Regarding claim 20, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu further discloses the biological sample is a Formalin-Fixed Paraffin-Embedded (FFPE) tissue sample [paragraph 0017].
Regarding claim 21, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu further discloses the second PCR product is analyzed by a next generation sequencing [paragraph 0024].
Liu et al., Picelli et al., and Iafrate et al.
Claim(s) 3-6, 8, 22, and 24-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20210180051A1, Filed Dec 31st, 2018) in view of Picelli et al. (Nat Protoc 9, 171–181 (2014)), and Iafrate et al. (US10450597B2, Flied Jan 26th 2015)
Regarding claim 3, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu does not disclose the RT primer comprises a stem-loop structure and an overhang structure having at least 5 random nucleotides.
Iafrate discloses the RT primer comprises a stem-loop structure [Fig. 3 and column 12, lines 65-67] and an overhang structure having at least 5 random nucleotides (e.g. molecular barcodes can be built into primers (e.g., RT primers, target-specific primers, extension sequence primers) such that each individual molecule produced by a primer obtains a unique barcode tag. [column 12, lines 42-49]. The reference also disclosed a variety of random nucleotides lengths [column 17, lines 3-27]).
As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to modify the method of Liu by incorporating the stem-loop RT primer with barcode taught by Iafrate as both references are directed to sequencing-base detection of genetic alterations using reverse transcription, barcoding, PCR amplification, and address the common goal of improving molecular identification accuracy and downstream sequencing performance. Iafrate teaches that RT primers comprise stem-loop structures and random nucleotide barcodes, Liu similarly teaches the use of random nucleotide barcode sequence in RT primers. Stem-loop RT primers were well-known in the art at the time of the invention as a design choice that provides improved priming specificity, structural stability, and efficient incorporation of barcode and adapter sequences. One of ordinary skill in the art would have recognized that substituting the RT primer of Liu with a stem-loop RT primer represents the use of a known alternative primer structure to perform the same function in the same manner. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B).
Regarding claim 4, Liu, Picelli, and Iafrate disclose a method for detecting a gene alteration in a biological sample of claim 3 as discussed fully above and incorporate here. Iafrate further discloses the stem-loop structure is a hairpin stem-loop structure or a Y shape stem-loop structure. [Fig. 3].
Regarding claim 5, Liu Liu, Picelli, and Iafrate disclose a method for detecting a gene alteration in a biological sample of claim 3 as discussed fully above and incorporate here. Iafrate further discloses the stem-loop structure comprises a barcode sequence. (e.g. primer complementary common regions base pair to form the stem of a hairpin having a loop portion that comprises the molecular barcode.[column 17, lines 33-40]).
Regarding claim 6, Liu, Picelli, and Iafrate disclose a method for detecting a gene alteration in a biological sample of claim 3 as discussed fully above and incorporate here. Iafrate further discloses the stem-loop structure is at least the length of the second universal primer sequence. (e.g. primer complementary common regions base pair to form the stem of a hairpin having a loop portion that comprises the molecular barcode. The loop and stem collectively having selectable lengths spanning at least 6-25 nucleotides or more. Because the applicant’s universal primers are 7-23 nucleotides, the lengths disclosed in Iafrate meets the claimed length requirements [column 17, lines 3-54]).
Regarding claim 8, Liu, Picelli, and Iafrate disclose a method for detecting a gene alteration in a biological sample of claim 3 as discussed fully above and incorporate here. Iafrate further discloses the stem of the stem-loop structure is 8 bp in length. (e.g. primers comprise stem-loop (hairpin) structure formed by two complementary common sequences, wherein the stem length is selectable within the disclosed ranges including 6-12 nucleotides. As set forth in MPEP 2144.05; In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003); "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness.").
Liu et al. and Iafrate et al.
Claim(s) 22, and 24-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20210180051A1, Filed Dec 31st, 2018) in view of Iafrate et al. (US10450597B2, Flied Jan 26th 2015)
Regarding claim 22, Liu discloses a kit for detecting a gene alteration in a biological sample, comprising:(a) a template switch oligo comprising a first universal primer;[paragraph 0069]
(c) one or more gene specific primers each comprising a first or second adapter sequence and universal primers each comprising a first or second adapter sequence, respectively, wherein the first adapter sequence of the gene specific primer is different from the second adapter sequence of the universal primer or the second adapter sequence of the gene specific primer is different from the first adapter sequence of the universal primer; (d) a primer pair complementing the first and second adapters, respectively, wherein each primer of the primer pair comprises a third or fourth adapter sequence, respectively, and wherein the third and fourth adapter sequences are different from each other; [paragraph 0072, table 1]
(e) a reverse transcriptase;(e.g. SMARTScribe™ Reverse Transcriptase [paragraph 0069]) (f) a DNA polymerase (e.g. Multiplex PCR Master Mix [paragraph 0071]); and (g) deoxy-ribonucleoside triphosphate (dNTP). [paragraph 0069]
However, Liu does not disclose the RT primer comprises a stem-loop structure and an overhang structure having at least 5 random nucleotides.
Iafrate discloses the RT primer comprises a stem-loop structure [Fig. 3 and column 12, lines 65-67] and an overhang structure having at least 5 random nucleotides (e.g. molecular barcodes can be built into primers (e.g., RT primers, target-specific primers, extension sequence primers) such that each individual molecule produced by a primer obtains a unique barcode tag. [column 12, lines 42-49]. The reference also disclosed a variety of random nucleotides lengths [column 17, lines 3-27]).
The rationale for combining the Liu and Iafrate references with respect to claim 22 is the same as set forth above for claim 3 and is incorporated herein by reference, as claim 22 does not introduce a limitation that would alter the motivation to combine or the predictable resulted achieved by the combination.
Regarding claim 24, Liu and Iafrate disclose a method for detecting a gene alteration in a biological sample of claim 22 as discussed fully above and incorporate here. Liu further discloses universal primer is less than 30 bp in length. (e.g. SEQ ID NO. 62 [paragraph 0071]).
Regarding claim 25, Liu and Iafrate disclose a method for detecting a gene alteration in a biological sample of claim 22 as discussed fully above and incorporate here. Iafrate further discloses the stem of the stem-loop structure is 8 bp in length. (e.g. primers comprise stem-loop (hairpin) structure formed by two complementary common sequences, wherein the stem length is selectable within the disclosed ranges including 6-12 nucleotides. As set forth in MPEP 2144.05; In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003); "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness.")
Regarding claim 26, Liu and Iafrate disclose a method for detecting a gene alteration in a biological sample of claim 22 as discussed fully above and incorporate here. Iafrate further discloses the overhang structure is a random hexamer with a length of 5 to 10 nucleotides.[column 4, lines 13-15]
Regarding claim 27, Liu and Iafrate disclose a method for detecting a gene alteration in a biological sample of claim 22 as discussed fully above and incorporate here. Liu further discloses the kit further comprises at least one labeled dNTP, wherein the dNTP is labeled with a biotin group, Digoxigenin (DIG) or other molecules [paragraph 0023].
Liu et al., Picelli et al., and Dongen et al.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20210180051A1, Filed Dec 31st, 2018) in view of Picelli et al. (Nat Protoc 9, 171–181 (2014)), and Dongen et al. (Leukemia 13, 1901–1928 (1999)).
Regarding claim 15, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu does not disclose the gene specific primer hybridizes to the target DNA within a distance of at least 25 bp from a fusion junction boundary.
Dongen discloses fusion RT-PCR primer design in which “numbers refer to the 5’ nucleotide position if each primer” and provide both (i) the fusion junction boundary nucleotide positions and (ii) tables listing the 5’ positions of gene-specific primers for fusion targets. For example, Dongen identifies a E2A-PBX1 fusion junction between E2A nucleotide 1518 and PBX1 nucleotide 388 (junction boundary), and further lists a gene-specific primer having a 5’ position of 1479 in E2A [Fig. 2 and Table 4]. Thus, the primer hybridizes 1518-1479 = 39 bp from the fusion junction (satisfy the limitation of “at least 25 bp”).
As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to combine these teachings to incorporate the primer placement teaching of Dongen into Liu and Picelli’s method. Liu and Picelli method directs to detecting gene alterations, including fusion evens, using gene-specific primers, but does not specify numerical constraints on primer placement relative to fusion junction. Dongen expressly teaches fusion-specific primer design in which gene-specific primers are positioned at defined nucleotide distances from fusion junction, as part of a standardized PCR strategy to improve amplification reliability, sensitivity, and reproducibility in fusion detection assays. A PHOSITA seeking to implement Liu and Picelli’s fusion detection method with predictable and reliable amplification performance, would have looked to Dongen for established guidance on primer placement relative to fusion junction, both references address detection of fusion genes using PCR-based techniques and share the same technical field and objective of accurate fusion identification. Incorporating Dongen’s teaching of positioning gene-specific primers at least 25 bp from a fusion junction represents a predictable use of known primer-design principles to optimize Liu’s method, yielding expected results, consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, C&D).
Liu et al., Picelli et al., and Skálová et al.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20210180051A1, Filed Dec 31st, 2018) in view of Picelli et al. (Nat Protoc 9, 171–181 (2014)), and Skálová et al. (Am J Surg Pathol. 2016;40(1):3-13.).
Regarding claim 16, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu and Picelli do not disclose gene specific primers are selected from the group consisting of SEQ ID NOs: ll, 12, 14-35 and any complementary sequence thereof.
Skálová discloses the use of gene specific RT-PCR primers for detecting fusion transcripts involving NTRK3 gene, including primers designed to hybridize to defined regions of the NTRK3 sequence fusion [table 2: “Primers for Detection of ETV6-NTRK3 Fusion Transcripts”]. The reference further teaches that such primers are routinely used in standard and nested RT-PCR assays to detect gene fusion. Notably, the primer TRKC1059 [table 2] in the reference has 100.0% identity in 17 residues overlap with SEQ ID NO. 31 of the present application.
As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to combine these teachings to use known gene-specific primers disclosed by Skálová, including primers identical to SEQ ID NO. 31, in Liu and Picelli’s method because both references directed to detecting gene fusions by RT-PCR, and substitution or selection of known primers for known target genes represents a routine design choice yielding predictable results, consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, A).
Liu et al., Picelli et al., and Atanassov et al.
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20210180051A1, Filed Dec 31st, 2018) in view of Picelli et al. (Nat Protoc 9, 171–181 (2014)), and Atanassov et al. (Plant Methods. 2009;5:14).
Regarding claim 17, Liu and Picelli discloses a method for detecting a gene alteration in a biological sample of claim 1 as discussed fully above and incorporate here. Liu and Picelli do not disclose the universal primer is selected from the group consisting of SEQ ID NOs:1-10.
Atanassov discloses PCR-based fusion and overlap extension methods employing universal primer sequences for amplification and fusion of DNA fragments. Atanassov teaches the routine use of universal primers (e.g. M13 forward and reverse primers, same as SEQ ID NO: 3 and 8 in the current application) flanking cloned DNA fragments for PCR amplification and fusion [pages 4 and 5]. These universal primers are fixed and used across different constructs, corresponding in function and structure to the claimed universal primers.
As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to combine these teachings to use M13 universal primers in Liu and Picelli ’s method. Liu already teaches the use of universal primers in the claimed method, and the particular selection of specific universal primer sequences represents a routine design choice. Atanassov is cited to confirm that the use of claimed predefined universal primers for PCR amplification was well known and conventional in the art at the time of the invention. It would have been obvious to a PHOSITA to substitute different universal primer, such as those cited in claim 17, for use in Liu and Picelli ’s method in order to facilitate efficient and reproducible amplification, as universal primers were commonly employed across PCR-base workflows, consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B).
Liu et al. and Coco et al.
Claim(s) 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20210180051A1, Filed Dec 31st, 2018) in view of Cocco et al. (Nat Rev Clin Oncol 15, 731–747 (2018)).
Regarding claim 28, Liu discloses a method of determining whether a subject is at increased risk of a particular type of cancer or at risk for a particular type of cancer associated with a particular genotype by detecting a gene alteration from a biological sample obtained from the subject (Example 4, Determine the Potential NTRK Gene Alteration [paragraph 0156]) . However, Liu does not disclose (b) treating the particular type of cancer in the subject.
Cocco discloses NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 response well to first-generation TRK inhibitors such as larotrectinib or entrectinib, which show high response rates (>75%) across diverse tumor types. Resistance can arise through NTRK kinase domain mutations, but may be addressed by second-generation TRK inhibitors, including LOXO-195 and TPX-0005, currently under clinical investigation [abstract].
As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to combine these teachings to use Liu’s gene alteration detection method to identify subjects having NTRK fusion and to treat the identified cancer using TRK inhibitors disclosed by Cocco. Liu discloses an example of NTRK fusion detection including primers designs. Cocco teaches that cancers having these fusions response well to TRK inhibitors. Hence it would have been obvious to one of ordinary skill in the art to apply Liu’s method for detecting NTRK fusions to identify affected subjects, then treat them using TRK inhibitors taught by Cocco. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143,A)
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/ Examiner, Art Unit 1684
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684