DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-6 are pending in the instant application.
Claim Objections
The disclosure is objected to because of the following informalities: page 13 of the instant specification contains a drawing.
As set forth in 37 C.F.R. 1.58 Chemical and mathematical formulae and tables.
The specification, including the claims, may contain chemical and mathematical formulae, but shall not contain drawings or flow diagrams.
Appropriate correction is required. For example, applicant may delete the drawing from the specification, include it as a figure, and include a description of the new figure in the “Brief Description of the Drawings” section of the specification, taking care not to introduce new matter into the specification.
Priority
It is noted that the instant application ultimately claims priority to provisional application 63/056,755, however the structures set forth in the claims are not present in the provisional application. Therefore the effective filing date of the claims 7/27/2021.
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.
Claims 1–6 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites the limitations “providing a fist primer primer probe which is allele specific and a second primer probe; wherein said first and second primer probes are targeted to said KRAS mutations and wherein said primer probes allow formation of a PCR process product”. The term “fist” is unclear. It appears to be a misspelling of the word “first”. Additionally, the terms “primer primer probe” and “primer probe” are unclear. The specification defines the terms “primer”, “probe”, “forward primer” and “reverse primer” at pages 8-9, however it lacks a definition for the phrases “primer primer probe” or “primer probe”. The function imparted by these phrases on the structures claimed are unclear because these phrases are not terms of art. For example, are these phrases meant to indicate structural requirements where a “primer primer probe” is a forward primer and the “primer probe” is a reverse primer or do these phrases also impart functional requirements such that the oligonucleotides encompassed are capable of functioning as a primer or as a probe? While it is known in the art that the term ‘primer’ refers to an oligonucleotide that is extendable on its 3’ end and that both primers and probes are capable of hybridizing to complementary DNA sequences, the metes and bounds of the phrases used in the claims are unknown. Also, the term “PCR process” appears redundant as the term “PCR” is normally meant to signify an amplification process. Accordingly, the use of the term “process” to apparently modify the term “PCR” is unclear. It is suggested the claims be amended to recite “PCR product” instead of “PCR process product”.
Claims 3 and 5 are unclear in the recitation of “cell-associated DNA” and “non cell-associated DNA”. The terms are not defined by the specification and the claim does not make the metes and bounds of the term “associated” clear. For example, does “cell-associated” refer to DNA that originates from a cell and is cell free or does it refer to DNA inside a cell? Does “non-cell associated” DNA refer to cell free DNA? The metes and bounds of each phrase are unclear and the difference between the two cannot be discerned from the specification or the claims.
The recitation of “said xenonucleic acid clamps” lacks sufficient antecedent basis in because the recitation before it only refers to a single XNA clamp. It is not clear what additional clamps are referred to in the use of the plural “clamps”. Additionally, the claims recite that the clamps have “aza-aza, thio-aza and oxy-aza chemical functionality”, however it is not clear if applicant intends that each clamp have all three or if these are meant to be recited in the alternative. Further, the term “functionality” is unclear in relation to the structures recited in the claims because each structure does not appear to have all three functional groups. The metes and bounds of the claims are therefore unclear.
Claim Rejections - 35 USC § 103
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.
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.
Claim 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over McKinzie (McKinzie et al., 2002, Detection of rare K-ras codon 12 mutations using allele-specific competitive blocker PCR, Mutation Research 517, 209-220) in view of Powell (2016) (Powell et al., US 2016/0194691 A1), Powell (2019) (Powell et al., US 2019/0330692 A1), and Makarov (US 2014/0038185 A1).
Regarding claim 1, McKinzie teaches using a method to detect human KRAS codon 12 mutations (McKinzie, abstract). McKinzie teaches the biological sample to be cultured TK6 cells from which human genomic DNA is isolated (pg. 211, part 2). As per the specification, “biological sample” can include both human and animal species (pg.9, specification). Regarding the recitation of “providing a fist primer primer probe which is allele specific and a second primer probe; wherein said first and second primer probes are targeted to said KRAS G12C mutations and wherein said primer probes allow formation of a PCR process product”: as set forth above in the 112(b) rejection, the phrase is unclear as to what “primer primer probe”, and “primer probe” mean. The specification does not define these terms. The specification does teach a forward primer, reverse primer and probes (pg. 11). Therefore, the broadest reasonable interpretation for these terms is taken to be primers for PCR amplification. McKinzie teaches that allele-specific competitive blocker PCR (ACB-PCR) reaction involves three primers, a mutant allele specific primer (MSP), a blocker primer (BP), which is designed to hybridize to the wildtype sequence, and a downstream reverse primer (pg. 214, col 2). McKinzie teaches an allele-specific amplification method in which the preferential amplification of the mutant allele occurs by using a primer that has more mismatches to the wild type allele than to the mutant allele (MSP). Additionally, a non-extendable primer with more mismatches to the mutant allele than to the wild-type allele (BP) competes with the MSP for binding to the wild type allele, thereby reducing background amplification from the wild type allele (abstract). McKinzie teaches performing a PCR amplification in a reaction solution under hybridization conditions thereby generating multiple amplicons. McKinzie teaches detecting said amplicons. ACB-PCR amplification products were analyzed by electrophoresis through 8% polyacrylamide/Tris acetate EDTA gels (pg. 213, section 2.5).
McKinzie does not teach providing a target specific xenonucleic acid (XNA) clamp oligomer probe specific for a wildtype polynucleotide sequence or admixing a primer pair comprising an allele specific mutant primer and the xenonucleic acid clamping probe with the target nucleic acid sample.
However, Powell (2016) teaches using XNA clamps. Powell (2016) teaches XNA probe clamping sequences are designed to bind specifically, by Watson-Crick base pairing, to wild-type sequences in the DNA templates derived from the biological sample of interest. Powell (2016) teaches the presence of the XNA probes in the PCR primer mix employed for the target amplification reaction causes inhibition of the polymerase mediated amplification of wildtype templates but does not impede the amplification of mutant template sequences (pg. 3, [0030]). Powell (2016) teaches in Table 1 the components for a reaction. In Fig. 1, Powell (2016) teaches the mechanism of the XNA clamping where the modified DNA oligo probe binds or hybridizes tightly to complementary DNA target sequences (wild type DNA) or clamps to wild type DNA and blocks further wild type amplification. This probe or XNA "clamp" does not bind to mutated DNA, allowing for multiple amplicons to be amplified and detected using PCR (pg. 1, abstract and pg.3, [0031], pg. 4, [0049]). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to modify the methods of McKinzie to use the XNA probe technology taught by Powell (2016). Powell (2016) teaches that XNA clamps allow for blocking DNA polymerase activity on wild type DNA template background (pg. 2, [0028]) and that XNAs hybridize tightly to complementary DNA target sequences only if the sequence is a complete match.
McKinzie and Powell (2016) do not teach xenonucleic acid clamps have aza-aza, thio-aza and oxy-aza chemical functionality and selected from the group consisting of the chemical structures set forth in the claims where base is selected from the group consisting of adenine, cytosine, guanine, thymine and uracil. Powell (2019) teaches preferred xenonucleic acids having aza-aza, thio-aza, and oxy-aza (pg. 2, [0015], FIG. 7B). Powell (2019) teaches that a target specific XNA clamp with oxy-aza, aza-aza and thio-aza moieties can be used so that during qPCR only the mutant templates are amplified (pg. 2, [0026]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to use the XNA structures taught by Powell (2019) in the method of McKinzie and Powell (2016) because Powell (2019) teaches these structures can be used in XNA clamps during PCR so that only mutant templates are amplified.
Regarding claim 2, Powell (2016) teaches how circulating tumor cells (CTC’s) and cell free DNA (cfDNA) derived from tumor cells are present in the peripheral blood of cancer patients (pg. 1, FIG. 6, [0013]). In example 2, Powell (2016) teaches PCR based enrichment of mutant DNA template sequences from template DNA derived from a lung cancer tumor biopsy sample (pg. 8, [0082]).
Regarding claim 3, Powell (2016) teaches biological samples consisting of genetic material present in circulating cells and cell free genetic material from biological fluids such as plasma (pg. 4, [0040]), DNA isolated from FFPE tissue blocks or fresh frozen sections (pg. 5, [0050]) and circulating tumor cells and cell free DNA derived from tumor cells (FIG. 6, pg. 1, [0013]).
McKinzie, Powell (2016), and Powell (2019) do not teach that the mutation is KRAS G12C.
Makarov teaches that KRAS mutations at KRAS locus include Gl2D, Gl2R, Gl2S, Gl3D, Gl2C, Gl2A and G12V (pg. 24, [0277]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to modify the teachings of McKinzie, Powell (2016), and Powell (2019) to include analysis of KRAS mutation G12C for the obvious benefit of detecting all KRAS mutations that may be present in a sample.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over McKinzie in view of Powell (2016), Powell (2019), and Makarov as applied to claims 1-3 above and further in view of Lianidou (Lianidou et al. 2018, Liquid biopsies, Genes, Chromosomes Cancer, 58:219-232).
The teachings of McKinzie, Powell (2016), Powell (2019) and Makarov are set forth above. Regarding claims 4 and 5, McKinzie, Powell (2016), Powell (2019) and Makarov do not teach the biological sample is obtained from a healthy human or animal subject. Lianidou teaches doing liquid biopsy to analyze circulating tumor cells, circulating tumor DNA, circulating miRNAs, and tumor derived extracellular vesicles that are shed from primary tumors and their metastatic sites into peripheral blood (pg. 219, FIG 1, introduction). Lianidou teaches analyzing circulating tumor cells in patients without signs of breast cancer recurrence (page 211, col 2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to include analysis of subjects without signs of cancer for the purpose of monitoring cancer recurrence or to use liquid biopsy to screen normal subjects for tumor derived mutations, since it has shown significant potential for early cancer diagnosis, screening and detection as taught by Lianidou (pg. 219, introduction). The specification does not define the term “healthy”, therefore the term has been given its broadest reasonable interpretation to include patients without signs of cancer recurrence as explained by Lianidou.
Claim 5 is rejected for the same reasons as claims 1-3 in the previous rejection, and applied to claim 5 as dependent from claim 4.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over McKinzie in view of Powell (2016), Powell (2019), and Makarov as set forth in claims 1-3 above and further in view of Zhao (Zhao et al, 2005, Detection of hepatitis B virus DNA by rea-time PCR using TaqMan MGB probe technology, World Journal of Gastroenterology, 1(4), 508-510).
The teachings of McKinzie, Powell (2016), Powell (2019) and Makarov are set forth above. McKinzie, Powell (2016), Powell (2019) and Makarov do not teach a probe in addition to an XNA probe clamp.
Zhao teaches use of a TaqMan-MGB probe between primers for amplification was designed to detect PCR products (pg. 508, Abstract). Zhao teaches that use of the TaqMan MGB probe, has specificity, sensitivity, remarkable accuracy and reproducibility (pg. 508, introduction). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to modify the teachings of McKinzie, Powell (2016), Powell (2019) and Makarov to incorporate a TaqMan probe taught by Zhao because Zhao teaches that real-time PCR using TaqMan probes is an accurate, sensitive and highly reproducible method for detection.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No.10,400,277, or unpatentable over claims 1-9 of U.S. Patent No.11,208,689, each in view of McKinzie, Powell (2016), Powell (2019), and Makarov.
The claims of ‘277 and ‘689 (hereinafter referred to as the patent claims) each teach a biological sample and isolating DNA from said biological sample containing a genetic variation, providing a target specific xenonucleic acid (XNA) clamp oligomer probe specific for a wildtype polynucleotide sequence; so that during the qPCR process only mutant templates are amplified, admixing the primer probes and the xenonucleic acid clamping probe with the target nucleic acid sample, and performing a PCR amplification process in a reaction solution under hybridization conditions thereby generating multiple amplicons.
The patent claims do not teach a first primer primer probe which is allele specific and a second primer probe; wherein said first and second primer probes are targeted to said KRAS mutations and wherein said primer probes allow formation of a PCR process product. In Fig. 2, McKinzie teaches that allele-specific competitive blocker PCR (ACB-PCR) reaction involves two primers, the mutant specific primer (MSP) and blocker primer (BP). McKinzie teaches an allele-specific amplification method in which the preferential amplification of the mutant allele occurs by using a primer that has more mismatches to the wild type allele than to the mutant allele (MSP). Additionally, a non-extendable primer with more mismatches to the mutant allele than to the wild-type allele (BP) competes with the MSP for binding to the wild type allele, thereby reducing background amplification from the wild type allele (abstract). McKinzie teaches detection of KRAS mutations.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to the patent claims with the teachings of McKinzie as directed to using an allele specific primer to detect KRAS mutation. It would have been obvious to a person of ordinary skill in the art to be motivated to use allele specific primers as taught by McKinzie in order to target polynucleotide sequence of KRAS mutation or any type of genetic variation.
The patent claims teach a subject having a neoplastic disease.
The patent claims and McKinzie do not teach the biological sample is selected from the group consisting of formalin-fixed paraffin embedded (FFPE) tissue, fresh frozen tumor specific tissue, circulating tumor cells, circulating cell-associated DNA from plasma, and circulating non-cell associated DNA from plasma. Powell (2016) teaches biological samples consisting of genetic material present in circulating cells and cell free genetic material from biological fluids such as plasma (pg. 4, [0040]), DNA isolated from FFPE tissue blocks or fresh frozen sections (pg. 5, [0050]) and circulating tumor cells and cell free DNA derived from tumor cells (FIG. 6, pg. 1, [0013]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to modify the teachings of the patent claims and McKinzie to use biological samples consisting of genetic material present in circulating cells and cell free genetic material from biological fluids such as plasma, DNA isolated from FFPE tissue blocks or fresh frozen sections and circulating tumor cells and cell free DNA derived from tumor cells of Powell (2016). A person of ordinary skill in the art would have recognized that It is an obvious benefit to use such biological sample as a diagnostic to diagnose cancer in patient tumors. Powell (2016) teaches as more and more somatic mutations are shown to be biomarkers for cancer prognosis and prediction of therapeutic efficacy, the need for efficient and effective methods to detect rare mutations in a sample is becoming more and more critical (pg. 1, [0007]).
The patent claims and McKinzie do not teach xenonucleic acid clamps have aza-aza, thio-aza and oxy-aza chemical functionality and selected from the group consisting of the following chemical structures where base is selected from the group consisting of adenine, cytosine, guanine, thymine and uracil. Powell (2019) teaches preferred xenonucleic acids having aza-aza, thio-aza, and oxy-aza (pg. 2, [0015], FIG. 7B). The oxy-aza nucleotide Monomers A, C and G are prepared with suitable protecting groups on the nucleotide bases (pg. 23, [0119]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to modify the teachings of the patent claims and McKinzie, to include the teachings of Powell (2019). The claims of ‘277 are shy in teachings regarding the structures of the XNA clamp. However, Powell (2019) teaches a target specific XNA clamp with oxy-aza, aza-aza and thio-aza moieties so that during qPCR only the mutant templates are amplified (pg. 2, [0026]). A person of ordinary skill in the art would have recognized that the method of detecting KRAS mutation or any sequence variations can be achieved using XNA probe clamp with its oxy-aza, aza-aza and thio-aza moieties which has a phosphodiester backbone that allows for it to hybridize tightly to the complementary DNA sequence (pg. 7, [0069]).
The patent claims and McKinzie do not teach that the mutation is KRAS G12C.
Makarov teaches KRAS mutations at KRAS locus include (Gl2D, Gl2R, Gl2S, Gl3D, Gl2C, Gl2A and G12V) (pg. 24, [0277]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to modify the teachings of the patent claims and McKinzie to include detection of KRAS G12C as taught by Makarov for the obvious benefit of detecting as many KRAS mutations as possible.
Claims 4-5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No.10,400,277, or unpatentable over claims 1-9 of U.S. Patent No.11,208,689, each in view of McKinzie, Powell (2016), Powell (2019), and Makarov as applied to claims 1-3 above and further in view of Lianidou (Lianidou et al. 2018, Liquid biopsies, Genes, Chromosomes Cancer, 58:219-232).).
The patent claims McKinzie, Powell (2016), Powell (2019) and Makarov do not teach biological sample is obtained from a healthy human or animal subject.
Lianidou teaches doing liquid biopsy to analyze circulating tumor cells, circulating tumor DNA, circulating miRNAs, and tumor derived extracellular vesicles that are shed from primary tumors and their metastatic sites into peripheral blood (pg. 219, FIG 1, introduction). Lianidou teaches analyzing circulating tumor cells in patients without signs of breast cancer recurrence (page 211, col 2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to include analysis of subjects without signs of cancer in the method of the patent claims, McKinzie, Powell (2016), Powell (2019) and Makarov for the purpose of monitoring cancer recurrence or to use liquid biopsy to screen normal subjects for tumor derived mutations, since it has shown significant potential for early cancer diagnosis, screening and detection as taught by Lianidou (pg. 219, introduction). The specification does not define the term “healthy”, therefore the term has been given its broadest reasonable interpretation to include patients without signs of cancer recurrence as explained by Lianidou.
Claim 6 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No.10,400,277, or unpatentable over claims 1-9 of U.S. Patent No.11,208,689, each in view of McKinzie, Powell (2016), Powell 2019), and Makarov as applied to claims 1-3 above and further in view of Zhao (Zhao et al, 2005, Detection of hepatitis B virus DNA by rea-time PCR using TaqMan MGB probe technology, World Journal of Gastroenterology, 1(4), 508-510).
The patent claims, McKinzie, Powell (2019), Powell (2016), and Makarov do not teach a probe in addition to an XNA probe clamp.
Zhao teaches a TaqMan-MGB probe between primers for amplification was designed to detect PCR products (pg. 508, Abstract). The TaqMan probe, in specific, the TaqMan MGB probe has specificity, sensitivity, remarkable accuracy and reproducibility (pg. 508, introduction).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to modify the teachings of the patent claims and McKinzie, Powell (2016), Powell (2019), and Makarov to incorporate the teachings of Zhao. Zhao teaches that real-time PCR is an accurate, sensitive and highly reproducible method for detection. The TaqMan probe, in specific, the TaqMan MGB probe has specificity and sensitivity, remarkable accuracy and reproducibility (pg. 508, introduction).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Winston Shen, can be reached on (571) 272-3157. The fax phone number for organization where this application or proceeding is assigned is (571) 273-8300.
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/JEHANNE S SITTON/ Primary Examiner, Art Unit 1682