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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-27, and the species elections of serum and “at least one week apart” in claim 1, of ALU in claim 10, of SEQ ID NOs: 4 and 5 of Table 2A in claim 14, of SEQ ID NOs: 7, 8, 15, & 16 in claim 15, of a patient is suffering from cancer in claim 24, and of cancer chemotherapy and an antineoplastic agent in claims 26 & 27 in the reply filed on 05/25/2026 is acknowledged. Group II, claims 28-30, and claim 2 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
A first office action on the merits of claims 1 & 3-27 is set forth herein and claims 2 & 28-30 are withdrawn from consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 & 3-27 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.
Regarding claims 1, 3-5, 8, 9, & 24-26, the claims recite to “a patient” and “a subject” in lines 2, 4, & 22 of claim 1 and further dependent claims switch from recitations of “patient” and “subject” and it is unclear if “patient” and “subject” are referring to the same individual.
Regarding claim 1, the claim recites the limitation “the first and second samples” in lines 6 & 14 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if this recitation is the result of a typographical error and is meant to recite back to “a first and second sample” in lines 3 of the claim. In addition, the claim recites the limitation “the quantitated RE targets” in lines 14 & 17 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the quantified RE targets” is referring to each of the first and second short RE targets and the long RE target. In addition, the recitation of “each quantified RE target” in line 16 of the claim is unclear if “each quantified RE target” is the result of a typographical error and should read “each quantified targets” and it is unclear if this recitation is referring to each of the first and second short RE targets and the long RE target. In addition, the recitation of “amount of short RE targets” in lines 18, 20, & 22-23 of the claim is unclear if “amount of short RE targets” is referring to each of the first and second short RE targets or is referring to other short RE targets.
Regarding claim 4, the recitation of “stage I, stage II or stage III” in line 1 of the claim is unclear if stage II and stage III are part of the same grouping of cancer or if this is the result of a typographical error and should read “stage I, stage II, or stage III”.
Regarding claim 12, the recitation of “short RE targets has” in line 2 of the claim is unclear if “short RE targets has” is referring to each of the first and second short RE targets and should read “first and second RE targets have” or is referring to other short RE targets or a singular short RE target.
Regarding claim 13, the recitation of “short RE targets has” in line 1 of the claim is unclear if “short RE targets has” is referring to each of the first and second short RE targets and should read “first and second RE targets have” or is referring to other short RE targets or a singular short RE target.
Regarding claim 14, the recitation of “primer pairs set forth in Table 2A, 2B or 2C” is indefinite. As stated in MPEP 2173.05(s), the claims should be complete to themselves and the reference to a table in the specification render the claim incomplete. Claims which recited tables are only permitted in exceptional circumstances where there is no practical way to define the invention in words or where it is more concise to incorporate by reference than duplicating a drawing or table into the claim.
Regarding claim 15, the claim recites the limitation “the short target sequence” in line 2 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the short target sequence” is referring to the short RE target sequence or sequences and if so it is unclear if the recitation is referring each of the first and second short RE targets and should read “first and second RE target sequences”. In addition, the claim recites SEQ ID NO: 7 as for both the forward and reverses primer type for fragment Yb8-97bp in the first table in the claim and it is unclear how the same SEQ ID NO: 7 is used as a forward and reverse primers to obtain a 97bp fragment. In addition, claim recites the limitation “the long target sequence” in line 4 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the long target sequence” is referring to the long RE target sequence. In addition, the recitation of SEQ ID NOs: 10, 11, 15, & 16 in both the table recited as comprising forward and reverse primers for amplifying short target sequence and in the table recited as comprising forward and reverse primers for amplifying long target sequence is unclear whether the primers of SEQ ID NOs: 10,11, 15, & 16 amplify short or long target sequences. Further, claim 1, from which claim 15 depends from recites “a long RE target sequence having a length of between 200bp and 300bp” and SEQ ID NOs: 10 & 11 are recited to amplify a long target sequence of 105bp in the second table recited in claim 15 and SEQ ID NOs: 15 & 16 are recited to amplify a long target sequence of 120bp in the second table recited in claim 15. Therefore, how a long RE target can be recited as having a length of between 200bp and 300bp in claim 1 and then be recited as having a length of less than 200bp in claim 15 which depends from claim 1.
Regarding claim 18, the recitation of “the providing and using steps being carried out in a single tube or well” in lines 1-2 of the claim is unclear as claim 1, from which claim 18 depends from, does not recited any “using” steps. Therefore, it is unclear what steps are encompassed by this recitation.
Regarding claim 20, the claim recites the limitation “the probe” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the probe” is meant to refer to a hybridization probe in claim 19.
Regarding claim 21, the claim recites the limitation “the observable label” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim.
Regarding claim 22, the claim recites the limitation “the observable label” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim.
Regarding claim 25, the recitation of “the quantitated short RE target” in line 1 of the claim is unclear if “the quantitated short RE target” is referring to each of the first and second short RE targets and should read “the quantitated first and second short RE target” or is referring to only one of the short RE targets. In addition, the recitation of “the quantitated short RE target amount represent one cancer cell in 500,000 total cells or greater, 1,000,000 total cells or greater or 1,500,000 cells or greater” in lines 1-3 of the claim is unclear what the relationship is between quantitated short RE target and a cancer cell. Does a certain concentration of quantitated short RE target represent a cancer cell? Does the presence of quantitated short RE target in a cancer sample represent a cancer cell? Does the presence of quantitated short RE target in a cancer sample represent a cancer cell in 500,000 total cells or more indicate a presence of cancer in the sample?
Claims 6, 7, 10, 11, 16, 17, 19, & 23 are rejected due to their dependence on claim 1 and claim 27 is rejected due to its dependence on claim 26.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 & 3-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method to quantitate the integrity of circulating cell free human DNA and implement a treatment of a patient comprising quantitating short and long RE targets and determining an increase in the amount of short RE targets and implementing a treatment of a patient having an increase in the amount of short RE targets wherein an increase in the amount of short RE targets in a second sample compared to the first sample above a threshold identifies the patient as having progressive disease of minimum residual disease (MRD). This recitation is a natural correlation between quantitating long and short RE targets and identifying a patients as having a progressive disease or MRD. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites obtaining threshold cycle numbers, comparing threshold cycle numbers for the quantitated RE targets, determining an increase in short RE targets, and comparing short RE targets in a second sample to a first sample, which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of providing a first and second sample comprising cfDNA comprising a first and second short RE target and a long RE target, quantitating the short and long RE targets, obtaining a threshold cycle number, comparing the threshold cycle number with a standard curve, determining an increase in the amount of short RE targets, and implementing a treatment of a patient, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
Although the claims recite “implement a treatment of a patient”, this step is conditional as it is implemented to a patient having an increase in the amount of short RE targets. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of detecting short and long RE targets. As such, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the steps of determining an increase in the amount of short RE targets are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
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(s) 1, 3-13, 16-21, 24, & 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sinha (United States Patent Application US 2016/0186239 A1), as cited on the IDS dated 10/07/2022, in view of Hao (Hao et al.; British Journal of Cancer, Vol. 111, pages 1482-1489, August 2014), as cited on the IDS dated 10/07/2022.
Regarding claim 1, Sinha teaches a multiplexed method of quantitating the integrity of circulating cell free human DNA (cfDNA) comprising providing a serum sample comprising cell free human DNA wherein the cfDNA comprises short nucleic retrotransposable element genomic target less than 180 bp (short RE target sequence having a length between about 60 bp to about 135bp), comprising detection of two short RE targets of ALU-Yb8 of 120bp and 80bp (a first and second RE target sequence that differ in length) and a long nucleic retrotransposable element genomic target that is more than 180 bp (long RE target sequence having a length between 200bp to 300bp), using quantitative PCR to separately and simultaneously quantitate the short and long RE targets, obtaining for each quantified RE target a threshold cycle number, and comparing the threshold cycle number with a standard curve to determine for each quantitated RE target a quantity of the short and long RE targets (paragraph [0012] lines 1-20; Fig. 3). In addition, Sinha teaches that this method of quantitating short and long RE targets may serve as an integrity value for the cfDNA (amount of short RE targets is indicative of the integrity f the cfDNA) for diagnostic applications wherein the diagnostic applications include one or more of detection, diagnosis, treatment monitoring, and surveillance of cancer (implement a treatment of a patient) (paragraph [0017] lines 1-7).
Sinha does not teach obtaining a first and second sample at least one week apart or that determining an increase in the amount of short RE targets in the second sample as compared to the first sample above a threshold level and then implementing a treatment of a patient having an increase in the amount of short RE targets in the second sample.
Hao teaches a method to verify concentrations and integrity index of circulating cfDNA in serum for use in diagnosis and progression monitoring of cancer patients comprising collecting serum samples taken before and after surgery (first and second samples), in which samples were taken before surgery (first sample) and a sample was taken 1-10 days post-surgery (second sample) (first and second sample are obtained at least one week apart), detecting long (247bp) and short (115bp) DNA fragments with qPCR by amplifying the ALU repeats (detecting long and short ALU RE targets with qPCR) and quantifying concentration of the ALU115 and ALU247 cfDNA (long and short ALU RE targets) through a standard curve (comparing threshold cycle number for each quantitated RE target with a standard curve to determine an amount of each of the quantitated RE targets) (abstract background lines 1-2; abstract methods lines 1-4; abstract results lines 1-4; pg. 1483 column 2 2nd full paragraph lines 1-22; pg. 1483 column 2 3rd full paragraph lines 1-4; pg. 1485 column 1 1st full paragraph lines 1-7; pg. 1485 paragraph bridging column 1 & 2 lines 1-4). Hao also teaches that at the post-surgery sample (second sample) displayed a slight increase in ALU115 (short ALU RE target) (determining an increase in the amount of short RE target in the second sample as compared to the first sample above a threshold level) enabling the serum DNA concentrations of ALU115 (short ALU RE target) as an integrity index and valuable tool in early diagnosis and monitoring of progression and prognosis in cancer in a patient (implement a treatment of a patient having an increase in the amount of short RE target in the second sample compared to the first sample above a threshold) (pg. 1482 column 1 1st full paragraph lines 10-11; pg. 1485 paragraph bridging column 1 & 2 lines 1-4; pg. 1488 column 1 1st full paragraph lines 7-13).
Sinha and Hao are considered to be analogous to the claimed invention because they are all in the same field of detecting short and long RE targets in circulating cell free DNA serum samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantitating the integrity of circulating cell free human DNA (cfDNA) for detection, treatment monitoring, and surveillance of cancer comprising quantifying short nucleic RE genomic target less than 180 bp, comprising detection of two short RE targets of ALU-Yb8 of 120bp and 80bp, and a long nucleic RE genomic target that is more than 180 bp through qPCR and standard curve analysis in Sinha to incorporate the verifying concentrations and integrity index of circulating cfDNA in serum for use in diagnosis and progression monitoring of cancer patients comprising collecting serum samples taken before and after surgery (first and second samples), detecting long (247bp) and short (115bp) DNA fragments with qPCR by amplifying the ALU repeats (detecting long and short ALU RE targets with qPCR), and detecting a slight increase in ALU115 (short ALU RE target) in the second sample as taught in Hao because Hao teaches that doing so would enable detection of the serum DNA concentrations of ALU115 (short ALU RE target) as an integrity index and provide a valuable tool in early diagnosis and monitoring of progression and prognosis in cancer in a patient.
Regarding claim 3, Hao teaches the first sample is obtained from the patient before surgery (first sample is obtained from the subject prior to administration of a neoadjuvant) and the second sample is taken 1-10 days post-surgery (second sample is obtained from the patient after neoadjuvant is administered and before another therapy is administered) (pg. 1485 column 1 1st full paragraph lines 1-7; pg. 1485 paragraph bridging column 1 & 2 lines 1-4).
Regarding claim 4, Hao teaches the cancer patients have stage I to stage III colorectal cancer (subject has stage I, stage II or stage III cancer) (Table 1).
Regarding claim 5, Hao teaches the first sample is obtained from the patient before surgery (first sample is obtained from the subject prior to administration of a cycle of therapy) and the second sample is taken 1-10 days post-surgery (second sample is obtained from the patient after the cycle of therapy is administered and before a next cycle of therapy is administered) (pg. 1485 column 1 1st full paragraph lines 1-7; pg. 1485 paragraph bridging column 1 & 2 lines 1-4).
Regarding claim 6, Hao teaches a method to verify concentrations and integrity index of circulating cfDNA in serum for use in diagnosis and progression monitoring of cancer patients comprising collecting serum samples taken before and after surgery (first and second samples), detecting long (247bp) and short (115bp) DNA fragments with qPCR by amplifying the ALU repeats (detecting long and short ALU RE targets with qPCR) and quantifying concentration of the ALU115 and ALU247 cfDNA (long and short ALU RE targets) through a standard curve, and detecting a slight increase in ALU115 (short ALU RE target) in the second sample enabling the serum DNA concentrations of ALU115 (short ALU RE target) as an integrity index and valuable tool in early diagnosis and monitoring of progression and prognosis in cancer in a patient (steps (a) through (f)) in which this method of repeated before surgery and multiple times after surgery (steps (a) through (f) are repeated through multiple cycles of therapy) (abstract background lines 1-2; abstract methods lines 1-4; abstract results lines 1-4; pg. 1482 column 1 1st full paragraph lines 10-11; pg. 1483 column 2 2nd full paragraph lines 1-22; pg. 1483 column 2 3rd full paragraph lines 1-4; pg. 1485 column 1 1st full paragraph lines 1-7; pg. 1485 paragraph bridging column 1 & 2 lines 1-4; pg. 1488 column 1 1st full paragraph lines 7-13).
Regarding claim 7, Hao teaches that at the post-surgery sample (second sample) displayed a slight increase in ALU115 (short ALU RE target), in which the increase in ALU115 (short RE target) may be due to residual tumor tissue (an increase in the amount of short RE targets in the second sample compared to the first samples above a threshold identifies the therapy an ineffective) (pg. 1482 column 1 1st full paragraph lines 10-11; pg. 1485 paragraph bridging column 1 & 2 lines 1-4; pg. 1487-1488 paragraph bridging pg. 1487 & 1488 lines 8-9; pg. 1488 column 1 1st full paragraph lines 7-13).
Regarding claim 8, Hao teaches that at the post-surgery sample (second sample) displayed a slight increase in ALU115 (short ALU RE target) enabling the serum DNA concentrations of ALU115 (short ALU RE target) as an integrity index and valuable tool in early diagnosis and monitoring of progression and prognosis in cancer in a patient (increase in the amount of short RE target in the second sample compared to the first sample above a threshold level identifies the patient as having progressive disease) (pg. 1482 column 1 1st full paragraph lines 10-11; pg. 1485 paragraph bridging column 1 & 2 lines 1-4; pg. 1488 column 1 1st full paragraph lines 7-13).
Regarding claim 9, Hao teaches that at the post-surgery sample (second sample) displayed a slight increase in ALU115 (short ALU RE target) enabling the serum DNA concentrations of ALU115 (short ALU RE target) as an integrity index and valuable tool in early diagnosis and monitoring of progression and prognosis in cancer in a patient, in which the increase in ALU115 (short RE target) may be due to residual tumor tissue (increase in the amount of short RE target in the second sample compared to the first sample above a threshold level identifies the patient as having minimum residual disease (MRD)) (pg. 1482 column 1 1st full paragraph lines 10-11; pg. 1485 paragraph bridging column 1 & 2 lines 1-4; pg. 1487-1488 paragraph bridging pg. 1487 & 1488 lines 8-9; pg. 1488 column 1 1st full paragraph lines 7-13).
Regarding claim 10, Sinha teaches the retrotransposable element genomic targets may be an interspersed ALU element (paragraph [0013] lines 1-4).
Regarding claim 11, Sinha teaches the retrotransposable element genomic target may have a copy number excess of 1000 copies per genome (paragraph [0013] lines 4-6).
Regarding claim 12, Sinha teaches the short nucleic retrotransposable element genomic target is less than 180 bp (short RE target sequence having a length from 70 bp to about 130bp, or from 60 bp to 120 bp) (paragraph [0012] lines 6-7).
Regarding claim 13, Sinha teaches the short nucleic retrotransposable element genomic target is less than 180 bp comprising detection of two short RE targets of ALU-Yb8 of 120bp and 80bp (the first short RE target has a length between 70 and 80 bp and the second short RE target has a length between 105 and 120 bp) (paragraph [0012] lines 6-7; Fig. 3).
Regarding claim 16, Sinha teaches the multiplexed method comprises adding a synthetic DNA sequence as an internal positive control and utilizing the internal positive control result in the comparing step to improve accuracy and reliability of the comparing step (paragraph [0014] lines 1-7).
Regarding claim 17, Sinha teaches the use of an internal positive control enables determination of the concentration of cell free DNA in the sample (paragraph [0015] lines 1-4).
Regarding claim 18, Sinha teaches the multiplexed method comprises the sample of serum placed in a single tube and the qPCR reactions for the quantification of the long and short RE targets carried out in the same tube (paragraph [0016] lines 1-5).
Regarding claim 19, Sinha teaches the multiplexed method comprises providing a hybridization probe corresponding to the short RE target and corresponding to the long RE target (providing a hybridization probe that hybridizes to the RE target) (paragraph [0019] lines 1-5).
Regarding claim 20, Sinha teaches the hybridization probe may include an observable label (paragraph [0019] lines 5-6).
Regarding claim 21, Sinha teaches the observable label may be a fluorescent label (paragraph [0019] lines 6-7).
Regarding claim 24, Sinha teaches the multiplexed method comprises a sample that comes from an individual that is suffering from cancer (paragraph 1-3).
Hao teaches the first and second samples are obtained from patients with colorectal cancer (patient is suffering from cancer) (pg. 1483 column 1 2nd full paragraph lines 1-2).
Regarding claim 25, it is noted, as discussed above, the recitation of “the quantitated short RE target amount represent one cancer cell in 500,000 total cells or greater, 1,000,000 total cells or greater or 1,500,000 cells or greater” in lines 1-3 of the claim is unclear what the relationship is between quantitated short RE target and a cancer cell. Does a certain concentration of quantitated short RE target represent a cancer cell? Does the presence of quantitated short RE target in a cancer sample represent a cancer cell? Does the presence of quantitated short RE target in a cancer sample represent a cancer cell in 500,000 total cells or more indicate a presence of cancer in the sample? Therefore, for the purposes of this rejection, the claim is given its broadest reasonable interpretation to encompass detection of quantitated short RE targets in a cancer cell as representing a cancer cell in 500,000 total cells or greater (detecting the presence of cancer).
Hao teaches detection and quantification of the concentration of ALU115 (short RE target) in a higher amount in the cancer patient samples compared to normal controls (detection of quantified short RE target in a cancer cell represents on cancer cell in 500,000 total cells or more (quantified short RE target detects presence of cancer))
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sinha (United States Patent Application US 2016/0186239 A1), as cited on the IDS dated 10/07/2022, and Hao (Hao et al.; British Journal of Cancer, Vol. 111, pages 1482-1489, August 2014), as cited on the IDS dated 10/07/2022 as applied to claims 1, 3-13, 16-21, 24, & 25 above, and further in view of Birsoy (United States Patent Application Publication US 2014/0348749 A1).
The teachings of Sinha and Hao with respect to claim 1 is discussed above.
Regarding claim 14, Sinha and Hao does not teach that the qPCR method uses primer pairs SEQ ID NO: 4 & 5 set forth in Table 2A.
Birsoy teaches a method of amplifying ALU repeat elements (RE targets) with real-time PCR comprising ALU forward primer SEQ ID NO: 13, which is identical to SEQ ID NO: 4 of the instant application, and ALU reverse primer SEQ ID NO: 14, which is identical to SEQ ID NO: 5 of the instant application (paragraph [0311] lines 13-17; pg. 76-77 sequence listing).
Sinha, Hao, and Birsoy are considered to be analogous to the claimed invention because they are all in the same field of detecting ALU RE targets in cell free samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantitating the integrity of circulating cell free human DNA (cfDNA) for detection, treatment monitoring, and surveillance of cancer comprising quantifying short nucleic RE genomic target less than 180 bp, and a long nucleic RE genomic target that is more than 180 bp through qPCR of Sinha to incorporate a primer pair of SEQ ID NO: 13 & 14 (which are identical to primer pair of SEQ ID NO: 4 and 5 of the instant application) as taught in Birsoy, because this involves simple substitution of one known element for another to obtain predictable results.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sinha (United States Patent Application US 2016/0186239 A1), as cited on the IDS dated 10/07/2022, and Hao (Hao et al.; British Journal of Cancer, Vol. 111, pages 1482-1489, August 2014), as cited on the IDS dated 10/07/2022 as applied to claims 1, 3-13, 16-21, 24, & 25 above, and further in view of Hoon (WO 2006/128192 A2, November 2006).
The teachings of Sinha and Hao with respect to claim 1 is discussed above.
Regarding claim 15, it is noted, as discussed above, the claim recites SEQ ID NO: 7 as for both the forward and reverses primer type for fragment Yb8-97bp in the first table in the claim and it is unclear how the same SEQ ID NO: 7 is used as a forward and reverse primers to obtain a 97bp fragment. Further, the applicant has elected SEQ ID NOs: 7, 8, 15, 7 16 for claim 15 (see response dated 05/25/2026), however claim 15 as currently amended does not recite a SEQ ID NO: 8. Therefore, for the purposes of this rejection, the claim is interpreted to encompass SEQ ID NO: 7 for a primer pair for amplifying the short target sequence and SEQ ID NO: 15 & 16 for a primer pair for amplifying the long target sequence.
Sinha teaches primers SEQ ID NO: 22, which is identical to SEQ ID NO: 15 of the instant application, and SEQ ID NO: 23, which is identical to SEQ ID NO: 16 of the instant application, for amplifying ALU RE targets (the forward and reverse primer pairs for amplifying the long target sequence are selected from SEQ ID NO: 15 & 16) (Table 3; pg. 15-16 sequence listing).
Sinha and Hao does not teach primer pair for amplifying the short target sequence comprises SEQ ID NO: 7.
Hoon teaches a method of determining the sequence integrity of circulating DNA in a sample comprising detecting an amount of ALU (RE target) with qPCR with forward primer SEQ ID NO: 3, which comprises SEQ ID NO: 7 from positions 1-18 (primer for amplifying the short target sequence selected from SEQ ID NO: 7) (abstract lines 1-3; pg. 2 lines 26-31; pg. 3 lines 26-27; pg. 4 lines 12-14).
Sinha, Hao, and Hoon are considered to be analogous to the claimed invention because they are all in the same field of detecting ALU RE targets in circulating cell free samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantitating the integrity of circulating cell free human DNA (cfDNA) for detection, treatment monitoring, and surveillance of cancer comprising quantifying short nucleic RE genomic target less than 180 bp, and a long nucleic RE genomic target that is more than 180 bp through qPCR with SEQ ID NOs: 22 & 23 (which are identical to the primer pair of SEQ ID NO: 15 & 16 of the instant application) of Sinha to incorporate a primer of SEQ ID NO: 3 (which are identical to primer of SEQ ID NO: 7 of the instant application from positions 1-18) as taught in Hoon, because this involves simple substitution of one known element for another to obtain predictable results.
Claim(s) 22 & 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sinha (United States Patent Application US 2016/0186239 A1), as cited on the IDS dated 10/07/2022, and Hao (Hao et al.; British Journal of Cancer, Vol. 111, pages 1482-1489, August 2014), as cited on the IDS dated 10/07/2022 as applied to claims 1, 3-13, 16-21, 24, & 25 above, and further in view of Fang (Fang et al.; Biosensors and Bioelectronics, Vol. 24, pages 2131-2136, November 2008).
The teachings of Sinha and Hao with respect to claims 1 & 10 are discussed above.
Regarding claims 22 & 23, Sinha and Hao does not teach the observable label is detected with a microfluidic device (see claim 22) or that the amount of short and long RE targets in the first and second sample are amplified in qPCR methods are measured using an electrical biosensor (see claim 23).
Fang teaches a electrochemical (EC) detection method in a microfluidic flow-through EC-qPCR device where both amplification of the target nucleic acid sequence and subsequent EC detection of the PCR amplicon are realized simultaneously in the same device (abstract lines 1-5). In addition, Fang teaches that this method of EC detection is advantageous as it does not require probe-modified electrodes and can by automated for a portable EC detection system for quantification of PCR amplicons (abstract lines 7-9; pg. 2136 column 1 1st full paragraph lines 1-24).
Sinha, Hao, & Fang are considered to be analogous to the claimed invention because they are all in the same field of detecting nucleic acid targets with qPCR. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantitating the integrity of circulating cell free human DNA (cfDNA) for detection, treatment monitoring, and surveillance of cancer comprising quantifying short nucleic RE genomic target less than 180 bp, comprising detection of two short RE targets of ALU-Yb8 of 120bp and 80bp, and a long nucleic RE genomic target that is more than 180 bp through qPCR and standard curve analysis in Sinha to incorporate detection of target nucleic acids with a microfluidic flow-through EC-qPCR (see claim 22) device and to incorporate detection of target nucleic acids in a sample amplified with qPCR using an electrical biosensor (see claim 23) as taught in Fang because Fang teaches that doing so would provide a method of EC detection is advantageous as it does not require probe-modified electrodes and can by automated for a portable EC detection system for quantification of PCR amplicons.
Claim(s) 26 & 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sinha (United States Patent Application US 2016/0186239 A1), as cited on the IDS dated 10/07/2022, and Hao (Hao et al.; British Journal of Cancer, Vol. 111, pages 1482-1489, August 2014), as cited on the IDS dated 10/07/2022 as applied to claims 1, 3-13, 16-21, 24, & 25 above, and further in view of Rago (Rago et al.; Cancer Research, Vol. 67, pages 9364-9370, October 2007).
The teachings of Sinha and Hao with respect to claim 1 is discussed above.
Regarding claims 26 & 27, Sinha and Hao does not teach treatment of the patient is a cancer chemotherapy comprising antineoplastic agents.
Rago teaches a method of determining circulating human DNA comprising RE targets in which circulating human DNA comprising RE targets was found to be decreased after successful treatment in which the treatment comprises treatments with antineoplastic agent chemotherapy (abstract lines 8-12; pg. 9368 column 1 4th full paragraph lines 1-8; pg. 9368 column 2 1st full paragraph lines 1-15). In addition, Rago teaches that this method provides utility in target validation studies and preclinical drug development programs (abstract lines 14-16).
Sinha, Hao, & Rago are considered to be analogous to the claimed invention because they are all in the same field of detecting RE targets in circulating cell free DNA samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantitating the integrity of circulating cell free human DNA (cfDNA) for detection, treatment monitoring, and surveillance of cancer comprising quantifying short nucleic RE genomic target less than 180 bp, comprising detection of two short RE targets of ALU-Yb8 of 120bp and 80bp, and a long nucleic RE genomic target that is more than 180 bp through qPCR and standard curve analysis in Sinha to incorporate treatment of a patient with a cytotoxic antineoplastic agent (chemotherapy) as taught in Rago because Rago teaches that doing so would provide utility in target validation studies and preclinical drug development programs.
Conclusion
Claims 1 & 3-27 are rejected.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/ Primary Examiner, Art Unit 1682
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