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 .
Claim Status
Claims 44-56 filed on 01/17/2024 are pending and under examination.
Information Disclosure Statement
The reference in the IDS submitted on 01/17/2024 that is lined through, under the non-patent literature section, were not considered because an English copy of the full documents were not provided.
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 44-56 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 claim 44, the recitation of “non-naturally occurring composition of amplified DNA” in lines 1, 4, & 6 of the claim is unclear what is encompassed by non-naturally occurring composition of DNA. For example, can the cell-free DNA only comprise donor-derived DNA? Does a cell-free DNA sample comprising partially donor and partially recipient derived cell-free DNA encompass a non-naturally occurring composition? In addition, the recitation of “cf-DNA” in line 7 of the claim is unclear if “cf-DNA” is meant to refer to “cell-free DNA” in lines 3 & 5 of the claim as “cf-DNA” is not previously defined in the claim.
Regarding claim 45, the recitation of “blood, plasma or serum sample” in lines 1-2 of the claim is unclear if plasma or serum is meant to refer to the same type of biological sample or if this is the result of a typographical error and should read “blood, plasma, or serum sample”.
Regarding claim 46, the recitation of “at least 30 SNV targets” in line 2 of the claim is unclear if SNV is meant to refer to “single nucleotide variant (SNV) targets” as “SNV” is defined in claim 48, or if it is meant to refer to something else since it is not defined in claim 46.
Regarding claim 50, the recitation of “non-naturally occurring composition of amplified DNA” in lines 4 & 6 of the claim is unclear what is encompassed by non-naturally occurring composition of DNA. For example, can the cell-free DNA only comprise donor-derived DNA? Does a cell-free DNA sample comprising partially donor and partially recipient derived cell-free DNA encompass a non-naturally occurring composition? In addition, the recitation of “cf-DNA” in lines 7, 9, & 10 of the claim is unclear if “cf-DNA” is meant to refer to “cell-free DNA” in lines 3 & 5 of the claim as “cf-DNA” is not previously defined in the claim.
Regarding claim 51, the recitation of “blood, plasma or serum sample” in lines 1-2 of the claim is unclear if plasma or serum is meant to refer to the same type of biological sample or if this is the result of a typographical error and should read “blood, plasma, or serum sample”.
Regarding claim 52, the recitation of “at least 30 SNV targets” in lines 2 of the claim is unclear if SNV is meant to refer to “single nucleotide variant (SNV) targets” as “SNV” is defined in claim 54, or if it is meant to refer to something else since it is not defined in claim 52.
Regarding claim 55, the recitation of “cf-DNA” in line 1 of the claim is unclear if “cf-DNA” is meant to refer to “cell-free DNA” in lines 3 & 5 of claim 50, from which claim 55 depends from, as “cf-DNA” is not previously defined in the claim.
Claims 47-49 are rejected due to their dependence on claim 44 and claims 53, 54, & 56 are rejected due to their dependence on claim 50.
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 50-56 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature 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 for treating a transplant complication in a heart transplant recipient comprising extracting cell-free DNA from a biological sample from the heart transplant recipient, amplifying the cell-free DNA, analyzing and quantifying the amount of total cell-free DNA, and administering a treatment for a transplant complication if the total cell-free DNA is above a threshold total. This recitation is a natural correlation between transplant complication and total cell-free DNA. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. 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 extracting cell-free DNA, performing PCR amplification, analyzing and quantifying total cell-free DNA, and administering a treatment, 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 “administering a treatment” to the heart transplant recipient, this step is conditional as it is determined by total cell-free DNA being equal to or above a threshold total cell-free DNA value. 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 gene expression or. 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 detecting total cell-free DNA through extraction, PCR amplification, and quantification, 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 § 102
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.
Claim(s) 44-46, 49, 50-52, 55, & 56 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vlaminck (Vlaminck et al.; Science Translational Medicine, Vol. 6, pages 1-9, June 2014).
It is noted as discussed above, the recitation of “non-naturally occurring composition of amplified DNA” in independent claims 44 & 50 is unclear what is encompassed by non-naturally occurring composition of DNA. For example, can the cell-free DNA only comprise donor-derived DNA? Does a cell-free DNA sample comprising partially donor and partially recipient derived cell-free DNA encompass a non-naturally occurring composition? Therefore, for the purposes of these rejections, the claims are given their broadest reasonable interpretation to encompass cell-free DNA samples comprising, at least in part, donor-derived (non-naturally occurring) cell-free DNA.
Regarding claim 44, Vlaminck teaches a noninvasive diagnostic method for high-throughput screening of circulating cell-free donor-derived DNA (non-naturally occurring composition of cell-free DNA) to measure acute rejection after heart transplantation through extracting cell-free DNA from whole-blood samples of the heart transplant recipient after transplant (biological sample), quantifying the cell-free DNA through quantitative PCR and sequencing (performing PCR amplification on the cell-free DNA), and analyzing the cell-free donor-derived DNA levels (analyzing the non-naturally occurring composition of amplified DNA by quantitative PCR to quantify an amount of total cf-DNA in the biological sample) (abstract lines 1-11; pg. 2 column 2 3rd full paragraph lines 1-15; pg. 2-3 paragraph bridging pg. 2 & pg. 3 lines 1-14; pg. 7 column 1 2nd full paragraph lines 1-16; pg. 7 column 2 3rd full paragraph lines 1-5; pg. 7 column 2 4th full paragraph lines 1-8; Fig. 4).
Regarding claim 45, Vlaminck teaches plasma is extracted from whole blood samples to extract cell-free DNA (biological sample is blood or plasma) (pg. 7 column 2 3rd full paragraph lines 1-5).
Regarding claim 46, Vlaminck teaches analyzing single nucleotide polymorphisms (SNPs) to discriminate between donor- and recipient-derived sequences in which over 13,000 SNPs were analyzed across all samples through PCR amplification and sequencing (comprises multiplex targeted PCR amplification of at least 30 SNV targets together in the same reaction) (pg. 1-2 paragraph bridging pg. 1 & 2 lines 1-15; pg. 7 column 2 4th full paragraph lines 1-8; Fig. 2).
Regarding claim 49, Vlaminck teaches a noninvasive diagnostic method for high-throughput screening of circulating cell-free donor-derived DNA (non-naturally occurring composition of cell-free DNA) to measure acute rejection after heart transplantation (transplant recipient is a heart transplant recipient) (abstract lines 1-11).
Regarding claim 50, Vlaminck teaches a noninvasive diagnostic method for high-throughput screening of circulating cell-free donor-derived DNA (non-naturally occurring composition of cell-free DNA) to measure acute rejection after heart transplantation through extracting cell-free DNA from whole-blood samples of the heart transplant recipient after transplant (biological sample), quantifying the cell-free DNA through quantitative PCR and sequencing (performing PCR amplification on the cell-free DNA), and analyzing the cell-free donor-derived DNA levels (analyzing the non-naturally occurring composition of amplified DNA by quantitative PCR to quantify an amount of total cf-DNA in the biological sample) (abstract lines 1-11; pg. 2 column 2 3rd full paragraph lines 1-15; pg. 2-3 paragraph bridging pg. 2 & pg. 3 lines 1-14; pg. 7 column 1 2nd full paragraph lines 1-16; pg. 7 column 2 3rd full paragraph lines 1-5; pg. 7 column 2 4th full paragraph lines 1-8; Fig. 4). Vlaminck also teaches that this method of measuring the levels of the cell-free donor-derived DNA in heart transplant recipients provide an opportunity to diagnose and treat acute rejection through chosen threshold values to maximize sensitivity or specificity of the quantified cell-free donor-derived DNA (administering a treatment for a transplant complication to the heart transplant recipient provided the total cf-DNA in the biological sample is equal to or above a threshold total) (pg. 6 column 2 1st full paragraph lines 1-12). Finally, Vlaminck teaches that cell-free donor-derived DNA levels in the heart transplant recipients with acute rejection (transplant complication) are at levels up to 10% (in which percent concentration represents g/100mL, therefore 10g/100mL (0.1g/mL) = 0.1 = 10% and further converted from g/mL to ng/mL which is equal to 100,000,000 ng/mL) (equal to or above a threshold total cf-DNA value between 8ng/mL and 15ng/mL) (Fig.4C).
Regarding claim 51, Vlaminck teaches plasma is extracted from whole blood samples to extract cell-free DNA (biological sample is blood or plasma) (pg. 7 column 2 3rd full paragraph lines 1-5).
Regarding claim 52, Vlaminck teaches analyzing single nucleotide polymorphisms (SNPs) to discriminate between donor- and recipient-derived sequences in which over 13,000 SNPs were analyzed across all samples through PCR amplification and sequencing (comprises multiplex targeted PCR amplification of at least 30 SNV targets together in the same reaction) (pg. 1-2 paragraph bridging pg. 1 & 2 lines 1-15; pg. 7 column 2 4th full paragraph lines 1-8; Fig. 2).
Regarding claim 55, Vlaminck teaches that cell-free donor-derived DNA levels in the heart transplant recipients with acute rejection (transplant complication) are at levels up to 10% (in which percent concentration represents g/100mL, therefore 10g/100mL (0.1g/mL) = 0.1 = 10% and further converted from g/mL to ng/mL which is equal to 100,000,000 ng/mL) (equal to or above a threshold total cf-DNA value between 8ng/mL and 9ng/mL) (Fig.4C).
Regarding claim 56, Vlaminck teaches that this method of measuring the levels of the cell-free donor-derived DNA in heart transplant recipients provide an opportunity to diagnose and treat acute rejection through chosen threshold values to maximize sensitivity or specificity of the quantified cell-free donor-derived DNA in which therapeutic protocols include immunosuppression (anti-rejection treatment) (pg. 6 column 2 1st full paragraph lines 1-12; pg. 7 column 1 1st full paragraph lines 1-3).
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) 47 & 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vlaminck (Vlaminck et al.; Science Translational Medicine, Vol. 6, pages 1-9, June 2014), in view of Beck (Beck et al.; Clinical Chemistry, Vol. 59, pages 1732-1741, August 2013).
The teachings of Vlaminck with respect to claim 44 & 50 are discussed above and incorporated herein.
Regarding claim 47, Vlaminck teaches quantifying the cell-free DNA through quantitative PCR and sequencing (7 column 2 4th full paragraph lines 1-8).
Vlaminck does not teach that the quantitative PCR is real-time PCR or digital PCR.
Beck teaches a method of quantifying cell-free DNA from donor and recipient DNA from heart transplant recipients through quantitative real-time PCR using digital droplet PCR (quantitative PCR is real-time PCR or digital PCR) (abstract background lines 1-10; abstract methods lines 1-11). In addition, Beck teaches that this method of using digital droplet PCR is rapid and cost-effective method to quantify cell-free DNA in heart transplant recipients as a biomarker in early detection of rejection enabling more effective therapeutic interventions (abstract background lines 1-10; abstract conclusions lines 1-6).
Vlaminck and Beck are considered to be analogous to the claimed invention because they are all in the same field of quantifying cell-free DNA in heart transplant recipients. 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 quantifying cell-free DNA using quantitative PCR in Vlaminck to incorporate the use of real-time or digital quantitative PCR as taught in Beck because Beck teaches that doing so would provide a rapid and cost-effective method to quantify cell-free DNA in heart transplant recipients as a biomarker in early detection of rejection enabling more effective therapeutic interventions.
Regarding claim 53, Vlaminck teaches quantifying the cell-free DNA through quantitative PCR and sequencing (7 column 2 4th full paragraph lines 1-8).
Vlaminck does not teach that the quantitative PCR is real-time PCR or digital PCR.
Beck teaches a method of quantifying cell-free DNA from donor and recipient DNA from heart transplant recipients through quantitative real-time PCR using digital droplet PCR (quantitative PCR is real-time PCR or digital PCR) (abstract background lines 1-10; abstract methods lines 1-11). In addition, Beck teaches that this method of using digital droplet PCR is rapid and cost-effective method to quantify cell-free DNA in heart transplant recipients as a biomarker in early detection of rejection enabling more effective therapeutic interventions (abstract background lines 1-10; abstract conclusions lines 1-6).
Vlaminck and Beck are considered to be analogous to the claimed invention because they are all in the same field of quantifying cell-free DNA in heart transplant recipients. 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 quantifying cell-free DNA using quantitative PCR in Vlaminck to incorporate the use of real-time or digital quantitative PCR as taught in Beck because Beck teaches that doing so would provide a rapid and cost-effective method to quantify cell-free DNA in heart transplant recipients as a biomarker in early detection of rejection enabling more effective therapeutic interventions.
Claim(s) 48 & 54 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vlaminck (Vlaminck et al.; Science Translational Medicine, Vol. 6, pages 1-9, June 2014), in view of Cha (Cha, Zarbl, Keohavong, & Thilly; PCR Methods and Applications, Vol. 2, pages 14-20, April 1992).
The teachings of Vlaminck with respect to claim 44 & 50 are discussed above and incorporated herein.
Regarding claim 48, Vlaminck teaches quantifying the cell-free DNA through quantitative PCR and sequencing (7 column 2 4th full paragraph lines 1-8).
Vlaminck does not teach that the quantitative PCR comprises performing PCR with a first primer pair and a second primer pair, wherein the first primer pair comprises a 3’ penultimate mismatch in a primer relative to a first allele of SNV target but a 3’ double mismatch to a second allele of the SNV target.
Cha teaches a method of allele-specific PCR through the use of primers that have a single mismatch to the mutated allele at the 3’ end of the primer (first primer pair comprises a 3’ penultimate mismatch relative to a first allele of the SNV target) and a double mismatch with the wildtype allele (a double 3’ mismatch relative to a second allele of the SNV target) and primers to the wildtype allele with no mismatches (second primer pair specifically amplifies the second allele) (abstract lines 1-17; pg. 14-15 paragraph bridging pg. 14 & 15 lines 1-21; Table 1). In addition, Cha teaches that this method achieve a sensitivity that enables measuring specific, infrequent mutations in samples (abstract lines 1-7).
Vlaminck and Cha are considered to be analogous to the claimed invention because they are all in the same field of use of amplification to detect single nucleotide variants. 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 quantifying cell-free DNA using quantitative PCR in Vlaminck to incorporate the use of primer pairs in an amplification reaction comprising a primer pair comprising a primer with a 3’ single mismatch to a first allele and a 3’ double mismatch to a second allele and a primer pair for amplifying the second allele as taught in Cha because Cha teaches that doing so would provide a pairs of primers that achieve a sensitivity to enables measuring specific, infrequent mutations in samples.
Regarding claim 54, Vlaminck teaches quantifying the cell-free DNA through quantitative PCR and sequencing (7 column 2 4th full paragraph lines 1-8).
Vlaminck does not teach that the quantitative PCR comprises performing PCR with a first primer pair and a second primer pair, wherein the first primer pair comprises a 3’ penultimate mismatch in a primer relative to a first allele of SNV target but a 3’ double mismatch to a second allele of the SNV target.
Cha teaches a method of allele-specific PCR through the use of primers that have a single mismatch to the mutated allele at the 3’ end of the primer (first primer pair comprises a 3’ penultimate mismatch relative to a first allele of the SNV target) and a double mismatch with the wildtype allele (a double 3’ mismatch relative to a second allele of the SNV target) and primers to the wildtype allele with no mismatches (second primer pair specifically amplifies the second allele) (abstract lines 1-17; pg. 14-15 paragraph bridging pg. 14 & 15 lines 1-21; Table 1). In addition, Cha teaches that this method achieve a sensitivity that enables measuring specific, infrequent mutations in samples (abstract lines 1-7).
Vlaminck and Cha are considered to be analogous to the claimed invention because they are all in the same field of use of amplification to detect single nucleotide variants. 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 quantifying cell-free DNA using quantitative PCR in Vlaminck to incorporate the use of primer pairs in an amplification reaction comprising a primer pair comprising a primer with a 3’ single mismatch to a first allele and a 3’ double mismatch to a second allele and a primer pair for amplifying the second allele as taught in Cha because Cha teaches that doing so would provide a pairs of primers that achieve a sensitivity to enables measuring specific, infrequent mutations in samples.
Claim(s) 50-52, 55, & 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moreira (Moreira et al.; Clinical Chemistry, Vol. 55, pages 1958-1966, August 2009), in view of Vlaminck (Vlaminck et al.; Science Translational Medicine, Vol. 6, pages 1-9, June 2014).
The teachings of Vlaminck with respect to claim 44 & 50 are discussed above and incorporated herein.
Regarding claim 50, Moreira teaches a method for assessing total cell-free DNA and donor derived cell free DNA as a rapid noninvasive biomarker for detection of transplant rejection through obtaining cell-free DNA from renal transplant recipients, analyzing total and donor derived cell free DNA (non-naturally occurring composition of cell-free DNA) through quantitative PCR (preparing non-naturally occurring composition of amplified DNA by performing PCR amplification on the obtained cell-free DNA), and quantifying the total cell-free DNA in the biological samples (abstract background lines 1-11; abstract methods lines 1-8; abstract results lines 1-8; pg. 1959 column 1 1st full paragraph lines 1-6; pg. 1959 column 2 1st full paragraph lines 1-40; pg. 1959-1960 paragraph bridging pg. 1959 & 1960 lines 1-8). Moreira also teaches that treatment can be administered after increase in total cell free DNA levels corresponding to rejection of the transplant (administering a treatment for a transplant complication to the transplant recipient provided the amount of cf-DNA in the biological sample is equal to or above a threshold total of cf-DNA) (pg. 1961 column 2 1st full paragraph lines 1-7) in which a cutoff total cell-free DNA concentration of 12,000 genome equivalents (GE)/mL correctly classified acute rejection episodes from non-acute rejection episodes (abstract results 1-8). Moreira also teaches that 1 GE = 6.6pg (0.0066ng), therefore a cutoff total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL (equal to or above a threshold total cf-DNA value between 8ng/mL and 15ng/mL) (pg. 1959 column 2 1st full paragraph lines 38-40).
Moreira does not teach extracting cell-free DNA from a heart transplant recipient.
Vlaminck teaches a noninvasive diagnostic method for high-throughput screening of circulating cell-free donor-derived DNA to measure acute rejection after heart transplantation through extracting cell-free DNA from whole-blood samples of the heart transplant recipient after transplant and quantifying the cell-free DNA through quantitative PCR and sequencing (abstract lines 1-11; pg. 2 column 2 3rd full paragraph lines 1-15; pg. 2-3 paragraph bridging pg. 2 & pg. 3 lines 1-14; pg. 7 column 1 2nd full paragraph lines 1-16; pg. 7 column 2 3rd full paragraph lines 1-5; pg. 7 column 2 4th full paragraph lines 1-8; Fig. 4). Vlaminck also teaches that this method provides a noninvasive method that is powerful and informative in monitoring allograft health post-transplant (abstract lines 10-11).
Moreira and Vlaminck are considered to be analogous to the claimed invention because they are all in the same field of quantifying cell-free DNA in transplant recipients. 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 quantifying cell free DNA from a biological sample from a renal transplant recipient in Moreira to incorporate quantifying cell free DNA from a biological sample from a heart transplant recipient as taught in Vlaminck because Vlaminck teaches that doing so would provide a provides a noninvasive method that is powerful and informative in monitoring allograft health post-transplant.
Regarding claim 51, Moreira teaches the biological sample is a blood sample (pg. 1959 column 1 1st full paragraph lines 1-6).
Regarding claim 52, Moreira does not teach that the PCR amplification comprises multiplex targeted PCR amplification of at least 30 SNV targets in the same reaction.
Vlaminck teaches analyzing single nucleotide polymorphisms (SNPs) to discriminate between donor- and recipient-derived sequences in which over 13,000 SNPs were analyzed across all samples through PCR amplification and sequencing (comprises multiplex targeted PCR amplification of at least 30 SNV targets together in the same reaction) (pg. 1-2 paragraph bridging pg. 1 & 2 lines 1-15; pg. 7 column 2 4th full paragraph lines 1-8; Fig. 2). Vlaminck also teaches that this method provides a noninvasive method that is powerful and informative in monitoring allograft health post-transplant (abstract lines 10-11).
Moreira and Vlaminck are considered to be analogous to the claimed invention because they are all in the same field of quantifying cell-free DNA in transplant recipients. 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 quantifying cell free DNA from a transplant recipient with quantitative PCR in Moreira to incorporate analyzing over 13,000 SNPs through PCR amplification and sequencing as taught in Vlaminck because Vlaminck teaches that doing so would provide a provides a noninvasive method that is powerful and informative in monitoring allograft health post-transplant.
Regarding claim 55, Moreira teaches that treatment can be administered after increase in total cell free DNA levels corresponding to rejection of the transplant (administering a treatment for a transplant complication to the transplant recipient provided the amount of cf-DNA in the biological sample is equal to or above a threshold total of cf-DNA) (pg. 1961 column 2 1st full paragraph lines 1-7) in which a cutoff total cell-free DNA concentration of 12,000 genome equivalents (GE)/mL correctly classified acute rejection episodes from non-acute rejection episodes (abstract results 1-8). Moreira also teaches that 1 GE = 6.6pg (0.0066ng), therefore a cutoff total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL (equal to or above a threshold total cf-DNA value between 8ng/mL and 9ng/mL) (pg. 1959 column 2 1st full paragraph lines 38-40).
Regarding claim 56, Moreira teaches the treatment is antirejection treatment (pg. 1963 column 1 1st full paragraph lines 2-5).
Claim(s) 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moreira (Moreira et al.; Clinical Chemistry, Vol. 55, pages 1958-1966, August 2009) and Vlaminck (Vlaminck et al.; Science Translational Medicine, Vol. 6, pages 1-9, June 2014) as applied to claims 50-52, 55, & 56 above, and further in view of Beck (Beck et al.; Clinical Chemistry, Vol. 59, pages 1732-1741, August 2013).
The teachings of Moreira and Vlaminck with respect to claim 50 is discussed above.
Regarding claim 53, Moreira teaches analyzing total and donor derived cell free DNA through quantitative PCR (abstract methods lines 1-8).
Moreira and Vlaminck does not teach that the quantitative PCR is real-time PCR or digital PCR.
Beck teaches a method of quantifying cell-free DNA from donor and recipient DNA from heart transplant recipients through quantitative real-time PCR using digital droplet PCR (quantitative PCR is real-time PCR or digital PCR) (abstract background lines 1-10; abstract methods lines 1-11). In addition, Beck teaches that this method of using digital droplet PCR is rapid and cost-effective method to quantify cell-free DNA in heart transplant recipients as a biomarker in early detection of rejection enabling more effective therapeutic interventions (abstract background lines 1-10; abstract conclusions lines 1-6).
Moreira, Vlaminck, and Beck are considered to be analogous to the claimed invention because they are all in the same field of quantifying cell-free DNA in transplant recipients. 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 quantifying cell-free DNA using quantitative PCR in Moreira to incorporate the use of real-time or digital quantitative PCR as taught in Beck because Beck teaches that doing so would provide a rapid and cost-effective method to quantify cell-free DNA in heart transplant recipients as a biomarker in early detection of rejection enabling more effective therapeutic interventions.
Claim(s) 54 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moreira (Moreira et al.; Clinical Chemistry, Vol. 55, pages 1958-1966, August 2009) and Vlaminck (Vlaminck et al.; Science Translational Medicine, Vol. 6, pages 1-9, June 2014) as applied to claims 50-52, 55, & 56 above, and further in view of Cha (Cha, Zarbl, Keohavong, & Thilly; PCR Methods and Applications, Vol. 2, pages 14-20, April 1992).
The teachings of Moreira and Vlaminck with respect to claim 50 is discussed above.
Regarding claim 54, Moreira teaches analyzing total and donor derived cell free DNA through quantitative PCR (abstract methods lines 1-8).
Moreira and Vlaminck does not teach that the quantitative PCR comprises performing PCR with a first primer pair and a second primer pair, wherein the first primer pair comprises a 3’ penultimate mismatch in a primer relative to a first allele of SNV target but a 3’ double mismatch to a second allele of the SNV target.
Cha teaches a method of allele-specific PCR through the use of primers that have a single mismatch to the mutated allele at the 3’ end of the primer (first primer pair comprises a 3’ penultimate mismatch relative to a first allele of the SNV target) and a double mismatch with the wildtype allele (a double 3’ mismatch relative to a second allele of the SNV target) and primers to the wildtype allele with no mismatches (second primer pair specifically amplifies the second allele) (abstract lines 1-17; pg. 14-15 paragraph bridging pg. 14 & 15 lines 1-21; Table 1). In addition, Cha teaches that this method achieve a sensitivity that enables measuring specific, infrequent mutations in samples (abstract lines 1-7).
Moreira, Vlaminck, and Cha are considered to be analogous to the claimed invention because they are all in the same field of use of amplification. 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 quantifying cell free DNA from a transplant recipient with quantitative PCR in Moreira to incorporate analyzing over 13,000 SNPs through PCR amplification and sequencing as taught in Vlaminck because Vlaminck teaches that doing so would provide a provides a noninvasive method that is powerful and informative in monitoring allograft health post-transplant and 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 quantifying cell-free DNA using quantitative PCR in Moreira to incorporate the use of primer pairs in an amplification reaction comprising a primer pair comprising a primer with a 3’ single mismatch to a first allele and a 3’ double mismatch to a second allele and a primer pair for amplifying the second allele as taught in Cha because Cha teaches that doing so would provide a pairs of primers that achieve a sensitivity to enables measuring specific, infrequent mutations in samples.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 44, 45, 49-51, 55, & 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 10, & 11 of U.S. Patent No. 10,385,396 B2 in view of Moreira (Moreira et al.; Clinical Chemistry, Vol. 55, pages 1958-1966, August 2009).
Regarding claims 44 & 49, the instant application claims a method of preparing a non-naturally occurring composition of amplified DNA from a biological sample of a transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, and analyzing to quantify the amount of total cell free DNA in the biological sample (see claim 44). The instant application also claims the transplant recipient is a heart transplant recipient (see claim 49).
U.S. Patent No. 10,385,396 B2 claims a method of treating a recipient of a transplant comprising determining an amount of cell free DNA extracted from a biological sample of the transplant recipient, determining risk associated based on the determined amount of cell free DNA comprising comparing determined amount of cell free DNA not native to a subject to a threshold value of cell free DNA, and administering an anti-rejection therapy when greater than threshold value of cell free DNA and claims that the transplant recipient is a heart transplant recipient (see claims 1 & 8).
U.S. Patent No. 10,385,396 B2 does not claim that the total amount of cell free DNA is determined by performing PCR amplification.
Moreira teaches a method for assessing total cell-free DNA and donor derived cell free DNA as a rapid noninvasive biomarker for detection of transplant rejection through obtaining cell-free DNA from renal transplant recipients, analyzing total and donor derived cell free DNA (non-naturally occurring composition of cell-free DNA) through quantitative PCR (preparing non-naturally occurring composition of amplified DNA by performing PCR amplification on the obtained cell-free DNA), and quantifying the total cell-free DNA in the biological samples (abstract background lines 1-11; abstract methods lines 1-8; abstract results lines 1-8; pg. 1959 column 1 1st full paragraph lines 1-6; pg. 1959 column 2 1st full paragraph lines 1-40; pg. 1959-1960 paragraph bridging pg. 1959 & 1960 lines 1-8).
The claim would have been prima facie obvious to one of ordinary skill in the art to have modified the method of determining the amount of cell free DNA in a biological sample of a heart transplant recipient in claims 1 & 8 of U.S. Patent No. 10,385,396 B2 to incorporate determining the total amount of cell free DNA in a heart transplant recipient through quantitative PCR (PCR amplification) as taught by Moreira for the quantification of total cell free DNA because Moreira teaches that this method provides a rapid and noninvasive method to detect transplant rejection.
Regarding claim 45, the instant application claims the biological sample is blood, plasma, or serum. U.S. Patent No. 10,385,396 B2 claims the biological sample is blood, plasma, or serum (see claim 11).
Regarding claims 50, 55, & 56, the instant application claims a method of treating a transplant complication in a heart transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, analyzing to quantify the amount of total cell free DNA in the biological sample, and administering a treatment provided the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL (see claims 50 & 55). The instant application also claims the treatment is anti-rejection treatment (see claim 56).
U.S. Patent No. 10,385,396 B2 claims a method of treating a recipient of a transplant comprising determining an amount of cell free DNA extracted from a biological sample of the transplant recipient, determining risk associated based on the determined amount of cell free DNA comprising comparing determined amount of cell free DNA not native to a subject to a threshold value of cell free DNA, and administering an anti-rejection therapy when greater than threshold value of cell free DNA and claims that the transplant recipient is a heart transplant recipient (see claims 1 & 8). U.S. Patent No. 10,385,396 B2 also claims that the therapy is anti-rejection therapy (see claim 10).
U.S. Patent No. 10,385,396 B2 does not claim that the total amount of cell free DNA is determined by performing PCR amplification or that the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL.
Moreira teaches a method for assessing total cell-free DNA and donor derived cell free DNA as a rapid noninvasive biomarker for detection of transplant rejection through obtaining cell-free DNA from renal transplant recipients, analyzing total and donor derived cell free DNA (non-naturally occurring composition of cell-free DNA) through quantitative PCR (preparing non-naturally occurring composition of amplified DNA by performing PCR amplification on the obtained cell-free DNA), and quantifying the total cell-free DNA in the biological samples (abstract background lines 1-11; abstract methods lines 1-8; abstract results lines 1-8; pg. 1959 column 1 1st full paragraph lines 1-6; pg. 1959 column 2 1st full paragraph lines 1-40; pg. 1959-1960 paragraph bridging pg. 1959 & 1960 lines 1-8). Moreira also teaches that treatment can be administered after increase in total cell free DNA levels corresponding to rejection of the transplant (administering a treatment for a transplant complication to the transplant recipient provided the amount of cf-DNA in the biological sample is equal to or above a threshold total of cf-DNA) (pg. 1961 column 2 1st full paragraph lines 1-7) in which a cutoff total cell-free DNA concentration of 12,000 genome equivalents (GE)/mL correctly classified acute rejection episodes from non-acute rejection episodes (abstract results 1-8). Moreira also teaches that 1 GE = 6.6pg (0.0066ng), therefore a cutoff total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL (equal to or above a threshold total cf-DNA value between 8ng/mL and 15ng/mL) (pg. 1959 column 2 1st full paragraph lines 38-40).
The claim would have been prima facie obvious to one of ordinary skill in the art to have modified the method of determining the amount of cell free DNA in a biological sample of a heart transplant recipient in claims 1 & 8 of U.S. Patent No. 10,385,396 B2 to incorporate determining the total amount of cell free DNA in a heart transplant recipient through quantitative PCR (PCR amplification) with a cutoff value of total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL for treatment as taught by Moreira for the quantification of total cell free DNA because Moreira teaches that this method provides a rapid and noninvasive method to detect transplant rejection.
Regarding claim 51, the instant application claims the biological sample is blood, plasma, or serum. U.S. Patent No. 10,385,396 B2 claims the biological sample is blood, plasma, or serum (see claim 11).
Claims 44, 45, 48-51, 55, & 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 6, & 9 of U.S. Patent No. 11,773,434 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to methods of measuring total cell free DNA in biological samples from heart transplant recipients.
It is noted that instant application claims it is a DIV of 16/623,707, now U.S. Patent No. 11,773,434, in the filing receipt dated 10/20/2023. According to MPEP 804.01(C):
The following are situations where the prohibition against nonstatutory double patenting rejections under 35 U.S.C. 121 does not apply:
…
(C) The restriction requirement was withdrawn because the requirement was written in a manner which made it clear to applicant that the requirement was made subject to the nonallowance of generic or other linking claims and such generic or linking claims are subsequently allowed.
An election of species was originally filed in the parent application 16/623,707, now U.S. Patent No. 11,773,434, which was then withdrawn in the notice of allowance office action dated 03/29/2023. Therefore, prohibition against nonstatutory double patenting rejections does not apply.
Regarding claims 44, 45, & 49, the instant application claims a method of preparing a non-naturally occurring composition of amplified DNA from a biological sample of a transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, and analyzing to quantify the amount of total cell free DNA in the biological sample (see claim 44). The instant application also claims the transplant recipient is a heart transplant recipient (see claim 49). The instant application claims the biological sample is blood, plasma, or serum (see claim 45). U.S. Patent No. 11,773,434 B2 claims a method for preparing amplified DNA from a sample from a heart transplant comprising determining whether an amount of cell free DNA is equal to or exceeds a threshold comprising extracting cell free DNA from the sample, wherein the sample is a blood, plasma, or serum sample, preparing a preparation of amplified DNA by performing PCR amplification, and analyzing the preparation of amplified DNA obtained to quantify an amount of cell free DNA and determine whether the amount of total cell fee DNA is equal or exceeds a threshold of total cell free DNA value of 8ng/mL (see claims 1 & 6).
Regarding claim 48, the instant application claims the quantitative PCR comprises for each SNV target, performing PCR using a first and second primer pair, wherein the first primer pair comprises a 3’ penultimate mismatch in a primer relative to a first allele of the SNV target but a 3’ double mismatch relative to a second allele, and wherein the second primer pair specifically amplifies the second allele. U.S. Patent No. 11,773,434 B2 claims for SNV, performing a quantification PCR assay comprising at least two primer pairs, wherein one primer pair comprises a 3’ penultimate mismatch in a primer relative to a one allele of the SNV target but a 3’ double mismatch relative to a another allele, and wherein the another primer pair specifically amplifies the other allele (see claim 5).
Regarding claims 50, 51, 55, & 56, the instant application claims a method of preparing a non-naturally occurring composition of amplified DNA from a biological sample of a transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, analyzing to quantify the amount of total cell free DNA in the biological sample, and administering a treatment provided the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL (see claims 50 & 55). The instant application also claims the treatment is anti-rejection treatment (see claim 56). The instant application claims the biological sample is blood, plasma, or serum (see claim 51). U.S. Patent No. 11,773,434 B2 claims a method for preparing amplified DNA from a sample from a heart transplant comprising determining whether an amount of cell free DNA is equal to or exceeds a threshold comprising extracting cell free DNA from the sample, wherein the sample is a blood, plasma, or serum sample, preparing a preparation of amplified DNA by performing PCR amplification, and analyzing the preparation of amplified DNA obtained to quantify an amount of cell free DNA, determine whether the amount of total cell fee DNA is equal or exceeds a threshold of total cell free DNA value of 8ng/mL, and administering a treatment for a transplant complication which is an anti-rejection treatment (see claims 2 & 9).
Claims 44, 45, 48, & 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15, 41, & 43 of copending Application No. 17/493,186 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to methods of measuring total cell free DNA in biological samples from heart transplant recipients.
Regarding claim 44, the instant application claims a method of preparing a non-naturally occurring composition of amplified DNA from a biological sample of a transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, and analyzing to quantify the amount of total cell free DNA in the biological sample. Copending Application No. 17/493,186 claims a method for assaying cell free DNA from a sample from a transplant recipient comprising extracting cell free DNA from the sample, performing an amplification based quantification assay or sequencing the cell free DNA, and quantifying the total amount of cell free DNA comprising determining whether the amount of total cell free DNA is equal to or exceeds a threshold total cell free DNA value of 15 ng/mL (see claim 1).
Regarding claim 45, the instant application claims the biological sample is blood, plasma, or serum. Copending Application No. 17/493,186 claims the sample is blood, plasma, or serum (see claim 41).
Regarding claim 48, the instant application claims the quantitative PCR comprises for each SNV target, performing PCR using a first and second primer pair, wherein the first primer pair comprises a 3’ penultimate mismatch in a primer relative to a first allele of the SNV target but a 3’ double mismatch relative to a second allele, and wherein the second primer pair specifically amplifies the second allele. Copending Application No. 17/493,186 claims for SNV, performing a quantification PCR assay comprising at least two primer pairs, wherein one primer pair comprises a 3’ penultimate mismatch in a primer relative to a one allele of the SNV target but a 3’ double mismatch relative to a another allele, and wherein the another primer pair specifically amplifies the other allele (see claim 15).
Regarding claim 49, the instant application also claims the transplant recipient is a heart transplant recipient. Copending Application No. 17/493,186 claims transplant recipient is a heart transplant recipient (see claim 43).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 50, 51, & 54-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15, 41, & 43 of copending Application No. 17/493,186 in view of Moreira (Moreira et al.; Clinical Chemistry, Vol. 55, pages 1958-1966, August 2009).
Regarding claims 50, 55, & 56, the instant application claims a method of treating a transplant complication in a heart transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, analyzing to quantify the amount of total cell free DNA in the biological sample, and administering a treatment provided the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL (see claims 50 & 55). The instant application also claims the treatment is anti-rejection treatment (see claim 56).
Copending Application No. 17/493,186 claims a method for assaying cell free DNA from a sample from a transplant recipient comprising extracting cell free DNA from the sample, performing an amplification based quantification assay or sequencing the cell free DNA, and quantifying the total amount of cell free DNA comprising determining whether the amount of total cell free DNA is equal to or exceeds a threshold total cell free DNA value of 15 ng/mL (see claim 1). Copending Application No. 17/493,186 also claims transplant recipient is a heart transplant recipient (see claim 43).
Copending Application No. 17/493,186 does not claim treating the transplant recipient provided the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL.
Moreira teaches a method for assessing total cell-free DNA and donor derived cell free DNA as a rapid noninvasive biomarker for detection of transplant rejection through obtaining cell-free DNA from renal transplant recipients, analyzing total and donor derived cell free DNA (non-naturally occurring composition of cell-free DNA) through quantitative PCR (preparing non-naturally occurring composition of amplified DNA by performing PCR amplification on the obtained cell-free DNA), and quantifying the total cell-free DNA in the biological samples (abstract background lines 1-11; abstract methods lines 1-8; abstract results lines 1-8; pg. 1959 column 1 1st full paragraph lines 1-6; pg. 1959 column 2 1st full paragraph lines 1-40; pg. 1959-1960 paragraph bridging pg. 1959 & 1960 lines 1-8). Moreira also teaches that treatment can be administered after increase in total cell free DNA levels corresponding to rejection of the transplant (administering a treatment for a transplant complication to the transplant recipient provided the amount of cf-DNA in the biological sample is equal to or above a threshold total of cf-DNA) (pg. 1961 column 2 1st full paragraph lines 1-7) in which a cutoff total cell-free DNA concentration of 12,000 genome equivalents (GE)/mL correctly classified acute rejection episodes from non-acute rejection episodes (abstract results 1-8). Moreira also teaches that 1 GE = 6.6pg (0.0066ng), therefore a cutoff total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL (equal to or above a threshold total cf-DNA value between 8ng/mL and 15ng/mL) (pg. 1959 column 2 1st full paragraph lines 38-40).
The claim would have been prima facie obvious to one of ordinary skill in the art to have modified the method of determining the amount of cell free DNA in a biological sample of a heart transplant recipient in claims 1 & 43 of Copending Application No. 17/493,186 to incorporate determining the total amount of cell free DNA in a heart transplant recipient with a cutoff value of total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL for treatment with anti-rejection therapy as taught by Moreira for the quantification of total cell free DNA because Moreira teaches that this method provides a rapid and noninvasive method to detect transplant rejection.
Regarding claim 51, the instant application claims the biological sample is blood, plasma, or serum. Copending Application No. 17/493,186 claims the sample is blood, plasma, or serum (see claim 41).
Regarding claim 54, the instant application claims the quantitative PCR comprises for each SNV target, performing PCR using a first and second primer pair, wherein the first primer pair comprises a 3’ penultimate mismatch in a primer relative to a first allele of the SNV target but a 3’ double mismatch relative to a second allele, and wherein the second primer pair specifically amplifies the second allele. Copending Application No. 17/493,186 claims for SNV, performing a quantification PCR assay comprising at least two primer pairs, wherein one primer pair comprises a 3’ penultimate mismatch in a primer relative to a one allele of the SNV target but a 3’ double mismatch relative to a another allele, and wherein the another primer pair specifically amplifies the other allele (see claim 15).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 44, 45, 48, & 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 57, & 89 of copending Application No. 16/623,719 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to methods of measuring total cell free DNA in biological samples from heart transplant recipients.
Regarding claim 44, the instant application claims a method of preparing a non-naturally occurring composition of amplified DNA from a biological sample of a transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, and analyzing to quantify the amount of total cell free DNA in the biological sample. Copending Application No. 16/623,719 claims a method for preparing amplified cell free DNA from a sample from a transplant recipient comprising extracting cell free DNA from the sample, performing a multiplexed targeted PCR of the cell free DNA, and quantifying the total amount of cell free DNA (see claim 1).
Regarding claim 45, the instant application claims the biological sample is blood, plasma, or serum. Copending Application No. 16/623,719 claims the sample is blood, plasma, or serum (see claim 1).
Regarding claim 48, the instant application claims the quantitative PCR comprises for each SNV target, performing PCR using a first and second primer pair, wherein the first primer pair comprises a 3’ penultimate mismatch in a primer relative to a first allele of the SNV target but a 3’ double mismatch relative to a second allele, and wherein the second primer pair specifically amplifies the second allele. Copending Application No. 16/623,719 claims for SNV, performing a quantification PCR assay comprising at least two primer pairs, wherein one primer pair comprises a 3’ penultimate mismatch in a primer relative to a one allele of the SNV target but a 3’ double mismatch relative to a another allele, and wherein the another primer pair specifically amplifies the other allele (see claim 57).
Regarding claim 49, the instant application also claims the transplant recipient is a heart transplant recipient. Copending Application No. 16/623,719 claims transplant recipient is a heart transplant recipient (see claim 89).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 50, 51, & 54-56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 57, 89, & 92 of copending Application No. 16/623,719 in view of Moreira (Moreira et al.; Clinical Chemistry, Vol. 55, pages 1958-1966, August 2009).
Regarding claims 50, 55, & 56, the instant application claims a method of treating a transplant complication in a heart transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, analyzing to quantify the amount of total cell free DNA in the biological sample, and administering a treatment provided the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL (see claims 50 & 55). The instant application also claims the treatment is anti-rejection treatment (see claim 56).
Copending Application No. 16/623,719 claims a method for preparing amplified cell free DNA from a sample from a transplant recipient comprising extracting cell free DNA from the sample, performing a multiplexed targeted PCR of the cell free DNA, and quantifying the total amount of cell free DNA, and further administering an anti-rejection therapy based on the determined total cell free DNA (see claim 1). Copending Application No. 16/623,719 also claims transplant recipient is a heart transplant recipient (see claim 89).
Copending Application No. 16/623,719 does not claim treating the transplant recipient provided the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL.
Moreira teaches a method for assessing total cell-free DNA and donor derived cell free DNA as a rapid noninvasive biomarker for detection of transplant rejection through obtaining cell-free DNA from renal transplant recipients, analyzing total and donor derived cell free DNA (non-naturally occurring composition of cell-free DNA) through quantitative PCR (preparing non-naturally occurring composition of amplified DNA by performing PCR amplification on the obtained cell-free DNA), and quantifying the total cell-free DNA in the biological samples (abstract background lines 1-11; abstract methods lines 1-8; abstract results lines 1-8; pg. 1959 column 1 1st full paragraph lines 1-6; pg. 1959 column 2 1st full paragraph lines 1-40; pg. 1959-1960 paragraph bridging pg. 1959 & 1960 lines 1-8). Moreira also teaches that treatment can be administered after increase in total cell free DNA levels corresponding to rejection of the transplant (administering a treatment for a transplant complication to the transplant recipient provided the amount of cf-DNA in the biological sample is equal to or above a threshold total of cf-DNA) (pg. 1961 column 2 1st full paragraph lines 1-7) in which a cutoff total cell-free DNA concentration of 12,000 genome equivalents (GE)/mL correctly classified acute rejection episodes from non-acute rejection episodes (abstract results 1-8). Moreira also teaches that 1 GE = 6.6pg (0.0066ng), therefore a cutoff total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL (equal to or above a threshold total cf-DNA value between 8ng/mL and 15ng/mL) (pg. 1959 column 2 1st full paragraph lines 38-40).
The claim would have been prima facie obvious to one of ordinary skill in the art to have modified the method of determining the amount of cell free DNA in a biological sample of a heart transplant recipient in claims 1 & 89 of Copending Application No. 16/623,719 to incorporate determining the total amount of cell free DNA in a heart transplant recipient with a cutoff value of total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL for treatment with anti-rejection therapy as taught by Moreira for the quantification of total cell free DNA because Moreira teaches that this method provides a rapid and noninvasive method to detect transplant rejection.
Regarding claim 51, the instant application claims the biological sample is blood, plasma, or serum. Copending Application No. 16/623,719 claims the sample is blood, plasma, or serum (see claim 1).
Regarding claim 54, the instant application claims the quantitative PCR comprises for each SNV target, performing PCR using a first and second primer pair, wherein the first primer pair comprises a 3’ penultimate mismatch in a primer relative to a first allele of the SNV target but a 3’ double mismatch relative to a second allele, and wherein the second primer pair specifically amplifies the second allele. Copending Application No. 16/623,719 claims for SNV, performing a quantification PCR assay comprising at least two primer pairs, wherein one primer pair comprises a 3’ penultimate mismatch in a primer relative to a one allele of the SNV target but a 3’ double mismatch relative to a another allele, and wherein the another primer pair specifically amplifies the other allele (see claim 57).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 44, 45, 46, & 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 13 of copending Application No. 16/623,725 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to methods of measuring total cell free DNA in biological samples from transplant recipients.
Regarding claims 44, 45, 46, & 48, the instant application claims a method of preparing a non-naturally occurring composition of amplified DNA from a biological sample of a transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, and analyzing to quantify the amount of total cell free DNA in the biological sample. The instant application also claims the biological sample is blood, plasma, or serum (see claim 45). The instant application also claims that the PCR amplification comprises multiplex target PCR amplification of at least 30 SNV targets together in the same reaction (see claim 46). The instant application claims the quantitative PCR comprises for each SNV target, performing PCR using a first and second primer pair, wherein the first primer pair comprises a 3’ penultimate mismatch in a primer relative to a first allele of the SNV target but a 3’ double mismatch relative to a second allele, and wherein the second primer pair specifically amplifies the second allele (see claim 48). Copending Application No. 16/623,725 claims a method for preparing amplified cell free DNA from a sample from a transplant recipient comprising extracting cell free DNA from the sample, wherein the sample id blood, plasma, or serum sample, performing a multiplexed targeted PCR of the cell free DNA to amplify at least 50 SNV targets in the same reaction, performing quantitative PCR to quantify the total amount of cell free DNA, performing quantitative PCR using at least two primer pairs, wherein one primer pair comprises a 3’ penultimate mismatch in a primer relative to a one allele of the SNV target but a 3’ double mismatch relative to a another allele, and wherein the another primer pair specifically amplifies the other allele (see claim 13).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 44 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/493,230 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to methods of measuring total cell free DNA in biological samples from heart transplant recipients.
Regarding claim 44, the instant application claims a method of preparing a non-naturally occurring composition of amplified DNA from a biological sample of a transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, and analyzing to quantify the amount of total cell free DNA in the biological sample. Copending Application No. 17/493,230 claims a method for assaying cell free DNA from a sample from a transplant recipient comprising extracting cell free DNA from the sample, performing a PCR amplification of the cell free DNA, and quantifying the total amount of cell free DNA comprising determining whether the amount of total cell free DNA is equal to or exceeds a threshold total cell free DNA value (see claim 1).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 50, 55, & 56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, & 85 of copending Application No. 17/493,230 in view of Moreira (Moreira et al.; Clinical Chemistry, Vol. 55, pages 1958-1966, August 2009).
Regarding claims 50, 55, & 56, the instant application claims a method of treating a transplant complication in a heart transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, analyzing to quantify the amount of total cell free DNA in the biological sample, and administering a treatment provided the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL (see claims 50 & 55). The instant application also claims the treatment is anti-rejection treatment (see claim 56).
Copending Application No. 17/493,230 claims a method for assaying cell free DNA from a sample from a transplant recipient comprising extracting cell free DNA from the sample, performing a PCR amplification of the cell free DNA, and quantifying the total amount of cell free DNA comprising determining whether the amount of total cell free DNA is equal to or exceeds a threshold total cell free DNA value and further claims determining a treatment for the subject based on the determined cell free DNA value (see claims 1, 4, & 85).
Copending Application No. 17/493,230 does not claim treating the transplant recipient, wherein the transplant recipient is a heart transplant recipient, provided the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL or that the treatment is an anti-rejection treatment.
Moreira teaches a method for assessing total cell-free DNA and donor derived cell free DNA as a rapid noninvasive biomarker for detection of transplant rejection through obtaining cell-free DNA from renal transplant recipients, analyzing total and donor derived cell free DNA (non-naturally occurring composition of cell-free DNA) through quantitative PCR (preparing non-naturally occurring composition of amplified DNA by performing PCR amplification on the obtained cell-free DNA), and quantifying the total cell-free DNA in the biological samples (abstract background lines 1-11; abstract methods lines 1-8; abstract results lines 1-8; pg. 1959 column 1 1st full paragraph lines 1-6; pg. 1959 column 2 1st full paragraph lines 1-40; pg. 1959-1960 paragraph bridging pg. 1959 & 1960 lines 1-8). Moreira also teaches that treatment can be administered after increase in total cell free DNA levels corresponding to rejection of the transplant (administering a treatment for a transplant complication to the transplant recipient provided the amount of cf-DNA in the biological sample is equal to or above a threshold total of cf-DNA) (pg. 1961 column 2 1st full paragraph lines 1-7) in which a cutoff total cell-free DNA concentration of 12,000 genome equivalents (GE)/mL correctly classified acute rejection episodes from non-acute rejection episodes (abstract results 1-8). Moreira also teaches that 1 GE = 6.6pg (0.0066ng), therefore a cutoff total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL (equal to or above a threshold total cf-DNA value between 8ng/mL and 15ng/mL) (pg. 1959 column 2 1st full paragraph lines 38-40).
The claim would have been prima facie obvious to one of ordinary skill in the art to have modified the method of determining the amount of cell free DNA in a biological sample of a transplant recipient and treating based on the determined cell free DNA value in claims 1, 4, & 85 of Copending Application No. 17/493,230 to incorporate determining the total amount of cell free DNA in a heart transplant recipient with a cutoff value of total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL for treatment with anti-rejection therapy as taught by Moreira for the quantification of total cell free DNA because Moreira teaches that this method provides a rapid and noninvasive method to detect transplant rejection.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 44, 45, 49, & 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 24, 26, & 29 of copending Application No. 17/493,293 (reference application) in view of Moreira (Moreira et al.; Clinical Chemistry, Vol. 55, pages 1958-1966, August 2009). Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to methods of measuring total cell free DNA in biological samples from transplant recipients.
Regarding claims 44 & 49, the instant application claims a method of preparing a non-naturally occurring composition of amplified DNA from a biological sample of a transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, and analyzing to quantify the amount of total cell free DNA in the biological sample. Copending Application No. 17/493,293 claims a method for preparing amplified cell free DNA from a sample from a transplant recipient comprising obtaining cell free DNA from the sample, performing a multiplexed targeted PCR of the cell free DNA, and quantifying the total amount of cell free DNA (see claim 1). The instant application also claims the transplant recipient is a heart transplant recipient (see claim 49).
Copending Application No. 17/493,293 claims a method of assessing a sample from a transplant subject comprising obtaining an amount of cell free DNA the sample of the transplant recipient, performing an assay to measure an amount of donor specific cell free DNA and total cell free DNA in a sample, and determining the amount of cell free DNA in the sample (see claim 1). Copending Application No. 17/493,293 also claims the transplant subject is a heart transplant subject (see claim 29).
Copending Application No. 17/493,293 does not claim that the total amount of cell free DNA is determined by performing PCR amplification.
Moreira teaches a method for assessing total cell-free DNA and donor derived cell free DNA as a rapid noninvasive biomarker for detection of transplant rejection through obtaining cell-free DNA from renal transplant recipients, analyzing total and donor derived cell free DNA (non-naturally occurring composition of cell-free DNA) through quantitative PCR (preparing non-naturally occurring composition of amplified DNA by performing PCR amplification on the obtained cell-free DNA), and quantifying the total cell-free DNA in the biological samples (abstract background lines 1-11; abstract methods lines 1-8; abstract results lines 1-8; pg. 1959 column 1 1st full paragraph lines 1-6; pg. 1959 column 2 1st full paragraph lines 1-40; pg. 1959-1960 paragraph bridging pg. 1959 & 1960 lines 1-8).
The claim would have been prima facie obvious to one of ordinary skill in the art to have modified the method of determining the amount of cell free DNA in a biological sample of a heart transplant recipient in claims 1 & 29 of copending Application No. 17/493,293 to incorporate determining the total amount of cell free DNA in a heart transplant recipient through quantitative PCR (PCR amplification) as taught by Moreira for the quantification of total cell free DNA because Moreira teaches that this method provides a rapid and noninvasive method to detect transplant rejection.
Regarding claim 45, the instant application claims the biological sample is blood, plasma, or serum. Copending Application No. 17/493,293 claims the biological sample is blood, plasma, or serum (see claim 26).
Regarding claims 50, 55, & 56, the instant application claims a method of treating a transplant complication in a heart transplant recipient comprising extracting cell free DNA from the biological sample, preparing a non-naturally occurring composition of amplified DNA by performing PCR amplification on the cell free DNA, analyzing to quantify the amount of total cell free DNA in the biological sample, and administering a treatment provided the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL (see claims 50 & 55). The instant application also claims the treatment is anti-rejection treatment (see claim 56).
Copending Application No. 17/493,293 claims a method of assessing a sample from a transplant subject comprising obtaining an amount of cell free DNA the sample of the transplant recipient, performing an assay to measure an amount of donor specific cell free DNA and total cell free DNA in a sample, and determining the amount of cell free DNA in the sample, and determining a treatment for the subject based on the amount of cell free DNA (see claims 7 & 24).
Copending Application No. 17/493,293 does not claim that the total amount of cell free DNA is determined by performing PCR amplification or that the total amount of cell free DNA is equal to or above a threshold total cell free DNA value between 8ng/mL and 15 ng/mL or between 8 ng/ml and 9 ng/mL in a heart transplant recipient.
Moreira teaches a method for assessing total cell-free DNA and donor derived cell free DNA as a rapid noninvasive biomarker for detection of transplant rejection through obtaining cell-free DNA from renal transplant recipients, analyzing total and donor derived cell free DNA (non-naturally occurring composition of cell-free DNA) through quantitative PCR (preparing non-naturally occurring composition of amplified DNA by performing PCR amplification on the obtained cell-free DNA), and quantifying the total cell-free DNA in the biological samples (abstract background lines 1-11; abstract methods lines 1-8; abstract results lines 1-8; pg. 1959 column 1 1st full paragraph lines 1-6; pg. 1959 column 2 1st full paragraph lines 1-40; pg. 1959-1960 paragraph bridging pg. 1959 & 1960 lines 1-8). Moreira also teaches that treatment can be administered after increase in total cell free DNA levels corresponding to rejection of the transplant (administering a treatment for a transplant complication to the transplant recipient provided the amount of cf-DNA in the biological sample is equal to or above a threshold total of cf-DNA) (pg. 1961 column 2 1st full paragraph lines 1-7) in which a cutoff total cell-free DNA concentration of 12,000 genome equivalents (GE)/mL correctly classified acute rejection episodes from non-acute rejection episodes (abstract results 1-8). Moreira also teaches that 1 GE = 6.6pg (0.0066ng), therefore a cutoff total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL (equal to or above a threshold total cf-DNA value between 8ng/mL and 15ng/mL) (pg. 1959 column 2 1st full paragraph lines 38-40).
The claim would have been prima facie obvious to one of ordinary skill in the art to have modified the method of determining the amount of cell free DNA in a biological sample of a transplant recipient to determine a treatment based on the determined cell free DNA values in claims 7 & 24 of copending Application No. 17/493,293 to incorporate determining the total amount of cell free DNA in a heart transplant recipient through quantitative PCR (PCR amplification) with a cutoff value of total cell-free DNA concentration of 12,000 GE/mL x 0.0066ng = 79.2 ng/mL for treatment as taught by Moreira for the quantification of total cell free DNA because Moreira teaches that this method provides a rapid and noninvasive method to detect transplant rejection.
Conclusion
Claims 44-56 are rejected.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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