DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the papers filed October 15, 2025. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Claims 103-114 are currently pending and have been examined herein.
Claim Rejections - 35 USC § 101
3. 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 103-114 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite an abstract idea. Claim 103 recites a step of “analyzing the non-naturally occurring composition of amplified cell free DNA to determine the percentage of donor specific cell free DNA based on quantities of major and minor alleles at the SNP loci”. The analyzing step broadly encompasses an activity that can be performed in the human mind. While some types of “analyzing” require sophisticated software, the claims do not require this. The “analyzing” could be performed by thinking about the quantities of major at minor alleles at the SNP loci that were detected. Addition the recitation of determining the percentage of donor specific cell free DNA based on the quantities of major and minor alleles at the SNP loci requires performing a mathematical calculation. Mathematical calculations are also abstract ideas.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Claim 105 further comprises administering an anti-rejection treatment to the transplant recipient when the percentage of donor specific cell free DNA and/or the amount of total cell free DNA exceeds a threshold. This administration step is conditional and only occurs when certain criteria are met (i.e., when the amount of DS cf-DNA and/or the amount of total cf-DNA exceeds a threshold). The claim broadly encompasses situations where the subject does not meet the criteria for treatment and in those situations the anti-rejection therapy is not administered. Since the administering step does not necessarily occur, the claims do not recite any steps or elements that integrate the judicial exceptions so as to practically apply the judicial exceptions.
In addition to the judicial exceptions, the claims require steps of extracting cf-DNA from a biological sample of a transplant recipient, wherein the extracted cell free DNA comprises a mixture of donor specific cfDNA and recipient cfDNA; preparing a non-naturally occurring composition of amplified cell free DNA by performing quantitative PCR on the extracted cell free DNA using 10-95 target specific primer pairs to amplify SNP that are homozygous in the recipient; and performing quantitative PCR on the extracted cell free DNA to determine the amount of total cell free DNA. The additionally recited limitations are not considered to integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exceptions.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions, the claims require steps of extracting cf-DNA from a biological sample of a transplant recipient, wherein the extracted cell free DNA comprises a mixture of donor specific cfDNA and recipient cfDNA; preparing a non-naturally occurring composition of amplified cell free DNA by performing quantitative PCR on the extracted cell free DNA using 10-95 target specific primer pairs to amplify SNP that are homozygous in the recipient; and performing quantitative PCR on the extracted cell free DNA to determine the amount of total cell free DNA. The additionally recited limitations do NOT amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art to the judicial exceptions.
The prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known.
For example Mitchell (US 2015/0086477 Pub 3/26/2015) teaches determining the amounts of cell free DNA, native, total, and/or non-native concentrations from biological samples. Mitchell teaches that non-native cell free DNA includes donor specific cf-DNA that is shed from a donated transplanted organ into the blood, plasma, serum, or urine of a transplant recipient (para 0064). Mitchell teaches measuring cell free DNA in samples drawn at three time points after aortic clamp removal in each of 11 new heart transplant recipients. Mitchell teaches the following time points: time point 1 (14-36 hours, day 1), time point 2 (84-126 hours, day 3-5), and time point 3 (160-206 hours, day 6-9) (para 0177). Mitchell teaches extracting cell free DNA (para 0165). Mitchell teaches that the amounts of total cf-DNA were obtained by TaqMan quantitative real time PCR (para 0166). Mitchell teaches that the amount of DS cf-DNA was determined by DANSR amplification followed by sequencing. Mitchell teaches that for DANSR, 192 genomic loci were targeted for amplification and the amplicons were sequenced (para 0167). Mitchell teaches that genotypes were determined for 192 loci and the loci were deemed “informative” for calculating DS cfDNA frequencies when recipient genotypes were homozygous and donor genotypes were either heterozygous or homozygous for the other allele (para 0171).
Grskovic (The Journal of Molecular Diagnostics Vol 18 No 6 November 2016) describes an assay to measure donor derived cell free DNA in solid organ transplant recipients. Grskovic teaches that the dd-cfDNA assay is based on targeted amplification of DNA regions harboring 266 SNPs and the measurement by NGS of each allele contribution at each SNP position. Grskovic teaches that cfDNA extracted from 1.25 mL plasma or reference materials (described above, used at 3, 8, or 60 ng) was preamplified in a single multiplex reaction with 266 primer pairs for 15 cycles. Preamplified material was further amplified using 48 limited complexity multiplexes (1 to 11 targets per reaction) on the Access Array microfluidic system (Fluidigm, South San Francisco, CA). Index sequences and Illumina sequencing adapters were added to each sample DNA by PCR, and the sample was qualified and quantified by capillary electrophoresis. Up to 16 amplified samples were pooled in equimolar amounts, purified using Agencourt AMPure XP beads (Beckman Coulter, Brea, CA), and sequenced on an Illumina MiSeq instrument (page 892, col 2). Grskovic teaches that the percent of dd-cfDNA was estimated from the background corrected alternative allele frequencies of the recipient homozygous SNPs (page 893, col 2).
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Response To Arguments
4. In the response the Applicants traversed the rejection under 35 USC 101. In the response the Applicants state that the claims have been amended. They argue that the claims as amended are similar to the claim found patent eligible by the Federal Circuit in Illumina v. Ariosa
Diagnostics. They argue that claim 103 is directed to a method for preparing a preparation of amplified DNA, and similarly recites related steps such as extracting DNA from a biological sample, preparing a preparation of amplified DNA by performing amplification, and analyzing the preparation of amplified DNA. They argue that because the claims are directed to a method of preparation, they are not directed to a patent-ineligible concept.
This argument has been fully considered but is not persuasive. Merely amending the preamble to recite “A method for preparing a non-naturally occurring composition of amplified cell free DNA” is insufficient to overcome the rejection. Just because the claims does are drawn to a method of preparation does not mean that they are automatically patent eligible. The Office must still consider whether the claim recites a judicial exception, whether the judicial exception is integrated into a practical application, and if the claim provides an inventive concept. This analysis is set forth above and it was determined that the claims are not eligible.
Next the Applicants point to Example 31 of the USPTO Subject Matter Eligibly Examples (May 2016). They argue that a technology is not routine and conventional merely because it had been discussed in scientific publications, but rather, it must be established that the technology was actually routinely or conventionally used by scientists at the time the invention was made and the application was filed. They argue that the references cited in the rejection
(Mitchell US 2015/0086477) and Grskovic (The Journal of Molecular Diagnostics (2016) 18:6)
fails to establish how a method of performing quantitative PCR using 10-95 target-specific primer pairs to amplify and quantify donor-specific cell-free DNA from a mixture of donor-specific cell-free DNA and recipient cell-free DNA was routinely and conventionally used before the priority date of the present application based on the teachings of the cited references.
This argument has been fully considered but is not persuasive. MPEP 2106.05(d) states that one or more of the following should be provided when determining if a element or combination of elements is well understood, routine, and conventional:
(a) A citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates the well-understood, routine, conventional nature of the additional element(s);
(b) A citation to one or more of the court decisions discussed in Subsection II below as noting the well-understood, routine, conventional nature of the additional element(s);
(c) A citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and
(d) A statement that the examiner is taking official notice of the well-understood, routine, conventional nature of the additional element(s).
The technology required in the claims is performing quantitative PCR.
Regarding (b) the rejection cites the following court decisions that show that nucleic acid amplification , including PCR, is well-understood, routine, and conventional activity.
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
Regarding (c) Mitchell (US 2015/0086477) discloses TaqMan quantitative real time PCR (para 0166). Grskovic (The Journal of Molecular Diagnostics (2016) 18:6) discloses real-time quantitative PCR (Figure 2 inset).
Regarding (d) the Examiner is taking Official notice that quantitative PCR has been around for greater than 20+ years and in unquestionably a well-known, routine, and conventional assay.
Further both Mitchell and Grskovic teach the analysis of cell free DNA from a sample obtained from a transplant recipient and Grskovic teaches the use of target specific primer pairs to amplify SNP loci that are homozygous in the recipient.
Additionally the Applicants argue that the claims are also patent-eligible because the judicial exception is integrated into a practical application. They argue that the presently claimed invention significantly improves on transplant diagnostic technology available in the marketplace, based on evaluation of donor-specific cfDNA from patient blood samples.
This argument has been reviewed but is not persuasive. Herein the “technology” used by the claim is performing quantitative PCR to detect cell free DNA. The additional elements cited by the Applicants, do not improve the technology of performing quantitative PCR to detect cell free DNA and do not improve any other technology. The additional elements cited by the Applicants, do not make the technology of performing quantitative PCR to detect cell free DNA and do not make any other technology work better. Applicants argue that the claims recite that the improvement is transplant diagnostics but the claims do not recite any steps of diagnosis. Further Applicants even argue that the claims are not diagnostic methods-they are methods of preparation. Therefore, there is no improvement nor is the exception integrated into a practical application.
Finally the Applicants argue that the claims recite non-conventional features of the claimed invention also satisfy the "significantly more" test. They argue that the steps of extracting cell-free DNA from a biological sample, amplifying 10-95 loci from the extracted cell-free DNA, and analyzing the amplification products to produce genetic data for the 10-95 loci, wherein “the percentage of donor-specific cell-free DNA based on quantities of major and minor alleles at the SNP loci,” when taken as a whole, have not been established to be routine, conventional, or well-known in genetic testing technology at the priority date of the present application.
This argument has been fully considered but is not persuasive. This argument has been already addressed above. The rejection is maintained.
Claim Rejections - 35 USC § 103
5. 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.
6. Claims 103-113 are rejected under 35 U.S.C. 103 as being unpatentable over Mitchell (US 2015/0086477 Pub 3/26/2015) in view of Grskovic (J Mol Diagn 2016 18:890-902 E-Pub 10/7/2016).
Regarding Claim 103 Mitchell teaches determining the amounts of cell free DNA, native, total, and/or non-native concentrations from biological samples. Mitchell teaches that non-native cell free DNA includes donor specific cf-DNA that is shed from a donated transplanted organ into the blood, plasma, serum, or urine of a transplant recipient (para 0064). Mitchell teaches measuring cell free DNA in samples drawn at three time points after aortic clamp removal in each of 11 new heart transplant recipients. Mitchell teaches the following time points: time point 1 (14-36 hours, day 1), time point 2 (84-126 hours, day 3-5), and time point 3 (160-206 hours, day 6-9) (para 0177). Mitchell teaches extracting cell free DNA (para 0165). Mitchell teaches that the amounts of total cf-DNA were obtained by TaqMan quantitative real time PCR (para 0166). Mitchell teaches that the amount of DS cf-DNA was determined by DANSR amplification followed by sequencing. Mitchell teaches that for DANSR, 192 genomic loci were targeted for amplification and the amplicons were sequenced (para 0167). Mitchell teaches that genotypes were determined for 192 loci and the loci were deemed “informative” for calculating DS cfDNA frequencies when recipient genotypes were homozygous and donor genotypes were either heterozygous or homozygous for the other allele (para 0171). Mitchell teaches that increased levels of DS cf-DNA were observed in all samples at time point 1 (FIG. 5A). In each case these levels rapidly declined with subsequent samples showing a significant decrease between time points 1 and 2 (FIG. 5A). The samples at time point 3 (day 6-9) were not different from baseline levels found in asymptomatic heart transplant recipients undergoing scheduled surveillance biopsy (para 0177). Thus Mitchell teaches a method for amplifying cell free DNA comprising: extracting cf-DNA from a biological sample of a transplant recipient, wherein the extracted cell free DNA comprises a mixture of donor specific cell free DNA and recipient cell free DNA; performing DANSAR amplification to amplify SNP loci that are homozygous in the recipient followed by sequencing to determine the percentage of DS cfDNA based on the quantity of major and minor alleles at the SNP loci, and performing quantitative PCR on the extracted cell free DNA to determine the amount of total cell free DNA.
Regarding Claim 104 Mitchell teaches that genotypes were determined for 192 loci and the loci were deemed “informative” for calculating DS cfDNA frequencies when recipient genotypes were homozygous and donor genotypes were either heterozygous or homozygous for the other allele (para 0171). Thus Mitchell teaches a method wherein the percentage of DS cf-DNA is determined based on both SNP loci that are homozygous for a different allele in the donor and SNP loci that are heterozygous in the donor.
Regarding Claim 105 Mitchell teaches the methods include a step of providing a therapy, such as an anti-rejection therapy to the transplant recipient where the amount, such as the percent of, non-native cf-DNA (e.g., DS cf-DNA) is above a certain threshold limit (para 0087).
Regarding Claim 106 Mitchell teaches a method wherein the biological sample is a blood, plasma, or serum sample (para 0079).
Regarding Claim 107 Mitchell teaches a method wherein the transplant recipient is a heart transplant recipient (para 0072).
Regarding Claim 108 Mitchell teaches that 33 samples were drawn at three time points in each of eleven new heart transplant recipient patients at 14-36 hours, 84-126 hours, and 160-206 hours following removal of aortic cross clamp and reperfusion of the donor organ (para 0161). Thus Mitchell teaches a method wherein the biological sample is collected from the transplant recipient within 24 hours of cross-clamp removal.
Regarding Claim 109 Mitchell teaches a method wherein the transplant recipient is a heart, kidney, liver, lung, pancreas, or intestine transplant recipient (para 0072).
Regarding Claim 110 Mitchell teaches that the method can be performed on a transplant recipient as early as 14-36 hours after transplant (para 0086). Thus Mitchell teaches a method wherein the biological sample is collected from the transplant recipient within 24 hours of a transplant surgery.
Regarding Claim 111 Mitchell teaches that the amounts of total cf-DNA were obtained by TaqMan quantitative real time PCR (para 0166). Thus Mitchell teaches a method wherein the quantitative PCR is real-time PCR.
Mitchell does not teach performing quantitative PCR on the extracted cell free DNA using 10-95 target specific primer pairs to amplify SNP loci that are homozygous in the recipient to determine the percentage of donor specific cell free DNA based on quantities of major and minor alleles at the SNP loci (clm 103). Mitchell does not teach a method wherein step (b) uses 20-95 target-specific primer pairs to amplify SNP loci that are homozygous in the recipient (clm 112). Michell does not teach a method wherein step (b) uses 40-95 target-specific primer pairs to amplify SNP loci that are homozygous in the recipient (clm 113).
However Grskovic (The Journal of Molecular Diagnostics Vol 18 No 6 November 2016) describes an assay to measure donor derived cell free DNA in solid organ transplant recipients. Grskovic teaches that the dd-cfDNA assay is based on targeted amplification of DNA regions harboring 266 SNPs and the measurement by NGS of each allele contribution at each SNP position. cfDNA extracted from 1.25 mL plasma or reference materials (described above, used at 3, 8, or 60 ng) was preamplified in a single multiplex reaction with 266 primer pairs for 15 cycles. Preamplified material was further amplified using 48 limited complexity multiplexes (1 to 11 targets per reaction) on the Access Array microfluidic system (Fluidigm, South San Francisco, CA). Index sequences and Illumina sequencing adapters were added to each sample DNA by PCR, and the sample was qualified and quantified by capillary electrophoresis. Up to 16 amplified samples were pooled in equimolar amounts, purified using Agencourt AMPure XP beads (Beckman Coulter, Brea, CA), and sequenced on an Illumina MiSeq instrument (page 892, col 2). Grskovic teaches that the percent of dd-cfDNA was estimated from the background corrected alternative allele frequencies of the recipient homozygous SNPs (page 893, col 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Mitchell by performing quantitative PCR on the extracted cell free DNA using 10-95 target specific primer pairs to amplify SNP loci that are homozygous in the recipient to determine the percentage of donor specific cf-DNA based on quantities of major and minor alleles at the SNP loci as suggested by Grskovic. One of skill in the art would have been motivated to use the methodology of Grskovic particularly since the reference teaches that the assay quantifies the fraction of dd-cfDNA in both unrelated and related donor-recipient pairs. The dd-cfDNA assay can reliably measure dd-cfDNA (limit of blank, 0.10%; limit of detection, 0.16%; limit of quantification, 0.20%) across the linear quantifiable range (0.2% to 16%) with across-run CVs of 6.8%. Precision was also evaluated for independently processed clinical sample replicates and is similar to across-run precision. Application of the assay to clinical samples from heart transplant recipients demonstrated increased levels of dd-cfDNA in patients with biopsy-confirmed rejection and decreased levels of dd-cfDNA after successful rejection treatment. This noninvasive clinical-grade sequencing assay can be completed within 3 days, providing the practical turnaround time preferred for transplanted organ surveillance (abstract). Further the claim is obvious because the substitution of one method for detecting donor specific cf-DNA (the method of Mitchell comprising DANSAR amplification followed by sequencing) for another method (the method of Grskovic comprising targeted PCR followed by NGS method of Grskovic) would have yielded predictable result to one of ordinary skill in the art at the time of the invention.
7. Claim 114 is rejected under 35 U.S.C. 103 as being unpatentable over Mitchell (US 2015/0086477 Pub 3/26/2015) in view of Grskovic (J Mol Diagn 2016 18:890-902 E-Pub 10/7/2016) and in further view of Panousis (US 2016/0258010 Pub 9/8/2016)
The teachings of Michell and Grskovic are presented above.
The combined references do not teach a method wherein the quantitative PCR comprises, for each of the SNP loci, performing a PCR using 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 the SNP locus but a 3’ double mismatch relative to a second allele of the SNP locus and specifically amplifies the first allele and wherein the second primer pair specifically amplifies the second allele.
However Panousis discloses an allele specific PCR assay for detection of the K65R mutation in the HIV-1 (para 0171). This mutation results from a single G to A transition (AAA to AGA). Panousis teaches the following primer pair was used to amplify the mutant:
Wildtype AAA
Mutant AGA
K65R forward 5’- CTCCARTATTTGCCATAAAACG -‘3 (SEQ ID NO: 23, PEN)
K65REV 5’- TATTCCTAATTGAACYTCCCA-‘3 (SEQ ID NO: 3)
SEQ ID NO: 23 has 3’ penultimate mismatch compared to the mutant allele and a double mismatch at the 3’ end relative to the wildtype allele. Panousis teaches that SEQ ID NO: 23 was able to amplify the mutant allele (para 0179, Fig 1).
Additionally Panousis teaches the following primer pair was used to amplify the wildtype:
Wildtype AAA
Mutant AGA
K65WT forward 5’- CTCCARTATTTGCCATAAAACA -‘3 (SEQ ID NO: 25, PEN)
K65REV 5’- TATTCCTAATTGAACYTCCCA-‘3 (SEQ ID NO: 3)
SEQ ID NO: 25 has 3’ penultimate mismatch compared to the wildtype allele and a double mismatch at the 3’ end relative to the mutant allele. Panousis teaches that SEQ ID NO: 25 was able to amplify the wildtype allele (para 0179, Fig 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Mitchell and Grskovic by performing Q-PCR using primers suggested by Panousis. In the instant case Panousis demonstrates that allele specific primers having penultimate mismatches are more efficient than those that have LNA at their 3’ ends (para 0179). One of skill in the art would have been motivated to perform allele specific PCR with allele specific primers having penultimate mismatches for the benefit of increasing the difference in amplification efficiency between mutant and wild type, thereby increasing selectivity and sensitivity of amplification for the allele of interest (see para 0097).
Response To Arguments
8. In the response the Applicants traversed the rejection under 35 USC 103. The Applicants argue that Grskovic relies on amplification of 266 SNPs for detection of transplant rejection, which is far more than the 10-95 loci required by the claimed method.
This argument has been fully considered but is not persuasive. In view of the open claim language used (i.e., “comprising”) the claims actually encompass additional SNP loci.
The Applicants argue that Grskovic uses sequencing to quantify dd-cfDNA, not quantitative PCR as claimed. In particular, the section titled "Percent dd-cfDNA Calculation" describes how the NGS data are used to estimate percent dd-cfDNA.
This argument has been fully considered but is not persuasive. Before the sequencing is performed, amplification is performed. Thus it is the combination of amplification and sequencing which ultimately result in quantifying the dd-cfDNA.
Regarding Claim 114 the Applicants argue that Panousis fails to cure the deficiencies of Mitchell and Grskovic.
This argument has been fully considered but is not persuasive. The Applicants arguments regarding what is missing in Mitchell and Grskovic have been fully addressed above. The response, as set forth above, applies equally to the present ground of rejection.
Double Patenting
9. 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.
10. Claims 103-114 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2-5, 9, 13, 15, 37, 41, and 43-44 of copending Application No. 16/623,725 in view of Mitchell (US 2015/0086477 Pub 3/26/2015). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding Claims 103, 112, and 114 both sets of claims are drawn to a method comprising (a) extracting cell-free DNA from a biological sample of a transplant recipient; (b) performing quantitative PCR on the extracted cell-free DNA, using 10- 95 target-specific primer pairs to amplify SNP loci, to determine the percentage of donor-specific cell-free DNA; and(c) performing quantitative PCR on the extracted cell-free DNA to determine the amount of total cell-free DNA (see clm 13 of the copending application). Regarding Claim 105 both sets of claims further comprise administering an anti-rejection treatment to the transplant recipient when the percentage of donor-specific cell-free DNA and/or the amount of total cell-free DNA exceeds a threshold (see clm 41 of the copending application). Regarding Claim 106 both sets of claims state the biological sample is a blood, plasma or serum sample (see clm 13 of the copending application). Regarding Claim 114 both sets of claims state that the quantitative PCR comprises, for each of the SNP loci, performing a PCR using 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 the SNP locus but a 3' double mismatch relative to a second allele of the SNP locus and specifically amplifies the first allele, and wherein the second primer pair specifically amplifies the second allele (see clm 13 of the copending application). The instant claims are different from the copending claims because they state that the percentage of donor-specific cell-free DNA is determined based on both SNP loci that are homozygous for a different allele in the donor and SNP loci that are heterozygous in the donor (clm 104). The instant claims are different from the copending claims because they state that the transplant recipient is a heart, kidney, liver, lung, pancreas, or intestine transplant recipient (clm 107, 109). The instant claims are different from the copending claims because they state that the biological sample is collected from the transplant recipient within 24 hours of cross-clamp removal/or surgery (clm 108, 110). The instant claims are different from the copending claims because they state that the quantitative PCR is real-time PCR or digital PCR (clm 111). However Mitchell teaches that the amounts of total cf-DNA were obtained by TaqMan quantitative real time PCR (para 0166). Mitchell teaches that genotypes were determined for 192 loci and the loci were deemed “informative” for calculating DS cfDNA frequencies when recipient genotypes were homozygous and donor genotypes were either heterozygous or homozygous for the other allele (para 0171). Mitchell teaches a method wherein the transplant recipient is a heart, kidney, liver, lung, pancreas, or intestine transplant recipient (para 0072). Mitchell teaches that the method can be performed on a transplant recipient as early as 14-36 hours after transplant (para 0086). Accordingly, it would have been obvious to have modified the method in the copending application in view of the teachings in Mitchell. One of skill in the art would have been motivated to use real time PCR since this was conventional in the art at the time of the invention. One of skill in the art would have been motivated to calculate the percentage of DS-cfDNA based on SNP that are homozygous for a different allele in the donor and SNP loci that are heterozygous in the donor since Mitchell teaches such SNPs are useful for differentiating between recipient and donor cfDNA. One of skill in the art would have been motivated to perform the method on the claimed transplant types for the benefit of being able to monitor transplant rejection in those transplant types. One of skill in the art would have been motivated to perform the method within 24 hours of surgery for the benefit since Mitchell teaches that the percentage of DS-cfDNA initially rises and then falls and if it doesn’t fall then there is a higher risk of rejection. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response To Arguments
11. In the response the Applicants traversed the double patenting rejection. They argue that the pending claims of the '725 application are different to the present claims, at least because they fail to recite "performing quantitative PCR on the extracted cell-free DNA or its derivative, using 10-95 target-specific primer pairs." To the contrary, claim 13 of the '725 application recites first "performing multiplex targeted PCR amplification on the cf-DNA to amplify at least 50 single nucleotide variant (SNV) targets together in the same reaction" and then "performing quantitative PCR on the amplified DNA using at least two primer pairs....".
This argument has been fully considered but is not persuasive. Both sets of claims require performing targeted PCR to amplify SNP loci. While the ‘725 application does not specifically recite that the targeted PCR is quantitative, the ‘725 application does recite elsewhere quantitative PCR. Additionally Mitchell discloses quantitative PCR. Thus it is maintained that it would have been obvious to modify the method of the ‘725 application by using quantitative targeted PCR to amplify the SNP loci. This would have been obvious because the substitution of one type of PCR for another type of PCR would have yielded predictable results to one of ordinary skill in the art at the time of the invention. The rejection is maintained.
12. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682