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 November 17, 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 Any rejections or objections not reiterated herein have been withdrawn.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 1-2, 4, 50, 57, 60, 66, 70, 74, 78, 89, and 92 are currently pending and have been examined herein.
Withdrawn Rejections
3. Claim 1 has been amended to recite the following limitations:
- (i) diagnosing the subject with a cellular rejection grade of CR0 if the amount DS cf-DNA is less than 0.2;(ii) diagnosing the subject with a cellular rejection grade of CR1 if the amount of DS cf-DNA is between 0.2 and 0.8; or (iii) diagnosing the subject with a cellular rejection grade of CR2 or greater if the amount of DS cf-DNA is greater than 0.8;
- diagnosing the subject with cardiac graft vasculopathy or determined to be at risk of cardiac arrest if the amount DS cf-DNA is equal to or greater than 0.2; and
- diagnosing the subject with antibody-mediated rejection if the amount DS cf-DNA is greater than 0.2.
The rejections made under 35 USC 102 and 103 have been withdrawn in view of the amendments made to claim 1. As amended claim 1 recites an active process step of “diagnosing” when previously these recitations were only present in a “wherein” clause.
Several of the the double patenting rejections have also been withdrawn in view of the amendments made to claim 1. As amended claim 1 recites an active process step of “diagnosing” when previously these recitations were only present in a “wherein” clause.
Claim Rejections - 35 USC § 101
4. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4, 50, 57, 60, 66, 70, 74, 78, 89, and 92 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 a law of nature.
Claim 1(b) recites the following limitation:
(i) diagnosing the subject with a cellular rejection grade of CRO is assigned to the subject if the amount DS cf-DNA is less than 0.2;
(ii) diagnosing the subject with a cellular rejection grade of CR1 is assigned to the subject if the amount of DS cf-DNA is between 0.2 and 0.8; or
(iii) diagnosing the subject with a cellular rejection grade of CR2 or greater is assigned to the subject if the amount of DS cf-DNA is greater than 0.8
This limitation recites a correlation between the amount of DS cfDNA and cellular rejection grade. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
Claim 1(c) recites the following limitation:
diagnosing the subject with cardiac graft vasculopathy or determined to be at risk of cardiac arrest if the amount DS cf-DNA is equal to or greater than 0.2
This limitation recites a correlation between the amount of DS cfDNA and cardiac graft vasculopathy/cardiac arrest. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
Claim 1(d) recites the following limitation:
diagnosing the subject with antibody-mediated rejection if the amount DS cf-DNA is greater than 0.2
This limitation recites a correlation between the amount of DS cfDNA and antibody-mediated rejection. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas.
Claim 1(b-d) recites a step of “analyzing” the preparation of amplified cf-DNA to quantify an amount of DS cf-DNA. The “analyzing” step broadly encompasses a mental process and/or mathematical concept. For example, one can quantify the amount of DS cf-DNA by thinking about the ratio of donor specific alleles to total DNA or by using an algorithm to estimate DS cf-DNA. Mental processes and mathematical concepts are considered to be abstract ideas.
Claim 1(b-d) recite a step of “diagnosing” the subject with a cellular rejection grade, cardiac graft vasculopathy/cardiac arrest, or anti-body mediated rejection based on the amount of DS cf-DNA. Herein “diagnosing” brodaly encompasses an activity that can be performed in the human mind. For example, one may “diagnose” by thinking about the amount of DS cf-DNA. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
The claims recite a step of “comparing” the amount of DS cf-DNA to a threshold DC cf-DNA value and/or a prior DS cf-DNA value (clms 2, 4). The broadest reasonable interpretation of the “comparing” step is that it may be accomplished by a mental processes. For example, one may “compare” the amount of DS-cfDNA and threshold/prior value by looking at both side by side in a laboratory report.
The claims recite a step of “determining” a treatment or monitoring regime for the subject based on the determined amount of DS cf-DNA (clm 4). The broadest reasonable interpretation of “determining” is that it may be accomplished by a mental processes. For example one could determine the appropriate treatment by thinking about the amount of DS cf-DNA.
Claim 60 recites steps of “determining”, “selecting”, “identifying”, “calculating”, and “determining”. The broadest reasonable interpretation of each of these steps is that they may be accomplished by a mental processes or by performing mathematical calculations, both of which are abstract ideas.
The claims recite a step of “suggesting” monitoring to a subject (clm 66). The broadest reasonable interpretation of the “suggesting” step is that it may be accomplished by a mental processes. For example, one may verbally suggest additional monitoring.
The claims recite a step of “suggesting” the use of one or more additional tests (clm 74). The broadest reasonable interpretation of the “suggesting” step is that it may be accomplished by a mental processes. For example, one may verbally suggest additional tests.
The claims recite a step of “selecting or suggesting” a treatment (clm 78). The broadest reasonable interpretation of the “suggesting” step is that it may be accomplished by a mental processes. For example, one may verbally suggest a treatment.
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 92 recites administering an anti-rejection therapy, or a treatment for cardiac allograft vasculopathy, or a treatment for cardiac arrest, or any combination thereof based on the diagnosis. A claim limitation can integrate a judicial exception by applying or using the judicial exception to effect a particular treatment or prophylaxis for a disease or a medical condition. Herein, there is nothing particular about the recited therapies/treatments. The recitations of anti-rejection therapy, a treatment for cardiac allograft vasculopathy, a treatment for cardiac arrest are considered to be general and non-specific. They are not specifically identified so that they do not encompass all applications of the judicial exceptions. Further it is noted that the claims encompass administering the same “anti-rejection therapy” to subjects with cellular rejection and antibody-mediated rejection. Thus the administration step is merely instructions to apply the exceptions in a generic way and does not provide a practical application of the judicial exceptions.
In addition to the judicial exceptions, the claims recite a step of taking a blood, plasma, or serum sample from the subject, extracting cf-DNA from the sample, and performing multiplexed targeted PCR amplification on the sample. The additionally recited steps 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 recite a step of taking a blood, plasma, or serum sample from the subject, extracting cf-DNA from the sample, and performing multiplexed targeted PCR amplification on the sample. The additionally recited steps 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 steps are recited at a high level of generality. Obtaining a sample and extracting nucleic acids such as cf-DNA in order to perform tests is well understood, routine, and conventional activity for those in the field of diagnostics. Further the step of performing multiplexed targeted PCR amplification is recited at a high level of generality such that it amounts to insignificant presolution activity, e.g., a mere data gathering step necessary to use the correlation. The multiplex PCR amplification does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
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, 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).
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
5. In the response the Applicants traversed the rejection under 35 USC 101. The Applicants argue that similar to the claim found patent eligible by the Federal Circuit in Illumina v. Ariosa Diagnostics, amended claim 1 of the instant application is directed to a method for preparing a preparation of amplified DNA, and similarly recites related steps such as extracting DNA from a sample, preparing a preparation of amplified DNA by performing PCR, and analyzing the preparation of amplified DNA. The Applicants argue that the claims are directed to methods of preparation and are not directed to patent eligible concepts.
This argument has been fully considered but is not persuasive. The instant claims are NOT analgous to those that were found patent eligible by the Federal Circuit in Illumina v. Ariosa Diagnostics. The instant claims recite correlations between the amount of DS cfDNA and (i) cellular rejection grades; (ii) cardiac allograph vasculopathy or cardiac arrest; and (iii)antibody-mediated rejection. These correlations are a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo. Additionally the claims recite numerous limitations that fall within the mental processes groupings of abstract ideas because they cover concepts peformed in the human mind, including observations, evaluation, judgment, and opinion. It is maintined that the claims recite judical exceptions.
Further the Applicants state that they disagree with the Examiners finding that the extra steps of claim 1 amount to well understood, routine, and conventional activity. The Examiner fails to establish how detecting cell-free DNA in a sample, using PCR to amplify and detect the cell-free DNA was routinely and conventionally used before the priority date of the present application.
This argument has been fully considered but is not persuasive. In addition to the judicial exceptions, the claims recite steps of taking a blood, plasma, or serum sample from the subject, extracting cf-DNA from the sample, and performing multiplexed targeted PCR amplification on the sample. The use of standard laboratory techniques to gather data used to observe a law of nature or other judical exception has consistently been found to be well-understood, routine, and conventional activity. These steps were previously known to the industry (see Grskovic (The Journal of Molecular Diagnostics Vol 18 No 6 November 2016)) and they are specified at a high level of generality. They do not provide an inventive concept.
Finally the Applicants argue that the instant claims are patent-eligible because when viewed as a whole, the claims amount to significantly more than the alleged judicial exception. They argue that the alleged judicial exception is integrated with the patent-eligible quantitative PCR and amplification steps into a practical application for subject evaluation based on donor-specific cell-free DNA from samples.
This argument has been fully considered but is not persuasive. The claim as a whole has been considered and the Examiner does NOT agree that the judicial exceptions have been integrated into a practical application. The steps that are recited in addition to the judical exception are nothing more than the collection of data which is insignificant extra-solution activity. Data gathering steps do not make an otherwise nonstatutory claim statutory. Further the claim does not practically apply the judical exceptions by including one or more additional elements that the courts have stated integrate the exception into a practical application (these are noted in the rejection). It is maintained that the claim as a whole fails to integrate the recited judical exceptions into a practical application of the exceptions.
Double Patenting
6. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
7a. Claims 1, 2, 4, 60, 78, 89, and 92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, 13, 17, 20, 22, 26, 28-31, 35, 39, 43-46, 51, 85 of US Application 17/493,230 in view of Grskovic (The Journal of Molecular Diagnostics Vol 18 No 6 November 2016). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding Claim 1 both sets of claims require determining an amount of DS cf-DNA in a biological sample from a transplant subject (see clm 1 of the copending application). Both sets of claims state that the subject is one that has a risk of having transplant rejection (see clms 1 of the Copending application). Both sets of claims recite (i) diagnosing the subject with a cellular rejection grade of CRO is assigned to the subject if the amount DS cf-DNA is less than 0.2; (ii) diagnosing the subject with a cellular rejection grade of CR1 is assigned to the subject if the amount of DS cf-DNA is between 0.2 and 0.8; or (iii) diagnosing the subject with a cellular rejection grade of CR2 or greater is assigned to the subject if the amount of DS cf-DNA is greater than 0.8 (clm 13 of the copending application). Regarding claim 2 both sets of claims require comparing the amount of DS cf-DNA to a threshold DS cf-DNA (see clm 2 of the copending application). Regarding claim 4 both sets of claims require comparing the amount of DS cf-DNA to a threshold DS cf-DNA and determining a treatment for the subject based on the determined amount of DS cf-DNA compared to the threshold DS cf-DNA value (see clms 4 of the Copending application). Regarding Claim 60 the instant claims are different from the claims of the Patent because they state that the amount of DS cf-DNA is determined or obtained by: (a) determining an allele of each of a plurality of loci; (b) selecting at least one informative locus from the plurality of loci based on the determining of the allele; (c) identifying a plurality of loci, the nucleic acids comprising first nucleic acids of the subject and second nucleic acids not native to the subject; (d) calculating an estimated allele frequency of a first allele at the at least one informative locus using a statistical distribution; and (e) determining the amount of DS cf-DNA based on the estimated allele frequency. However it is noted that this methodology for determining the amount of DS cf-DNA is disclosed in the specification of the application. Portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the parent. Regarding Claim 78 both sets of claims comprise treating the subject (see clm 85 of the Copending application). Regarding Claim 89 both set of claims state that the transplant is a heart transplant (see clm 22 of the copending application).
The instant claims are different that those of the copending application because they require performing multiplexed targeted polymerase chain reaction (PCR) amplification on the sample to determine an amount of donor-specific cell-free DNA (DS cf-DNA) in the sample (clm 1). Additionally the instant claims are different because they recite administering an anti-rejection therapy to the subject (clm 92).
However Grskovic 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 pre-amplified in a single multiplex reaction with 266 primer pairs for 15 cycles. Pre-amplified 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). Additionally the subjects of Grskovic are heart transplant subjects. Further Grskovic teaches administering an anti-rejection therapy to the subject (Fig 6c inset). Accordingly, it would have been obvious to have modified the method of the copending application by determining the amount of donor specific cell free DNA using a method comprising multiplexed targeted PCR 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).
7b. Claim 50 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, 13, 17, 20, 22, 26, 28-31, 35, 39, 43-46, 51, 85 of US Application 17/493,230 in view of Grskovic (The Journal of Molecular Diagnostics Vol 18 No 6 November 2016) as applied to claim 1 above and in further view of Mitchell (WO 2013/159035 Pub 10/24/2013). The claims of the copending application in view of Grskovic are discussed above. This combination does not teach the limitations of claim 50. However Mitchell provides a graph showing DS cf-DNA pre and post biopsy. In Fig 5B levels of DS cf-DNA pre and post endomyocardial biopsy (6 patients, 12 samples) (post biopsy, range 8-35 minutes). The sample indicated by the arrow had the shortest collection time (8 minutes) after biopsy (page 8). Here the biopsy is being interpreted as an "injury" to the transplanted organ. Accordingly, it would have been obvious to one to have modified the method of the copending application by determining the amount of DS cf-DNA in a sample taken from the subject within 15 minutes following injury for the benefit of being able to get a post biopsy baseline.
7c. Claim 57 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, 13, 17, 20, 22, 26, 28-31, 35, 39, 43-46, 51, 85 of US Application 17/493,230 in view of Grskovic (The Journal of Molecular Diagnostics Vol 18 No 6 November 2016) as applied to claim 1 above and in further view of Panousis (US 2016/0258010 Pub 9/8/2016).
The claims of the copending application in view of Grskovic are discussed above. This combination does not teach the limitations of claim 57. 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 have modified the method of the copending application in view of 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).
7d. Claims 66, 70, and 74 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 10, 13, 17, 20, 22, 26, 28-31, 35, 39, 43-46, 51, 85 of US Application 17/493,230 in view of Grskovic (The Journal of Molecular Diagnostics Vol 18 No 6 November 2016) as applied to claims 1 and 4 above and in further view of De Vlaminck (Science Translational Medicine June 18, 2014 Vol 6 Issue 241 pages 1-8). The claims of the copending application in view of Grskovic are discussed above. This combination does not teach the limitations of claim 66, 70, 74, and 80. However De Vlaminck discloses a method called “genome transplant dynamics” (GTD) that quantifies donor specific DNA. De Vlaminck teaches that GTS can be used for the discrimination of rejecting and nonrejecting grafts and demonstrated utility of the technique for the detecting of ACR and AMR in adult and pediatric heart transplant patients. De Vlaminck teaches that cfdDNA measurements have the potential to replace the endomyocardial biopsy and the these measurements can possibly be used for other aspects of patient management such as predicting rejection events and managing immunosuppressant dosing (page 1). Additionally De Vlaminck teaches that the GTD assay allows for improved modulation and tracking efficacy of anti-rejection therapies. Further De Vlaminck teaches that the GTD assay allows for early diagnosis of acute rejection and therefore presents an opportunity for early diagnosis and treatment (page 6 col 1-2). De Vlaminc teaches monitoring the amount of DS cf-DNA over a period of 15 months (see Fig 4). Finally De Vlaminck teaches that the GTD test is not able to distinguish graft damage from AMR versus ACR, which have different therapeutic consequences and outcomes. Hence, the GTD assay may require follow-up testing, such as biopsy or measurement of donor-specific anti–human leukocyte antigen antibodies, if rejection is determined (page 6, col 1). Accordingly, it would have been obvious to have modified the copending claims in view of Grskovic by determining a monitoring regimen for the transplant subject and suggesting such monitoring to the subject. Thus the skill artisan would have been motivated to come up with a monitoring plan for each transplant subject based on DS cf-DNA levels and then suggest the plan to the subject for the benefit of being able to predict rejection events and start treatment earlier. Further since the levels of DS cfDNA increase with severity of rejection, it would have been obvious to perform more frequent monitoring of DS cf-DNA levels on subjects with increasing DS cf-DNA. One of skill in the art would have been motivated to monitor these patients more frequently since accurate and timely diagnosis of allograft rejection is essential for long term survival of solid organ transplants (page 1, col 1). Finally it would have been obvious to to have modified the method of the copending claims in view of Grskovic by using an additional test to assess transplant rejection as suggested by De Vlaminck. One of skill in the art would have been motivated to use additional assays particular since De Vlaminck teaches that tests based on the amount of DS cfDNA cannot differentiate between graft damage, AMR, and ACR.
Response To Arguments
8. In the response the Applicants traversed the double patenting rejections. Applicant argues that the Office has not established that the claims of the instant application are anticipated or rendered obvious by the claims of the above-referenced patents and patent applications.
This argument has been fully considered. The double patenting rejections have been reconsidered in view of the amendments made to claim 1. The rejections have either been withdrawn or modified to address the claims as amended.
9. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1634