DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed March 19, 2026. Currently, claims 23, 25-28, 30, 32, 41, 50-58, 64-66 are pending. Claims 55-58 have been withdrawn as drawn to non-elected subject matter.
Election/Restrictions
Applicant's election without traverse of Group I, Claims 1-8, 15, 22-32, 41, 50-54, 64-70, 73-76, 78-82 in the paper filed October 22, 2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application claims priority to
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Drawings
The drawings are acceptable.
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 23, 25-28, 30, 32, 41, 50-53, 64-66 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
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, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
The claims are taken to be directed to an abstract idea, a law of nature and a natural phenomenon.
The claims are directed to “a method for detecting and monitoring transplant rejection status”.
Claim 23 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. the mathematical formula of “a ratio of donor-derived to donor derived and recipient derived cell free DNA”)
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Question 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. While the claim recites obtaining a sample and determining the amount of cell-free nucleic acids, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method. Thus, the claim is “directed to” the exception.
Accordingly, the claims are directed to judicial exceptions.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non patent ineligible elements, are sufficient to “’transform the nature of the claim’ into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more from a statement of a natural principle for at least these reasons:
The claims do not include applying the judicial exception, or by use of, a particular machine. The claims do not tie the steps to a “particular machine" and therefore do not meet the machine or transformation test on these grounds. The use of machines generally does not impose a meaningful limit on claim scope.
The claims also do not add a specific limitation other than what is well-understood, routine and conventional in the field. The determining an amount of cell-free donor derived nucleic acids with ddPCR is mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine the amount of cell free nucleic acid in a sample without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The determining step essentially tells users to determine the markers through whatever known processes they wish to use.
The step of determining the determining an amount of cell-free donor derived nucleic acids was well known in the art at the time the invention was made. The steps are recited at a high level of generality. The claim merely instructs a scientist to use any analysis to determine the amount of cell-free donor derived nucleic acids. The claims do 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.
Additionally, the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements were well known. Specifically, the specification teaches determining the number of nucleic acids were well-known in the art (para 54).
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.
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 these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments
The response traverses the rejection. The response asserts the claims have been amended to remove the natural correlation. This argument has been considered but is not convincing because the response does not address the mathematical calculation judicial exception. Thus, for the reasons above and those already of record, the rejection is maintained.
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.
Claims 23, 25-26, 28, 32, 41, 50-54, 64-66 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Demko et al. (WO 2022/182878, provisional February 25, 2021) in view of Hong et al. (Basic Res Cardiol. Vol. 108, No. 3, May 2013) or Villari et al. (Urol. Int. DOI: 10.1159/000508796, September 21, 2020).
Demko teaches a method for detecting donor-derived cell free DNA in transplant recipients. Demko teaches the transplant donor is a non-human mammalian subject such as a pig and the recipient is a human subject (page 2). In particular Demko teaches extracting cell-free DNA from a transplant recipient who has received transplantation of one or more organs, performing targeted amplification at 200-50000 target loci in a single reaction using primer pairs, sequencing the amplification products by high-throughput sequencing to obtain a sequencing reads and quantifying the amount of donor-derived cell-free DNA and the amount of total cell-free DNA based on the sequencing reads and determining whether the amount of donor-derived cell-free DNA exceeds a cutoff threshold indicating transplant rejection or graft injury (abstract). Demko teaches the threshold may be a copy number of donor-derived cell-free DNA. Demko teaches using a tracer DNA, i.e. a spike in control to improve accuracy and precision of the method and help quantify over a wider input range, assess efficiency of different steps at different size ranges and calculate fragment size-distribution of input material (page 31). Demko teaches the tracer may be added before or after isolation of the cell-free DNA. Demko also teaches the tracer may be added after extraction and before isolation of cell free DNA. Demko teaches next high throughput sequencing to sequence the amplicons (page 30). Demko also teaches the sequence may be determined by qPCR or digital droplet PCR (ddPCR) analysis (page 31).
Demko does not teach use of digital PCR for a multi-copy donor specific target.
However, Hong teaches absolute quantification of cardiac stem cells following transplantation in mice. The method relies upon multiple-copy gene Rbmy, which significantly increases sensitivity of detection of male donor cells in female recipients. Hong teaches using a normal diploid human peripheral blood mononuclear cell for the internal standard.
Moreover, Villari teaches detection of transplants using DYS14 gene sequence of the Y chromosome. The DYS14 sequence was selected since it was Y-specific and it was a multiple-copy gene that allowed a very sensitive detection of Y-related cfDNA (page 3, col. 1). Villari teaches selecting a multiple-copy gene for detection and quantification that allows the achievement of higher sensitivity than single-copy genes (page 4, col. 2).
Therefore, it would have been prima facie obvious at the time the invention was made to have modified the methods of Demko for detecting donor-derived cell free DNA in transplant recipients with the digital PCR assay taught by Hong and Villari. Both Hong and Villari teach using multiple copy genes in transplant detection assays because the detection is more sensitive. Villari teaches ddPCR allows estimation of the absolute quantification at low concentrations and size distribution of cfDNA samples. Villari teaches selecting a multiple-copy gene for detection and quantification that allows the achievement of higher sensitivity than single-copy genes Therefore, the ordinary artisan would have been motivated to have substituted a multi-copy donor-specific target for analysis for the benefits taught by Hong and Villari.
Claims 27, 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Demko et al. (WO 2022/182878, provisional February 25, 2021) in view of Hong et al. (Basic Res Cardiol. Vol. 108, No. 3, May 2013) or Villari et al. (Urol. Int. DOI: 10.1159/000508796, September 21, 2020) as applied to claims 23, 25-26, 28, 32, 41, 50-54, 64-66 above and further in view of Maar et al. (Bio-Radiations, “Expanded Droplet Digital PCR multiplexing capability using two different strategies, September 11, 2019).
Neither Demoko, Hong, nor Villari teach multiplex digital assay for analysis of transplant nucleic acid detection.
However, Maar teaches droplet digital PCR (ddPCR) allows easy multiplexing of numerous targets within each fluorescent channel. Multiplexing with ddPCR allows improved sensitivity and precision as well as increased low-level detection in limited sample types like liquid biopsies. Maar teaches this is especially useful in very rare targets in high -resolution copy number analysis.
Therefore, it would have been prima facie obvious prior to the effective fining date of the claimed invention to have modified the methods of Demoko in view of Villari or Hope to perform multiplex ddPCR as taught by Maar. The ordinary artisan would have recognized that the use of multiplex ddPCR would allow detection of multiple targets within a single assay to detect low level targets. The ordinary artisan would be motivated to detect multiple targets for increased confidence in the assays.
Conclusion
No claims allowable over the art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Witlam teaches copy number may be used with digital droplet PCR to monitor chimerism after transplantation. Witlam teaches digital droplet PCR (ddPCR) allows absolute quantification without requirement for a standard curve and better performance at lower concentrations in part because of simplicity distinguishing positive droplets containing target from those with no template (page 39-40). Witlam teaches using ACE gen target as a non-polymorphic-two-copy reference marker.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on (571)272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
April 8, 2026