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 .
Priority
Applicant’s claim to priority from Foreign Application EP19152365.3 filed 01/17/2019 and from PCT/EP2020/050959 filed 01/16/2020 is hereby acknowledged.
Application Status
This Application is a National Stage entry of PCT/EP2020/050959 filed 01/16/2020 under U.S.C. 35 §371.
Amendments to claims filed 01/20/2026 are hereby acknowledged. Claims 1, 3-5, 7-9 are currently amended. Claims 16-17 are newly added. Claims 10-15 are cancelled. Therefore, claims 1-9 and 16-17 are pending and under consideration in this office action.
Any objection or rejection not reiterated herein has been overcome by Applicant’s amendments and/or arguments, and is therefore withdrawn.
Applicant amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/30/2026 was filed after the mailing date of the Office Action on 09/19/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The replacement sheets for drawings submitted on 01/20/2026 are hereby acknowledged and are acceptable.
Specification
The correction for Specification filed 01/20/2026 are hereby acknowledged.
Claim Objections
Claim 1 is objected to because of the following informalities: the claim recites “FCGR1B Fragment Of IgG Receptor Ib)”. The claim should recite “FCGR1B (Fragment Of IgG Receptor Ib)”. The recitation is grammatically incorrect because FCGR1B is an abbreviation for Fragment of IgG Receptor 1B and therefore this should be denoted with the use of parentheses.
Claim 4 is objected to because the amended terms “non-TCMR” are not shown as amended such as “ non-TCMR” .
Appropriate correction is required.
The following rejections are maintained from previous Office Action dated 09/19/2025, and are modified as necessitated by Applicant’s amendments:
Claim Rejections - 35 USC § 101
35 U.S.C. §101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-9 and 16-17 are rejected under 35 U.S.C. §101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea).
Claim 1 is drawn to “A method of (a) providing a peripheral blood sample from a subject who has received a solid organ transplant; (b) extracting RNA molecules from the sample; (c ) reverse transcribing the extracted RNA molecules to obtain a complementary DNA (cDNA); (d) quantifying using real-time quantitative reverse-transcription PCR (real-time RT-qPCR) the cDNA to determine one or more RNA expression levels of a set of genes comprising at least CXCL10 (C-X-C motif Chemokine Ligands 10), FCGR1A (Fragment of IgG Receptor Ia), FCGR1B Fragment of IgG Receptor Ib) and TIMP1 (TIMP Metallopeptidase inhibitor 1); ( e) processing the RNA expression levels using a trained machine learning model to determine a score; (f) detecting, based at least on the score, that the subject is experiencing a graft rejection or has an increasing risk of developing the graft rejection wherein the graft rejection is not a T cell-mediated rejection (non-TCMR); and (g) based at least in part on the detecting in (f), performing a biopsy of the transplanted organ for the subject or treating the subject for the graft rejection or the increased risk of developing the graft rejection with an immunosuppressive therapy”.
The claim recites judicial exceptions: genes that are expressed naturally in cells, a process of “determining” that is a mental process, and a trained machine learning model that is a mathematical algorithm used for the determining steps.
The claims do not include additional elements, when considered separately and in combination, that are sufficient to amount to significantly more than the judicial exception.
Subject Matter Eligibility Test for Products and Processes
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES
Claims 1-9 and 16-17 are directed to "A method” that includes using a real-time RT-PCR.
Step 2A, Prong One - Does the Claim Recite an Abstract Idea, Law of Nature, or Natural Phenomenon? YES
Abstract ideas have been identified by the courts by way of example, including
fundamental economic practices, certain methods of organizing human activities, an idea 'of itself,' and mathematical relationships/formulas.
The claims recite four judicial exceptions:
1) a "mental" process of determining, detecting, and the comparing/processing of expression profiles and scores, therefore collecting data and interpreting the information which corresponds to "an abstraction"; an idea having no particular concrete or tangible form; and
2) applying a trained machine learning model to determine a score, which is applying a mathematical algorithm, and identifying a subject “experiencing a graft rejection or has an increased risk of developing said graft rejection”;
4) Experiencing a graft rejection is a natural process. Therefore, a subject being at risk for a graft rejection is also a natural process. Measuring levels of markers in a blood sample of a subject experiencing or at risk for a graft rejection is also measuring natural products from a natural sample, and establishing the connection between these levels of markers and a natural phenomenon or the risk of this natural phenomenon occurring is linking natural facts using a mental process.
5) The genes recited , i.e. CXCL10 (C-X-C Motif Chemokine Ligand 10), FCGR1A (Fragment Of lgG Receptor Ia), FCGRIB (Fragment Of lgG Receptor lb), TIMP1 (TIMP Metallopeptidase Inhibitor 1), GBP4 (Guanylate Binding Protein 4), KLRC1 (Killer Cell Lectin Like Receptor C1), GBP1 (Guanylate Binding Protein 1) and IL 15 (Interleukin 15), are all known genes/ biomarkers, and are present naturally in cells or blood samples. These genes are expressed and their encoded proteins are present in blood samples of subjects as part of Law of Nature.
Thus, the claimed invention describes multiple judicial exceptions, which corresponds to "an abstraction"; an idea, having no particular concrete or tangible form.
Step 2A, Prong Two - Does the Claim Recite an Additional Elements that Integrate the
Judicial Exception into a Practical Application? NO
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. However, absent are any additional elements recited in the claim beyond the judicial exception(s) which integrate the exception into a practical application of the exception.
The phrase "integration into a practical application" requires an additional element or a
combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception. The claim limitations "providing a peripheral blood sample from a subject who has received a solid organ transplant”, “extracting RNA molecules from the samples”, “reverse transcribing the extracted RNA molecules to obtain a complementary DNA (cDNA)’, and “quantifying using real-time quantitative reverse-transcription PCR (real-time RT-qPCR) the cDNA to determine one or more RNA expression levels of a set of genes comprising at least CXCL10 (C-X-C Motif Chemokine Ligand 10), FCGR1A (Fragment Of lgG Receptor Ia), FCGRIB (Fragment Of lgG Receptor lb) and TIMP1 (TIMP Metallopeptidase Inhibitor 1)," (claim 1) and " wherein the set of genes further comprises one or more of GBP4 (Guanylate Binding Protein 4), KLRC1 (Killer Cell Lectin Like Receptor C1), GBP1 (Guanylate Binding Protein 1) and IL 15 (Interleukin 15)" (claim 2), are steps of collecting sample, producing data, and data gathering activity. They do not apply, rely on, or use, integrate the judicial exception into a practical application. The genes cited are expressed as part of a natural phenomenon.
The process of “measuring” is the only specific active step not involving a mental process.
Examiner interprets that the “providing a peripheral blood sample”, “extracting RNA molecules” , “reverse transcribing”, “quantifying” and “performing a biopsy” and “or treating the subject” step themselves, the active method steps, are not really the main focus of the claims. Examiner interprets the claims as relying upon a measuring step to collect the information (data collection/gathering); Examiner interprets the claims as drawn to mental processes involving comparison and determining the risk of experiencing or of developing graft rejection based upon the application of mathematical algorithms to interpret the data collected during a natural phenomenon.
There are no further/additional steps which applies either the identified judicial exceptions into a practical application. Thus, the claims do not provide for any element/step that integrates the law of nature into a practical application.
Step 2B - Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO
The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to "significantly more" than the judicial exception(s) itself. The claims as a whole are evaluated as to whether they amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. See M.P.E.P. 2106.05. However, the additional elements, individually and in combination, do not amount to "significantly more".
Under the Step 2B analysis, claims 1-9 and 16-17 provide certain additional "physical" elements/steps beside measuring gene expression in blood samples of subjects. As explained with respect to Step2A Prong Two, the claims are drawn to measuring in a peripheral blood sample from a subject the RNA expression levels of a set of genes comprising at least CXCL10 (C-X-C Motif Chemokine Ligand 10), FCGR1A (Fragment Of lgG Receptor Ia), FCGRIB (Fragment Of lgG Receptor lb) and TIMP1 (TIMP Metallopeptidase Inhibitor 1)," (claim 1) and " wherein the set of genes further comprises one or more of GBP4 (Guanylate Binding Protein 4), KLRC1 (Killer Cell Lectin Like Receptor C1), GBP1 (Guanylate Binding Protein 1) and IL 15 (Interleukin 15)" (claim 2)).
The “quantifying” step, requires collecting blood samples which is routine in methods for data collection and comparison, in view of Alakulppi (Alakulppi, N.S. et al. “Diagnosis of acute renal allograft rejection by analyzing whole blood mRNA expression of lymphocyte marker molecules”. Transplantation, Vol. 83 (2007), pp: 791-798) (see page 792, right column, second paragraph and Figure 1) and Roedder (Roedder, S. et al. “The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study” PLOS Medicine, Vol. 11 (2014), p:e1001759) (see page 2, right column, Figure 1, and page 3, “Sample collection and Processing” section and “Quantitative Polymerase Chain Reaction” section).
Regarding claim 1(d), the technique of quantifying is quantitative PCR amplification, which is a routine method, as taught by Roedder ( see abstract and page 3, right column).
Regarding the genes listed, they have been isolated, cloned by others, and used as biomarkers of inflammation, immune response, cellular stress and/or cell death and critical illness in prior art ( see section 2.1 and section 2.9.2 and Tables 2 and 3, in Parlato et al. “Host response biomarkers in the diagnosis of sepsis: a general overview”. Sepsis: Diagnostic Methods and Protocols, Methods in Molecular Biology, Vol. 1237, Chapter 15 (2015), pp: 149-211).
Regarding claim 1(g) being drawn to “performing a biopsy of the transplanted organ for the subject”, performing a biopsy is another routine method of collecting samples used for data collection. There is no specifics to this biopsy that would make one of ordinary skills in the art think that this step should be performed in a specific and novel way that is the goal of the invention. Roeder teaches that performing assays on blood samples is made for prediction, up to three months prior to detection by the current gold standard, which is biopsy (see abstract, “Methods and Findings” paragraph).
Regarding claim 1(g) reciting “or treating the subject for the graft rejection or the increased risk of developing the graft rejection with an immunosuppressive therapy”,
the additional element in the claim to apply, rely on, or use the judicial exception, does not seem to be required by the claim, since the claim uses the term “OR”, and does not imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception.
Indeed, while searching the instant Specification for a method to treat using immunosuppressive agents, the term “immunosuppressive” was found twice, related to “Definitions” on pages 9 and 10 (see lines 31-37 on page 9 and lines 1-5 on page 10). The disclosure states “Nevertheless, the existing immunosuppressive armamentarium is insufficient in preventing patients from developing humoral alloreactivity, with occurrence of circulating donor-specific HLA antibodies (DSAs) and ABMR” (pages 9 (line 37) to page 10 (lines 1-3).
Immunosuppressive agent are named within Table 1, pages 20-22, listing the conditions of patients from whom the biopsies were taken, i.e. “Immunosuppression at time of biopsy” (page 22).
When searching the Disclosure for the term “treatment”, the term is mentioned three times in the “Definition” segment, on page 13 (lines 6, 10 and 12). When searching for the term “treating”, the term is not found.
There is no disclosure of a new treatment and/or combination of treatment, using an off-label-repositioned drug or a new immunosuppressive drug for treating the subjects for the graft rejection or the increased risk of developing the graft rejection as claimed.
Therefore, Examiner interprets that the Disclosure relates to methods of diagnosing, using collection of data from clinical trials, for decision-making. Examiner interprets that the claims are drawn to establishing a novel correlation between judicial exceptions to better stratify patients, but without significantly more.
The recited determination, comparative analysis and determination of weight factor using an algorithm are judicial exceptions. Mere instructions to apply an exception to a collection of data cannot provide an inventive concept. Absent from the claims is a limitation(s) that has more than a nominal relationship to the judicial exception. There is no limitation(s) that utilize the recited abstract idea in a manner that imposes a meaningful limit on it. There is no limitation(s) that integrates the recited judicial exception into a novel practical application, such that the claim is not directed to the judicial exception.
Thus, when viewed both individually and as an ordered combination, the claimed
elements/steps in addition to the identified judicial exceptions are found insufficient to supply an inventive concept because the elements/steps are considered routine and conventional. The claim limitations do not transform the abstract idea that they recite into patent-eligible subject matter because "the claims simply instruct the practitioner to implement the abstract idea with routine, conventional activity."
Accordingly, the claims do not qualify as patent-eligible subject matter.
The following rejections are newly added as necessitated by Applicant’s amendments:
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-6, 9 and 16-17 are rejected under 35 U.S.C. §103 as being unpatentable over Naides (Naides, S.J. et al. WO 2014/074501 A1, published May 15, 2014; previously cited), Roedder (Roedder, S. et al. “The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study”. PLOS Medicine, Vol.11 (2014), p: e1001759; previously cited), Wang ( Wang, A. et al. “Computational models for transplant biomarker discovery”. Frontiers in Immunology, Vol. 6 (2015), p: 458), Grey (Grey, D. et al. “Increased CD64 expression of polymorphonuclear neutrophils indicates infectious complications following solid organ transplantation”. Cytometry Part A, Vol. 79A (2011), pp: 446-460; previously cited), and Yan (Yan, Q. et al. “Expression of MMP2 and TIMP-1 in renal tissue of patients with chronic active antibody-mediated renal graft rejection”. Diagnostic Pathology, Vol. 7 (2012), p: 141; previously cited).
Regarding claims 1 and 6, Naides teaches a method for diagnosing acute graft rejection in patient having renal transplantation (see title, abstract and [0001]). Naides teaches that renal graft rejection comprises one or more conditions selected from the group consisting of acute cellular rejection (ACR), acute tubular necrosis (ATN), antibody mediated rejection (ABMR), chronic cellular rejection, borderline rejection, diabetic nephropathy, transplant nephropathy, and minimal interstitial fibrosis or tubular atrophy (see [0005]).
Regarding claim 1(a)-(d) and (f), Naides teaches Molecular detection assays wherein RNA is extracted from peripheral blood (see [0042], and page 15, claim 13). Naides teaches measuring the expression levels of the genes in two, three or more control samples as well as test sample (see [0013]-[0016]). Naides teaches the measuring of the combined expressions of ABL1, CD160, NK3, GZMB, perforin 1, FOXP3, and CXCL10 genes ([0005] and see page 14, claims 1-2, and pages 15-16, claim 17).
Naides teaches determining from the measured expression levels of a set of genes the relative expression levels (see [0013], page 14 see claim 1).
Naides teaches comparing the determined expression levels of subjects with a reference expression level (see [0016], page 15, claims 8 and 10-11).
Naides teaches determining based on the comparing whether said subject is likely experiencing a graft rejection (see [0019] and page 14, claim 1, and page 15, claim 7).
Naides also teaches that CXCL10, FOXP3, GZMB or PRF1 gene expressions are likely to specifically identify patients suffering from ATN or ACR if at least two of them are overexpressed. Naides claims that the method with a gene signature including CXCL10 is for identifying a renal transplant patient likely to suffer renal graft rejection (Naides’ s claims 1 and 17 on pages 14-15), said renal graft rejection comprising one or more conditions selected from the group consisting of acute cellular rejection (ACR), acute tubular necrosis (ATN), antibody mediated rejection (ABMR), chronic cellular rejection, borderline rejection, diabetic nephropathy, transplant nephropathy, and minimal interstitial fibrosis or tubular atrophy (page 14, claim 2).
Naides teaches measuring the gene expression using RT-PCR (see [0028]). Naides teaches real-time PCR (see [0042], and page 15, claim 14).
Regarding claim 1 (e), Naides also teaches “a virtual control sample” that can be prepared by mathematically summarizing the expression of the gene in more than one control samples (see {0015]).
Regarding claim 1 (g), the claim recites: “performing a biopsy of the transplanted organ for the subject”; Naides teaches transplant recipients undergoing renal biopsy for cause (elevated creatinine) (see [0041]).
Naides also teaches treatments for patients (see [0034]-[0037]); Naides also teaches treatment options for acute cellular rejection, e.g. corticosteroids as an initial treatment (see [0037] and claims 16 and 20, pages 15-16).
Regarding claim 3, Naides also teaches measuring and comparing gene expressions, and normalizing gene expression (see [0053]). Naides teaches normalization against a control that is a housekeeping gene (see [0017]).
Naides does not teach a method to diagnose antibody-mediated graft rejection specifically comprising measuring FCGR1A, FCGR1B and TIMP1 genes’ expressions. Naides does not teach “gene expression profiles”. Although implied, Naides does not teach quantitative PCR specifically (claim 11) either. Naides does not teach “trained machine learning model” to determine a score.
However, Roedder teaches a method, a molecular assay to improve diagnosis and patient monitoring after renal transplantation (see title and abstract). Roedder teaches a simple blood quantitative real-time PCR (QPCR) test called kidney Solid Organ Response Test (kSORT) to predict acute rejection and improve the risk stratification assessment in transplantation (see page 2, left column, “Introduction” section, last sentence). Roedder teaches gene expression profiles and determining the expression of gene profiled compared to a reference profile (see page 5, left column, “Selection of 43 genes for AR screening” section, and right column, “kSORT and kSAS development on ABI Viia7 data for prospective analysis of acute rejection” section, and page 6, left column, first paragraph).
Roedder teaches that a training set of 143 samples and statistical analyses are used to obtain a 17-gene set (kSORT) (see page 15, “Editor’s summary” section, “What did the researchers do and find?” paragraph; see page 2, right column, first paragraph, lines 18-20 and Figure 2).
Roedder does not specifically address kSORT as a machine learning model to analyze and extract relevant molecular markers that can predict graft rejection. However, Wang reviews computational models for transplant biomarker discovery (see title). Wang-1 teaches advances in theories and mathematical models relevant to transplant biomarkers developments (see summary, page 1). Wang-1 refers to Roedder (reference #15) within the list of “Stepwise-Based Models” used to eliminate false-positive/negative signals from microarray data (see page 4, right column, “Stepwise-based Models” section, and see page 5, “Elastic-Net” section). Wang specifically addresses Elastic-Net as a LASSO-based and improved, machine learning model (see page 5, left column, “Elastic-Net” section; and page 6, left column, “Prediction models for biomarker risk analysis” section).
Roedder further teaches that CXCL10 as a marker for acute rejection (AR) (see page 5, left column, “selection of 43 genes for AR screening” section). Roedder teaches that the gene signature selected does not discriminate between antibody-mediated and cell-mediated acute rejection (see page 8, left column, first paragraph).
Examiner interprets this teaching as CXCL10 being a gene that predicts acute rejection and being a common gene between antibody-mediated and cell-mediated acute rejection, confirming claims 1 and 2 of Naides.
Regarding claim 2, it recites “wherein the set of genes further comprises one or more of GBP4 (Guanylate Binding Protein 4), KLRC1 (Killer Cell Lectin Like Receptor C1), GBP1 (Guanylate Binding Protein 1) and IL 15 (Interleukin 15)”.
Roedder teaches that AR patients’ blood samples are enriched in infiltrated leukocytes, particularly trafficking monocytes and Natural Killer cells and some markers of these cells appear in the 43-rejection-gene set genes selected, among which GBP1 is present (see page 5, “selection of 43 genes for AR screening” paragraph).
Regarding claims 3 and 9, Roedder also teaches housekeeping genes for normalization (see page 5, left column, “QPCR data preprocessing and normalization” section). Roedder teaches statistical analysis and specifically a linear regression algorithm ( see page 5, right column, lines 27-32). According to Wang, Roedder’s 17-gene model kSORT was obtained using Elastic-Net, which is a trained machine learning model (see page 5, left column, “Elastic-Net” section; and page 6, left column, “Prediction models for biomarker risk analysis” section).
Regarding claim 1’s genes list in (d), Grey teaches the presence of polymorphonuclear neutrophils in peripheral blood samples of subjects, and that biomarkers associated with those cells, as taught by Roedder, can be useful for monitoring and risk stratification of patients post-transplantation. Grey teaches that an increase in CD64 ’s gene expression indicates a risk of post-transplantation infectious complication (see title). Grey teaches that “CD64” includes the three isoforms called FCGR1A, FCGR1B and FCGR1C (see page 455, right column). Grey also teaches that Fc receptors’ s expression in the cell are key for the generation of a balanced immune response (see page 455, right column). Grey also teaches that CD64 expression is a valuable marker in the evaluation of patients with suspected acute inflammation or infection (see page 457, right column).
Regarding claim 1’s genes list in (d), and claims 4-5, Yan teaches specifically chronic active antibody-mediated renal graft rejection (see title). Yan also teaches that TIMP-1’s expression is rare in normal kidney tissue, but there is a significant expression in AMR subjects (see page 2, right column, “Results” section). TIMP-1 ‘s expression increases with aggravation of the disease (see page 3, left column, first paragraph, and figures 6-8). Yan teaches that TIMP-1 over expression might participate in renal interstitial fibrosis and be involved in the course of inflammatory reaction (see page 5, right column), hallmarks of renal transplant rejection according to Naides (Naides’s [0005], page 2, and [0006]-[0007]).
It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the CXCL10 gene taught by Naides with the CD64 genes taught by Grey and TIMP-1 gene taught by Yan. CXCL10 gene is taught by both Naides and Roedder, confirming that this gene is valuable as a biomarker for renal graft rejection. Grey teaches that infectious post-transplantation complications can be predicted using a biomarker, CD64 i.e. FCGR1A and FCGR1B, associated with circulating blood cells, a biomarker important not only in infection but also in acute inflammation. Roedder also teaches an additional marker, GBP1, related to infiltration of leukocytes present in peripheral blood cells, that can be used for monitoring and predicting graft rejection. Yan teaches a specific relationship between antibody-mediated graft rejection and TIMP-1’s expression in kidney tissue.
One with ordinary skills in the art, interested in finding whether these genes can be usable to predict antibody-mediated graft rejection, could have performed this combination of genes CXCL10, CD64 and TIMP-1, as these are markers are associated either with risk for rejection (i.e. acute inflammation/immune response post-transplantation, CD64, i.e. FCGR1A and B; and GBP1), acute rejection (CXCL10), specific antibody-mediated graft rejection and chronic rejection (TIMP-1).
One motivated in a non-invasive method of assessing risk of rejection, diagnosing acute rejection, and monitoring patient in chronic rejection status, could have modified the method taught by Naides, using the teachings of Roedder comprising a comparison step relying on a linear regression algorithm, and applied it to the expression profiles of CXCL10, CD64, GBP1 and TIMP-1 genes using Q-PCR.
One with ordinary skills in the art could have performed this modification, before the effective filing date, with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 16, Roedder teaches the training of a 17-gene model (kSORT) for acute rejection classification in 143 adult samples form real-life settings (see Figure 2). Roedder teaches the prediction of Biopsy-confirmed acute rejection prior to clinical graft dysfunction (see page 8, right column, second paragraph). Subject with elevated predicted AR (acute rejection) had graft dysfunction, while subjects with low AR score likely responded to AR treatment (see Figure 4).
The obviousness of combination of references Naides, Roedder, Wang, Grey and Yan is described above. Roedder teaches the elements of claim 16. Therefore, the elements of claim 16 are rendered obvious by the combination of references as well.
Regarding claim 17, it recites “wherein the immunosuppressive therapy comprises cyclosporine, tacrolimus, mycophenolate, azathioprine, an mTOR inhibitor, or a corticosteroid”. Naides teaches that treatment options for acute cellular rejection such as corticosteroids are known (See [0037]). Naides further teaches administration of corticosteroid or mycophenolate (see pages 15-16, claims 16 and 20).
Roedder teaches the demographics of patients in the AART (Assessment of Acute Rejection in Renal Transplantation) study (see page 4, Table 1). Roedder teaches that in this clinical trial, antibodies were used such as basuliximab and daclizumab, but also corticosteroids or mycophenolate (see Table 1).
Grey teaches immunosuppressive therapies using prednisolone, tacrolimus and mycophenolate mofetil, with alternatively use of cyclosporin A instead of tacrolimus (see page 448, left and right paragraphs).
Yan teaches triple immunosuppressive therapy using cyclosporine + mycophenolate mofetil + prednisone in 28 patients and tacrolimus + mycophenolate mofetil + prednisone in 17 patients, and sirolimus + mycophenolate mofetil + prednisone (see page 2, left column, lines 6-11).
The obviousness of combination of references Naides, Roedder, Wang, Grey and Yan is described above. Naides, Roedder, Grey and Yan teach the elements of claim 17. Therefore, the elements of claim 17 are rendered obvious by the combination of references as well.
Response to Arguments
Applicant's arguments filed 01/20/2026 have been fully considered but they are not persuasive.
Regarding the rejections under 35 U.S.C. § 101 of the claims 1-6, 9 and 16-17, Applicant argues on page 9 of Remarks that “Claim 1 recites a combination of at least five elements (a), (b), (c), (d), and (g), which was not routine nor conventional as of the earliest benefit date of the invention”.
In response, the earliest benefit date of the invention is not in consideration for rejection under 35 U.S.C. §101. As stated in MPEP §2104: “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 requirement of this title”. 35 U.S.C. § 101 has been interpreted as imposing four requirements, which are described in Sections I-IV, i.e., Double patenting prohibited, Naming of inventor, subject matter eligibility and Utility. While analyzing the Subject matter eligibility, it is noted that the claimed invention is a process using judicial exceptions, within routine practices.
However, when considering the effective filing date of the invention in the continuity map, it is clear that the Foreign Application EP19152365.3 from which Applicant is claiming priority is filed 01/17/2019. In 2015, Wang reviewed algorithms and machine learning models for transplant biomarker discovery (see Wang, A. et al. “Computational models for transplant biomarker discovery”. Frontiers in Immunology, Vol. 6 (2015), p: 458). Real-time and quantitative PCR were well established and used by Naides in 2014 (see [0028] and see [0042], and page 15, claim 14). Roedder teaches quantitative real-time PCR in 2014 (see page 2, left column, “Introduction” section, last sentence). Therefore, these techniques are routine experimentation and well known in prior art at the time of the filing of EP19152365.3. Performing biopsies as following post organ transplantation and after acute rejection prediction, is also described as a Gold standard by Roedder in 2014 (see Abstract). The model kSORT described in Roedder in 2014 is also performed from information obtained in clinical trials, treating subject with kidney transplantation, and using immunosuppressive therapies (see Table 1).
Therefore all the techniques that are used and claimed in claim 1, are routine practice.
Regarding the rejections under 35 U.S.C. § 103 of the claims 1-6, 9 and 16-17, Applicant argues on pages 10-12 of Remarks, against Naides specifically in section A and B.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The combination of references Naides, Roedder, Wang, Grey and Yan is described above. This new rejection addresses elements of the claims that are newly added. The combination of references renders obvious a method of detecting based on score a subject experiencing a graft rejection, wherein the graft rejection is a T cell-mediated rejection or a non-TCMR, e.g., an antibody-mediated rejection (ABMR), both.
Claim 1(f)’s broad and reasonable interpretation encompasses other types of rejections, but does not require the “selective detection” of one type of rejection over another, it only requires that the rejection be a non-TCMR, which is described/included in the method of Naides modified by Roedder, Wang, Grey and Yan.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the selective diagnosis of a graft rejection excluding a non-TCMR) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
No claim is allowed.
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.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636