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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed July 28, 20026 in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 28, 2026 has been entered.
Status of Claims / Response to Amendment
This office action is in response to an amendment filed on July 28, 2026.
Claims 1-4, 6-8, 11, 13, 15-22, 24-26, 28-38 were previously pending. Applicant amended claims 1-2, 18-19, 21-22, 24 and 28-29; cancelled claims 3-4, 6-8, 11, 13, 15-16, 25-26 and 30-38.
Claims 1-2, 17-22, 24, and 28-29 are currently pending and under consideration.
All of the previously presented rejections have been withdrawn as being obviated by the amendment of the claims, which introduces new combinations of elements that were not previously considered in the prior rejection (e.g., claim 1 has been amended to recite: “determining expression levels of each of CXCL11, CD74, IL32, STAT1, SERPINA1, B2M, TBP, NAMPT, and IL18BP”).
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
This office action contains new grounds for rejection necessitated by amendment.
Priority
The priority date of the instant claims 1-2, 17-22, 24 and 28-29 is 05/29/2020, filling date of the US provisional application NO. 63/032,267.
Claim Objections
Claim 22 is objected to because of the following informalities:
In claim 22, line 9, "the trained is generated by…" should read
"the trained classifier was[[is]] generated by… ," to properly refer back to claim 1, which recites "the trained classifier was trained … . "
Claim Interpretation -- Updated
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
Regarding claim 1, the claim has been amended to recite a "trained classifier," which is not expressly defined in the specification.
The commonly understood meaning of "trained classifier" is a machine learning model (i.e., a computer algorithm) that uses training data with known class labels to predict the class label of new data 1.
Regarding claim 1, it has been amended to recite "wherein the trained classifier was trained using urinary microvesicular RNA samples from kidney- transplant subjects classified as biopsy-confirmed any-cause rejection-positive or biopsy- confirmed rejection-negative."
MPEP§ 2111.04 states: "Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure." Also per MPEP 2111.04, a wherein clause can limit a method claim if it contributes meaning and purpose to the manipulative steps.
In this instant case, the "wherein" clause does not introduce any additional steps or modify any existing step. This clause is interpreted as not limiting the claimed method because it is recited in the past tense and does not modify any active step required by the claim. Further, the specification does not clearly explain how the recited training process, in the past tense, distinguishes the trained classifier, algorithmically or functionally, from other trained classifiers known in the art that are capable of performing the claimed function of receiving expression levels as input and generating a score corresponding to kidney transplant rejection risk.
Accordingly, the "wherein" clause is not limiting and does not distinguish the claimed method over the prior art.
For the purpose of applying prior art, regarding claim 1, it has been amended to recite "administering to the subject at least one kidney transplant rejection therapy when the score is greater than or equal to the predetermined cutoff value ," which is contingent claim language that describe a condition that determines whether the administering step is required or not.
The recited administering step in claim 1 is interpreted under BRI as a contingent limitation that does not limit the scope of the claimed method.
MPEP §2111.04 states: "The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met."
Here, the limitation "administering … when the score is greater than or equal to the predetermined cutoff value " formulated as contingent language is not essential to the operation of the claimed method, as it does not require an action upon every practice of the claim. For instance, in the scenario which the score is lower than the cutoff value, the administering step is not performed.
For the purpose of applying prior art, claim 1 has been amended to recite "determining expression levels of each of CXCL11, CD74, IL32, STAT1, SERPINA1, B2M, TBP, NAMPT, and IL18BP."
The claimed method is interpreted as not being limited to determining expression levels only for the recited genes.
The claim does not exclude determining expression levels of additional genes. This is evidenced by claim 19, which depends from claim 1 and further requires "determining an expression level of at least one reference biomarker."
This interpretation is also consistent with the specification, which describes determining gene expression in a exosome nucleic acid sample using "TaqMan® OpenArray® Human Inflammation Panel. The panel consists of 586 TagMan assays for genes that have been studied as targets for a range of inflammatory diseases and includes 21 endogenous control assays." (Example 1, [00520] lines 1-4).
Accordingly, the claimed method encompasses gene expression profiling approaches (e.g., microarray, gene expression qPCR panel, RNA sequencing, etc. ) that measure individual expression levels of genes including, but not limited to, the recited genes in the claim.
For the purpose of applying prior art, claim 1 recites a "score." The application's disclosure does not expressly define the term "score." Therefore, under BRI and within the context of the claim, the term "score" is interpreted to encompass any numerical value.
Claim Rejections - 35 USC § 101 -- New
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, 17-22, 24 and 29 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) without significantly more.
Independent claim 1 recites a method comprising isolating microvesicles, determining gene expression levels of microvesicular RNA, inputting the expression levels into a trained classifier to generate a score corresponding to any-cause kidney transplant rejection risk, comparing the score to a predetermined cutoff value, and depending on the result of the comparing step, administering kidney transplant rejection therapy.
Therefore, the claims are drawn to diagnosis steps to observe expression levels of biomarkers in biological sample from a subject, and determine kidney transplant rejection risk based on the observed expression levels.
Following the analysis below the claims are not patent eligible under 35 U.S.C. 101.
Step 1 - Whether the Claim is to a Statutory Category : YES. The claims are drawn to a method, therefore to one of the four statutory categories.
Step 2A Prong 1 - Whether the Claim Recite an Abstract idea, Law of Nature, or Natural Phenomenon: Yes.
The claims relies on the natural correlation of gene expression biomarkers and the risk of a subject having a physiological condition (i.e., kidney transplant rejection), which is a naturally occurring relationship. As stated in MPEP 2106.04(b)(I), laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature.
Also, as evident from the specification, the disclosure relies on differential gene expression between subjects with different rejection conditions to determine the risk of transplant rejection ([00520-00530]; [00548] identification of a multi-gene signature (CXCL 11, CD74, IL32, STATL CXCL14, SERPINAl, B2M, C3, PYCARD, BMP7, TBP, NAMPT, IFNGRl, IRAK2, IL18BP) that discriminated biopsies with any-cause rejection from norejection.). A subject naturally possesses a gene expression pattern, associated with a physiological condition is classified as naturally occurring principles/relations.
Additionally, by reciting determine gene expression levels and "generate a score corresponding to kidney transplant rejection risk," the claimed method indicates diagnosis of kidney transplant rejection based on the recited gene markers.
The courts have repeatedly held that diagnostic claims based on naturally occurring correlations, without additional elements that impose meaningful limits on the judicial exception, are ineligible under 35 U.S.C. 101. See Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC, 927 F.3d 1333, 1352 (Fed. Cir. 2019) (en banc) (Moore, J., dissenting) (expressing that the current interpretation of Section 101 eliminated diagnostic testing as patentable subject matter). Diagnostic testing claims fail because the novel step across the claims involves the mental step of reading the results and comparing them to a known relationship, or otherwise observing a natural law. See id. at 1336 (Lourie, J., concurring) (acknowledging that the only consistent interpretation of Supreme Court decisions resolving issues of patentable subject matter requires invalidating patents for diagnostic tests that merely observe natural laws); Roche Molecular Sys., Inc. v. CEPHEID, 905 F.3d 1363, 1372 (Fed. Cir. 2018) (explaining that observation of the relationship between the sample and known phenomena does not involve an inventive concept).
It is now well settled under Federal Circuit case law that the use of conventional techniques in a standard way to observe nucleic acids in a biological sample is not eligible for patentability under 35 U.S.C. § 101. CareDx, Inc. v. Natera, Inc., 40 F.4th 1371, 1377 (Fed. Cir. 2022).
In conclusion, the claims recite laws of nature and natural phenomena.
Step 2A Prong 2- Whether the Claim Recite Additional Elements that Integrate the Judicial Exception into a Practical Application: No. The claim does not integrate the judicial exception into a practical application.
For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must “transform the nature of the claim” into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981.
Here, the additional elements in the claim do not transform the claimed natural correlation to something that are markedly different than their naturally occurring counterparts in their natural state, nor do they integrate the recited judicial exception into a practical application of the exception.
The steps recited in the claim merely applies the judicial exception in the field of molecular diagnostics, using well-known approaches, for purpose of identifying transplant rejection risk, therefore these language merely indicate a field of use or technological environment in which to apply a judicial exception.
Specifically, while claim 1 broadly recites steps of isolating microvesicles, determining the expression level of biomarkers, and inputting the expression levels into an algorithm to generate a score, these steps merely observes the naturally occurring correlation and reflect extra-solution activities for data gathering, without any additional elements that impose a meaningful limit on the judicial exception. See MPEP §2106.04(d).
Thus, these method steps merely observe the judicial exception and do not integrate it into a practical application.
The administering step has been considered but does not render the claim patent-eligible under 35 U.S.C. 101 for two reasons.
First, the administering step is contingent and not required by every embodiment of the claimed invention.
Claim 1 recites "administering to the subject at least one kidney transplant rejection therapy when the score is greater than or equal to the predetermined cutoff value," which, as discussed in the claim interpretation section above, is a contingent limitation that does not limit the scope of the claimed method.
MPEP §2111.04 states: "The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met."
The limitation "administering … when the score is greater than or equal to the predetermined cutoff value " formulated as contingent language is not essential to the operation of the claimed method, as it does not require an action upon every practice of the claim. For instance, in the scenario which the score is lower than the cutoff value, the administering step is not performed.
Because this administering step is not required by every embodiment of the claimed invention, and is only applicable in certain situations, it does not sufficiently transform the judicial exception into a practical application.
Second, even if the administering step is required, it fails to transform the claimed method into patent-eligible subject matter because it does not recite a treatment that is sufficiently particular.
MPEP 2106.04(d)(2) states the following regarding consideration for particular treatment in Step 2A Prong Two:
"In order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. "
"The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s)."
Here, claim 1 only broadly recites administering "at least one kidney transplant rejection therapy," without specifically identifying any treatment that goes beyond merely applying the exception in a generic manner.
Thus, this administering step does not integrate the observed natural correlation of claim 1 into a practical application.
Step 2B- Whether a Claim Amounts to Significantly More: No.
According to MPEP§ 2106.05, The second part of the Alice/Mayo test is often referred to as a search for an inventive concept. Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 217, 110 USPQ2d 1976, 1981 (2014) (citing Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71-72, 101 USPQ2d 1961, 1966 (2012)). An “inventive concept” is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself. Alice Corp., 573 U.S. at 27-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).
In this instant case, the claims, when considered as a whole, do not recite any inventive concept with additional elements that amount to significantly more than the judicial exception. The claims do not appear to add markedly different characteristics that significantly modify or use the naturally occurring correlation in a manner that is not naturally occurring.
Claim 1 recites a step of "isolating a plurality of microvesicles from a biological sample." However, the act of isolating RNA of specific genes from microvesicles relies on the natural phenomenon that microvesicles contain and preserve RNA (see in specification [0069]-[0070]). As such, this isolating step is also based on a judicial exception and, therefore, cannot constitute something significantly more that goes beyond the judicial exception.
Furthermore, approaches for isolating microvesicles and extracting RNA for down-stream analysis is well-known and routine in the art , with commercial kits specifically made available to support such isolation (e.g., "Qiagen's “exoRNeasy Serum/Plasma Maxi Kit” see Fig 1 in Enderle et al., Characterization of RNA from Exosomes and Other Extracellular Vesicles Isolated by a Novel Spin Column-Based Method. PLoS One. 2015 Aug 28;10(8):e0136133. doi: 10.1371/journal.pone.0136133. PMID: 26317354; PMCID: PMC4552735.).
Also, as recognized by the courts, determining the marker expression level through molecular biology techniques such as PCR amplification and sequencing, represents well-understood, routine, conventional activity in the life science arts. See University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014).
Inputting gene expression levels into a trained classifier algorithm to generate an score is a well-known approach to observe and analyze gene expression, at the time of filling for the present application (see Salomon et al. US20170137885A1 - Gene expression profiles associated with sub-clinical kidney transplant rejection; published on 2017-05-18, [0023]; [0109] ; MODLIN et al, WO2019018540A1 - Methods for detection of plasma cell dyscrasia ; published on 2019-01-24, [0088]; Huang et al. Applications of Support Vector Machine (SVM) Learning in Cancer Genomics. Cancer Genomics Proteomics. 2018 Jan-Feb;15(1):41-51. doi: 10.21873/cgp.20063. PMID: 29275361; PMCID: PMC5822181; see p. 42-43, "Cancer Classification and Subtyping").
The dependent claims do not recite additional elements that amount to significantly more than the judicial exception, as they either further describe the judicial exception or represent mere general linkage of the judicial exception to the additional elements in the claims (MPEP § 2106.05(h)). Claim 24 further describes the administering step and recites a wide variety of therapeutic agents, it does not further limit the claimed method because the administering step is not required.
In conclusion, the claims are not patent eligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103 -- New
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.
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 1-2, 17-22, 24 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Salomon (Salomon et al. US20170137885A1 - Gene expression profiles associated with sub-clinical kidney transplant rejection; Published on 2017-05-18), in view of
Skog (Skog et al. WO2017192945A1 - Profiling microvesicle nucleic acids and uses thereof as signatures in diagnosis of renal transplant rejection; Published on 2017-11-09; cited as Foreign Patent Document #027 in IDS filed on 08/02/2023); and
Haas (Haas et al., The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018 Feb;18(2):293-307. doi: 10.1111/ajt.14625. Epub 2018 Jan 21. PMID: 29243394; PMCID: PMC5817248);
as evidenced by
TaqMan (TaqMan® OpenArray® Human Inflammation Panel Cat.NO. 4475369; 2013);
Skog 2 (WO2015021158A1- Urine biomarker cohorts, gene expression signatures, and methods of use thereof); and
Wikipedia (TaqMan- Wikipedia; Archived February 02, 2020 on WaybackMachine).
A) Salomon teaches methods for analyzing gene expression using a trained classifier to determine transplant rejection risk, and treating kidney transplant rejection (e.g., Fig. 1; [0041]; [0100]; [0127])).
Regarding claim 1, Salomon teaches:
determining an expression level of genes from microvesicle RNA isolated from the plurality of microvesicles using microarray ([0019]; determining expression levels of genes from a subject having a kidney transplant, using an array ; [0025] “microarray assay comprises the use of an Affymetrix Human Genome U133 Plus 2.0 GeneChip,”; see also [0081]);
inputting the expression levels into a trained classifier to generate a score corresponding to any-cause kidney transplant rejection risk ([0017] ““for cause” biopsy”; [0096] “Having determined values or other designations of expression levels of individual genes providing an indication of presence or susceptibility to subAR (or SCAR) or lack thereof, the values or designations may be combined to provide an aggregate value for all of the genes in the signature being analyzed. … the score may be used to evaluate severity of a transplant condition, such as by comparing the score with a score normally associated with subAR ”; [0100] “using a trained classifier or algorithm to analyze sample data, particularly to detect subAR. In some instances, the expression levels from sample are used to develop or train an algorithm or classifier provided herein.” ; [0103]; [0107]-[0108]; [0145] a computer program that receives gene expression profile and performs classification; [0080]-[0081] gene expression profile can be measured via microarray ),
comparing the score to a predetermined cutoff value ([0096] “the score may be used to evaluate severity of a transplant condition, such as by comparing the score with a score normally associated with subAR… scores at a plurality of timepoints maybe compared in order to assess the relative condition of the subject. For example, if the subject's score rises over time, that may indicate that the subject has subAR and that his or her condition is worsening over time.”; see also [0124] “The above described methods can provide a composite or aggregate value … the value of one patient can be compared with a scale of values for a population of patients having undergone kidney transplant to determine whether the patient's risk relative to that of other patients.”).
Salomon teaches obtaining a sample from a kidney transplant recipient for gene expression analysis (Fig. 1; [0013]); isolating RNA from cell-free source, noting that any method known in the art can be used to obtain sample suitable for its analysis ([0075-0076]). It explicitly identifies exosomes as a suitable sample type([0073]).
Although Salomon does not expressly teach isolating microvesicles, and determining expression levels of each of CXCL11, CD74, IL32, STAT1, SERPINA1, B2M, TBP, NAMPT, and IL18BP from the isolated microvesicular RNA, these features would have been obvious in view of Skog.
Skog teaches methods of analyzing microvesicle biomarkers in a biological sample (e.g., urine sample) to aid in diagnosis, prognosis, monitoring, or therapy selection for kidney transplant rejection (e.g., Abstract; [00011]).
Skog teaches isolating a plurality of microvesicles from a biological sample from the subject ([00010]; claim1). Skog further teaches determining expression levels of each of CXCL11, CD74, IL32, STAT1, SERPINA1, B2M, TBP, NAMPT, and IL18BP from microvesicular RNA isolated from the plurality of microvesicles by performing analysis of RNA signature using the TaqMan® OpenArray® Human Inflammation Panel (claim 1, “detecting a level of expression of at least one biomarker in the extracted nucleic acids”; [00089]; [00098-00099]), which comprises determining the expression levels of CXCL11 (Assay ID: Hs00171138_m1) ; CD74 (Hs00269961_m1); IL32 (Hs00170403_m1) ; STAT1 (Hs01013989_m1); SERPINA1 (Hs01097800_m1); B2M (Hs99999907_m1); TBP (Hs99999910_m1); NAMPT(Hs00237184_m1); IL18BP (Hs00601694_g1), as evidenced by TaqMan.
Skog highlights various methods known in the art for isolating exosomes for RNA extraction:
"[00010] In some embodiments, the methods and kits described herein isolate the microvesicle fraction by capturing the microvesicles to a surface and subsequently lysing the microvesicles to release the nucleic acids, particularly RNA, contained therein. The methods and kits provided herein isolate the microvesicle fraction using any suitable technique. In some embodiments, the microvesicles are isolated using the methods and capture surfaces described in PCT Publication No. WO 2014/107571 and in PCT Publication No. WO 2016/007755, the contents of each of which are hereby incorporated by reference in their entirety. In some embodiments, the microvesicles are isolated from a urine sample using the methods and capture surfaces described in PCT Publication No. WO 2015/021158, the contents of which are hereby incorporated by reference in their entirety."
Skog further suggests analyzing exosomes as promising, non-invasive method for kidney transplant rejection monitoring:
“[00097] Patients with end stage renal disease usually undergo transplantation, however, as many as 10-15% of these patients develop acute kidney rejection. Methods for monitoring clinical rejection include increase in serum creatinine and urinary protein secretion. These methods are not very accurate and may not reflect subclinical rejection. Currently, the patients are often monitored by repeat biopsies that may result in increased complications and cost. An accurate, non-invasive method would allow for earlier diagnosis and minimize the amount of immunosuppression needed to manage these patients.
Extracellular vesicles such as exosomes (also referred to herein as microvesicles or the microvesicle fraction) are a promising new platform for biomarkers and can be used to monitor RNA and protein expression. Exosomes shed from the rejected kidney into the urine are likely originating from glomerular podocytes, renal tubular cells and from immune cells activated during rejection.”
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention, to apply the known method of determining gene expression profiles of exosome RNA using TaqMan inflammation microarray, disclosed in Skog to the method of using a trained classifier in analyzing RNA gene expression profile and determining transplant rejection risk in Salomon.
A skilled artisan, in view of Skog's teaching, would have been motivated to analyze the gene expression in exosomes as a non-invasive approach in monitoring kidney transplant rejection, in order to mitigate increased complication and cost due to repeated biopsies.
The person of ordinary skill would have had a reasonable expectation of success because the references disclose technically compatible teachings.
Skog provides established methods for exosome isolation that can be directly applied to obtain RNA samples for determining gene expression levels, which are suitable inputs for Salomon’s trained classifier in determining transplant rejection risk.
Both references teach analyzing gene expression using arrays for determining transplant rejection risks. Skog teaches TaqMan® OpenArray® Human Inflammation Panel; Salomon teaches Affymetrix Human Genome U133 Plus 2.0 GeneChip, both are commercially available, and a skilled artisan would have readily understood that either array would have been suitable for gene expression analysis. Using one commercially available microarray instead of another would have been an obvious substitution of functionally equivalent assay tools.
Further, a skilled artisan would have been particularly interested in using an inflammation-specific gene panel (TaqMan® OpenArray® Human Inflammation Panel, disclosed in Skog), because the presence of inflammation is a well-known indicator for classifying kidney transplant rejection, as supported by Haas (Table 5).
Additionally, this combination would have been obvious as it represents the KSR principle of predictable use of prior art elements (i.e., exosomes isolation for gene expression analysis) according to a known method (i.e., analyzing gene expression data for transplant rejection risk determination) to yield predictable results. (See MPEP §2143).
B) Regarding claim 2, it recites "wherein any-cause kidney transplant rejection comprises T-cell mediated rejection, borderline rejection, active antibody-mediated rejection, chronic active antibody-mediated rejection, or any combination thereof.”
This limitation is obvious in view of the combined teachings of Skog, Salomon and Haas because it does not further limit the claimed method.
Per MPEP 2111.04, a wherein clause can limit a method claim if it contributes meaning and purpose to the manipulative steps.
In this instant case, the "wherein" clause does not introduce any additional steps or modify any existing step. It further describes any-cause kidney transplant rejection, which is not required by ant of the active steps in base claim 1.
Therefore, this claim language is interpreted as descriptive statement without any associated active steps and does not distinguish the claims from the prior art.
Regarding claims 17-18, Skog teaches a urine sample in paragraph [0010]: “In some embodiments, the microvesicles are isolated from a urine sample using the methods and capture surfaces described in PCT Publication No. WO 2015/021158, the contents of which are hereby incorporated by reference in their entirety.”
Here, Skog incorporates Skog 2 (WO2015021158A1) in its entirety, which teaches obtaining a first-catch urine sample ([0058]). Thus, Skog teaches the limitation in claim 18, as evidenced by Skog 2.
Regarding claim 19, it is obvious in view of the combined teachings of Skog, Salomon and Haas.
Skog teaches determining an expression level of at least one reference biomarker from the microvesicular RNA ([0098] RNA from the exosomes are analyzed using the OpenArray® Human Inflammation Panel. OpenArray® is a TaqMan qPCR array Human Inflammation Panel consists of 586 target and 21 endogenous control assays. ”); normalizing the expression level of each of CXCL11, CD74, IL32, STAT1, SERPINAl, B2M, TBP, NAMPT, and IL18BP to the expression level of the at least one reference biomarker ([0027] “normalization was calculated by subtracting the mean Crt value for the 7 control assays from Figures 3A-3G from the raw Crt values”).
Salomon teaches inputting normalized expression level of an array into trained classifier. ([0064]-[0065]; [0093]; [0189]).
Regarding claim 20, Skog teaches PGK1 ([0026]).
Regarding claim 21, Skog teaches quantitative PCR (qPCR) ([0098]).
Regarding claim 22, the claim recites a wherein clause that further describes how the trained classifier was generated. This claim is obvious in view of the combined teachings of Skog, Salomon and Haas because it does not further limit the claimed method.
Per MPEP 2111.04, a wherein clause can limit a method claim if it contributes meaning and purpose to the manipulative steps.
Here, as currently interpreted, claim 22 does not further limit the claimed method because, according to base claim 1, the trained classifier was trained before the claimed method takes place, in other words, it has already been generated.
Further, the specification does not clearly explain how the recited generation steps distinguishes the trained classifier, algorithmically or functionally, from other trained classifiers known in the art. Accordingly, the "wherein" clause does not distinguish the claimed method over the prior art.
Regarding claim 24, Salomon teaches administering to the subject at least one therapeutically effective amount of at least one immunosuppressant ([0127] lines 11-13).
Regarding claim 29, Skog teaches a targeted quantitative PCR panel comprising primers or probes for CXCL11, CD74, IL32, STAT1, SERPINAl, B2M, TBP, NAMPT, and IL18BP ([00089]; [00098-00099] analysis of RNA signature using the OpenArray® Human Inflammation Panel, which is a TaqMan qPCR array, thus a skilled artisan would readily understand this assay comprises primers and probes, see Wikipedia).
Subject Matter Not Taught/Suggested in Prior Art
Claim 28 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following subject matter is not taught or suggested in the prior art:
Regarding claim 28, the prior art fails to teach or suggest all the claimed limitations.
Claim 28 further defines the step of inputting the expression levels into a trained classifier in claim 1, reciting "wherein the gene expression inputs to the trained classifier consist of expression levels, or normalized expression levels, of CXCL11, CD74, IL32, STAT1, SERPINA1, B2M, TBP, NAMPT, and IL18BP."
Therefore, in view of the claim language "consist of," claim 28 requires the gene expression inputs to the trained classifier to be of a closed group of genes. Additional genes are not permitted.
Although the combined teachings of Skog, Salomon and Haas discloses generating gene expression profiles using a gene panel comprising the recited genes, and using the gene expression levels to generate a score with a trained classifier, as discussed in the prior art rejection, the disclosed panel (e.g.,TaqMan® OpenArray® Human Inflammation Panel, disclosed in Skog) comprises additional genes beyond those specifically recited in claim 28, and therefore does not meet the closed group limitation.
No prior art teaches or suggests using the expression levels of a group of genes consisting only of CXCL11, CD74, IL32, STAT1, SERPINA1, B2M, TBP, NAMPT, and IL18BP, for assessing kidney transplant rejection risk. Although these genes are known in the art, among others, as being related to inflammation, which may indicate transplant rejection, the prior art does not provide a reason to specifically select only the nine recited genes over other inflammation-related genes in a given inflammation panel, for score generation by a trained classifier.
Conclusion
Claims 22 and 28 are objected to; claims 1-2, 17-22, 24 and 29 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIAN NMN YU whose telephone number is (703)756-4694. The examiner can normally be reached Monday - Friday 8:30 am - 5:30 pm.
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/TIAN NMN YU/Examiner , Art Unit 1681
1 See Gupta et al. Machine learning models for secure data analytics: A taxonomy and threat model. Computer Communications. 2020 Mar 1;153:406-40.:
"Supervised learning models (classification models).
Classification models apply to the only situation where the class labels of test data are given. It is a two-step process such as-(i) learning step and (ii) classification step. In the learning step, the model is trained and is called as the classifier and is used to predict the class label of the new data in the classification step."(p. 422, 7.3.1. Past-trends)
See also Mocherla et al. (2017). Evaluation of Naive Bayes and Support Vector Machines for Wikipedia. Applied Artificial Intelligence, 31(9–10), 733–744.
"Classification is a machine learning technique for assigning labels to unseen data based on models built using an algorithm and labeled data. It consists of a training phase and a testing phase. Classification is also considered as a supervised learning technique because of the presence of a training phase. It can be performed on any type of data – text, images, videos, web data, numbers, etc." (introduction).
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