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 .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 25 June 2026 has been entered.
Claim Status
3. Claims 1-41 have been cancelled. Claims 42-48 were newly added in the reply of 25 June 2026.
Claims 48 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Note that claim 48 requires detecting the expression level of the additional gene of NAIP and/or TYMS, whereas Applicant elected the combination of genes limited to DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 genes.
Claims 42-47 read on the elected species and have been examined herein.
4. Applicant's arguments and the amendments to the claims have been fully considered but do not place the application in condition for allowance. All rejections not reiterated herein are hereby withdrawn.
In particular, the previous rejection of claims 1, 6-11, 13, 18, 22, 26, 35-37, 40 and 41as reciting an improper Markush grouping has been rendered moot by the cancellation of claims 1, 6-11, 13, 18, 22, 26, 35-37, 40 and 41. The rejection does not apply to the newly added claims because new claims 42-47 require the combination of each of the DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 genes.
The previous rejection of claims 1, 6-11, 13, 18, 22, 26, 35-37, 40 and 41 under 35 U.S.C. 101 has been rendered moot by the cancellation of these claims. However, new claims 42-47 are rejected under 35 U.S.C. 101 for the reasons set forth below.
The previous rejection of claims 18, 22, 26, 35-37, 40 and 41 under 35 U.S.C. 112(d) has been rendered moot by the cancellation of these claims.
The previous rejection of claims 1, 6-11, 13, 18, 22, 26, 35-37, 40 and 41 under 35 U.S.C. 112(a) - enablement - has been rendered moot by the cancellation of these claims.
New Claim Rejections - 35 USC § 101
5. 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 42-47 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. Claim 45 recites the correlation between a reference expression level and acute (liver transplant) rejection. That is the claim recites “a reference expression level that is associated with presence or absence of acute rejection.” As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
Claims 42-47 recite the judicial exception of an abstract idea and particularly mental processes.
As stated in MPEP 2106.04(a)(2) III “the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions.”
The claims recite “determining the mRNA expression level of each gene of the set of genes in the blood sample.” As broadly recited and absent a limiting definition for “determining,” the claims encompass methods wherein the determining step is accomplished by reading information in a database and from this information, determining expression levels. The claims do not require performing an active, laboratory step of measuring mRNA levels in a blood sample from a subject or of obtaining a blood sample from a subject and assaying the blood sample to determine mRNA expression levels of each of the genes in the set of genes. Accordingly, the determining step is considered to be an abstract idea / process.
Claim 45 requires performing a step of comparing the expression level of each of the genes to a reference expression level. As broadly recited, the comparing step may be accomplished by critical thinking processes and thereby is the judicial exception of an abstract idea.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). Regarding claim 45, to any extent that claim 42 may be amended to recite a step of measuring the mRNA expression levels of each of the genes in a blood sample from the subject, such a measuring step is part of the data gathering process necessary to observe the judicial exception. This step does not practically apply the judicial exception.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible.
Regarding claim 45, to any extent that claim 42 may be amended to recite a step of measuring the mRNA expression levels of each of the genes in a blood sample from the subject, a general step of measuring mRNA expression levels would be considered to be well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification. For example, para [0025] indicates that methods of PCR and sequencing (to detect gene expression) were well known in the prior art. At para [0014], the specification teaches that methods of detecting gene expression using microarrays, such as the Affymetrix Human Genome U133 Plus 2.0 GeneChip, were well known in the prior art. See also paragraph [0051-0052].
Further, the specification teaches that “Methods of isolation and amplification of mRNA are well known in the art” (para [0050]).
See also MPEP 2106.05(d) II which states 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.
i. 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);
ii. 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);
iii. 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);…
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;…
vii. 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); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite detecting the expression level of particular genes, the identity of the genes is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence so as to add something ‘significantly more’ to the recited judicial exceptions.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Note that with respect to claims 42-44 and 46-47, this rejection may be obviated by amendment of claim 42 to recite “…the method comprising measuring the mRNA expression level of each gene of the set of genes in the blood sample.”
Claim Rejections - 35 USC § 112(b) - Indefiniteness
6. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 44 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 44 is indefinite over the recitation of “wherein the normal liver function is determined by a liver function test (LFT) in which total bilirubin (TB) is less than 1.5 mg/dL, direct bilirubin is less than 0.5 mg/dL, alkaline phosphatase (AP) is less than 200 U/L, and alanine transaminase (ALT) is less than 60 U/L (males) or less than 36 U/L (females).” First it is unclear as to what is meant by “a liver function test (LFT) in which.” For instance, it is unclear as to whether the test only measures the values that follow the recitation of “in which” or if a normal liver function is defined as one in which the values that follow “in which” occur. It is further unclear as to whether the subject has a normal liver function only if each of the recited values is determined to be present in the subject or if the claim intends to only define what would be measured by a liver function test and it is determined that the subject has a normal liver function if the subject has one of the recited test results - i.e., has 1.3mg/dL of total bilirubin or has 60 U/L of ALT if the subject is a male.
New Claim Rejections - 35 USC § 102
7. 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 42, 43 and 45-46 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fueyo et al (U.S. 2011/0130303; previously cited), as evidenced by the present specification at paragraphs [0014] and [0051].
Fueyo et al discloses methods for detecting a liver transplant rejection or lack thereof in a subject who has undergone a liver transplant, comprising: obtaining a blood sample from a subject; assaying mRNAs present in the blood sample to determine gene expression levels (e.g., para [0029], [0031], [0033], [0035] and [0077]). Fueyo teaches detecting gene expression levels using Affymetrix Human Genome U133 Plus 2.0 microarrays (para [0077)).
It is a property of the Affymetrix Human Genome U133 Plus 2.0 microarrays that they include probes for detecting the expression level of each of the DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 genes. This fact is evidenced by the teachings of the present specification at paragraphs [0014] and [0051] which discloses detecting the expression levels of each of these genes using the Affymetrix Human Genome U133 Plus 2.0 microarrays. Note that the present specification is cited only to establish what is inherent to the teachings of Fueyo.
Thus, Fueyo teaches methods comprising: determining the expression level of each of the DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 genes in a blood sample from a subject who has undergone a liver transplant.
It is noted that the claims recite “the method comprising determining the mRNA expression level of each gene of the set of genes in the blood sample” and also recite “wherein the gene signature set consists of the genes.”
MPEP 2111.03 sets forth that “When the phrase ‘consists of’ appears in a clause of the body of a claim, rather than immediately following the preamble, there is an "exceptionally strong presumption that a claim term set off with ‘consisting of’ is closed to unrecited elements. Multilayer Stretch Cling Film Holdings, Inc. v. Berry Plastics Corp., 831 F.3d 1350, 1359, 119 USPQ2d 1773, 1781 (Fed. Cir. 2016) (a layer ‘selected from the group consisting of’ specific resins is closed to resins other than those listed). However, the ‘consisting of’ phrase limits only the element set forth in that clause; other elements are not excluded from the claim as a whole. Mannesmann Demag Corp. v. Engineered Metal Products Co., 793 F.2d 1279, 230 USPQ 45 (Fed. Cir. 1986). See also In re Crish, 393 F.3d 1253, 73 USPQ2d 1364 (Fed. Cir. 2004)” (Emphasis added).
Herein, what constitutes the “set of genes” is an arbitrary designation and the open claim language of “comprising” in the recitation of “method comprising” permits determining the expression level of any number of genes in addition to the genes in the set of genes.
Therefore, while the “consists of’ language for the set of genes closes the set of genes, the claims do not exclude measuring the mRNA expression level of other genes, including other genes that hybridize to probes present on the Affymetrix Human Genome U133 Plus 2.0 GeneChip microarray.
Regarding claim 43, Fueyo teaches that the subjects from which blood samples were obtained included non-tolerant subjects who had “normalized liver function tests” (para [0076]) and thereby subjects having normal liver function at the time the expression level of the set of genes is determined.
Regarding claim 45, Fueyo teaches comparing the expression profile obtained from the blood sample of the subject to a control, reference expression level of the genes, including a reference profile from healthy subjects or tolerant subjects (e.g., para [0010-0011], and [0072]) and thereby a reference level that is associated with absence of acute rejection.
Regarding claim 46, Fueyo (e.g., para [0076]) teaches that the subjects include tolerant recipients in which blood was collected after >1year after successful immunosuppressive drug discontinuation and thereby subjects not receiving immunosuppressive therapy at the time the expression level of the set of genes is determined.
8. Claim(s) 42, 43 and 45-47 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Salomon et al (U.S. US 20170183735; cited in the IDS), as evidenced by the present specification at paragraphs [0014] and [0051].
Salomon et al discloses methods for detecting a liver transplant rejection or lack thereof in a subject who has undergone a liver transplant, comprising: obtaining a blood sample from a subject; assaying mRNAs present in the blood sample to determine gene expression levels, including the RRM2 and MEST genes; and (c) detecting, prognosing or diagnosing transplant rejection or injury, or lack thereof in the subject based on the expression levels detected in (b) (see, e.g., para [0007] and Table 4).. Salomon teaches detecting gene expression levels using Affymetrix Human Genome U133+PM microarrays (para [0017], [0044], [0060], and [0103]).
It is a property of the Affymetrix Human Genome U133+PM microarrays that they include probes for detecting the expression level of each of the DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 genes. This fact is evidenced by the teachings of the present specification at paragraphs [0014] and [0051] which discloses detecting the expression levels of each of these genes using the Affymetrix Human Genome U133+PM microarrays. Note that the present specification is cited only to establish what is inherent to the teachings of Salomon.
Thus, Salomon teaches methods comprising: determining the expression level of each of the DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 genes in a blood sample from a subject who has undergone a liver transplant.
It is noted that the claims recite “the method comprising determining the mRNA expression level of each gene of the set of genes in the blood sample” and also recite “wherein the gene signature set consists of the genes.”
MPEP 2111.03 sets forth that “When the phrase ‘consists of’ appears in a clause of the body of a claim, rather than immediately following the preamble, there is an "exceptionally strong presumption that a claim term set off with ‘consisting of’ is closed to unrecited elements. Multilayer Stretch Cling Film Holdings, Inc. v. Berry Plastics Corp., 831 F.3d 1350, 1359, 119 USPQ2d 1773, 1781 (Fed. Cir. 2016) (a layer ‘selected from the group consisting of’ specific resins is closed to resins other than those listed). However, the ‘consisting of’ phrase limits only the element set forth in that clause; other elements are not excluded from the claim as a whole. Mannesmann Demag Corp. v. Engineered Metal Products Co., 793 F.2d 1279, 230 USPQ 45 (Fed. Cir. 1986). See also In re Crish, 393 F.3d 1253, 73 USPQ2d 1364 (Fed. Cir. 2004)” (Emphasis added).
Herein, what constitutes the “set of genes” is an arbitrary designation and the open claim language of “comprising” in the recitation of “method comprising” permits determining the expression level of any number of genes in addition to the genes in the set of genes.
Therefore, while the “consists of’ language for the set of genes closes the set of genes, the claims do not exclude measuring the mRNA expression level of other genes, including other genes that hybridize to probes present on the Affymetrix Human Genome U133+PM microarray.
Regarding claim 43, Salomon teaches that the subjects from which blood samples were obtained included non-tolerant subjects who had normal liver function following the transplant (e.g., para [0049], [0077] and [0082]) and thereby subjects having normal liver function at the time the expression level of the set of genes is determined.
Regarding claim 45, Salomon teaches comparing the expression profile obtained from the blood sample of the subject to that has a well-functioning normal transplant (TX; e.g., para [0007]) and thereby a reference level that is associated with absence of acute rejection.
Regarding claim 46, Salomon teaches that the subject can be a subject that is not receiving immunosuppressive therapy at the time the expression level of the set of genes is determined (e.g., para [0032]).
Regarding claim 47, Salomon teaches during expression levels “at one or more time points” after the liver transplant (para [0050]). Salomon also teaches monitoring expression levels over time (para [0075] and [0077]). Thereby, Salomon teaches that gene expression levels are determined at multiple time points in the subject that has undergone a liver transplant.
Claim Rejections - 35 USC § 103
9. 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.
Claim(s) 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fueyo et al (U.S. 2011/0130303), as evidenced by the present specification at paragraphs [0014] and [0051].
The teachings of Fueyo are presented above.
Regarding claim 47, Fueyo does not specifically state that the subject whose gene expression levels were measured using the Affymetrix U133 GeneChip had blood samples collected at multiple time points.
However, Fueyo exemplifies methods in which gene expression levels are measured by qRT-PCR at two time points (e.g., para [0082]). The gene expression levels at the different time points were compared to classify the subject as tolerant or non-tolerant following the liver transplant.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the microarray expression analysis method of Fueyo so as to have analyzed collected blood samples from the subjects at two different times and then to have measured the gene expression levels at the two different times. One would have been motivated to have done so in order to have achieved the advantage set forth by Fueyo that the gene expression levels could be compared over time to determine if the subject had changes in their phenotype of tolerant or non-tolerant and/or to identify additional gene expression levels indicative of risk of changing from tolerant to non-tolerant.
10. Claim(s) 44 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fueyo et al (U.S. 2011/0130303), as evidenced by the present specification at paragraphs [0014] and [0051], in view of LabCorp (2004. Sample Report for Hepatic Function Panel (7); 2 pages, available via URL: < files.labcorp.com/testmenu-d8/sample_reports/322755.pdf>) and LabCorp (2013. LABupdate, New ALT Reference Intervals for Children and Adults, available via URL: <labcorp.com/assets/5286>, 2 pages).
The teachings of Fueyo are presented above.
Regarding claim 44, Fueyo does not teach that normal liver function is determined using a liver function test and the subject has a total bilirubin (TB) level of less than 1.5 mg/dL, a direct bilirubin level less than 0.5 mg/dL, an alkaline phosphatase (AP) level less than 200 U/L, and “alanine transaminase (ALT) is less than 60 U/L (males) or less than 36 U/L (females).
However, LabCorp (2004) teaches a hepatic/liver function test which measures a panel of 7 functions / markers as shown below:
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LabCorp (2013) provides updated ALT normal intervals that are specific for males and females and for different age groups:
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474
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The reference intervals provided by LabCorp (2004) for each of total bilirubin, direct bilirubin, and alkaline phosphatase and LabCorp (2013) for alanine transaminase (ALT) are all within the maximum levels recites in claim 44.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Fueyo so as to have specifically determined that the subject had a normal liver function by performing the liver function test disclosed by LabCorp (2004) and to have determined that the subject had a normal liver function if their levels were within the reference interval disclosed by LabCorp (2004) - i.e. a total bilirubin level of between 0-1.2 mg/dL, which is less than 1.5 mg/d, a direct bilirubin level between 0-0.4 mg/dL, which is less than 0.5 mg/dL, an alkaline phosphatase (AP) level between 39-147 U/L, which is less than 200 U/L, and LabCorp (2013) of an alanine transaminase (ALT) level less than 33 for females > 18 and less than 45 for males > 18, which is less than 60 U/L for males and less than 33 U/L for females. One would have been motivated to have done so because the liver function test disclosed by LabCorp is a conventional test and includes accepted reference levels for classifying a subject’s liver function as normal.
includes accepted reference levels for classifying a subject’s liver function as normal.
11. Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Salomon et al (U.S. 2 20170183735), as evidenced by the present specification at paragraphs [0014] and [0051], in view of LabCorp (2004. Sample Report for Hepatic Function Panel (7); 2 pages, available via URL: < files.labcorp.com/testmenu-d8/sample_reports/322755.pdf>) and LabCorp (2013. LABupdate, New ALT Reference Intervals for Children and Adults, available via URL: <labcorp.com/assets/5286>, 2 pages).
The teachings of Salomon are presented above.
Regarding claim 44, Salomon does not teach that normal liver function is determined using a liver function test and that the subject with normal liver function has a total bilirubin (TB) level of less than 1.5 mg/dL, a direct bilirubin level less than 0.5 mg/dL, an alkaline phosphatase (AP) level less than 200 U/L, and “alanine transaminase (ALT) is less than 60 U/L (males) or less than 36 U/L (females).
However, LabCorp (2004) teaches a hepatic/liver function test which measures a panel of 7 functions / markers as shown below:
PNG
media_image1.png
204
934
media_image1.png
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LabCorp (2013) provides updated ALT normal intervals that are specific for males and females and for different age groups:
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media_image2.png
184
474
media_image2.png
Greyscale
The reference intervals provided by LabCorp (2004) for each of total bilirubin, direct bilirubin, and alkaline phosphatase and LabCorp (2013) for alanine transaminase (ALT) are all within the maximum levels recites in claim 44.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Salomon so as to have specifically determined that the subject had a normal liver function by performing the liver function test disclosed by LabCorp (2004) and to have determined that the subject had a normal liver function if their levels were within the reference interval disclosed by LabCorp (2004) - i.e. a total bilirubin level of between 0-1.2 mg/dL, which is less than 1.5 mg/d, a direct bilirubin level between 0-0.4 mg/dL, which is less than 0.5 mg/dL, an alkaline phosphatase (AP) level between 39-147 U/L, which is less than 200 U/L, and LabCorp (2013) of an alanine transaminase (ALT) level less than 33 for females > 18 and less than 45 for males > 18, which is less than 60 U/L for males and less than 33 U/L for females. One would have been motivated to have done so because the liver function test disclosed by LabCorp is a conventional test and includes accepted reference levels for classifying a subject’s liver function as normal.
12. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Levitsky et al ( Blood and Biopsy Genomic Signatures of Acute Rejection in Liver Transplant Recipients. Am J Transplant. 2017;17 (suppl 3)) teaches methods of identifying mRNA signatures in blood and graft tissue samples from patients who have undergone a liver transplant. It is disclosed that mRNA expression profiles were identified that distinguish between acute rejection (AR) and other types of liver injury in liver transplant recipients. Levitsky does not provide the identity of the genes that are differentially expressed between subjects having acute rejection (AR) and subjects having non-acute rejection (non-AR) with graft dysfunction or having a normal liver transplant (TX)
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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