DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the amendment filed on 26 November 2025. Applicant's arguments and 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 All rejections not reiterated herein are hereby withdrawn.
Claim Status
3. Claims 1, 4, 6-11, 13, 16, 18, 21-22, 26-32, 34-37, 40 and 41 are pending.
Claims 4, 21, 27-32 and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.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 claims 4, 21, 27-32 and 34 require detecting the expression level of all of the genes in claim 1, whereas Applicant elected the subset of the genes of claim 1 wherein the subset consists of the DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 genes.
Claims 1, 6-11, 13, 16, 18, 22, 26, 35-37, 40 and 41 read on the elected species and have been examined herein. These claims encompass non-elected species - i.e., non-elected genes and non-elected combinations of genes other than the combination of the DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 genes. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Non-Compliant Amendment
4. The status identifiers used for claims 4, 21, 27-32 and 34 are not correct as these claims are directed to non-elected subject matter and should be accompanied by the status identifier of “(Withdrawn)” or “(Withdrawn – Currently amended), as appropriate.
As set forth in MPEP 714, “For any amendment being filed in response to a restriction or election of species requirement and any subsequent amendment, any claims which are non-elected must have the status identifier (withdrawn). Any non-elected claims which are being amended must have either the status identifier (withdrawn) or (withdrawn – currently amended) and the text of the non-elected claims must be presented with markings to indicate the changes. Any non-elected claims that are being canceled must have the status identifier (canceled).”
MPEP provides the following list of acceptable alternative status identifiers:
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435
908
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Note use of the correct status identifiers is not optional. Future responses must include the correct status identifiers.
Maintained Improper Markush Grouping Rejection
5. Claims 1, 6-11, 13, 16, 18, 22, 26, 35-37, 40 and 41 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of: the NHS actin remodeling regulator (NHS), endothelial PAS domain protein 1 (EPAS1), complement component 4 binding protein alpha (C4BPA), lymphocyte cytosolic protein 2 (LCP2), deleted in lymphocytic leukemia 2 (DLEU2), NHS like 1 (NHSL1), required for meiotic nuclear division 5 homolog A (RMND5A), lymphocyte activating 3 (LAG3), chitinase 3 like 2 (CH13L2), gelsolin (GSN), ASAP1 intronic transcript 2 (ASAP1-IT2), NLR family apoptosis inhibitory protein (NAIP), geminin DNA replication inhibitor (GMNN), C-type lectin domain family 4 member E (CLEC4E), X inactive specific transcript (XIST), long intergenic non- protein coding RNA 877 (LINC00877), A-kinase anchoring protein 12 (AKAP12), ATPase family AAA domain containing 2 (ATAD2), stathmin 1 (STMN1), protein phosphatase 1 regulatory subunit 12B (PPP1 R12B), mesoderm specific transcript (MEST), ribonucleotide reductase regulatory subunit M2 (RRM2), senataxin (SETX), thymidylate synthetase (TYMS), GATA binding protein 2 (GATA2), and KIAA1324 gene and combinations thereof are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 2117 states that “A Markush claim may be rejected under judicially approved "improper Markush grouping" principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an "improper Markush grouping" if either: (1) the members of the Markush group do not share a "single structural similarity" or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.” (see MPEP 2117IIA).
Herein, the recited alternative species do not share a single structural similarity, as each gene has a different chemical structure in that it consists of a different nucleotide sequence. The only structural similarity present is that all of the genes comprise nucleotides. The fact that the genes comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides alone is not essential to the asserted common activity of being correlated with acute rejection (AR) or no acute rejection of a liver transplant, or the prognosis or diagnosis of a liver transplant rejection. Accordingly, while the different genes are asserted to have the property of having an expression level correlated with acute rejection or no acute rejection of a liver transplant, they do not share a substantial structural similarity essential to this activity.
Further, the recited genes do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that the genes behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited genes possess the common property of having an expression level that is indicative of response to a liver transplant recipient, and particularly one of the responses of acute rejection or no acute rejection of a liver transplant.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. In particular, this rejection may be obviated by amendment of the claims to recite analyzing the expression level of each of the DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2genes.Response to arguments:
Applicant cites Ex parte Larson, 15 USPQ 68 (Bd. App. 1931) and characterizes the decision as “controlling Board precedent” establishing that “a Markush group is proper where an Applicant asserts that its members perform an equivalent function within a claimed process.” Applicant cites additional PTAB decisions in support of this position and argues “(t)he application identifies the members of the claims' Markush groups as sharing functional equivalence (Figure 3, Table 3). Thus, Board precedent for a proper Markush claim is satisfied, and the improper Markush grouping rejection should be withdrawn on this basis alone.
These arguments have been fully considered but are not persuasive. The cited PTAB decisions are not in fact “controlling.” They are based on the specific fact patterns in those applications. The present rejection is based on, and consistent with, the guidance provided in the MPEP, particularly MPEP 2117. Contrary to Applicant’s assertion, it is not sufficient that the specification teaches only that the species have a common use. Rather, the recited species should share a single structural similarity or belong to “the same recognized physical or chemical class or to the same art-recognized class,” in addition to sharing a common use / function. Regarding “the same recognized physical or chemical class or to the same art-recognized class,” MPEP 2117 II.A states:
“A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.”
Herein there is no evidence of record to establish that it was known from “the knowledge in the art” that the recited genes behave in the same manner in the context of the invention (methods of diagnosing transplant rejection) and can be substituted for one another. Thus, Applicant has established only that the members of the Markush group have a common use, but has not established that every member has both a “structural similarity” and a “common use.”
Applicant asserts that in process claims, there is no requirement for the members of the Markush group to recite a common structure and that the members need only recite a common property.
This interpretation is not correct. MPEP 2117 II states:
“A Markush claim may be rejected under judicially approved "improper Markush grouping" principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an "improper Markush grouping" if either: (1) the members of the Markush group do not share a "single structural similarity" or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “
That is, a Markush grouping is not proper, and an improper Markush rejection is appropriate, when either of the two elements is lacking. There is no separate criteria that applies only to claims to processes.
Applicant cites Ex Parte Ren, Appeal No. 2015-004371 (Bd. Pat. App &Int. Dec. 28, 2016), U.S. Application No. 11/992,332 and asserts that this decision concluded that “the Markush group was proper, at least in part, because the alternatives in the Markush group were all nucleic acids.”
However, the present fact pattern is not similar to that of Ex parte Ren. In Ex parte Ren, the claimed ta-siRNAs all shared a common miRNA binding site and phase region complementary to a target gene in the plant and it was this common structure that was essential to the activity of the trans-acting small interfering tRNAs to inhibit gene growth. The PTAB did not conclude that a Markush grouping is proper because the species were drawn to nucleic acids per se.
The rejection is maintained for the reasons of record.
Maintained Claim Rejections - 35 USC § 101
6. 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, 6-11, 13, 16, 18, 22, 26, 35-37, 40 and 41 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. The claims recite the correlation between the level of gene expression of the 9 elected genes and the occurrence of acute rejection (AR) or no acute rejection in a liver transplant recipient (claim 1) and the diagnosis or prognosis of liver transplant rejection (claim 18). 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.”
The claims also 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.”
Claims 1, 4, 6-11, 13 and 16 recite “classifying” the subject as undergoing AR or at risk of undergoing AR or as not undergoing or at risk of undergoing AR. Classifying a subject may be accomplished mentally through critical thinking processes and thereby is an abstract idea. While the claims recite that the classifying step requires using a trained algorithm, the use of a generic computer or software program to implement an abstract idea (i.e., the step of classifying a subject) does not itself impart patent eligibility.
As stated in MPEP 2106.04(a)(2) III “The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation” and that “Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer.”
Thus, the use of a generic software program or algorithm to evaluate the expression levels and classify a subject does not constitute something more than an abstract idea.
Further, regarding claims 1, 4, 6-11, 13 and 16, neither the specification nor the claim sets forth what is intended to be encompassed by “adjusting or initiating” the immunosuppressive therapy. As broadly recited “adjusting or initiating the immunosuppressive therapy” may be accomplished through critical thinking processes or verbally and thereby is an abstract idea. This step does not require administering an increased dosage or a decreased dosage of an immunosuppressive therapy to a subject who is currently receiving an immunosuppressive therapy.
Claim 8 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.
Claims 18, 22, 26, 35-37, 40 and 41 require “prognosing or diagnosing the liver transplant rejection” based on the detected expression levels. Neither the specification nor the claims set forth a limiting definition for “prognosing” or “diagnosing” and the claims do not set forth how “prognosing” or “diagnosing” are accomplished. As broadly recited, “prognosing” and “diagnosing” may be accomplished mentally and thus are an abstract step / process. “Prognosing” and “diagnosing” may also be accomplished verbally. Such verbal communication is also abstract, having no particular concrete or tangible form.
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). The additionally recited steps of obtaining nucleic acids and detecting or measuring the expression levels of genes using the obtained nucleic acids are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Regarding claims 1, 4, 6-11, 13 and 16, as discussed above the step of adjusting or initiating immunosuppressive therapy is an abstract step and thereby is a judicial exception and not something in addition to the recited judicial exceptions. See MPEP 2106.04(d)(2):
Examiners should keep in mind that 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. An example of such a limitation is a step of "administering amazonic acid to a patient" or a step of "administering a course of plasmapheresis to a patient." If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. For example, a step of "prescribing a topical steroid to a patient with eczema" is not a positive limitation because it does not require that the steroid actually be used by or on the patient, and a recitation that a claimed product is a "pharmaceutical composition" or that a "feed dispenser is operable to dispense a mineral supplement" are not affirmative limitations because they are merely indicating how the claimed invention might be used.
Regarding claims 18, 22, 26, 35-37, 40 and 41, the treating step is recited at a high degree of generality such that subjects having any prognosis or diagnosis for liver transplant rejection are treated in the same manner with an immunosuppressive therapy. As evidenced by claim 26, the subject may have acute rejection, acute dysfunction with no rejection or a normal well-functioning liver transplant, and subjects diagnosed or prognosed as having any of these conditions are then treated / administered an immunosuppressive agent. Also, as evidenced by claim 37, the claims encompass not administering any immunosuppressive agent since the claims encompass “stopping administration of the drug” covering any type of treatment and not necessarily a treatment that is specific for patients undergoing liver transplant rejection or injury. Also, the recitation in claim 37 of “administering an additional drug, administering a higher dose of the same drug, administering a lower dose of the same drug or stopping administering the same drug” is broad and general, covering any treatment for any diagnosis or prognosis. The administering step is not considered to be a practical application of the recited judicial exceptions. Rather, the administering step is merely an “apply it” limitation.
Regarding specific treatments, see MPEP 2106.04(d)(2):
When determining whether a claim applies or uses a recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, the following factors are relevant.
a. The Particularity Or Generality Of The Treatment Or Prophylaxis
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). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application….
b. Whether The Limitation(s) Have More Than A Nominal Or Insignificant Relationship To The Exception(s)
The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). For example, consider a claim that recites a natural correlation (law of nature) between blood glucose levels over 250 mg/dl and the risk of developing ketoacidosis (a life-threatening medical condition). The claim also recites "treating a patient having a blood glucose level over 250 mg/dl with insulin". Insulin acts to lower blood glucose levels, and administering insulin to a patient will reduce the patient’s blood glucose level, thereby lowering the risk that the patient will develop ketoacidosis. Thus, in the context of this claim, the administration step is significantly related to the recited correlation between high blood glucose levels and the risk of ketoacidosis. Because insulin is also a "particular" treatment, this administration step integrates the law of nature into a practical application. Alternatively, consider a claim that recites the same law of nature and also recites "treating a patient having a blood glucose level over 250 mg/dl with aspirin." Aspirin is not known in the art as a treatment for ketoacidosis or diabetes, although some patients with diabetes may be on aspirin therapy for other medical reasons (e.g., to control pain or inflammation, or to prevent blood clots). In the context of this claim and the recited correlation between high blood glucose levels and the risk of ketoacidosis, administration of aspirin has at best a nominal connection to the law of nature, because aspirin does not treat or prevent ketoacidosis. This step therefore does not apply or use the exception in any meaningful way. Thus, this step of administering aspirin does not integrate the law of nature into a practical application.
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. The broadly recited steps of obtaining nucleic acids and detecting or measuring gene expression in the obtained nucleic acids were 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.
Also regarding the use of a trained algorithm to classify a subject as undergoing or at risk of undergoing acute rejection or not undergoing or not at risk of undergoing acute rejection, MPEP 2106.05(a) states that ”Limitations that the courts have found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include: i. Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, e.g., a limitation indicating that a particular function such as creating and maintaining electronic records is performed by a computer, as discussed in Alice Corp., 134 S. Ct. at 2360, 110 USPQ2d at 1984 (see MPEP § 2106.05(f))”
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.Response to arguments:
Applicant argues:
“The claims encompass an unacknowledged treatment option, initiating an immunosuppressive therapy to a subject who was not actively receiving immunosuppressive therapy, but the Office's observation does not detract from the fact that an active method step is required following the determination and classification steps. The adjustment or initiation step integrates the expression level of one or more genes and the subject classification into the practical application of how to treat a subject that has received a liver transplant with an immunosuppressive therapy. The specification makes clear that the "adjusting or initiation of the immunosuppressive therapy comprises increasing dose or frequency of the immunosuppressive therapy in the subject undergoing or at risk of undergoing AR" and "the adjusting of the immunosuppressive therapy comprises decreasing dose or frequency of the immunosuppressive therapy in the subject not undergoing or not at risk of undergoing AR." Application, para. [0007]. These are active steps that directly follow from the gene expression levels detected in the subject and thus are more than a natural phenomenon that exists apart from any human action.”
Applicant further argues that claim 18 recites treating the subject with an immunosuppressive therapy and thereby recites more than “an apply it” limitation.
These arguments have been fully considered but are not persuasive. As set forth in the rejection, adjusting or initiating therapy does not require an active process step of administering a new therapy or administering a different dosage of a therapy. The adjusting and initiating steps are akin to “prescribing” a modification of the patient’s therapy, which as set forth in MPEP 2106.04(d)(2), does not integrate a judicial exception into a practical application the judicial exception. The cited portion of the specification does not define adjusting or initiating as requiring an active process step. The cited portions of the specification teaches that “in some embodiments, the adjusting or initiation of the immunosuppressive therapy comprises increasing dose or frequency of the immunosuppressive therapy in the subject undergoing or at risk of undergoing AR” and “in some embodiments, the adjusting of the immunosuppressive therapy comprises decreasing dose or frequency of the immunosuppressive therapy in the subject not undergoing or not at risk of undergoing AR. This does not constitute a limiting definition for adjusting or initiating immunosuppressive therapy and does not indicate that adjusting or initiating requires an active step of administering the therapy. Similarly, the specification does not provide a limiting definition for “treating” which requires that treating constitutes an active step of administering. Again, as broadly recited, these steps may be performed mentally or verbally, such as by deciding to increase or decrease the immunosuppressive therapy or prescribing an increase or decrease in the immunosuppressive therapy. Thereby, these steps do not constitute a practical application of the judicial exception. While Applicant points to the specification as teaching that “treatment can include "administration of steroid boluses and the addition of other drugs to the maintenance therapy, or the administration of anti- lymphocyte antibodies," only claims 10 and 37 recite an “administering” step. If Applicant intends for the claims to require an active step of administering the immunosuppressive therapy at an increased (or decreased) dosage or to administer an immunosuppressive therapy for the first time, then the claims should be amended to recite such a limitation.
The response argues that “the treatment steps are not generic but rather are specifically tailored to liver transplant management. It is argued “The Office has offered no reason as to why the treatment step should be read out of the claims for the purposes of Step 2A prong two, other than to imply that treating a subject with an immunosuppressive therapy is not a requirement of the claim.
Applicant’s second statement does not correctly characterize the rejection. The rejection explains that the broadly recited adjusting, initiating and treatment steps encompass an abstract idea and thereby do not practically apply the recited judicial exceptions. The rejection goes on to explain to the extent that Applicant intends to recite an administering step, the broadly recited adjusting, initiating and treatment steps are not a specific treatment. Further, it is maintained that the majority of the claims do not recite a specific treatment. For example, claim 1 recites “adjusting or initiating the immunosuppressive therapy in the subject based on the classification of the subject in step (b).” Claim 18 recites “treating the subject prognosed or diagnosed with liver transplant rejection with immunosuppressive therapy.” The subject may have acute rejection, acute dysfunction with no rejection or a normal well-functioning liver transplant, and subjects diagnosed or prognosed as having any of these conditions are then treated / administered an immunosuppressive agent. As such, the claims encompass treating subjects in the same manner based on any classification or any diagnosis or prognosis of the subject.
The response argues “under Vanda Pharmaceuticals, a nonroutine or unconventional step is not required. The active administration step serves as an integration and practical application of all the preceding steps in the claims, which the Office alleges are judicial exceptions, which is all that is required for subject-matter eligibility of a method of treatment under §101.”
This argument has also been fully considered but is not persuasive. As discussed above, the majority of the claims do not recite an active administration step. While claim 10 recites an administering step, the claim includes administering the recited therapies to the subjects irregardless of whether the subjects have acute rejection, acute dysfunction with no rejection or a normal well-functioning liver transplant since the claim does not specify a classification of the subject. This does not constitute a practical application of the judicial exception. Claim 37 recites “wherein the subject has received a drug before performing the method, and the change in treatment comprises administering a higher dose of the drug, administering a lower dose of the drug, stopping administration of the drug, administering an alternative drug, or administering an additional drug.” Thus, any immunosuppressive drug which is the same drug is administered to the patient at either a higher or lower dosage, or a different or an additional drug is administered to the subject when the subject has any diagnosis or prognosis. Further, in claim 18, for subjects not diagnosed with liver transplant rejection, no treating step occurs. See particularly claim 26 which clarifies that the method includes diagnosing / prognosing the subject as having acute dysfunction no rejection (ADNR), or a well-functioning normal transplant (TX). In these instances, at step (d), the subjects would not treated.
Further, the fact pattern herein is distinct from that in the Vanda decision. The claims in the Vanda decision required administering 12mg/day or less of iloperidone to subjects having a CYP2D6 poor metabolizer genotype and administering more than 12mg/day, up to 24mg/day, of iloperidone to subjects that do not have a CYP2D6 poor metabolizer genotype. Thereby, the two groups of patients were clearly treated in different manners based on the determined CYP2D6 genotype. In contrast, in the present claims, the initiating, or adjusting or treating steps (or administering step in claims 10 and 37) are performed on subjects having any classification (in claim 1) or any diagnosis or prognosis (in claim 18) and each of the claims does not require administering a specific treatment.
New Claim Rejections - 35 USC § 112(d)
7. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 18, 22, 26,35-37, 40 and 41 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 18, 22, 26,35-37, 40 and 41 recite “analyzing the nucleic acid to measure expression level of one or more genes listed in claim 1.” Claims 18, 22, 26,35-37, 40 and 41 do not include all of the limitations of claim 1 from which they depend because claim 1 is drawn to a method of adjusting or initiating immunosuppressive therapy and is not drawn to a list of genes. Claims 18, 22, 26,35-37, 40 and 41 do not require each of the process steps of claim 1 and thereby do not properly depend from claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Maintained Claim Rejections - 35 USC § 112(a) - Enablement
8. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6-11, 13, 16, 18, 22, 26, 35-37, 40 and 41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
This rejection was previously presented in the Office action of 28 August 2025 and is maintained for the reasons set forth therein.
Response to arguments:
The response argues “(t)he working examples provide gene expression data from a 36-gene probe set, including the claimed genes, that successfully distinguished AR and TX with high predictive accuracy (AUC 0.92 in discovery cohort, further validated in an independent CTOT-14 cohort).”
This argument is not persuasive because it is not directed to limitations recited in the claims. The elected species is limited to the combination of the DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 genes. With respect to the non-elected species, the claims recite “one or more genes” selected from the listed genes. The claims do not require the 36 gene set which was shown to have an expression pattern that could be used to distinguish AR from TX.
The response argues:
“The Application teaches that expression levels of at least 2, 3, 4, 5, 10, 15, 20, 25, 30, or 35 (e.g., 10-30) genes shown in Table 3 are determined, and expression levels of the top 5, top 10, top 15, top 20, top 25, top 30, or top 35, genes listed in Table 3 are determined. Application, para. [0057]. Thus, in view of the methodology presented in the working examples and explicit contemplation of gene panels comprising fewer than 36 genes, Applicant submits that undue experimentation is not required to practice the full scope of the instant claims.”
However, providing literal basis for the concept of assaying for a subset of genes, including the elected 9 genes, or any one single gene, does not establish that the claimed method can be performed without undue experimentation. It is not a question of whether methods are known in the prior art for assaying for gene expression levels. There must be a showing that it is predictable that a subject who has received a liver transplant can be classified as undergoing or at risk of undergoing acute rejection (AR) or not undergoing AR or at risk of undergoing AR (claim 1) or the subject can be diagnosed or given any prognosis (claim 18) based on the expression level of all or any one of the 9 genes (or any single gene from the recited list of genes). However, the teachings and guidance provided in the specification do not establish that such broadly claimed methods can be predictably performed without undue experimentation. As discussed in the rejection, Table 3 lists 36 Affymetrix probe sets and provides the log fold gene expression changes for “AR/TX” and “AR/ADNR.” However, for several of the “AR/ADNR” changes, the change in gene expression levels are not significant to distinguish between AR and ADNR. For example, the log fold change for LAG3 is 0.149092445 and for GSN, it is -0.112941939. With respect to claim 18, only by combining TX and ADNR data into a non-AR category was it possible to use the 36 gene probe set to prognose or diagnose the liver transplant patients as having AR versus TX (e.g., para [0105]). There is no information in the specification regarding using one or all of the elected genes of DLEU2, LAG3, CHI3L2, GSN, GMNN, CLEC4E, ATAD2, MEST and RRM2 to diagnose a subject undergoing or at risk of undergoing AR or as not undergoing or not at risk of undergoing AR or as having any diagnosis or prognosis, following a liver transplant.
It is again pointed out regarding the non-elected species, that while claim 1 has been amended to recite 26 genes, the results provided in the specification were obtained using the 36 “genes” in Table 3. However, 10 of the genes are listed in Table 3 as “unidentified.” The nucleotide sequences for the probes in the probe set and the specificity of the probe set for a particular target nucleic acid are not provided in the present disclosure. Thus, the specification 3 does not adequately each of the genes that are detected by the probesets and thereby does not adequately describe 10 of the 36 genes that are disclosed in the present specification as having a gene expression profile that, in combination, distinguishes between liver transplant recipients undergoing or at risk of undergoing AR and liver transplant recipients not undergoing or not at risk of undergoing AR (e.g., subjects having either ADNR or TX).
The response states “for the purposes of advancing prosecution, the claimed "samples" are amended to "blood samples," to address the Office's comments regarding the use of blood samples in the working examples.”
However, while claim 18 has been amended to recite “obtaining a blood sample,” claims 1, 6-11, 13 and 16 recite “determining an expression level of one or more genes using nucleic acid obtained from the subject.” Thus, these claims are not limited to methods in which the nucleic acids are obtained from a blood sample.
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Salomon et al (U.S. US 20170183735; cited in the IDS and cited in the Office action of 08/28/2025) discloses methods of detecting, prognosing or diagnosing a liver transplant rejection or injury or lack thereof in a subject who has undergone a liver transplant, comprising: (a) obtaining nucleic acids extracted from a sample from a subject, including a blood sample; (b) detecting expression levels in the sample of at least 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 also teaches treating patients determined to have AR or at risk of AR by initiating immunosuppressive therapy or increasing an existing immunosuppressive regimen (para [0048] and [0092]).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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