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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 23 October 2025 has been entered.
3. Applicant's arguments and amendments to the claims presented in the reply of 23 October 2025 have been fully considered but do not place the application in condition for allowance. All rejections not reiterated herein are hereby withdrawn.
Claim Status
4. Claims 1-11, 13-15, 17-19 and 21 are pending and have been examined herein.
Note that in the reply of 28 February 2025, Applicant elected the combination of each of the 26 genes of STMN1, MEST, TYMS, SETX, PPP1R12B, RRM2, KIAA1324, GATA2, LYST, PRUNE2, LOC440434, C18orf49, DNAJC3, GRAMD1B, MGC21881, PIK3R5, PPTC7, KLHL34, TIMM10, NTSE, NOG, SLC6A6, UBE2J1, CDKN2A, JMJDIC, and MX1.
5. In the reply of 23 October 2025, Applicant requested that the examiner contact the attorney of record to set up a telephonic interview after reviewing their response and prior to issuing an Office action.
In a telephone call with Brandon Chan on 15 December 2025, it was agreed that an interview would not be held at this time and an Office action would be forthcoming. For future interview requests, the examiner encouraged Applicant’s representative to contact the examiner by telephone or to use the USPTO Automated Interview Request (AIR) form to arrange an interview at a mutually convenient time. See MPEP § 713 for further information regarding interviews.
Claim Objections
6. Claims 1-11, 13-15, 17-19 and 21 are objected to because of the following informalities:
Claims 1-11, 13-15, 17-19 and 21 are objected to because an “and” should be inserted prior to the last step of “(f) treating the liver transplant subject having AR, ADNR or TX” so that the claims are close-ended.
Claim 21 recites “wherein step (d) of analyzing the cDNA synthesized in step (c) comprising performing” whereas the claim should recite “wherein step (d) of analyzing the cDNA synthesized in step (c) comprises performing
Appropriate correction is required.
Maintained Objection to the Specification - New Matter
7. The amendment filed 18 June 2025 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: the 4 pages of text that is to be added to the specification after paragraph [0102].
In the response of 23 October 2025, the response states that support for the amendment to add the 4 pages of text to the specification is found in priority application PCT/US2014/054735, incorporated by reference in the originally filed specification and particularly support is found at para [0251] of the application which published as W02015035367.
However, the W02015035367 document generally discloses performing gene expression profiling by extracting RNA from Paxgene tubes using the Paxgene Blood RNA system (PreAnalytix) and GlobinClear (Ambion), preparing biotinylated cRNA with Ambion MessageAmp Biotin H kit (Ambion), and hybridizing the biotinylated RNA to Affymetrix Human Genome U133 Plus 2.0 GeneChips. PCT/US2014/054735 (W02015035367) does not provide the details of how these steps are performed and does not support for each of the limitations recited in the 4 pages of text that are to be inserted into the present specification.
For example, PCT/US2014/054735 does not teach each of the steps for RNA extraction and isolation, reverse transcription and first strand synthesis and second strand synthesis set forth in the text added to the specification, including the recitations of “Test Set 2,” centrifugation at 3000-5000 x g using a swing-out rotor, and does not cite U.S. Patent Nos. 6,602,718 and 6,617,170 as disclosing a stabilization solution. These are merely examples of the embodiments in the amendment to the specification amendment filed 18 June 2025 for which there is no support in PCT/US2014/054735.
Applicant is required to cancel the new matter in the reply to this Office Action.
If Applicant maintains that PCT/US2014/054735 provides basis for the amendment to the specification, Applicant should point to specific teachings (e.g., by paragraph number) in that application to establish basis for each of the recitations set forth in the amendment.
Maintained - Improper Markush Grouping Rejection
8. Claims 1-11, 13-15 and 17-19 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 combinations of 5 or more of the genes comprising STMN1, MEST, TYMS, SETX, TYMS, PPP1R12B, RRM2, KIAA1324, GATA2, LYST, PRUNE2, LOC440434, C18orf49, DNAJC3, GRAMD1B, MGC21881, PIK3R5, PPTC7, KLHL34, TIMM10, NTSE, NOG, SLC6A6, UBE2J1, CDKN2A, JMJDIC, or MX1 genes 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), acute dysfunction no rejection (ADNR) or a well-functioning normal transplant (TX) of a liver transplant recipient. Accordingly, while the different genes are asserted to have the property of having an expression level correlated with AR, ADNR or TX, 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 being indicative of response to a liver transplant, and particularly one of the responses of AR, ADNR or TX .
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 STMN1, MEST, TYMS, SETX, TYMS, PPP1R12B, RRM2, KIAA1324, GATA2, LYST, PRUNE2, LOC440434, C18orf49, DNAJC3, GRAMD1B, MGC21881, PIK3R5, PPTC7, KLHL34, TIMM10, NTSE, NOG, SLC6A6, UBE2J1, CDKN2A, JMJDIC, and MX1 genes.Response to Remarks:
The response states:
“Claim 1 now recites that the gene expression levels are detected as to "at least five genes" and "the five genes" are from the enumerated genes as indicated with the recitation "the five gene genes are five genes from the group consisting of STMN1 . . . and MX1". Applicants respectfully assert that claim 1 and the claims dependent thereon do not recite an improper Markush group, and that the prosecution to date evidences that the claim 1 and the claims dependent thereon do not recite an improper Markush group.”
These arguments have been fully considered but are not persuasive. The claims still encompass improper Markush groupings of sets of 5 or 6 or 7 or more of the 26 genes listed in claim 1. As set forth in the rejection, the genes do not share a single structural similarity essential to the asserted common activity of being correlated with AR, ADNR or TX. Alternatively, 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 being indicative of an AR, ADNR or TX response to a liver transplant.
The rejection is maintained for the reasons set forth above.
Maintained Claim Rejections - 35 USC § 101
9. 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 1-11, 13-15, 17-19 and 21 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 26 listed genes and the occurrence of AR, ADNR or TX in a liver transplant recipient. 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.”
The claims require performing the step of “determining” whether the liver transplant recipient has AR, ADNR or TX based on the detected expression levels or based on a comparison to a reference expression level (claims 4-10). The broadest reasonable interpretation of this step is that it may be accomplished by critical thinking processes. Such determining thereby encompasses an abstract idea.
Similarly, regarding claims 5-8, the assigning a value or other designation and combining values or designations can be accomplished through critical thinking processes and are an abstract idea.
Further, the claims recite using a trained algorithm as part of the step of determining whether the subject has AR, ADNR or TX. However, the use of a generic computer or software program to implement the abstract step of “determining” 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.”
Herein, the use of a generic computer to evaluate the expression levels or apply a generic algorithm to assign values or designations does not constitute something more than an abstract idea.
The claims as amended also recite a step (f) of treating the liver transplant patient having AR, ADNR or TX. Step (f) as broadly recited includes prescribing the above treatments to the patients - e.g., prescribing that the subject is treated with an increased dosage of an immunosuppressant agent or prescribing that the subject receives additional immunosuppressant drugs. Note that claims 1-11, 13-15, 17-18 and 21 do not actually require administering the treatments to the patients other than in (ii) of administering a steroid “when the liver transplant subject has ADNR.” Since the claims include methods wherein the subject has AR or TX or the results are uninformative (claim 7), there is no requirement that the claims include the step of administering a steroid to the subject. The broadly recited treating by prescribing step may be accomplished verbally. Such verbal communication is an abstract process, 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 of interest by extracting mRNA from a sample or obtaining nucleic acids derived from mRNA from a sample, and detecting the expression levels of genes using the nucleic acids of interest are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Claim 1 as amended now recites: “(f) treating the liver transplant subject having AR, ADNR, or TX, wherein,(i) when the liver transplant subject has AR, the step of treating comprises increasing dosage of the immunosuppressant drug of the immunosuppressant treatment regimen or increasing a number of immunosuppressant drugs administered to the liver transplant subject in the immunosuppressant treatment regimen; and(ii) when the liver transplant subject has ADNR, the step of treating comprises decreasing dosage of the immunosuppressant drug of the immunosuppressant treatment regimen or decreasing a number of immunosuppressant drugs administered to the liver transplant subject in the immunosuppressant treatment regimen and/or administering a steroid to the liver transplant subject; or (iii) when the liver transplant subject has TX, the step of treating comprises decreasing dosage of the immunosuppressant drug of the immunosuppressant treatment regimen or decreasing a number of immunosuppressant drugs administered to the liver transplant subject in the immunosuppressant treatment regimen.”
As discussed above, step (f) as broadly recited includes prescribing the treatments to the subjects. The claims do not actually require administering the treatments in (i) or (iii) or the immunosuppressive drugs in (ii) to the patients. Such prescribing is itself the judicial exception of an abstract idea and is 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.
Additionally, the claims do not require that step (f) is performed after step (e). Rather, the claims broadly recite “treating the liver transplant subject having AR, ADNR, or TX.” In view of the open claim language of comprising, step (f) may be performed at any point in the claim, including prior to step (a). In these instances, the treating step is part of the data gathering process and not a practical application of the recited judicial exception.
Lastly, the treating step is considered to be conditional and need not occur since the claims recite at (d) “determining whether the liver transplant subject has: AR, according to expression levels that have been associated with AR;ADNR, according to expression levels that have been associated with ADNR; or the well-functioning normal transplant (TX), according to expression levels that have been associated with TX.” The “whether” language leaves open the possibility that the subject is not determined to have AR, ADNR or TX. This is consistent with the limitation in claim 7 of “providing an indication… that the expression level is uninformative.”
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 of interest and detecting gene expression in the nucleic acids of interest were well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification. For example, para [0030] indicates that methods of PCR and sequencing (to detect gene expression) were well known in the prior art. At para [0017], 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 [0060-0064].
Further, the specification teaches that “Methods of isolation and amplification of mRNA are well known in the art” (para [0060]). Regarding claim 2, the particularly recited method of isolating RNA was also well known in the prior art. See, for example, Augello et al (U.S. Patent No. 6,617,170; e.g., col. 10, line 45 to col. 11, line 4 and col. 13, lines 7-29) and Augello et al (U.S. Patent No. 6,602,718; e.g., col. 8, lines 18-44; and col. 10, line 43 to col. 11, line 4); and Krawiec et al (Laboratory Animals. 2009. 43: 394-398; e.g., p. 395, col. 1).
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 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 having AR, ADNR or TX, and regarding the assigning step in claims 5-8, 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)).” Herein, the claims do not require the use of any particular algorithm to classify the subject as having AR, ADNR or TX.
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 Remarks:
The response states:
“claim 1 recites a step (f) of treatment following a diagnosis or classification of the liver of the liver transplant subject into each of the possible AR, ADNR, or TX categories or outcomes from performing steps (a) through (e) of the claimed method.
Accordingly, the invention as claimed in claim 1 and the claims dependent thereon integrate the judicial exception into a practical application and/or include such additional elements that transform the judicial exception into a patent-eligible concept. The Office Action does not make a prima facie case that that Applicants did not have patent eligible subject matter that amounts to more than the judicial exception in the invention as claimed in claim 1 and the claims dependent thereon. Applicants respectfully assert that the claims herewith integrate the judicial exception into a practical application and/or include such additional elements that transform the judicial exception into a patent-eligible concept, and that the prosecution to date evinces that the claims integrate the judicial exception into a practical application and/or include such additional elements that transform the judicial exception into a patent-eligible concept.
These arguments and the amendments to the claims have been fully considered but are not persuasive. Claim 1 does not in fact recite “treatment following a diagnosis or classification of the liver of the liver transplant subject into each of the possible AR, ADNR, or TX categories or outcomes from performing steps (a) through (e) of the claimed method.” Rather, claim 1 more broadly recites “f) treating the liver transplant subject having AR, ADNR, or TX.” In view of the open claim language of “comprising” and because the claims do not require that step (f) occurs after steps (a)-(e), the claims include methods wherein the treating occurs at any point in the method including prior to step (a). In such instances, the treating step is part of the data gathering process and is not a practical application of the judicial exception. Further, for the reasons discussed in the above rejection, the broadly recited “treating” encompasses prescribing the treatment to be administered to the patient. With the exception of claim 19 and step (f)(ii) of administering a steroid if the subject has ADNR, the claims do not actually require administering the treatments to the subjects. Such prescribing (of the changes in the treatment regimens) is the judicial exception of an abstract process and is not a practical application of the judicial exception.
Lastly, the claims do not appear to actually require that the subject is determined to have one of AR, ADNR or TX. The claims recite at (d) “determining whether the liver transplant subject has: AR, according to expression levels that have been associated with AR;ADNR, according to expression levels that have been associated with ADNR; or the well-functioning normal transplant (TX), according to expression levels that have been associated with TX.” The “whether” language leaves open the possibility that the subject is not determined to have AR, ADNR or TX. This is consistent with the limitation in claim 7 of “providing an indication… that the expression level is uninformative.” Also the claims do not clarify what constitutes “expression levels that have been associated” AR, ADNR or TX and thereby it is unclear as to what the determining is based on.
This rejection may be obviated by amendment of claim 1 to recite:
“(e) applying a trained algorithm to the mRNA expression levels of the STMN1, MEST, TYMS, SETX, PPP1R12B, RRM2, KIAA1324, GATA2, LYST, PRUNE2, LOC440434, C18orf49, DNAJC3, GRAMD1B, MGC21881, PIK3R5, PPTC7, KLHL34, TIMIM10, NT5E, NOG, SLC6A6, UBE2J1, CDKN2A, JMJD1C, and MX1 genes detected in (d) to determine that the subject has AR, ADNR or TX; and (f) administering a treatment to the liver transplant subject determined in (e) to have AR, ADNR or TX, wherein the administering comprises: (i) administering to a subject determined to have AR an increased dosage of an immunosuppressant drug in the immunosuppressant regimen or an increased number of immunosuppressant drugs in the immunosuppressant treatment regimen; (ii) administering to a subject determined to have ADNR a decreased dosage of an immunosuppressant drug in the immunosuppressant treatment regimen or a decreased number of immunosuppressant drugs in the immunosuppressant treatment regimen and/or a steroid; and (iii) administering to a subject determined to have TX a decreased dosage of an immunosuppressant drug in the immunosuppressant treatment regimen or a decreased number of immunosuppressant drugs in the immunosuppressant treatment regimen.”
If the above amendment is made to claim 1, the dependent claims (e.g., claims 7 and 13-19) should be amended to ensure that they are consistent with the amendment to claim 1.
New Claim Rejections - 35 USC § 112(b) - Indefiniteness
10. 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.
Claims 1-11, 13-15 and 17-19 are 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.
Claims 1-11, 13-15, 17-19 and 21 are indefinite. The claims recite “(e) applying a trained algorithm of the gene expression levels determined in (d) and based on the expression levels determined in step (d), determining whether the liver transplant subject has: AR, according to expression levels that have been associated with AR; ADNR, according to expression levels that have been associated with ADNR; or the well-functioning normal transplant (TX), according to expression levels that have been associated with TX.” However, the claims do not recite what constitutes “expression levels that have been associated with” AR, ADNR and TX. The claims do not recite a step of associating expression levels with AR, ADNR and TX and do not set forth what genes or what expression levels of genes are associated with AR, ADNR or TX.
Claims 4-10 are indefinite over the recitation of a gene associated with AR, a gene associated with ADNR and a gene associated with TX. Neither the specification nor the claims clearly define what constitutes a gene associated with AR, ADNR or TX. It is unclear as to which of the 26 genes or any other gene has the attribute that it is associated with AR, ADNR or TX per se. This rejection may be obviated by amendment of claim 4 to recite “for each of the genes…in determining whether the liver transplant subject has AR, comparing the expression level of the gene in the liver transplant subject to a reference expression level of the gene in subjects having AR…”.
Claim 7 is indefinite. The claim is drawn to a “method of determining whether a liver transplant subject on an immunosuppressant treatment regimen has acute rejection (AR), acute dysfunction no rejection (ADNR), or a well-functioning normal transplant (TX).” However, claim 7 recites “wherein the expression level of each of the at least five genes is assigned a value or other designation providing an indication that the liver transplant subject has or is at risk of AR or ADNR, has the well-functioning normal transplant, or that the expression level is uninformative.” Thus, the claim includes methods wherein it is determined that the expression levels are uninformative. It is unclear as to how the subject is determined to have AR, ADNR or TX, as required by the preamble of the claim, when the expression levels are uninformative.
Maintained / Modified Claim Rejections - 35 USC § 112 - Enablement
11. 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 1-11, 13-15, 17-19 and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the claimed methods which encompass assaying the nucleic acids of interest to detect the expression levels of a set of genes comprising STMN1, MEST, TYMS, SETX, TYMS, PPP1R12B, RRM2, KIAA1324, GATA2, LYST, PRUNE2, LOC440434, C18orf49, DNAJC3, GRAMD1B, MGC21881, PIK3R5, PPTC7, KLHL34, TIMM10, NT5E, NOG, SLC6A6, UBE2J1, CDKN2A, JMJD1C, and MX1; and applying a trained algorithm of the gene expression levels of each of the genes in the set of genes and based on the expression levels of each of the genes in the set of genes in the blood sample, determining whether the liver transplant subject has AR, ADNR or TX,
does not reasonably provide enablement for methods in which the subject is determined to have AR, ADNR or TX based on the expression level of only 5 of the genes in the set of 26 genes. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
The claims are drawn to methods that determine whether a liver transplant subject on an immunosuppressant treatment regimen has acute rejection (AR), acute dysfunction no rejection (ADNR), or a well-functioning normal transplant (TX) based on the expression level of five genes in a blood sample from the subject, wherein the 5 genes are selected from: STMN1, MEST, TYMS, SETX, TYMS, PPP1R12B, RRM2, KIAA1324, GATA2, LYST, PRUNE2, LOC440434, C18orf49, DNAJC3, GRAMD1B, MGC21881, PIK3R5, PPTC7, KLHL34, TIMM10, NT5E, NOG, SLC6A6, UBE2J1, CDKN2A, JMJD1C, and MX1.
The present disclosure has not established that a liver transplant recipient can be determined to have one of AR, ADNR or TX based on the expression level of only 5 of the genes in the gene set of 26 genes.
Rather, in Example 1, the specification teaches the analysis of mRNA levels in blood samples of human subjects who have undergone a liver transplant to identify genes that are differentially expressed among subjects having AR versus ADNR versus TX (see Table 4), or between subjects having AR versus HCV versus HCV+AR (see Table 5). The specification also teaches the analysis of liver biopsy samples for differential gene expression to identify genes that classify a subject as having AR versus HCV versus HCV +AR (Table 6).
The specification (Table 4) teaches that the 26 genes in the claims were part of a 263 gene set of genes that were differentially expressed in liver transplant recipients having AR versus ADNR versus TX. That is, the specification states “We also have a signature from whole blood that can distinguish AR, ADNR and TX samples with AUC's ranging from 0.87-0.92” and this gene signature includes the STMN1, MEST, TYMS, SETX, PPP1R12B, RRM2, KIAA1324, GATA2, LYST, PRUNE2, LOC440434, C18orf49, DNAJC3, GRAMD1B, MGC21881, PIK3R5, PPTC7, KLHL34, TIMM10, NT5E, NOG, SLC6A6, UBE2J1, CDKN2A, JMJD1C, and MX1 genes.
The specification does not, however, identify particular subsets of only 5 genes whose expression level in blood can be used to distinguish between AR, ADNR and TX. Many of the genes in Table 4 are expressed at similar levels in AR, ADNR and TX and there is no guidance provided in the specification as to a threshold of differential expression that is required to distinguish between AR, ADNR and TX. For instance, in Table 4, CDKN2A has a mean expression level of 13.7, 13. 9 and 11.5 in ADNR, AR and TX, respectively. Similarly, in Table 4, the expression level of PRUN2 does not appear to be significantly different in ADNR subjects (15.8) as compared to AR subjects (15.2). Note that the range of expression levels in different liver transplant recipients is not provided in the specification. It is unclear as to whether the reported differences in the level of expression of CDKN2A, together with other genes in the 26 gene set showing low levels of variability between AR, ADNR and TX could be used to provide a diagnosis of AR versus ADNR versus TX. Further, it is unpredictable as to whether the TYMS gene expression level can be used as part of a subset of only 5 genes to distinguish between ADNR and TX since at entry 58 of Table 4 one of the probe sets for TYMS includes a mean expression level is 11.1 for ADNR and 11.2 for TX, whereas a different probe set for TYMS at entry 63 of Table 4 includes a mean expression level of 50 for ADNR and a mean expression level of 44.4 for TX.
The specification does not provide any guidance as to particular subsets of genes in the recited set of 26 genes which can be used to determine if a liver transplant patient has AR, ADNR or TX. It is unpredictable as to which subsets of 5 genes can be used to distinguish between AR, ADNR and TX given that many of the genes are not expressed at substantially distinct levels in each of AR, ADNR and TX.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “(t)he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art.” The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Further, the Court in Genetech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “(I)t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement."
Additionally, as set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention.
Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed. Response to Remarks:
In the response, Applicant states:
“Claim 1 now recites that the gene expression levels are detected as to "at least five genes" and "the five genes" are from the enumerated genes as indicated with the recitation "the five gene genes are five genes from the group consisting of STMN1 . . . and MX1". Accordingly, no undue or unreasonable experimentation is needed to practice the invention as claimed in claim 1 and the claims dependent thereon. The Office Action does not make a prima facie case that undue or unreasonable experimentation is needed to practice the invention as claimed in claim 1 and the claims dependent thereon.”
These arguments and the amendments to the claims have been fully considered but are not persuasive. The response does not clearly explain why the amendment to the claims to recite “at least five genes” and “the five genes” obviates the rejection. It is maintained that the specification teaches that AR, ADNR and TX can be distinguished from one another by determining the gene expression level of each of the 263 genes recited in Table 4 of the specification, whereas claim 1 recites detecting only a subset of 5 of the 26 genes listed therein. While it would not require undue experimentation to assay for the gene expression level of 5 of the 26 genes in a blood sample from a subject who has received a liver transplant, the claims are not limited to such methods. Rather, the claims require that the results of the detection of the expression level of the 5 genes, or “at least 5 genes,” is used to determine if the subject has AR, ADNR or TX. For the reasons discussed in detail in the above rejection, the present disclosure does not enable methods wherein a liver transplant recipient is determined to have one of AR, ADNR or TX based on the expression level of only 5 of the genes in the gene set of 26 genes. The rejection explains that undue experimentation would be required to practice the broadly claimed method because there is no guidance provided in the specification as to which of the 5 genes could be used alone to distinguish each of AR, ADNR and TX from one another and the results of the experimentation required to try to identify a subset of 5 genes is unpredictable given that many of the genes are expressed at similar levels in subjects having AR, ADNR or TX. The response does not point to any teachings in the specification which establish that it has enabled methods of detecting and distinguishing between AR, ADNR and TX in subjects who have received a liver transplant and are receiving immunosuppressive therapy based on the expression level of a representative number of subsets of 5 of the 26 genes. It does not appear that the specification provides such information. Nor does the specification provide guidance to suggest that such subsets of 5 genes can be predictably identified without undue experimentation.
The rejection is maintained for the reasons of record.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682