DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
It is acknowledged that in the response filed June 18, 2026, Applicant elected BIN2 as the single mRNA transcript, without traverse. It is acknowledged that Applicant amended claims 1, 4, 6-11, 14, 18, and 19 and added new claims 20-22.
Upon further consideration, the requirement for species election between elected species directed to “all of the mRNA transcripts of Table A” and the following non-elected species is withdrawn: BIN2, TSPAN13, FKBP5, CD274, FCGR1B, DDX39B, TRAPPC5, BANP, RHOC, CALM3, and GADD45B.
In view of the above noted withdrawal of the election of species requirement, applicant isadvised that if any of the claim represented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claims may be subject to provisional statutory and/or non-statutory double patenting rejections over the claims of the instant application. Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP §804.01.
Claims 1, 4, 6-11, 14, and 18-22 are currently pending and have herein been examined to the extent that they read on the elected species. The additionally recited species have been withdrawn from consideration as being directed to non-elected subject matter.
Priority
It is acknowledged that the instant application is a continuation of international PCT Application No. PCT/US2022/038728, filed July 28, 2022 and that it claims benefit of provisional application 63/227,276, filed July 29, 2021. However, provisional application 63/227,276 did not have sufficient evidence of support for the claimed mRNA transcripts (there is no Table A and/or equivalent listing of associated gene targets), and therefore the effective filing date of the claims of the instant application is considered to be July 28, 2022.
Claim Objections
Claim 1 is objected to because of the following informalities: In claim 1, line 15, “one of more of” should read “one or more of.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim(s) 1, 4, 6-11, 14, and 18-22 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, 4, 6-11, 14, 18 and 19 are rejected for the recitation of “the at least one immunosuppressant drug,” “a further immunosuppressant drug,” and “a different immunosuppressive drug” in claim 1, as lacking antecedent basis. It is unclear whether the kidney transplant recipient is required to have been receiving immunosuppressive therapy, and what the recited immunosuppressive drug is meant to be. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 1, 4, 6-11, 14, 18, and 19 are rejected for the recitation of “a blood sample” in both line 12 and line 14 of claim 1. It is unclear whether the claim is requiring that the dd-cfDNA and mRNA levels be assessed from the exact same blood sample from a transplant recipient, or if they could be assessed from samples or aliquots obtained at different times. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 1, 4, 6-11, 14, and 18-22 are rejected for the recitation of having “a likelihood of rejection” in claims 1, 9, 20, and 22, as being indefinite. All transplant recipients have a likelihood of rejection, and thus it is unclear how the recited claim language is intended to limit the invention. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement. If what is meant is that transplant recipients are given a particular probability score for their probability of transplant rejection, the claim must be amended to reflect that meaning.
Claims 1, 4, 6-11, 14, and 18-22 are rejected for the recitation of “0.7%” in claims 1 and 20, as indefinite. For example, it is unclear whether 0.7% is intended to represent the proportion of cfDNA originating from a donor relative to the total cfDNA, or if it is intended to represent the proportion relative to some other value (e.g. comparing representation of genotypes at a particular locus). As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claim 6 is rejected for referring to specific figures and/or tables in the specification (“mRNA transcripts of Table A”). MPEP 2173.05(s) states that “Where possible claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into a claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.”
Claim 8 is rejected because the specification defines two states: (1) “non-rejection” or “TX”, and (2) “rejection” or “non-TX” in par. 23-24. In the specification, “non-rejection” is defined using serum creatinine levels which are <2.3 mg/dl and/or <20% increase compared to prior values (par. 23). “Rejection” is defined using serum creatinine levels which are greater than or equal to 2.3 mg/dl and/or an increase in creatinine of 20% or more compared to prior values (par. 24). Claim 7 corresponds to the “non-rejection” state, but claim 8 recites contradictory conditions to the “rejection” state: it requires “a serum creatinine level of 2.3 mg/dL or higher, or an increase of serum creatinine compared to baseline of no more than 10% or no more than 20%.” It is unclear whether the claim is intended to contradict the conditions described in the specification or whether the language of claim 8 is erroneous. Clarification is requested. For the purposes of compact prosecution, claim 8 will be interpreted to mean “a serum creatinine level of 2.3 mg/dL or higher, or an increase of serum creatinine compared to baseline of 20% or more.”
Regarding claim 14, the phrase “significantly different” is a relative term which renders the claim indefinite. “Significantly different” is not defined in the claim, but described in the specification as meaning “significantly different, such as through a T-test and an associated P value that indicates statistical significance” (par. 31). This definition is not clear and limiting: any p-value could be chosen to render any different significant or not. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claim 21 is rejected because it is unclear if the claim is describing a property of the method or requiring an active step of distinguishing between antibody-mediated rejection and acute cellular rejection. If the former, would any method equivalent to the claimed method (requiring analysis of both dd-cfDNA and specific mRNA levels) inherently be capable of distinguishing between antibody-mediated rejection and acute cellular rejection (as suggested by par. 86), or is the claim meant to limit the method to some other, more specific requirement? If the latter, it is not clear exactly how the dd-cfDNA and mRNA levels are intended to distinguish between acute cellular rejection and antibody-mediated rejection. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement. To accommodate the multiple possible interpretations of claim 21, it has been rejected under two combinations of references in the section for 35 U.S.C. 103 below.
Improper Markush Rejection
Claim 6 is rejected on the basis that it/they contain(s) 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 claims recite the following Markush groups:
claim 6: “the group of mRNA transcripts comprises 1-120… or all of the mRNA transcripts of Table A”
These Markush groupings 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:
MPEP 2117(II) 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)).
MPEP 2117(II) further state that alternatives (1) share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class and (2) share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent in the context of the claimed invention.
MPEP § 2117(II)(A) states that “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, the members of the Markush grouping are all mRNA transcripts of Table A. These do not belong to the same recognized physical or chemical class or to the same art-recognized class because there is no expectation from the art that each of the recited transcripts would function in the same way in the claimed method. It is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention.
MPEP § 2117(II)(B) states that “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 explained in subsection IIA above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structure feature that is essential to a common use. The members of the Markush grouping are all mRNA transcripts. While they are all made up of nucleic acid sequences, the shared structure of the comprised nucleic acids is not essential to any asserted common use.
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.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 4, 6-11, 14, and 18-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4, Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. The claims recite a correlation between the level of dd-cfDNA and the expression levels of mRNA transcripts in a blood sample of a kidney transplant recipient and the likelihood of kidney transplant rejection. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas. The claims recite steps of “determining” expression levels and likelihoods of rejection. Neither the specification nor the claims set forth how these steps are accomplished. The broadest reasonable interpretation of the “determining” steps are that they may be accomplished by a mental process. For example, one may “determine” expression levels or likelihood of rejection by looking at data and thinking about the expression level or likelihood of rejection. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exception(s) into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or a technological field;
An additional element that applies or used a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing;
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions, the claims recite “increasing the frequency or dosage” of a drug and/or ”administering” a drug. These steps are not particular, i.e., specifically identified so that they do not encompass all application of the judicial exceptions. These steps are merely instruction to apply the exception in generic ways. Thus, the administration steps do not integrate the judicial exceptions into a practical application.
In addition to the judicial exceptions, the claims recite various wherein clauses which provide limitations for the subject of the method (e.g. claim 1(i)-(ii), 7-9), analysis steps conducted prior to the method (e.g. 10, 11, 14, 18, 19), and properties of the method (e.g. claims 21, 22). These are merely instruction to apply the exception in generic ways. Thus, they do not integrate the judicial exception into a practical application.
Step 2B: Evaluate Whether the Claim Provides and Inventive Concept
In addition to the judicial exceptions, the claims recite “increasing the frequency or dosage” of a drug and/or ”administering” a drug as well as limitations of the subject, prior analysis, and properties of the method. These steps do not amount to significantly more because they simply append well-understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
These steps are recited a high level of generality. Increasing the frequency or dosage of a drug, administering a drug, and applying limitations of the subject, prior analysis, and properties of the method merely instruct a scientist to use any known technique for increasing the frequency or dosage of a drug, administering a drug, restricting the subject of a method, or optimizing a method. The claims do not require the use of any particular non-conventional reagents or equipment or methodology. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well-understood, routine, and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well-understood, routine, and conventional nature of additional elements because it teaches that the additional elements are well-known or commercially available. For example, the specification teaches the following:
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Further, it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, and 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.
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);
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);
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);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
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)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4, 6-11, 14, 18, and 20-22 are rejected under 35 U.S.C. 103 as unpatentable over Kurian et al. (published November 14, 2019; Canadian Patent Application CA3100002), Mitchell et al. (published August 17, 2018; International Publication No WO 2019/035995), and Woodward et al. (published May 26, 2016; Patent Application Publication No. US20160145682).
Regarding claims 1 and 20, Kurian teaches methods of determining that a kidney transplant recipient is indicated as having a likelihood of rejection (par. 11). Kurian teaches a method of treating rejection in a kidney transplant recipient who was indicated to have a likelihood of rejection, the method comprising: increasing the frequency or dosage of a treatment, administering a further treatment, or administering a different treatment (par. 133). Kurian teaches that treatment may include immunosuppressive drugs (par. 134).
Kurian’s method of assessing the likelihood of rejection comprises analysis of the expression levels of a group of at least 1-120 miRNA transcripts from Table 3 of the reference in a sample from the kidney transplant recipient (par. 73). Kurian teaches obtaining samples from blood (par. 9). Table 3, spanning pg. 64-70 of the reference, comprises the following:
Claimed mRNA transcript
Location in reference
BIN2
Table 3, #64
TSPAN13
Table 3, #59
FKBP5
Table 3, #82
CD274
Table 3, #92
FCGR1B
Table 3, #52
DDX39B
Table 3, #12
TRAPPC5
Table 3, #87
BANP
Table 3, #68 or 102
RHOC
Table 3, #16
CALM3
Table 3, #13
GADD45B
Table 3, #37
Therefore, it is considered that Kurian teaches the required combinations of mRNA transcripts recited in claim 1.
Regarding claim 1, Kurian does not explicitly teach assessing likelihood of rejection using a level of donor derived cell-free DNA (dd-cfDNA) in a blood sample from the kidney transplant recipient being at or above a pre-determined threshold value of> 0.7%.
Mitchell teaches using a level of donor derived cell-free DNA (dd-cfDNA) in a blood sample (pg. 9, 2nd par.; pg. 17, 2nd par.) from a transplant recipient being at or above a value of> 0.7% as indicating the likelihood of rejection (pg. 30, par. 1). Although this threshold value is an empirically optimized cutoff value, Mitchell teaches that (pre-)determination of a threshold value may include empirically derived values (pg. 12, par. 2). Therefore, the limitation is considered to have been met.
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Kurian and Mitchell. One would have been motivated to do so because the level of dd-cfDNA in a sample has exquisite sensitivity in rejection surveillance (pg. 30, par. 1) and because Woodward teaches that the combination of cfDNA and gene expression analysis may be more informative regarding transplant rejection/non-rejection than either analysis alone (par. 243). One would have had reasonable expectation of success because Kurian, Mitchell, and Woodward all explicitly consider detection of transplant rejection in systems including kidney transplants (Mitchell: pg. 13, last par. – pg. 14, 1st par.; Woodward: par. 9), and because Woodward demonstrates the successful use of a combination of gene expression and dd-cfDNA analyses for discrimination between rejection and non-rejection (par. 243, Fig. 6c)
Regarding claims 4 and 6, Kurian teaches the analysis of at least 1-120 mRNA transcripts (see pg. 3, par. 5 and Table 3). These transcripts include at least 11 of the mRNA transcripts of Table A, as discussed in the rejection of claim 1 above. 1-120 mRNA transcripts overlaps with the claimed ranges of 10-300/10-200 mRNA transcripts (instant claim 4) and the claimed ranges of 2-120/5-120/10-120/2-128/5-128/10-128/5-50/10-50 mRNA transcripts (instant claim 6) of Table A with sufficient specificity that the limitations are considered to have been met.
Regarding claim 7, Kurian teaches kidney transplant recipients having a serum creatinine level of < 2.3 mg/dL, or an increase of serum creatinine compared to baseline of no more than 10% or no more than 20% (par. 40-41).
Regarding claim 8, Kurian teaches kidney transplant recipients having a serum creatinine level of 2.3 mg/dL or higher, or an increase of serum creatinine compared to baseline of 20% or more (par. 55).
Regarding claim 9, Kurian teaches indicating kidney transplant recipients as having a likelihood of rejection within 1 month, 3 months, 1 year etc. of having undergone a transplant (pg. 9, par. 9). This overlaps the claimed ‘at least one month, at least two months, at least three months, at least six months, or at least one year after transplantation’ with sufficient specificity that the limitation is considered to have been met.
Regarding claims 10 and 18, Kurian teaches that the expression level of the group of mRNA transcripts was determined by reverse transcription PCR (RT-PCR), hybridization to an array, or next generation sequencing (pg. 9, par. 9 and 10).
Regarding claim 11, Kurian teaches that sequencing may comprise whole genome sequencing of DNA (pg. 29, par. 69). As discussed in the rejection of claim 1 above, Mitchell teaches quantification of the level of dd-cfDNA. Mitchell does so with a q-PCR-based assay (pg. 33, 2nd par.). However, it would be obvious to substitute the use of whole genome sequencing to quantify dd-cfDNA levels because the methods are used for the same purpose (i.e. they are both ways of determining the relative expression levels of DNA) and therefore may be considered functional equivalents. One would have had reasonable expectation of success because both Kurian and Mitchell are concerned with quantification of nucleic acids including DNA, and because whole genome sequencing is a well-known and routine method of DNA quantification.
Regarding claim 14, Kurian teaches normalizing the expression level of a group of mRNA transcripts against the level of at least one reference mRNA transcript in the blood sample, wherein the at least one reference mRNA transcript does not show significantly different expression levels in transplant rejection compared to non-transplant rejection subjects (par. 77, 79).
Regarding claim 21, Kurian does not explicitly teach that the method is capable of distinguishing likelihood of acute cellular rejection from antibody-mediated rejection, wherein the dd-cfDNA level indicates presence or absence of antibody-mediated rejection, and wherein the expression levels of the group of mRNA transcripts indicate presence or absence of acute cellular rejection. However, the recited capability may be interpreted as a natural outcome of the method, consistent with instant specification par. 86, which explains that the basis for this property is that “the gene expression profile from analysis of mRNA transcripts preferentially detects acute cellular rejection while the dd-cfDNA assay preferentially detects antibody mediated rejection.” Because the combination of Kurian and Mitchell teaches the claimed method, it is considered that this property flows naturally from the combination, and therefore that the limitation has been met.
Regarding claim 22, Kurian teaches methods having a positive predictive value (PPV) for indicating the kidney transplant recipient as having a likelihood of rejection of at least 80-95% (par. 5).
Claim 19 is rejected under 35 U.S.C. 103 as unpatentable over Kurian et al. (published November 14, 2019; Canadian Patent Application CA3100002), Mitchell et al. (published August 17, 2018; International Publication No WO 2019/035995), and Woodward et al. (published May 26, 2016; Patent Application Publication No. US20160145682), as applied to claim 1 above, and further in view of Cohen et al. (published May 2, 2019; Patent Application Publication No. US 20190131016).
Kurian, Mitchell, and Woodward teach the limitations of claim 1, as discussed above.
Regarding claim 19, Kurian teaches the use of wide variety of algorithms to analyze sample data, including neural networks and random forest models (par. 87, par. 90-94). Mitchell teaches the use of threshold values of dd-cfDNA data, as discussed in the rejection of claim 1 above.
Regarding claim 19, Kurian and Mitchell do not explicitly teach determining the pre-determined threshold value of dd-cfDNA is accomplished by multivariate regression algorithm that comprises dd-cfDNA and expression levels of the group of mRNA transcripts in a set of transplant recipients who received a kidney transplant.
Cohen teaches determining threshold values for assessing likelihood of malignancy wherein the data used to determine said likelihood is derived from subjects having particular risk factors (par. 19, 78). Cohen teaches that this may be accomplished through multivariate regression, neural network, random forest, decision tree, or other well-known methods for modeling multiple variables (par. 78).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to use the multivariate regression model in place of the models recited in Kurian because the methods are used for the same purpose (i.e. the analysis of sample data to determine outcome probabilities and probability thresholds) and therefore the methods may be considered functional equivalents. One would have had reasonable expectation of success because Cohen demonstrates the use of multivariate regression in analyzing biomarker data (par. 78, 371; Table 3), Mitchell explains that selection of threshold values is a matter of routine experimentation (Mitchell: pg. 11-12), and because the use of thresholds or cutoffs for predicting risk or distinguishing between disease states is well-known (Cohen: par. 114-117; Mitchell pg. 14, 2nd par.).
Claim 21 is rejected under 35 U.S.C. 103 as unpatentable over Kurian et al. (published November 14, 2019; Canadian Patent Application CA3100002), Mitchell et al. (published August 17, 2018; International Publication No WO 2019/035995), and Woodward et al. (published May 26, 2016; Patent Application Publication No. US20160145682), as applied to claim 20 above, and further in view of Garg et al. (published Oct. 2017; Garg et al. Transplant Rev (Orlando). 2017 Oct;31(4):257-267; provided as NPL #1 in IDS dated 1/26/24).
Kurian, Mitchell, and Woodward teach the limitations of claim 20, as discussed above.
Regarding claim 21, Kurian does not explicitly teach that the method is capable of distinguishing likelihood of acute cellular rejection from antibody-mediated rejection, wherein the dd-cfDNA level indicates presence or absence of antibody-mediated rejection, and wherein the expression levels of the group of mRNA transcripts indicate presence or absence of acute cellular rejection. If the recited property is inherent to the claimed method, it would flow naturally from the combination of Kurian, Mitchell, and Woodward, as discussed above in the rejection of claim 21 above. The rejection of claim 21 set forth below addresses the limitation if it is intended to require an active step of discrimination between the two types of rejection.
Garg teaches discriminating between antibody-mediated rejection (ABMR) and acute cellular rejection (ACR) using dd-cfDNA from the blood of kidney transplant recipients (pg. 265, col. 1, last par.).
It would have been obvious to person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Kurian, Mitchell, and Woodward with the teachings of Garg. One would have been motivated to do so in order to identify the best therapy for an individual or to adequately measure response to therapy, and one would have had reasonable expectation of success because Garg establishes that such a method of discrimination has previously been successful (pg. 265, col. 1, last par – col. 2, 1st par.).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 4, 6-11, 14, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S Patent No. 12,209,283, in view of Mitchell et al. (published August 17, 2018; International Publication No WO 2019/035995) and Woodward et al. (published May 26, 2016; Patent Application Publication No. US20160145682).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods. Both sets of claims require:
Treatment with immunosuppressive drugs (ref claim 1)
Kidney transplant recipients as subject (ref claim 1)
Indication of likelihood of rejection using mRNA expression levels comprising at least TSPAN13 (ref claim 3) from blood samples (ref claim 1)
Microarray, sequencing, or qPCR (ref claim 1)
Although the reference patent does not explicitly require indication of the likelihood of rejection using a level of dd-cfDNA at or above a pre-determined threshold value of 0.7%, it would be obvious to one with ordinary skill in the art that dd-cfDNA levels would provide benefit in diagnostic methods for transplant rejection because Woodward teaches that the combination of cfDNA and gene expression data may be more informative than either alone (par. 243) and Mitchell teaches the use of dd-cfDNA in at or above a value of > 0.7% as indicating with exquisite sensitivity the likelihood of transplant rejection (pg. 30, par. 1). Although this threshold value is an empirically optimized cutoff value, Mitchell does discuss that (pre-)selection of a threshold value may include empirically derived values (pg. 12, par. 2).
Claims 1, 4, 6-11, 14, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-43 of U.S Patent No. 11,821,037, in view of Mitchell et al. (published August 17, 2018; International Publication No WO 2019/035995) and Woodward et al. (published May 26, 2016; Patent Application Publication No. US20160145682).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods. Both sets of claims require:
Treatment with immunosuppressive drugs (ref claim 1, 15)
Kidney transplant recipients as subject (ref claim 1)
Indication of likelihood of rejection using mRNA expression levels (ref claim 1a, referring to Table F, comprising at least BIN2 and FKBP5)
Blood samples (ref claim 9-11)
Microarray or qPCR (ref claim 31, 34)
Although the reference patent does not explicitly require indication of the likelihood of rejection using a level of dd-cfDNA at or above a pre-determined threshold value of 0.7%, it would be obvious to one with ordinary skill in the art that dd-cfDNA levels would provide benefit in diagnostic methods for transplant rejection because Woodward teaches that the combination of cfDNA and gene expression data may be more informative than either alone (par. 243) and Mitchell teaches the use of dd-cfDNA in at or above a value of > 0.7% as indicating with exquisite sensitivity the likelihood of transplant rejection (pg. 30, par. 1). Although this threshold value is an empirically optimized cutoff value, Mitchell does discuss that (pre-)selection of a threshold value may include empirically derived values (pg. 12, par. 2).
Claims 1, 4, 6-11, 14, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S Patent No. 10,870,888, in view of Mitchell et al. (published August 17, 2018; International Publication No WO 2019/035995) and Woodward et al. (published May 26, 2016; Patent Application Publication No. US20160145682).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods. Both sets of claims require:
Treatment with immunosuppressive drugs (ref claim 1)
Kidney transplant recipients as subject (ref claim 21)
Indication of likelihood of rejection using mRNA expression levels from blood samples (ref claim 1, 10, 16, 30, comprising at least CALM3 and FKBP5)
Microarray or sequencing (ref claim 1)
Although the reference patent does not explicitly require indication of the likelihood of rejection using a level of dd-cfDNA at or above a pre-determined threshold value of 0.7%, it would be obvious to one with ordinary skill in the art that dd-cfDNA levels would provide benefit in diagnostic methods for transplant rejection because Woodward teaches that the combination of cfDNA and gene expression data may be more informative than either alone (par. 243) and Mitchell teaches the use of dd-cfDNA in at or above a value of > 0.7% as indicating with exquisite sensitivity the likelihood of transplant rejection (pg. 30, par. 1). Although this threshold value is an empirically optimized cutoff value, Mitchell does discuss that (pre-)selection of a threshold value may include empirically derived values (pg. 12, par. 2).
Claims 1, 4, 6-11, 14, and 18-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 9, 10, and 18-35 of co-pending Application No. 19/110,541, in view of Mitchell et al. (published August 17, 2018; International Publication No WO 2019/035995).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods. Both sets of claims require:
Kidney transplant recipients as subject (ref claim 22)
Indication of likelihood of rejection using
mRNA expression levels (ref claim 3, 10 – referring to Table A/3 in specification and comprising at least BIN2, TSPAN13, FKBP5, CD274, FCGR1B, DDX39B, TRAPPC5, BANP, RHOC, CALM3, and GADD45B)
dd-cfDNA levels (ref claim 3, 21) >0.7% (ref claim 23)
Microarray, next-generation sequencing, or qPCR (ref claim 30, 31)
Likelihood of rejection indicated at least one month after transplantation (ref claim 28)
Normalization (ref claim 34)
PPV >80% (ref claim 18)
Although the reference application does not explicitly require a step of treatment with immunosuppressive drugs, it would be obvious to do so because Mitchell teaches that treatment of transplant rejections with immunosuppressive therapy has been shown to improve treatment outcomes (pg. 13, par. 2). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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