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. Applicant’s election without traverse of Invention III in the reply filed on October 10, 2025 is acknowledged. Additionally in response to the election of species requirement the Applicants elected (i) genes associated with an immune response regulating pathway of inflammation and (ii) DCAF12 without traverse.
3. Claims 1-42 are currently pending.
Claims 1-5, 20-21, 27, 32-39, 40-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter (either a nonelected invention or species), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on October 10, 2025.
Applicants are reminded that the current status of all of the claims in the application, including any previously canceled or withdrawn claims, must be given. It is noted that claims 20-21 and 26 have the wrong status identifiers. Correction is required.
The claims have been examined to the extent that the claims read on genes associated with an immune response regulating pathway of inflammation. Genes associated with corticosteroid sensitivity and T cell activation have been withdrawn from consideration as being directed to non-elected subject matter. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim 18 has been examined to the extent that the claims read on DCAF12. The additionally recited genes have been withdrawn from consideration as being directed to non-elected subject matter. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 101
4. 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 6-19, 22-26, 28-31, and 39 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judicial exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
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 abstract ideas.
Claims 6-12 recite the following steps:
c) generating a gene expression score by applying a trained classifier to the expression level of the one or more genes,
d) generating a combined score by correlating the gene expression score and the amount or level of transplant-derived cell-free nucleic acids.
These steps are considered to encompass mathematical concepts (mathematical relationships, mathematical formulas or equations, and mathematical calculations). Mathematical concepts are abstract ideas.
Claims 6-12 recite the following step:
e) detecting immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection, wherein these are detected based on the combined score relative to a cut-off value.
The “detecting” step encompasses a mental processes. For example, one may “detect” immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection by comparing the combined score to the cut-off value and thinking about the result of the comparison. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
The instant claims recite a law of nature.
The claims recite a correlation between the expression level of the gene and amount of transplant derived cf-nucleic acid AND immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection. 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.
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 exceptions 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 technical field;
An additional element that applies or uses 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; and
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.
Claims 10 and 11 further the following step:
f) optionally treating the rejection or risk thereof, by administering to the recipient…
Since the administering step is optional, these claims do not practically apply judicial exception by including a final step of administering a particular treatment to the subject identified as having rejection or risk of rejection to thereby treat transplant rejection. It is noted that even if this was a required step, some of the recited treatments are general and non-specific (e.g., anti-rejection agent). Applicants are reminded that a treatment or prophylaxis limitation must be “particular”, i.e., specifically identified so that it does not encompass all applications of the judicial exceptions.
In addition to the judicial exceptions, Claims 6-12 recite the following steps:
a) providing nucleic acids from a first sample obtained from the transplant recipient comprising RNA, and providing nucleic acids from a second sample obtained from the transplant recipient comprising cell-free nucleic acids that are derived from the transplant and cell-free nucleic acids that are derived from the transplant recipient,
b) determining an expression level of one or more genes associated with an immune response-regulating pathway of inflammation in the first sample and determining an amount or a level of transplant-derived cell-free nucleic acids in the second sample,
These steps are NOT considered to integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exceptions.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions, Claims 6-12 recite the following steps:
a) providing nucleic acids from a first sample obtained from the transplant recipient comprising RNA, and providing nucleic acids from a second sample obtained from the transplant recipient comprising cell-free nucleic acids that are derived from the transplant and cell-free nucleic acids that are derived from the transplant recipient,
b) determining an expression level of one or more genes associated with an immune response-regulating pathway of inflammation in the first sample and determining an amount or a level of transplant-derived cell-free nucleic acids in the second sample,
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.
The steps are recited at a high level of generality. Providing samples in order to perform tests is well understood, routine, and conventional activity for those in the field of diagnostics. Determining an expression level and a level of transplant-derived cf-nucleic acid merely instructs a scientist to use any known assay. The claims do not require the use of any particular non-conventional reagents. 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 applicants invention and at the time the application was filed.
The prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available.
For example Woodward (US 2016/0145682 Pub 5/26/2016) teaches methods of monitoring the status of a transplanted organ in a subject, the method including: a) providing cell-free DNA from a sample obtained from a subject who is the recipient of an organ transplant from a donor, b) sequencing a panel of single nucleotide polymorphisms (SNPs) from the cell-free DNA, where the panel of SNPs is suitable for differentiating between donor-derived cell-free DNA and recipient-derived cell-free DNA, c) assaying variance in SNP allele distribution patterns in the panel as compared to expected homozygous or heterozygous distribution patterns to determine the level of donor-derived cell-free DNA, and d) diagnosing the status of the transplanted organ in the subject, where a change in levels or variance of the donor-derived cell-free DNA over a time interval is indicative of the status of the transplanted organ (para 0010). Woodward teaches that in some embodiments, the methods further involve performing an AlloMap test to aid in determining the status of the allograft in a transplant recipient. AlloMap tests involve performing quantitative real-time polymerase chain reaction (qRT-PCR) assays using RNA that has been isolated from peripheral blood mononuclear cells (PBMC). The expression of a select number of genes is analyzed and this gene expression data is used to provide information relating to the status of an allograft in a transplant recipient (para 0078).
Further it is noted 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.
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 § 112(b)
5. 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 6-19, 22-26, 28-31, and 39 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 6-19, 22-26, 28-31, and 39 are rejected over the recitation of the phrase “one or more genes associated with an immune response regulating pathway of inflammation”. This phrase is indefinite because it is not defined in the claim or the specification, and one of ordinary skill in the art would not know what genes are encompassed by this language and what genes are not encompassed by this language. In the absence of a clear definition, 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 Rejections - 35 USC § 112(a)
6. 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.
7. Claims 6-17, 19, 22-26, 28-31, and 39 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description rejection.
The claims are drawn to methods for (i) detecting or monitoring immune quiescence (ii) discriminating between immune quiescence and active rejection (iii) discriminating between T cell mediated rejection and antibody mediated rejection, (iv) discriminating between immune quiescence, T cell mediated rejection, and antibody mediated rejection, (v) detecting, monitoring and/or guiding treatment of active rejection, (vi) detecting a distinguishing T cell mediated rejection from antibody mediated rejection, and (vii) discriminating between immune quiescence and a state of immune activation.
The claims recite the following steps:
b) determining an expression level of one or more genes associated with an immune response-regulating pathway of inflammation in the first sample and determining an amount or a level of transplant-derived cell-free nucleic acids in the second sample;
c) generating a gene expression score by applying a trained classifier to the expression level of the one or more genes,
d) generating a combined score by correlating the gene expression score and the amount or level of transplant-derived cell-free nucleic acids.
In the instant case, the claims do not set forth the genes associated with an immune response regulating pathway of inflammation in terms of sufficient relevant identifying characteristics. The claims encompass measuring a large genus of genes that have been identified only in terms of their function. The claimed genes must be associated with an immune response regulating pathway of inflammation AND also be correlated with immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection.
The specification [0101] teaches that exemplary informative genes, as listed in Table 1, below, are related to immune response-regulating pathways, particularly to the immune response-regulating pathways of inflammation, corticosteroid sensitivity, and T cell activation. Five exemplary informative genes are described in detail in Table 1.
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The specification [0102] teaches that four of the five exemplary informative genes belong to gene clusters. DCAF12 and MARCH8, for example, are related to the immune response-regulating pathway of inflammation and correlate with each other by a factor of 0.88. FLT3 and IL1R2 are related to the immune response-regulating pathway of corticosteroid sensitivity and correlate with each other by a factor of 0.67. PDCD1 is related to the immune response-regulating pathway of T cell activation.
The specification provides written description for the following genes associated with an immune response regulating pathway of inflammation: DCAF12 and MARCH8. The specification does not describe any other species within the claimed genus to show possession of those species.
Regarding the genus of genes associated with an immune response regulating pathway of inflammation, the specification does not describe any structural features of DCAF12 and MARCH8 that would have been expected to be shared by members of the claimed genus. The specification does not describe any physical and/or chemical characteristics of DCAF12 and MARCH8 that would be expected to be shared by members of the claimed genus. All members of the genus have the same function, i.e., they are associated with an immune response regulating pathway of inflammation AND are correlated with immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection, but no correlation between their structure and this common function is disclosed. The level of knowledge and skill in the art does not allow those skilled in the art to structurally envisage or recognize additional members of the claimed genus. Because the structure of the species within the claimed genus is expected to vary unpredictably from the structure of DCAF12 and MARCH8, the disclosed genes associated with an immune response regulating pathway of inflammation are not a “representative number” of species within the claimed genus.
Because DCAF12 and MARCH8 are not representative of the entire claimed genus, and the specification does not disclose structural features shared by members of the genus, the description of DCAF12 and MARCH8 would not have put the applicant in possession of common structural attributes or features shared by members of the genus that structurally distinguish the members of the genus from non-members of the genus at the time of filing. Thus the description of DCAF12 and MARCH8 is not sufficient to describe the claimed genus of genes must be associated with an immune response regulating pathway of inflammation AND also be correlated with immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection. Accordingly, the specification does not provide a representative number of species or sufficient common structural features to show that the applicant would have been in possession at the claimed genus as a whole at the time of filing.
8. Claims 6-19, 22-26, 28-31, and 39 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.
Scope of the Claims/Nature of the Invention
The claims are drawn to methods for (i) detecting or monitoring immune quiescence (ii) discriminating between immune quiescence and active rejection (iii) discriminating between T cell mediated rejection and antibody mediated rejection, (iv) discriminating between immune quiescence, T cell mediated rejection, and antibody mediated rejection, (v) detecting, monitoring and/or guiding treatment of active rejection, (vi) detecting a distinguishing T cell mediated rejection from antibody mediated rejection, and (vii) discriminating between immune quiescence and a state of immune activation in a transplant recipient having received a transplant. In view of the recitation of “transplant recipient” the claims broadly encompass ANY type of transplant recipient (i.e., kidney, heart, uterus, bone, heart valves, corneas, stem cells, etc.). Claim 29 states that the transplant is a solid organ transplant. Claim 30 states that the transplant is a kidney transplant, a heart transplant, a lung transplant, a pancreas transplant, a liver transplant, an intestinal transplant, a vascularized composite allograft transplant, or any combination thereof.
The claims recite a step of providing nucleic acids from a first sample obtained from the transplant recipient comprising RNA, and providing nucleic acids from a second sample obtained from the transplant recipient comprising cell-free nucleic acids that are derived from the transplant and cell-free nucleic acids that are derived from the transplant recipient. In view of the recitation of the phrase “sample” the claims broadly encompass ANY type of sample (blood, serum, urine, saliva, kidney tissue, heart tissue, etc.). Only claims 22 and 23 are limited to specific sample types namely, whole blood, serum, plasma, and urine samples.
The claims recite a step of determining an expression level of one or more genes associated with an immune response-regulating pathway of inflammation in the first sample and determining an amount or a level of transplant-derived cell-free nucleic acids in the second sample. In the instant case, the claims do not set forth the genes associated with an immune response regulating pathway of inflammation in terms of sufficient relevant identifying characteristics. The claims encompass measuring a large genus of genes that have been identified only in terms of their function. The claimed genes must be associated with an immune response regulating pathway of inflammation AND also be correlated with immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection. Only claim 18 is limited to specific genes, wherein DCAF12 was elected for examination.
The claims recite a step of generating a gene expression score by applying a trained classifier to the expression level of the one or more genes. The claims do not set forth how this score is generated and therefore encompass ANY method of generating an expression score.
The claims recite a step of generating a combined score by correlating the gene expression score and the amount or level of transplant-derived cell-free nucleic acids. The claims do not set forth how this combined score is generated and therefore encompass ANY method of generating an combined score.
The claims recite the following “wherein” clauses:
-wherein the combined score being equal to or below a cut-off value indicates that the transplant recipient is likely experiencing immune quiescence (clm 6);
-wherein the combined score being equal to or below a cut-off value indicates that the transplant recipient is likely experiencing immune quiescence and wherein the combined score being equal to or above the cut-off value indicates that the transplant recipient is likely experiencing active rejection or is at risk of developing active rejection (clm 7);
- wherein the combined score being equal to or above a first cut-off value indicates that the transplant recipient is likely experiencing T cell-mediated rejection or is at risk of developing T cell-mediated rejection, and wherein the combined score being equal to or above a second cut-off value indicates that the transplant recipient is likely experiencing antibody- mediated rejection or is at risk of developing antibody-mediated rejection (clm 8);
-wherein the combined score being equal to or above a first cut-off value indicates that the transplant recipient is likely experiencing T cell-mediated rejection or is at risk of developing T cell-mediated rejection, wherein the combined score being equal to or above a second cut-off value indicates that the transplant recipient is likely experiencing antibody- mediated rejection or is at risk of developing antibody-mediated rejection, and wherein the combined score being below the first and second cut-off values indicates that the transplant recipient is likely experiencing immune quiescence (clm 9);
-wherein the combined score being equal to or above a cut-off value indicates that the transplant recipient is likely experiencing active rejection or is at risk of developing active rejection (clm 10);
- wherein the combined score being equal to or above a first cut-off value indicates that the transplant recipient is likely experiencing T cell-mediated rejection or is at risk of developing T cell-mediated rejection, and wherein the combined score being equal to or above a second cut-off value indicates that the transplant recipient is likely experiencing antibody- mediated rejection or is at risk of developing antibody-mediated rejection (clm 11);
-wherein the combined score being equal to or above a cut-off value indicates that the transplant recipient is likely experiencing a state of immune activation caused by infection or is at risk of developing a state of immune activation caused by infection, and wherein the combined score being equal to or below the cut-off value indicates that the transplant recipient is likely experiencing immune quiescence (clm 12).
In each of these wherein clauses the combined score is compared to a “cut off value” and depending on whether the score is greater than or less than the “cut off value” the subject has quiescence, active rejection, TCMR, AMR, or immune activation caused by an infection. Since the claims do not set forth the “cut off values” for each of these conditions, the claims broadly encompass determining that the subject has quiescence, active rejection, TCMR, AMR, or immune activation caused by an infection based off of ANY cut off value.
The claims recite a step of detecting immune quiescence, active rejection, TCMR, AMR, or immune activation caused by an infection based on the combined score relative to the cut off values.
The nature of the invention requires a reliable correlation between the expression level of ANY gene associated with an immune response regulating pathway of infection combined with the level of DS cf-DNA and immune quiescence, active rejection, TCMR, AMR, or immune activation caused by an infection. Additionally the claims require a reliable correlation between the expression level of DCAF12 combined with the level of DS cf-DNA and immune quiescence, active rejection, TCMR, AMR, or immune activation caused by an infection.
Teachings in the Specification and Examples
The specification teaches that the inventors assessed the utility of a 5 gene expression signature and donor derived cfDNA levels to detect transplant rejection.
The specification (para 0316) teaches that a classifier using 5 informative genes (DKAF12, MARCH8, FLT3, IL1R2, and PDCD1) was developed and validated in three independent sets of samples, on a total of 169 quiescence (or non-rejection) samples and 66 rejection samples from 222 kidney allograft recipients.
The specification (para 0317) teaches that for each transplant recipient for whom paired dd-cfDNA and GEP samples, obtained within 30 days prior to biopsy, were available, dd-cfDNA levels were determined using AlloSure®.
The specification (para 0318) teaches that the classifier for the 5-gene expression signature produced quantitative gene expression signature scores in the range from 0 to 20. In all validation sets, the gene expression signature scores differed significantly between the quiescence groups and the rejection groups, whereby higher scores were associated with a higher risk of rejection.
The specification (para 0344) teaches that for dd-cfDNA, validated levels of 0.5% and 1% were evaluated. At a threshold of 0.5%, dd-cfDNA had a sensitivity of 85.7% and specificity of 75% in the determination of rejection; at a threshold of 1%, dd-cfDNA had a sensitivity and specificity of 59.5% and 84.5%, respectively, in the determination of rejection. For the 5-gene expression profiling (GEP), score thresholds of 10.5 and 11.5 were evaluated. At a score threshold of 10.5, the GEP assay had a sensitivity and specificity of 69%; at a score threshold of 11.5, the GEP assay had a sensitivity and specificity of 52% and 83%, respectively.
The specification (para 0345) teaches that for the GEP and dd-cfDNA combination with a GEP score of 10.5 and dd-cfDNA levels of 0.5%, the sensitivity and specificity for rejection were 93% and 51%.
The specification (para 0346) teaches that for the GEP and dd-cfDNA combination with a GEP score of 11.5 and dd-cfDNA levels of 1%, the sensitivity and specificity for rejection were 31% and 98%.
The specification (para 0347) teaches that the GEP and dd-cfDNA levels individually differentiated rejection (R) from non-rejection (NR) with an AUC of 0.75 and 0.86, respectively. The AUC for GEP and dd-cfDNA combined analysis was 0.88.
The specification (para 0348) teaches that the combined analysis of GEP and dd-cfDNA levels made possible not only to differentiate rejection from non-rejection, but also to differentiate TCMR and ABMR. (See FIG. 16 and 17).
State of the Art and the Unpredictability of the Art
While methods of gene expression levels and DD-cfDNA levels are known in the art, methods of correlating biomarkers with a phenotype (immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection) are highly unpredictable. The unpredictability will be discussed below.
The claims require determining an expression level of one or more genes associated with an immune response-regulating pathway of inflammation. The claims do not set forth the genes associated with an immune response-regulating pathway of inflammation in terms of sufficient relevant identifying characteristics. The claims encompass measuring a potentially large genus of genes associated with an immune response-regulating pathway of inflammation that have been identified only in terms of their function. The specification discloses two genes that are considered to be genes associated with an immune response-regulating pathway of inflammation, namely DCAF12 and MARCH8. The specification does not disclose any other genes associated with an immune response-regulating pathway of inflammation that can differentiate between immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection. The level of knowledge and skill in the art does not allow those skilled in the art to structurally envision or recognize additional members of the claimed genus. Because the structure of the species which the claimed genus is expected to vary unpredictably from the structure of the disclosed genes associated with an immune response-regulating pathway of inflammation, the specification does not provide enablement for the use of ANY genes associated with an immune response-regulating pathway of inflammation in the claimed methods.
In the instant case, methods of (i) detecting or monitoring immune quiescence (ii) discriminating between immune quiescence and active rejection (iii) discriminating between T cell mediated rejection and antibody mediated rejection, (iv) discriminating between immune quiescence, T cell mediated rejection, and antibody mediated rejection, (v) detecting, monitoring and/or guiding treatment of active rejection, (vi) detecting a distinguishing T cell mediated rejection from antibody mediated rejection, and (vii) discriminating between immune quiescence and a state of immune activation in a transplant recipient having received a transplant based on the expression level of DCAF12 and the level of DD-cfDNA would be highly unpredictable. This is because there is no data in the specification demonstrating that the expression level of DCAF12 and the level of DD-cfDNA can discriminate between the phenotypes that are claimed. The specification only provides evidence that a 5-gene expression signature in combination with DD-cfDNA can discriminate between the phenotypes that are claimed. In the absence of evidence to the contrary this is highly unpredictable and the specification does not provide enablement for the use of a single gene (DCAF12) in combination with the level of DD-cfDNA.
The claims require (i) generating a gene expression score by applying a trained classifier and (ii) generating a combined score by correlating the gene expression score and the level of DD-cfDNA. However neither the claims nor the specification provide sufficient guidance for generating the scores. There are many different ways that are known in the art for generating scores based on expression data. However it is highly unpredictable if one were to use any of those other ways if they would end up with same results that were obtained using the scoring methods of the inventors.
The claims are drawn to methods of (i) detecting or monitoring immune quiescence (ii) discriminating between immune quiescence and active rejection (iii) discriminating between T cell mediated rejection and antibody mediated rejection, (iv) discriminating between immune quiescence, T cell mediated rejection, and antibody mediated rejection, (v) detecting, monitoring and/or guiding treatment of active rejection, (vi) detecting a distinguishing T cell mediated rejection from antibody mediated rejection, and (vii) discriminating between immune quiescence and a state of immune activation in a transplant recipient having received a transplant and require comparing a combined score to certain cut-off values. However the claims do not set forth what the cut-off values would be for immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection. This information is critical to practicing the claimed invention. In the instant case it is highly unpredictable which cut-off values should be used and this could only be determined by performing further experimentation which is undue.
Because the claims broadly encompass the claims encompass measuring expression and DD-cfDNA in ANY type of biological sample, it is relevant to point out that it is highly unpredictable as to whether the results obtained with peripheral blood could be extrapolated to other sample types. In general, mRNA expression is cell/tissue type specific. In the absence of evidence to the contrary it is highly unpredictable if the differential expression of the 5 gene signature comprising DACF12, MARCH8, FLT3, IL1R2, and PDCD1 in peripheral blood samples will also occur in a representative number of additional types of biological samples and that such changes will be correlated with immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection.
Because the claims broadly encompass ANY type of transplant, it is relevant to point out that it is highly unpredictable as to whether the genes that are predictive in kidney transplants would work for other transplant types. It is expected that biomarkers for rejection of one type of cancer will not function as biomarkers for other types of cancer. In the instant case the inventors only measured DACF12, MARCH8, FLT3, IL1R2, and PDCD1 in subjects that had received kidney transplants. In the absence of evidence to the contrary it is highly unpredictable if DACF12, MARCH8, FLT3, IL1R2, and PDCD1 will function in the claimed methods if they were practiced on subjects that had received other types of transplants(i.e., heart, uterus, bone, heart valves, corneas, stem cells, etc.).
Finally regarding claim 12 it is highly unpredictable if the claimed methods are capable of discriminating between immune quiescence and a state of immune activation caused by an infection. There is no evidence in the specification to support this and even if additional experimentation were to be performed it would be unpredictable. As such the specification does not provide enabling support for the method of claim 12.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claims encompass methods of (i) detecting or monitoring immune quiescence (ii) discriminating between immune quiescence and active rejection (iii) discriminating between T cell mediated rejection and antibody mediated rejection, (iv) discriminating between immune quiescence, T cell mediated rejection, and antibody mediated rejection, (v) detecting, monitoring and/or guiding treatment of active rejection, (vi) detecting a distinguishing T cell mediated rejection from antibody mediated rejection, and (vii) discriminating between immune quiescence and a state of immune activation in a transplant recipient having received a transplant based on the expression level of ANY gene associated with an immune response regulating pathway of inflammation and the level of DD-cfDNA.
In order to practice the breadth of the claimed invention one of skill in the art would first have to recruit subjects that have received a representative number of different types of transplants. The subjects would have to include those with quiescence, active rejection, ABMR, TCMR, and immune activation from infections. Then one of skill in the art would need to create a list of all of the genes that are involved in immune response regulating pathways of inflammation. Then those genes would all have to be measured in different samples types obtained from each of the subjects along with DD-cfDNA. Then extensive data analysis would need to be performed to determine combinations of genes along with DD-cfDNA levels that would function in the claimed methods. The specification has merely provided an invitation for further experimentation. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years’ work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a “predictable” factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
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.
Claim Rejections - 35 USC § 102
9. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 6, 7, 10, 13, 18-19, 22-25, 28-31, and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Woodward (US 2016/0145682 Pub 5/26/2016). The rejection is further evidenced by the prior art of Deng (American Journal of Transplantation 2006 Vol 6 pages 150-160).
Woodward teaches methods of monitoring the status of a transplanted organ in a subject, the method including: a) providing cell-free DNA from a sample obtained from a subject who is the recipient of an organ transplant from a donor, b) sequencing a panel of single nucleotide polymorphisms (SNPs) from the cell-free DNA, where the panel of SNPs is suitable for differentiating between donor-derived cell-free DNA and recipient-derived cell-free DNA, c) assaying variance in SNP allele distribution patterns in the panel as compared to expected homozygous or heterozygous distribution patterns to determine the level of donor-derived cell-free DNA, and d) diagnosing the status of the transplanted organ in the subject, where a change in levels or variance of the donor-derived cell-free DNA over a time interval is indicative of the status of the transplanted organ (para 0010). Woodward teaches that in some embodiments, the methods further involve performing an AlloMap test to aid in determining the status of the allograft in a transplant recipient. AlloMap tests involve performing quantitative real-time polymerase chain reaction (qRT-PCR) assays using RNA that has been isolated from peripheral blood mononuclear cells (PBMC). The expression of a select number of genes is analyzed and this gene expression data is used to provide information relating to the status of an allograft in a transplant recipient. The AlloMap test is known in the art. (para 0078). Woodward further teaches that in some embodiments, the methods of the present disclosure involve determining a combination score that may be used to convey the status of an allograft in a transplant recipient. Combination scores are generally calculated based on the results of multiple (e.g. two or more) assays used to probe the status of the allograft in the transplant recipient. For example, combination scores may be calculated based on the determined levels of donor-derived cell-free DNA in the transplant recipient and based on the results of a gene expression profiling assay such as, for example, an AlloMap test, which measures select gene expression. Combination scores may be calculated based on a single sample taken from a transplant recipient, or they may be based on samples taken from a transplant recipient over a time interval. Combination scores may be used to determine the status of an allograft in a transplant recipient and/or inform the need to adjust immunosuppressive therapy being administered to the transplant recipient (para 0078). Woodward teaches that FIG. 6A-FIG. 6C illustrates that dd-cfDNA is a signal unique from gene expression profiling of blood markers, and the combination of both can better identify rejection. FIG. 6A illustrates dd-cfDNA levels from heart transplant recipients. FIG. 6B illustrates AlloMap data from the transplant recipients in FIG. 6A. FIG. 6C illustrates combined dd-cfDNA data and AlloMap data. The values for dd-cfDNA (FIG. 6A) and AlloMap (FIG. 6B) were scaled to the same range and additively combined. The combined score is better at discriminating rejection from non-rejection than either cfDNA or gene expression alone, as measured by the area under the curve of a receiver-operator characteristics plot (para 0019). Woodward also teaches comparing the scores to threshold values to determine the status of the allograft as being stable (no rejection/immune quiescence) or active rejection (paras 0063-0067). Further as evidenced by Deng it is a property of the AlloMap test produces a score between 0 and 40 based on the combined expression levels of 11 genes in total, including WDR40A (also known as DCAF12) (page 153 and Fig 2). The AlloMap score is generated by applying a trained classifier to the expression level of the 11 genes (page 152, Figure 1 inset). An AlloMap score greater than 20 is indicative of rejection (page 153).
Regarding Claims 6, 7, and 10 Woodward teaches (i) methods of detecting/monitoring immune quiescence; (ii) methods of discriminating between immune quiescence and active rejection; and (iii) methods of detecting, monitoring, and guiding treatment of active rejection, wherein the methods comprise
a) providing nucleic acids from a first sample obtained from the transplant recipient comprising RNA, and providing nucleic acids from a second sample obtained from the transplant recipient comprising cell-free nucleic acids that are derived from the transplant and cell-free nucleic acids that are derived from the transplant recipient,
b) determining an expression level of a gene associated with an immune response-regulating pathway of inflammation (DCAF12);
c) generating a gene expression score by applying a trained classifier to the expression levels of the one or more genes (the AlloMap score),
d) generating a combined score by correlating the gene expression score and the amount or level of transplant-derived cell-free nucleic acids,
e) detecting immune quiescence (non-rejection) if the combined score is determined to be equal to or below the cut-off value and detecting active rejection or risk of active rejection if the combined score is determined to be equal to or above the cut-off value.
Regarding Claim 13 Woodward teaches a method that comprises sequencing a panel of selected single nucleotide polymorphisms (SNPs) from the cell-free nucleic acids, wherein the panel of selected SNPs is suitable for differentiating between transplant-derived cell-free nucleic acids and recipient-derived cell-free nucleic acids (para 0010).
Regarding Claim 18 Woodward teaches measuring gene expression using the AlloMap test. As evidenced by Deng, it is a property of this test that it measures DCAF12.
Regarding Claim 19 Woodward teaches measuring gene expression using the AlloMap test. As evidenced by Deng the method comprises determining expression levels of genes that correlate with the expression of DCAF12 and comprises generating a gene expression score by applying a trained classifier to the expression levels of the one or more genes with correlating expression.
Regarding Claim 22 Woodward teaches that the samples can be whole blood samples, serum samples, or plasma samples (para 0028).
Regarding Claim 23 Woodward teaches that the samples can be plasma samples or urine samples (para 0028).
Regarding Claim 24 Woodward teaches a method wherein the first sample (PBMC) and the second sample (plasma) are both derived from blood samples (Ex 7).
Regarding Claim 25 Woodward teaches a method wherein the expression levels are determined by RNA analysis (para 0223).
Regarding Claim 28 Woodward teaches measuring gene expression using the AlloMap test. As evidenced by Deng, it is a property of this test that it normalizes gene expression levels (page152).
Regarding Claim 29 Woodward teaches a method wherein the transplant is a solid organ transplant (para 0027).
Regarding Claim 30 Woodward teaches a method wherein the transplant is a kidney transplant, a heart transplant, a lung transplant, a pancreas transplant, a liver transplant (para 0027).
Regarding Claim 31 Woodward teaches a method wherein the transplant is a cellular allograft (para 0027).
Regarding Claim 39 Woodward teaches a method wherein the cell-free nucleic acids are DNA (para 0028).
Claim Rejections - 35 USC § 103
10. 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.
11. Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Woodward (US 2016/0145682 Pub 5/26/2016) as applied to claim 6 above and in further view of An (US 2013/0116578 Pub 5/9/2013) It is noted that the rejection of claim 6 was evidenced by the prior art of Deng (American Journal of Transplantation 2006 Vol 6 pages 150-160).
Woodward (as evidenced by Deng) does not teach a method wherein the combined score is generated by equal weighting of the gene expression score and the amount or level of transplant-derived cell-free nucleic acids (clm 14). Woodward (as evidenced by Deng) does not teach a method wherein the combined score is generated by unequal weighting of the gene expression score and the amount or level of transplant-derived cell-free nucleic acids (clm 15).
However An teaches a method of determining a heart failure risk score according to one or more physiological parameters (abstract). An teaches that combined scores can be weighted scores and that the weighted scores can be equal or unequal (para 0055).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Woodward by calculating weighted scores using equal weighting and/or unequal weighting as suggested by An. One of skill in the art would have been motivated to try both methods of weighting for the benefit of seeing if one method produces a score that differentiates transplant rejection better than the other.
12. Claims 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Woodward (US 2016/0145682 Pub 5/26/2016) as applied to claim 6 above and in further view of Bloom (J Am Soc Nephrol 2017 Mar 9; 28(7) pages 2221-2232). It is noted that the rejection of claim 6 was evidenced by the prior art of Deng (American Journal of Transplantation 2006 Vol 6 pages 150-160).
Woodward (as evidenced by Deng) does not teach a method wherein the transplant recipient has no clinically indicated need for a biopsy (clm 16). Woodward (as evidenced by Deng) does not teach a method wherein the transplant recipient has a clinically indicated need for a biopsy (clm 17).
However Bloom teaches that donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals (not clinically indicated need for a biopsy) and at the time of clinically indicated biopsies (abstract).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Woodward by performing analysis on samples from transplant recipients when there is no clinical biopsy need as suggested by Bloom. One of skill in the art would have been motivated to do this for the benefit of being able to monitor the absence of active transplant rejection. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Woodward by performing analysis on samples when clinical biopsy is needed as suggested by Bloom. One of skill in the art would have been motivated to do this for the benefit of using an additional tool to help differentiate between the presence and absence of active rejection.
13. Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Woodward (US 2016/0145682 Pub 5/26/2016) as applied to claims 6 and 25 above and in further view of Coenye (Biofilm 3 (January 13, 2021) 100043). It is noted that the rejection of claim 6 was evidenced by the prior art of Deng (American Journal of Transplantation 2006 Vol 6 pages 150-160).
Woodward (as evidenced by Deng) does not teach a method wherein the expression levels are determined by RNA-sequencing (clm 24).
However Coenye discloses measuring gene expression with RNA-sequencing. Coenye teaches that the data available suggest that RNA-seq methods and data analysis approaches are robust enough to not always require validation by qPCR and/or other approaches, although there are situations where this may be of added value (page 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Woodward by measuring gene expression using RNA-sequencing as suggested by Coenye. The claim would have been obvious because the substitution of one method of detecting gene expression (microarray or qPCR) for another (RNA-sequencing) would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Improper Markush Grouping
14. Claim 18 is 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 § 706.03(y).
The claim recites the following Markush grouping:
-at least one gene selected from the group consisting of DCAF12, FLT3, IL1R2, PDCD1, and MARCH8.
The Markush grouping is 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 706.03(y) 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 “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 706.03(y)IIA).
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 associated with an immune response regulating pathway of inflammation AND also being correlated with immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection. Accordingly, the different genes 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 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 associated with an immune response regulating pathway of inflammation AND also be correlated with immune quiescence/active rejection/T cell mediated rejection/antibody mediated rejection/immune activation caused by infection. In fact the recited genes are not all associated with the same pathways. The specification [0102] teaches that four of the five exemplary informative genes belong to gene clusters. DCAF12 and MARCH8, for example, are related to the immune response-regulating pathway of inflammation and correlate with each other by a factor of 0.88. FLT3 and IL1R2 are related to the immune response-regulating pathway of corticosteroid sensitivity and correlate with each other by a factor of 0.67. PDCD1 is related to the immune response-regulating pathway of T cell activation. Thus, the groups of genes do not all share a common use/function.
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.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached at 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682