DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the papers filed April 27, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Applicant’s election without traverse of Invention III and the species of (i) genes associated with an immune response regulating pathway of inflammation and (ii) DCAF12 are reiterated for the record.
3. Claims 1-5, 11, 13, 16-17, 19-44 are currently pending.
Claims 1-5, 20, 27, 32-38, 40-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter (either a nonelected invention or species), there being no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.
It is noted that claim 11 has been amended such that it now requires at least 5 genes comprising DCAF12, FLT3, IR1R2, PDCD1, and MARCH8. In view of this amended claim 21 is no longer withdrawn and has been examined herein.
Claim Rejections - 35 USC § 112(b)
4. 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 21 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 21 is rejected over the recitation of the phrase “the one or more genes associated an immune response-regulating pathway of inflammation, corticosteroid sensitivity, or T cell activation”. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(d)
5. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 25 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In the instant case claim 25 fails to further limit the method of claim 11 because claim 11 already recites that the expression levels of the at least five genes comprising DCAF12, FLT3, IR1R2, PDCD1, and MARCH8 is detected in RNA from the first sample. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 11, 13, 16-17, 19, 21, 22-26, 28-31, 39, and 43-44 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 a method of detecting T cell mediated rejection 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 at least five genes comprising DCAF12, FLT3, IR1R2, PDCD1, and MARCH8 in the first sample and determining an amount or a level of transplant-derived cell-free nucleic acids in the second sample.
The claims recite a step of determining the transplant recipient is experiencing T cell-mediated rejection or a risk of developing the T cell-mediated based at least on the expression level of the at least five genes comprising DCAF12, FLT3, IL1R2, PDCD1, and MARCH8 in the first sample and the amount or level of transplant-derived cell-free nucleic acids in the second sample.
The claims recite a step in responsive to the determining in treating either the T cell-mediated rejection, or the risk of developing the T cell-mediated rejection by administering to the transplant recipient methylprednisolone, T cell depletion agent rabbit anti-thymocyte globulin (rATG), rapamycin, mycophenolic acid, or any combination thereof.
The nature of the invention requires a reliable correlation between the expression level of DCAF12, FLT3, IL1R2, PDCD1, and MARCH8 combined with the level of DS cf-DNA and T cell mediated rejection.
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 determining gene expression levels and DD-cfDNA levels are known in the art, methods of correlating biomarkers with a phenotype (T cell mediated rejection) are highly unpredictable. The unpredictability will be discussed below.
Since the claims broadly encompass determining an expression level of DCAF12, FLT3, IL1R2, PDCD1, and MARCH8 and determining an amount of 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 T cell mediated rejection.
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.).
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 detecting T cell mediated rejection in a transplant recipient having received ANY type of transplant based on the expression of DACF12, MARCH8, FLT3, IL1R2, and PDCD1 in ANY sample type.
In order to practice the breadth of the claimed invention one of skill in the art would first have to recruit subjects with TCMR which have a representative number of different types of transplants. Then one would have to measure DACF12, MARCH8, FLT3, IL1R2, and PDCD1 in a representative number of different sample types. Then extensive data analysis would need to be performed to determine if the levels of DACF12, MARCH8, FLT3, IL1R2, and PDCD1 in each of the sample types correlate with the presence of TCMR. 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.
Response To Arguments
7. In the response the Applicants traversed the rejection under 35 112(a). The Applicants state that claim 11 has been amended to clarify the recited subject matter and align the claim with, for example, at Example 1 and Example 2 in the instant specification as filed. Applicant respectfully submits that one of skill in the art would not require undue experimentation to make or use the instant claims as amended.
The amendments have been fully considered but do not overcome the rejection because the claims still encompass measuring gene expression in any sample type and they still encompass any transplant type. For the reasons set forth above, it would still require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Claim Rejections - 35 USC § 103
8. 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.
9. Claims 11, 13, 19, 21-25, 28-31, 39, 43, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Woodward (US 2016/0145682 Pub 5/26/2016) in view of Dedrick (Journal of Immunotoxicology 4:201-207, 2007) and Wong (Expert Opinion on Emerging Drugs 22:2 123-136).
Regarding Claim 11 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 Fig 1 illustrates that donor-derived cell-free DNA (dd-cfDNA) is greater in plasma taken from heart transplant recipients experiencing acute cellular rejection than from those not experiencing rejection (para 0014). 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 (para 0078). Thus Woodward teaches a method of detecting T-cell mediated rejection (also known as acute cellular rejection) in a transplant recipient having received a transplant. Woodward teaches 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. Woodward teaches b) determining an expression level of at least five genes comprising DCAF12, FLT3, IL1R2, PDCD1, and MARCH8 in the first sample and determining an amount or level of transplant derived cell free nucleic acids in the second sample. It is a property of the AlloMap test that it includes each of the claimed genes. Woodward teaches determining that a transplant recipient is experiencing a T cell mediated rejection (also known as acute cellular rejection) based on the amount or level of transplant derived cell free nucleic acids in the second sample (Fig 1).
While Woodward teaches determining an expression level of at least five genes comprising DCAF12, FLT3, IL1R2, PDCD1, and MARCH8, the reference does not specifically teach that the expression level of these genes is correlated with T cell mediated rejection (also known as acute cellular rejection).
However Dedrick teaches that gene expression profiling of peripheral blood cells can provide dynamic information regarding the host response to immune-mediated disorders. AlloMap® molecular expression testing from XDx monitors the expression of 20 genes in peripheral blood mononuclear cells (PBMC) to discriminate cardiac allograft recipients of 15 years or greater who are at low risk for acute cellular rejection (ACR). The AlloMap test classifier is based on the expression level of 11 genes, encoding proteins with diverse functions, which are differentially expressed in stable patients with moderate to severe ACR compared to patients without ACR (abstract). Dedrick teaches that the informative genes include WDR40A (also known as DCAF12), FLT3, IL1R2, PDCD1, and MARCH8 (see Table 1). Dedrick teaches that PDCD1, MARCH8, and WDR40A are each increased in moderate to severe ACR in comparison to transplant subjects without ACR and FLT3 and IL1R2 are each decreased in moderate to severe ACR in comparison to transplant subjects without ACR (see Table 2). Thus Dedrick teaches that the expression level of these genes can be used to detect T cell mediated rejection (also known as acute cellular rejection).
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 including the analysis of the expression levels of DCAF12, FLT3, IL1R2, PDCD1, and MARCH8 when determining whether a transplant recipient is experiencing a T cell mediated rejection as suggested by Dedrick. In the instant case Woodward teaches that the amount of dd-cfDNA can be used as a biomarker for ACR. Dedrick teaches that the expression levels of DCAF12, FLT3, IL1R2, PDCD1, and MARCH8 can be used as biomarkers for ACR. One of skill in the art would have been motivated to combine these biomarkers in a method for determining that a transplant recipient is experiencing T cell mediated rejection particularly since Woodward teaches that Fig 6 illustrates that dd-cfDNA is a signal unique from gene expression profiling of blood markers and the combination of both can better identify rejection (para 0019).
The combined references do not teach administering to the transplant recipient methylprednisolone, T cell depletion agent rabbit anti-thymocyte globulin (rATG), rapamycin, mycophenolic acid, or any combination thereof (clm 11).
However Wong is a review article that discusses emerging drugs for T-cell mediated rejection in liver and kidney transplantation. Wong discloses treating a transplant recipient with methylprednisolone, rapamycin, mycophenolic acid (pages 124, 125, 126, ).
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 and Dedrick by administering to the transplant recipient methylprednisolone, rapamycin, mycophenolic acid as suggested by Wong. One of skill in the art would have been motivated to administer one of these treatments to a subject experiencing a T cell mediated rejection since Wong teaches that these treatments are considered standard care in immunosuppressive therapy.
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 13 Woodward further teaches measuring the expression of one or more genes with expression levels that correlate with DCAF12, FLT3, IL1R2, PDCD1, and MARCH8 since Woodward teaches using the AlloMap test. In the instant case it is a property that the AlloMap test additionally measures genes correlated with DCAF12, FLT3, IL1R2, PDCD1, and MARCH8.
Regarding Claim 21 Woodward teaches measuring gene expression using the AlloMap test. It is a property of the AlloMap test that is measures the expression level of DCAF12, FLT3, IL1R2, PDCD1, and MARCH8.
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 of DCAF12, FLT3, IL1R2, PDCD1, and MARCH8 are determined by RNA analysis (para 0223).
Regarding Claim 28 Woodward teaches measuring gene expression using the AlloMap test. It is a property of this test that the expression levels of DCAF12, FLT3, IL1R2, PDCD1, and MARCH8 are normalized relative to reference genes.
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).
Regarding Claim 43 Woodward teaches a method wherein the transplant is a kidney transplant (para 0027).
Regarding Claim 44 Woodward teaches a method wherein the first sample is PBMC derived from blood samples (Ex 7).
10. Claims 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Woodward (US 2016/0145682 Pub 5/26/2016) in view of Dedrick (Journal of Immunotoxicology 4:201-207, 2007) and Wong (Expert Opinion on Emerging Drugs 22:2 123-136) as applied to claim 6 above and in further view of Bloom (J Am Soc Nephrol 2017 Mar 9; 28(7) pages 2221-2232).
The teachings of Woodward, Dedrick, and Wong are presented above.
The combined references do not teach a method wherein the transplant recipient has no clinically indicated need for a biopsy (clm 16). The combined references do 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, Dedrick, and Wong 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.
11. Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Woodward (US 2016/0145682 Pub 5/26/2016) in view of Dedrick (Journal of Immunotoxicology 4:201-207, 2007) and Wong (Expert Opinion on Emerging Drugs 22:2 123-136) as applied to claim 11 and 25 above and in further view of Coenye (Biofilm 3 (January 13, 2021) 100043).
The teachings of Woodward, Dedrick, and Wong are presented above.
The combined reference do 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, Dedrick, and Wong 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.
Response To Arguments
12. In the response the Applicants traversed the rejections under 35 USC 102/103. Applicants argue that claim 11 recites features that are not disclosed in the prior art.
The extensive amendments made to claim 11 necessitated a new searched aimed at identifying the prior art most relevant to the claims as amended and consideration of that prior art with regard to whether it rendered obvious the claimed invention. The amended claims have been deemed obvious in view of the prior art for the reasons set forth above.
13. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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