DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDS) filed 21 December 2023 (#1 disclosing 6 NPL; #2 disclosing 33 U.S. Patents, 2 U.S. Patent Application Publications, 2 Foreign Patent Documents, and 50 NPL) and 18 June 2024 are considered, initialed, and attached hereto.
Claim Status
Claims 1-18 are pending and under examination.
Specification
The disclosure is objected to because of the following informalities:
In [000262], there is reference to “brown” in Figures 10A-10E and 11A-11E. No color drawings have been accepted at this time. No color drawings appear to have been filed. If applicant wishes to include color drawings, a petition would have to be filed under 37 CFR 1.84(a)(2) or (b)(2) and granted.
Throughout the specification, Chronic Kidney Disease is abbreviated as both CDK and CKD, consistency across the application is required.
Appropriate correction is required.
The use of the terms IDEXX, TaqMan, SYBR, Roche, BIACORE, Texas Red, DNASTAR, Applied Biosystems, Life Technologies, TWEEN, Qiagen, RNeasy, Nanodrop, and Quantstudio, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 11 is objected to because of the following informalities: the list of DNA polymerase, blocking oligonucleotides, buffers, and a detecting label is inconsistently delimited with semicolons in some locations and commas in others. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
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 15-18 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.
Claim 15 recites the limitation "the sample" in line 3. There is insufficient antecedent basis for this limitation in the claim. Claims 16-18 are rejected based on their dependency on claim 15.
Claim 15 recites the limitation "the primers" in lines 7-8. There is insufficient antecedent basis for this limitation in the claim. Claims 16-18 are rejected based on their dependency on claim 15.
Claim 15 recites the limitation "the reaction tubes" in line 9. There is insufficient antecedent basis for this limitation in the claim because it is unclear whether it refers to the sample reaction tubes, positive reaction tubes, negative reaction tubes, or some combination thereof (the recitation “a […] sample reaction tube” includes plural references per instant specification [00046]). Claims 16-18 are rejected based on their dependency on claim 15.
Claim 15 recites the limitation "FAP" in line 9. It is unclear in claim 15 what FAP is an acronym for. Claims 16-18 are rejected based on their dependency on claim 15.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Brokopp et al. (US 2013/0156785, published 20 June 2013), herein Brokopp.
Regarding claim 1, Brokopp teaches a PCR diagnostic assay comprising quantifying the amount the amount of fibroblast activation protein (FAP) nucleic acid present in a sample from a subject (“a method of determining the presence of an inflammatory disease and/or cardiovascular disease or condition in a patient is provided comprising assaying a sample taken from said patient for expression of FAP” [0011]; “A method of determining the presence of an inflammatory and/or cardiovascular disease or condition in a patient comprising assaying (i) a sample of a body fluid taken from said patient for expression of Fibroblast Activation Protein (FAP)” Claim 1; “The relative number of FAP mRNA gene transcripts in cells can also be determined by reverse transcription of FAP mRNA gene transcripts, followed by amplification of the reverse-transcribed transcripts by polymerase chain reaction (RT-PCR). The levels of FAP mRNA gene transcripts can be quantified in comparison with an internal standard” [0079]. Claim 1 recites an intended use of the assay: “for differentially identifying early stage Chronic Kidney Disease (CDK) from late stage CDK in a subject”. MPEP §2111.02 II. states: “To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim.” The PCR diagnostic assay comprising quantifying the amount of FAP nucleic acid present in a sample from a subject is capable of performing the intended use as recited. Therefore, Brokopp anticipates claim 1.
Regarding claim 2, Brokopp teaches the PCR diagnostic assay of claim 1 as discussed above, wherein the subject is a companion animal selected from cats, dogs, or horses (“"Subject" as used herein might be defined to include human, domestic (e.g. cats, dogs etc.), agriculture (e.g. cows, horses, sheep etc.)” [0041]).
Regarding claim 3, Brokopp teaches the PCR diagnostic assay of claim 2 as discussed above, wherein the companion animal is a cat (“cats” [0041]).
Regarding claim 4, Brokopp teaches the PCR diagnostic assay of claim 1 as discussed above, wherein the sample is urine (“the term "body fluid" relates to fluids e.g. […] urine” [0043]).
Regarding claim 5, Brokopp teaches the PCR diagnostic assay of claim 1 as discussed above, wherein the nucleic acid is mRNA (“The relative number of FAP mRNA gene transcripts” [0079]).
For the reasons above, claims 1-5 are anticipated by Brokopp.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Brokopp et al. (US 2013/0156785, published 20 June 2013), herein Brokopp, as applied to claims 1-5, in view of Mortimer et al. (US 2019/0085406, published 21 March 2019), herein Mortimer.
Regarding claim 6, Brokopp teaches the PCR diagnostic assay of claim 5 as discussed in the 35 U.S.C. 102 rejection above. However, Brokopp does not teach that the mRNA is isolated from endosomes in the urine. This deficiency is made up for in the teachings of Feldman.
Regarding claim 6, Mortimer teaches the isolation of mRNA from endosomes (“one or more of the cell-free nucleic acids are isolated from […] endosomes” [0140]; “A cell-free nucleic acid can be a ribonucleic acid (“RNA”), e.g., mRNA” [0126]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine the method of mRNA isolation taught by Mortimer with the method of Brokopp that involves quantification of FAP mRNA. In combination the method of Mortimer isolates mRNA from which FAP mRNA is quantified by the method of Brokopp, so both methods merely perform the same function as they do separately. One of ordinary skill in the art would have a reasonable expectation of success in this combination because the mRNA isolated by the method of Mortimer is a standard input to the method of quantification as taught by Brokopp. Therefore, the invention as a whole of claim 6 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Feldman et al. (in IDS filed 18 June 2024)(US 2020/0081008, published 12 March 2020), herein Feldman, in view of Mortimer et al. (US 2019/0085406, published 21 March 2019), herein Mortimer.
Regarding claim 7, Feldman teaches a PCR diagnostic assay (“A method of the disclosure can comprise detecting the presence of a biomarker […] A biomarker can be used for diagnosis” [0052]; “Biomarker detection can comprise use of […] polymerase chain reaction (PCR) including PCR-based methods such as RT-PCR and quantitative PCR (qPCR)” [0103]) comprising obtaining a urine sample from the subject (“A biological sample can be […] urine” [0084]), using mRNA as a template to produce cDNA by reverse transcription (“RNA can be isolated from the sample with a suitable technique […] the isolated RNA sample can be processed further without storage. The RNA can be reverse-transcribed (e.g., using RT-PCR) to generate cDNA” [0102]), amplifying the cDNA by reacting the cDNA with primers to make an amplification product (“The cDNA can be amplified” [0102]; “Biomarkers can be assayed by allele-specific PCR, which can include specific primers to amplify” [0107]), and quantitating or detecting the amplification product (“qPCR can be performed on the cDNA […] Data from the qPCR can be analyzed to detect expression levels” [0102]). However, while Feldman teaches isolation of mRNA from exosomes in urine (“An exosome can be a source of a biomarker. Exosomes can be present in […] urine” [0091]; “Expression analysis can be carried out on, for example, RNA extracted from exosome” [0105]), Feldman does not teach isolation of mRNA from endosomes. Claim 7 recites an intended use of the assay: “for differentially identifying early stage Chronic Kidney Disease (CDK) from late stage CDK in a subject”. MPEP §2111.02 II. states: “To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim.” The PCR diagnostic assay comprising quantifying an amplification product derived from mRNA present in a sample from a subject is capable of performing the intended use as recited.
Regarding claim 7, Mortimer teaches the isolation of mRNA from endosomes (“one or more of the cell-free nucleic acids are isolated from […] endosomes” [0140]; “A cell-free nucleic acid can be a ribonucleic acid (“RNA”), e.g., mRNA” [0126]).
Regarding claim 8, Feldman teaches that the subject is a companion animal selected from cats, dogs, or horses (“Subjects can be […] horses […] dogs, and cats” [0144]).
Regarding claim 9, Feldman teaches that the companion animal is a cat (“Subjects can be […] cats” [0144]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine the method of mRNA isolation taught by Mortimer with the method of Feldman that involves quantification of mRNA. In combination the method of Mortimer isolates mRNA from which mRNA is quantified by the method of Feldman, so both methods merely perform the same function as they do separately. One of ordinary skill in the art would have a reasonable expectation of success in this combination because the mRNA isolated by the method of Mortimer is a standard input to the method of quantification as taught by Feldman. Therefore, the invention as a whole of claims 7-9 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claims 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Feldman et al. (in IDS filed 18 June 2024)(US 2020/0081008, published 12 March 2020), herein Feldman, in view of Mortimer et al. (US 2019/0085406, published 21 March 2019), herein Mortimer, as applied to claims 7-9 above, and further in view of Golz et al. (in IDS filed 18 June 2024)(US 2009/0010919, published 8 January 2009), herein Golz.
Regarding claim 12, the combination of Feldman and Mortimer teach the PCR diagnostic assay of claim 7 as discussed above. However, Feldman and Mortimer do not teach that the amplification product is analyzed using a probe specific for FAP to determine if FAP is present.
Regarding claim 12, Golz teaches a method of PCR wherein the amplification produce is analyzed using a probe specific for FAP to determine if FAP is present (“PCR provides additional uses for oligonucleotides based upon the nucleotide sequence which encodes FAP. Such probes used in PCR may be of recombinant origin, chemically synthesized, or a mixture of both. Oligomers may comprise discrete nucleotide sequences employed under optimized conditions for identification of FAP” [0063]; “Fluorogenic nuclease assays are a real time quantitation method that uses a probe to monitor formation of amplification product. The basis for this method of monitoring the formation of amplification product is to measure continuously PCR product accumulation using a dual-labelled fluorogenic oligonucleotide probe, an approach frequently referred to in the literature simply as the "TaqMan method"” [0073]).
Regarding claim 13, Golz teaches a method of PCR wherein the probe includes a fluorophore as a fluorescent label (“The labels used for labeling the probes or primers of the current invention and which can provide the signal corresponding to the quantity of amplification product can take a variety of forms […] labels which can be employed include, but are not limited to, fluorophors” [0087]).
Regarding claim 14, Golz teaches a method of PCR wherein the fluorophore is FAM (“labels useful for attachment to probes or primers are commercially available including fluorescein and various fluorescein derivatives such as FAM” [0088]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the analysis by quantification of the amplification product using a probe specific for FAP, as taught by Golz, for the analysis by quantification of the amplification product of a biomarker in the PCR diagnostic assay taught by the combination of Feldman and Mortimer. One of ordinary skill in the art would be able to perform this substitution and would expect that the results of the substitution would be predictable because both methods are concerned with the quantification of PCR and the substitution merely exchanges one target for another and one method of quantification for another. Therefore, the invention as a whole of claim 12-14 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Golz et al. (in IDS filed 18 June 2024)(US 2009/0010919, published 8 January 2009), herein Golz, in view of Qiagen ("PCR controls", https://www.qiagen.com/us/knowledge-and-support/knowledge-hub/bench-guide/pcr/reference-genes-and-controls/pcr-controls, retrieved from Wayback Machine snapshot dated 28 April 2021).
Regarding claim 15, Golz teaches a PCR diagnostic assay (“PCR provides additional uses for oligonucleotides based upon the nucleotide sequence which encodes FAP […] identification of FAP in specific tissues or diagnostic use” [0063]) comprising (a) extracting mRNA from a sample obtain from a subject (“The polynucleotide sequences encoding FAP may be used […] in PCR technologies […] utilizing fluids or tissues from patient biopsies” [0353]; “Total cellular RNA was isolated from cells” [0398]); (b) using a reverse transcriptase reaction to obtain a cDNA template (“For relative quantitation of the mRNA distribution of FAP, total RNA from each cell or tissue source was first reverse transcribed […] Omniscript reverse transcriptase” [0397]; “FAP cDNA molecules can be made with standard molecular biology techniques, using FAP mRNA as a template” [0095]); (c) adding the cDNA into PCR tubes of a PCR reaction system to obtain a corresponding sample reaction tube, wherein the PCR reaction system contains the primers for detecting FAP (“An amplification technique, such as PCR, can be used to obtain additional copies of polynucleotides of the invention, using […] cDNA as a template” [0095]; “For relative quantitation of the distribution of FAP mRNA in cells and tissues the Perkin Elmer ABI Prism 7700 Sequence Detection system or Biorad iCycler was used […] PCR reactions were set up to quantitate FAP […] The FAP forward primer sequence was: Primer1 (SEQ ID NO: 3). The FAP reverse primer sequence was Primer2 (SEQ ID NO: 4) […] template cDNA” [0398]; “The ABI 7700 […] to quantify the relative amount of PCR target contained within each tube” [0075-0076]); (d) performing a PCR reaction by placing the reaction tubes on a PCR instrument, setting parameters, and performing PCR reaction to produce a FAP amplification product (“For relative quantitation of the distribution of FAP mRNA in cells and tissues the Perkin Elmer ABI Prism 7700 Sequence Detection system or Biorad iCycler was used […] PCR reactions were set up to quantitate FAP […] Thermal cycling parameters were 2 min at 50°C., followed by 10 min at 95°C., followed by 40 cycles of melting at 95°C. for 15 sec and annealing/extending at 60°C. for 1 min” [0398]); quantifying the FAP in the sample as compared to a control; wherein the presence of FAP amplification product indicates the presence of fibrosis (“Differences in threshold cycle number are used to quantify the relative amount of PCR target contained within each tube” [0076]; “Gastrointestinal diseases comprise […] fibrosis” [0205]; “the human FAP or mRNA can be utilized to diagnose of gastroenterological disorders” [0206]; “If the amount of signal in the patient sample is significantly altered from that of a comparable control sample, […] the presence of altered levels of nucleotide sequences encoding FAP in the sample indicates the presence of the associated disorder” [0354]). Claim 15 recites an intended use of the assay: “for differentially identifying early stage Chronic Kidney Disease (CDK) from late stage CDK in a subject”. MPEP §2111.02 II. states: “To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim.” The PCR diagnostic assay comprising quantifying the FAP in a sample from a subject is capable of performing the intended use as recited.
Regarding claim 15, however, Golz does not teach the use of a positive control. This deficiency is made up for in the teachings of Qiagen.
Regarding claim 15, Qiagen teaches using a positive control in PCR reactions and that these can be used to provide quantitative information or for testing for the presence or absence of a target (“A positive control can be an absolute standard, which is a nucleic acid template of known copy number that provides quantitative information […] A positive control can also be a known positive sample, which is usually a substitute for an absolute standard and used only to test for the presence or absence of a target”; page 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify or combine the method of quantifying FAP in a PCR diagnostic assay of Golz with the teaching of using a positive control in PCR assays of Qiagen. Qiagen’s teaching that positive controls enable quantification would motivate one of ordinary skill to combine it with the method of Golz because the method of Golz uses the quantification of a target, FAP, to diagnose. One of ordinary skill in the art would have a reasonable expectation of success in the combination of Golz and Qiagen because both are concerned with performing PCR assays and the inclusion of a positive control does not harm the ability for the other reactions of the assay to take place. Therefore, the invention as a whole of claim 15 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claims 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Golz et al. (in IDS filed 18 June 2024)(US 2009/0010919, published 8 January 2009), herein Golz, in view of Qiagen ("PCR controls", https://www.qiagen.com/us/knowledge-and-support/knowledge-hub/bench-guide/pcr/reference-genes-and-controls/pcr-controls, retrieved from Wayback Machine snapshot dated 28 April 2021) as applied to claim 15 above, and further in view of Brokopp et al. (US 2013/0156785, published 20 June 2013), herein Brokopp.
Regarding claim 16, the combination of Golz and Qiagen teach the PCR diagnostic assay of claim 15 as discussed above. However, Golz and Qiagen do not teach that the subject is a companion animal selected from cats, dogs, or horses.
Regarding claim 16, Brokopp teaches a PCR diagnostic assay measuring FAP wherein the subject is a companion animal selected from cats, dogs, or horses (see 35 U.S.C. 102 rejections of claims 1 and 2).
Regarding claim 17, Brokopp teaches a PCR diagnostic assay measuring FAP wherein the companion animal is a cat (see 35 U.S.C. 102 rejections of claims 1-3).
Regarding claim 18, Brokopp teaches a PCR diagnostic assay measuring FAP wherein the sample is urine (see 35 U.S.C. 102 rejections of claims 1 and 4).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the subjects and samples taught by Brokopp for the subjects and samples taught by the combination of Golz and Qiagen. One of ordinary skill in the art would be able to substitute the subject and samples of Brokopp for the subjects and samples in the combination of Golz and Qiagen and would expect that the results of the substitution would be predictable because both Brokopp and Golz use the samples from subjects for quantifying FAP mRNA in the samples, so the substitution is merely exchanging inputs to the PCR assay that are known to be usable in PCR assays. Therefore, the invention as a whole of claims 16-18 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Allowable Subject Matter
Claims 10 and 11 are objected to as being dependent upon a rejected base claim (claim 7), but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Claim 10 is free of the prior art because the prior art does not contain a primer having a nucleotide sequence as set forth in SEQ ID NO:7. Claim 11 is free of the prior art by virtue of its dependency on claim 10.
Conclusion
Claims 1-9 and 12-18 are rejected. Claims 10-11 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jeffrey Lawrence Bellah whose telephone number is (571)272-1024. The examiner can normally be reached M-Th, 7:30-5 ET.
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/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683