DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of the species election in the reply filed on 12/30/2025 is acknowledged. Claims 5, 18-20, 22, & 23 are withdrawn due to species elections. The traversal is on the ground(s) for the reasons set for in the Applicant’s response dated 08/18/2025 which the Applicant maintains that the claims are drawn to a single unified inventive concept and do not impose a serious burden of search or examination. This is not found persuasive because this is Further, with regards to a serious burden of search of examination, as discussed in the previous office action dated 06/18/2025, the species of patentably distinct species require a different field of search such as searching different classes/subclasses or employing different search strategies.
The requirement is still deemed proper and is therefore made FINAL.
A first office action on the merits of claims 1-4, 6-17, & 21 with the species elections as described above in paragraph 2 is set forth herein.
Priority
4. The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/276,494, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The provisional application, 63/276,494, does not have support for all of the limitations in claim 1 of the instant application. The provisional application, 63/276,494, does not provide support for specific exosome biomarkers and microRNAs listed in claim 1. For example, the provisional application, 63/276,494, does not provide support for CD9, CD81, miR-10a, miR-21, miR-101, miR-125, miR-145, and miR-146a. Accordingly, claim 1 and dependent claims 2-4, 6-17, & 21 are not entitled to the benefit of the prior applications. Therefore, claims 1-4, 6-17, & 21 are given an effective priority date of 11/03/2022.
Information Disclosure Statement
The listing of references in the specification, at pages 147-151, is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 6-17, & 21 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.
Regarding claim 1, the claim recites the limitations of “the chronic lung disease” in line 6 and “the disease” in line 34 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the chronic lung disease” and “the disease” is meant to refer back to “a progressive chronic lung disease” in line 4 of the claim or refers to a different chronic lung disease. In addition, the recitation of “characterizing the purified enriched population of exosomes, wherein.” In lines 13 of the claim is unclear if there is a typographical error and should read “characterizing the purified enriched population of exosomes, wherein:” . In addition, the claim recites the limitation of “the purified enriched population of exosomes” in line 11 of the claim and there is insufficient antecedent basis for this limitation in the claim. In addition, the claim recites the limitation of “the population of exosomes” in lines 14, 16, 18, 20, 22, 24, 26, & 36 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the population of exosomes” is meant to refer back to “the purified enriched population of exosomes” in line 13 of the claim or refers to a different population of exosomes. In addition, the recitation of “size of exosomes in the population of exosomes ranges from 30 m to 150 μm” in lines 16-17 of the claim is unclear. It is unclear how a population of exosomes can be in a range starting at a larger size of 30m to a range of a smaller size of 150μm. In addition, the instant specification at paragraph [00212] teaches that the term “exosomes” is used to refer to extracellular bilayered membrane bound vesicles of endosomal origin in a size range of around 40 to 160 nm in diameter. Therefore, it is also unclear, as the specification of the instant application defines exosomes as having a size range of about 40 to 160nm, if the recitation is the result of a typographical error and should read “size of exosomes in the population of exosomes ranges from 30 nm to 150 nm”. Finally, the recitation of “comprises a total protein of at least 100-200 μg” in lines 18-19 of the claim is unclear if “a total protein of at least 100-200 μg” refers to one type of protein with a size of at least 100-200 μg or refers to a total protein content of at least 100-200 μg in the sample.
Regarding claim 2, the recitation of “is quantified by determining forced expiratory volume (FEV1); forced vital capacity (FVC) and FEV/FVC %” in lines 2-3 of the claim is unclear. It is unclear if FVC and FEV/FVC quantify the same lung function, or if this is the result of a typographical error and should read “is quantified by determining forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV/FVC %”.
Regarding claim 3, the recitation of “urine, bile, pancreatic juice, cerebrospinal fluid or a peritoneal fluid” in lines 2-3 of the claim is unclear. It is unclear if cerebrospinal fluid and peritoneal fluid are a part of the same biological sample type, or if this is the result of a typographical error and should read “urine, bile, pancreatic juice, cerebrospinal fluid, or a peritoneal fluid”.
Regarding claim 10, the claim recites the limitation “the chronic lung disease” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the chronic lung disease” is meant to refer back to “a progressive chronic lung disease” in line 4 of claim 1, from which claim 10 depends from, or refers to a different chronic lung disease. In addition, the recitation of “progressive inflammation, progressive fibrosis or a combination thereof” in lines 2-3 of the claim is unclear. It is unclear if progressive fibrosis or a combination are a part of the same group of types of symptoms in a chronic lung disease, or if this is the result of a typographical error and should read “progressive inflammation, progressive fibrosis, or a combination thereof”.
Regarding claim 11, the claim recites the limitation “the fibrotic lung disease” in line 1 of the claim and there is insufficient antecedent basis for this limitation in the claim.
Regarding claim 12, the claim recites the limitation of “the population of exosomes” in lines 2-3, 6-7, 10, 14, 17-18, 20, & 24 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the population of exosomes” is meant to refer back to “the purified enriched population of exosomes” in line 13 of claim 1, from which claim 12 ultimately depends from, or refers to a different population of exosomes.
Regarding claim 13, the recitation of “inflammation, an excess accumulation of extracellular matrix, cell senescence; or a pathway comprising fibrogenic signaling” in lines 2-3 of the claim is unclear. It is unclear if a pathway comprising fibrogenic signaling is a part of the same group of types of modulation, or if it is part of its own independent group, or if this is the result of a typographical error and should read “inflammation, an excess accumulation of extracellular matrix, cell senescence, or a pathway comprising fibrogenic signaling”.
Regarding claim 14, the recitation of “c-Jun, AKT expression and MMP-9 activity” in lines 2-3 of the claim is unclear. It is unclear if AKT expression and MMP-9 activity are a part of the same markers for fibrosis, or if this is the result of a typographical error and should read “c-Jun, AKT expression, and MMP-9 activity”.
Regarding claim 15, the recitation of “a mitogen-activated protein kinase pathway, a phosphoinositide 3-kinase pathway; a canonical Wnt-β catenin pathway, and a Notch signaling pathway” in lines 2-4 of the claim is unclear. It is unclear if a pathway comprising a canonical Wnt-β catenin pathway and a Notch signaling pathway is a part of the same group of pathways comprising fibrogenic signaling, or if it is part of its own independent group, or if this is the result of a typographical error and should read “a mitogen-activated protein kinase pathway, a phosphoinositide 3-kinase pathway, a canonical Wnt-β catenin pathway, and a Notch signaling pathway”.
Regarding claim 17, the claim recites the limitation “the fibrotic disease” in lines 1-2 of the claim and there is insufficient antecedent basis for this limitation in the claim and it is unclear if “the fibrotic disease” is meant to refer back to “a fibrotic lung disease” in line 30 of claim 1, from which claim 17 depends from, or refers to a different fibrotic disease.
Claims 4 & 6 are rejected due to their dependence on claim 3, claims 7-9 are rejected due to their dependence on claim 1, claim 16 is rejected due to its dependence on claim 13, and claim 21 is rejected due to its dependence on claim 17.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4 & 6-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method for noninvasively diagnosing and staging a progressive lung disease by diagnosing and determining a stage of chronic lung disease comprising characterizing two or more exosome biomarkers and comprising dysregulated expression of two or more microRNAs, and medically managing the diagnosed the fibrotic lung disease. This recitation is a natural correlation between chronic fibrotic lung disease and expression of two or more exosome biomarkers and two or more microRNAs. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites determining a stage of the chronic lung cancer which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of collecting biological sample, centrifuging and ultracentrifuging, characterizing expression of two or more exosome biomarkers and two or more microRNAs, and medical management through treatment, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
Although the claims recite “treating the diagnosed fibrotic lung disease” and “administering an active therapeutic agent including an immunomodulator, an analgesic, an anti-inflammatory agent, an anti-fibrotic agent, an anti-viral agent, a proton pump inhibitor, or oxygen therapy” to the subject, this step is conditional as it is requires diagnosis of fibrotic lung disease with the expression of two or more exosome biomarkers and two or more microRNAs. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of detecting gene expression. As such, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the step of collecting a biological sample is considered insignificant post solution activity. The steps of detecting exosome biomarker and microRNA expression are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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(s) 1, 2, & 7-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Njock (Njock et al.; Thorax, Vol. 74, pages 309-312, September 2018), as cited on the IDS dated 04/12/2023, in view of Yang (Yang et al.; Gene, Vol. 562, pages 138-144, February 2015), as cited on the IDS dated 04/12/2023, Zhao (Zhao et al.; Scientific Reports, Vol. 10, pages 1-16, March 2020), and Zhu (Zhu et al.; ThermoFisher Scientific presentation, "A comparative Proteomics Study of Six Serum Exosome Isolation Procedures", 2020).
Regarding claim 1, it is noted as discussed above, the recitation of “size of exosomes in the population of exosomes ranges from 30 m to 150 μm” in lines 16-17 of the claim is unclear. It is unclear how a population of exosomes can be in a range starting at a larger size of 30m to a range of a smaller size of 150μm. In addition, the instant specification at paragraph [00212] teaches that the term “exosomes” is used to refer to extracellular bilayered membrane bound vesicles of endosomal origin in a size range of around 40 to 160 nm in diameter. Therefore, it is also unclear, as the specification of the instant application defines exosomes as having a size range of about 40 to 160nm, if the recitation is the result of a typographical error and should read “size of exosomes in the population of exosomes ranges from 30 nm to 150 nm”. Therefore, for the purposes of this rejection, the claim is given its broadest reasonable interpretation and is interpreted to recite “size of exosomes in the population of exosomes ranges from 30 nm to 150 nm”.
Njock teaches a method for detecting dysregulated miRNA levels and detection of exosome biomarkers for diagnosis and determination of disease severity in patients with idiopathic pulmonary fibrosis (IPF), a progressive fibrosing interstitial lung disease (progressive chronic fibrotic lung disease), comprising collecting biological samples from IPF patients and healthy subjects, centrifuging the samples at 800g (low speed) to form and collect a supernatant (clarified supernatant), ultracentrifuging the collected supernatant (clarified supernatant) to isolate and obtain purified enriched population of exosomes, and characterizing the enriched population of exosomes through expression of CD63, CD9, and CD81 (two or more exosome biomarkers selected from CD9 and CD63), and measuring the differentially expressed miRNA expression (dysregulated expression) of various miRNAs including miRNA-142-3p and miRNA-let-7d-5p (two or more microRNAs) for diagnosis, measuring IPF progression (monitoring overtime the population of exosomes derived from IPF patients compared to healthy subjects), and treatment through therapeutic approaches (medically managing the diagnosed fibrotic lung disease to reduce or slow its progression) (abstract lines 1-14; pg. 310-311 paragraph bridging pg. 310 & 311 lines 1-26; Figure 1; Figure 2; supplementary methods and materials pg. 2 1st full paragraph lines 1-14; supplementary methods and materials pg. 2 2nd full paragraph lines 1-11; supplementary methods and materials pg. 3 1st full paragraph lines 1-11; supplementary Table S1). Njock also teaches that the average size distribution of the exosomes is 140nm ± 19.1 nm (size of exosomes ranges from 30 to 150nm) and measuring the total protein level and RNA content in the isolated exosome populations (pg. 310-311 paragraph bridging pg. 310 & 311 lines 1-2; Figure 1; supplementary methods and materials pg. 3 1st full paragraph lines 10-11; supplementary methods and materials pg. 3 2nd full paragraph lines 1-2).
Njock does not teach that the population of exosomes comprises a total protein content of at least 100-200 μg, total RNA content of at lease 100-200 ng, number of exosomes at least 10E10 particles, or that measuring dysregulated miRNAs comprises measuring the expression of miR-199.
Yang teaches measuring differentially expressed miRNA expression in patients with IPF compared to healthy control subjects comprising measuring the expression of miR-199a-5p and miR-let-7d (measuring dysregulated expression of two or more microRNAs) (abstract methods lines 1-5; abstract results lines 1-13). Yang also teaches that measuring differential expression in the identified miRNAs aids in diagnosis, prognosis, and treatment of IPF (pg. 143 column 1 3rd full paragraph lines 1-5).
Zhao teaches isolating and measuring exosomes from human, rat, and mouse samples for miRNA analysis in which the total RNA content was 50 to 200 ng per 500 μL of sample (exosomes comprises a total RNA content of at least 100-200 ng) and a total concentration of exosome particles were 1.12E12 (number of exosomes comprises at least 10E10 particles) (abstract lines 1-9; pg. 2 2nd full paragraph lines 1-6; Figure 1; Figure 2). In addition, Zhao teaches that their method confirms the rationality of exploring exosome miRNAs as noninvasive biomarkers in samples from human, rat, and mouse (abstract lines 1-12).
Zhu teaches methods of isolating exosomes from human samples with ultracentrifugation with various different commercial exosome isolation kits and measuring the total protein content using the different isolation procedures in which some procedures isolated a total protein content of 190-348 μg/mL of sample (exosomes comprises a total RNA content of at least 100-200 μg) (abstract methods lines 1-9; Figure 1). In addition, Zhu teaches that different procedures can be used when determining desired exosome protein yield from exosome isolation procedures (conclusions paragraph 1 lines 1-4).
Njock, Yang, Zhao, and Zhu are considered to be analogous to the claimed invention because they are all in the same field of exosome isolation and analysis of exosome miRNA or protein contents. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting dysregulated miRNA levels and detection of exosome biomarkers for diagnosis and determination of disease severity in patients with idiopathic pulmonary fibrosis (IPF) comprising measuring expression of CD63, CD9, and CD81 (two or more exosome biomarkers selected from CD9 and CD63) and measuring the differentially expressed miRNA expression (dysregulated expression) of various miRNAs including miRNA-142-3p and miRNA-let-7d-5p (two or more microRNAs) in Njock to incorporate measuring the differential expression of miR-199a-5p in IPF patients as taught in Yang because Yang teaches that doing so would identify differentially expressed miRNAs that aid in diagnosis, prognosis, and treatment of IPF. In addition, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of isolating exosomes and measuring the total protein level and RNA content in the isolated exosome populations obtained from IPF patients in Njock to incorporate measuring a total RNA content was 50 to 200 ng per 500 μL of sample (exosomes comprises a total RNA content of at least 100-200 ng) and a total concentration of exosome particles were 1.12E12 (number of exosomes comprises at least 10E10 particles as taught in Zhao and to incorporate measuring a total protein content of 190-348 μg/mL of sample (exosomes comprises a total RNA content of at least 100-200 μg) as taught in Zhu because Zang and Zhu teaches that these methods of isolating exosomes exploring exosome miRNAs as noninvasive biomarkers and determining desired exosome protein yield from exosome isolation procedures.
Regarding claim 2, Njock teaches quantifying lung function by determining FEV1, FVC, and the percentage of FEV1/FVC in patients (supplementary methods and materials pg. 2 1st full paragraph lines 10-11; supplementary Table S1).
Regarding claim 7, Njock teaches the patient biological sample is obtained from a human subject (supplementary methods and materials pg. 2 1st full paragraph lines 10-11; supplementary Table S1).
Regarding claim 8, Njock teaches the patient biological sample is obtained from a human subject (supplementary methods and materials pg. 2 1st full paragraph lines 10-11; supplementary Table S1).
Regarding claim 9, Njock teaches the comparison of the expression between patients with IPF compared to healthy control subjects were modeled by adjusting for age and sex (healthy control is age and sex matched to the subject (pg. 311 column 1 2nd full paragraph lines 1-10; Figure 2).
Regarding claims 10 & 11, Njock teaches diagnosis and determination of disease severity in patients with idiopathic pulmonary fibrosis (IPF), a progressive fibrosing interstitial lung disease (progressive chronic fibrotic lung disease is IPF) (abstract lines 1-14).
Regarding claim 12, Njock teaches that the expression of miR-let-7d-5p is downregulated in patients biological samples with IPF compared to healthy control subjects (expression of one or more of miR-let-7d in a population of exosomes derived from the biological sample of the subject compared to a healthy control is decreased) (pg. 310-311 paragraph bridging pg. 310 & 311 lines 12-18; Figure 1; Figure 2).
Yang teaches that expression of miR-199a-5p is significantly increased in IPF patients compared to healthy controls and the expression of miR-let-7d is significantly under expressed in IPF patients compared to healthy controls (expression of miR-199 in a population of exosomes from the biological sample compared to a healthy control is increased and the expression of one or more of miR-let-7d in a population of exosomes derived from the biological sample of the subject compared to a healthy control is decreased) (abstract results lines 8-13).
Claim(s) 3, 4, & 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Njock (Njock et al.; Thorax, Vol. 74, pages 309-312, September 2018), as cited on the IDS dated 04/12/2023, Yang (Yang et al.; Gene, Vol. 562, pages 138-144, February 2015), as cited on the IDS dated 04/12/2023, Zhao (Zhao et al.; Scientific Reports, Vol. 10, pages 1-16, March 2020), and Zhu (Zhu et al.; ThermoFisher Scientific presentation, "A comparative Proteomics Study of Six Serum Exosome Isolation Procedures", 2020) as applied to claims 1, 2, & 7-12 above, and further in view of Klass (United States Patent Application Publication US 2017/0108503 A1, April 2017), as cited on the IDS dated 04/12/2023.
The teaches of Njock, Yang, Zhao, and Zhu with respect to claim 1 is discussed above.
Regarding claims 3, 4, & 6, Njock, Yang, Zhao, and Zhu does not teach the biological sample is a body fluid of urine.
Klass teaches a method for diagnosis of a disease or condition through characterizing exosomes for the identification of biomarkers comprising miRNAs in which exosomes can be obtained from a variety of biological fluid samples including urine (paragraph [0003] lines 1-9; paragraph [0004] lines 1-7; paragraph [0006] lines 1-10; paragraph [0007] lines 1-7; paragraph [0010] lines 1-12; paragraph [0106] lines 1-4). Klass also teaches that this method provides a more sensitive and specific method of disease detection and monitoring and method for therapeutic decision-making (paragraph [0005] lines 1-6).
Njock, Yang, Zhao, Zhu, and Klass are considered to be analogous to the claimed invention because they are all in the same field of exosome isolation and analysis of exosome miRNA or protein contents. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting dysregulated miRNA levels and detection of exosome biomarkers for diagnosis in patients with idiopathic pulmonary fibrosis (IPF) in sputum biological samples in Njock to incorporate the use of urine biological samples as taught in Klass because Klass teaches that doing so would provide a more sensitive and specific method of disease detection and monitoring and method for therapeutic decision-making.
Claim(s) 13, 15, 16, 17, & 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Njock (Njock et al.; Thorax, Vol. 74, pages 309-312, September 2018), as cited on the IDS dated 04/12/2023, Yang (Yang et al.; Gene, Vol. 562, pages 138-144, February 2015), as cited on the IDS dated 04/12/2023, Zhao (Zhao et al.; Scientific Reports, Vol. 10, pages 1-16, March 2020), and Zhu (Zhu et al.; ThermoFisher Scientific presentation, "A comparative Proteomics Study of Six Serum Exosome Isolation Procedures", 2020) as applied to claims 1, 2, & 7-12 above, and further in view of Spagnolo (Spagnolo, Tzouvelekis, & Bonella; Frontiers in Medicine, Vol. 5, pages 1-13, July 2018).
The teaches of Njock, Yang, Zhao, and Zhu with respect to claim 1 is discussed above.
Regarding claims 13, 15, & 16, Njock Yang, Zhao, and Zhu does not teach that medically managing modulates one or more of a pathway comprising fibrogenic signaling.
Spagnolo teaches treatment methods for medically managing a patient with IPF comprising treatment with pirfenidone, a agent with anti-fibrotic, anti-inflammatory, and anti-oxidant properties (medically modulates one or more of a pathway comprising fibrogenic signaling), in which pirfenidone targets mediators in early inflammation including TGF-β pathway (transforming growth factor TGFβ signaling) such as targeting Smad proteins in the pathway (the pathway comprising fibrogenic signaling is one ore more of a Smad pathway) (abstract lines 1-18; pg. 2 column 2 1st full paragraph lines 1-11; pg. 4 column 1 1st full paragraph lines 1-12). Spagnolo also teaches that treatment with agents that modulates fibrogenic signaling are able to slow down functional decline and disease progression with an acceptable safety profile (abstract lines 11-16).
Njock, Yang, Zhao, Zhu, and Spagnolo are considered to be analogous to the claimed invention because they are all in the same field of managing disease progression. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting dysregulated miRNA levels and detection of exosome biomarkers for diagnosis in patients with idiopathic pulmonary fibrosis (IPF) for diagnosis, measuring IPF progression, and treatment through therapeutic approaches in Njock to incorporate medically managing IPF with pirfenidone that modulates fibrogenic signaling as taught in Spagnolo because Spagnolo teaches that doing so would provide a treatment that can slow down functional decline and disease progression of IPF with an acceptable safety profile.
Regarding claims 17 & 21, Spagnolo teaches that the anti-fibrotic agent is pirfenidone or nintedanib (abstract lines 1-18; pg. 2 column 2 1st full paragraph lines 1-11; pg. 4 column 1 1st full paragraph lines 1-12).
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Njock (Njock et al.; Thorax, Vol. 74, pages 309-312, September 2018), as cited on the IDS dated 04/12/2023, Yang (Yang et al.; Gene, Vol. 562, pages 138-144, February 2015), as cited on the IDS dated 04/12/2023, Zhao (Zhao et al.; Scientific Reports, Vol. 10, pages 1-16, March 2020), Zhu (Zhu et al.; ThermoFisher Scientific presentation, "A comparative Proteomics Study of Six Serum Exosome Isolation Procedures", 2020), and Spagnolo (Spagnolo, Tzouvelekis, & Bonella; Frontiers in Medicine, Vol. 5, pages 1-13, July 2018) as applied to claims 13, 15, & 16 above, and further in view of Biernacka (Biernacka, Dobaczewski, & Frangogiannis; Growth Factors, Vol. 29, pages 1-12, October 2011).
The teaches of Njock, Yang, Zhao, Zhu, and Spagnolo with respect to claim 13 is discussed above.
Regarding claim 14, Njock, Yang, Zhao, Zhu, and Spagnolo does not teach that the markers for fibrosis and downstream fibrotic pathways comprise αv-integrin, collagen type I mRNA expression, c-Jun, AKT expression, and MMP-9 activity.
Biernacka teaches TGF-β signaling pathway as the central mediator in fibrogenesis in which markers for fibrosis in this fibrogenic TGF-β signaling pathway comprises αVβ8 integrin (αv-integrin), type I collagen gene transcription, c-Jun-N-terminal kinase, PI3 kinase/AKT, and MMP-9 (abstract lines 1-12; pg. 2-3 paragraph bridging pg. 2 & 3 lines 25-34; pg. 4 2nd full paragraph lines 1-15; pg. 5 1st full paragraph lines 1-6). In addition, Biernacka teaches that understanding the role of TGF-β in fibrosis enables potential for TGF-β-mediated pathways as attractive therapeutic targets for patients with fibrotic conditions.
Njock, Yang, Zhao, Zhu, Spagnolo, and Biernacka are considered to be analogous to the claimed invention because they are all in the same field of managing fibrotic disease progression. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of medically managing a patient with IPF comprising treatment with pirfenidone, an agent with anti-fibrotic agent, in which pirfenidone targets mediators in early inflammation including TGF-β pathway in Spagnolo to incorporate markers for fibrosis comprising αv-integrin, collagen type I mRNA expression, c-Jun, AKT expression, and MMP-9 activity as taught in Biernacka because Biernacka teaches that doing so would enables potential for TGF-β-mediated pathways as attractive therapeutic targets for patients with fibrotic conditions.
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Njock (Njock et al.; Thorax, Vol. 74, pages 309-312, September 2018), as cited on the IDS dated 04/12/2023, Yang (Yang et al.; Gene, Vol. 562, pages 138-144, February 2015), as cited on the IDS dated 04/12/2023, Zhao (Zhao et al.; Scientific Reports, Vol. 10, pages 1-16, March 2020), Zhu (Zhu et al.; ThermoFisher Scientific presentation, "A comparative Proteomics Study of Six Serum Exosome Isolation Procedures", 2020), and Spagnolo (Spagnolo, Tzouvelekis, & Bonella; Frontiers in Medicine, Vol. 5, pages 1-13, July 2018) as applied to claims 13, 15, & 16 above, and further in view of Csete (United States Patent Application Publication US 2020/0384034 A1, December 2020), as cited on the IDS dated 04/12/2023.
The teaches of Njock, Yang, Zhao, Zhu, and Spagnolo with respect to claim 13 is discussed above.
Regarding claim 14, Njock, Yang, Zhao, Zhu, and Spagnolo does not teach that the markers for fibrosis and downstream fibrotic pathways comprise αv-integrin, collagen type I mRNA expression, c-Jun, AKT expression, and MMP-9 activity.
Csete teaches a method of obtaining a urine sample from a subject, isolating exosomes from the sample, measuring levels of miRNAs in the sample, and determining lung injury/disease in which measuring urine-derived exosome expression comprises integrin mRNA, collagen type I mRNA, c-Jun protein, pAKT expression, and MMP-9 activity (paragraph [0068] lines 1-31; paragraph [0289] lines 1-2; paragraph [0290] lines 1-2; paragraph [0291] lines 1-4; paragraph [0292] lines 1-3; paragraph [0293] lines 1-2; paragraph [0368] lines 1-11; FIG. 21). Csete also teaches that this method has utility as both a diagnostic and therapeutic candidate utilized in precision medicine in a subject with pulmonary fibrosis (paragraph [0287] lines 1-7).
Njock, Yang, Zhao, Zhu, Spagnolo, and Csete are considered to be analogous to the claimed invention because they are all in the same field of managing fibrotic disease progression. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of medically managing a patient with IPF comprising treatment with pirfenidone, an agent with anti-fibrotic agent, in which pirfenidone targets mediators in early inflammation including TGF-β pathway in Spagnolo to incorporate markers for fibrosis comprising integrin mRNA, collagen type I mRNA, c-Jun protein, pAKT expression, and MMP-9 activity as taught in Csete because Csete teaches that doing so has utility as both a diagnostic and therapeutic candidate utilized in precision medicine in a subject with pulmonary fibrosis.
Conclusion
Claims 1-4, 6-17, & 21 are rejected.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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