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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/29/2025 has been entered.
Applicant Response
Applicant's response, filed 12/29/2025, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 1-16, 19, 21-31 and 33 are canceled.
Claims 17-18, 20 and 32 are pending and under examination herein.
Claims 17-18, 20 and 32 are rejected.
Priority
The instant application is a Continuation of 15759484 , filed 03/12/2018 ,which is a National Stage entry of PCT/EP2016/071727 , International Filing Date: 09/14/2016, and also claims foreign priority to 15306412.6, filed 09/14/2015. As such, the effective filing date assigned to each of claims 17-18, 20 and 32 is 09/14/2015. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawing were accepted by the examiner in the office action mailed 12/20/2024.
Claim Rejections - 35 USC § 112
The rejections of claims 24 and 33 under 35 U.S.C. 112(b) are withdrawn in view of cancelation of the claims in the claim amendments filed 12/29/2025.
The rejection of claim 20 under 35 U.S.C. 112(b) is withdrawn in view of claim amendments filed 12/29/2025.
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 32 remains rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 32 remains rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: diagnosing a subject with NASH/classifying a subject as a receiver or non-receiver of a treatment for NASH, as the methods of claim 17 on which claim 32 depends from, do not recite any steps for diagnosing/classifying a subject, but rather only recites steps for measuring the levels of biomarkers and combining the levels in a NASH score.
Response to applicant’s arguments
Applicant states claim 32 has been amended to depend from claim 20, which defines the steps (p 7, para 1).
It is respectfully submitted that this is not persuasive, as the amended claim still depends from claim 17.
Claim Rejections - 35 USC § 101
The rejections of claim 20 under 35 U.S.C. 101 were withdrawn in the office action mailed 09/02/2025 view of the claim amendments filed 04/21/2025, which integrated the recited judicial exceptions into practical application, specifically through the administration of the compound of formula (I) to subjects classified as a receiver of the treatment for NASH. Claims 32 appears to be free of a rejection under 35 U.S.C. 101 for the reasons discussed above for claim 20.
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 17-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea/law of nature/natural phenomenon without significantly more. In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). This rejection is newly recited and necessitated by claim amendments.
In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 17 recites (f) specifically combining the level(s) of marker(s) determined in step (d) and the level of hsa-miR-34a-5p determined in step (e) in a NASH score.
These recitations equate to steps of collecting information, analyzing data and making observations, evaluations and judgements that can be carried out in the human mind. Specifically, combining the levels of biomarkers in a NASH score can be practically performing the human mind as claimed, since the mind can combine values to determine a score as broadly claimed and are similar to the concepts of collecting and comparing known information in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011) and collecting information, analyzing it, and reporting certain results of the collection and analysis in Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016) that the courts have identified as concepts that can be practically performed in the human mind. Therefore, each of the above recited limitations fall under the “Mental Processes” grouping of abstract ideas. Furthermore, the steps of determining the score from the biomarker levels equate to organizing information and manipulating information through mathematical correlations and reciting a mathematical equation, similar to the concepts of taking existing information, manipulating the data using mathematical functions, and organizing this information into a new form in Digitech Image Techs., LLC v. Electronics for Imaging, Inc., 758 F.3d 1344, 1350, 111 USPQ2d 1717, 1721 (Fed. Cir. 2014). Therefore, these limitations fall under the “mathematical concepts” grouping of abstract ideas. As such, claims 17-18 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology, applies or uses the recited judicial exception to affect a particular treatment for a condition, implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, effects a transformation or reduction of a particular article to a different state or thing or applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception. Rather, the instant claims recite additional elements that amount to mere data gathering and insignificant extra-solution activity. Specifically, the claims recite the following additional elements:
Claim 17 recites (a) providing blood samples from said subject, (b) separating a cell-free, platelet-free plasma sample from one of said blood samples, (c) extracting total RNA from said cell-free, platelet-free plasma sample, (d) measuring in one of said blood samples obtained in step (a) the level(s) of one or more marker(s) selected from (i) alpha 2 macroglobulin, (ii) glycated haemoglobin (HbAlc) and (iii) N-terminal pro-peptide of collagen type III, each of which is measured by an antibody specific to it, and (e) measuring in the total RNA extracted in step (c) hsa-miR-34a-5p, using a nucleic acid specific to SEQ ID NO:3.
Claim 18 recites wherein the separation of a cell-free, platelet-free plasma sample from one of the blood samples of said subject comprises the following steps: - adding the blood sample in a citrate containing tube, - centrifugating said blood sample at 1,500xg for collecting the supernatant containing the cell-free plasma, and - centrifugating said cell-free plasma at 13,000xg for collecting the supernatant containing the cell-free, platelet-free plasma sample.
Claims 17 and 18 recite limitations for gathering data and equate to mere data gathering activity to obtain the data necessary for the mental evaluations and judgements (see MPEP 2106.05(g)). Furthermore, the courts have found that performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989) and determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) to be mere gathering and therefore do not add more than insignificant extra-solution activity to the judicial exception. There is no indication that any of these additional elements provide a practical application of the recited judicial exception outside of the judicial exception itself. As such, claims 17-18 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). Further analyzing the additional elements under step 2B, the additional elements as described above do not rise to the level of significantly more than the judicial exception. As directed in the Berkheimer memorandum of 19 April 2018 and set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims under the 2B analysis, the instant specification discloses the use of commercial kits, assays and systems for RNA extraction and measuring miRNA markers using nucleic acids specific to the recited SEQ ID. Nos, and therefore these steps are well-understood, routine and conventional (p 22, line 14- p 35; table 2). Furthermore, the courts have found that limitations for determining the level of a biomarker in blood by any means is well-understood, routine and conventional (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)). Therefore, they do not change the conventionality of the additional elements recited in the claims. Furthermore, the prior art to Inglis et al. (J Vis Exp. 2015 Mar 17;(97):52484.; hereafter referred to as Inglis) discloses adding the blood sample into a tube with ACD-Solution A (i.e. a citrate containing tube), centrifuging the samples at 1,500 x g for 10 min at RT to separate the plasma from the buffy coat and red cells, transferring 1.2 ml aliquots of the plasma supernatant to 1.5 ml centrifuge tubes, being careful not to disturb the bottom layers containing the buffy coat and red cells, and then spin at 13,000 x g for 10 min at RT to remove platelets and large cell fragments (p 2, section 1.1; fig 1). Inglis further discloses the differential centrifugation method described here is based on common protocols for isolating PPP, which typically require an initial centrifugation between 1,200-1,500 x g for 10-20 min to remove cells, followed by a second centrifugation between 10,000-13,000 x g for 10-30 min to remove platelets (p 13, para 7).
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 17-18 are not patent eligible.
Claim Rejections - 35 USC § 103
The rejection of claims 23-24, 30 and 33 under 35 U.S.C. 103 are withdrawn in view of cancelation of the claims in the claim amendments filed 12/29/2025.
The rejections of claims 17-18 under 35 U.S.C. 103 as being unpatentable over Wienhues-Thelen et al. (US US20070178442A1; previously cited; hereafter referred to as Wienhues-Thelen), in view of Inglis et al. (J Vis Exp. 2015 Mar 17;(97):52484.; previously cited; hereafter referred to as Inglis), Motawi et al. ( (09/26/2022 IDS, NPL # 5; previously cited; hereafter referred to as Motawi) as evidenced by miRBase (miRNA Entry for MI0000268, 08/26/2015; previously cited) are withdrawn in view of Applicant’s Arguments.
The rejections of claims 20 and 32 under 35 U.S.C. 103 as being unpatentable over Wienhues-Thelen et al. (US US20070178442A1; previously cited; hereafter referred to as Wienhues-Thelen), in view of Inglis et al. (J Vis Exp. 2015 Mar 17;(97):52484.; previously cited; hereafter referred to as Inglis), and Motawi et al. ( (09/26/2022 IDS, NPL # 5; previously cited; hereafter referred to as Motawi) as evidenced by miRBase (miRNA Entry for MI0000268, 08/26/2015; previously cited) and further in view of Darteil et al. (US2012/0252725; previously cited; 09/26/2022 IDS) are withdrawn in view of Applicant’s Arguments.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Wienhues-Thelen et al. (US US20070178442A1; previously cited; hereafter referred to as Wienhues-Thelen), in view of Inglis et al. (J Vis Exp. 2015 Mar 17;(97):52484.; previously cited; hereafter referred to as Inglis), Motawi et al. ( (09/26/2022 IDS, NPL # 5; previously cited; hereafter referred to as Motawi) as evidenced by miRBase (miRNA Entry for MI0000268, 08/26/2015; previously cited), He et al. (Cellular signalling 2012, 24, no. 12: 2268-2272; newly cited; hereafter referred to as He), and Cermelli et al. (PLOS ONE 2011, 6(8): e23937; newly cited). This rejection is newly recited.
With respect to claims 17, Wienhues-Thelen discloses a method for the detection of the presence and/or the severity of a liver disease of NASH, in a patient comprising measuring levels of biomarkers such alpha-2-macroglobulin (A2M) and N-terminal propeptide of type III procollagen (PIIINP) from a blood and plasma sample, and combining and evaluating the obtained data by statistical methods like logistic binary regression to determine the best combinations, resulting in scores to obtain a result in assisting in diagnosing the disease (abstract; claim 1-4; para 0027-para 0028; para 0045; para 0056-0057). For further clarification, Wienhues-Thelen discloses timely and accurate diagnosis of liver fibrosis is essential to effective medical treatment and that the method is also used for monitoring of clinical development of fibrosis during therapeutic treatment, indicating it can be used to classify a patient as a receiver or non-receiver to treatment based on their biomarkers (para 0004; para 0013. Therefore, the idea of combining the levels of measured biomarkers into scores to diagnose/stage NASH or classify the patient as a receiver/non-receiver of treatment is known within the art.
Wienhues-Thelen further discloses A2M may be detected by an immunological assay using specific antibodies according to test formats known to a person skilled in the art and that PIIINP could also be determined immunological methods (para 0044; para 0048).
However, with respect to claim 17, Wienhues-Thelen does not disclose separating a cell-free, platelet free plasma sample from the blood sample or extracting RNA and measuring markers of hsa-miR-34a-5p in the extracted RNA.
With respect to claims 18, Wienhues-Thelen also does not disclose the steps for separating a cell-free, platelet free plasma sample from the blood sample, by adding the blood sample to a citrate containing tube, centrifuging it at 1,500xg and then at 13,000xg.
However, with respect to claims 17, the prior art to Inglis, in the same field of endeavor, discloses processing blood samples to separate a cell-free, platelet-free plasma sample from the blood sample (p 2, section 1.1)
With respect to claims 18, Inglis discloses adding the blood sample into a tube with ACD-Solution A (i.e. a citrate containing tube), centrifuging the samples at 1,500 x g for 10 min at RT to separate the plasma from the buffy coat and red cells, transferring 1.2 ml aliquots of the plasma supernatant to 1.5 ml centrifuge tubes, being careful not to disturb the bottom layers containing the buffy coat and red cells, and then spin at 13,000 x g for 10 min at RT to remove platelets and large cell fragments (p 2, section 1.1; fig 1).
Inglis further discloses the differential centrifugation method described here is based on common protocols for isolating PPP, which typically require an initial centrifugation between 1,200-1,500 x g for 10-20 min to remove cells, followed by a second centrifugation between 10,000-13,000 x g for 10-30 min to remove platelets (p 13, para 7).
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 modify the steps for detecting the presence or severity of NASH using blood and plasma samples as discloses by Wienhues-Thelen, with the method of separating the plasma sample from the blood as disclosed by Inglis, because the differential centrifugation method described here by Inglis is based on common protocols for isolating PPP, as disclosed by Inglis. There would be a reasonable expectation of success because the steps of separating the plasma from the blood sample would not impede the analysis steps of Wienhues-Thelen, and would instead provide samples to use to gather data for the analysis.
With respect to claims 17, Motawi discloses serum microRNAs were deregulated in HCC versus controls (abstract). Motawi also discloses how MiRNAs changed during liver fibrosis progression was explored to determine if they could be a biomarker for liver fibrosis to cirrhosis to HCC, and that serum levels of mature miRNAs were evaluated including has-miR-34a-5p (p 4, para 1-3).Motawi discloses the endpoint is miRNA could discriminate HCC from late fibrosis (p 9, para 2-4; table 3). Motawi further discloses all studied miRNAs were differentially expressed in serum of HCV related HCC patients versus controls (p 13, para 3). Motawi further discloses using miRNA-specific miScript primer assays (p 4, para 3). MiRBase discloses the sequence of has-mir34a-5p is the same as SEQ ID NO:3 disclosed by the instant application (i.e.uggcagugucuuagcugguugu) (p 2).
The instant specification discloses in p 2, lines 5-6 that fibrosis are features of NASH evaluated from biopsies. Motawi teaches monitoring of fibrosis is mandatory as it reflects disease progression, ultimately to HCC, and as liver biopsy for fibrosis staging presents invasiveness, sample variability, and other limitations, circulating miRNAs were proposed as novel non-invasive methods to assess histological disease severity in chronic HCV, and further discloses using miR-34a, and specifically miR-34a-5p, because this was one of the few miRNA associated with liver fibrosis progression in chronic HCV patients (p 2, para 3). This suggests that miR-34a-5p is known to be informative to interpreting fibrosis progression, which is a condition associated with many liver diseases, including NASH.
Furthermore, the prior art to He also discloses liver fibrosis is the excessive accumulation of extracellular matrix that occurs in most types of chronic liver diseases and that it is likely that miR-34a plays a role in the development of liver fibrosis and could also be explored as novel disease markers for the diagnosis or monitoring of the progression of liver fibrosis (p 2268, col 2, para 2; p 2269, col 2, para 1).
This suggests that miR-34a-5p is known to be informative to interpreting fibrosis progression, which is a condition associated with many liver diseases, including NASH.
Furthermore, the prior art to Cermelli et al. also examined whether circulating levels of miR-34a correlate with hepatic histological disease severity in patients with chronic hepatitis C infection (CHC) or non-alcoholic fatty-liver disease (NAFLD), including NASH, and can potentially serve as circulating markers for disease stage assessment, based on studies done on the levels of miR-34a found in HCC (abstract; p 1, col 2, para 1; p 5, col 1, para 1). Therefore, it was known in the art, at the effective filing date for the invention, that miR-34a may be an informative marker for NASH, and the basis for this study were previous studies related to HCC.
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 modify the steps for detecting the presence or severity of NASH using blood and plasma samples as discloses by Wienhues-Thelen, with the method of mRNA profiling of miR-34a-5p disclosed by Motawi, because miR-34a, and specifically miR-34a-5p, is a known biomarker for liver fibrosis as disclosed by Motawi, He and Cermelli et al. There would be a reasonable expectation of success because using miRNA expression levels would not impede the analysis steps of Wienhues-Thelen, and would instead provide more data for the analysis of Wienhues-Thelen to find combinations of biomarkers that can diagnose presence and/or severity of NASH.
Therefore, the invention is prima facie obvious.
Claims 20 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Wienhues-Thelen et al. (US US20070178442A1; previously cited; hereafter referred to as Wienhues-Thelen), in view of Inglis et al. (J Vis Exp. 2015 Mar 17;(97):52484.; previously cited; hereafter referred to as Inglis), Motawi et al. ( (09/26/2022 IDS, NPL # 5; previously cited; hereafter referred to as Motawi) as evidenced by miRBase (miRNA Entry for MI0000268, 08/26/2015; previously cited), He et al. (Cellular signalling 2012, 24, no. 12: 2268-2272; newly cited; hereafter referred to as He), and Cermelli et al. (PLOS ONE 2011, 6(8): e23937; newly cited), as applied to claim 17 above, and further in view of Darteil et al. (US2012/0252725; previously cited; 09/26/2022 IDS). This rejection is newly recited.
With respect to claims 20 and 32, Wienhues-Thelen, in view of Inglis, Motawi as evidenced by miRBase, He and Cermelli discloses the steps of claim 17, as applied above.
With respect to claim 20 Wienhues-Thelen discloses the obtained data is combined and evaluated by statistical methods like logistic binary regression, resulting in scores (para 0057). Wienhues-Thelen further discloses method can be used for monitoring therapeutic treatment of liver fibrosis and staging of liver fibrosis (abstract; claims 3-4).
However, with respect to claims 20 and 32, Wienhues-Thelen does not disclose administering a compound of formula (I) to a subject diagnosed with NASH or classified as a receiver of treatment.
With respect to claims 20 and 32, the prior art to Darteil, in the same field of endeavor, discloses the claimed compound for the treatment of NASH (claims 1, 7, 11, and 12). Darteil further discloses this compound can be used to treat NAFLD and NASH (a form of NAFLD), which is characterized by liver inflammation, steatosis, and others conditions (para 0003; para 0008-0009). Darteil further discloses the compounds and compositions of the invention provide advantageous therapeutic tool for the treatment of liver disorders, and in particular fatty liver diseases including NAFLD and NASH, due to the hepatoprotective effects of the compounds of General Formula (I) (para 0181).
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 modify the steps for detecting the presence or severity of NASH using blood and plasma samples as discloses by Wienhues-Thelen, with the method of treatment with administration of the compound discloses by Darteil, because the compounds and compositions of the invention provide advantageous therapeutic tool for the treatment of liver disorders, and in particular fatty liver diseases including NAFLD and NASH, due to the hepatoprotective effects of the compounds of General Formula (I), as disclosed by Darteil. There would be a reasonable expectation of success because administering treatment to subjected diagnosed with NASH or classified as a receiver of treatment would not impede the method steps of Wienhues-Thelen. Therefore, the invention is prima facie obvious.
Response to applicant’s arguments
Applicant states the claims have been amended so the claims only require a specific combination of biomarkers used, through the step of “specifically combining the level(s) of marker(s) determined in [steps(d) and (e)) (Applicant’s Arguments, p 7, para 3).
It is respectfully submitted that this is not persuasive, as the claims do not limit the biomarkers to only the steps and biomarkers listed (i.e. comprising vs. consisting).
Applicant further states the motivation to use the level of hsa-miR-34a-5p in combinations with other biomarkers to diagnose, determine the activity/stage/severity of or for classifying a subject as a receiver or non-receiver of a treatment for NASH is not disclosed by the cited art, and specifically that the prior art to Motawi is directed towards HCV related HCC, not NASH, and further that Motawi teaches conflicting results between their study and prior study which may teach against using hsa-miR-34a-5p for interpretation of fibrosis progression (Applicant’s Arguments, p 7, para 4-p12, para 1).
It is respectfully submitted that this is not persuasive. The prior art to He and Cermelli et al. have been cited to elaborate on and further clarify the motivation.
As discussed above, the instant specification discloses in p 2, lines 5-6 that fibrosis are features of NASH evaluated from biopsies. Motawi teaches monitoring of fibrosis is mandatory as it reflects disease progression, ultimately to HCC, and as liver biopsy for fibrosis staging presents invasiveness, sample variability, and other limitations, circulating miRNAs were proposed as novel non-invasive methods to assess histological disease severity in chronic HCV, and further discloses using miR-34a, and specifically miR-34a-5p, because this was one of the few miRNA associated with liver fibrosis progression in chronic HCV patients (p 2, para 3).
Furthermore, the prior art to He et al. (Cellular signalling 2012, 24, no. 12: 2268-2272; newly cited; hereafter referred to as He)also discloses liver fibrosis is the excessive accumulation of extracellular matrix that occurs in most types of chronic liver diseases and that it is likely that miR-34a plays a role in the development of liver fibrosis and could also be explored as novel disease markers for the diagnosis or monitoring of the progression of liver fibrosis (p 2268, col 2, para 2; p 2269, col 2, para 1).
This suggests that miR-34a-5p is known to be informative to interpreting fibrosis progression, which is a condition associated with many liver diseases, including NASH.
Furthermore, the prior art to Cermelli et al. (PLOS ONE 2011, 6(8): e23937; newly cited) also examined whether circulating levels of miR-34a correlate with hepatic histological disease severity in patients with chronic hepatitis C infection (CHC) or non-alcoholic fatty-liver disease (NAFLD), including NASH, and can potentially serve as circulating markers for disease stage assessment, based on studies done on the levels of miR-34a found in HCC (abstract; p 1, col 2, para 1; p 5, col 1, para 1). Therefore, it was known in the art, at the effective filing date for the invention, that miR-34a may be an informative marker for NASH, and the basis for this study were previous studies related to HCC. Therefore, there would be motivation to use miR-34a-5p as a marker for NASH.
Double Patenting
The rejections of claims 23-24, 30 and 33 on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US12104209B2 in view of Wienhues-Thelen et al. (US US20070178442A1; previously cited; hereafter referred to as Wienhues-Thelen), in view of Inglis et al. (J Vis Exp. 2015 Mar 17;(97):52484.; previously cited; hereafter referred to as Inglis), and Motawi et al. ( (09/26/2022 IDS, NPL # 5; previously cited; hereafter referred to as Motawi) as evidenced by miRBase (miRNA Entry for MI0000268, 08/26/2015; previously cited), and further in view of Darteil et al. (US2012/0252725; previously cited; 09/26/2022 IDS) are withdrawn in view of cancelation of the claims in the claim amendments filed 12/29/2025.
The rejections of claims 23-24, 30 and 33 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. US11371098B2 in view of Wienhues-Thelen et al. (US US20070178442A1; previously cited; hereafter referred to as Wienhues-Thelen), in view of Inglis et al. (J Vis Exp. 2015 Mar 17;(97):52484.; previously cited; hereafter referred to as Inglis), and Motawi et al. ( (09/26/2022 IDS, NPL # 5; previously cited; hereafter referred to as Motawi) as evidenced by miRBase (miRNA Entry for MI0000268, 08/26/2015; previously cited), and further in view of Darteil et al. (US2012/0252725; previously cited; 09/26/2022 IDS) are withdrawn in view of cancelation of the claims in the claim amendments filed 12/29/2025.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 17-18, 20, and 32 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US12104209B2 in view of Wienhues-Thelen et al. (US US20070178442A1; previously cited; hereafter referred to as Wienhues-Thelen), in view of Inglis et al. (J Vis Exp. 2015 Mar 17;(97):52484.; previously cited; hereafter referred to as Inglis), and Motawi et al. ( (09/26/2022 IDS, NPL # 5; previously cited; hereafter referred to as Motawi) as evidenced by miRBase (miRNA Entry for MI0000268, 08/26/2015; previously cited), and further in view of Darteil et al. (US2012/0252725; previously cited; 09/26/2022 IDS). Newly recited portions are necessitated by claim amendments.
Claims 17-18, 20, and 32 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. US11371098B2 in view of Wienhues-Thelen et al. (US US20070178442A1; previously cited; hereafter referred to as Wienhues-Thelen), in view of Inglis et al. (J Vis Exp. 2015 Mar 17;(97):52484.; previously cited; hereafter referred to as Inglis), and Motawi et al. ( (09/26/2022 IDS, NPL # 5; previously cited; hereafter referred to as Motawi) as evidenced by miRBase (miRNA Entry for MI0000268, 08/26/2015; previously cited) , and further in view of Darteil et al. (US2012/0252725; previously cited; 09/26/2022 IDS). Newly recited portions are necessitated by claim amendments.
Response to applicant’s arguments
Applicant states the instant claims do not use YKL-40, and one skilled in the art would not have been motivated to combine the ‘209 claims, which use YKL-40, with the cited art with a reasonable expectation of success (Applicant’s Arguments, p 11, para 4). Applicant’s further states the ‘098 patent claims require measuring the level of biomarkers consisting of the recites group which is distinct from the claimed markers, and further recites an increase in each level of the biomarkers relative to a control sample is indicative of NASH while the instant claims use a score by combining the levels (Applicant’s Arguments, p 12, para 2).
It is respectfully submitted that this is not persuasive. The instant claims do not limit the steps to only consisting of the markers recited, and the biomarkers of instant claim 17, steps d and e are captured by steps (a)(i)-(a)(iv) of claim 1 of the ‘098 patent.
Furthermore, the prior art to Wienhues-Thelen discloses a method for the detection of the presence and/or the severity of a liver disease of NASH, in a patient comprising measuring levels of biomarkers such alpha-2-macroglobulin (A2M) and N-terminal propeptide of type III procollagen (PIIINP) from a blood and plasma sample, and combining and evaluating the obtained data by statistical methods like logistic binary regression to determine the best combinations, resulting in scores to obtain a result in assisting in diagnosing the disease (abstract; claim 1-4; para 0027-para 0028; para 0045; para 0056-0057). For further clarification, Wienhues-Thelen discloses timely and accurate diagnosis of liver fibrosis is essential to effective medical treatment and that the method is also used for monitoring of clinical development of fibrosis during therapeutic treatment, indicating it can be used to classify a patient as a receiver or non-receiver to treatment based on their biomarkers (para 0004; para 0013. Therefore, the idea of combining the levels of measured biomarkers into scores to diagnose/stage NASH or classify the patient as a receiver/non-receiver of treatment is known within the art.
Wienhues-Thelen further discloses A2M may be detected by an immunological assay using specific antibodies according to test formats known to a person skilled in the art and that PIIINP could also be determined immunological methods (para 0044; para 0048).
Furthermore, the instant specification discloses in p 2, lines 5-6 that fibrosis are features of NASH evaluated from biopsies. Motawi teaches monitoring of fibrosis is mandatory as it reflects disease progression, ultimately to HCC, and as liver biopsy for fibrosis staging presents invasiveness, sample variability, and other limitations, circulating miRNAs were proposed as novel non-invasive methods to assess histological disease severity in chronic HCV, and further discloses using miR-34a, and specifically miR-34a-5p, because this was one of the few miRNA associated with liver fibrosis progression in chronic HCV patients (p 2, para 3). This suggests that miR-34a-5p is known to be informative to interpreting fibrosis progression, which is a condition associated with many liver diseases, including NASH.
Therefore, one skilled in the art would have been motivated to combine the ‘209 claims with the cited art with a reasonable expectation of success, as the idea of combining the levels of measured biomarkers into scores to diagnose/stage NASH or classify the patient as a receiver/non-receiver of treatment is known within the art. And, while the ‘098 patent does not recite calculating a score, the prior to Wienhues-Thelen teaches calculating a score, and the idea of combining the levels of measured biomarkers into scores to diagnose/stage NASH or classify the patient as a receiver/non-receiver of treatment is known within the art. Therefore, the rejections are maintained.
Conclusion
No claims allowed.
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/N.D./ Examiner, Art Unit 1686
/Karlheinz R. Skowronek/ Supervisory Patent Examiner, Art Unit 1687