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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2 February 2026 has been entered.
Response to Amendment
Amendments to the specification and claims filed on 2 February 2026 are acknowledged. Claim 1 is amended, and claims 7-9 are newly canceled. Claims 1 and 10-20 are pending; claims 10-20 are withdrawn; and claim 1 is examined hereon on the merits.
In response to the amendments filed on 2 February 2026, the objections to the specification are withdrawn; the rejections under 35 U.S.C. 112(a) are withdrawn; the rejection under 35 U.S.C. 101 is modified; and the rejection over the prior art is changed.
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.
Claim 1 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature and an abstract idea, without significantly more.
Independent claim 1 is "A method for evaluating a degree of liver fibrosis, comprising: ….calculating a predicted value of liver fibrosis based on the concentrations of the bile acids; and outputting a classification of the degree of liver fibrosis as stage 1-2 liver fibrosis or stage 3-4 liver fibrosis based on the predicted value." A correlation between biomarker concentrations and a predicted value of liver fibrosis or between biomarker concentrations and a classification of the degree of liver fibrosis as stage 1-2 liver fibrosis or stage 3-4 liver fibrosis is an example of a law of nature. See MPEP 2106.04(b), I.
Moreover, the steps of "calculating a predicted value of liver fibrosis" and "outputting a classification of the degree of liver fibrosis …based on the predicted value" are directed to an abstract idea that includes mathematical concepts and mental process.
The recited mathematical concepts include a mathematical relationship between the concentrations of the bile acids and a predicted value of liver fibrosis and/or a classification of the degree of liver fibrosis. The recited mathematical concepts further include a mathematical calculation of the recited calculating step. The courts have identified mathematical concepts as judicial exceptions for the reason that "a mathematical formula as such is not accorded the protection of our patent laws,’" Diehr, 450 U.S. at 191, 209 USPQ at 15 (citing Benson, 409 U.S. 63, 175 USPQ 673), and thus "the discovery of [a mathematical formula] cannot support a patent unless there is some other inventive concept in its application." Flook, 437 U.S. at 594, 198 USPQ at 199. "[A] scientific truth, or the mathematical expression of it, is not patentable invention[.]" Mackay Radio & Telegraph Co. v. Radio Corp. of Am., 306 U.S. 86, 94, 40 USPQ 199, 202 (1939). See MPEP 2106.04(a)(2), I.
The recited mental process is classifying the degree of liver fibrosis as stage 1-2 liver fibrosis or stage 3-4 liver fibrosis based on the predicted value, which can be performed in the human mind. Likewise, the broadly recited limitation of "calculating a predicted value of liver fibrosis based on the concentrations of the bile acids" encompasses mathematical calculations that could be practically performed in the human mind. The courts consider a mental process (thinking) that "can be performed in the human mind, or by a human using a pen and paper" to be an abstract idea. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1372, 99 USPQ2d 1690, 1695 (Fed. Cir. 2011). As the Federal Circuit explained, "methods which can be performed mentally, or which are the equivalent of human mental work, are unpatentable abstract ideas the ‘basic tools of scientific and technological work’ that are open to all.’" 654 F.3d at 1371, 99 USPQ2d at 1694 (citing Gottschalk v. Benson, 409 U.S. 63, 175 USPQ 673 (1972)). See also Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012) ("‘[M]ental processes[] and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work’" (quoting Benson, 409 U.S. at 67, 175 USPQ at 675)); Parker v. Flook, 437 U.S. 584, 589, 198 USPQ 193, 197 (1978) (same). See MPEP 2106.04(a)(2), III.
These judicial exceptions are not integrated into a practical application. Claim 1 does not clearly recite any application of the law of nature or the abstract idea. Even if the step of "outputting a classification of the degree of liver fibrosis…" is narrowly interpreted as an application, this classifying is not a practical application because this step merely requires producing an abstract idea. A step of classifying can be performed in the human mind. The specification does not provide a special definition of "outputting" that requires use of a computer, and according the broadest reasonable interpretation of "outputting" is "producing" or "turning out."1 However, even if the "outputting" step were narrowly interpreted as requiring a computer, a generically recited step of outputting with a computer does not add a meaningful limitation to the abstract idea because it amounts to simply implementing the abstract idea on a computer. Moreover, the data gathering step of claim 1is required to use the correlation ("detecting concentrations of bile acids in a sample") and does not add a meaningful limitation to the method because it is insignificant extra-solution activity. See MPEP 2106.05(g).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Claim 1 recites a non-abstract step that is addition to the judicial exception(s): "detecting concentrations of bile acids in a sample." However, the courts have recognized that determining a level of a biomarker is a well-understood, routine, conventional activity when claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity. See MPEP 2106.05(d), II. The courts have found that a mere data gathering step that is required to use a correlation does not add a meaningful limitation to the method because it is insignificant extra-solution activity. See MPEP 2106.05(g). Moreover, the prior art of Jia (WO 2017/210147 or US 2020/0378991) discloses this additional element, as set forth in the rejection under 35 USC 103 below. Moreover, the "outputting" step according to its broadest reasonable interpretation merely requires a step of producing or turning out, as previously set forth. Even if the "outputting" step were narrowly interpreted as requiring a computer, a generically recited step of outputting with a computer does not add a meaningful limitation to the abstract idea because it amounts to simply implementing the abstract idea on a computer.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Jia (WO 2017/210147 or US 2020/0378991; paragraph numbering refers to latter document; previously relied upon).
Regarding claim 1, Jia discloses a method for evaluating degree of liver fibrosis ([0011], [0016], [0073], [0137], Fibrosis S1 vs. S2 vs. S3 in Table 6; Example 15; Fig. 12A), comprising
detecting concentrations of bile acids in a sample ([0018], [0269], Table 6), wherein the bile acids comprise glycocholic acid (GCA), taurocholic acid (TCA), chenodeoxycholic acid (CDCA), glycochenodeoxycholic acid (GCDCA), taurochenodeoxycholic acid (TCDCA), deoxycholic acid (DCA), glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), lithocholic acid (LCA), glycolithocholic acid (GLCA), taurolithocholic acid (TLCA), ursodeoxycholic acid (UDCA), glycoursodeoxycholic acid (GUDCA), tauroursodeoxycholic acid (TUDCA) and cholic acid (CA) (control and fibrosis stages S1, S2 and S3 and cirrhosis C PA, CP B, and CP C in Table 6, Example 8, pages 26-27).
calculating (using canonical discriminant analysis, [0049], [0286]) a predicted value of liver fibrosis ("1," "2," "3," "4," "5," or "6," Fig. 12A, Table 17) based on the concentrations of the bile acids ("FIG. 12A depicts a plot established with functions generated with canonical discriminant analysis of all the measured bile acids," [0049]; "Stage Classification with all the measured bile acids," Table 17 header, [0286]);
and outputting a classification of the degree of liver fibrosis based on the predicted value ("1" corresponds to non-cirrhosis stage S1, "2" corresponds to non-cirrhosis stage S2, "3" corresponds to non-cirrhosis stage S3, "4" corresponds to cirrhosis stage S4: CP A, "5" corresponds to cirrhosis stage S4: CP B, and "6" corresponds to cirrhosis stage S4: CP C; Fig. 12A key, [0285], [0286]).
Accordingly, Jia discloses that canonical discriminant analysis is used with all the measured bile acids (i.e., the bile acids of Table 6) for stage classification into six possible classifications (S1, S2, S3, C PA, CP B, and CP C).
Jia does not disclose, for the embodiment of Example 15, stage classification into only two possible classifications ("outputting a classification of the degree of liver fibrosis as stage 1-2 liver fibrosis or stage 3-4 liver fibrosis based on the predicted value").
However, the six classifications of Jia's Example 15 are narrower categories than the claimed broader classification of either stage 1-2 liver fibrosis or stage 3-4 liver fibrosis and each fall within one of the two claimed categories (S1 and S2 are "stage 1-2 liver fibrosis" and S3, C PA, CP B, and CP C are "stage 3-4 liver fibrosis"). Moreover, Jia provides the following teaching ([0137], bolding added):
As fibrosis can progress in a gradual increase in fibrosis, the present invention can optionally be used to provide new fibrosis classifications (e.g. by severity or progression) that are defined according to changes in biomarker levels (e.g. by a model score) and that might not necessarily directly correspond to the biopsy-based stage classifications. As fibrosis can progress in a gradual increase in fibrosis, the present invention can optionally be used to provide new fibrosis classifications (e.g. by severity or progression) that are defined according to changes in biomarker levels (e.g. by a model score) and that might not necessarily directly correspond to the biopsy-based stage classifications. For example, fibrosis can optionally be stratified into two stages, e.g. mild (e.g. S0-S2 or a stage somewhat coextensive with S0-S2) and severe (e.g. S3-S4 or a stage somewhat coextensive with S3-S4). Alternatively, fibrosis can be classified using a model stratifying into 4 or more discrete stages, or classified using a continuous stage model (e.g. wherein a higher score indicates a greater degree of fibrosis but with no discrete stages separated by cutoffs).
It is noted that the instant specification equates "S0-S2" with "stage 1-2" and "S3-S4" with "stage 3-4" ([0024], [0026] of published application).
The use of a known technique to improve similar methods in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. __,__, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
For the benefit of providing a simple classification of either "mild" or "severe" liver fibrosis, it would have been obvious to one of ordinary skill in the art before the time of filing to modify Jia's method of Example 15 with a step of outputting a classification of the degree of liver fibrosis as stage 1-2 liver fibrosis or stage 3-4 liver fibrosis based on the predicted value, as taught by Jia in paragraph [0137].
Response to Arguments
Applicant's arguments filed on 2 February 2026 have been considered and are not fully persuasive and/or are moot in view of the new grounds of rejection.
Applicant traverses the rejections under 35 U.S.C. 101, arguing the following:
The amended claim 1 is directed to a "practical application of a specific diagnostic model" that solves a technical problem in the field of hepatology: accurate non-invasive staging of liver fibrosis.
In response, a step of classifying or staging of liver fibrosis cannot be interpreted as a practical application because this step merely requires producing an abstract idea. A step of classifying (staging) can be performed in the human mind.
Applicant further argues that "The amended claim 1 now recites concrete steps: (a) detecting specific biomarkers, (b) calculating a predicted value, and (c) outputting a clinical classification." In response, the case law concerning 35 U.S.C. 101 cited in the MPEP does not use "concrete-ness" as a relevant factor. If applicant intends to argue that all of steps (a), (b), and (c) are non-abstract, the examiner respectfully disagrees. The recited step of (b) calculating a predicted value broadly encompasses mathematical calculations that could be practically performed in the human mind. The recited step of (c) outputting a classification broadly requires producing a classification that can be performed in the human mind.
Applicant further argues the following:
This is not merely a natural correlation or abstract idea; it is a "man-made diagnostic tool" that transforms raw biomarker data into a clinically actionable outcome.
In response, the only outcome recited in claim 1 is outputting an abstract classification, as opposed to a non-abstract clinical application as was the case in the claims under consideration in Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117, 126 USPQ2d 1266 (Fed. Cir. 2018). Regarding the argument that the claims recite a man-made diagnostic tool, any formalism of a naturally occurring principle must by necessity also be a man-made construct, and abstract ideas are man-made.
Applicant further argues that "The model achieves significantly higher accuracy (AUC up to 0.928) than prior art methods (APRI, FIB-4), demonstrating an inventive application of mathematics to a real-world problem." In response, superiority of the judicial exemption(s) when compared to the prior art is not a factor when evaluating subject matter eligibility. [Evidence of unexpected results are properly evaluated when judging 35 USC 103. In the case of claim 1, the broadly recited step of "calculating a predicted value of liver fibrosis based on the concentrations of the bile acids" is not commensurate in scope to the disclosed calculation that provided an AUC of 0.928, which is evaluation model 2 (BASA). Moreover, it is not clear that the disclosed evaluation model 2 (BASA) is superior to Example 15 of the prior art of Jia, which discloses accuracy of stage classification for more precise fibrosis staging groups than stage 1-2 (S0-S2) versus stage 3-4 (S3-S4).]
Applicant further argues the following:
The "outputting" step integrates the model into a diagnostic process, which is a tangible, technical application consistent with "CardioNet v. InfoBionic" and other Fed. Cir. precedents.
In response, it is unclear to which "CardioNet v. InfoBionic" Federal Circuit decision Applicant refers. In CardioNet, LLC v. InfoBionic, Inc., No. 20-2123 (Fed. Cir. 2021) [https://www.cafc.uscourts.gov/opinions-orders/20-2123.opinion.10-29-2021_1857410.pdf], the Court concluded that U.S. 7,099,715 claims subject matter that is ineligible for patent under 35 U.S.C. § 101, including method claim 1 which recites a step of "outputting information corresponding to the identified heart beats to a communications channel of a distributed cardiac activity monitoring system." The rejection of instant claim 1 under U.S.C. § 101 is consistent with this Federal Circuit decision.
Regarding the prior art of Jia, Applicant argues the following (bolding added):
Jia discloses a broad panel of biomarkers for distinguishing between disease states (e.g., NASH vs. fibrosis, fibrosis vs. cirrhosis). It does not disclose or suggest the use of a specific set of bile acids "for grading liver fibrosis into stages S0-S2 vs. S3-S4".
In response, claim 1 recites "wherein the bile acids comprise…." The transitional phrase "comprises" is inclusive or open-ended and does not exclude additional, unrecited elements. Claim 1 does not require evaluation of the degree of the liver fibrosis based upon only the bile acids recited in claim 1. In the embodiment of Example 15 and Fig. 12A, Jia generates a plot from functions generated with canonical discriminant analysis of all the measured bile acids, which means all of the bile acids of Table 16. Table 16 of Jia includes the fifteen bile acids of claim 1 plus seven additional bile acids, which is permitted by the open-ended claim language. Moreover, in paragraph [0137], Jia teaches that "fibrosis can optionally be stratified into two stages, e.g. mild (e.g. S0-S2 or a stage somewhat coextensive with S0-S2) and severe (e.g. S3-S4 or a stage somewhat coextensive with S3-S4)."
Applicant further argues "Jia does not teach the specific regression equations (BAS or BASA) with the recited coefficients, nor the threshold value of 0.63 for staging." In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., specific regression equations or a threshold value) are not recited in the rejected claim. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant further argues "The claimed method addresses a more difficult technical problem (grading rather than binary diagnosis) and achieves superior accuracy, as demonstrated in the specification." In response, Example 15 of Jia addresses a more difficult and specific technical problem than recited in claim 1 because Example 15 of Jia predicts patients as falling within one of six fibrosis stage classifications, rather than merely one of two fibrosis stage classifications as recited in claim 1.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHELLE ADAMS whose telephone number is (571)270-5043. The examiner can normally be reached M, T, Th, and F, 12-4 P.M.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lyle Alexander can be reached at (571) 272-1254. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHELLE ADAMS/ Examiner, Art Unit 1797
/JENNIFER WECKER/Primary Examiner, Art Unit 1797
1 The second definition of the verb "outputted, output, outputting" at https://www.dictionary.com/browse/output is "to produce; turn out."