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 .
Status of the Claims
Claims 1-20 are pending and examined herein.
Priority
This application, filed March 16, 2023, claims benefit of provisional application 63/321,009 filed on March 17, 2022. This priority is acknowledged and the claims examined herein are treated as having an effective filing date of March 17, 2022.
Information Disclosure Statement
The Information Disclosure Statement filed March 16, 2023 are acknowledged and have been considered.
Claim Objections
Claim 20 is objected to because of the following informalities:
Claim 20 states "The method of claim 1" when it should read as "The method of claim 11". . Appropriate correction is required.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception and a law of nature without significantly more. Claim 1 recites “A method of determining a likelihood of liver transplant in a subject…”, whereas claim 11 recites “A method of treating a subject having hepatotoxicity”. Although their preambles differ, the body of the claims recite nearly identical limitations such as “measuring an amount of CXCL14 in the blood sample at the series of time points; comparing the amount of CXCL14 in the blood samples..., determining a treatment of the subject based on the trend in the amount of CXCL14 in the blood samples…”. The steps are judicial exceptions because they are merely observing naturally occurring correlations (laws of nature). This judicial exception is not integrated into a practical application because there is no practical application recited in the claims such as performing the treatment in a way that is particular, and not merely instructions to "apply" the exception in a generic way. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps amount to mere data gathering that does not go beyond well-understood, routine, and conventional activity; as detailed below.
Step 1 – Whether a claim is to a statutory category - YES
The instantly claimed invention is directed to a method of determining a likelihood of liver transplant in a subject with acetaminophen induced hepatotoxicity, and a method of treating a subject having hepatotoxicity. Therefore, the instantly claimed invention falls into one of the four statutory categories.
Step 2A Prong 1 – Whether the claim is directed to a judicial exception (i.e. Does the claim recite an abstract idea, law of nature, or natural phenomenon?) - YES
Claims 1 and 11 recite the following steps which fall under the law of nature and/or mathematical concepts grouping of abstract ideas:
Claim 1 discloses a method of determining a likelihood of liver transplant in a subject. Claim 11 discloses a method of treating a subject having hepatotoxicity. Both claim methods comprise measuring the levels of CXCL14 in a blood sample, and determining the treatment and whether a liver transplant is needed based on the trend observed in CXCL14 values across multiple time points.
The broadest reasonable interpretation of this step is “comparing” the levels of CXCL14 in the blood samples to the CXCL14 levels in the time points to “determine” a trend in the levels to “determine” if a liver transplant is needed, which are abstract ideas, specifically, abstract mental processes.
Regarding the step of “comparing,” the courts have held similar claims to be abstract mental processes, as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014) which involved claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind. The claims are also similar to that in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011), which involved a claim to “collecting and comparing known information” (both of these court cases are discussed in MPEP 2106.04(a)(2) (II)(A)). The step of “determining” also constitutes an abstract mental process, involving assessing the comparison of expression levels of the biomarker in a test sample, and then making an evaluation or judgment as to whether the test subject has a particular disease. The “comparing” and “determining” steps could be performed in the human mind, or by a human using pen and paper, insofar as it reads on comparing levels and drawing conclusions from this about the health status of a subject.
Furthermore, the “determining” step can also be regarded as a law of nature, namely, the naturally occurring correlation between levels of CXCL14 marker and liver damage.
Thus, claim 1 falls into a judicial exception.
Step 2A: Prong 2 - Does the claim recite additional elements that integrate the judicial exception into a practical application? The Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception.
Claims 1-20 do not recite any additional element that integrate the exception into a practical application of the exception. The additional steps of preparing a report (claim 1), establishing the length of the sampling time period (claims 2-3. 15-16), establishing predetermined biomarker cut-off values (claims 6-7, 19-20), or measuring other liver damage biomarkers (claims 8-10) are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data.
As in In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989), such activity involving performing clinical tests on individuals constitutes mere data gathering, and does not go beyond insignificant extra-solution activity. See MPEP §§ MPEP 2106.04(d)(I) and 2106.05(g).
The additional steps of coordinating performance of the treatment on the subject (claim 11), and performing the treatment on the subject (claim 12) that may or may not be a liver transplant (claims 13 and 14) are insufficient to integrate the exception into a practical application because the treatment step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.
There are no subsequent steps recited after the “determining” step that would practically apply the method depending on the results of the measurements, e.g., treatment or other process steps that are performed after the test subject has been diagnosed with a disease.
Step 2B; Whether the additional elements contribute an “inventive concept”. In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05.
Briefly, the claims 1-20 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following reasons. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional steps of preparing a report (claim 1), establishing the length of the sampling time period (claims 2 and 3), establishing biomarker cut-off values (claims 6 and 7), measuring other liver damage biomarkers (claims 8-10), coordinating performance of the treatment on the subject (claim 11), and performing the treatment on the subject (claim 12) that may or may not be a liver transplant (claims 13 and 14), do not add a meaningful limitation to the instant method as they would have been routinely used by those of ordinary skill in the art as supported by Bonkovsky et al. (U.S. Patent No. 9,664,693 B2)) in view of Chalin et al. (2018), "Serum CXCL10, CXCL11, CXCL12, and CXCL14 chemokine patterns in patients with acute liver injury." Cytokine, and Liu et al. (2004), "Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity." Gastroenterology.
Bonkovsky teaches the method of measuring chemokines and other liver biomarkers to determine the severity of liver damage and whether these subjects will require a liver transplant (abstract), and also performing the transplant liver damage is life-threatening (claim 2). Furthermore, Bonkovsky teaches the measurement of samples at multiple timepoints (column 18, paragraph 3), establishing predetermined biomarker cut-off values (claim 1), and measuring other non-chemokine liver damage biomarkers (claim 1).
Chalin teaches the measurement of serum CXCL14 in subjects with acetaminophen induced liver injury (abstract).
Liu teaches the measurement of liver damage biomarkers following acetaminophen induced hepatotoxicity that express the trends recited in the instant application.
See a detailed discussion of what these references teach in the prior art rejections below.
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to a law of nature and abstract idea without significantly more. For additional guidance, applicant is directed generally to MPEP § 2106.
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.
Claims 1-5, 8, 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over Bonkovsky et al. (U.S. Patent No. 9,664,693 B2, referred to herein as Bonkovsky) in view of Chalin et al. (2018), "Serum CXCL10, CXCL11, CXCL12, and CXCL14 chemokine patterns in patients with acute liver injury." Cytokine, (referred to herein as Chalin), and Liu et al. (2004), "Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity." Gastroenterology, (referred to herein as Liu), as evidenced by Bellera et al. (2008), “Detecting trends in noisy data series: application to biomarker series." American journal of epidemiology, (referred to herein as Bellera).
Regarding claims 1 and 11, Bonkovsky teaches a method of determining a likelihood of liver transplant in a subject having liver damage (abstract), and a method of treating a subject having liver damage (column 3, lines 1-5). Bonkovsky also teaches obtaining a plurality of blood samples from the subject at a series of time points over a plurality of days (column 18, lines 50-54), measuring amounts of chemokines in these blood samples (column 20, lines 34-43), and using these chemokine levels to make a diagnosis and/or to prescribe a treatment (which may be liver transplant) for the subject and/or to inform the subject (claim 2; column 11, lines 54-63), and coordinating performance of the treatment on the subject (column 2, lines 53-65).
Bonkovsky does not recite that the subjects have consumed acetaminophen and diagnosed with hepatotoxicity, or that the chemokine measured in the blood samples is CXCL14. Bonkovsky also does not teach identifying the trend in CXCL14 levels across the sample time points.
However, Chalin teaches the measurement of CXCL14 in blood samples of subjects that consumed acetaminophen and were diagnosed with hepatotoxicity (abstract; table 2).
Furthermore, Liu teaches the measurement of a liver damage biomarker (serum alanine transaminase) at a series of time points time points and using the data to observe a trend to determine the progression and severity of acetaminophen hepatotoxicity (abstract; fig. 5). Bonkovsky and Liu are considered to be analogous to the claimed invention because both are in the same field of determining severity of drug induced liver injury.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Bonkovsky to measure CXCL14 in subjects with acetaminophen induced hepatotoxicity because Chalin teaches that CXCL14 (and other CXCL chemokines) are expressed in human subjects after acetaminophen induced acute liver injury (abstract; page 501, paragraph 2). Therefore, a person of ordinary skill would have had a reasonable expectation of success of substituting one of the chemokines measured in Bonkovsky with the CXCL14 chemokine of Chalin, as Bonkovsky establishes that several chemokine types measured in acute liver injury subjects can be highly predictive of early death or liver transplant (abstract).
It also would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method recited in Bonkovsky as modified by Chalin to include the time series sampling technique and identifying the trend in CXCL14 levels. An artisan would have been motivated to make this modification to improve the accuracy of measuring the severity and predicting negative outcomes of acetaminophen hepatotoxicity, as disclosed in Liu., by determining if the liver damage is worsening, improving, or staying constant over the time period. It is merely applying a known technique to a known method ready for improvement to yield predictable results.
While Liu did not teach the identification of the specific trend types as recited in claim 1 of the instant application, using time series measurements are commonly used to “define a change in health status or in a disease state on the basis of a sustained rise (or decline) in a biomarker over time”, as evidenced by Bellera (abstract). It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Bonkovsky in view of Chalin and Liu to identify the trend pattern as referenced by “(a)”, “(b)”, and ”(c)” in claim 1 of the instant application, as there is a finite number of possible trends that could be expected when measuring such biomarker data, therefore it would be “obvious to try”.
Regarding claims 2 and 15, Bonkovsky teaches wherein the time period is at least 2 days (column 18, lines 50-54).
Regarding claims 3 and 16, Bonkovsky teaches wherein the time period is at least 3 days (column 18, lines 50-54).
Regarding claims 4-5, 17-18 Liu teaches the measurement of liver damage biomarkers following acetaminophen induced hepatotoxicity that express the trends of 1) the amount of biomarker starts at a maximum and then decreases, and 2) the amount of biomarker increases to a maximum and then decreases, but Liu does not teach that the biomarker is CXCL14. However, Chalin teaches the measurement of CXCL14 in blood samples of subjects that consumed acetaminophen and were diagnosed with hepatotoxicity.
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Bonkovsky in view of Liu to measure CXCL14 as the biomarker, as disclosed in Chalin, because “commonly used biomarkers for liver damage, such as serum aminotransferases, alkaline phosphatase, and other enzymes, have limited sensitivity and specificity” – (Bonkovsky, column 1, lines 47-50). A person of ordinary skill would have had a reasonable expectation of success in selecting CXCL14 as the biomarker because Chalin teaches that CXCL14 can be measured in the serum of liver damage patients (abstract).
Regarding claim 8, Bonkovsky teaches further comprising measuring at least one of ALT, bilirubin, or prothrombin (table 2).
Regarding claim 12, Bonkovsky teaches further comprising performing the treatment on the subject (column 3, lines 2-5).
Regarding claim 13, Bonkovsky teaches wherein the treatment includes the liver transplant (claim 2).
Regarding claim 14, Bonkovsky teaches wherein the treatment excludes the liver transplant (column 13, lines 8-14).
Claims 6-7 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Bonkovsky in view of Chalin and Liu as applied to claims 1 and 11 above, and further in view of Jia et al. (2017), "CXCL14 is a candidate biomarker for Hedgehog signalling in idiopathic pulmonary fibrosis." Thorax 72.9 (2017): 780-787 (referred to herein as Jia).
The teachings of Bonkovsky in view of Chalin and Liu are incorporated herein.
Regarding claims 6-7 and 19-20, Bonkovsky in view of Chalin and Liu teaches the methods of measuring CXCL14 in the blood to determine the likelihood of a liver transplant and treating a subject with acetaminophen induced hepatotoxicity. Bonkovsky teaches the use of predetermined biomarker cut-off values to determine when the liver damage is severe/life-threatening, and also teaches that the standard treatment for severe damage is liver transplant (claims 1 and 2). Chalin teaches that elevated CXCL14 levels up to 2647 pg/mL are associated with acute liver injury (table 3).
However, Bonkovsky in view of Chalin and Liu does not teach the predetermined cut-off levels of CXCL14 in plasma of 3000 pg/mL (claims 6 and 19) and 5000 pg/mL (claims 7 and 20) to determine if the treatment is a liver transplant.
Regarding claims 6-7 and 19-20, Jia teaches the measurement of CXCL14 in the blood plasma of subjects with severe diseases (idiopathic pulmonary fibrosis or cancer), with some patients having levels greater than 3000 pg/mL (figure 5).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Bonkovsky in view of Chalin and Liu to determine that plasma CXCL14 levels in the range of 3000-5000 pg/mL is related to severe liver injury and a liver transplant is the appropriate treatment. Chalin teaches that elevated CXCL14 levels nearing 3000 pg/mL are associated with acute liver injury, and Jia teaches that subjects with severe disease that require treatment have plasma CXCL14 levels ranging from 1000 – 4000 pg/mL (figure 5). Therefore, it would have been obvious to person of ordinary skill in the art that to extrapolate that CXCL14 levels in the range of 3000-5000 pg/mL constitutes severe liver damage, for which Bonkovsky teaches the standard treatment is liver transplant.
It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955).
Routine optimization of Bonkovsky’s method in view of Chalin, Liu, and Jia, of the use of predetermined biomarker cut-off values to determine when the liver damage is severe/life-threatening would have led to the claimed CXCL14 cut-off values as taught in the instant application because Chalin and Jia teaches that CXCL14 values of 3000-5000 pg/mL constitutes severe liver damage as discussed above. The person of ordinary skill in the art would have found it obvious to optimize the method of Bonkovsky’s in view of Chalin, and Liu by selecting from the CXCL14 ranges taught by Jia because Jia teaches that these ranges are associated with severe disease, and that determining them would have required only routine experimentation.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Bonkovsky in view of Chalin and Liu as applied to claims 1 and 8 above, and further in view of Harrison et al. (1990). “Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure”. British medical journal, 301(6758), 964-966 (referred to herein as Harrison) and further evidenced by Deng et al. (2015), "Selected cytokines serve as potential biomarkers for predicting liver inflammation and fibrosis in chronic hepatitis B patients with normal to mildly elevated aminotransferases." Medicine 94.45 (referred to herein as Harrison).
The teachings of Bonkovsky et al. in view of Chalin et al. and Liu are incorporated herein.
Regarding claim 9 and 10, Bonkovsky teaches measuring bilirubin as an additional biomarker (table 2).
However, Bonkovsky in view of Chalin and Liu does not teach that the resulting data supports the treatment, nor the measurement of prothrombin at a plurality of time points supports the treatment.
Regarding claims 9 and 10, Harrison teaches the measurement of prothrombin time for 7 days in subjects with acetaminophen (paracetamol) induced acute liver failure (abstract; table 2).
It would have been obvious to person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Bonkovsky in view of Chalin and Liu to measure prothrombin at a plurality of time points to support the treatment, as disclosed in Harrison, because it acts as an accurate prognostic indicator of the need for a liver transplant (abstract).
A skilled artisan would have been motivated to make this modification because Bonkovsky teaches that diagnosing and providing an accurate prognosis for liver damage is difficult with the commonly used biomarkers such as ALT (column 1, lines 47-54). Multiple biomarkers can more accurately diagnosis liver damage because different biomarkers may be elevated depending on the cause of the liver injury. For example, Deng teaches that many patients with HBV infection can have significant liver inflammation and fibrosis while having normal or only slightly elevated ALT levels, making it a poor diagnostic indicator in this case (abstract). However, Deng also teaches that plasma CXCL11 measured in the same subjects is an accurate indicator of liver inflammation, showing the diagnostic advantage of measuring multiple biomarkers (abstract). A person of ordinary skill would have had a reasonable expectation of success in measure prothrombin at a plurality of time points to support the treatment because Harrison teaches that the “measurement of the prothrombin time is reproducible and nearly always available” - (page 964, column 2, paragraph 1).
Conclusion
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/A.J.H./ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/ Supervisory Patent Examiner, Art Unit 1677
February 6, 2026