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 .
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.
Status of the Claims
Claims 1, 11, 13, 14, and 20 been amended by Applicant’s amendment filed 05/08/2026. New claims 21 and 22 have been added. Claims 1-22 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 is acknowledged and has been considered.
Amended 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 1-5, 8-12, 14-18, and 21 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 claims are directed to a judicial exception, mainly they are abstract ideas, specifically, mental processes that can be performed in the human mind, and/or are merely observing naturally occurring correlations (laws of nature/natural correlation). These judicial exceptions are not integrated into a practical application because there is no practical application recited in the claims such as performing a 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. Regarding the identification of a correlation between the presence of a biomarker in a bodily sample and disease state the courts have held similar claims to be laws of nature and/or natural phenomena, as in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017) which involved claims to simply instruct a user to apply a natural law, by correlating naturally occurring enzyme levels with disease risk. In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services V. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
Thus, claims 1 and 11 fall 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 1-5, 8-12, 14-18, and 21 do not recite any additional element that integrate the exception into a practical application of the exception. The additional steps of determining a treatment and preparing and providing a report (claims 1 and 11), establishing the length of the sampling time period (claims 2-3, 15-16), establishing level trends (claims 4, 5, 17 and 18), measuring other liver damage biomarkers (claims 8-10), or performing a treatment (claims 12 and 21) are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data and/or merely instructions to "apply" the exception in a generic way.
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 step of coordinating performance of the treatment on the subject (claim 11) and performing the treatment on the subject (claims 12 and 21) are insufficient to integrate the exception into a practical application because the treatment step is not particular i.e., specifically identified so that it does not encompass all applications of the judicial exceptions, 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 1-11 and 15-20 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 determining a treatment and preparing and providing a report (claims 1 and 11), establishing the length of the sampling time period (claims 2-3, 15-16), establishing level trends (claims 4, 5, 17 and 18), measuring other liver damage biomarkers (claims 8-10), or performing a treatment (claims 12 and 21), 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, Jia et al. (2017), "CXCL14 is a candidate biomarker for Hedgehog signalling in idiopathic pulmonary fibrosis." Thorax 72.9 (2017): 780-787, and Harrison et al. (1990). “Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure”. British medical journal, 301(6758), 964-966.
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, Table 3).
Liu teaches the measurement of a liver damage biomarker (serum alanine transaminase, cytokines, and chemokines) 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).
Jia teaches the increased levels 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 (abstract; Fig. 5).
Harrison teaches the measurement of prothrombin time for 7 days in subjects with acetaminophen (paracetamol) induced acute liver failure (abstract; Table 2).
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.
Amended Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-5, 8, 11-18, 21, and 22 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, 11, and 22, 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 teaches that in certain embodiments, the origin of the liver damage is drug induced liver damage (DILI) (column 7, lines 36-42). Bonkovsky also teaches obtaining a plurality of blood samples from subjects with DILI at a series of time points over a plurality of days (column 18, lines 50-54), measuring the concentration of chemokines and albumin in the blood samples (column 8, lines 1-15; 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 teaches the measurement of several biomarkers to act as biomarkers of liver damage and predict the need of a transplant or death (column 4, lines 30-60). Bonkovsky also teaches the use of ELISA to measures the chemokines in the blood (column 8, lines 22-30).
However, Bonkovsky does not recite that the subjects with DILI have consumed acetaminophen, 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.
Chalin teaches the measurement of serum CXCL10, CXCL11, CXCL12, and CXCL14 chemokine patterns in patients with acute liver injury (abstract; table 2). Chalin teaches that CXCL14 levels are elevated in the blood of acute liver injury (ALI) patients (Table 3), as well as that circulating CXCL14 levels have been shown to be higher in an ALI mouse model (page 503, column 2, 1st full paragraph). Chalin teaches the measurement of CXCL14 levels in patients with ALI due to toxic injury, which includes some patients that experienced acetaminophen intoxication (n=5) (Table 2). Chalin also teaches that the level of CXCL14 was highly significantly elevated for the acute viral infection and vascular groups (Table 3).
Liu teaches the measurement of a liver damage biomarker (serum alanine transaminase, cytokines, and chemokines) 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). Liu teaches that several chemokines had increased expression in response to acetaminophen-induced hepatotoxicity (page 1765, column 2, 3rd paragraph). Liu also teaches measuring biomarkers of acetaminophen hepatotoxicity over a 4-day time period, and that some biomarkers do not decrease over a time period of at least 2 days (Fig. 1, Fig. 5, Fig. 7).
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 of determining a likelihood of liver transplant in a subject having drug induced liver damage as taught by Bonkovsky, to measure CXCL14 in subjects with acetaminophen induced hepatotoxicity, as taught by Chalin, because: 1) Chalin teaches that blood CXCL14 levels are increased in response to ALI in both humans and animal models, and 2) Liu establishes that many chemokines have increased expression in response to acetaminophen-induced hepatotoxicity, and 3) Bonkovsky teaches the measurement of several chemokines to act as biomarkers of liver damage and predict the need of a transplant or death. Due to the established relationship between increased CXCL14 levels and ALI, in combination with the established relationship between increased chemokine levels and acetaminophen-induced hepatotoxicity, measuring CXCL14 as a biomarker for determining acetaminophen induced liver damage would be “obvious to try”.
A skilled artisan would have been motivated to modify the method Bonkovsky to measure CXCL14 in order to better improve the accuracy of measuring the severity and predicting negative outcomes of acetaminophen hepatotoxicity. A person of ordinary skill would have had a reasonable expectation of success in making these modifications because all three references are in the same field of endeavor of measuring biomarkers of ALI. Furthermore, the method of Bonkovsky teaches the use of ELISA to measures the chemokines in the blood, the same method and tissue used by Chalin to measure CXCL14, which is a method that is well-understood, routine and conventional in the field.
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 by Bonkovsky as modified by Chalin to include the time series sampling technique and identifying the trend in chemokine levels, as taught by Liu. 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 taught 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. Bonkovsky, Chalin, and Liu are considered to in the same field of determining severity of drug induced liver injury.
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 with acute liver injury.
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 acute liver damage patients (abstract).
Regarding claim 8, Bonkovsky teaches further comprising measuring at least one of ALT, bilirubin, or prothrombin (Table 2).
Regarding claims 12, 13, and 21, Bonkovsky teaches further comprising performing the treatment on the subject, which in certain embodiments, comprises the step of performing a liver transplant for the individual if the individual is identified as having life-threatening liver damage (column 3, lines 2-5).
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 (column 4, lines 50-60; column 2, lines 65-67 – column 3, lines 1-5). 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 (Fig. 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 (Fig. 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 in view of Chalin and Liu are incorporated herein.
Regarding claims 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.
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).
Response to Arguments
Applicant's arguments filed 05/08/2026 have been fully considered but they are not persuasive except to the extent expressly indicated below.
Applicant’s arguments on page 7 with respect to the objection of claim 20 as having incorrect claim dependency have been fully considered and are persuasive. Claim 20 has been amended by Applicant to depend from claim 11 rather than claim 1. Accordingly, the objection of claim 20 has been withdrawn.
The rejections of claims 1-20 under 35 U.S.C. 103 are maintained. New rejections of added claims 21 and 22 have been made under 35 U.S.C. 103 above.
Applicant’s arguments on pages 7-12 with respect to the rejection of claims 1-5, 8, 11-18 under 35 U.S.C. 103 over Bonkovsky in view of Chalin and Liu, claims 6-7 and 19-20 under 35 U.S.C. 103 over Bonkovsky in view of Chalin, Liu, and Jia, and claims 9-10 under 35 U.S.C. 103 over Bonkovsky in view of Chalin, Liu, and Harrison have been fully considered but are not persuasive.
Applicant argues on page 8 with respect to the rejection of claims 1-20 under 35 U.S.C. 103 that with regards to whether all the claimed elements were taught or suggested in the prior art, and a conclusion that one of ordinary skill in the art could have combined the elements as-claimed to yield a predictable result, that “Neither are present in the instant rejection”. Applicant goes on to cite a part of the rejection and argues that “However, contrary to these conclusions, Chalin does not teach that CXCL14 is a biomarker for acetaminophen-induced liver damage at all, and certainly not for mortal damage”. However, this is technically not what was claimed in the rejection as evident by the portion cited by the Applicant on page 9, which states “…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)”.
Furthermore, the rejection does not rely on Chalin alone to teach the entire claimed method. In light of this, asserting that the combination of Bonkovsky, Chalin, and Liu would not be obvious purely because Chalin does not specifically teach that CXCL14 is a biomarker for acetaminophen-induced liver damage would be to attack the references individually, where the rejection is based on a combination of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The rejection relies on the combined teachings of Bonkovsky, Chalin, and Liu to establish that the claimed method would have been obvious to one of ordinary skill in the art. Chalin is relied upon for the teaching that CXCL14 levels are elevated in the blood of acute liver injury (ALI) patients (viral infection and vascular) (Table 3), as well as the teaching that circulating CXCL14 levels have been shown to be higher in an ALI mouse model (page 503, column 2, 1st full paragraph). Bonkovsky is relied upon for the teaching of a method of determining a likelihood of liver transplant in a subject having drug induced liver injury using blood chemokine levels as a biomarker. Liu is relied upon for teaching of a series of time points measurements and the increased expression of chemokines in response to acetaminophen-induced hepatotoxicity.
Furthermore, regarding the Applicant’s argument that Chalin does not teach CXCL14 as a biomarker of acetaminophen induced hepatoxicity, the statement is correct. However, it would have still been obvious to measure CXCL14 in light of the combined teachings of the three references because: 1) Chalin teaches that blood CXCL14 levels are increased in response to ALI in both humans and animal models, and 2) Liu establishes that many chemokines have increased expression in response to acetaminophen-induced hepatotoxicity, and 3) Bonkovsky teaches the measurement of several chemokines to act as biomarkers of liver damage and predict the need of a transplant or death. Due to the established relationship between increased CXCL14 levels and ALI, in combination with the established relationship between increased chemokine levels and acetaminophen-induced hepatotoxicity, measuring CXCL14 as a biomarker for determining acetaminophen induced liver damage would be “obvious to try”. A skilled artisan would have been motivated to modify the method Bonkovsky to measure CXCL14 in order to better improve the accuracy of measuring the severity and predicting negative outcomes of acetaminophen hepatotoxicity. A person of ordinary skill would have had a reasonable expectation of success in making these modifications because all three references are in the same field of endeavor of measuring biomarkers of ALI. Furthermore, the method of Bonkovsky teaches the use of ELISA to measures the chemokines in the blood, the same method and tissue used by Chalin to measure CXCL14, which is a method that is well-understood, routine and conventional in the field.
Regarding the Applicant’s argument on pages 10-11 that that Chalin teaches away from the measurement of CXCL14 as a biomarker of acetaminophen induced liver damage, this argument has been fully considered but is not persuasive. Applicant argues that “Because Chalin teaches that CXCL14 is not elevated in subjects with acetaminophen intoxication, it teaches away from its use as a biomarker for interrogating liver damage caused by acetaminophen as-claimed”. However, this statement is incorrect and there is an important distinction needed. Chalin does not teach a comparison between CXCL14 levels in subjects with acetaminophen intoxication and healthy donors, therefore the claim that Chalin teaches that CXCL14 is not elevated in subjects with acetaminophen intoxication cannot be made. What Chalin does teach is that CXCL14 levels in the “Toxic” group were not significantly different from those in the healthy donor group (Table 3). While subjects with acetaminophen intoxication were included in the “Toxic” group (n=27), they represented only a small portion of this group as a whole (n=5).
One of ordinary skill in the art would understand that drawing conclusions on the perceived effect size in one subgroup (acetaminophen intoxication) when the statistical comparisons were made using a combined population of subgroups (Acute Alcoholic Hepatitis, Mushrooms intoxication, Drug intoxication (other than acetaminophen), etc.) would be of poor reasoning due to the potential confounding effects of the various groups. Arguing that Chalin teaches that CXCL14 is not elevated in subjects with acetaminophen intoxication is inaccurate, as Chalin did not, and probably could not due to low statistical model power as the result of the low sample size (n=5), make a comparison of CXCL14 levels between acetaminophen intoxication and healthy donors. Therefore, Chalin does not teach away from the use of CXCL14 as a biomarker of acetaminophen intoxication. Furthermore, even if Chalin did teach what was claimed by the Applicant, it would be similar to the results shown by the Applicant in the specification with regards to their human data, where survivors demonstrated no significant difference in plasma CXCL14 levels between surviving patients with no injury and high injury (Fig. 2B).
Therefore, due to the reasons above, the Applicant’s argument that “…the mere suggestion that CXCL14 is elevated in some forms of acute liver damage such as viral infection or vascular damage is unavailing because the reference specifically distinguishes these observations from those in subjects with acetaminophen intoxication, which were not significant in Chalin's study” is not persuasive.
Additionally, Applicant argues on pages 11-12 that the instantly claimed method provides surprising technical advantages compared to previously described methods. This argument has been fully considered but is not persuasive. Applicant recites paragraphs [0066]- [0077] of the specification and the associated figures to demonstrate that CXCL14 “…is also an
unexpectedly good biomarker at least because it is remarkably sensitivity in distinguishing between survivors and non-survivors” based on the results demonstrating that “…CXCL14 levels at all three days were predictive of death with 100% sensitivity at day 3”. However, Bonkovsky also teaches a biomarker measured in drug induced liver damage patients where all of patients who died within 6 months of drug induced liver damage onset had values below this cutoff with 100% sensitivity (column 25, lines 38-47; Table 7). Therefore, the claim that the results of the instant application show remarkable sensitivity in distinguishing between survivors and non-survivors is not unseen in the art.
Furthermore, it is established in MPEP 2145(II) that prima facie obviousness is not rebutted by merely recognizing additional advantages present but not recognized in the prior art. Therefore, the applicants declaratory evidence alleging unexpected results does not rebut the prima facie case of obviousness presented in the above rejection.
Therefore, due to the reasons above, the applicant’s arguments that the Office has not established a prima facie case of obviousness and that the unexpectedly good results rebut a conclusion of obviousness, are not persuasive and the rejection of claims 1-20 under 35 U.S.C. 103 are maintained. The rejections have been modified only to clarify and further support the rationale in the rejection. Additionally, the above rationale also applies to the rejections under 35 U.S.C. 103 of newly added claims 21 and 22.
Applicant’s arguments on pages 12-16 with respect to the rejection of claims 1-20 under 35 U.S.C. 101 for being directed to a judicial exception without significantly more have been fully considered but they are not persuasive except to the extent expressly indicated below. The rejections under 35 U.S.C. 101 are maintained and have been updated, where appropriate, in view of Applicant's claim amendments. Any modification to the statement of the rejection, including reliance on additional prior art, is necessitated by Applicant's amendments to the claims and is made to address the newly added or clarified claim limitations.
Applicant argues on pages 13-14 that “Under Step 2B, the instant claims are directed to an inventive concept at least because (i) the claims capture an "improvement" under MPEP § 2106.05 I.A.ii. in the technology field of liver transplant selection; and (ii) "[a]dding a specific limitation other than what is well-understood, routine, conventional activity in the field, or adding unconventional steps that confine the claim to a particular useful application" under MPEP § 2106.05 I.A.v.”. Applicant further states that “…the Office's attention is drawn to the arguments presented above with respect to non-obviousness…” and that “…the instantly claimed method is a dramatic improvement over the state of the art…” and “…the combination of measuring the CXCL14 biomarker and pairing that with a treatment recommendation of liver transplant VS. no liver transplant based thereon is not common or routine in the art”. These points with regards to the obviousness and the context of the improvement over the state of the art of the invention have been addressed in the rejections and discussions above. In short, the applicant’s arguments that the Office has not established a prima facie case of obviousness and that the unexpectedly good results rebut a conclusion of obviousness were rebutted, and therefore, the Applicants argument that claims add an inventive concept and that “…the answer to the Step 2B inquiry is "Yes" and the claims are patent eligible” is not persuasive.
Applicant also argues on pages 15-16 that the judicial exceptions under 35 U.S.C. 101 do not apply to at least claims 12-14 and newly added claims 21-22, as they specify the treatment is performed and therefore integrate the exception into a practical application. This argument has been fully considered but is not persuasive except to the extent expressly indicated below. The rejection of claims 1-5, 8-12, 14-18, and 21 under 35 U.S.C. 101 are maintained and have been updated, where appropriate, in view of Applicant's claim amendments. Any modification to the statement of the rejection, including reliance on additional prior art, is necessitated by Applicant's amendments to the claims and is made to address the newly added or clarified claim limitations. However, the rejection of claims 6-7, 13, 19 and 20 under 35 U.S.C. 101 have been withdrawn because the treatment is specific (liver transplant) and/or based on a specific threshold of biomarker levels (CXCL14), which integrates the judicial exceptions into a practical application by applying the exception in a specific way.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALEXANDER J. HOFFMAN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 August 3, 2026
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