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 .
Priority
The instant application is a U.S. national phase of PCT/GB2021/050714, filed on 3/24/2021. The instant application claims foreign priority to GB2004471.5, filed 3/27/2020, and a receipt of a certified copy of that document in English to perfect priority is acknowledged. Therefore the effective filing date of the instant claims is considered to be the filing date of the foreign application, 3/27/2020. See 37 CFR 1.55.
DETAILED ACTION
Applicant’s amendment filed on 12/1/2025 is acknowledged. Claims 1-19 are currently amended. Claim 20 is canceled.
In view of Applicant’s cancelation of claim 20, the 35 U.S.C. § 112(a) and 35 U.S.C. § 112(b) rejections previously set forth in the Non-Final Rejection mailed on 6/30/2025 are withdrawn.
In view of Applicant’s amendment of claim 2 to recite “a blood sample” in line 3 and “said blood sample of (a)” in lines 6 and 10, the 35 U.S.C. 112(b) rejection previously set forth in the Non-Final Rejection mailed on 6/30/2025 is withdrawn.
In view of Applicant’s deletion of the limitation “preferably F1-F2 liver fibrosis” in claim 12, the 35 U.S.C. § 112(b) rejection previously set forth in the Non-Final Rejection mailed on 6/30/2025 is withdrawn.
In view of Applicant’s deletion of the limitation “preferably type 2 diabetes” in claim 14, the 35 U.S.C. § 112(b) rejection previously set forth in the Non-Final Rejection mailed on 6/30/2025 is withdrawn.
Claims 1-19 remain pending.
Claim Objections
Claims 1-16 and 18-19 are objected to because of the following informalities:
In claim 1, it is redundant to separately recite the determining steps of a) and c) and the comparing steps of b) and d), which can be recited together, respectively, for conciseness.
Likewise, in claim 2, it is redundant to separately recite the determining steps of a), c), and e) and the comparing steps of b), d), and f), which can be recited together, respectively, for conciseness.
Claims 3-16 and 18-19 are missing commas after the preamble recitations and before the recitation of “wherein”. Furthermore, the recitation of “non-invasive” is unnecessary in the preambles, since the independent claims from which they depend already recite this limitation. The preambles of claims 3-16 and 18-19 may be amended to concisely recite: “The method of claim x,”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
New Rejection Necessitated by Amendment: Claim 1 recites “[a] non-invasive method of identifying subjects having advanced or severe (F3/F4) fibrosis of the liver” in lines 1-2. It is not clear how the method identifies subjects having advanced or severe (F3/F4) fibrosis of the liver, since no such active method step is recited that identifies subjects having F3/F4 fibrosis of the liver. Step e) recites “it is inferred that the subject has an increased likelihood of having advanced or severe (F3/F4) fibrosis of the liver.” Inferring the likelihood that the subject has F3/F4 fibrosis of the liver does not necessarily identify that the subject has F3/F4 fibrosis of the liver. Therefore, the method of claim 1 does not recite any active method step that clearly identifies that the subject has F3/F4 fibrosis of the liver.
Claims 3-6 and 11-16 are also rejected for being dependent on a rejected base claim and failing to remedy the issue set forth above.
New Rejection Necessitated by Amendment: Claim 2 recites “[a] “non-invasive method of identifying subject having advanced or severe (F3/F4) fibrosis of the liver” in lines 1-2. It is not clear how the method identifies subjects having advanced or severe (F3/F4) fibrosis of the liver, since no such active method step is recited that identifies subjects having F3/F4 fibrosis of the liver. Step g) recites “it is inferred that the subject has an increased likelihood of having advanced or severe (F3/F4) fibrosis of the liver.” Inferring the likelihood that the subject has F3/F4 fibrosis of the liver does not necessarily identify that the subject has F3/F4 fibrosis of the liver. Therefore, the method of claim 2 does not recite any active method step that clearly identifies that the subject has F3/F4 fibrosis of the liver.
Claims 7-10 are also rejected for being dependent on a rejected base claim and failing to remedy the issue set forth above.
Maintained Rejection: Claim 10 contains the trademark/trade name “XF cell mito stress test kit from Agilent Technologies.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a kit which determines reserve respiratory capacity by measuring the difference between the maximum oxygen consumption rate (OCR) and basal respiration and, accordingly, the identification/description is indefinite.
New Rejection Necessitated by Amendment: Claim 17 recites “[a] non-invasive method of identifying subjects having advanced or severe (F3/F4) fibrosis of the liver” in lines 1-2. It is not clear how the method identifies subjects having advanced or severe (F3/F4) fibrosis of the liver, since no such active method step is recited that identifies subjects having F3/F4 fibrosis of the liver. Step f) recites “inferring from the comparison of step (e) whether fibrosis has changed wherein if the values from step (b) and step (d) are different, then it is inferred that fibrosis has changed in the subject.” The step of inferring does not relate to identifying subjects having advanced or severe (F3/F4) fibrosis of the liver but to predicting a change in fibrosis. Thus, the method of claim 17 does not recite any active method step that clearly identifies that the subject has F3/F4 fibrosis of the liver.
Claims 18 and 19 are also rejected for being dependent on a rejected base claim and failing to remedy the issue set forth above.
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.
Maintained Rejection: Claims 1-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. Claim 1 recites “if the level of CPS-1 expression of (a) is higher than the level of CPS-1 expression determined from a blood sample from a subject with mild to moderate fibrosis of the liver, and the level of glutamate of (c) is higher than the level of glutamate determined from a blood sample from a subject with mild to moderate fibrosis of the liver, then it is inferred that the subject has an increased likelihood of having advanced or severe (F3/F4) fibrosis of the liver.” The invention of claim 1 correlates a level of CPS-1 and glutamate in a blood sample from a subject to a state of liver fibrosis in the subject, which is a natural process. Claim 2 recites “if the level of arginine of (a) is lower than the level of arginine determined from a blood sample from a subject with mild to moderate fibrosis of the liver, and the citrulline/ornithine ratio of (c) is lower than the citrulline/ornithine ratio determined from a blood sample from a subject with mild to moderate fibrosis of the liver, and the reserve capacity of (e) is lower than the reserve capacity determined from a blood sample from a subject with mild to moderate fibrosis of the liver, then it is inferred that the subject has an increased likelihood of having advanced or severe (F3/F4) fibrosis of the liver.” The invention of claim 2 correlates a level of arginine, a ratio of citrulline/ornithine, and a reserve capacity in a blood sample to a state of liver fibrosis in the subject, which is a natural process. Claim 17 recites “comparing the values from step (b) to the values from step (d); f) inferring from the comparison of step (e) whether fibrosis has changed wherein if the values from step (b) and step (d) are different, then it is inferred that fibrosis has changed in the subject.” The invention of claim 17 correlates a difference in levels of CPS-1 and glutamate or levels of arginine, a citrulline/ornithine ratio, and reserve capacity to change in fibrosis state of the liver in a subject, which is a natural process. This judicial exception is not integrated into a practical application because claims 1, 2, and 17 each recite elements that are considered to be insignificant extra-solution activity for data gathering and an abstract mental step. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements recited are either directed to the natural phenomenon or directed to insignificant extra-solution data gathering activity.
Regarding claim 1, the step “a) determining a level of carbamoyl phosphate synthetase 1 (CPS-1) expression in a blood sample from a subject” is insignificant extra-solution data gathering activity. The step “b) comparing the level of CPS-1 expression of (a) to the level of CPS-1 expression determined from a blood sample from a subject with mild to moderate fibrosis of the liver” is an abstract process that can be practically performed in the human mind. The step “c) determining a level of glutamate in said sample” is insignificant extra-solution data gathering activity. The step “d) comparing the level of glutamate of (c) to the level of glutamate determined from a blood sample from a subject with mild to moderate fibrosis of the liver” is an abstract process that can be practically performed in the human mind. The step “e) wherein if the level of CPS-1 expression of (a) is higher than the level of CPS-1 expression determined from a blood sample from a subject with mild to moderate fibrosis of the liver, and the level of glutamate of (c) is higher than the level of glutamate determined from a blood sample from a subject with mild to moderate fibrosis of the liver, then it is inferred that the subject has an increased likelihood of having advanced or severe (F3/F4) fibrosis of the liver” is an abstract process that can be practically performed in the human mind. Moreover, El-Sheikh et al. (J. of Pathol., Microbiol., and Immunol., 2019, Vol. 127, pp.93-105; of record in the IDS filed 9/23/2022) provide evidence that carbamoyl phosphate synthetase 1 (CPS1) is a non-invasive serum marker for hepatic (liver) fibrosis, and teach CPS1 levels were higher in patients with severe fibrosis than patients with moderate fibrosis (see Abstract, p.94, left column, 1st passage, right column, 1st paragraph, p.95, left column, 2nd passage, p.96, left column, 2nd passage-right column, 1st paragraph, Figs. 1-3, and Table 2). Thus, the use of a level of CPS1 to determine a level of fibrosis of the liver is well-understood, routine, and conventional in the relevant field. Furthermore, Gaggani et al. (Hepatology, 2018, Vol. 67(1), pp.145-158; of record in the IDS filed 9/23/2022) provide evidence that glutamate levels are strongly associated with the severity of liver fibrosis (see Abstract, p.146, right column, 1st passage, paragraph bridging p.146-147, p.148, left column, 1st passage-1st paragraph, p.152, right column, 1st paragraph, p.153, paragraph bridging left and right columns, p.155, right column, 1st passage, and Fig. 5). Thus, the association of glutamate levels to a severity of liver fibrosis is well-understood, routine, and conventional in the relevant field. Therefore, claim 1 is directed to correlating the levels of CPS1 and glutamate in blood to a severity of liver fibrosis, which is a natural phenomenon.
Regarding claim 2, the step “a) determining the level of arginine in a blood sample from a subject” is insignificant extra-solution data gathering activity. The step “b) comparing the level of arginine of (a) to the level of arginine determined from a blood sample from a subject with mild to moderate fibrosis of the liver” is an abstract process that can be practically performed in the human mind. The step “c) determining the citrulline/ornithine ratio in said blood sample of (a)” is insignificant extra-solution data gathering activity. The step “d) comparing the citrulline/ornithine ratio of (c) to the citrulline/ornithine ratio determined from a blood sample from a subject with mild to moderate fibrosis of the liver” is an abstract process that can be practically performed in the human mind. The step “e) determining the reserve capacity in said blood sample of (a)” is insignificant extra-solution data gathering activity. The step “f) comparing the reserve capacity of (e) to the reserve capacity determined from a blood sample from a subject with mild to moderate fibrosis of the liver” is an abstract process that can be practically performed in the human mind. The step “g) wherein if the level of arginine of (a) is lower than the level of arginine determined from a blood sample from a subject with mild to moderate fibrosis of the liver, the citrulline/ornithine ratio of (c) is lower than the citrulline/ornithine ratio determined from a blood sample from a subject with mild to moderate fibrosis of the liver, and the reserve capacity of (e) is lower than the reserve capacity determined from a blood sample from a subject with mild to moderate fibrosis of the liver, then it is inferred that the subject has an increased likelihood of having advanced or severe (F3/F4) fibrosis of the liver” is an abstract process that can be practically performed in the human mind. Therefore, claim 2 is directed to correlating the levels of arginine, ratio of citrulline to ornithine, and level of reserve capacity in blood to a severity of liver fibrosis, which is a natural phenomenon.
Claim 3 recites “wherein the CPS-1 level determined is the plasma CPS-1 level,” which is insignificant extra-solution data gathering activity that does not add more to the judicial exception. Furthermore, Weerasinghe et al. (Am. J. Physiol. Gastrointest. Liver Physiol., 2014, Vol. 307(3), pp.G355-G364; of record) demonstrate that CPS1 is a marker of hepatocyte damage and detectability of CPS1 is similar in serum and plasma (see Abstract, p.G355, right column, last paragraph, p.G361, right column, 1st paragraph, and Fig. 5C).
Claim 4 recites “wherein the CPS-1 level is determined by quantitative sandwich immunoassay,” which is insignificant extra-solution data gathering activity that does not add more to the judicial exception. Furthermore, El-Sheikh et al. disclose measuring CPS1 by ELISA (see Abstract, p.94, right column, 1st paragraph, p.95, left column, 2nd passage, and p.102, right column, 1st passage).
Claim 5 recites “wherein said quantitative sandwich immunoassay comprises an ELISA assay,” which is insignificant extra-solution data gathering activity that does not add more to the judicial exception. Furthermore, El-Sheikh et al. disclose measuring CPS1 by ELISA (see Abstract, p.94, right column, 1st paragraph, p.95, left column, 2nd passage, and p.102, right column, 1st passage).
Claim 6 recites “wherein the level of glutamate is determined using mass spectrometry,” which is insignificant extra-solution data gathering activity that does not add more to the judicial exception. Furthermore, Gaggini et al. disclose measuring the glutamate levels using gas chromatography-mass spectrometry (see Abstract and p.147, right column, last paragraph).
Claim 7 recites “wherein the level of arginine is determined using mass spectrometry,” which is insignificant extra-solution data gathering activity that does not add more to the judicial exception.
Claim 8 recites “wherein the levels of citrulline/ornithine are determined using mass spectrometry,” which is insignificant extra-solution data gathering activity that does not add more to the judicial exception.
Claim 9 recites “wherein the reserve capacity is determined as maximal OCR minus basal respiration,” which is insignificant extra-solution data gathering activity that does not add more to the judicial exception.
Claim 10 recites “wherein the reserve capacity is determined using the ‘XF cell mito stress test kit’ from Agilent Technologies,” which is insignificant extra-solution data gathering activity that does not add more to the judicial exception.
Claim 11 recites “wherein the subject is suspected of having liver fibrosis,” which is directed to the natural phenomenon of correlating a level of CPS1 and glutamate of the blood sample to a severity of liver fibrosis. Thus, claim 11 is directed to the natural phenomenon without significantly more.
Claim 12 recites “wherein the subject has been previously identified as having F0-F2 liver fibrosis, preferably F1-F2 liver fibrosis,” which is directed to the natural phenomenon of correlating a level of CPS1 and glutamate of the blood sample to a severity of liver fibrosis. Thus, claim 12 is directed to the natural phenomenon without significantly more.
Claim 13 recites “wherein the subject is suspected of having, or has, metabolic syndrome,” which is directed to the natural phenomenon of correlating a level of CPS1 and glutamate of the blood sample to a severity of liver fibrosis. Furthermore, Gaggini et al. disclose that increased amino acid levels are associated with metabolic diseases, since the liver is the site of protein and amino acid metabolism and teach glutamate is increased in metabolic diseases and liver fibrosis (see passage bridging pp.145-146, p.146, right column, 1st passage, p.148, left column, 1st paragraph, p.151, left column, 1st paragraph, p.154, left column, 1st paragraph, and p.156, left column, 1st paragraph). Thus, claim 13 is directed to the natural phenomenon without significantly more.
Claim 14 recites “wherein the subject is suspected of having, or has, diabetes, preferably type 2 diabetes,” which is directed to the natural phenomenon of correlating a level of CPS1 and glutamate of the blood sample to a severity of liver fibrosis. Furthermore, Gaggini et al. disclose that increased amino acid levels are associated with type 2 diabetes mellitus like in liver fibrosis (see p.146, left column, 1st passage, and p.154, left column, 1st paragraph). Thus, claim 14 is directed to the natural phenomenon without significantly more.
Claim 15 recites “wherein the subject is suspected of having, or has, Non-Alcoholic Fatty Liver Disease (NAFLD),” which is directed to the natural phenomenon of correlating a level of CPS1 and glutamate of the blood sample to a severity of liver fibrosis. Furthermore, Gaggini et al. disclose that NAFLD, like liver fibrosis, is associated with increased amino acids, such as glutamate (see p.146, left column, 1st passage and p.151, left column, 1st paragraph). Thus, claim 15 is directed to the natural phenomenon without significantly more.
Claim 16 recites “wherein the subject is suspected of having, or has, Non-Alcoholic Steatohepatitis (NASH),” which is directed to the natural phenomenon of correlating a level of CPS1 and glutamate of the blood sample to a severity of liver fibrosis. Furthermore, Gaggini et al. disclose glutamate levels are increased in patients with NASH similar to liver fibrosis (see p.155, right column, 1st passage and Fig. 5). Thus, claim 16 is directed to the natural phenomenon without significantly more.
Regarding claim 17, the step of “a) providing a first blood sample from a subject taken at a first time point;” is insignificant extra-solution data gathering activity. The step of “b) either i. determining the level of carbamoyl phosphate synthetase 1 (CPS-1) expression in said sample and determining the level of glutamate in said sample, or ii. determining the level of arginine in said sample, determining the citrulline/ornithine ratio in said sample and determining the reserve capacity in said sample;” are insignificant extra-solution data gathering activity. The step of “c) providing a second blood sample from a subject taken at a second time point” is insignificant extra-solution data gathering activity. The step of “d) determining the same characteristics as were determined in step (b) for said second blood sample of step (c)” is insignificant extra-solution data gathering activity. The step of “e) comparing the values from step (b) to the values from step (d)” is an abstract process that can be practically performed in the human mind. The step of “f) inferring from the comparison step of (e) whether fibrosis has changed wherein if the values from step (b) and step (d) are different, then it is inferred that fibrosis has changed in the subject” is an abstract process that can be practically performed in the human mind. Moreover, El-Sheikh et al. (J. of Pathol., Microbiol., and Immunol., 2019, Vol. 127, pp.93-105; of record in the IDS filed 9/23/2022) provide evidence that carbamoyl phosphate synthetase 1 (CPS1) is a non-invasive serum marker for hepatic (liver) fibrosis, and teach CPS1 levels were higher in patients with severe fibrosis than patients with moderate fibrosis (see Abstract, p.94, left column, 1st passage, right column, 1st paragraph, p.95, left column, 2nd passage, p.96, left column, 2nd passage-right column, 1st paragraph, Figs. 1-3, and Table 2). Thus, the use of a level of CPS1 to determine a level of fibrosis of the liver is well-understood, routine, and conventional in the relevant field. Furthermore, Gaggani et al. (Hepatology, 2018, Vol. 67(1), pp.145-158; of record in the IDS filed 9/23/2022) provide evidence that glutamate levels are strongly associated with the severity of liver fibrosis (see Abstract, p.146, right column, 1st passage, paragraph bridging pp.146-147, p.148, left column, 1st passage-1st paragraph, p.152, right column, 1st paragraph, p.153, paragraph bridging left and right columns, p.155, right column, 1st passage, and Fig. 5). Thus, the association of glutamate levels to a severity of liver fibrosis is well-understood, routine, and conventional in the relevant field. Therefore, claim 17 is directed correlating a change of either the levels of CPS1 and glutamate in two blood samples to a change of fibrosis in a subject, which is a natural phenomenon, or the levels of arginine, ratio of citrulline to ornithine, and level of reserve capacity in two blood samples to a change of fibrosis in a subject, which is a natural phenomenon.
Claim 18 recites “wherein if the level of CPS-1 expression in said second sample and the level of glutamate in said second sample are higher than the levels for said first sample, then it is inferred that fibrosis has advanced or increased in said patient, and wherein if the level of CPS-1 expression in said second sample and the level of glutamate in said second sample are lower than the levels for said first sample, then it is inferred that fibrosis has receded or decreased in said patient,” which is an abstract process that can be practically performed in the human mind. Thus, claim 18 is directed to an abstract idea without significantly more.
Claim 19 recites “wherein if the level of arginine in said second sample and the reserve capacity in said second sample are lower than the levels for said first sample, then it is inferred that fibrosis has advanced or increased in said patient, and wherein if the level of arginine in said second sample, the citrulline/ornithine ratio in said second sample and the reserve capacity in said second sample are higher than the levels for said first sample, then it is inferred that fibrosis has receded or decreased in said patient,” which is an abstract process that can be practically performed in the human mind. Thus, claim 19 is directed to an abstract idea without significantly more.
Therefore, the claimed inventions are directed to the natural phenomenon of correlating the levels of CPS1 and glutamate in blood to a severity or change in liver fibrosis or correlating the levels of arginine, ratio of citrulline to ornithine, and level of reserve capacity in blood to a severity or change in liver fibrosis, which are natural processes. The additional elements recited in claims 1, 2, and 17 do not amount to more than the judicial exception because the additional elements are directed to insignificant extra-solution data gathering activity and abstract ideas. The dependent claims do not recite anything that amounts to more than the exception because the additional claims are directed to the natural phenomenon, abstract ideas, or insignificant extra-solution data gathering activity.
Claim Rejections - 35 USC § 103
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.
Maintained Rejection: Claims 1, 4-6, 11-12, and 14-18 are rejected under 35 U.S.C. 103 as being unpatentable over El-Sheikh et al. (J. of Pathol., Microbiol., and Immunol., 2019, Vol. 127, pp.93-105; of record in the IDS filed 9/23/2022) in view of Gaggani et al. (Hepatology, 2018, Vol. 67(1), pp.145-158; of record in the IDS filed 9/23/2022).
Regarding claim 1, El-Sheikh teaches that carbamoyl phosphate synthetase 1 (CPS1) is a non-invasive serum marker for hepatic (liver) fibrosis, and teaches serum CPS1 levels were higher in patients with severe fibrosis than patients with moderate fibrosis (see Abstract, p.94, left column, 1st passage, right column, 1st paragraph, p.95, left column, 2nd passage, p.96, left column, 2nd passage-right column, 1st paragraph, Figs. 1-3, and Table 2). Thus, El-Sheikh teaches determining a level of CPS1 expression in a serum blood sample from a subject, comparing the level of CPS1 expression to a level of CPS1 expression in a blood sample from a patient with moderate fibrosis, and non-invasively determining that the patient has severe fibrosis because the level of CPS1 is higher than a level from a patient with moderate fibrosis.
El-Sheikh does not teach determining the level of glutamate in said blood sample, comparing the level of glutamate in said sample to the level of glutamate determined from a blood sample from a subject with mild to moderate fibrosis of the liver, wherein if the level of glutamate of said sample is higher than the level of glutamate determined from a blood sample from a subject with mild to moderate fibrosis of the liver, then it is inferred that the subject has an increased likelihood of having advanced or severe (F3/F4) fibrosis of the liver.
Gaggini teaches that glutamate levels are strongly associated with the severity of liver fibrosis, and teaches determining the concentration of glutamate in blood samples taken from subjects with F0-F4 fibrosis and comparing the concentrations (see Abstract, p.146, right column, 1st passage, paragraph bridging pp.146-147, p.148, left column, 1st passage-1st paragraph, p.152, right column, 1st paragraph, p.153, paragraph bridging left and right columns, p.155, right column, 1st passage, and Fig. 5). Thus, Gaggini teaches determining the level of glutamate in a blood sample, comparing the level of glutamate in the blood sample taken from the subject to a level of glutamate in blood samples from subjects with F0-F4 fibrosis, and determining that level of glutamate is strongly associated with the severity of liver fibrosis as depicted in Figure 5.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have further determined a level of glutamate in a blood sample from a subject, as taught by Gaggini, in the method of determining a level of CPS1 expression in a blood serum sample from a subject, as taught by El-Sheikh, and to compare the levels of CPS1 and glutamate determined in the blood sample to a level of CPS1 and glutamate in a patient with moderate fibrosis of the liver, as taught by El-Sheikh and Gaggini, to determine if the subject has advanced or severe fibrosis of the liver. One of ordinary skill in the art would have been motivated to because Gaggini teaches the level of glutamate in blood is strongly associated with the severity of the liver fibrosis, yielding predictable results. There would have been a reasonable expectation of success because El-Sheikh and Gaggini teach their methods using blood samples from subjects.
Regarding claims 4 and 5, El-Sheikh teaches determining a level of CPS1 in serum blood samples using ELISA (see p.94, right column, 1st passage).
Regarding claim 6, Gaggini teaches measuring the glutamate levels using gas chromatography-mass spectrometry (see Abstract and p.147, right column, last paragraph).
Regarding claim 11, El-Sheikh teaches the subjects are chronically infected with hepatitis C virus (HCV) along with healthy subject and examined biopsy samples of the liver taken from the subjects to determine a stage of fibrosis (see p.94, left column, 2nd passage, right column, 2nd passage-2nd paragraph). Thus, it is interpreted that El-Sheikh suspected the HCV and healthy subjects as having liver fibrosis since they analyzed the subjects for liver fibrosis.
Regarding claim 12, El-Sheikh teaches determining the stage of fibrosis in the HCV subjects and healthy subjects used in the method (see p.94, right column, 2nd passage-2nd paragraph). It would have been obvious to perform the method of El-Sheikh in view of Gaggini using subjects previously determined to have no fibrosis (F0) to moderate fibrosis (F2) in order to track the progression of the liver fibrosis in the patient. One of ordinary skill in the art would have been motivated to determine if the liver fibrosis is getting better or worse in order to appropriately treat the liver fibrosis, yielding predictable results.
Regarding claims 14-16, El-Sheikh does not teach the subject is suspected, or has, either type 2 diabetes, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis.
Gaggini teaches nonalcoholic fatty liver disease (NAFLD) develops into fibrosis and nonalcoholic steatohepatitis (NASH) (see p.145, paragraph bridging left and right columns). Gaggini further teaches glutamate levels are increased in subjects with type 2 diabetes mellitus (T2DM), NAFLD, and nonalcoholic steatohepatitis, and further teaches most patients with T2DM have NAFLD/NASH (see p.151, left column, 1st paragraph, p.153, right column, last paragraph, p.155, left column, 1st passage, and Figs. 3-5).
Therefore, it would it have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have performed the method of El-Sheikh in view of Gaggini using subjects suspected of having or having T2DM, NAFLD, or NASH, as taught by Gaggini, to arrive at the claimed invention. One of ordinary skill would have been motivated to because Gaggini teaches each of these diseases are also associated with high levels of glutamate, like liver fibrosis, and inter-related, yielding predictable results.
Regarding claim 17, El-Sheikh teaches that carbamoyl phosphate synthetase 1 (CPS1) is a non-invasive serum marker for hepatic (liver) fibrosis, and teaches serum CPS1 levels were higher in patients with severe fibrosis than patients with moderate fibrosis (see Abstract, p.94, left column, 1st passage, right column, 1st paragraph, p.95, left column, 2nd passage, p.96, left column, 2nd passage-right column, 1st paragraph, Figs. 1-3, and Table 2). Thus, El-Sheikh teaches determining a level of CPS1 expression in a serum blood sample from a subject, comparing the level of CPS1 expression to a level of CPS1 expression in a blood sample from a patient with moderate fibrosis, and non-invasively determining that the patient has severe fibrosis because the level of CPS1 is higher than a level from a patient with moderate fibrosis.
El-Sheikh does not teach determining the level of glutamate in said blood sample, providing a second blood sample from a subject taken at a second time point; determining the same characteristics determined in the first blood sample for said second blood sample, comparing the values determined in the first and second blood samples, and inferring from the comparison whether fibrosis has changed wherein if the values are different, then it is inferred that fibrosis has changed in the subject.
Gaggini teaches that glutamate levels are strongly associated with the severity of liver fibrosis, and teaches determining the concentration of glutamate in blood samples taken from subjects with F0-F4 fibrosis and comparing the concentrations (see Abstract, p.146, right column, 1st passage, paragraph bridging pp.146-147, p.148, left column, 1st passage-1st paragraph, p.152, right column, 1st paragraph, p.153, paragraph bridging left and right columns, p.155, right column, 1st passage, and Fig. 5). Thus, Gaggini teaches determining the level of glutamate in a blood sample, comparing the level of glutamate in the blood sample taken from the subject to a level of glutamate in blood samples from subjects with F0-F4 fibrosis, and determining that level of glutamate is strongly associated with the severity of liver fibrosis as depicted in Figure 5.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have further determined a level of glutamate in a blood sample from a subject, as taught by Gaggini, in the method of determining a level of CPS1 expression in a blood serum sample from a subject, as taught by El-Sheikh, and to take a second blood sample and determine CPS1 expression and glutamate levels to compare the levels of CPS1 and glutamate determined in the first blood sample to a level of CPS1 and glutamate in a second blood sample taken from a subject. One of ordinary skill in the art would have been motivated to because Gaggini teaches the level of glutamate in blood is strongly associated with the severity of the liver fibrosis, yielding predictable results. One of ordinary skill in the art would have been motivated to repeat the steps of determining the levels of CPS1 and glutamate using a second blood sample taken a separate time in order to compare and detect the progression of the liver fibrosis.
Regarding claim 18, in view of El-Sheikh teaching CPS1 is significantly higher in blood serum of advanced and severe liver fibrosis, and Gaggini teaching glutamate levels are increased in patients with liver fibrosis and strongly associated with severity of liver fibrosis, it would have been obvious to determine whether the fibrosis has worsened/advanced if the levels of CPS1 and glutamate in the second sample are higher than the first sample or that has receded/decreased if the levels of CPS1 and glutamate in the second sample are lower than the first sample.
Thus, claims 1, 4-6, 11-12, and 14-18 are prima facie obvious.
Maintained Rejection: Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over El-Sheikh et al. (J. of Pathol., Microbiol., and Immunol., 2019, Vol. 127, pp.93-105; of record in the IDS filed 9/23/2022) in view of Gaggani et al. (Hepatology, 2018, Vol. 67(1), pp.145-158; of record in the IDS filed 9/23/2022), as applied to claims 1, 4-6, 11-12, and 14-18 above, and further in view of Weerasinghe et al. (Am. J. Physiol. Gastrointest. Liver Physiol., 2014, Vol. 307(3), pp.G355-G364; of record).
El-Sheikh in view of Gaggini teach the invention of claim 1 as outlined in the rejection above.
Regarding claim 3, El-Sheikh teaches determining the level of CPS1 expression in blood serum samples (see p.94, right column, 1st paragraph).
El-Sheikh and Gaggini do not teach the CPS1 level is determined from plasma.
Weerasinghe demonstrates that CPS1 is a marker of hepatocyte damage and detectability of CPS1 is similar in serum and plasma (see Abstract, p.G355, right column, last paragraph, p.G361, right column, 1st paragraph, and Fig. 5C).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have detected the level of CPS1 in plasma, as taught by Weerasinghe, in the method of determining a level of CPS1 and glutamate in a blood sample, as taught by El-Sheikh in view of Gaggini, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to because Weerasinghe teaches detectability of CPS1 as a marker of hepatocyte damage is similar in serum and plasma, yielding predictable results. Thus, claim 3 is prima facie obvious.
Maintained Rejection: Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over El-Sheikh et al. (J. of Pathol., Microbiol., and Immunol., 2019, Vol. 127, pp.93-105; of record in the IDS filed 9/23/2022) in view of Gaggani et al. (Hepatology, 2018, Vol. 67(1), pp.145-158; of record in the IDS filed 9/23/2022), as applied to claims 1, 4-6, 11-12, and 14-18 above, and further in view of Kral et al. (Surgery, 2004, Vol. 135(1), pp.48-58; of record).
El-Sheikh in view of Gaggini teach the invention of claim 1 as outlined in the rejection above.
Regarding claim 13, El-Sheikh and Gaggini do not teach the subject is suspected of having, or has, metabolic syndrome.
Kral teaches the metabolic syndrome, obesity, is a determinant of liver fibrosis and cirrhosis, i.e., severe fibrosis (see Abstract, p.48, right column, 1st paragraph and p.53, right column, 1st paragraph).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to detect liver fibrosis using the method of El-Sheikh in view of Gaggini in a subject with obesity metabolic syndrome, as taught by Kral, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to determine a severity of liver fibrosis in a subject with obesity metabolic syndrome because Kral teaches obesity is a determinant of liver fibrosis and cirrhosis, yielding predictable results. Thus, claim 13 is prima facie obvious.
Closest Prior Art
The closest prior art to the invention of claim 2 is US2016/0317484 to Summar et al. Summar et al. demonstrate detecting levels of arginine and an ornithine/citrulline ratio in plasma samples taken from patients having breast cancer and that have undergone a bone marrow transplant (see paragraphs [0266], [0268], [0274], and [0276]-[0279]). The plasma levels of arginine and the ratio of ornithine/citrulline were determined before and after administration of chemotherapy in the transplant cancer patients (see paragraphs [0276]-[0278]). The Examiner has not found a teaching or suggestion in the art to use the levels of arginine and ornithine/citrulline ratio for determining a likelihood of advanced or severe (F3/F4) liver fibrosis in a subject and arrive at the claimed invention.
Response to Arguments
Applicant's arguments filed 12/1/2025 have been fully considered but they are not persuasive.
In Applicant’s Remarks, see paragraph bridging pp.7-8, Applicant argues the trade name is required in claim 10, since the contents of the claimed kit are not known by any other name and do not have a publicly available composition. Applicant further argues the reagents cannot be defined by replacing the trade names with generic equivalent language as no such language is believed to exist. This is not found persuasive.
MPEP § 2173.05(u) sets forth that if the trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. § 112(b). Claim 10 intends to identify a particular product, and thus is indefinite. Applicant should utilize the “How It Works” section of Appendix A to recite the required steps and known components of the kit that carry out determining reserve capacity.
In Applicant’s Remarks, see p.8, 3rd paragraph,-paragraph bridging pp.8-9, Applicant argues that the invention of claims 1, 2, and 17 encompass an active selection step of the F3/F4 liver fibrosis group of patients, thus, the claimed method practically identifies and diagnoses patients with severe disease in need of treatment. Applicant further argues the claimed inventions are directed to a non-invasive method of identifying subjects having advanced or severe (F3/F4) fibrosis of the liver. Applicant argues that, to their knowledge, there were no non-invasive tests for liver fibrosis in the prior art, thus Applicant’s inventions is directed to significantly more than a natural phenomenon. This is not found persuasive.
Applicant’s argument is not commensurate in scope with the claimed invention. No such active selection step for a group of patients with F3/F4 liver fibrosis is recited in claims 1, 2, and 17, as currently amended. Claims 1, 2, and 17 recite identifying a subject having advanced or severe (F3/F4) fibrosis of the liver in the preambles but do not clearly recite any active method step regarding identifying a subject having F3/F4 fibrosis of the liver. Claim 1 recites “it is inferred that the subject has an increased likelihood of having advanced or severe (F3/F4) fibrosis of the liver.” Claim 2 recites “it is inferred that the subject has an increased likelihood of having advanced or severe (F3/F4) fibrosis of the liver.” Claim 17 recites “inferring from the comparison of step (e) whether fibrosis has changed wherein if the values from step (b) and step (d) are different, then it is inferred that fibrosis has changed in the subject.” The steps of inferring recited in claims 1 and 2 do not clearly indicate identifying a subject having F3/F4 liver fibrosis. The step of inferring recited in claim 17 does not relate to identifying subjects having advanced or severe (F3/F4) fibrosis of the liver but to predicting a change in fibrosis. Thus, claims 1, 2, and 17 do not comprise actively selecting a group of F3/F4 liver fibrosis patients. With regards to the arguments that the methods of claims 1, 2, and 17 are non-invasive, this feature is not a contribution over the prior art and was previously recognized. Specifically, El-Sheikh et al. (J. of Pathol., Microbiol., and Immunol., 2019, Vol. 127, pp.93-105; of record in the IDS filed 9/23/2022) teach that carbamoyl phosphate synthetase 1 (CPS1) is a non-invasive serum marker for hepatic (liver) fibrosis, and teach serum CPS1 levels were higher in patients with severe fibrosis than patients with moderate fibrosis (see Abstract, p.94, left column, 1st passage, right column, 1st paragraph, p.95, left column, 2nd passage, p.96, left column, 2nd passage-right column, 1st paragraph, Figs. 1-3, and Table 2). Thus, El-Sheikh et al. teach determining a level of CPS1 expression in a serum blood sample from a subject, comparing the level of CPS1 expression to a level of CPS1 expression in a blood sample from a patient with moderate fibrosis, and non-invasively determining that the patient has severe fibrosis because the level of CPS1 is higher than a level from a patient with moderate fibrosis. Furthermore, Gaggini et al. (Hepatology, 2018, Vol. 67(1), pp.145-158; of record in the IDS filed 9/23/2022) teach that glutamate levels are strongly associated with the severity of liver fibrosis, and teaches determining the concentration of glutamate in blood samples taken from subjects with F0-F4 fibrosis and comparing the concentrations (see Abstract, p.146, right column, 1st passage, paragraph bridging pp.146-147, p.148, left column, 1st passage-1st paragraph, p.152, right column, 1st paragraph, p.153, paragraph bridging left and right columns, p.155, right column, 1st passage, and Fig. 5). Thus, Gaggini et al. teach determining the level of glutamate in a blood sample, comparing the level of glutamate in the blood sample taken from the subject to a level of glutamate in blood samples from subjects with F0-F4 fibrosis, and determining that level of glutamate is strongly associated with the severity of liver fibrosis as depicted in Figure 5. The combination of El-Sheikh et al. and Gaggani et al. demonstrate non-invasive methods and the required active method steps of the claims were well-understood, routine, and conventional in the relevant field of liver fibrosis diagnostics.
In Applicant’s Remarks, see p.10, 1st paragraph,-p.11, 1st paragraph, Applicant argues that one of ordinary skill in the art would not have been motivated to combine the disclosures of El-Sheikh and Gaggini given the plethora of prior art in the field and nothing to specifically direct them to those particular documents or the metabolites discussed therein. Applicant further argues that no-one had assembled the steps of the claimed invention into a non-invasive test for severe fibrosis of the liver. Applicant further argues hindsight analysis was used to arrive at the claimed invention. Applicant argues the skilled person would have had to analyze the literature on over 400 metabolites and experimentally confirm the most likely indicators from the metabolites. This is not found persuasive.
El-Sheikh et al. teaches that carbamoyl phosphate synthetase 1 (CPS1) is a non-invasive serum marker for hepatic (liver) fibrosis, and teaches serum CPS1 levels were higher in patients with severe fibrosis than patients with moderate fibrosis (see Abstract, p.94, left column, 1st passage, right column, 1st paragraph, p.95, left column, 2nd passage, p.96, left column, 2nd passage-right column, 1st paragraph, Figs. 1-3, and Table 2). Thus, El-Sheikh et al. teach determining a level of CPS1 expression in a serum blood sample from a subject, comparing the level of CPS1 expression to a level of CPS1 expression in a blood sample from a patient with moderate fibrosis, and non-invasively determining that the patient has severe fibrosis because the level of CPS1 is higher than a level from a patient with moderate fibrosis. Furthermore, Gaggini et al. teach that glutamate levels are strongly associated with the severity of liver fibrosis, and teaches determining the concentration of glutamate in blood samples taken from subjects with F0-F4 fibrosis and comparing the concentrations (see Abstract, p.146, right column, 1st passage, paragraph bridging pp.146-147, p.148, left column, 1st passage-1st paragraph, p.152, right column, 1st paragraph, p.153, paragraph bridging left and right columns, p.155, right column, 1st passage, and Fig. 5). Thus, Gaggini et al. teach determining the level of glutamate in a blood sample, comparing the level of glutamate in the blood sample taken from the subject to a level of glutamate in blood samples from subjects with F0-F4 fibrosis, and determining that level of glutamate is strongly associated with the severity of liver fibrosis as depicted in Figure 5. It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have further determined a level of glutamate in a blood sample from a subject, as taught by Gaggini, in the method of determining a level of CPS1 expression in a blood serum sample from a subject, as taught by El-Sheikh, and to compare the levels of CPS1 and glutamate determined in the blood sample to a level of CPS1 and glutamate in a patient with moderate fibrosis of the liver, as taught by El-Sheikh and Gaggini, to determine if the subject has advanced or severe fibrosis of the liver. One of ordinary skill in the art would have been motivated to because Gaggini teaches the level of glutamate in blood is strongly associated with the severity of the liver fibrosis, yielding predictable results. There would have been a reasonable expectation of success because El-Sheikh and Gaggini teach their methods using blood samples from subjects. Thus, the combination of El-Sheikh and Gaggani demonstrate non-invasive methods of determining the stage of liver fibrosis from a sample of blood taken from the patient, and one of ordinary skill in the art would have been motivated to combine their teachings for the reasons above. Therefore, no hindsight reason is required to arrive at the claimed invention, and the prior art render obvious the claimed invention.
In Applicant’s Remarks, see p.11, last paragraph, Applicant argues a person of ordinary skill in the art would not be motivated to combine El-Sheikh, Gaggini, or Weerasinghe given the plethora of prior art in the field and claims nothing specifically directs the person to these documents. Applicant further argues nothing in Weerasinghe would have motivated one to assemble the individual steps of the present claimed method into a non-invasive test for severe fibrosis of the liver. This is not found persuasive.
The arguments with respect to combining El-Sheikh and Gaggini have been addressed above. With respect to Weerasinghe, Weerasinghe specifically demonstrates that CPS1 is a marker of hepatocyte damage, i.e., liver cell damage, and detectability of CPS1 is similar in serum and plasma (see Abstract, p.G355, right column, last paragraph, p.G361, right column, 1st paragraph, and Fig. 5C). Thus, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have detected the level of CPS1 in plasma, as taught by Weerasinghe, in the method of determining a level of CPS1 and glutamate in a blood sample, as taught by El-Sheikh in view of Gaggini, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to because Weerasinghe teaches detectability of CPS1 as a marker of hepatocyte damage is similar in serum and plasma, yielding predictable results. Thus, it was within the purview of the person of ordinary skill in the art to arrive at the claimed invention with a reasonable expectation of success.
In Applicant’s Remarks, see p.12, 2nd paragraph, Applicant argues a person of ordinary skill in the art would not be motivated to combine El-Sheikh, Gaggini, or Kral given the plethora of prior art in the field and claims nothing specifically directs the person to these documents. Applicant further argues nothing in Kral would have motivated one to assemble the individual steps of the present claimed method into a non-invasive test for severe fibrosis of the liver. This is not found persuasive.
The arguments with respect to combining El-Sheikh and Gaggini have been addressed above. With respect to Kral, Kral specifically teaches the metabolic syndrome, obesity, is a determinant of liver fibrosis and cirrhosis, i.e., severe fibrosis (see Abstract, p.48, right column, 1st paragraph and p.53, right column, 1st paragraph). Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to detect liver fibrosis using the method of El-Sheikh in view of Gaggini in a subject with obesity metabolic syndrome, as taught by Kral, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to determine a severity of liver fibrosis in a subject with obesity metabolic syndrome because Kral teaches obesity is a determinant of liver fibrosis and cirrhosis, yielding predictable results. Thus, it was within the purview of the person of ordinary skill in the art to arrive at the claimed invention with a reasonable expectation of success.
For the reasons set forth above, the 35 U.S.C. § 103 rejections are maintained.
Conclusion
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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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/J.P.S./Examiner, Art Unit 1657