Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
This office action for the 18/569619 application is in response to the communications filed September 22, 2025.
Claims 19-26 were added as new September 22, 2025.
Claims 9, 15, 16 and 18 were amended September 22, 2025.
Claim 13 was cancelled September 22, 2025.
Claims 9-12, 15, 16 and 18-26 are currently pending and considered below.
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 9-12, 15, 16 and 18-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
As per claim 9,
Step 1: The claim recites subject matter within a statutory category as a process.
Step 2A is a two-prong inquiry, in which Prong 1 determines whether a claim recites a judicial exception. Prong 2 determines if the additional limitations of the claim integrates the recited judicial exception into a practical application. If the additional elements of the claim fail to integrate the judicial exception into a practical application, claim is directed to the recited judicial exception, see MPEP 2106.04(II)(A).
Step 2A Prong 1: The claim contains subject matter that recites an abstract idea, with the steps of a method for the diagnosis and treating of at-risk nonalcoholic steatohepatitis (NASH) in a human patient with a metabolic disorder, comprising: (i) calculating a nonalcoholic fatty liver disease score (NFS) from the age, body-mass index, aspartate amino transferase (AST)/alanine aminotransferase (ALT) ratio, platelet count and hyperglycemia status of said patient; and (ii) calculating a nonalcoholic steatohepatitis score (NIS4) for said patient, based on the level of hsa-miR-34a-5p, alpha-2 macroglobulin (A2M), YKL-40 and glycated haemoglobin (HbA1c) measured in a blood or blood-derived sample of said patient; and determining the presence or absence of at-risk NASH in said patient based on said scores; wherein the NFS test is implemented before or after the NIS4 test; (iii) administering an anti-NASH or anti-fibrotic agent to the patient diagnosed as having at-risk NASH selected from the group consisting of signal-regulating kinase 1 (ASK1) inhibitors, GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, Glucagon-like peptide-1 (GLP-1) analogs, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, Glucagon-like peptide-1 (GLP-1) receptor agonists, LY-3305677 long-acting Oxyntomodulin, nitazoxanide (NTZ), tizoxanide (TZ), prodrugs of TZ, RM-5061, orlistat (Xenical), pioglitazone, thyroid receptor 0 (THR 0) agonists, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan. These steps, as drafted, under the broadest reasonable interpretation recite:
certain methods of organizing human activity (e.g., fundamental economic principles or practices including: hedging; insurance; mitigating risk; etc., commercial or legal interactions including: agreements in the form of contracts; legal obligations; advertising, marketing or sales activities or behaviors; business relations; etc., managing personal behavior or relationships or interactions between people including: social activities; teaching; following rules or instructions; etc.) but for recitation of generic computer components. That is, other than reciting steps as performed by the generic computer components, nothing in the claim element precludes the step from being directed to certain methods of organizing human activity. For example, the identified abstract idea, law of nature, or natural phenomenon identified above, in the context of this claim, encompasses a certain method of organizing human activity, namely managing personal behavior or relationships or interactions between people. This is because each of the limitations of the abstract idea recites a list of rules or instructions that a human person can follow in the course of their personal behavior. If a claim limitation, under its broadest reasonable interpretation, covers at least the recited methods of organizing human activity above, but for the recitation of generic computer components, then it falls within the “Certain Methods of Organizing Human Activity” grouping of abstract ideas. Accordingly, the claim recites an abstract idea. See MPEP 2106.04(a).
Step 2A Prong 2: The claim does not recite additional elements that integrate the judicial exception into a practical application. In fact, the claim does not recite any element other than what is abstract.
Accordingly, this claim is directed to an abstract idea.
Step 2B: The claim does not recite additional elements that amount to significantly more than the judicial exception. As discussed above with respect to discussion of integration of the abstract idea into a practical application, no additional elements exist.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 10,
Claim 10 depends from claim 9 and inherits all the limitations of the claim from which it depends. Claim 10 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein the calculated NFS is compared to a NFS low cutoff value and the calculated NIS4 is compared to a NIS4 low cutoff value.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 11,
Claim 11 depends from claim 10 and inherits all the limitations of the claim from which it depends. Claim 11 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein if the calculated NFS is lower than said NFS low cutoff value or if the calculated NIS4 is lower than said NIS4 low cutoff value, then the patient is diagnosed as not having at-risk NASH.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 12,
Claim 12 depends from claim 10 and inherits all the limitations of the claim from which it depends. Claim 12 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein if the calculated NFS is greater or equal to said NFS low cutoff value and if the calculated NIS4 is greater or equal to said NIS4 low cutoff value, then the patient is diagnosed as having at-risk NASH.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 15,
Claim 15 depends from claim 9 and inherits all the limitations of the claim from which it depends. Claim 15 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein the agent is administered to the patient if the calculated NFS and the calculated NIS4 are above the NFS low cutoff and the NIS4 low cutoff, respectively.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 16,
Claim 16 depends from claim 9 and inherits all the limitations of the claim from which it depends. Claim 16 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“administering an anti-NASH or anti-fibrotic agent to a patient diagnosed as having at-risk NASH, wherein the agent is selected from the group consisting of signal-regulating kinase 1 (ASK1) inhibitors, GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, elafibranor, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, Glucagon-like peptide-1 (GLP-1) analogs, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, Glucagon-like peptide-1 (GLP-1) receptor agonists, LY-3305677, long-acting Oxyntomodulin, nitazoxanide (NTZ), tizoxanide (TZ), prodrugs of TZ, RM-5061, orlistat (Xenical), pioglitazone, thyroid receptor 3 (THR 3) agonists, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196,Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 18,
Claim 18 depends from claim 16 and inherits all the limitations of the claim from which it depends. Claim 18 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein the agent is administered to the patient if the calculated NFS and the calculated NIS4 are above the NFS low cutoff and the NIS4 low cutoff, respectively.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 19,
Claim 19 depends from claim 9 and inherits all the limitations of the claim from which it depends. Claim 19 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein the anti-NASH or anti-fibrotic agent administered to the patient diagnosed as having at-risk NASH is selected from the group consisting of lanifibranor, resmetirom, saroglitazar magnesium, and semaglutide.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 20,
Step 1: The claim recites subject matter within a statutory category as a process.
Step 2A is a two-prong inquiry, in which Prong 1 determines whether a claim recites a judicial exception. Prong 2 determines if the additional limitations of the claim integrates the recited judicial exception into a practical application. If the additional elements of the claim fail to integrate the judicial exception into a practical application, claim is directed to the recited judicial exception, see MPEP 2106.04(II)(A).
Step 2A Prong 1: The claim contains subject matter that recites an abstract idea, with the steps of a method of performing noninvasive tests in a subject, the method comprising: (i) measuring in a subject body weight, height, aspartate amino transferase (AST), alanine aminotransferase (ALT), platelet count, albumin, fasting glucose, fasting insulin, and determining age, and calculating a nonalcoholic fatty liver disease fibrosis score (NFS) from the age, body-mass index, aspartate amino transferase (AST)/alanine aminotransferase (ALT) ratio, platelet count and hyperglycemia status of said subject; and (ii) in a subject having a NFS greater than 0.675, measuring in a blood or blood-derived sample of said subject levels of hsa-miR-34a-5p, alpha-2 macroglobulin (A2M), YKL-40 and glycated haemoglobin (HbAlc) and calculating a nonalcoholic steatohepatitis score (NIS4) based on the level of hsa-miR-34a-5p, alpha-2 macroglobulin (A2M), YKL-40 and glycated haemoglobin (HbAlc) measured in the blood or blood-derived sample of said subject; and (iii) in a subject having a NIS4 score greater than 0.36 administering a therapeutically effective amount of an anti-NASH or anti-fibrotic agent to the patient diagnosed as having at-risk NASH, wherein said anti-NASH or anti-fibrotic agent is selected from the group consisting of signal-regulating kinase 1 (ASK1) inhibitors, GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, Glucagon-like peptide-1 (GLP-1) analogs, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, Glucagon-like peptide-1 (GLP-1) receptor agonists, LY-3305677, long-acting Oxyntomodulin, nitazoxanide (NTZ), tizoxanide (TZ), prodrugs of TZ, RM-5061, orlistat (Xenical), pioglitazone, thyroid receptor R(THR(3) agonists, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan. These steps, as drafted, under the broadest reasonable interpretation recite:
certain methods of organizing human activity (e.g., fundamental economic principles or practices including: hedging; insurance; mitigating risk; etc., commercial or legal interactions including: agreements in the form of contracts; legal obligations; advertising, marketing or sales activities or behaviors; business relations; etc., managing personal behavior or relationships or interactions between people including: social activities; teaching; following rules or instructions; etc.) but for recitation of generic computer components. That is, other than reciting steps as performed by the generic computer components, nothing in the claim element precludes the step from being directed to certain methods of organizing human activity. For example, the identified abstract idea, law of nature, or natural phenomenon identified above, in the context of this claim, encompasses a certain method of organizing human activity, namely managing personal behavior or relationships or interactions between people. This is because each of the limitations of the abstract idea recites a list of rules or instructions that a human person can follow in the course of their personal behavior. If a claim limitation, under its broadest reasonable interpretation, covers at least the recited methods of organizing human activity above, but for the recitation of generic computer components, then it falls within the “Certain Methods of Organizing Human Activity” grouping of abstract ideas. Accordingly, the claim recites an abstract idea. See MPEP 2106.04(a).
Step 2A Prong 2: The claim does not recite additional elements that integrate the judicial exception into a practical application. In fact, the claim does not recite any element other than what is abstract.
Accordingly, this claim is directed to an abstract idea.
Step 2B: The claim does not recite additional elements that amount to significantly more than the judicial exception. As discussed above with respect to discussion of integration of the abstract idea into a practical application, no additional elements exist.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 21,
Claim 21 depends from claim 20 and inherits all the limitations of the claim from which it depends. Claim 21 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein if the calculated NFS is lower than 0.675 or if the calculated NIS4 is lower than 0.36, then the subject is not administered an anti-NASH or anti-fibrotic compound.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 22,
Claim 22 depends from claim 20 and inherits all the limitations of the claim from which it depends. Claim 22 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein the anti-NASH or anti-fibrotic compound is selected from the group consisting of GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, exenatide, albiglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, LY-3305677, long-acting Oxyntomodulin; nitazoxanide (NTZ), tizoxanide (TZ), RM-5061, orlistat (Xenical), pioglitazone, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 23,
Step 1: The claim recites subject matter within a statutory category as a process.
Step 2A is a two-prong inquiry, in which Prong 1 determines whether a claim recites a judicial exception. Prong 2 determines if the additional limitations of the claim integrates the recited judicial exception into a practical application. If the additional elements of the claim fail to integrate the judicial exception into a practical application, claim is directed to the recited judicial exception, see MPEP 2106.04(II)(A).
Step 2A Prong 1: The claim contains subject matter that recites an abstract idea, with the steps of a method of performing noninvasive tests in a subject comprising: (i) measuring in a blood or blood-derived sample of the subject levels of hsa-miR-34a-5p,alpha-2 macroglobulin (A2M), YKL-40 and glycated haemoglobin (HbAlc) and calculating a nonalcoholic steatohepatitis score (NIS4) based on the level of hsa-miR-34a-5p, alpha-2 macroglobulin (A2M), YKL-40 and glycated haemoglobin (HbAlc) measured in the blood or blood-derived sample of said subject; (ii) in a subject having a NIS4 greater than 0.36 measuring body weight, height, aspartate amino transferase (AST), alanine aminotransferase (ALT), platelet count, albumin, fasting glucose, fasting insulin, and determining age, and calculating a nonalcoholic fatty liver disease fibrosis score (NFS) from the age, body-mass index, aspartate amino transferase (AST)/alanine aminotransferase (ALT) ratio, platelet count and hyperglycemia status of said patient; and (iii) in a subject having a NFS score greater than 0.675 administering an anti-NASH or anti-fibrotic agent selected from the group consisting of signal-regulating kinase 1 (ASK1) inhibitors, GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, Glucagon-like peptide-1 (GLP-1) analogs, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, Glucagon-like peptide-1 (GLP-1) receptor agonists, LY-3305677, long-acting Oxyntomodulin, nitazoxanide (NTZ), tizoxanide (TZ), prodrugs of TZ, RM-5061, orlistat (Xenical), pioglitazone, thyroid receptor p (THR(3) agonists, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan. These steps, as drafted, under the broadest reasonable interpretation recite:
certain methods of organizing human activity (e.g., fundamental economic principles or practices including: hedging; insurance; mitigating risk; etc., commercial or legal interactions including: agreements in the form of contracts; legal obligations; advertising, marketing or sales activities or behaviors; business relations; etc., managing personal behavior or relationships or interactions between people including: social activities; teaching; following rules or instructions; etc.) but for recitation of generic computer components. That is, other than reciting steps as performed by the generic computer components, nothing in the claim element precludes the step from being directed to certain methods of organizing human activity. For example, the identified abstract idea, law of nature, or natural phenomenon identified above, in the context of this claim, encompasses a certain method of organizing human activity, namely managing personal behavior or relationships or interactions between people. This is because each of the limitations of the abstract idea recites a list of rules or instructions that a human person can follow in the course of their personal behavior. If a claim limitation, under its broadest reasonable interpretation, covers at least the recited methods of organizing human activity above, but for the recitation of generic computer components, then it falls within the “Certain Methods of Organizing Human Activity” grouping of abstract ideas. Accordingly, the claim recites an abstract idea. See MPEP 2106.04(a).
Step 2A Prong 2: The claim does not recite additional elements that integrate the judicial exception into a practical application. In fact, the claim does not recite any element other than what is abstract.
Accordingly, this claim is directed to an abstract idea.
Step 2B: The claim does not recite additional elements that amount to significantly more than the judicial exception. As discussed above with respect to discussion of integration of the abstract idea into a practical application, no additional elements exist.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 24,
Claim 24 depends from claim 23 and inherits all the limitations of the claim from which it depends. Claim 24 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein the anti-NASH or anti-fibrotic agent is selected from the group consisting of GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, exenatide, albiglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, LY-3305677, long-acting Oxyntomodulin; nitazoxanide (NTZ), tizoxanide (TZ), RM-5061, orlistat (Xenical), pioglitazone, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 25,
Claim 25 depends from claim 9 and inherits all the limitations of the claim from which it depends. Claim 25 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein the anti-NASH or anti-fibrotic agent is selected from the group consisting of GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, exenatide, albiglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, LY-3305677, long-acting Oxyntomodulin; nitazoxanide (NTZ), tizoxanide (TZ), RM-5061, orlistat (Xenical), pioglitazone, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
As per claim 26,
Claim 26 depends from claim 16 and inherits all the limitations of the claim from which it depends. Claim 26 merely further defines the abstract idea and/or introduces additional elements that are insufficient to provide a practical application or something significantly more:
“wherein the agent is selected from the group consisting of GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, exenatide, albiglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, LY-3305677, long-acting Oxyntomodulin, nitazoxanide (NTZ), tizoxanide (TZ), RM-5061, orlistat (Xenical), pioglitazone, resmetirom, rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan.” further describes the abstract idea. This claim limitation is still directed to “Certain Methods of Organizing Human Activity” and therefore continues to recite an abstract idea.
Looking at the limitations of the claim as an ordered combination adds nothing that is not already present when looking at the elements taken individually. There is no indication that the combination of elements improves the functioning of a computer or improves any other technology. Their collective functions merely recite an abstract idea and/or provide conventional computer implementation which does not impose a meaningful limit to integrate the abstract idea into a practical application and/or amount to no more than limitations which amount to elements that have been recognized as well-understood, routine, and conventional activity in particular fields.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 9-12, 15, 16 and 18-26 are rejected under 35 U.S.C. 103 as being unpatentable over Brozek (US 2022/0162702) in view of Uslusoy et al. (Uslusoy, Hüseyin Saadettin. “Noninvasive Predictors for Liver Fibrosis in Patients with Nonalcoholic Steatohepatitis.” World Journal of Hepatology, Volume 3, Number 8, 2011, Pages 219-227, https://doi.org/10.4254/wjh.v3.i8.219; herein referred to as Uslusoy).
As per claim 9,
Brozek teaches a method for the diagnosis and treatingof at-risk nonalcoholic steatohepatitis (NASH) in a human patient with a metabolic disorder:
(Paragraphs [0002] and [0008] of Brozek. The teaching describes that the present invention relates to a method for the diagnosis of non-alcoholic steatohepatitis (NASH), for the classification of a subject as a receiver or non-receiver of a treatment for NASH, or for monitoring the efficiency of a treatment for NASH. Non-alcoholic steatohepatitis (NASH) is a progressive disease of the liver characterized histologically by fatty acid accumulation, hepatocyte damage and inflammation resembling alcoholic hepatitis. NASH can lead to liver fibrosis, cirrhosis, liver failure and/or hepatocellular carninoma (HCC). Along with the obesity and type-2 diabetes rates in the world, the incidence of NASH has increased in recent years, and patients who develop NASH have an increased rate of liver-related mortalities. Since the prevalence of these diseases is increasing, the prevalence of NASH is also expected to increase and therefore, NASH has become a worldwide emerging public health issue. These major concerns underscore the need for the development of more sensitive and reliable method for a diagnostic of NASH.)
Brozek further teaches (i) calculating a nonalcoholic fatty liver disease score (NFS):
(Paragraphs [0019] and [0020] of Brozek. The teaches describes that the term “non-alcoholic steatohepatitis” refers to a non-alcoholic fatty liver disease (NAFLD) condition characterized by the concomitant presence of liver steatosis, hepatocyte ballooning and liver inflammation at histological examination, in the absence of excessive alcohol consumption and after excluding other liver diseases like viral hepatitis (HCV, HBV). According to the invention, the term “steatosis” refers to the process describing the abnormal retention of lipids or fat accumulation within the liver. According to the present invention, the “NAFLD-Activity score” or “NAS” refers to the sum of steatosis, hepatocellular ballooning, lobular inflammation scores)
Brozek further teaches (ii) calculating a nonalcoholic steatohepatitis score (NIS4) for said patient, based on the level of hsa-miR-34a-5p, alpha-2 macroglobulin (A2M), YKL-40 and glycated haemoglobin (HbA1c) measured in a blood or blood-derived sample of said patient:
(Paragraphs [0046]-[0050] of Brozek. The teaching describes that a biological fluid can be a sample of blood, of a blood-derived fluid (for example serum or plasma, in particular platelet-free plasma, e.g. a cell-free, citrate-derived platelet-free plasma sample), of saliva, of cerebrospinal fluid or of urine. In a particular embodiment, the body fluid is blood, plasma or serum, deprived of platelets or not. In another particular embodiment, step i) comprises the measure of the level of hsa-miR34a, A2M, YKL-40 and HbA1c. In the present application, the combination of these four markers is also referred to as NIS4.)
Brozek further teaches determining the presence or absence of at-risk NASH in said patient based on said scores, wherein the NFS test is implemented before or after the NIS4 test:
(Paragraphs [0020]-[0024], [0041] and [0052]-[0056] of Brozek. The teaching describes According to the present invention, the “NAFLD-Activity score” or “NAS” refers to the sum of steatosis, hepatocellular ballooning, lobular inflammation scores, as follows: S: Steatosis score: 0: <5%; 1: 5-33%; 2: 34-66% and 3: >66%; LI: Lobular Inflammation score (foci/x20 field): 0: none; 1: <2; 2: 2-4 and 3: >4; HB: Ballooning degeneration score: 0: none; 1: few; 2: many cells/prominent ballooning. Therefore, NASH refers to a NAFLD condition characterized by the following liver biopsy-derived grades: NAS≥3, with at least 1 point in steatosis, at least 1 point in lobular inflammation and at least 1 point in the hepatocyte ballooning scores. According to the present invention, the term NASH refers, without limitation, to different stages of NASH, including NASH, severe NASH, active NASH, fibrosing NASH and active NASH with significant fibrosis (i.e. an active NASH characterized by liver fibrosis stage of 2 or of more than 2, such as a fibrosis stage equal to 2, 3 or 4). The method of the present invention can be used in the context of all these kinds of NASH. In a particular embodiment, a NIS4 score is used in combination to the measured stiffness. The NIS4 score is more particularly calculated as provided in WO2017167934. If S2 is greater or equal to a threshold value, the subject is classified as having or potentially having a NASH and/or is classified as a receiver of a treatment for NASH. If S2 is lower than a threshold value, the subject may be classified as a receiver or non-receiver, in particular as a non-receiver, of a treatment for NASH and/or the subject is classified as a receiver, or potential receiver, of diet and lifestyle advices for managing his/her NASH.)
Brozek further teaches (iii) administering an anti-NASH or anti-fibrotic agent to the patient diagnosed as having at-risk NASH selected from the group consisting of signal-regulating kinase 1 (ASK1) inhibitors, GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, Glucagon-like peptide-1 (GLP-1) analogs, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, Glucagon-like peptide-1 (GLP-1) receptor agonists, LY-3305677 long-acting Oxyntomodulin, nitazoxanide (NTZ), tizoxanide (TZ), prodrugs of TZ, RM-5061, orlistat (Xenical), pioglitazone, thyroid receptor 0 (THR 0) agonists, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan:
(Paragraphs [0069]-[0122] of Brozek. The teaching describes an anti-NASH or anti-fibrotic compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been identified thanks to a method according to the invention. In particular, the invention relates to an anti-NASH compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been classified as a receiver of said treatment thanks to a method according to the invention. Illustrative anti-NASH and anti-fibrotic compounds include Fatty Acid Synthase (FAS) inhibitors. In a particular embodiment, the FAS inhibitor is TVB-2640. Glucagon-like peptide-1 (GLP-1) analogs like semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901.)
Brozek does not explicitly teach (i) calculating a nonalcoholic fatty liver disease score (NFS) from the age, body-mass index, aspartate amino transferase (AST)/alanine aminotransferase (ALT) ratio, platelet count and hyperglycemia status of said patient.
However, Uslusoy teaches that age, body-mass index, aspartate amino transferase (AST)/alanine aminotransferase (ALT) ratio, platelet count and hyperglycemia status of said patient are all relevant factors for determining a nonalcoholic fatty liver disease score.
(Abstract, Methods; Discussion of Uslusoy. The teaching describes that 81 patients (40 male, 41 female) who were diagnosed with fatty liver by ultrasonographic examination and fulfilled the inclusion criteria participated in the study. Anamnesis, anthropometric, clinical and laboratory features of all cases were recorded and then liver biopsy was performed after obtaining patient consent. Steatosis, necroinflammation and liver fibrosis were examined according to age ≥ 45, gender, body mass index, central obesity, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 1, γ-glutamyltransferase (GGT)/ALT > 1, platelet count, insulin, c-peptide levels and the presence of hypertension, diabetes, hypertriglyceridemia and insulin resistance. Boza et al found no significant association between BMI and histological changes. In the latest study, high HOMA-IR values and ALT levels were the only independent predictors of NASH. Gholam et al. stated that except for BMI and hyperglycemia, insulin resistance and the metabolic syndrome were associated with the presence of NASH and fibrosis.)
It would have been obvious to one of ordinary skill in the art before the time of filing to calculate the NAS score (a nonalcoholic fatty liver disease score) of Brozek, the factors used to calculate the nonalcoholic fatty liver disease measurements of Uslusoy. The Comments, Research frontiers of Uslusoy describe that the methods used to determine NAFLD apart from liver biopsy many noninvasive methods were improved. These methods are generally based on blood tests. The studies on noninvasive methods are still going on to determine the most sensitive and specific tools. This means that determining a nonalcoholic fatty liver disease score based on these factors of Uslusoy would have improved the metrics of Brozek due to the increased data and avoidance of biopsy. One of ordinary skill in the art in possession of Brozek would have looked to Uslusoy to make these improvements without yielding unexpected results.
As per claim 10,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 9.
Brozek further teaches wherein the calculated NFS is compared to a NFS low cutoff value and the calculated NIS4 is compared to a NIS4 low cutoff value:
(Paragraphs [0020]-[0024], [0041] and [0052]-[0056] of Brozek. The teaching describes According to the present invention, the “NAFLD-Activity score” or “NAS” refers to the sum of steatosis, hepatocellular ballooning, lobular inflammation scores, as follows: S: Steatosis score: 0: <5%; 1: 5-33%; 2: 34-66% and 3: >66%; LI: Lobular Inflammation score (foci/x20 field): 0: none; 1: <2; 2: 2-4 and 3: >4; HB: Ballooning degeneration score: 0: none; 1: few; 2: many cells/prominent ballooning. Therefore, NASH refers to a NAFLD condition characterized by the following liver biopsy-derived grades: NAS≥3, with at least 1 point in steatosis, at least 1 point in lobular inflammation and at least 1 point in the hepatocyte ballooning scores. According to the present invention, the term NASH refers, without limitation, to different stages of NASH, including NASH, severe NASH, active NASH, fibrosing NASH and active NASH with significant fibrosis (i.e. an active NASH characterized by liver fibrosis stage of 2 or of more than 2, such as a fibrosis stage equal to 2, 3 or 4). The method of the present invention can be used in the context of all these kinds of NASH. In a particular embodiment, a NIS4 score is used in combination to the measured stiffness. The NIS4 score is more particularly calculated as provided in WO2017167934. If S2 is greater or equal to a threshold value, the subject is classified as having or potentially having a NASH and/or is classified as a receiver of a treatment for NASH. If S2 is lower than a threshold value, the subject may be classified as a receiver or non-receiver, in particular as a non-receiver, of a treatment for NASH and/or the subject is classified as a receiver, or potential receiver, of diet and lifestyle advices for managing his/her NASH.)
As per claim 11,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 10.
Brozek further teaches wherein if the calculated NFS is lower than said NFS low cutoff value or if the calculated NIS4 is lower than said NIS4 low cutoff value, then the patient is diagnosed as not having at-risk NASH:
(Paragraphs [0020]-[0024], [0041] and [0052]-[0056] of Brozek. The teaching describes According to the present invention, the “NAFLD-Activity score” or “NAS” refers to the sum of steatosis, hepatocellular ballooning, lobular inflammation scores, as follows: S: Steatosis score: 0: <5%; 1: 5-33%; 2: 34-66% and 3: >66%; LI: Lobular Inflammation score (foci/x20 field): 0: none; 1: <2; 2: 2-4 and 3: >4; HB: Ballooning degeneration score: 0: none; 1: few; 2: many cells/prominent ballooning. Therefore, NASH refers to a NAFLD condition characterized by the following liver biopsy-derived grades: NAS≥3, with at least 1 point in steatosis, at least 1 point in lobular inflammation and at least 1 point in the hepatocyte ballooning scores. According to the present invention, the term NASH refers, without limitation, to different stages of NASH, including NASH, severe NASH, active NASH, fibrosing NASH and active NASH with significant fibrosis (i.e. an active NASH characterized by liver fibrosis stage of 2 or of more than 2, such as a fibrosis stage equal to 2, 3 or 4). The method of the present invention can be used in the context of all these kinds of NASH. In a particular embodiment, a NIS4 score is used in combination to the measured stiffness. The NIS4 score is more particularly calculated as provided in WO2017167934. If S2 is greater or equal to a threshold value, the subject is classified as having or potentially having a NASH and/or is classified as a receiver of a treatment for NASH. If S2 is lower than a threshold value, the subject may be classified as a receiver or non-receiver, in particular as a non-receiver, of a treatment for NASH and/or the subject is classified as a receiver, or potential receiver, of diet and lifestyle advices for managing his/her NASH.)
As per claim 12,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 10.
Brozek further teaches wherein if the calculated NFS is greater or equal to said NFS low cutoff value and if the calculated NIS4 is greater or equal to said NIS4 low cutoff value, then the patient is diagnosed as having at-risk NASH:
(Paragraphs [0020]-[0024], [0041] and [0052]-[0056] of Brozek. The teaching describes According to the present invention, the “NAFLD-Activity score” or “NAS” refers to the sum of steatosis, hepatocellular ballooning, lobular inflammation scores, as follows: S: Steatosis score: 0: <5%; 1: 5-33%; 2: 34-66% and 3: >66%; LI: Lobular Inflammation score (foci/x20 field): 0: none; 1: <2; 2: 2-4 and 3: >4; HB: Ballooning degeneration score: 0: none; 1: few; 2: many cells/prominent ballooning. Therefore, NASH refers to a NAFLD condition characterized by the following liver biopsy-derived grades: NAS≥3, with at least 1 point in steatosis, at least 1 point in lobular inflammation and at least 1 point in the hepatocyte ballooning scores. According to the present invention, the term NASH refers, without limitation, to different stages of NASH, including NASH, severe NASH, active NASH, fibrosing NASH and active NASH with significant fibrosis (i.e. an active NASH characterized by liver fibrosis stage of 2 or of more than 2, such as a fibrosis stage equal to 2, 3 or 4). The method of the present invention can be used in the context of all these kinds of NASH. In a particular embodiment, a NIS4 score is used in combination to the measured stiffness. The NIS4 score is more particularly calculated as provided in WO2017167934. If S2 is greater or equal to a threshold value, the subject is classified as having or potentially having a NASH and/or is classified as a receiver of a treatment for NASH. If S2 is lower than a threshold value, the subject may be classified as a receiver or non-receiver, in particular as a non-receiver, of a treatment for NASH and/or the subject is classified as a receiver, or potential receiver, of diet and lifestyle advices for managing his/her NASH.)
As per claim 15,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 9.
Brozek further teaches wherein the agent is administered to the patient if the calculated NFS and the calculated NIS4 are above the NFS low cutoff and the NIS4 low cutoff, respectively:
(Paragraphs [0020]-[0024], [0041] and [0052]-[0056] of Brozek. The teaching describes According to the present invention, the “NAFLD-Activity score” or “NAS” refers to the sum of steatosis, hepatocellular ballooning, lobular inflammation scores, as follows: S: Steatosis score: 0: <5%; 1: 5-33%; 2: 34-66% and 3: >66%; LI: Lobular Inflammation score (foci/x20 field): 0: none; 1: <2; 2: 2-4 and 3: >4; HB: Ballooning degeneration score: 0: none; 1: few; 2: many cells/prominent ballooning. Therefore, NASH refers to a NAFLD condition characterized by the following liver biopsy-derived grades: NAS≥3, with at least 1 point in steatosis, at least 1 point in lobular inflammation and at least 1 point in the hepatocyte ballooning scores. According to the present invention, the term NASH refers, without limitation, to different stages of NASH, including NASH, severe NASH, active NASH, fibrosing NASH and active NASH with significant fibrosis (i.e. an active NASH characterized by liver fibrosis stage of 2 or of more than 2, such as a fibrosis stage equal to 2, 3 or 4). The method of the present invention can be used in the context of all these kinds of NASH. In a particular embodiment, a NIS4 score is used in combination to the measured stiffness. The NIS4 score is more particularly calculated as provided in WO2017167934. If S2 is greater or equal to a threshold value, the subject is classified as having or potentially having a NASH and/or is classified as a receiver of a treatment for NASH. If S2 is lower than a threshold value, the subject may be classified as a receiver or non-receiver, in particular as a non-receiver, of a treatment for NASH and/or the subject is classified as a receiver, or potential receiver, of diet and lifestyle advices for managing his/her NASH.)
As per claim 16,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 9.
Brozek further teaches administering an anti-NASH or anti-fibrotic agent to a patient diagnosed as having at-risk NASH, wherein the agent is selected from the group consisting of signal-regulating kinase 1 (ASK1) inhibitors, GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, elafibranor, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, Glucagon-like peptide-1 (GLP-1) analogs, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, Glucagon-like peptide-1 (GLP-1) receptor agonists, LY-3305677, long-acting Oxyntomodulin, nitazoxanide (NTZ), tizoxanide (TZ), prodrugs of TZ, RM-5061, orlistat (Xenical), pioglitazone, thyroid receptor 3 (THR 3) agonists, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196,Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan:
(Paragraphs [0069]-[0122] of Brozek. The teaching describes an anti-NASH or anti-fibrotic compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been identified thanks to a method according to the invention. In particular, the invention relates to an anti-NASH compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been classified as a receiver of said treatment thanks to a method according to the invention. Illustrative anti-NASH and anti-fibrotic compounds include Fatty Acid Synthase (FAS) inhibitors. In a particular embodiment, the FAS inhibitor is TVB-2640. Glucagon-like peptide-1 (GLP-1) analogs like semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901.)
As per claim 18,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 16.
Brozek further teaches wherein the agent is administered to the patient if the calculated NFS and the calculated NIS4 are above the NFS low cutoff and the NIS4 low cutoff, respectively:
(Paragraphs [0020]-[0024], [0041] and [0052]-[0056] of Brozek. The teaching describes According to the present invention, the “NAFLD-Activity score” or “NAS” refers to the sum of steatosis, hepatocellular ballooning, lobular inflammation scores, as follows: S: Steatosis score: 0: <5%; 1: 5-33%; 2: 34-66% and 3: >66%; LI: Lobular Inflammation score (foci/x20 field): 0: none; 1: <2; 2: 2-4 and 3: >4; HB: Ballooning degeneration score: 0: none; 1: few; 2: many cells/prominent ballooning. Therefore, NASH refers to a NAFLD condition characterized by the following liver biopsy-derived grades: NAS≥3, with at least 1 point in steatosis, at least 1 point in lobular inflammation and at least 1 point in the hepatocyte ballooning scores. According to the present invention, the term NASH refers, without limitation, to different stages of NASH, including NASH, severe NASH, active NASH, fibrosing NASH and active NASH with significant fibrosis (i.e. an active NASH characterized by liver fibrosis stage of 2 or of more than 2, such as a fibrosis stage equal to 2, 3 or 4). The method of the present invention can be used in the context of all these kinds of NASH. In a particular embodiment, a NIS4 score is used in combination to the measured stiffness. The NIS4 score is more particularly calculated as provided in WO2017167934. If S2 is greater or equal to a threshold value, the subject is classified as having or potentially having a NASH and/or is classified as a receiver of a treatment for NASH. If S2 is lower than a threshold value, the subject may be classified as a receiver or non-receiver, in particular as a non-receiver, of a treatment for NASH and/or the subject is classified as a receiver, or potential receiver, of diet and lifestyle advices for managing his/her NASH.)
As per claim 19,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 9.
Brozek further teaches wherein the anti-NASH or anti-fibrotic agent administered to the patient diagnosed as having at-risk NASH is selected from the group consisting of lanifibranor, resmetirom, saroglitazar magnesium, and semaglutide:
(Paragraphs [0069]-[0122] of Brozek. The teaching describes an anti-NASH or anti-fibrotic compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been identified thanks to a method according to the invention. In particular, the invention relates to an anti-NASH compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been classified as a receiver of said treatment thanks to a method according to the invention. Illustrative anti-NASH and anti-fibrotic compounds include Fatty Acid Synthase (FAS) inhibitors. In a particular embodiment, the FAS inhibitor is TVB-2640. Glucagon-like peptide-1 (GLP-1) analogs like semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901.)
As per claim 20,
Claim 20 is substantially similar to claim 9. Accordingly, Claim 20 is rejected for the same reasons as claim 9.
Claim 20 specifies measuring blood in a subject that has a NFS greater than 0.675. Claim 9 measures the blood of all subjects which would include all subjects over this score.
Claim 20 further specifies that therapy is administered to subjects with an NIS4 score greater than 0.36. Claim 9 administers therapy to all at-risk subjects. At-risk subjects have NIS4 scores greater than 0.36.
As per claim 21,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 20.
Brozek further teaches wherein if the calculated NFS is lower than 0.675 or if the calculated NIS4 is lower than 0.36, then the subject is not administered an anti-NASH or anti-fibrotic compound:
(Paragraphs [0020]-[0024], [0041], [0052]-[0056] and [0177] of Brozek. The teaching describes According to the present invention, the “NAFLD-Activity score” or “NAS” refers to the sum of steatosis, hepatocellular ballooning, lobular inflammation scores, as follows: S: Steatosis score: 0: <5%; 1: 5-33%; 2: 34-66% and 3: >66%; LI: Lobular Inflammation score (foci/x20 field): 0: none; 1: <2; 2: 2-4 and 3: >4; HB: Ballooning degeneration score: 0: none; 1: few; 2: many cells/prominent ballooning. Therefore, NASH refers to a NAFLD condition characterized by the following liver biopsy-derived grades: NAS≥3, with at least 1 point in steatosis, at least 1 point in lobular inflammation and at least 1 point in the hepatocyte ballooning scores. According to the present invention, the term NASH refers, without limitation, to different stages of NASH, including NASH, severe NASH, active NASH, fibrosing NASH and active NASH with significant fibrosis (i.e. an active NASH characterized by liver fibrosis stage of 2 or of more than 2, such as a fibrosis stage equal to 2, 3 or 4). The method of the present invention can be used in the context of all these kinds of NASH. In a particular embodiment, a NIS4 score is used in combination to the measured stiffness. The NIS4 score is more particularly calculated as provided in WO2017167934. If S2 is greater or equal to a threshold value, the subject is classified as having or potentially having a NASH and/or is classified as a receiver of a treatment for NASH. If S2 is lower than a threshold value, the subject may be classified as a receiver or non-receiver, in particular as a non-receiver, of a treatment for NASH and/or the subject is classified as a receiver, or potential receiver, of diet and lifestyle advices for managing his/her NASH. A Steatosis score of 0 is lower than the NFS score of 0.675 which demonstrates that the patient does not have a condition that permits the treatment)
As per claim 22,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 20.
Brozek further teaches wherein the anti-NASH or anti-fibrotic compound is selected from the group consisting of GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, exenatide, albiglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, LY-3305677, long-acting Oxyntomodulin; nitazoxanide (NTZ), tizoxanide (TZ), RM-5061, orlistat (Xenical), pioglitazone, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan:
(Paragraphs [0069]-[0122] of Brozek. The teaching describes an anti-NASH or anti-fibrotic compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been identified thanks to a method according to the invention. In particular, the invention relates to an anti-NASH compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been classified as a receiver of said treatment thanks to a method according to the invention. Illustrative anti-NASH and anti-fibrotic compounds include Fatty Acid Synthase (FAS) inhibitors. In a particular embodiment, the FAS inhibitor is TVB-2640. Glucagon-like peptide-1 (GLP-1) analogs like semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901.)
As per claim 23,
Claim 23 is substantially similar to claim 9. Accordingly, Claim 23 is rejected for the same reasons as claim 9.
Claim 23 specifies measuring blood in a subject that has an NIS4 score greater than 0.36. Claim 9 measures the blood of all subjects which would include all subjects over this score.
Claim 23 further specifies that therapy is administered to subjects with an NSF score greater than 0.675. Claim 9 administers therapy to all at-risk subjects. At-risk subjects include those that have NSF scores greater than 0.675.
As per claim 24,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 23.
Brozek further teaches wherein the anti-NASH or anti-fibrotic agent is selected from the group consisting of GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, exenatide, albiglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, LY-3305677, long-acting Oxyntomodulin; nitazoxanide (NTZ), tizoxanide (TZ), RM-5061, orlistat (Xenical), pioglitazone, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan:
(Paragraphs [0069]-[0122] of Brozek. The teaching describes an anti-NASH or anti-fibrotic compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been identified thanks to a method according to the invention. In particular, the invention relates to an anti-NASH compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been classified as a receiver of said treatment thanks to a method according to the invention. Illustrative anti-NASH and anti-fibrotic compounds include Fatty Acid Synthase (FAS) inhibitors. In a particular embodiment, the FAS inhibitor is TVB-2640. Glucagon-like peptide-1 (GLP-1) analogs like semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901.)
As per claim 25,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 9.
Brozek further teaches wherein the anti-NASH or anti-fibrotic agent is selected from the group consisting of GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, exenatide, albiglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, LY-3305677, long-acting Oxyntomodulin; nitazoxanide (NTZ), tizoxanide (TZ), RM-5061, orlistat (Xenical), pioglitazone, resmetirom (MGL3196), rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan:
(Paragraphs [0069]-[0122] of Brozek. The teaching describes an anti-NASH or anti-fibrotic compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been identified thanks to a method according to the invention. In particular, the invention relates to an anti-NASH compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been classified as a receiver of said treatment thanks to a method according to the invention. Illustrative anti-NASH and anti-fibrotic compounds include Fatty Acid Synthase (FAS) inhibitors. In a particular embodiment, the FAS inhibitor is TVB-2640. Glucagon-like peptide-1 (GLP-1) analogs like semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901.)
As per claim 26,
The combined teaching of Brozek and Uslusoy teaches the limitations of claim 16.
Brozek further teaches wherein the agent is selected from the group consisting of GS-4997 (selonsertib), ambrisentan, BMS-963272, BMS-986036, BMS-986251, BMS-986263, dapagliflozin, dulaglutide, empagliflozin, fenofibrate, HepaStem, lanifibranor, liraglutide, LYS006, MET409, MET642, MGL-3196, exenatide, albiglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901, LY-3305677, long-acting Oxyntomodulin, nitazoxanide (NTZ), tizoxanide (TZ), RM-5061, orlistat (Xenical), pioglitazone, resmetirom, rosiglitazone, saroglitazar magnesium, seladelpar, semaglutide, sitagliptin, TERN-101, TERN-201, tropifexor (LJN452), GKT-831, PXS-4728A, PBI-4050, MSDC-0602, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), and emricasan:
(Paragraphs [0069]-[0122] of Brozek. The teaching describes an anti-NASH or anti-fibrotic compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been identified thanks to a method according to the invention. In particular, the invention relates to an anti-NASH compound for use in a method for treating NASH, NASH with fibrosis, or active NASH with significant fibrosis in a subject in need thereof, wherein the subject has been classified as a receiver of said treatment thanks to a method according to the invention. Illustrative anti-NASH and anti-fibrotic compounds include Fatty Acid Synthase (FAS) inhibitors. In a particular embodiment, the FAS inhibitor is TVB-2640. Glucagon-like peptide-1 (GLP-1) analogs like semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205, ORMD-0901.)
Response to Arguments
Applicant's arguments filed September 22, 2025 have been fully considered.
Applicant’s arguments pertaining to rejections made under 35 U.S.C. 101 are not persuasive.
The Applicant argues that the pending claims are eligible under 35 U.S.C. 101 as providing a particular treatment or prophylaxis to a patient, similar to Vanda. Further, claim 20 (the Applicant mistakenly argued as if 19 recited these limitations) that the specific score of NIF4 greater than 0.36 treatment would be administered to the patient. Such treatment would avoid unnecessary administration of medication to a patient.
The Examiner respectfully disagrees with this argument. The pending claims are not similar to the specific treatment or prophylaxis as provided by Vanda. Specifically, Vanda required a single specific medication to a specific medical condition at varying levels of specific medication dosages. This is what is meant by a particular treatment. In contrast, the treatment being administered can be any of several medications at an undefined dose strength. This is not a particular treatment given that there is no particularity to what is being treated (general anti-NASH or anti-fibrotic) with no particularity to what medication (a litany of potential treatments with an undefined dosage). Accordingly, the pending claims fail to provide a specific treatment to a disease as taught by Vanda.
Applicant’s arguments pertaining to rejections made under 35 U.S.C. 103 are not persuasive.
The Applicant argues that Brozek does not teach a method specialized for diagnosing and treating at-risk NASH in a human patient. At-risk Nash patients with a metabolic disorder are a particular subclass of NASH patients.
The Examiner respectfully disagrees with this argument. Brozek teaches scoring a plurality of patients for NASH and stratifies these patients based on their scoring methods. At-risk NASH patients with metabolic disorders are interpreted as being subsumed into this larger testing category. As the Applicant readily admits, this category of NASH patients is a subset. Brozek teaches the testing of all NASH patients.
The Applicant further argues that Brozek does not teach a NFS score that is based on BMI, AST/ALT ratio, platelet count and hyperglycemia.
The Examiner respectfully disagrees with this argument. The Examiner does not rely on Brozek to teach this limitation, but rather on the combined teaching of Brozek and Uslusoy. Accordingly, the Applicant is arguing against a position that the Examiner has not taken in a piecemeal analysis of the references.
The Applicant further argues that Uslusoy does not teach determining a NFS prior to patient treatment.
The Examiner respectfully disagrees with this argument. The Examiner does not rely on Uslusoy to teach this limitation, but rather on the combined teaching of Brozek and Uslusoy. Accordingly, the Applicant is arguing against a position that the Examiner has not taken in a piecemeal analysis of the references.
The Applicant further argues that based on the above arguments, the combined teaching of Brozek and Uslusoy cannot result in teaching the limitations of claim 9.
The Examiner respectfully disagrees with this argument. As was shown above, the Applicant only considered the cited references individually for what they did not teach as opposed to an ordered combination for what they did teach. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations 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 Applicant further argues that one of ordinary skill in the art in possession of Brozek would not have looked to Uslusoy for improvements because the results of Uslusoy were not statistically significant and recommended an invasive procedure as opposed to the non-invasive procedure disclosed by Brozek.
The Examiner respectfully disagrees. The entire point of Uslusoy was to determining a predictive measure of fibrosis markers using non-invasive means. See Abstract. Simply because this particular paper showed no statistically significant measurements, it does not follow that their methods, including body-mass index, aspartate amino transferase (AST)/alanine aminotransferase (ALT) ratio, platelet count and hyperglycemia status as relevant markers to fibrosis should be eschewed. All science is predicated on the failure and retesting of processes. Uslusoy was relied upon to teach the relevance of body-mass index, aspartate amino transferase (AST)/alanine aminotransferase (ALT) ratio, platelet count and hyperglycemia status in NAFLD. If these biomarkers are not relevant to NAFLD, then they are just as relevant to the claimed invention. The point is, Uslusoy teaches their use in fibrosis determination just as claimed. The paper’s results of not being statistically significant has no bearing on the positively stated incentives for combination taught by Uslusoy.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHAD A NEWTON whose telephone number is (313)446-6604. The examiner can normally be reached M-F 8:00AM-4:00PM (EST).
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/CHAD A NEWTON/Primary Examiner, Art Unit 3681